The number of discernible colors perceived by dichromats in natural scenes and the effects of colored lenses.
The number of discernible colors perceived by normal trichromats when viewing natural scenes can be estimated by analyzing idealized color volumes or hyperspectral data obtained from actual scenes. The purpose of the present work was to estimate the relative impairment in chromatic diversity experienced by dichromats when viewing natural scenes and to investigate the effects of colored lenses. The estimates were obtained computationally from the analysis of hyperspectral images of natural scenes and using a quantitative model of dichromats' vision. The color volume corresponding to each scene was represented in CIELAB color space and segmented into cubes of unitary side. For normal trichromats, the number of discernible colors was estimated by counting the number of non-empty cubes. For dichromats, an algorithm simulating for normal observers the appearance of the scenes for dichromats was used, and the number of discernible colors was then counted as for normal trichromats. The effects of colored lenses were estimated by prior filtering the spectral radiance from the scenes with the spectral transmittance function of the lenses. It was found that in dichromatic vision the number of discernible colors was about 7% of normal trichromatic vision. With some colored lenses considerable improvements in chromatic diversity were obtained for trichromats; for dichromats, however, only modest improvements could be obtained with efficiency levels dependent on the combination of scene, lens and type of deficiency.


Influence of antiretroviral therapy on bone metabolism of patients with chronic hepatitis B: a review.
Hepatitis B is a major public health problem worldwide and associated with significant mortality. To prevent or delay the deleterious effects of chronic infection by the hepatitis B virus, patients should be carefully followed, and antiviral therapy indicated according to specific recommendations. Currently, available drugs inhibit viral replication and slow or stop the progression of inflammation and fibrosis of the liver. However, the drugs for oral use in the treatment of hepatitis B, jointly referred to as nucleoside/nucleotide analogs, are indicated for prolonged use and have potential side effects. The reduction in bone mineral density was associated with the use of tenofovir, already evaluated in patients infected with HIV because the drug is also part of the therapeutic arsenal for this viral infection. There are few studies on the effects of tenofovir in patients with mono hepatitis B. Therefore, this literature review proposes to examine how hepatitis B acts in the body and the mechanisms by which antiretroviral drugs (especially tenofovir) can affect bone metabolism.


Pupillary dilation elicited by attending to two disks with different luminance.
Pupils become smaller when people attend to a bright disk as compared to a dark disk. However, people can divide their attention into several distinct positions, which is referred to as divided attention, and pupillary responses under such conditions have not been investigated. In this study, we examined how pupils would respond when people attended to two disks presented at two distinct positions by conducting three experiments. We found that the pupillary response when attending to two disks with different luminance was larger than when attending to a single brighter disk and was comparable to that when attending to a single darker disk, whereas the pupillary response when attending to two disks with identical luminance was not larger than when attending to a single disk (irrespective of the disk luminance). Furthermore, we found that the magnitude of pupillary dilation was determined by the magnitude of the luminance difference between two disks. These results make a useful contribution to the literature on human pupillary responses.


Precision-Microfabricated Fiber-Optic Probe for Intravascular Pressure and Temperature Sensing.
Small form-factor sensors are widely used in minimally invasive intravascular diagnostic procedures. Manufacturing complexities associated with miniaturizing current fiber-optic probes, particularly for multi-parameter sensing, severely constrain their adoption outside of niche fields. It is especially challenging to rapidly prototype and iterate upon sensor designs to optimize performance for medical devices. In this work, a novel technique to construct a microscale extrinsic fiber-optic sensor with a confined air cavity and sub-micron geometric resolution is presented. The confined air cavity is enclosed between a 3 μm thick pressure-sensitive distal diaphragm and a proximal temperature-sensitive plano-convex microlens segment unresponsive to changes in external pressure. Simultaneous pressure and temperature measurements are possible through optical interrogation via phase-resolved low-coherence interferometry (LCI). Upon characterization in a simulated intravascular environment, we find these sensors capable of detecting pressure changes down to 0.11 mmHg (in the range of 760 to 1060 mmHg) and temperature changes of 0.036 °C (in the range 34 to 50 °C). By virtue of these sensitivity values suited to intravascular physiological monitoring, and the scope of design flexibility enabled by the precision-fabricated photoresist microstructure, it is envisaged that this technique will enable construction of a wide range of fiber-optic sensors for guiding minimally invasive medical procedures.


Progress in Immunization Safety Monitoring - Worldwide, 2020-2022.
Effective surveillance of adverse events following immunization (AEFIs) primarily relies on the collaboration of two partners: national regulatory authorities (NRAs) and national expanded programs on immunization (EPIs). In December 2020, the World Health Organization (WHO) Global Advisory Committee for Vaccine Safety recommended a new case-based indicator of national capacity to monitor immunization safety: at least one serious AEFI reported per 1 million total population per year. To achieve this indicator, WHO-affiliated countries and territories (WHO countries) rely upon data generated from functional AEFI surveillance systems. This report describes 2020-2022 global, regional, and national progress in use of the newly introduced immunization safety monitoring indicator and progress on joint AEFI reporting from national EPIs and NRAs. Among WHO countries, 51 (24%) of 214 implemented the new indicator in 2020, 111 (52%) of 214 implemented it in 2021, and 92 (43%) of 215 in 2022. In 2020, 41 (19%) WHO countries reported AEFI data jointly from EPIs and NRAs; this increased to 55 (26%) in 2021 and 57 (27%) in 2022. These findings, resulting in part from the intensified support for COVID-19 vaccination, demonstrate that national AEFI surveillance systems increasingly support the timely use and sharing of case-based immunization safety data, but work is still needed to strengthen global vaccine safety monitoring.


Reinforcement shapes clines in female mate discrimination in Drosophila subquinaria.
Reinforcement of species boundaries may alter mate recognition in a way that also affects patterns of mate preference among conspecific populations. In the fly Drosophila subquinaria, females sympatric with the closely related species D. recens reject mating with heterospecific males as well as with conspecific males from allopatric populations. Here, we assess geographic variation in behavioral isolation within and among populations of D. subquinaria and use cline theory to understand patterns of selection on reinforced discrimination and its consequences for sexual isolation within species. We find that selection has fixed rejection of D. recens males in sympatry, while significant genetic variation in this behavior occurs within allopatric populations. In conspecific matings sexual isolation is also asymmetric and stronger in populations that are sympatric with D. recens. The clines in behavioral discrimination within and between species are similar in shape and are maintained by strong selection in the face of gene flow, and we show that some of their genetic basis may be either shared or linked. Thus, while reinforcement can drive extremely strong phenotypic divergence, the long-term consequences for incipient speciation depend on gene flow, genetic linkage of discrimination traits, and the cost of these behaviors in allopatry.


Nearest neighbor classification in 3D protein databases.
In molecular databases, structural classification is a basic task that can be successfully approached by nearest neighbor methods. The underlying similarity models consider spatial properties such as shape and extension as well as thematic attributes. We introduce 3D shape histograms as an intuitive and powerful approach to model similarity for solid objects such as molecules. Errors of measurement, sampling, and numerical rounding may result in small displacements of atomic coordinates. These effects may be handled by using quadratic form distance functions. An efficient processing of similarity queries based on quadratic forms is supported by a filter-refinement architecture. Experiments on our 3D protein database demonstrate the high classification accuracy of more than 90% and the good performance of the technique.


[Relapsing polychondritis: clinical and therapeutic analysis of 15 Mexican cases].
relapsing polychondritis (RP) is a rare multisystem disease of unknown etiology, characterized by recurrent episodes of inflammation and cartilage destruction. The aim was to present fifteen cases, analyzed in a clinical and therapeutic perspective. fifteen cases from three different cities of Mexico, diagnosed with Damiani criteria, were included. Clinical features, treatment given and outcome were recorded. nine men and six women with mean age of 52.4 years met the criteria for RP; the average change was 86.7 months. The dominant clinical manifestations were: 83 % auricular chondritis, 66 % dysphonia, 60 % arthritis and 53 % with eye involvement. Treatment included: 93 % received corticosteroids, 60 % received methotrexate, 46 % received no steroidal anti-inflammatory treatment, 46 % received immunosuppressant therapy, and two cases received biologic therapy. The clinical course showed 34 relapses in 12 cases. Complications included hoarseness in seven cases, tracheal stenosis in six case, and hearing loss in three cases. There were five deaths, three from respiratory complications, one from renal failure and another from a cerebral vascular event. the fifteen cases with RP presented were characterized by multisystem clinical courses and serious respiratory complications. The diagnostic and therapeutic situations merited highly medical specialized approaches.


A novel 13C-urea breath test device for the diagnosis of Helicobacter pylori infection: continuous online measurements allow for faster test results with high accuracy.
The aim of this study is to determine the accuracy of a novel laptop sized 13C-Urea breath test analyzer that continuously measures expired breath and to use its advantages to decrease testing time. One hundred and eighty-six subjects (mean age of 47.8 years) were tested simultaneously by the BreathID system (Oridion, Israel), and by the traditional IRMS. BreathID continuously measured the expired breath for a ratio of 13CO(2):12CO(2.) This value was expressed as delta over baseline (DOB) and displayed graphically on a screen in real time. One hundred and one subjects were positive and 85 were negative for H. pylori by isotope ratio mass spectrometry (IRMS). The correlation for the BreathID system at 30 minutes was 100% for positive cases and 98% for negative cases. Analysis of the continuous curves generated by the BreathID for all patients permitted definition of different DOB thresholds for a positive or negative result at shorter time intervals. Thus, after 6 minutes a conclusive test result could be obtained for 64% of subjects, and after 10 minutes for 92% of subjects. The 13C-Urea breath test utilizing the technology of molecular correlation spectrometry is an accurate method for determining infection by H. pylori. The advantage of continuous measurements can shorten testing time without compromising accuracy.


Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology.
Anti-NMDAR encephalitis is a newly characterized syndrome with a progressive, predictable clinical course and the possibility of effective treatment. Accurate and timely diagnosis is critical to selection and implementation of treatments, and optimal patient outcomes. Outcomes are improved with early diagnosis via indirect immunofluorescence or cell-based assays, and the rapid and appropriate administration of immunosuppressant and anti-psychotic therapies. Three possible scenarios accounting for the immunopathogenesis of anti-NMDAR encephalitis are presented, with the most probable one being that of paraneoplastic autoimmunity. Future efforts in this disorder should focus on elucidating the mechanisms that contribute to initiation of this antibody response, as well as exploring the role of tumors, infectious triggers and immune-reactivation. Finally, accessible tools need to be developed that allow for reliable identification of specific antibody markers against synaptic proteins.


Antinociceptive and anti-inflammatory effects of Urtica dioica leaf extract in animal models.
This study was aimed to examine the antinociceptive and anti-inflammatory effects of Urtica dioica leaf extract in animal models. Hydroalcoholic extract of the plant leaves was prepared by percolation method. Male Swiss mice (25-35 g) and male Wistar rats (180-200 g) were randomly distributed in control, standard drug, and three experimental groups (n=6 in each group). Acetic acid-induced writhing, formalin test, and carrageenan-induced paw edema were used to assess the antinociceptive and anti-inflammatory effects. The extract dose-dependently reduced acetic acid-induced abdominal twitches. In formalin test, the extract at any of applied doses (100, 200, and 400 mg/kg) could not suppress the licking behavior of first phase while doses of 200 and 400 mg/kg significantly inhibited the second phase of formalin test. In carrageenan test, the extract at a dose of 400 mg/kg significantly inhibited the paw edema by 26%. The results confirm the folkloric use of the plant extract in painful and inflammatory conditions. Further studies are needed to characterize the active constituents and the mechanism of action of the plant extract.


Compartmentalization of 11-oxidoreductase within fetal lung alveolus.
The role of 11-oxidoreductase in the cellular process of fetal lung surfactant production and its localization within the alveolar domain have been investigated. In organotypic cultures of fetal rat lung, cortisol and cortisone markedly stimulate saturated phosphatidylcholine synthesis by the alveolar type II cell; a 10-fold excess of 11-ketoprogesterone blocks the bioactivity of cortisone. Both cortisol and cortisone also stimulate fibroblast-pneumonocyte factor production, whereas 11-ketoprogesterone blocks the effect of cortisone, but not of cortisol, suggesting that cortisone stimulation of fibroblast-pneumonocyte factor production depends on its conversion to cortisol by 11-oxidoreductase. A survey of the cells that are present in the alveolar domain revealed that 11-oxidoreductase activity is only present in the fibroblast. Localization of both 11-oxidoreductase and fibroblast-pneumonocyte factor production within the same cell emphasizes the significance of 11-oxidoreductase in the regulation of fetal lung surfactant production.


Prevalence of airflow obstruction according GOLD, ATS and ERS criteria in symptomatic ever-smokers referring to a pulmonary rehabilitation department.
To evaluate in a Pulmonary Rehabilitation (PR) setting the prevalence of airflow obstruction (AO) in either current or former smokers > or = 45 years old both with dyspnoea and with chronic productive cough, using European Respiratory society (ERS) statement (FEV1/SVC < 88 and < 89% predicted in men and women, respectively), American Thoracic Society (ATS) statement (FEV1/FVC < 75%), and Global Initiative for Chronic Obstructive Lung Disease (GOLD) statement (FEV1/FVC < 70%). Lung function tests were performed in each patient who was referred to our PR department due to respiratory diagnosis or symptoms. For analysis, in patients showing AO we used post-bronchodilator lung function values. In 184 ever-smoker patients with symptoms of chronic obstructive pulmonary disease (COPD), the prevalence rates of AO were as follows: ERS = 89.7%, ATS = 76.6%, and GOLD = 63.6%. Patients with AO according ERS criteria showing moderate to severe (M/S) obstruction (i.e., FEV1 < 70% predicted) were 119. Patients with ERS M/S AO but without AO using either ATS or GOLD criteria were 8.4% and 19.3%, respectively. Prevalence of AO is highly dependent on which guidelines it is based. ATS and particularly GOLD statement can cause a large under-diagnosis even of moderate to severe COPD. Diagnosis of COPD may be overlooked if SVC is not performed.


Optimal Hyperspectral Band Selection for Tissue Oxygenation Mapping with Generative Adversarial Network.
Tissue oxygenation assessment using hyperspectral imaging is an emerging technique for the diagnosis and pre- and post-treatment monitoring of ischemic patients. However, the high spectral resolution of hyperspectral imaging leads to large data sizes and a long imaging time. In this study, we propose a method that utilizes multi-objective evolutionary algorithms to determine the optimal hyperspectral band combination when developing a deep learning model for predicting tissue oxygenation from hyperspectral images. Our results confirm that the deep learning model effectively predicts tissue oxygenation images for various oxygenation states. Moreover, we demonstrate that a high-performance prediction model can be developed using only a small number of spectral bands, indicating the potential for more efficient non-contact tissue oxygenation mapping with the proposed method.Clinical Relevance- The proposed method allows for the non-contact and efficient acquisition of two-dimensional tissue oxygenation information in various oxygenation states.


The dimensions and composition of stereociliary rootlets in mammalian cochlear hair cells: comparison between high- and low-frequency cells and evidence for a connection to the lateral membrane.
The sensory bundle of vertebrate cochlear hair cells consists of actin-containing stereocilia that are thought to bend at their ankle during mechanical stimulation. Stereocilia have dense rootlets that extend through the ankle region to anchor them into the cuticular plate. Because this region may be important in bundle stiffness and durability during prolonged stimulation at high frequencies, we investigated the structure and dimensions of rootlets relative to the stereocilia in apical (low-frequency) and basal (high-frequency) regions of rodent cochleae using light and electron microscopy. Their composition was investigated using postembedding immunogold labeling of tropomyosin, spectrin, beta-actin, gamma-actin, espin, and prestin. The rootlets have a thick central core that widens at the ankle, and are embedded in a filamentous meshwork in the cuticular plate. Within a particular frequency region, rootlet length correlates with stereociliary height but between regions it changes disproportionately; apical stereocilia are, thus, approximately twice the height of basal stereocilia in equivalent rows, but rootlet lengths increase much less. Some rootlets contact the tight junctions that underlie the ends of the bundle. Rootlets contain spectrin, tropomyosin, and beta- and gamma-actin, but espin was not detected; spectrin is also evident near the apical and junctional membranes, whereas prestin is confined to the basolateral membrane below the junctions. These data suggest that rootlets strengthen the ankle region to provide durability and may contact with the lateral wall either to give additional anchoring of the stereocilia or to provide a route for interactions between the bundle and the lateral wall.


Patient-specific radiation risk-based tube current modulation for diagnostic CT.
Modern CT scanners use automatic exposure control (AEC) techniques, such as tube current modulation (TCM), to reduce dose delivered to patients while maintaining image quality. In contrast to conventional approaches that minimize the tube current time product of the CT scan, referred to as mAsTCM in the following, we herein propose a new method referred to as riskTCM, which aims at reducing the radiation risk to the patient by taking into account the specific radiation risk of every dose-sensitive organ. For current mAsTCM implementations, the mAs product is used as a surrogate for the patient dose. Thus, they do not take into account the varying dose sensitivity of different organs. Our riskTCM framework assumes that a coarse CT reconstruction, an organ segmentation, and an estimation of the dose distribution can be provided in real time, for example, by applying machine learning techniques. Using this information, riskTCM determines a tube current curve that minimizes a patient risk measure, for example, the effective dose, while keeping the image quality constant. We retrospectively applied riskTCM to 20 patients covering all relevant anatomical regions and tube voltages from 70 to 150 kV. The potential reduction of effective dose at same image noise is evaluated as a figure of merit and compared to mAsTCM and to a situation with a constant tube current referred to as noTCM. Anatomical regions like the neck, thorax, abdomen, and the pelvis benefit from the proposed riskTCM. On average, a reduction of effective dose of about 23% for the thorax, 31% for the abdomen, 24% for the pelvis, and 27% for the neck has been evaluated compared to today's state-of-the-art mAsTCM. For the head, the resulting reduction of effective dose is lower, about 13% on average compared to mAsTCM. With a risk-minimizing TCM, significant higher reduction of effective dose compared to mAs-minimizing TCM is possible.


