Reliability and Validity Analysis of the Distal Radioulnar Joint Ballottement Test.
Triangular fibrocartilage complex injuries can cause distal radioulnar joint (DRUJ) instability, which can be evaluated clinically with the DRUJ ballottement test. However, the reliability and validity of the test are unclear. This study aimed to analyze the reliability and validity of the test using a tracking device on healthy participants and patients with triangular fibrocartilage complex injuries. In this cross-sectional study, three orthopedic hand surgeons performed the DRUJ ballottement test using a technique of holding the carpal bones to the radius on 25 healthy participants (50 hands; 10 men and 15 women; mean age, 33 years; range, 20-51 years) and eight patients with triangular fibrocartilage complex injuries (16 hands; six men and two women; mean age, 43 years; range, 27-59 years). We used a three-dimensional electromagnetic tracking device to quantify the movement of the DRUJ and verify the reliability and validity of the test. The intrarater and interrater intraclass correlation coefficients for DRUJ movement were 0.77 and 0.61, respectively, and the kappa coefficient for grading of DRUJ instability was 0.79. The correlation coefficient between DRUJ movement measured using the tracking device and instability judged clinically was 0.77. A comparison of healthy participants and the patients showed significantly greater DRUJ movement in the patients. The test showed substantial intrarater and interrater reliability for assessing DRUJ movement and instability. The significant positive correlation between DRUJ movement and instability indicates the concurrent validity of the test. Moreover, the test showed discriminative validity in identifying mild or moderate DRUJ instability. The DRUJ ballottement test using the holding technique has a relatively high diagnostic accuracy and can be used to assess DRUJ instability.


Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus.
Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome. Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome. The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.


Multilocus sequence typing of Mycoplasma agalactiae.
Mycoplasma agalactiae is the main cause of contagious agalactia, a serious disease of sheep and goats, which has major clinical and economic impacts. We have developed a multilocus sequence typing (MLST) scheme using the sequenced genomes of the M. agalactiae strains PG2 and 5632. An MLST scheme based on the genes gltX, metS, gyrB, tufA and dnaA was designed and in total 3468 bp of sequence were analysed for each strain. MLST offers a highly discriminatory typing method for M. agalactiae and was capable of subdividing 53 strains into 17 distinct sequence types, largely according to geographical origin. MLST detected unexpected diversity in recent isolates from Spain, identifying two novel outliers, and enabled typing of novel Mongolian isolates for the first time. Genetic diversity in the sequenced regions was largely due to mutation, with recombination playing a much smaller role. A web-accessible database has been set up for this MLST scheme for M. agalactiae: http://pubmlst.org/magalactiae/. MLST offers a robust, objective molecular epidemiological tool for M. agalactiae that that enables interlaboratory comparison of data.


Juice quality of two new mandarin-like hybrids (Citrus clementina Hort. ex Tan x Citrus sinensis L. Osbeck) containing anthocyanins.
Tacle and Clara [Monreal clementine (Citrus clementina Hort. ex Tan) x Tarocco orange (Citrus sinensis L. Osbeck)] are two new triploid citrus hybrids developed by the CRA-Istituto Sperimentale per l'Agrumicoltura (Acireale, Italy). The fruits are easy-peeling and juicy, have a pleasant taste like the Tarocco orange, and are sweet like the Monreal clementine. In addition, a distinctively attractive characteristic of these mandarin-like fruits is the red-pigmented flesh caused by the presence of anthocyanins. This study reports the juice quality attributes of fresh fruits harvested at different ripening stages and of cold-stored fruits kept for 104 days at 6+/-1 degrees C and 90-95% relative humidity. Physico-chemical analyses showed that the fresh-fruit juice yield ranged between 39 (Tacle) and 41% (Clara); these values were 11-14% lower after 104 days of storage. Vitamin C content in the Clara juice was decisively higher than that in the Tacle juice. Juice anthocyanins and other polyphenols increased during cold storage. These results show that low-temperature storage enhances the functional attributes of Tacle and Clara fruit juices.


