Genome sequence and analysis of the tuber crop potato.
Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.


2D transition metal dichalcogenide nanosheets for photo/thermo-based tumor imaging and therapy.
Two-dimensional (2D) graphene-like nanomaterials show wide applications in the fields of nanodevices, sensors, energy materials, catalysis, drug delivery, bioimaging, and tissue engineering. Recently, many studies have been focused on the synthesis and application of 2D transition metal dichalcogenide (TMD) nanosheets for various biomedical applications. In particular, 2D TMD nanosheets exhibit great advantages for tumor imaging and therapy compared to some traditional nanomaterials due to their high specific surface area, good biocompatibility, easy modification, and ultrahigh light and heat conversion efficiency. In this review, we summarize the recent advances in the synthesis, modification, and photo/thermo-based tumor imaging and therapy of 2D TMD nanosheets. The important studies on tumor bioimaging with TMD nanosheets, such as X-ray computed tomography, magnetic resonance imaging, and photoacoustic imaging, are demonstrated and discussed. In another section, the physical photothermal and photodynamic therapies as well as the pharmacological therapy of tumors with TMD nanosheet-based nanohybrids are introduced. It is expected that this work will be valuable for readers to understand the synthesis and modification of TMD nanosheets to design novel 2D functional nanomaterials for photo/thermo-based tumor imaging and therapy in one aspect, and in another aspect will extend the applications of TMD-based nanomaterials in materials science, analytical science, electrocatalysis, tissue engineering, and others.


Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles. There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.


Systemic administration of Rosmarinus officinalis attenuates the inflammatory response induced by carrageenan in the mouse model of pleurisy.
Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.


The interaction between the complement system and hemostatic factors.
To discuss the crosstalk between the complement system and hemostatic factors (coagulation cascade, platelet, endothelium, and Von Willebrand Factor), and the consequences of this interaction under physiologic and pathologic conditions. The complement and coagulation systems are comprised of serine proteases and are genetically related. In addition to the common ancestral genes, the complement system and hemostasis interact directly, through protein-protein interactions, and indirectly, on the surface of platelets and endothelial cells. The close interaction between the complement system and hemostatic factors is manifested both in physiologic and pathologic conditions, such as in the inflammatory response to thrombosis, thrombosis at the inflamed area, and thrombotic complications of complement disorders. The interaction between the complement system and hemostasis is vital for homeostasis and the protective response of the host to tissue injury, but also results in the pathogenesis of several thrombotic and inflammatory disorders.


Alternate Pacing of Border-Collision Period-Doubling Bifurcations.
Unlike classical bifurcations, border-collision bifurcations occur when, for example, a fixed point of a continuous, piecewise C1 map crosses a boundary in state space. Although classical bifurcations have been much studied, border-collision bifurcations are not well understood. This paper considers a particular class of border-collision bifurcations, i.e., border-collision period-doubling bifurcations. We apply a subharmonic perturbation to the bifurcation parameter, which is also known as alternate pacing, and we investigate the response under such pacing near the original bifurcation point. The resulting behavior is characterized quantitatively by a gain, which is the ratio of the response amplitude to the applied perturbation amplitude. The gain in a border-collision period-doubling bifurcation has a qualitatively different dependence on parameters from that of a classical period-doubling bifurcation. Perhaps surprisingly, the differences are more readily apparent if the gain is plotted vs. the perturbation amplitude (with the bifurcation parameter fixed) than if plotted vs. the bifurcation parameter (with the perturbation amplitude fixed). When this observation is exploited, the gain under alternate pacing provides a useful experimental tool to identify a border-collision period-doubling bifurcation.


Characterization of urge to cough and cough symptoms associated with the common cold: results of a US internet survey.
Our knowledge of cough physiology is limited despite years of study. Even less is known about the sensation of urge to cough. Given that limited clinical data are available about urge to cough and cough attributes during a common cold, we sought to gain insights into experiences and perceptions related to these symptoms. An internet survey consisting of 51 questions was fielded in the United States. Eligible survey participants included men and women aged 18 years and older who had suffered from a cold with cough within the three months preceding the survey. Participants who confirmed suffering from recurrent cough, asthma, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, or gastrointestinal reflux were excluded. Of 19,530 initial respondents, 8011 had a cold in the past three months. Of these, 6484 (81%) had experienced cough symptoms; 2708 respondents with cough due to cold and no exclusionary condition made up the analysis sample. Most respondents (62%) reported that cough developed one to two days after the onset of cold symptoms, and 45% felt that cough worsened their other cold symptoms. In 69% of respondents, cough outlasted other cold symptoms. Urge to cough was reported by 98% of respondents, and among these respondents, 64% described it as uncontrollable and 65% rated severity as moderate. More than half of respondents (57%) considered the sensation of urge to cough and the act of coughing as equally bothersome. Although urge to cough and inability to control cough were the most bothersome aspects of cough due to cold, few (<20%) respondents asked healthcare providers for treatment recommendations. Symptoms of urge to cough and cough are common and have a significant impact on cold sufferers. Understanding attributes of these symptoms may provide insights for effective management and the development of novel treatment strategies.


Continuous 1.3-million-year record of East African hydroclimate, and implications for patterns of evolution and biodiversity.
The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake-level variability derived from drill core data from Lake Malawi, East Africa (9-15° S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world's largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ∼800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high-amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species.


Predominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: therapeutic implications.
mTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only a marginal effect on the phosphorylation status of 4E-BP1, another mTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad-spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches.


Adjustment Effects of Maximum Intensity Tolerance During Whole-Body Electromyostimulation Training.
Intensity regulation during whole-body electromyostimulation (WB-EMS) training is mostly controlled by subjective scales such as CR-10 Borg scale. To determine objective training intensities derived from a maximum as it is used in conventional strength training using the one-repetition-maximum (1-RM), a comparable maximum in WB-EMS is necessary. Therefore, the aim of this study was to examine, if there is an individual maximum intensity tolerance plateau after multiple consecutive EMS application sessions. A total of 52 subjects (24.1 ± 3.2 years; 76.8 ± 11.1 kg; 1.77 ± 0.09 m) participated in the longitudinal, observational study (38 males, 14 females). Each participant carried out four consecutive maximal EMS applications (T1-T4) separated by 1 week. All muscle groups were stimulated successively until their individual maximum and combined to a whole-body stimulation index to carry out a possible statement for the development of the maximum intensity tolerance of the whole body. There was a significant main effect between the measurement times for all participants (p < 0.001; 𝜂2 = 0.39) as well as gender specific for males (p = 0.001; 𝜂2 = 0.18) and females (p < 0.001; 𝜂2 = 0.57). There were no interaction effects of gender × measurement time (p = 0.394). The maximum intensity tolerance increased significantly from T1 to T2 (p = 0.001) and T2 to T3 (p < 0.001). There was no significant difference between T3 and T4 (p = 1.0). These results indicate that there is an adjustment of the individual maximum intensity tolerance to a WB-EMS training after three consecutive tests. Therefore, there is a need of several habituation units comparable to the identification of the individual 1-RM in conventional strength training. Further research should focus on an objective intensity-specific regulation of the WB-EMS based on the individual maximum intensity tolerance to characterize different training areas and therefore generate specific adaptations to a WB-EMS training compared to conventional strength training methods.


Advances in wrist arthroscopy.
Since its introduction more than three decades ago, wrist arthroscopy has continually evolved. The procedure has a wide list of indications, including diagnostic and management applications. The scope of practice for the wrist arthroscopic surgeon includes management of triangulofibrocartilage complex pathology, evaluation and management of carpal instability, assistance in fracture reduction of the radius and scaphoid, treatment of trapeziometacarpal synovitis and arthritis, distal ulnar and carpal bone excisions, and salvage procedures. In addition, innovations such as new portals and smaller arthroscopes have expanded the applications of wrist arthroscopy.


Effects of exercise training in patients with congestive heart failure: a critical review.
Congestive heart failure is a potentially debilitating disorder that affects a significant number of patients. The age-adjusted death rate has doubled over the past decade. Patients live an average of 4 to 5 years, and nearly all suffer from fatigue and breathlessness, which limits exercise capacity and produces a poor quality of life. Patients have usually been advised to avoid exercise because of concerns that they would experience a further decline in cardiac function. However, it has been demonstrated that exercise capacity is not related to the degree of left ventricular systolic dysfunction. This has led to the suggestion that peripheral changes in skeletal muscle and blood supply may play a major role in determining the exercise capacity of patients with congestive heart failure. Studies have demonstrated abnormalities of skeletal muscle blood flow, metabolism and structure, all of which are consistent with the impaired performance observed in these patients. Although the effects of exercise training have been examined in only a relatively few number of patients, the results have been promising. Exercise training has been found to improve exercise capacity and reduce symptoms. However, to our knowledge no data exist as to the impact of exercise training on left ventricular function, hospital stay or mortality in this population. Even though the early results are promising, they require confirmation of feasibility, clinical benefit and safety in larger, long-term randomized trials. It should be determined whether training has a long-term beneficial impact on measures more closely related to daily activities and quality of life. Ultimately, it would be important to determine whether training has an impact on mortality and morbidity.