When one tail isn't enough: abnormal caudal regeneration in lepidosaurs and its potential ecological impacts.
Abnormal caudal regeneration, the production of additional tails through regeneration events, occurs in lepidosaurs as a result of incomplete autotomy or sufficient caudal wound. Despite being widely known to occur, documented events generally are limited to opportunistic single observations - hindering the understanding of the ecological importance of caudal regeneration. Here we compiled and reviewed a robust global database of both peer-reviewed and non-peer reviewed records of abnormal regeneration events in lepidosaurs published over the last 400 years. Using this database, we qualitatively and quantitatively assessed the occurrence and characteristics of abnormal tail regeneration among individuals, among species, and among populations. We identified 425 observations from 366 records pertaining to 175 species of lepidosaurs across 22 families from 63 different countries. At an individual level, regenerations ranged from bifurcations to hexafurcations; from normal regeneration from the original tail to multiple regenerations arising from a single point; and from growth from the distal third to the proximal third of the tail. Species showing abnormal regenerations included those with intra-vertebral, inter-vertebral or no autotomy planes, indicating that abnormal regenerations evidently occur across lepidosaurs regardless of whether the species demonstrates caudal autotomy or not. Within populations, abnormal regenerations were estimated at a mean ± SD of 2.75 ± 3.41% (range 0.1-16.7%). There is a significant lack of experimental studies to understand the potential ecological impacts of regeneration on the fitness and life history of individuals and populations. We hypothesised that abnormal regeneration may affect lepidosaurs via influencing kinematics of locomotion, restrictions in escape mechanisms, anti-predation tactics, and intra- and inter-specific signalling. Behaviourally testing these hypotheses would be an important future research direction.


Spermatocytic seminoma.
Spermatocytic seminoma is a rare germ cell tumor distinct from classical seminoma, both clinically and pathologically. It affects older men, has not been associated with a history of cryptorchidism, and has no known counterpart in ovary or any other site. Pathologically, it is characterized by 3 distinct cell types, lack of cytoplasmic glycogen, and scant to absent lymphocytic infiltrate. Gain of chromosome 9 is the most consistent genetic abnormality. There have been few case reports of sarcomas arising in spermatocytic seminoma and only an occasional report of metastasis. It is important to differentiate this condition from its frequent mimics, such as classic seminoma and embryonal carcinoma, because patients with spermatocytic seminoma may not require further treatment after surgery.


Microarterial synthetic graft repair: interstitial cellular components.
Although the histologic changes occurring during healing on the lumen surface of large vessel synthetic vascular grafts have been well characterized, the cells populating the interstices of microvascular grafts have not been examined in detail. Since microvascular grafts are required to provide vascular continuity under quite different physiological and hemodynamic conditions as compared with large vessel grafts, these interstitial cells within the synthetic graft material may also vary as a function of graft size. Monoclonal antibodies, light microscopy, and scanning and transmission electron microscopy were used in this study to identify the cells present within the 30-microns pores of 1-mm diameter polytetrafluoroethylene and replamineform silicone rubber grafts. Identified cells included few capillary endothelial cells enclosing erythrocytes, rare proliferating endothelial cells, few macrophages, rare foreign body giant cells, and a majority of fibroblasts. There was no evidence of smooth muscle cells or myofibroblasts within the interstices of these microvascular prostheses 12 weeks after implantation in the rabbit central ear artery. The graft types differed by the presence of foreign body giant cells and more densely packed collagen between cells in the replamineform silicone rubber graft interstices.


Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals.
Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals. Three stage retrospective patient record review study in 21 hospitals of 8400 patient records of discharged or deceased patients in 2004. The records were reviewed by trained nurses and physicians between August 2005 and October 2006. In addition to the determination of presence, the degree of preventability, and causes of adverse events, also location, timing, classification, and most responsible specialty of the adverse events were measured. Moreover, patient and admission characteristics and the quality of the patient records were recorded. In this paper we report on the design of the retrospective patient record study on the occurrence of adverse events in Dutch hospitals. Attention is paid to the strengths and limitations of the study design. Furthermore, alterations made in the original research protocol in comparison with former international studies are described in detail.


Differentiation of HL-60 myeloid leukaemia cells is associated with a transient block in the G2 phase of the cell cycle.
The human promyelocytic leukaemia cell line HL-60 can be induced to differentiate towards mature granulocytes by treatment with dibutyryl cyclic adenosine-3',5'-monophosphate (dbcAMP). Differentiation begins within 16-24 h of treatment and is associated with a time- and dose-dependent accumulation of cells in the G0/G1 phase of the cell cycle with a concomitant decrease in the number of cells in the S and G2 + M phases. Using acridine orange staining, we found that the RNA content of the cells also decreased following differentiation. Stathmokinetic analysis of HL-60 cell populations following dbcAMP treatment showed no effect on the total number of cells in the G0/G1 or S phases, or the rate of progression of cells through these cell cycle compartments. In contrast, dbcAMP was found to induce a transient arrest of the cells in the G2 phase. We also found that differentiation induced by dbcAMP did not require progression of the cells through the cell cycle. Cells arrested in either G1/S by hydroxyurea or G2 + M by colcemid eventually expressed markers of mature granulocytes. These results demonstrate that dbcAMP modulates cell cycle progression. However, these cell cycle changes alone are insufficient to induce granulocytic differentiation of HL-60 cells.


Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn.
Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn. Selective lesion of the descending serotonergic (5-HT) pathway by prior intrathecal administration of 5,7-dihydroxytryptamine attenuated hypersensitivity at early time points following ankle injection of CFA. In a separate study ablation of the mu opioid receptor expressing (MOR+) cells of the RVM, by microinjection of the toxin dermorphin-saporin, resulted in a more prolonged attenuation of hypersensitivity post CFA. Microarray analysis was carried out to identify changes in dorsal horn gene expression associated with descending facilitation by the MOR+ pathway at 7d post joint inflammation. This analysis led to the identification of a number of genes including the chemokines Cxcl9 and Cxcl10, their common receptor Cxcr3, and the proinflammatory gene Nos2 (inducible nitric oxide synthase, iNOS). These findings demonstrate that joint pain behaviour is dependent in part on descending facilitation via the RVM, and identify a novel pathway driving CXC chemokine and iNOS expression in the dorsal horn.


Cited2 is required for normal hematopoiesis in the murine fetal liver.
Cited2 (cAMP-responsive elementbinding protein [CBP]/p300-interacting transactivators with glutamic acid [E] and aspartic acid [D]-rich tail 2) is a newly identified transcriptional modulator. Knockout of the Cited2 gene results in embryonic lethality with embryos manifesting heart and neural tube defects. Cited2-/- fetal liver displayed significant reduction in the numbers of Lin(-)c-Kit+Sca-1+ cells, Lin(-)c-Kit+ cells, and progenitor cells of different lineages. Fetal liver cells from Cited2-/- embryos gave rise to markedly reduced number of colonies in the colony-forming unit assay. Primary and secondary transplantation studies showed significantly compromised reconstitution of T-lymphoid, B-lymphoid, and myeloid lineages in mice that received a transplant of Cited2-/- fetal liver cells. Competitive reconstitution experiments further showed that fetal liver hematopoietic stem cell (HSC) function is severely impaired due to Cited2 deficiency. Microarray analysis showed decreased expression of Wnt5a and a panel of myeloid molecular markers such as PRTN3, MPO, Neutrophil elastase, Cathepsin G, and Eosinophil peroxidase in Cited2-/- fetal livers. Decreased expression of Bmi-1, Notch1, LEF-1, Mcl-1, and GATA2 was also observed in Cited2-/- Lin(-)c-Kit+ cells. The present study uncovers for the first time a novel role of Cited2 in the maintenance of hematopoietic homeostasis during embryogenesis and thus provides new insights into the molecular regulation of hematopoietic development.


Induction of tolerance to small bowel allografts in high-responder rats by combining anti-CD4 with CTLA4Ig.
This study was designed to investigate the effectiveness of combined perioperative anti-CD4 and human (h)CTLA4Ig therapy in preventing allorejection of small bowel transplantation in high-responder Lewis rat recipients of ACI grafts. Anti-CD4 (5 mg/kg x 4 days) or hCTLA4Ig (0.5 mg/rat x 2 days) therapy alone delayed, but did not prevent, allograft rejection after small bowel transplantation of ACI into Lewis rats. All grafts were rejected in 18 and 10 days, respectively. However, a regimen of anti-CD4 (5 mg/kg x 4 days) combined with hCTLA4Ig (0.5 mg/rat x 2 days) allowed indefinite survival of ACI small bowel allografts. Second donor-matched heart grafts were permanently accepted, whereas third-party (Sprague-Dawley) heart allografts were rejected by the tolerant recipients. These data suggest that these two reagents produced a synergistic effect in preventing allorejection of small bowel transplantation.