Cellular responses to T-2 toxin and/or deoxynivalenol that induce cartilage damage are not specific to chondrocytes.
The relationship between T-2 toxin and deoxynivalenol (DON) and the risk of Kashin-Beck disease is still controversial since it is poorly known about their selectivity in cartilage damage. We aimed to compare the cytotoxicity of T-2 toxin and DON on cell lines representative of cell types encountered in vivo, including human chondrocytes (C28/I2), human hepatic epithelial cells (L-02) and human tubular epithelial cells (HK-2). In addition, we determined the distribution of T-2 toxin and DON in Sprague-Dawley (SD) rats after a single dose exposure. T-2 toxin or DON decreased proliferation in a time- and concentration-dependent manner and their combination showed a similar antagonistic effect in C28/I2, L-02 and HK-2 cells. Moreover, we observed cell cycle arrest and apoptosis, associated with increased oxidative stress and decline in mitochondrial membrane potential induced by T-2 toxin and/or DON. In vivo study showed that T-2 toxin and DON did not accumulate preferentially in the knee joint compared to liver and kidney after an acute exposure in SD rats. These results suggest that T-2 toxin and/or DON inhibit proliferation and induce apoptosis through a possible mechanism involving reactive oxygen species-mediated mitochondrial pathway that is not specific for chondrocytes in vitro or joint tissues in vivo.


Getting back together after a break-up: Relationship advice for anatomists and surgeons.
The "surgeon-anatomist" was originally a single individual who self-pursued knowledge and understanding of anatomy as the foundation for successful surgical outcomes. However, recent advances in medical education have ironically led to the separation of anatomy and surgery. This physical and emotional "divorce" of anatomists and surgeons into separate individuals has created several critical educational issues for medical and surgical educators including a general lack of anatomical knowledge in medical students and misalignment of graduate medical education procedural specialty training with the Accreditation Council of Graduate Medical Education Core Competencies and now the Next Accreditation System. There are numerous opportunities for anatomists and surgeons to work together to improve educational instruction of established difficult anatomical regions, procedural training, or even develop new techniques and procedures. Similarly, anatomists with specialized training in medical education would be invaluable partners to ensure that procedural assessments align with instructional technologies for truly longitudinal curricula that starts at the medical student level, but stops at the patient outcomes of attending surgeons. This mutually beneficial relationship would be similar to multidisciplinary care teams and current surgeon and PhD/EdD partnerships. The restoration of the relationship between anatomists and surgeons would be invaluable to surgical education and remains an exciting research opportunity.


Value of sputum cytology in the differential diagnosis of alveolar cell carcinoma from bronchogenic adenocarcinoma.
A total of 90 cases in which a cytologic diagnosis of pulmonary adenocarcinoma has been previously made by consecutive sputum cytology were reviewed in order to estimate the possibility of a correct differential diagnosis of alveolar cell carcinoma (bronchioloalveolar) from bronchogenic adenocarcinoma. The diagnosis by sputum cytology in all cases was correlated with data from a subsequent biopsy, operation or autopsy. Using certain specific differential diagnostic cytologic parameters, striking differences were noted in the exfoliated cells in sputum samples; these related to cell size, clustering effects, pleomorphism, mucin production, cytoplasm, nuclei and nucleoli. Based on the observations made in this study, it is suggested that sputum cytology is not only a valuable method of detecting malignant cells but can also be quite useful to correctly type all cases of alveolar cell carcinoma and 93.75% cases of bronchogenic adenocarcinoma.


IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells.
IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4(+) central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4(+) T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases.


Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma.
Ewing sarcoma (ES) is a malignant pediatric bone and soft tissue tumor. Patients with metastatic ES have a dismal outcome which has not been improved in decades. The major challenge in the treatment of metastatic ES is the lack of specific targets and rational combinatorial therapy. We recently found that protein phosphatase 1 regulatory subunit 1A (PPP1R1A) is specifically highly expressed in ES and promotes tumor growth and metastasis in ES. In the current investigation, we show that PPP1R1A regulates ES cell cycle progression in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1, which leads to retinoblastoma (Rb) protein hyperphosphorylation. In addition, we show that PPP1R1A promotes normal transcription of histone genes during cell cycle progression. Importantly, we demonstrate a synergistic/additive effect of the combinatorial therapy of PPP1R1A and insulin-like growth factor 1 receptor (IGF-1R) inhibition on decreasing ES cell proliferation and migration in vitro and limiting xenograft tumor growth and metastasis in vivo. Taken together, our findings suggest a role of PPP1R1A as an ES specific cell cycle modulator and that simultaneous targeting of PPP1R1A and IGF-1R pathways is a promising specific and effective strategy to treat both primary and metastatic ES.