Effect of balance training on recovery of stability in children with cerebral palsy.
This study examined the effect of massed practice in balance recovery of stability in six children (four males, two females; mean age 9 years 2 months, SD 2 years, range 7 years 5 months to 12 years 11 months) with cerebral palsy (CP). Four children were diagnosed with spastic diplegia (Gross Motor Function Classification System [GMFCS] level II) and two with spastic hemiplegia (GMFCS level I). A single-subject, multiple-baseline experimental design involving three pairs of children matched for diagnosis was used. A moveable forceplate system was used to test and train reactive balance control. Area per second (i.e. area covered by the center of pressure over a one second period) and time to stabilization from center of pressure measures were calculated following perturbations. The intervention phase consisted of massed practice on the moving platform (100 perturbations/day for 5 days). Analysis included hierarchical linear modeling and a repeated measures ANOVA. All children demonstrated a significant improvement in their ability to recover stability as demonstrated by reduced center of pressure area and time to stabilization following training. These improvements were still present 30 days following completion of training. Results suggest that postural control mechanisms in school-age children (7 to 13 years) with CP are modifiable.


Resistance to antimalarials by Plasmodium falciparum in Arso PIR, Irian Jaya, Indonesia.
Between 1987 and 1990, susceptibility of Plasmodium falciparum to chloroquine and to Fansidar was measured in vivo in 151 volunteers using the standard 7-day test. All volunteers lived in Arso PIR, Irian Jaya. A 25 mg/kg dose of chloroquine base was administered over a three-day period to 92 volunteers positive for P. falciparum rings (greater than 10 rings/200 white blood cells). Fifty volunteers (54%) showed results consistent with resistance. Twenty-nine were classified RII, and 21 RIII. In November 1989, a single curative dose of Fansidar was administered to 59 volunteers divided among three groups with 18 months, four years, and life-long exposure to endemic malaria. The proportion of volunteers in each group still positive for P. falciparum on day 7 of followup was 54%, 0%, and 14%, respectively. Thus, immune status profoundly effected clinically response to Fansidar. Standard in vitro microtests were also performed on parasites from 11 volunteers against chloroquine, amodiaquine, quinine, pyrimethamine/sulfadoxine, and and mefloquine. Nine of ten isolates showed in vitro growth consistent with resistance to chloroquine. Tests with other drugs showed few isolates with results considered indicative of susceptibility. Arso PIR has a severe drug resistance problem.


Estimating lifetime or episode-of-illness costs under censoring.
Many analyses of healthcare costs involve use of data with varying periods of observation and right censoring of cases before death or at the end of the episode of illness. The prominence of observations with no expenditure for some short periods of observation and the extreme skewness typical of these data raise concerns about the robustness of estimators based on inverse probability weighting (IPW) with the survival from censoring probabilities. These estimators also cannot distinguish between the effects of covariates on survival and intensity of utilization, which jointly determine costs. In this paper, we propose a new estimator that extends the class of two-part models to deal with random right censoring and for continuous death and censoring times. Our model also addresses issues about the time to death in these analyses and separates the survival effects from the intensity effects. Using simulations, we compare our proposed estimator to the inverse probability estimator, which shows bias when censoring is large and covariates affect survival. We find our estimator to be unbiased and also more efficient for these designs. We apply our method and compare it with the IPW method using data from the Medicare-SEER files on prostate cancer.


Occurrence of antibiotics in wastewater treatment facilities in Wisconsin, USA.
Samples from several wastewater treatment facilities in Wisconsin were screened for the presence of 21 antibiotic compounds. These facilities spanned a range of community size served (average daily flow from 0.0212 to 23.6 million gallons/day), secondary treatment processes, geographic locations across the state, and they discharged the treated effluents to both surface and ground waters (for ground water after a soil passage). A total of six antibiotic compounds were detected (1-5 compounds per site), including two sulfonamides (sulfamethazine, sulfamethoxazole), one tetracycline (tetracycline), fluoroquinolone (ciprofloxacin), macrolide (erythromycin-H(2)O) and trimethoprim. The frequency of detection of antibiotics was in the following order: tetracycline and trimethoprim (80%)>sulfamethoxazole (70%)>erythromycin-H(2)O (45%)>ciprofloxacin (40%)>sulfamethazine (10%). However, the soluble concentrations were in the parts-per-billion (ppb) range (<or=1.3 microg/L), and importantly were unaffected by the size of the wastewater treatment facility. The concentrations detected were within an order of magnitude of those reported for similar systems in Europe and Canada: they were within a factor of two in comparison to those reported for Canada but generally lower relative to those measured in wastewater systems in Europe. Only sulfamethoxazole and tetracycline were detected in groundwater monitoring wells adjacent to the treatment systems. Future intensive wastewater monitoring programs in Wisconsin may be limited to the six antibiotic compounds detected in this study.


Exploring the fate, transport and risk of Perfluorooctane Sulfonate (PFOS) in a coastal region of China using a multimedia model.
Perfluorooctane Sulfonate (PFOS) and related substances have been widely applied in both industrial processes and domestic products in China. Exploring the environmental fate and transport of PFOS using modeling methods provides an important link between emission and multimedia diffusion which forms a vital part in the human health risk assessment and chemical management for these substances. In this study, the gridded fugacity based BETR model was modified to make it more suitable to model transfer processes of PFOS in a coastal region, including changes to PFOS partition coefficients to reflect the influence of water salinity on its sorption behavior. The fate and transport of PFOS in the Bohai coastal region of China were simulated under steady state with the modified version of the model. Spatially distributed emissions of PFOS and related substances in 2010 were estimated and used in these simulations. Four different emission scenarios were investigated, in which a range of half-lives for PFOS related substances were considered. Concentrations of PFOS in air, vegetation, soil, fresh water, fresh water sediment and coastal water were derived from the model under the steady-state assumption. The median modeled PFOS concentrations in fresh water, fresh water sediment and soil were 7.20ng/L, 0.39ng/g and 0.21ng/g, respectively, under Emission Scenario 2 (which assumed all PFOS related substances immediately degrade to PFOS) for the whole region, while the maximum concentrations were 47.10ng/L, 4.98ng/g and 2.49ng/g, respectively. Measured concentration data for PFOS in the Bohai coastal region around the year of 2010 were collected from the literature. The reliability of the model results was evaluated by comparing the range of modeled concentrations with the measured data, which generally matched well for the main compartments. Fate and transfer fluxes were derived from the model based on the calculated inventory within the compartments, transfer fluxes between compartments and advection fluxes between sub-regions. It showed that soil and costal water were likely to be the most important sinks of PFOS in the Bohai costal region, in which more than 90% of PFOS was stored. Flows of fresh water were the driving force for spatial transport of PFOS in this region. Influences of the seasonal change of fresh water fluxes on the model results were also analyzed. When only seasonal changes of the fresh water flow rates were considered, concentrations of PFOS in winter and spring were predicted to be higher than that under annual average conditions, while the concentrations in summer and autumn were lower. For PFOS fluxes entering the sea, opposite conclusions were drawn compared to the concentrations. Environmental risks from the presence of PFOS in fresh water were assessed for this region through comparison with available water quality criteria values. The predicted concentrations of PFOS in the Bohai coastal region provided by the model were lower than the water quality criteria published by the United States Environmental Protection Agency and Chinese researchers, while the concentrations in more than 80% of the sampling locations exceeded the European Union Water Framework Directive Environmental Quality Standards values. Seasonal variations of flow rate might cause a significant increase in environmental risks.


The development and validation of a general measure of well-being: the BBC well-being scale.
The concept of maximising well-being, as opposed to merely treating mental disorder, is a powerful current theme in the area of mental health. Clearly this emphasises the need for appropriate valid and reliable measures of general well-being. This paper examines the appropriateness of a number of measures in this area and concludes that existing assessment tools fail to address the full range of aspects of personal well-being. This paper therefore presents the psychometric properties, validity and reliability of a new measure of well-being-the BBC Well-being Scale. A total of 1,940 participants completed the new measure, the Goldberg scales of anxiety and depression, the 'List of Threatening Experiences' life events scale, a modified version of the Response Styles Questionnaire and a modified version of the Internal, Personal and Situational Attributions Questionnaire presented via the internet. Exploratory factor-analysis suggested a three-factor solution including themes of psychological well-being, physical health and well-being and relationships. The total 24-item scale had good internal consistency (α = .935) and correlated significantly with key demographic variables and measures of concurrent validity. The new measure--the BBC Well-being Scale-is recommended for research and clinical purposes.