Polarized targeting of epithelial cell proteins in thyrocytes and MDCK cells.
Polarized trafficking signals may be interpreted differently in different cell types. In this study, we have compared the polarized trafficking of different proteins expressed endogenously in primary porcine thyroid epithelial cells to similar proteins expressed in MDCK cells. As in MDCK cells, NH4Cl treatment of filter-grown thyrocytes caused mis-sorted soluble proteins to exhibit enhanced secretion to the apical medium. In independent studies, thrombospondin 1 (a thyroid basolaterally secreted protein) was secreted basolaterally from MDCK cells. Likewise, the 5'-deiodinase (a thyroid basolateral membrane protein) encoded by the DIO1 gene was also distributed basolaterally in transfected MDCK cells. Consistent with previous reports, when the secretion of human growth hormone (an unglycosylated regulated secretory protein) was examined from transfected MDCK cells, the release was nonpolarized. However, transfected thyrocytes secreted growth hormone apically in a manner dependent upon zinc addition. Moreover, two additional regulated secretory proteins expressed in thyrocytes, thyroglobulin (the major endogenous glycoprotein) and parathyroid hormone (an unglycosylated protein expressed transiently), were secreted apically even in the absence of zinc. We hypothesize that while cellular mechanisms for interpreting polarity signals are generally similar between thyrocytes and MDCK cells, thyrocytes allow for specialized packaging of regulated secretory proteins for apical delivery, which does not require glycosylation but may involve availability of certain ions as well as appropriate intracellular compartmentation.


Antigenic epitopes of three tumor-associated antigens of well-differentiated squamous cell carcinoma of the larynx for use in monitoring patients in specific active immunochemotherapy trials.
Laryngeal tumor-associated antigen (LX-TAA-1) monoclonal antibody-derived epitopes were tested by enzyme immunoassay (ELISA) against a coded series of 30 non-laryngeal squamous cancer sera, 32 laryngeal squamous cancer sera and 36 non-squamous cancer sera. Epitope LX-TAA-1 a62 cross-reacted with 46% of non-laryngeal squamous and with 16% non-squamous cancer sera. Epitope i5 cross-reacted with 50% non-laryngeal squamous cancer sera and with 11% non-squamous cancer sera. LX-TAA-1 epitope f18 cross-reacted with 26% of non-laryngeal squamous cancer sera but with only one, at weaker titer, of the non-squamous cancer serums (2%). Preliminary screening had ruled out any reactivity to 92 normal, age- and sex-matched sera. One hundred percent of laryngeal squamous cancer sera showed reactivity to one or more of the three epitopes. These results from highly sensitive testing imply that epitope f18 protein is probably a unique gene product of certain squamous cancer cells in the body. Serial titrations of immunized patient sera indicated that epitope f18 produces a strong but very early reactivity and appears to be a marker for early post-immunization response in patients on immunotherapy, with epitope i5 showing a low but continuing positive response starting at 7 months post-immunization. This is in contrast to our studies in other cancer systems where earlier responses are usual.


Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols.
Oxysterols, oxygenated derivatives of cholesterol, are found abundantly in the plasma and atherosclerotic plaques, a common risk factor for thoracic aortic aneurysms (TAAs). Among the oxysterols, namely 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC), lead both to induction of reactive oxygen species (ROS) in cells and to apoptosis in smooth muscle cells (SMCs) probably due to increased oxidative stress. Since loss of SMCs through apoptosis is a major event in TAA formation, it is important to understand the molecular pathways of apoptosis in response to ROS in TAAs. Very little is known about the effect of oxysterols on TAA SMCs. Therefore, we investigated molecular pathways participating in the oxysterol induced cell death of TAAs. Our results showed that TAA SMCs died mainly as a result of apoptosis as suggested by cellular shrinkage, blebbing, DNA condensation/fragmentation in response to oxysterol treatment. There was no significant difference in oxysterol induced cell death between TAA and control SMCs. Addition of antioxidant molecules prevented cell death, hence ROS appears to be involved in the apoptosis of these cells. While oxysterol treatment increased caspase 3 activity, cell death was not rescued in its absence. Efficient silencing of other targets including apoptotic proteins (p53, Bax), and survival proteins (Akt1, Akt2) showed that apoptosis can occur through p53, and Bax independent pathways. Silencing Akt1 or Akt2 did not lead to further cell death. These results indicate that oxysterols can induce several cell death pathways in TAA SMCs.


K-NN regression to improve statistical feature extraction for texture retrieval.
This correspondence presents an iterative method based upon k -nearest neighbors ( k-NN) regression to improve the performance of statistical feature extraction for texture image retrieval. The idea exploits the fact that an ideal feature extraction system would extract similar signatures from images characterized by the same texture and different signatures from dissimilar textures. Under the assumption that conventional statistical feature extraction contributes to sufficiently good retrieval performance, the signatures of k retrieved textures are used to update the signature of the query image using the k -NN regression algorithm. Extensive experiments show significant improvements with respect to retrieval performance in comparison to conventional statistical feature extraction.


Maximizing the benefit of health workforce secondment in Botswana: an approach for strengthening health systems in resource-limited settings.
To address health systems challenges in limited-resource settings, global health initiatives, particularly the President's Emergency Plan for AIDS Relief, have seconded health workers to the public sector. Implementation considerations for secondment as a health workforce development strategy are not well documented. The purpose of this article is to present outcomes, best practices, and lessons learned from a President's Emergency Plan for AIDS Relief-funded secondment program in Botswana. Outcomes are documented across four World Health Organization health systems' building blocks. Best practices include documentation of joint stakeholder expectations, collaborative recruitment, and early identification of counterparts. Lessons learned include inadequate ownership, a two-tier employment system, and ill-defined position duration. These findings can inform program and policy development to maximize the benefit of health workforce secondment. Secondment requires substantial investment, and emphasis should be placed on high-level technical positions responsible for building systems, developing health workers, and strengthening government to translate policy into programs.


[A model for epidemiological study in general practice: mortality. Study of cohort in Pavia].
For defining the health state of the population and demonstrating that computed general practice can be a preferential observation point for epidemiological study, we analyzed, as general practitioners, database of a dynamic cohort of 1501 subjects (m:724, f:777) living in Pavia and monitored from 1/1/1992 to 12/31/2001. In this paper we present mortality data compared to Italy in 1994. During the period, 209 deaths occurred (m:107, f:102). Differently from Italy, in Pavia cancer was the first cause of death in both sexes. When cardiovascular fatal events were analysed, age of death occurred 8.7 years in advance in males, while age of death for cancer was similar in both sexes. Sudden death represented one quarter of cardiovascular deaths. General practitioners' database can be an important and useful epidemiological source to detect areas with different risks of illness. Furthermore database offers the possibility to determine mortality rate for illness like sudden death not included in national statistical studies.


A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages.
Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.


Analysis of the Arabidopsis floral proteome: detection of over 2 000 proteins and evidence for posttranslational modifications.
The proteome of the Arabidopsis flower has not been extensively studied previously. Here, we report a proteomic analysis of the wild type Arabidopsis flower. Using both two-dimensional electrophoresis/mass spectrometry (2-DGE/MS) and multi-dimensional protein identification technology (MudPIT) approaches, we identified 2,446 proteins. Although a single experiment or analysis uncovered only a subset of the proteins we identified, a combination of multiple experiments and analyses facilitated the detection of a greater number of proteins. When proteins are grouped according to RNA expression levels revealed by microarray experiments, we found that proteins encoded by genes with relatively high levels of expression were detected with greater frequencies. On the other hand, at the level of the individual gene/protein, there was not a good correlation between protein spot intensity and microarray values. We also obtained strong evidence for post-translational modification from 2-DGE and MudPIT data. We detected proteins that are annotated to function in protein synthesis, folding, modification, and degradation, as well as the presence of regulatory proteins such as transcription factors and protein kinases. Finally, sequence and evolutionary analysis of genes for active methyl group metabolisms suggests that these genes are highly conserved. Our results allow the formulation of hypotheses regarding post-translational regulation of proteins in the flower, providing new understanding about Arabidopsis flower development and physiology.


Impact on stroke subtype diagnosis of early diffusion-weighted magnetic resonance imaging and magnetic resonance angiography.
The purpose of the present study was to assess the diagnostic usefulness of early diffusion-weighted MRI (DWI) and MR angiography (MRA) in patients with ischemic stroke. Past approaches to stroke diagnosis required a series of diagnostic tests over several days of hospitalization. New magnetic resonance methodologies that include DWI and MRA may allow more rapid characterization of stroke pathophysiology. However, no previous study has assessed the impact on formal stroke subtype diagnosis of early imaging with DWI/MRA. We analyzed 46 consecutive patients with acute ischemic stroke who underwent DWI/MRA within 24 hours of admission. Initial diagnoses were rendered with use of the 2 most widely used formal stroke subtype classification schemes, the TOAST and the Oxfordshire methods, which were applied to patients after CT/conventional MRI but before DWI/MRA. Modified TOAST and Oxfordshire diagnoses were then rendered based on the results of day 1 DWI, MRA, and DWI plus MRA. Final TOAST/Oxfordshire diagnoses at discharge were taken as the gold standard. Compared with final diagnoses, pre-MRI TOAST diagnoses matched final diagnoses in 48%, improving to 83% after DWI alone, 56% after MRA alone, and 94% after DWI plus MRA. For the TOAST diagnostic subtypes of large-vessel atherothromboembolism and small-vessel disease, pre-MRI diagnoses matched final diagnoses in 56% and 35% of patients, respectively, improving to 89% and 100% after DWI/MRA. Pre-MRI Oxfordshire diagnoses matched final diagnoses in 67% of patients, improving to 100% after DWI. The use of DWI/MRA within 24 hours of hospitalization substantially improves the accuracy of the diagnosis of early ischemic stroke subtype. When initial management and clinical trial eligibility decisions are influenced by stroke subtype, day 1 multimodal MRI is advantageous as a guide to therapy.