Embolization therapy for benign prostatic hyperplasia: influence of embolization particle size on gland perfusion.
To assess the influence of embolic size on the therapy response of prostatic arterial embolization (PAE) based on perfusional changes seen on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Twelve beagles underwent PAE, four dogs with each particle size: A: 100-300 μm; B: 300-500 μm; and C: 500-700 μm. Prior to and 1 month after the embolization all dogs underwent prostate DCE MRI. After embolization, time to maximal perfusion intensity for prostate parenchyma increased in B (188 vs. 135 sec, P = 0.023) and C (200 vs. 120 sec, P = 0.001), while it did not change for A (139 vs. 124 sec, P = 0.39). The maximal relative intensity increased after embolization in C (3.84 vs. 2.38, P < 0.001), while it did not change for A (2.50 vs. 2.44, P = 0.36) and B (3.23 vs. 2.9, P = 0.21). The extent of visualized intraprostatic urethral wall increased after embolization in B compared with A and C, 239.5 ± 138.1% vs. 56.1 ± 34.3, P = 0.04. Enhancement changes correlated with prostate volume changes: prostate volumes in A decreased less as compared with B and C (77 ± 34% vs. 56 ± 14%), P = 0.02. The enhancement and morphological data are useful to monitor response to therapy after embolization. Embolization with 300-500 and 500-700 μm particle may provide better results than with 100-300 μm particles in a canine model.


Morphological and molecular characterization of developing vertebral fusions using a teleost model.
Spinal disorders are a major cause of disability for humans and an important health problem for intensively farmed animals. Experiments have shown that vertebral deformities present a complex but comparable etiology across species. However, the underlying molecular mechanisms involved in bone deformities are still far from understood. To further explicate the mechanisms involved, we have examined the fundamental aspects of bone metabolism and pathogenesis of vertebral fusions in Atlantic salmon (Salmo salar). Experimentally, juvenile salmon were subjected to hyperthermic conditions where more than 28% developed fused vertebral bodies. To characterize the fusion process we analyzed an intermediate and a terminal stage of the pathology by using x-ray, histology, immunohistochemistry, real-time quantitative PCR and in situ hybridization. At early stage in the fusion process, disorganized and proliferating osteoblasts were prominent at the growth zones of the vertebral body endplates. PCNA positive cells further extended along the rims of fusing vertebral bodies. During the developing pathology, the marked border between the osteoblast growth zones and the chondrocytic areas connected to the arches became less distinct, as proliferating cells and chondrocytes blended through an intermediate zone. This cell proliferation appeared to be closely linked to fusion of opposing arch centra. During the fusion process a metaplastic shift appeared in the arch centra where cells in the intermediate zone between osteoblasts and chondrocytes co-expressed mixed signals of chondrogenic and osteogenic markers. A similar shift also occurred in the notochord where proliferating chordoblasts changed transcription profile from chondrogenic to also include osteogenic marker genes. In progressed fusions, arch centra and intervertebral space mineralized. Loss of cell integrity through cell proliferation and metaplastic shifts seem to be key events in the fusion process. The fusion process involves molecular regulation and cellular changes similar to those found in mammalian deformities, indicating that salmon is suitable for studying general bone development and to be a comparative model for spinal deformities.


Decreased measures of experimental anxiety in rats bred for high alcohol preference.
A prevalent notion holds that acute anti-anxiety actions of ethanol are important for the reinforcing properties of this drug, and might predispose individuals with pre-existing anxiety disorders for developing ethanol dependence. This notion remains controversial, and human studies have yielded conflicting results. Ethanol dependence is likely a heterogenous disorder, and the discrepancies might be explained by a different relationship between anxiety and alcohol reinforcement in different subtypes of alcoholism. Recent results in experimental animals suggest that antianxiety actions of ethanol are important reinforcers of voluntary ethanol consumption in heterogeneous rats. Here, we examined whether the relationship is different in the AA line of rats bred for high voluntary ethanol intake. Behavior was studied in two established animal models of anxiety, a punished drinking conflict test, and the elevated plus maze. In the conflict test, the AA line displayed a markedly disinhibited behavior over a range of shock intensities, compared both with their counterpart, the ANA line, and with regular Wistar rats. On the plus maze, both AA and Wistar rats showed lower measures of experimental anxiety than ANA subjects. The phenotype of the animals was confirmed using a two-bottle free choice alcohol drinking procedure. The disinhibited behavior and spontaneous ethanol preference of the AA line differs from what has been found in heterogeneous rats, and displays similarities to genetically transmitted type II alcoholism according to the nomenclature of Cloninger.