Rapidly progressive stage IVB mycosis fungoides treated with low-dose total skin electron beam therapy.
Mycosis fungoides (MF) is the most common subtype of primary cutaneous T-cell lymphoma. Normally, MF has an indolent course although patients can progress to an advanced disease state (stages IIB-IVB). Advanced-stage disease is typically aggressive, leaving patients with debilitating symptoms and a decreased quality of life. Moreover, advanced-stage MF often proves refractory to therapy and carries a very poor prognosis. Total skin electron beam (TSEB) therapy is a well-established and successful treatment for early stage MF; however, its efficacy dramatically decreases with advanced-stage disease. In fact, TSEB in advanced-stage MF is generally considered to be palliative. Current consensus guidelines recommend a dose of 30-36 Gy to be delivered in 8-10 weeks; however, limited studies exist to determine the ideal treatment in Stage IV MF. Herein, we describe a case of a 50-year-old male who developed rapidly progressive stage IVB (T3N3M1B0) MF and was treated with low-dose (24 Gy) TSEB over 8 weeks. The patient was not treated with any systemic therapy before starting TSEB due to the widespread nature and the speed of disease progression. Remarkably, our patient showed nearly complete (95%) response of his MF with no apparent side effects from radiation. Furthermore, he has remained in remission over 4 years, requiring only a small boost to a few "shadowed" areas. Our case illustrates the benefit of using TSEB in stage IV MF. Additionally, our experience shows that low-dose TSEB can occasionally be efficacious in stage IV disease.


Crosslinking of the human Fc receptor for IgA (FcalphaRI/CD89) triggers FcR gamma-chain-dependent shedding of soluble CD89.
CD89/FcalphaRI is a 55- to 75-kDa type I receptor glycoprotein, expressed on myeloid cells, with important immune effector functions. At present, no information is available on the existence of soluble forms of this receptor. We developed an ELISA for the detection of soluble CD89 (sCD89) forms and investigated the regulation of sCD89 production. PMA/ionomycin stimulation of monocytic cell lines (U937, THP-1, and MM6), but not of neutrophils, resulted in release of sCD89. Crosslinking of CD89 either via its ligand IgA or with anti-CD89 mAbs similarly resulted in sCD89 release. Using CD89-transfected cells, we showed ligand-induced shedding to be dependent on coexpression of the FcR gamma-chain subunit. Shedding of sCD89 was dependent on signaling via the gamma-chain and prevented by addition of inhibitors of protein kinase C (staurosporine) or protein tyrosine kinases (genistein). Western blotting revealed sCD89 to have an apparent molecular mass of 30 kDa and to bind IgA in a dose-dependent fashion. In conclusion, the present data document a ligand-binding soluble form of CD89 that is released upon activation of CD89-expressing cells. Shedding of CD89 may play a role in fine-tuning CD89 immune effector functions.


Clear and Single Binocular Vision in Near 3D Displays.
Accommodation/convergence mismatch induced by 3D displays can cause discomfort symptoms such as those induced by accommodation/convergence mismatch in clinical vergence testing. We found that the limits of clear and single vision during vergence tests are very different between 3D and clinical tests. Clinical vergences should not be used as substitutes for measures of vergences in 3D displays. The purposes of this study were to determine whether the limits of clear and single binocular vision derived from phoropter prism vergence tests match the limits measured in a 3D display and to determine whether vergence mode, smooth versus jump, affected those limits in the 3D display. We tested the phoropter prism vergence limits of clear and single vision at 40 cm in 47 binocular young adults. In separate sessions, we tested, in a 3D display, the analogous 40-cm vergence limits for smooth vergence and jump vergence. The 3D fixation target was a Maltese cross whose visual angle changed congruently with target disparity. Our mean phoropter vergence blur and break values were similar to those reported in previous studies. The mean smooth divergence limit was less in the 3D display (9.8Δ) than in the phoropter (12.8Δ). Most smooth convergence limits were much larger in the 3D display than in the phoropter, reaching the 35Δ limit of the 3D display without blur or diplopia in 24 subjects. Mean jump vergence limits were significantly smaller than smooth vergence limits in the 3D display. The limits of clear and single binocular vision derived from phoropter vergence tests were not a good approximation of the analogous limits in our 3D display.


Design and methods of the Healthy Kids & Families study: a parent-focused community health worker-delivered childhood obesity prevention intervention.
One third of U.S. children and two thirds of adults are overweight or obese. Interventions to prevent obesity and thus avert threats to public health are needed. This paper describes the design and methods of the Healthy Kids & Families study, which tested the effect of a parent-focused community health worker (CHW)-delivered lifestyle intervention to prevent childhood obesity. Participants were English or Spanish-speaking parent-child dyads (n = 247) from nine elementary schools (grades K-6) located in racial/ethnically diverse low-income communities in Worcester, Massachusetts. Using a quasi-experimental design with the school as the level of allocation, the study compared the lifestyle intervention vs. an attention-control comparison condition. The lifestyle intervention was guided by social cognitive theory and social ecological principles. It targeted the child's social and physical home environment by intervening with parental weight-related knowledge, beliefs, and skills for managing child obesogenic behaviors; and addressed families' needs for community resources supportive of a healthy lifestyle. The two-year CHW-delivered intervention was structured based on the 5As model (Agenda, Assess, Advise, Assist, Arrange follow up) and included two in person sessions and two telephone follow-ups per year with the parent, with a personalized letter and print materials sent after each contact. Parents also received quarterly newsletters, Facebook messages, and invitations to community events. The attention-control comparison condition used the same format and contact time as the intervention condition, but targeted positive parenting skills. Measurements occurred at baseline, and at 6-, 12-, 18- and 24-month follow-up. Assessments included anthropometrics, accelerometry, global positioning system (GPS), and self-report surveys. The primary outcome was child body mass index (BMI) z score. Secondary outcomes were parent BMI; and parent and child diet, physical activity, sedentariness, and utilization of community resources supportive of a healthy lifestyle. A CHW-delivered parent-focused lifestyle intervention may provide a translatable model for targeting the high priority public health problem of childhood obesity among low-income diverse communities. If demonstrated effective, this intervention has potential for high impact. ClinicalTrials NCT03028233. Registered January 23,2017. The trial was retrospectively registered.


Early life stress accelerates age-induced effects on neurogenesis, depression, and metabolic risk.
Early life stress (ELS) affects hippocampal neurogenesis, increases depressive-like behavior, and causes mild metabolic imbalance in early adulthood (2 months). However, whether these effects worsen in mid life remains unclear. To test whether age-dependent effects of ELS on hippocampal neurogenesis are related to deficient hypothalamic-pituitary-adrenal (HPA) axis feedback that causes increased comorbidity of depression and metabolic risk, we evaluated the effects of periodic maternal separation (MS180) in young (4-months-old) and middle-aged (10-months-old) adult rats. MS180 caused more severe depressive-like behavior in middle-aged adults than in young animals. There were no behavioral phenotypic differences between young MS180 and control middle-aged groups. MS180 similarly affected glucose tolerance, increased fasting corticosterone, insulin, and the quantitative insulin sensitivity check index (QUICKI) at both ages. However, middle-aged adult MS180 rats showed more severe age-induced obesity (>40% BW) than controls (>22% BW). MS180 differentially affected dorsal and ventral neurogenesis. In young adults, MS180 animals only showed a decrease in dorsal hippocampal neurogenesis as compared to their age-matched counterparts. In contrast, at 10 months of age, MS180 caused a similar decrease in both dorsal and ventral hippocampal neurogenesis as compared to age-matched controls, and a more severe decrease as compared to young animals. Taken together, our data indicate that MS180 animals show an early onset of age-induced alterations on depression and metabolic risk, and these effects relate to alterations in hippocampal neurogenesis.


Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88).
Spasticity is most commonly defined as an inappropriate, velocity dependent, increase in muscle tonic stretch reflexes, due to the amplified reactivity of motor segments to sensory input. It forms one component of the upper motor neuron syndrome and often leads to muscle stiffness and disability. Spasticity can, therefore, be measured through electrophysiological, biomechanical and clinical evaluation, the last most commonly using the Ashworth scale. None of these techniques incorporate the patient experience of spasticity, nor how it affects people's daily lives. Consequently, we set out to construct a rating scale to quantify the perspectives of the impact of spasticity on people with multiple sclerosis. Qualitative methods (in-depth patient interviews and focus groups, expert opinion and literature review) were used to develop a conceptual framework of spasticity impact, and to generate a pool of items with the potential to convert this framework into a rating scale with multiple dimensions. This item pool was administered, in the form of a questionnaire, to a sample of people with multiple sclerosis and spasticity. Guided by Rasch analysis, we constructed and validated a rating scale for each component of the conceptual framework. Decisions regarding item selection were based on the integration and assimilation of seven specific analyses including clinical meaning, ordering of thresholds, fit statistics and differential item functioning. The qualitative phase (17 patient interviews, 3 focus groups) generated 144 potential scale items and a conceptual model with eight components addressing symptoms (muscle stiffness, pain and discomfort and muscle spasms,), physical impact (activities of daily living, walking and body movements) and psychosocial impact (emotional health, social functioning). The first postal survey was sent to 272 people with multiple sclerosis and had a response rate of 88%. Findings supported the development of scales for each component but demonstrated that five item response options were too many. The 144-item questionnaire, reformatted with four-item response options, was administered with four validating instruments to an independent sample of 259 people with multiple sclerosis (response rate 78%). From the responses, an 88-item instrument with eight subscales was developed that satisfied criteria for reliable and valid measurement. Correlations with other measures were consistent with predictions. The 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) is a reliable and valid, patient-based, interval-level measure of the impact of spasticity in multiple sclerosis. It has the potential to advance outcomes measurement in clinical trials and clinical practice, and provides a new perspective in the clinical evaluation of spasticity.


Pain-free and pain-controlled survival after sectioning the nervus intermedius in nervus intermedius neuralgia: a single-institution review.
Nervus intermedius neuralgia (NIN) or geniculate neuralgia is a rare facial pain condition consisting of sharp, lancinating pain deep in the ear and can occur alongside trigeminal neuralgia (TN). Studies on the clinical presentation, intraoperative findings, and ultimately postoperative outcomes are extremely limited. The aim of this study was to examine the clinical presentation and surgical findings, and determine pain-free survival after sectioning of the nervus intermedius (NI). The authors conducted a retrospective chart review and survey of patients who were diagnosed with NIN at one institution and who underwent neurosurgical interventions. Pain-free survival was determined through chart review and phone interviews using a modified facial pain and quality of life questionnaire and represented as Kaplan-Meier curves. The authors found 15 patients with NIN who underwent microsurgical intervention performed by two surgeons from 2002 to 2016 at a single institution. Fourteen of these patients underwent sectioning of the NI, and 8 of 14 had concomitant TN. Five patients had visible neurovascular compression (NVC) of the NI by the anterior inferior cerebellar artery in most cases where NVC was found. The most common postoperative complaints were dizziness and vertigo, diplopia, ear fullness, tinnitus, and temporary facial nerve palsy. Thirteen of the 14 patients reportedly experienced pain relief immediately after surgery. The mean length of follow-up was 6.41 years (range 8 months to 14.5 years). Overall recurrence of any pain was 42% (6 of 14), and 4 patients (isolated NIN that received NI sectioning alone) reported their pain was the same or worse than before surgery at longest follow-up. The median pain-free survival was 4.82 years ± 14.85 months. The median pain-controlled survival was 6.22 years ± 15.78 months. In this retrospective review, sectioning of the NI produced no major complications, such as permanent facial weakness or deafness, and was effective for patients when performed in addition to other procedures. After sectioning of the NI, patients experienced 4.8 years pain free and experienced 6.2 years of less pain than before surgery. Alone, sectioning of the NI was not effective. The pathophysiology of NIN is not entirely understood. It appears that neurovascular compression plays only a minor role in the syndrome and there is a high degree of overlap with TN.


Tracking perceptual decision mechanisms through changes in interhemispheric functional connectivity in human visual cortex.
The role of long-range integration mechanisms underlying visual perceptual binding and their link to interhemispheric functional connectivity, as measured by fMRI, remains elusive. Only inferences on anatomical organization from resting state data paradigms not requiring coherent binding have been achieved. Here, we used a paradigm that allowed us to study such relation between perceptual interpretation and functional connectivity under bistable interhemispheric binding vs. non-binding of visual surfaces. Binding occurs by long-range perceptual integration of motion into a single object across hemifields and non-binding reflects opponent segregation of distinct moving surfaces into each hemifield. We hypothesized that perceptual integration vs. segregation of surface motion, which is achieved in visual area hMT+, is modulated by changes in interhemispheric connectivity in this region. Using 7T fMRI, we found that perceptual long-range integration of bistable motion can be tracked by changes in interhemispheric functional connectivity between left/right hMT+. Increased connectivity was tightly related with long-range perceptual integration. Our results indicate that hMT+ interhemispheric functional connectivity reflects perceptual decision, suggesting its pivotal role on long-range disambiguation of bistable physically constant surface motion. We reveal for the first time, at the scale of fMRI, a relation between interhemispheric functional connectivity and decision based perceptual binding.


Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.
This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.


The Impact of Intergenerational Relationship on Health and Well-Being of Older Chinese Americans.
Among older adults, intergenerational support can help to improve well-being. This study examines the correlation between intergenerational relationships and the subjective well-being among older Chinese immigrants in the United States. Hierarchical multiple regression analyses were applied to test the association between intergenerational relationships and self-rated well-being. The mediating effects of sense of control and the moderation effects of support from friends were also tested. A cross-sectional sample of 2717 older Chinese immigrants, aged 60 years and older, with children and grandchildren was drawn from the Population Study of Chinese Elderly. Study measures included four items concerning intergenerational relationships: the Pearlin Mastery Scale, two items on seeking support from friends, and single items measuring self-rated health status and quality of life. Only the feeling of closeness with children was positively linked with subjective well-being, while coresidence and frequency of talking were not. Support from friends moderated the association with self-rated health status, while sense of control partially mediated the association between feeling of closeness and both self-rated health status and quality of life. A stronger sense of closeness with children correlates to self-rated health status and quality of life among older Chinese immigrants. The effects of sociocultural changes affecting Chinese American families, and potential implications for older adults' health, could be addressed through strategies to develop emotional closeness with their families and to support sense of control and well-being among older Chinese adults. J Am Geriatr Soc 67:S557-S563, 2019.


Maternal overnutrition during critical developmental periods leads to different health adversities in the offspring: relevance of obesity, addiction and schizophrenia.
Maternal overnutrition during sensitive periods of early development increases the risk for obesity and neuropsychiatric disorders later in life. However, it still remains unclear during which phases of early development the offspring is more vulnerable. Here, we investigate the effects of maternal high-fat diet (MHFD) at different stages of pre- or postnatal development and characterize the behavioral, neurochemical and metabolic phenotypes. We observe that MHFD exposure at pre-conception has no deleterious effects on the behavioral and metabolic state of the offspring. Late gestational HFD exposure leads to more prominent addictive-like behaviors with reduced striatal dopamine levels compared to early gestational HFD. Conversely, offspring exposed to MHFD during lactation display the metabolic syndrome and schizophrenia-like phenotype. The latter, is manifested by impaired sensory motor gating, and latent inhibition as well as enhanced sensitivity to amphetamine. These effects are accompanied by higher striatal dopamine levels. Together, our data suggest that MHFD exposure during specific stages of development leads to distinct neuropathological alterations that determine the severity and nature of poor health outcome in adulthood, which may provide insight in identifying effective strategies for early intervention.


Examining a conceptual framework of intimate partner violence in men and women arrested for domestic violence.
There is a paucity of research developing and testing conceptual models of intimate partner violence, particularly for female perpetrators of aggression. Several theorists' conceptual frameworks hypothesize that distal factors-such as personality traits, drinking patterns, and marital discord-influence each other and work together to increase the likelihood of physical aggression. The purpose of the present study was to investigate these variables in a relatively large sample of men and women arrested for domestic violence and court-referred to violence intervention programs. We recruited 409 participants (272 men and 137 women) who were arrested for domestic violence. We assessed perpetrator alcohol problems, antisociality, trait anger, relationship discord, psychological aggression, and physical abuse. We also assessed the alcohol problems, psychological aggression, and physical abuse of their relationship partners. We used structural equation modeling to examine the interrelationships among these variables in both genders independently. In men and women, alcohol problems in perpetrators and their partners contributed directly to physical abuse and indirectly via psychological aggression, even after perpetrator antisociality, perpetrator trait anger, perpetrator relationship discord, and perpetrator and partner psychological and physical aggression were included in the model. The only significant gender difference found was that, in male perpetrators, trait anger was significantly associated with relationship discord, but this path was not significant for women perpetrators. The results of the study provide further evidence that alcohol problems in both partners are important in the evolution of psychological aggression and physical violence. There were minimal differences between men and women in the relationships of most distal risk factors with physical aggression, suggesting that the conceptual framework examined may fit equally well regardless of perpetrator gender. This finding suggests that, in arrested men and women, violence intervention programs might have improved outcomes if they offered adjunct or integrated alcohol treatment.