Location of first attack predicts the site of subsequent relapses in multiple sclerosis.
Predictors of attack location in relapsing-remitting multiple sclerosis (RRMS) are poorly known. It has been suggested that the site of the first relapse may influence the location of the subsequents. We aimed to ascertain this hypothesis in a sample of patients consecutively recruited in two Italian MS Centres, with at least two MS attacks. The following data were collected from medical records: demographic data, locations involved in the first two (or three) MS attacks (optic nerve, spinal cord, brain stem/cerebellum, cerebral hemispheres, according to symptoms presented), time elapsed between relapses and onset of disease-modifying treatment (DMT). We enrolled 199 patients (67% females; MS onset age 30.0 ± 8.69 years), in 148 of whom we could define the precise attack location. In 70/148 patients (47%) the second attack involved exactly the same location as the first. There was an increased risk of relapsing in the same location of the first attack when this involved the optic nerve (OR 4.5, 95% CI 2.2-9.2, p < 0.0001), the brainstem/cerebellum (OR 3.5, 95% CI 1.7-6.9, p < 0.0001), or the spinal cord (OR 3.0, 95% CI 1.5-5.9, p = 0.001). The location of third relapse (N = 90) was equally influenced by the site of first attack. In 24 patients with optic neuritis in both the two first attacks, the side coincided in 50% of cases. The location of first attack has a major role in influencing the site of subsequent ones in RRMS.


Association between childhood trauma exposure and pro-inflammatory cytokines in schizophrenia and bipolar-I disorder.
Elevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among individuals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma. Participants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire. The SZ group had significantly higher levels of IL-6, TNF-α and CRP when compared with the HC group (all p < 0.05, d = 0.41-0.63), as well as higher levels of TNF-α when compared with the BD group (p = 0.014, d = 0.50); there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups. These results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.


Towards the Use of Adsorption Methods for the Removal of Purines from Beer.
Beer corresponds to a fermented alcoholic beverage composed of several components, including purine compounds. These molecules, when ingested by humans, can be catabolized into uric acid, contributing to uric acid's level increase in serum, which may lead to hyperuricemia and gout. To assure a proper management of this disease, physicians recommend restrictive dietary measures, particularly by avoiding the consumption of beer. Therefore, it is of relevance to develop efficient methods to remove purine compounds from alcoholic beverages such as beer. In this review, we provide an introduction on fermented alcoholic beverages, with emphasis on beer, as well as its purine compounds and their role in uric acid metabolism in the human body in relation to hyperuricemia and gout development. The several reported enzymatic, biological and adsorption methods envisaging purine compounds' removal are then reviewed. Some enzymatic and biological methods present drawbacks, which can be overcome by adsorption methods. Within adsorption methods, adsorbent materials, such as activated carbon or charcoal, have been reported and applied to beer or wort samples, showing an excellent capacity for adsorbing and removing purine compounds. Although the main topic of this review is on the removal of purine compounds from beer, other studies involving other matrices rather than beer or wort that are rich in purines are included, since they provide relevant clues on designing efficient removal processes. By ensuring the selective removal of purine compounds from this beverage, beer can be taken by hyperuricemic and gouty patients, avoiding restrictive dietary measures, while decreasing the related healthcare economic burden.


CEP78 is mutated in a distinct type of Usher syndrome.
Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20-30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone-rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells.


Isolation of Vibrio alginolyticus from wounds and blood of a burn patient.
Isolation of Vibrio alginolyticus from the wounds and blood of a burn patient is reported. Numerous tissue biopsy sites as well as one blood culture yielded the organism. The case history and a review of the hospital course of the patient is provided where relevant to the presence and identification of the organism. The bacteriologic, biochemical, and anti-microbial identification of the organism is described. Taxonomy, habitat, and pathogenicity of V. alginolyticus are discussed.


[Pure agraphia with topographical disorientation caused by right hemisphere lesion].
A 69-year-old, right-handed, Japanese male patient presented with pure agraphia with topographical disorientation after hemorrhage in the right parietal lobe. Upon developing cerebral hemorrhage, he was referred to our hospital for close examination of agraphia. There was no paresis or clumsiness in his extremities. His speech was fluent and well-articulated. Neither aphasia nor reading impairments was found, although there was a clear writing impairment with effort and hesitation. His writing of both kanji and kana letters contained additional, absent or deformed strokes or parts. No hemianopia, prosopagnosia, constructional disturbances and dressing apraxia were found. He could recognize familiar buildings or landscapes, but often lost his way around well-known areas. MR images revealed subcortical lesions of precuneus, superior and inferior parietal lobules in the right hemisphere, around the posterior horn of the lateral ventricle. He revealed pure agraphia and topographical disorientation after the right brain haemorrhage, without dementia or personality change. These findings indicate that the right parietal lobe participates in the kinesthetic movements of writing. Some authers have been documented cases of aphasic agraphia or alexia with agraphia caused by right hemisphere damage in dextrals, but pure agraphia caused by the lesion in the right hemisphere is very rare.


The Role of Three-Dimensional Magnetic Resonance Elastography in the Diagnosis of Nonalcoholic Steatohepatitis in Obese Patients Undergoing Bariatric Surgery.
The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three-dimensional magnetic resonance elastography (3D-MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D-MRE (mf3D-MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI-PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D-MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D-MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI-PDFF correlated with steatosis (P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross-validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross-validated AUROC = 0.82. Conclusion: The mf3D-MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.


Signal transduction involving Ras-GTPase contributes to development of hypertension and end-organ damage in spontaneously hypertensive rats-treated with L-NAME.
The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223+/-4 mmHg) as compared to that of SHR controls (165+/-3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192+/-4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium-hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.


Genome wide association for addiction: replicated results and comparisons of two analytic approaches.
Vulnerabilities to dependence on addictive substances are substantially heritable complex disorders whose underlying genetic architecture is likely to be polygenic, with modest contributions from variants in many individual genes. "Nontemplate" genome wide association (GWA) approaches can identity groups of chromosomal regions and genes that, taken together, are much more likely to contain allelic variants that alter vulnerability to substance dependence than expected by chance. We report pooled "nontemplate" genome-wide association studies of two independent samples of substance dependent vs control research volunteers (n = 1620), one European-American and the other African-American using 1 million SNP (single nucleotide polymorphism) Affymetrix genotyping arrays. We assess convergence between results from these two samples using two related methods that seek clustering of nominally-positive results and assess significance levels with Monte Carlo and permutation approaches. Both "converge then cluster" and "cluster then converge" analyses document convergence between the results obtained from these two independent datasets in ways that are virtually never found by chance. The genes identified in this fashion are also identified by individually-genotyped dbGAP data that compare allele frequencies in cocaine dependent vs control individuals. These overlapping results identify small chromosomal regions that are also identified by genome wide data from studies of other relevant samples to extents much greater than chance. These chromosomal regions contain more genes related to "cell adhesion" processes than expected by chance. They also contain a number of genes that encode potential targets for anti-addiction pharmacotherapeutics. "Nontemplate" GWA approaches that seek chromosomal regions in which nominally-positive associations are found in multiple independent samples are likely to complement classical, "template" GWA approaches in which "genome wide" levels of significance are sought for SNP data from single case vs control comparisons.


Coelectrotransfer to skeletal muscle of three plasmids coding for antiangiogenic factors and regulatory factors of the tetracycline-inducible system: tightly regulated expression, inhibition of transplanted tumor growth, and antimetastatic effect.
We describe an approach employing intramuscular plasmid electrotransfer to deliver secretable forms of K1-5 and K1-3-HSA (a fusion of K1-3 with human serum albumin), which span, respectively, five and three of the five kringle domains of plasminogen. A tetracycline-inducible system (Tet-On) composed of three plasmids coding, respectively, for the transgene, the tetracycline transcriptional activator rtTA, and the silencer tTS was employed. K1-3-HSA and K1-5, produced from C2C12 muscle cells, were found to inhibit endothelial cell (HMEC-1) proliferation by 30 and 51%, respectively. In vivo, the expression of the transgene upon doxycycline stimulation was rapid, stable, and tightly regulated (no background expression) and could be maintained for at least 3 months. Blood half-lives of 2.1 and 3.7 days were found for K1-5 and K1-3-HSA, respectively. The K1-5 protein was secreted from muscle into blood at a level of 45 ng/ml, which was sufficient to inhibit MDA-MB-231 tumor growth by 81% in nude mice and B16-F10 melanoma cell lung invasion in C57BL/6 mice by 73%. PECAM-1 immunostaining studies revealed modest tumor vasculature in mice expressing K1-5. In contrast, K1-3-HSA, although secreted into blood at much higher level (250 ng/ml) than K1-5, had no effect on tumor growth.


[The dynamics of the chronotropic effect of a single vagal stimulus in cats under the action of met-enkephalin and neurotensin].
Following a burst of pulses applied to the vagus nerve with progressively incremental delay after the P wave of the ECG, the narrow zone of the cardiac cycle was identified where even a small shift of the vagal burst position evoked an abrupt alteration of the chronotropic effect magnitude. Met-enkephalin potentiated the phase-dependent vagal chronotropic effect, whereas neurotensin moved its limits toward the initial part of the P-P interval.