Collagen VII plays a dual role in wound healing.
Although a host of intracellular signals is known to contribute to wound healing, the role of the cell microenvironment in tissue repair remains elusive. Here we employed 2 different mouse models of genetic skin fragility to assess the role of the basement membrane protein collagen VII (COL7A1) in wound healing. COL7A1 secures the attachment of the epidermis to the dermis, and its mutations cause a human skin fragility disorder coined recessive dystrophic epidermolysis bullosa (RDEB) that is associated with a constant wound burden. We show that COL7A1 is instrumental for skin wound closure by 2 interconnected mechanisms. First, COL7A1 was required for re-epithelialization through organization of laminin-332 at the dermal-epidermal junction. Its loss perturbs laminin-332 organization during wound healing, which in turn abrogates strictly polarized expression of integrin α6β4 in basal keratinocytes and negatively impacts the laminin-332/integrin α6β4 signaling axis guiding keratinocyte migration. Second, COL7A1 supported dermal fibroblast migration and regulates their cytokine production in the granulation tissue. These findings, which were validated in human wounds, identify COL7A1 as a critical player in physiological wound healing in humans and mice and may facilitate development of therapeutic strategies not only for RDEB, but also for other chronic wounds.


Developing a HACCP-like system for improving animal health and welfare in organic egg production - based on an expert panel analysis.
In the process of developing a generic Hazard Analysis and Critical Control Point (HACCP)-like system for securing animal health and welfare in organic egg production, an expert panel analysis was used to perform the initial hazard analysis. Eighteen advisers and researchers in organic egg production were included in the expert panel. In a series of four questionnaires, the expert panel first scored 34 health and welfare problems seen in Danish organic egg production. Based on scorings of severity and occurrence, 10 problems were selected for further analysis. The experts subsequently suggested and scored risk factors for those problems and finally suggested control points, alarm values indicating the need for corrective actions in order to control the risk factors and monitoring frequencies of these. The 10 selected problems were hunger, thirst, piling, crop impaction, blackhead, pasteurellosis, bone fractures, cannibalism, predators and red mites. A total of 154 different risk factors were suggested for these problems. The 41 risk factors which rated highest in a combined scoring of importance and occurrence were selected for further analysis. There was a high degree of consensus between experts when scoring both problems and risk factors. The level of consensus, as defined by an interquartile range 1, was 79% to 100% when scoring the health and welfare problems (scale 1-5) and 77% to 95% when scoring the risk factors (scale 1-4). On average, 5.8 control points were suggested for every risk factor. Alarm values were often not detailed enough to be of practical significance and further analysis is needed in order to define these. The experts were highly diverse in their suggested monitoring frequencies and establishment of monitoring schemes should be part of developing the farm specific systems. An expert panel analysis based on questionnaires was a useful tool during the first steps of developing a HACCP plan, conducting a hazard analysis and suggesting control points. However, care should be taken regarding the panel's size and fields of expertise in order to assure that the panel fully covers the field of interest throughout the study. A further development of the hazard analysis into a farm-specific HACCP system would include assembling an on-farm HACCP team consisting of farmers and advisors for the practical application of control points, alarm values and monitoring schemes. The results from the fourth questionnaire would be useful as input for this work.


First Report of Cucumber mosaic virus in Eryngium yuccifolium (Rattlesnake Master) in Ohio.
Rattlesnake master (Eryngium yuccifolium) is a wildflower that is native to Ohio. In recent years, native wildflowers have become very popular with home gardeners, and conservationists have begun to reestablish these plants in their native ranges. As native perennial wildflowers become more common, it is important to determine if they might serve as possible perennial reservoirs of viruses. A plot of 20 species native to Ohio was established on the Waterman Agricultural and Natural Resources Laboratory, The Ohio State University, Columbus, Ohio. In the summers of 1999 and 2001, random samples were collected from established plantings. Some sampled plants did not show symptoms of virus infection; however, all samples of E. yuccifolium appeared chlorotic, slightly mottled, and stunted. Using double-stranded RNA (dsRNA) analysis (1), these plants were assayed for viral infection. dsRNA profiles obtained from symptomatic E. yuccifolium resembled that of Cucumber mosaic virus (CMV). These results were confirmed with an enzyme-linked immunosorbent assay (ELISA; Agdia Inc., Elkhart, IN) for CMV. dsRNA-containing samples of E. yuccifolium produced ELISA absorbance values (A405) of 0.231 to 0.713 when compared with the negative control. All 14 samples of E. yuccifolium tested positive for CMV. To our knowledge, this is the first report of CMV in E. yuccifolium, which should serve as the basis for a more extensive survey, since CMV can potentially infect a wide variety of ornamental and nonornamental hosts. Reference: (1) R. Valverde et al. Plant Dis. 74:255, 1990.


Generating single microwave photons in a circuit.
Microwaves have widespread use in classical communication technologies, from long-distance broadcasts to short-distance signals within a computer chip. Like all forms of light, microwaves, even those guided by the wires of an integrated circuit, consist of discrete photons. To enable quantum communication between distant parts of a quantum computer, the signals must also be quantum, consisting of single photons, for example. However, conventional sources can generate only classical light, not single photons. One way to realize a single-photon source is to collect the fluorescence of a single atom. Early experiments measured the quantum nature of continuous radiation, and further advances allowed triggered sources of photons on demand. To allow efficient photon collection, emitters are typically placed inside optical or microwave cavities, but these sources are difficult to employ for quantum communication on wires within an integrated circuit. Here we demonstrate an on-chip, on-demand single-photon source, where the microwave photons are injected into a wire with high efficiency and spectral purity. This is accomplished in a circuit quantum electrodynamics architecture, with a microwave transmission line cavity that enhances the spontaneous emission of a single superconducting qubit. When the qubit spontaneously emits, the generated photon acts as a flying qubit, transmitting the quantum information across a chip. We perform tomography of both the qubit and the emitted photons, clearly showing that both the quantum phase and amplitude are transferred during the emission. Both the average power and voltage of the photon source are characterized to verify performance of the system. This single-photon source is an important addition to a rapidly growing toolbox for quantum optics on a chip.


Characteristics and outcomes of patients with normal left atrial pressure undergoing transcatheter mitral valve repair.
A subset of patients at the time of transcatheter mitral valve repair (TMVR) will have normal left atrial pressure (LAP) (<13 mm Hg) despite having severe mitral regurgitation (MR). The goal of this study was to determine clinical characteristics and outcomes in patients with normal LAP undergoing TMVR. A single-centre retrospective cohort of consecutive patients who underwent transcatheter edge-to-edge mitral valve clip and continuous LAP monitoring between 5/1/2014 and 5/1/2018 was analysed. One-year mortality was compared by Kaplan-Meier survival curves. Multivariable analysis was performed to identify predictors of normal LAP and 1 year mortality. Of the 204 patients undergoing TMVR, 65% were men and the mean age was 81. Of these patients, 31 (15%) had normal LAP (mean LAP 10.5 mm Hg, mean V wave 16.5 mm Hg) and 173 had elevated LAP (mean LAP 19 mm Hg, mean V wave 32.5 mm Hg). The prevalence of severe MR was not different between groups, although the normal LAP group had significantly lower effective regurgitant orifice area and regurgitant volume. Other notable baseline characteristics including prior cardiac surgery, atrial fibrillation, hypertension, diabetes, congestive heart failure, body mass index, mechanism of MR and ejection fraction were similar between groups. However, there was an increased prevalence of chronic lung disease (CLD) (45.2% vs 17.3%, p<0.001) in the normal LAP group. On multivariate analysis, the only significant predictor of normal LAP was the presence of CLD (OR 4.79 (1.83-12.36), p=0.001) and 1-year mortality was significantly higher in the normal LAP group (32.3% vs 12.7%, p=0.006). After adjustment for comorbidities, normal LAP was no longer a predictor of 1-year mortality (RR 1.62 (0.64-4.06), p=0.32); however, CLD (RR 3.44 (1.37-8.67), p=0.01) remained a statistically significant predictor. Normal LAP at the time of TMVR is associated with a higher incidence of CLD which independently predicts increased 1-year mortality. In patients with CLD and apparently severe MR, measurement of LAP may help identify those with lower likelihood of benefit from TMVR.


Perceived emotional social support in bereaved spouses mediates the relationship between anxiety and depression.
Prior research has shown that anxiety symptoms predict later depression symptoms following bereavement. Nevertheless, no research has investigated mechanisms of the temporal relationship between anxiety and later depressive symptoms or examined the impact of depressive symptoms on later anxiety symptoms following bereavement. The current study examined perceived emotional social support as a possible mediator between anxiety and depressive symptoms in a bereaved sample of older adults (N =250). Anxiety and depressive symptoms were measured at Wave 1 (immediately after bereavement), social support was measured at Wave 2 (18 months after bereavement), and anxiety and depressive symptoms were also measured at Wave 3 (48 months after bereavement). Using Bayesian structural equation models, when controlling for baseline depression, anxiety symptoms significantly positively predicted depressive symptoms 48 months later, Further, perceived emotional social support significantly mediated the relationship between anxiety symptoms and later depressive symptoms, such that anxiety symptoms significantly negatively predicted later emotional social support, and emotional social support significantly negatively predicted later depressive symptoms. Also, when controlling for baseline anxiety, depressive symptoms positively predicted anxiety symptoms 48 months later. However, low emotional social support failed to mediate this relationship. Low perceived emotional social support may be a mechanism by which anxiety symptoms predict depressive symptoms 48 months later for bereaved individuals.


Inspecting close maternal relatedness: Towards better mtDNA population samples in forensic databases.
Reliable data are crucial for all research fields applying mitochondrial DNA (mtDNA) as a genetic marker. Quality control measures have been introduced to ensure the highest standards in sequence data generation, validation and a posteriori inspection. A phylogenetic alignment strategy has been widely accepted as a prerequisite for data comparability and database searches, for forensic applications, for reconstructions of human migrations and for correct interpretation of mtDNA mutations in medical genetics. There is continuing effort to enhance the number of worldwide population samples in order to contribute to a better understanding of human mtDNA variation. This has often lead to the analysis of convenience samples collected for other purposes, which might not meet the quality requirement of random sampling for mtDNA data sets. Here, we introduce an additional quality control means that deals with one aspect of this limitation: by combining autosomal short tandem repeat (STR) marker with mtDNA information, it helps to avoid the bias introduced by related individuals included in the same (small) sample. By STR analysis of individuals sharing their mitochondrial haplotype, pedigree construction and subsequent software-assisted calculation of likelihood ratios based on the allele frequencies found in the population, closely maternally related individuals can be identified and excluded. We also discuss scenarios that allow related individuals in the same set. An ideal population sample would be representative for its population: this new approach represents another contribution towards this goal.


Magnitude and pattern of hypertension in the Niger Delta: a systematic review and meta-analysis of community-based studies.
Emerging evidence found that health inequality in the Niger Delta region in Nigeria has continued to worsen due to epidemiological and environmental risks transitions. This study aims to provide an up-to-date review and the secular trends of hypertension prevalence in Niger Delta. We systematically searched databases of MEDLINE, EMBASE, African index Medicus and African Journal online from inception to December 30, 2016 for population-based studies providing prevalence estimates of hypertension in the Niger Delta. Eligible studies were included in a random-effect meta-analysis of prevalence and secular trend. The review was reported according to MOOSE guideline. Overall, 34 eligible studies comprising of data on 32715 participants with mean-age of 38.43 ± 2.0 years were identified and included in the meta-analysis. The pooled result showed that across study settings, the prevalence of hypertension in rural population tended to be higher than those in urban areas, 32.0% (95% confidence interval (CI) 25.13-39.28) vs 24.07% (95% CI 18.13-30.58), however, the difference did not reach a statistical significant level, (P < 0.183). The overall mean SBP was 130.15 (95% CI 126.85-133.45) mmHg, and the DBP was 80.72 (95% CI 78.45-82.95). The estimates also vary significantly in men compared to women; 30.26% (95% CI 23.76-37.17) vs 22.99% (17.60-28.86), P < 0.0001, and among those older than 65 years compared to those aged 45-64 years, and more than 2-fold compared to those between 15-44 years, P < 0.001. We also observed a continuous increase in prevalence of hypertension in the region (trend = 0.139, P = 0.0001), such that for every 10 years increase in participants' mean age, the prevalence of hypertension increases by 10.43% (95% CI 5.73-15.14), P < 0.001. This study found evidence that hypertension is a major public health issue in the Niger Delta communities suggesting a positive relationship between socio-economic and lifestyle factors. Improved surveillance and care, as well as better management of the underlying risk factors, primarily undetected or uncontrolled high blood pressure, remains an important public health priority.


Provider-based barriers to provision of intrauterine contraception in general practice.
Intrauterine contraception (IUC) is highly effective, safe and long-lasting, but is not a popular method of contraception among British women. This study examined barriers to the uptake of IUC in general practice in England. A sequential mixed-method approach to explore the views of practitioners regarding the provision of IUC. We e-surveyed 208 practitioners from 69 practices in a region of England and subsequently interviewed 14 practitioners from eight practices. Just under half of general practitioners (GPs) (46.8%; 58/124), and only 8.2% (4/49) of nurses reported being trained to fit IUC. Lack of knowledge of IUC was a barrier to fitting, and also to recommending IUC, especially by practitioners who were not trained to fit. There was discordance between reported knowledge of eligibility for IUC and the likelihood of recommending IUC. Respondents were less likely to recommend IUC to young, nulliparous women, women who had experienced a previous ectopic pregnancy, a recent sexually transmitted infection (STI), or an abnormal cervical smear. The qualitative data indicate that risk aversion and limited training, together with practitioners' assessments that women are uninterested, may lead to IUC being precluded as a suitable method. Increased practitioner education, for those not trained to fit IUC, may remove a barrier to the uptake of IUC in general practice. More research is required on the discordance between the practitioners' views on the characteristics of women considered suitable for IUC, and the criteria set out in the UK Medical Eligibility Criteria (UKMEC) guidelines.


Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.
Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease.


Constitutive synthesis of activator protein 1 transcription factor after viral transformation of mouse fibroblasts.
Transcription factor activator protein 1 (AP1) interacts with the promoter region of a number of genes that are stimulated by growth factors present in serum or by agents such as phorbol 12-myristate 13-acetate (PMA) that partially mimic their action. To investigate the possible role of AP1 in the control of cellular growth and in transformation of mammalian cells, we monitored its activity by binding to a specific DNA probe in normal or transformed mouse NIH 3T3 cells. A 3- to 4-fold increase in the DNA-binding activity was found after serum stimulation of quiescent NIH 3T3 cells. A 2- to 3-fold activation was found after treatment with PMA or dibutyryl-cAMP, suggesting that different signal-transducing pathways could activate AP1 factor in these cells. PMA stimulation was dependent on new protein synthesis. In contrast to normal cells, a high serum-independent AP1 DNA-binding activity was found in NIH 3T3 cells transformed by simian virus 40. These results suggest that constitutive AP1 synthesis may be a crucial step in cellular transformation.


Okadaic acid-sensitive protein phosphatases constrain phrenic long-term facilitation after sustained hypoxia.
Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nm) before SH (25 min, 11% O(2)). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O(2)). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.


Use of multidimensional fluorescence resonance energy transfer to establish the orientation of cholecystokinin docked at the type A cholecystokinin receptor.
Fluorescence resonance energy transfer (FRET) represents a powerful tool to establish relative distances between donor and acceptor fluorophores. By utilizing several donors situated in distinct positions within a docked full agonist ligand and several acceptors distributed at distinct sites within its receptor, multiple interdependent dimensions can be determined. These can provide a unique method to establish or confirm three-dimensional structure of the molecular complex. In this work, we have utilized full agonist analogues of cholecystokinin (CCK) with Aladan distributed throughout the pharmacophore in positions 24, 29, and 33, along with receptor constructs derivatized with Alexa (546) at positions 94, 102, 204, and 341 in the helical bundle and first, second, and third extracellular loops, respectively. These provided 12 FRET distances to overlay on working models of the CCK-occupied receptor. These established that the carboxyl terminus of CCK resides at the external surface of the lipid bilayer, adjacent to the receptor amino-terminal tail, rather than being inserted into the helical bundle. They also provide important experimentally derived constraints for understanding spatial relationships between the docked ligand and the flexible extracellular loop regions. Multidimensional FRET provides a new independent method to establish and refine structural insights into ligand-receptor complexes.