[Clinical and laboratory evaluation of patients treated with oral anticoagulation].
To evaluate the clinical and laboratory management of patients taking anti-vitamin K drugs (AVK). We studied retrospectively 952 visits of 100 outpatients taking AVK drugs for 7.6 months. There were 56 men and 44 women, 54 patients had acute arterial occlusion, 34 presented venous thromboembolism and 12 had cardiopathy. Anticoagulation level was estimated by the prothrombin time reported as international normalized ratio (INR). Seventy-three patients were considered stable, as they had one visit every at least 3 weeks, and their INR was within the therapeutic range in 59% of their visits, whereas 27 patients were less stable and had 36% of their visits within the therapeutic range. Insufficient anticoagulation was due to poor compliance (22%), vitamin K rich diet (19%) and underdosage (16%). Four patients presented minor bleedings, and there was no recurrence of thromboembolism. Careful clinical and laboratory management, using the INR, are necessary to avoid hemorrhage and thrombotic complications in patients taking oral anticoagulants.


Essential Amino Acid Profile in Parenteral Nutrition Mixtures: Does It Meet Needs?
The study compares the essential amino acid (EAA) composition of different parenteral nutrition (PN) mixtures with whey protein EAA profile and the theoretical daily EAA requirements (set by WHO/FAO/UNU or IAAO method). According to the individual EAA profile, the potential effect of several PN mixtures was evaluated on the skeletal muscle mass (SMM) of patients on home PN. Eight AA solutions and fifteen complete PN mixtures were considered. Twenty-nine clinically stable patients with short bowel syndrome on home total PN were retrospectively evaluated. SMM was estimated by bioelectrical impedance analysis. The prescribed doses of EAA that showed a significant increase in home PN patients muscle mass were considerably greater than the theoretical ones, showing an EAA profile similar to whey protein. At the daily dose of 1 g of total AA s/kg body weight (BW), the considered PN mixtures mostly failed to improve SMM. Only prescribed doses which included more than 0.25 g/kg BW of total BCAA with at least 0.10 g/kg BW leucine, 0.08 g/kg BW isoleucine, and 0.06 g/kg BW methionine showed a significant increase in SMM. The theoretical daily requirement for each EAA was met by all considered PN solutions when the prescribed daily dose of total AAs was set at 1 g/kg BW. Nevertheless, our data suggest that only an increase in total BCAA, also richer in single AA leucine, isoleucine, and methionine, is associated with the maintenance and/or increase of SMM. According to these preliminary observations, we support the prescription of an EAA composition of PN mixtures close to that of whey protein for the preservation of SMM in patients on long-term total PN.


A neural hierarchy for illusions of time: duration adaptation precedes multisensory integration.
Perceived time is inherently malleable. For example, adaptation to relatively long or short sensory events leads to a repulsive aftereffect such that subsequent events appear to be contracted or expanded (duration adaptation). Perceived visual duration can also be distorted via concurrent presentation of discrepant auditory durations (multisensory integration). The neural loci of both distortions remain unknown. In the current study we use a psychophysical approach to establish their relative positioning within the sensory processing hierarchy. We show that audiovisual integration induces marked distortions of perceived visual duration. We proceed to use these distorted durations as visual adapting stimuli yet find subsequent visual duration aftereffects to be consistent with physical rather than perceived visual duration. Conversely, the concurrent presentation of adapted auditory durations with nonadapted visual durations results in multisensory integration patterns consistent with perceived, rather than physical, auditory duration. These results demonstrate that recent sensory history modifies human duration perception prior to the combination of temporal information across sensory modalities and provides support for adaptation mechanisms mediated by duration selective neurons situated in early areas of the visual and auditory nervous system (Aubie, Sayegh, & Faure, 2012; Duysens, Schaafsma, & Orban, 1996; Leary, Edwards, & Rose, 2008).


Preparation of CoFe2O4/activated carbon@chitosan as a new magnetic nanobiocomposite for adsorption of ciprofloxacin in aqueous solutions.
Ciprofloxacin (CIP) is considered as a biological resistant pollutant. The CoFe2O4/activated carbon@chitosan (CoFe2O4/AC@Ch) prepared as a new magnetic nanobiocomposite and used for adsorption of CIP. CoFe2O4/AC@Ch was characterized by Fourier transform-infrared (FT-IR), field emission scanning electron microscope (FESEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), vibrating-sample magnetometer (VSM), and Brunauer-Emmett-Teller (BET) surface area measurements. The pHZPC value of the nanobiocomposite was estimated to be 6.4 by solid addition method. The prepared magnetic nanobiocomposites can be separated easily from water by an external magnet and reused. The effect of CIP concentration (10-30 mg/L), adsorbent dosage (12-100 mg/L), contact time (5-30 min) and pH (3-11) as independent variables on ciprofloxacin removal efficiency was evaluated. Optimum conditions were obtained in CIP concentration: 10 mg/L, adsorbent dosage: 100 mg/L, contact time: 15 min and pH: 5. In this condition, maximum CIP removal was obtained as 93.5%. The kinetic and isotherm equations showed that the process of adsorption followed the pseudo-second order kinetic and Langmuir isotherm. The results indicate that the prepared magnetic nanobiocomposite can be used as good adsorbent for the removal of CIP from aqueous solution and can be also recycled.


Antisymmetric grating coupler: experimental results.
The principle of an antisymmetric grating coupler was recently proposed theoretically as a planar waveguide add-drop multiplexer. It has the potential to enhance significantly the functionality of an add-drop multiplexer based on grating-assisted coupling. Here we realize the concept experimentally in an all-fiber geometry. We show that conventional devices exhibit two high-reflection bands. In contrast, the antisymmetric grating coupler has only a single reflection band, thereby dramatically improving its filtering characteristics.


Self-assembly of broadband white-light emitters.
We use organic cations to template the solution-state assembly of corrugated lead halide layers in bulk crystalline materials. These layered hybrids emit radiation across the entire visible spectrum upon ultraviolet excitation. They are promising as single-source white-light phosphors for use with ultraviolet light-emitting diodes in solid-state lighting devices. The broadband emission provides high color rendition and the chromaticity coordinates of the emission can be tuned through halide substitution. We have isolated materials that emit the "warm" white light sought for many indoor lighting applications as well as "cold" white light that approximates the visible region of the solar spectrum. Material syntheses are inexpensive and scalable and binding agents are not required for film deposition, eliminating problems of binder photodegradation. These well-defined and tunable structures provide a flexible platform for studying the rare phenomenon of intrinsic broadband emission from bulk materials.


Angular methoxy-substituted furo- and pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3.
The voltage-gated potassium channel Kv1.3 constitutes an attractive target for immunosuppression because of its role in T-lymphocyte activation and its functionally restricted expression to lymphocytes. Blockade of Kv1.3 channels by margatoxin has previously been shown to prevent T-cell activation and attenuate immune responses in vivo. In the present study, several furo- and pyranoquinoline derivatives were synthesized and screened for their blocking activities of Kv1.3 channels, stably expressed in mice-fibroblasts L929. In addition the activities of the compounds on Kv currents of the neuroblastoma cell line N1E-115 were determined. The most potent compounds, the angular furoquinolinone 8-methoxy-2-(1'-methylethyl)-5-methyl-4,5-dihydrofuro[3,2-c]quinolin-4-one (8c) and the angular pyranoquinolinone 9-methoxy-2,2,6-trimethyl-2,6-dihydro-5H-pyrano[3,2-c]quinolin-5-one (9a), inhibited Kv1.3 channels with half-blocking concentrations of 5 and 10 microM, respectively, and displayed 8-fold (8c) and 2-fold (9a) selectivity over Kv currents of N1E-115 cells. Thus, compounds 8c and 9a might function as a template for the development of novel immunosuppressants.


The Mps1 kinase modulates the recruitment and activity of Cnn1(CENP-T) at Saccharomyces cerevisiae kinetochores.
Kinetochores are conserved protein complexes that bind the replicated chromosomes to the mitotic spindle and then direct their segregation. To better comprehend Saccharomyces cerevisiae kinetochore function, we dissected the phospho-regulated dynamic interaction between conserved kinetochore protein Cnn1(CENP-T), the centromere region, and the Ndc80 complex through the cell cycle. Cnn1 localizes to kinetochores at basal levels from G1 through metaphase but accumulates abruptly at anaphase onset. How Cnn1 is recruited and which activities regulate its dynamic localization are unclear. We show that Cnn1 harbors two kinetochore-localization activities: a C-terminal histone-fold domain (HFD) that associates with the centromere region and a N-terminal Spc24/Spc25 interaction sequence that mediates linkage to the microtubule-binding Ndc80 complex. We demonstrate that the established Ndc80 binding site in the N terminus of Cnn1, Cnn1(60-84), should be extended with flanking residues, Cnn1(25-91), to allow near maximal binding affinity to Ndc80. Cnn1 localization was proposed to depend on Mps1 kinase activity at Cnn1-S74, based on in vitro experiments demonstrating the Cnn1-Ndc80 complex interaction. We demonstrate that from G1 through metaphase, Cnn1 localizes via both its HFD and N-terminal Spc24/Spc25 interaction sequence, and deletion or mutation of either region results in anomalous Cnn1 kinetochore levels. At anaphase onset (when Mps1 activity decreases) Cnn1 becomes enriched mainly via the N-terminal Spc24/Spc25 interaction sequence. In sum, we provide the first in vivo evidence of Cnn1 preanaphase linkages with the kinetochore and enrichment of the linkages during anaphase.