Leukotriene B4 modulates in vivo expression of delayed-type hypersensitivity by a receptor-mediated mechanism: regulation by lipoxin A4.
Leukotriene B4 (LTB4) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors. Recent characterization of a high-affinity LTB4 receptor on the surface of guinea pig CD4+ T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed-type hypersensitivity (DTH) to tuberculin (PPD). In the absence of PPD, intradermal injections of LTB4 or LTB4/LTD4 receptor antagonists did not elicit delayed-onset erythema at 24 h. When injected together with PPD, LTB4 (1 fmol to 1 pmol) caused a significant 25 to 30% decrease in DTH expression, whereas LTB4 receptor antagonists SC-41930, LY-223982, ONO-4057 (0.1-10 nmol), caused a highly significant (P < .01) 25 to 50% increase. The effect of SC-41930 on DTH expression was inhibited by a 10-fmol dose of LTB4. LTD4 receptor antagonist LY-171883 had no effect on DTH expression. Lipoxin A4 (LXA4) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density. It caused a small but significant enhancement of DTH expression at 1-nmol doses when injected with PPD. Lipoxin B4 had no effect. Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4. LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site. We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor-mediated mechanism.


Children with high and intermediate imperforate anus: remembering and talking about medical treatment carried out early in life.
Treatment of children with high and intermediate imperforate anus entails several different surgical procedures during the first 3-12 months of life, which are accompanied by a strict follow-up treatment regimen. It has not been studied whether the children remember this treatment carried out early in life. Research has shown that small children may demonstrate so-called non-verbal memories of salient events occurring in early childhood. The purpose was to examine whether children with imperforate anus showed distressing memories of previous medical treatment and whether parent-child dialog about medical treatment is related to the child's psychosocial functioning later in life. Parents of 25 children (9 boys, 16 girls) with high and intermediate imperforate anus participated in the study. The mean age among the children was 10.5 years (range 8.0-13.6). A comparison group of 30 children (5 boys and 25 girls) with juvenile chronic arthritis also participated in the study. The mean age was 10.6 years (range 7.8-13.6). All parents answered the Child Behavior Checklist (CBCL/4-18) and a study-specific questionnaire. Children in both groups were reported to show distressing memories of early treatment. Children who had been talked to showed good psychosocial function and were in a better mood and less angry than those who had not been talked to. Parent-child discussions about the child's experiences of medical treatment did not seem to be harmful or in any other way detrimental to the child, instead such discussions seemed to facilitate the child's psychosocial functioning.


Agreement Between the OptoGait and Instrumented Treadmill System for the Quantification of Spatiotemporal Treadmill Running Parameters.
The measurement of spatiotemporal gait parameters is commonly utilized to assess gait in healthy and injured individuals. The OptoGait system is a portable system and can be mounted to a treadmill to collect data in a clinical, training, or research setting. The purpose of this method comparison study was to examine the agreement of spatiotemporal gait parameters calculated by the OptoGait compared to an instrumented treadmill system during running. Thirty healthy runners ran on an instrumented treadmill with the OptoGait 1-m system mounted along the treadmill platform. Spatiotemporal running variables of step rate, step length, and contact time were calculated during the final minute of treadmill running. The level of agreement between the OptoGait and treadmill was analyzed using intraclass correlation coefficients [ICC (2,3)] for step rate, step length, and contact time. Step rate and step length demonstrated excellent agreement. Contact time demonstrated good agreement. Intraclass correlation coefficients for spatiotemporal parameters ranged from 0.83 to 0.99. The OptoGait demonstrated good to excellent agreement in the evaluation of running step rate, step length, and contact time and should be considered for use in clinical, training, or research settings.


Pancreatic cancer presenting as a Sister Mary Joseph's nodule.
A 69-year-old man presented with a painful umbilical nodule of 1 month duration. On examination the nodule was blackish in colour with a serous discharging fluid and was 2×2 cm in size, tender and fixed to the skin. There were no scars or sinuses at the umbilicus and no palpable mass or organomegaly on systemic examination. The patient underwent wide local excision of the skin nodule and on histopathology was reported as metastatic adenocarcinoma of the skin. A CT of the abdomen was performed to look for the primary site, which showed a 5×4 cm lesion in the tail of the pancreas. A biopsy from the pancreatic lesion was taken which was reported as an adenocarcinoma. CA19-9 was more than 1000 U/mL. The patient was advised palliative chemotherapy with gemcitabine. He was unwilling to take any further treatment in view of the advanced nature of the disease.


The effects of minimum legal drinking age 21 laws on alcohol-related driving in the United States.
To examine trends in alcohol consumption and alcohol-related crashes among people younger than 21 in the United States and to review evidence on the effects of minimum legal drinking age (MLDA) laws. Trends in alcohol-related crashes and alcohol consumption among young people were examined, and studies on the effects of lowering and raising the drinking age were reviewed. MLDA laws underwent many changes during the 20th century in the United States. Since July 1988, the MLDA has been 21 in all 50 states and the District of Columbia. Surveys tracking alcohol consumption among high school students and young adults found that drinking declined since the late 1970 s, and most of the decline occurred by the early 1990 s. These were the years when states were establishing, or reinstating, a MLDA-21. Among fatally injured drivers ages 16-20, the percentage with positive BACs declined from 61% in 1982 to 31% in 1995, a bigger decline than for older age groups; declines occurred among the ages directly affected by raising MLDAs (ages 18-20) and among young teenagers not directly affected (ages 16-17). Almost all studies designed specifically to gauge the effects of drinking age changes show MLDAs of 21 reduce drinking, problematic drinking, drinking and driving, and alcohol-related crashes among young people. Yet many underage people still drink, many drink and drive, and alcohol remains an important risk factor in serious crashes of young drivers, especially as they progress through the teenage years. Stepped-up enforcement of MLDA and drinking and driving laws can reduce underage drinking. Recent efforts to lower MLDAs to 18 and issue licenses to drink upon completion of alcohol education have gained local and national media attention. There is no evidence that alcohol education can even partially replace the effect of MLDA-21. The cause and effect relationship between MLDAs of 21 and reductions in highway crashes is clear. Initiatives to lower the drinking age to 18 ignore the demonstrated public health benefits of MLDAs of 21. Lowering the drinking age to 18 will increase highway crash deaths among young people.


Heparin attenuates metastasis mainly due to inhibition of P- and L-selectin, but non-anticoagulant heparins can have additional effects.
Heparin and low molecular weight heparin (LMWH) are widely used for treatment of cancer patients with thrombosis, a common complication of malignant disease. Several recent prospective clinical studies indicate that heparin might improve outcomes of human cancer. Meanwhile, experimental evidence from mouse models consistently demonstrates that heparin efficiently inhibits metastasis. We have previously shown that P- and L-selectin play independent roles in supporting the initial stages of hematogeneous metastasis. Heparin is a known potent inhibitor of such selectin-mediated interactions. Here we provide evidence that the absence of both P- and L-selectin (PL -/- mice) dramatically improved survival in an experimental metastasis model. The use of clinically acceptable amounts of heparin did not further aff5ct metastasis rates in such mice. However, a non-anticoagulant derivative of heparin with P- and L-selectin inhibitory properties reduced metastasis to similar levels as observed in PL -/- mice. The virtual elimination of metastasis by a single treatment with a modified heparin without anticoagulant activity strongly suggests that heparin primarily reduces metastatic disease by inhibiting P- and L-selectin interactions. However, such heparins could have further effects at higher doses.


Effect of different physicochemical de-tartration methods on red grape juice quality.
Grape contains a great deal of tartaric acid and minerals such as Potassium and Calcium which during ripening of grape increase in concentrations and result in potassium and calcium tartrate precipitation in grape juice. There have been different methods introduced for de-tartration but none of them have been completely successful. These methods can be categorized into two different groups of physicochemical and instrumental methods. In this study application of cold treatment, cream of tartar (Potassium bitartrate), Carboxymethyl Cellulose (CMC), and Mannoprotein were investigated. Then all these samples were stored at 5 °C to stimulate tartrate crystals precipitation and were investigated for color indices change, the amount of sediments, acidity, pH and taste. Among these methods addition of Mannoprotein and CMC were proved to have ability in stabilizing tartrate crystals in red grape juice.


CRISPR/Cas9-Based RGEN-ISL Allows the Simultaneous and Specific Visualization of Proteins, DNA Repeats, and Sites of DNA Replication.
Visualizing the spatiotemporal organization of the genome will improve our understanding of how chromatin structure and function are intertwined. Here, we describe a further development of the CRISPR/Cas9-based RNA-guided endonuclease-in situ labeling (RGEN-ISL) method. RGEN-ISL allowed the differentiation between vertebrate-type (TTAGGG)n and Arabidopsis-type (TTTAGGG)n telomere repeats. Using maize as an example, we established a combination of RGEN-ISL, immunostaining, and EdU labeling to visualize in situ specific repeats, histone marks, and DNA replication sites, respectively. The effects of the non-denaturing RGEN-ISL and standard denaturing FISH on the chromatin structure were compared using super-resolution microscopy. 3D structured illumination microscopy revealed that denaturation and acetic acid fixation impaired and flattened the chromatin. The broad range of adaptability of RGEN-ISL to different combinations of methods has the potential to advance the field of chromosome biology.