Neotropical Ablabesmyia Johannsen (Diptera: Chironomidae, Tanypodinae)-part I.
This is a series of three manuscripts about the genus Ablabesmyia. In the first new species are described, three species are re-examined and keys to males, pupae and larvae of known neotropical species are provided and an emended generic diagnosis of Ablabesmyia is given. The second manuscript will analyze the molecular data of Neotropical species and the third one will check, through a phylogenetic analysis, the truth of subgenera. In this study, twenty-four new species of Ablabesmyia Johannsen are described and figured: A. arquata, A. cauame, A. commata, A. communiba, A. cordeiroi, A, depaulai, A. diversa, A. ducke, A. fazzari, A. fusariae, A. gessnerae, A. gigas, A. jaquirana, A. laurindoi, A. manauara, A. martha, A. novema, A. parannulata, A. parareissi, A. pinhoi, A. rafaeli, A. separata, A. strixinoae and A. suiamissu. We re-examined A. cinctipes (Johannsen), A. infumata (Edwards) and A. metica Roback. The species were collected in Brazil, in lentic systems. Keys to males, pupae and larvae of known neotropical species of the genus Ablabesmyia are provided and an emended generic diagnosis of Ablabesmyia is given.


Standalone Ayurveda management of Hodgkin's lymphoma: A case report.
The abnormal and uncontrolled growth of lymphatic cells present in the lymphatic system, the lymph nodes, spleen, thymus, and bone marrow is called lymphoma. Hodgkin's lymphoma is a type of malignant growth in lymphatic tissues. Despite conventional anticancer therapy and remedy, there has been no cure for it. No direct reference to Hodgkin's lymphoma has been found in Ayurveda, although the clinical manifestations of Apachi like enlarged lymph nodes in the neck, armpits, or groin, painless swelling, and itchy skin, are similar to those seen in Hodgkin's lymphoma. A case of Hodgkin's lymphoma in a 34-year-old female who presented with multiple enlarged lymph nodes in the right supra clavicle at the neck, along with pain and swelling at site, right ear discharge, burning chest, and headache for the last two years. Biopsy confirmed it to be Hodgkin's lymphoma. The patient was treated with Arbudh hara Kashya, Kanchanar, Haridra, Gomutra, Rodhra Rasa, Tapyadi Loha, Swarna Vasant Malati, vaikrant Bhasma, Heerak Bhasma, Amritbhalatak Avaleha, Sanjivini Vati, Lavan Bhaskar Churna, Swarjika Kshara, Tablet Anacarcin, Kachnar Guggulu in form of ShamanaChikitsa. Local application in the form Kachanaradi Lepa was advised after local swedan with ArkpatraandErandpantra. The nodular heterogeneous mass and growth on neck of the patient reduced with clinical gradation from 17 to 4 with reduction in first lymph node from 122 mm to 80 mm and in the second lymph node from 108 mm to 20 mm, while in the third lymph node reduced from 32 mm to zero with Ayurveda treatment alone. Thus, a patient with Hodgkin's lymphoma was treated with Ayurveda successfully without conventional therapy.


Integrating risk adjustment and enrollee premiums in health plan payment.
In two important health policy contexts - private plans in Medicare and the new state-run "Exchanges" created as part of the Affordable Care Act (ACA) - plan payments come from two sources: risk-adjusted payments from a Regulator and premiums charged to individual enrollees. This paper derives principles for integrating risk-adjusted payments and premium policy in individual health insurance markets based on fitting total plan payments to health plan costs per person as closely as possible. A least squares regression including both health status and variables used in premiums reveals the weights a Regulator should put on risk adjusters when markets determine premiums. We apply the methods to an Exchange-eligible population drawn from the Medical Expenditure Panel Survey (MEPS).


Cancer screening practices of adult survivors of retinoblastoma at risk of second cancers.
The aim of the current study was to investigate the pattern of cancer screening behavior in adult retinoblastoma survivors, who are at high risk of developing second cancers. Self-reported cancer screening practices were investigated in a cohort of retinoblastoma survivors to evaluate whether they were receiving adequate screening for specific cancers and compare these rates with those of other adult survivors of childhood cancer and the general population. The prevalence of breast self-examination, clinical breast examination, mammography, Papanicolaou (Pap) test, testicular self-examination, and magnetic resonance imaging (MRI) or computed tomography (CT) scanning was determined from computer-aided telephone interviews with 836 retinoblastoma survivors aged >18 years. Among female survivors, 87% had a Pap test within the past 2 years, and 76% of females age >40 years reported having a mammogram within the past 2 years; 17.4% of male survivors had performed monthly testicular self-examinations. A significantly higher proportion of hereditary compared with nonhereditary survivors reported having undergone an MRI or CT scan in the past 5 years. Higher education, greater contact with the medical care system, and having a second cancer were found to be associated positively with most screening practices. Cancer screening practices reported by retinoblastoma survivors were similar to national screening rates for breast, cervical, and testicular cancer. To the authors' knowledge, the current study provides the first report of cancer screening practices of retinoblastoma survivors. Survivors of hereditary retinoblastoma should be encouraged to maintain, if not increase, their current screening practices to ensure early detection of second cancers in this high-risk population.


Association between metabolically healthy central obesity in women and levels of soluble receptor for advanced glycation end products, soluble vascular adhesion protein-1, and the activity of semicarbazide-sensitive amine oxidase.
To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). 47 lean healthy, 17 COH (presenting waist-to-height ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. Central obesity associated with low sRAGE levels (lean healthy: 1503±633 pg/mL; COH: 1103±339 pg/mL, P<0.05; COU: 1106±367 ng/mL, P<0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. COH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies.


Sterol transport by the human breast cancer resistance protein (ABCG2) expressed in Lactococcus lactis.
The human breast cancer resistance protein (BCRP, also know as ABCG2, MXR, or ABCP) is one of the more recently discovered ATP-binding cassette (ABC) transporters that confer resistance on cancer cells by mediating multidrug efflux. In the present study, we have obtained functional expression of human BCRP in the Gram-positive bacterium Lactococcus lactis. BCRP expression conferred multidrug resistance on the lactococcal cells, which was based on ATP-dependent drug extrusion. BCRP-mediated ATPase and drug transport activities were inhibited by the BCRP-specific modulator fumitremorgin C. To our knowledge these data represent the first example of the functional expression of a mammalian ABC half-transporter in bacteria. Although members of the ABCG subfamily (such as ABCG1 and ABCG5/8) have been implicated in the transport of sterols, such a role has not yet been established for BCRP. Interestingly, the BCRP-associated ATPase activity in L. lactis was significantly stimulated by (i) sterols including cholesterol and estradiol, (ii) natural steroids such as progesterone and testosterone, and (iii) the anti-estrogen anticancer drug tamoxifen. In addition, BCRP mediated the efflux of [3H]estradiol from lactococcal cells. Our findings suggest that BCRP may play a role in the transport of sterols in human, in addition to its ability to transport multiple drugs and toxins.


The nuclear magnetic resonance relaxation data analysis in solids: general R1/R1(ρ) equations and the model-free approach.
The advantage of the solid state NMR for studying molecular dynamics is the capability to study slow motions without limitations: in the liquid state, if orienting media are not used, all anisotropic magnetic interactions are averaged out by fast overall Brownian tumbling of a molecule and thus investigation of slow internal conformational motions (e.g., of proteins) in solution can be conducted using only isotropic interactions. One of the main tools for obtaining amplitudes and correlation times of molecular motions in the μs time scale is measuring relaxation rate R(1)(ρ). Yet, there have been a couple of unresolved problems in the quantitative analysis of the relaxation rates. First, when the resonance offset of the spin-lock pulse is used, the spin-lock field can be oriented under an arbitrary angle in respect to B(0). Second, the spin-lock frequency can be comparable or even less than the magic angle spinning rate. Up to now, there have been no equations for R(1)(ρ) that would be applicable for any values of the spin-lock frequency, magic angle spinning rate and resonance offset of the spin-lock pulse. In this work such equations were derived for two most important relaxation mechanisms: heteronuclear dipolar coupling and chemical shift anisotropy. The validity of the equations was checked by numerical simulation of the R(1)(ρ) experiment using SPINEVOLUTION program. In addition to that, the applicability of the well-known model-free approach to the solid state NMR relaxation data analysis was considered. For the wobbling in a cone at 30° and 90° cone angles and two-site jump models, it has been demonstrated that the auto-correlation functions G(0)(t), G(1)(t), G(2)(t), corresponding to different spherical harmonics, for isotropic samples (powders, polycrystals, etc.) are practically the same regardless of the correlation time of motion. This means that the model-free approach which is widely used in liquids can be equally applied, at least assuming these two motional models, to the analysis of the solid state NMR relaxation data.


Noninvasive (13)C-octanoic acid breath test shows delayed gastric emptying in patients with amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons. However, ALS has been recognized to also involve non-motor systems. Subclinical involvement of the autonomic system in ALS has been described. The recently developed (13)C-octanoic acid breath test allows the noninvasive measurement of gastric emptying. With this new technique we investigated 18 patients with ALS and 14 healthy volunteers. None of the patients had diabetes mellitus or other disorders known to cause autonomic dysfunction. The participants received a solid standard test meal labeled with (13)C-octanoic acid. Breath samples were taken at 15-min intervals for 5 h and were analyzed for (13)CO(2) by isotope selective nondispersive infrared spectrometry. Gastric emptying peak time (t(peak)) and emptying half time (t(1/2)) were determined. All healthy volunteers displayed normal gastric emptying with a mean emptying t(1/2) of 138 +/- 34 (range 68-172) min. Gastric emptying was delayed (t(1/2) > 160 min) in 15 of 18 patients with ALS. Emptying t(1/2) in ALS patients was 218 +/- 48 (range 126-278) min (p < 0.001). These results are compatible with autonomic involvement in patients with ALS, causing delayed gastric emptying of solids and encouraging the theory that ALS is a multisystem disease rather than a disease of the motor neurons only.


Treatment of Metastatic Carcinoma of an Unknown Primary to the Heart with Checkpoint Inhibitor Therapy.
Secondary cardiac malignancies are much more common than primary cancers. Metastatic cancers to the heart from other solid organs are well known and carry a poor prognosis. An 83-year-old Hispanic veteran presented with breathlessness, cough, and weight loss. Imaging studies showed extensive pericardial effusion and multiple pericardial/epicardial masses. Biopsy showed poorly differentiated metastatic carcinoma with no definitive origin, based on lab, imaging, and extensive immunohistochemistry (IHC) studies. Gene panel testing showed microsatellite stable status. Programmed cell death 1 ligand (PD-L1) IHC was 100% in the tumor cells. He was started on pembrolizumab and had a complete resolution of symptoms. Subsequent imaging studies showed improvement in the multiple pericardial/epicardial masses. Immune checkpoint inhibitor (ICI) therapy has changed the treatment landscape of many malignancies since the approval of the first ICI, ipilimumab, for melanoma in 2011. To the best of our knowledge, this is the first reported case of successful treatment by ICI therapy in undifferentiated metastatic carcinoma of an unknown primary source to the heart.


Improving nutrition and health through non-timber forest products in Ghana.
Nutrition and health are fundamental pillars of human development across the entire life-span. The potential role of non-timber forest products (NTFPs) in improving nutrition and health and reduction of poverty has been recognized in recent years. NTFPs continue to be an important source of household food security, nutrition, and health. Despite their significant contribution to food security, nutrition, and sustainable livelihoods, these tend to be overlooked by policy-makers. NTFPs have not been accorded adequate attention in development planning and in nutrition-improvement programmes in Ghana. Using exploratory and participatory research methods, this study identified the potentials of NTFPs in improving nutrition and food security in the country. Data collected from the survey were analyzed using the SPSS software (version 16.0). Pearson's correlation (p < 0.05) showed that a significant association exists between NTFPs and household food security, nutrition, and income among the populations of Bibiani-Bekwai and Sefwi Wiawso districts in the western region of Ghana. NTFPs contributed significantly to nutrition and health of the poor in the two districts, especially during the lean seasons. The results of the survey also indicated that 90% of the sampled population used plant medicine to cure various ailments, including malaria, typhoid, fever, diarrhoea, arthritis, rheumatism, and snake-bite. However, a number of factors, including policy vacuum, increased overharvesting of NTFPs, destruction of natural habitats, bushfires, poor farming practices, population growth, and market demand, are hindering the use and development of NTFPs in Ghana. The study also provides relevant information that policy-makers and development actors require for improving nutrition and health in Ghana.


Effective ways of restoring muscular imbalances of the rotator cuff muscle group: a comparative study of various training methods.
Many studies have compared different training methods for improving muscular performance, but more investigations need to be directed to the restoration of muscular imbalances. To determine the most effective training for altering strength ratios in the shoulder rotator cuff. Forty eight physical education students were randomly assigned to four groups (12 per group): (a) experimental group who carried out multijoint dynamic resistance training for shoulder internal and external rotation movement (pull ups or lat pull downs, overhead press, reverse pull ups, push ups) (MJDR group); (b) experimental group who exercised the same muscle group using dumbbells weighing 2 kg (isolated group); (c) experimental group who followed an isokinetic strengthening programme for the rotator cuff muscle group (isokinetic group); (d) control group who had no strength training. Testing was performed in the supine position with the glenohumeral joint in 90 degrees of abduction in the coronal plane, with a range of motion of 0-90 degrees of external rotation and 0-65 degrees of internal rotation at angular velocities of 60, 120, and 180 degrees /s. The test procedure was performed before and after the exercise period of six weeks. One way analysis of variance found no differences between the groups for the initial tests. Analysis of variance with repeated measures showed that the strength ratios in all the experimental groups had altered after the exercise period, with the isokinetic group showing the most significant improvement. Isokinetic strengthening is the most effective method of altering strength ratios of the rotator cuff muscle.


Pneumorrhachis associated with bronchial asthma, subcutaneous emphysema and pneumomediastinum.
Pneumorrhachis is defined as the presence of air in the epidural space or subarachnoid space. The air may migrate along fascial planes from the posterior mediastinum, through the neural foramina, and into the epidural space. Pneumorrhachis is rare, and even more so in the paediatric population. Pneumorrhachis in itself usually is asymptomatic, does not tend to migrate and reabsorbs spontaneously. The combination of pneumomediastinum with epidural pneumorrhachis without thoracic trauma has rarely been reported in the literature. The present case report describes the presence of pneumomediastinum, subcutaneous emphysema, and pneumorrhachis in a child asthmatic patient who had a history of fever, violent cough.


The effects of breathing-related sleep disorders on mood disturbances in the general population.
Results of clinical studies suggest that there may be a relationship between breathing-related sleep disorders and depressive disorders. This study aims to assess the impact of breathing-related sleep disorder on major depressive disorder in the general population. A cross-sectional telephone survey was carried out between 1994 and 1999 in the general population of the United Kingdom, Germany, Italy, Portugal, and Spain. A total of 18,980 randomly selected subjects aged 15 to 100 years and representative of the general population of their respective countries participated in the study. The questionnaire included a series of questions about sleep quality, breathing-related sleep disorder symptoms, mental disorders, and medical conditions. Data are presented using point prevalence. 2.1% of the subjects were found with obstructive sleep apnea syndrome at the time of the interview, and 2.5% had some other type of DSM-IV breathing-related sleep disorder diagnosis. The association of DSM-IV breathing-related sleep disorder diagnosis and major depressive disorder diagnosis was found in 0.8% of the sample. As many as 18% of individuals with a major depressive disorder diagnosis also have a DSM-IV breathing-related sleep disorders diagnosis, and 17.6% of subjects with a DSM-IV breathing-related sleep disorders diagnosis have a major depressive disorder diagnosis. Multivariate models showed that even after controlling for obesity and hypertension, the odds of having a DSM-IV breathing-related sleep disorders diagnosis was 5.26 for individuals with a major depressive disorder diagnosis. About 800 of 100,000 individuals have both a breathing-related sleep disorder and a major depressive disorder. The identification of 1 of these 2 disorders should prompt the investigation of the other disorder since nearly a fifth of them have the other disorder.


Roflumilast May Increase Risk of Exacerbations When Used to Treat Poorly Controlled Asthma in People with Obesity.
Rationale: People with obesity often have severe, difficult-to-control asthma. There is a need to develop better treatments for this population. One potential treatment is roflumilast, a phosphodiesterase 4 inhibitor, as it is reported to have efficacy for the treatment of asthma and can promote weight loss. Objectives: To investigate the potential efficacy of roflumilast for the treatment of poorly controlled asthma in people with obesity. Methods: A randomized, double-masked, placebo-controlled trial of 24 weeks of roflumilast versus placebo for the treatment of poorly controlled asthma in people with obesity (body mass index of 30 kg/m2 or higher). The primary outcome was a change in ACT (Asthma Control Test) score. Results: Twenty-two people were randomized to roflumilast and 16 to placebo. Roflumilast had no effect on change in the ACT (increased by 2.6 [interquartile range (IQR), 0.5-4.4] in those on roflumilast vs. 2.0 [IQR, 0.7-3.3] in those on placebo). Participants assigned to roflumilast had a 3.5-fold (relative risk [RR] 95% confidence interval [CI], 1.3-9.4) increased risk of an episode of poor asthma control and an 8.1-fold (RR 95% CI, 1.01-65.0) increased risk of an urgent care visit for asthma. Ten participants (56%) assigned to roflumilast required a course of oral corticosteroids for asthma exacerbations, and none in the placebo group. Participants losing 5% or more of their body weight experienced a clinically and statistically significant improvement in asthma control (ACT increased by 4.4 [IQR, 2.5-6.3] vs. 1.5 [IQR, 0.0-3.0] in those who lost less than 5%). Conclusions: Roflumilast had no effect on asthma control. Of concern, roflumilast was associated with an increased risk of exacerbation in obese individuals with poorly controlled asthma. These results highlight the importance of studying interventions in different subpopulations of people with asthma, particularly people with obesity and asthma who may respond differently to medications than lean people with asthma. Weight loss of at least 5% was associated with improved asthma control, indicating that interventions other than roflumilast promoting weight loss may have efficacy for the treatment of poorly controlled asthma in people with obesity. Clinical trial registered with www.clinicaltrials.gov (NCT03532490).


Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors.
The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Clin Cancer Res; 23(13); 3251-62. ©2017 AACR.