G-compass: a web-based comparative genome browser between human and other vertebrate genomes.
G-compass is designed for efficient comparative genome analysis between human and other vertebrate genomes. The current version of G-compass allows us to browse two corresponding genomic regions between human and another species in parallel. One-to-one evolutionarily conserved regions (i.e. orthologous regions) between species are highlighted along the genomes. Information such as locations of duplicated regions, copy number variations and mammalian ultra-conserved elements is also provided. These features of G-compass enable us to easily determine patterns of genomic rearrangements and changes in gene orders through evolutionary time. Since G-compass is a satellite database of H-InvDB, which is a comprehensive annotation resource for human genes and transcripts, users can easily refer to manually curated functional annotations and other abundant biological information for each human transcript. G-compass is expected to be a valuable tool for comparing human and model organisms and promoting the exchange of functional information. G-compass is freely available at http://www.h-invitational.jp/g-compass/. email@example.com


Effect of maternal obesity on the risk of fetal loss after amniocentesis and chorionic villus sampling.
To estimate the risk of fetal loss in obese women undergoing amniocentesis and chorionic villus sampling (CVS). This was a retrospective cohort study of all women undergoing amniocentesis or CVS. The primary outcome was any fetal loss before 24 weeks of gestation. A secondary analysis was performed examining pregnancy loss within 14 days of the procedure, excluding termination of pregnancy. Obese (body mass index [BMI] 30.0 or higher) and nonobese (BMI lower than 30.0) patients were compared, and the postprocedure loss rate was also estimated by BMI strata. Obese and nonobese patients were compared with univariable and bivariate statistics; multivariable logistic regression models were developed to estimate the effect of maternal obesity. Between obese (n=2,742) and nonobese (n=8,037) women undergoing amniocentesis, no difference existed in the risk of fetal loss before 24 weeks of gestation (4.7% [combined background and procedure loss] compared with 4.2%, adjusted odds ratio [OR] 1.1, 95% confidence interval [CI] 0.8-1.5). For women undergoing CVS, no difference in the risk of pregnancy loss was seen between obese (n=855) and nonobese (n=4,125) women (6.4% compared with 6.3%, adjusted OR 1.0, 95% CI 0.7-1.3). Compared with women not undergoing a procedure, the attributable risk for obese women was 0.3% (95% CI -0.2 to 0.9) amniocentesis and 0.1% (95% CI -0.1 to 0.2) CVS. The difference in fetal loss between the BMI 40.0 or higher and BMI lower than 25.0 groups after amniocentesis was significant after adjusting for maternal age (adjusted OR 2.2, 95% CI 1.2-3.9). This study had greater than 90% power to detect a 50% increase in the risk of pregnancy loss after amniocentesis and CVS (with an α error of 0.05). A BMI of 30.0-40.0 does not increase the risk for fetal loss after invasive prenatal diagnostic procedures. A higher loss rates with class III obesity (BMI 40.0 or higher) was observed for amniocentesis procedures. II.


Statin prescription among patients with type 2 diabetes in Botswana: findings and implications.
There is evidence of statin benefit among patients with diabetes regardless of cholesterol levels or prior cardiovascular disease history. Despite the evidence, there is under-prescription of statins in clinical practice. This study aimed to assess statin prescriptions and associated factors among patients with type 2 diabetes in Botswana. The study was a secondary data analysis of 500 randomly selected type 2 diabetes patients at a specialised diabetes clinic at Gaborone, Botswana. We assessed the proportion of statin-eligible patients who are prescribed statins and evaluated the adjusted associations between various factors and statin prescriptions. Overall, 477 (95.4%) participants were eligible for a statin prescription. Clinicians prescribed statins in 217 (45.5%) of eligible participants, and only one (4.4%) ineligible participant. The probability of a statin prescription was higher in participants with high baseline low-density lipoprotein cholesterol (risk ratio [RR]: 1.49; 95%CI: 1.17-1.89), increasing duration of diabetes (RR: 1.01; 95%CI 1.00-1.03) and the presence of chronic kidney disease (RR: 1.35; 95%CI: 1.06-1.74). A large proportion with type 2 diabetes in Gaborone is not receiving statins. Clinicians did not consider most guideline-recommended indications for statin prescriptions. The findings call for improvement in diabetes quality of care by implementing evidence-based guideline recommendations.


Aryl hydrocarbon receptor inhibition promotes hematolymphoid development from human pluripotent stem cells.
The aryl hydrocarbon receptor (AHR) plays an important physiological role in hematopoiesis. AHR is highly expressed in hematopoietic stem and progenitor cells (HSPCs) and inhibition of AHR results in a marked expansion of human umbilical cord blood-derived HSPCs following cytokine stimulation. It is unknown whether AHR also contributes earlier in human hematopoietic development. To model hematopoiesis, human embryonic stem cells (hESCs) were allowed to differentiate in defined conditions in the presence of the AHR antagonist StemReginin-1 (SR-1) or the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We demonstrate a significant increase in CD34+CD31+ hematoendothelial cells in SR-1-treated hESCs, as well as a twofold expansion of CD34+CD45+ hematopoietic progenitor cells. Hematopoietic progenitor cells were also significantly increased by SR-1 as quantified by standard hematopoietic colony-forming assays. Using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-engineered hESC-RUNX1c-tdTomato reporter cell line with AHR deletion, we further demonstrate a marked enhancement of hematopoietic differentiation relative to wild-type hESCs. We also evaluated whether AHR antagonism could promote innate lymphoid cell differentiation from hESCs. SR-1 increased conventional natural killer (cNK) cell differentiation, whereas TCDD treatment blocked cNK development and supported group 3 innate lymphoid cell (ILC3) differentiation. Collectively, these results demonstrate that AHR regulates early human hematolymphoid cell development and may be targeted to enhance production of specific cell populations derived from human pluripotent stem cells.


7 Tesla (T) human cardiovascular magnetic resonance imaging using FLASH and SSFP to assess cardiac function: validation against 1.5 T and 3 T.
We report the first comparison of cardiovascular magnetic resonance imaging (CMR) at 1.5 T, 3 T and 7 T field strengths using steady state free precession (SSFP) and fast low angle shot (FLASH) cine sequences. Cardiac volumes and mass measurements were assessed for feasibility, reproducibility and validity at each given field strength using FLASH and SSFP sequences. Ten healthy volunteers underwent retrospectively electrocardiogram (ECG) gated CMR at 1.5 T, 3 T and 7 T using FLASH and SSFP sequences. B1 and B0 shimming and frequency scouts were used to optimise image quality. Cardiac volume and mass measurements were not significantly affected by field strength when using the same imaging sequence (P > 0.05 for all parameters at 1.5 T, 3 T and 7 T). SSFP imaging returned larger end diastolic and end systolic volumes and smaller left ventricular masses than FLASH imaging at 7 T, and at the lower field strengths (P < 0.05 for each parameter). However, univariate general linear model analysis with fixed effects for sequence and field strengths found an interaction between imaging sequence and field strength (P = 0.03), with a smaller difference in volumes and mass measurements between SSFP and FLASH imaging at 7 T than 1.5 T and 3 T. SSFP and FLASH cine imaging at 7 T is technically feasible and provides valid assessment of cardiac volumes and mass compared with CMR imaging at 1.5 T and 3 T field strengths.


Postprandial lipemia--effect of lipid-lowering drugs.
Exaggerated postprandial hyperlipidemia has been associated with cardiovascular disease. The mechanisms underlying this association are likely to depend on a multitude of effects. Potentially atherogenic remnants of triglyceride-rich lipoproteins (TRL) accumulate in the postprandial state. In addition, TRL may promote the formation of small dense LDL. There are some indications that the postprandial period is a hypercoagulable state and endothelial function seems to be hampered after acute fat intake. Conventional lipid lowering drugs such as statins and fibrates have the potency of reducing postprandial hyperlipidemia, but the fibrates seem to be more effective in this respect. There is a complete lack of prospective studies linking inefficient postprandial lipid metabolism with clinical endpoints and there is also a need to include investigations of postprandial lipid metabolism in the evaluation of novel drugs affecting lipid metabolism and insulin resistance.