Impact of land cover types on soil aggregate stability and erodibility.
Gökçeada is the biggest island, and it is also known as the organic island of Turkey. Approximately 65% of the Gökçeada lands have slope > 12%. Climate, topography, land cover, and soil characteristics are considered to be the main natural factors affecting soil erosion severity in the Gökçeada. Prevention of soil degradation, hence the preservation or improvement of the overall quality of the soil, is directly related to the presence of stable soil aggregates. In addition, the resistance to weathering and replacement of soil particles are also relevant aspects in terms of sustainability. Aggregate stability (AS) and erodibility of land (Kfac) are related to soil properties. However, this relationship can vary under different circumstances. In this study, 248 surface soil samples have been taken from forest and semi-natural areas (FSNA) and agricultural areas (AGRA) according to CORINE 2006. Eleven selected soil properties were measured, and their impacts on AS and Kfac (RUSLE-K) were determined by using the CRT (classification and regression tree) in Gökçeada. Results showed that the relations among soil characteristics changed according to the land cover classes. Total organic carbon is much more associated with AS in AGRA, while total carbon is associated with AS in FSNA. The effect of calcium carbonate on Kfac was higher than other soil properties when the land cover type was ignored. On the other hand, in AGRA, the effect of between clay content on Kfac was greater than those of FSNA.


Treatment options in androgen-independent prostate cancer.
Metastatic prostate cancer is a leading cause of cancer-related death in men. Although most patients will respond to androgen ablation as initial systemic therapy, nearly all patients will develop androgen-independent prostate cancer (AI CaP) and will succumb to the disease. Advances in molecular biology have demonstrated mutations in and persistent expression of the human androgen receptor in metastatic disease. Furthermore, recent evidence indicates that an apoptotic block through p53 mutations or bcl-2 overexpression may have a potential role in the poor responses seen with standard chemotherapy. Presently, the six general treatment options available for AI CaP are best supportive care, radiation therapy, radioisotopes, secondline hormonal therapy, chemotherapy (single agent or combination), and investigational therapies such as monoclonal antibodies, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, and antiangiogenesis agents, among others. None of these modalities have produced durable remissions, although some have demonstrated palliative benefit. The next generation of clinical trials should not consist of futile hormonal manipulations or repetitive chemotherapy. Therapeutic strategies aimed at circumventing molecular blocks to cell death or targeting unique cancer molecules and genes will be more likely to improve quality of life and longevity. Furthermore, the aggressive use of palliative care will ensure effective caring for patients and the healing of families in the absence of cure.


Cross-cultural beliefs about memory and aging for self and others: South Korea and Canada.
Young adults in Canada (N = 161) and South Korea (N = 165) rated either themselves or typical others at target ages 25, 45, and 65 years. In both countries, poorer memory was anticipated with each increase in age on all 3 memory belief factors: capacity, change, and locus. Both groups demonstrated a self-protective bias about age-related decline, with Koreans showing a greater effect. These findings demonstrate the cross-cultural generality of negative memory stereotypes of middle and old age and the importance of self-other distinctions in age biases.


Partial characterization of an equine conceptus prostaglandin inhibitory factor.
Equine conceptuses are thought to produce antiluteolytic factors that inhibit endometrial PGF2alpha and, thus, prevent luteolysis in pregnant mares. The aim of the present study was to characterize partially the chemical nature of the prostaglandin inhibitory factor (PIF) produced by equine conceptuses in vitro. Embryos were collected from pregnant mares 13 +/- 0.5 days after ovulation and were cultured for 24 h. Harvested equine conceptus conditioned media (CCM) were assayed for antiluteolytic activity by determining the inhibition of endometrial PGF2alpha synthesis in vitro. Significant antiluteolytic activity was found in the CCM at 12, 18 and 24 h. After size fractionation, antiluteolytic activity was observed in the 3-10 kDa fraction and the activity was not destroyed by proteinase K digestion. In contrast, treatment with dextran-coated charcoal removed the antiluteolytic activity from the CCM at 12, 18 and 24 h of culture (P < 0.05). These results indicate that the prostaglandin inhibitory factor is a low molecular mass (3-10 kDa) proteinase K-resistant substance that may be adsorbed by dextran-coated charcoal. The chemical nature, antiluteolytic activity and time of synthesis of the PIF by early equine conceptuses indicate that the PIF identified in the present study may be involved in the maternal recognition of pregnancy factors in mares.


Silicification of Betula Woody Tissue in vitro.
Pieces of Betula twigs were placed in solutions of sodium metasilicate (5,000 to 10,000 parts per million) and allowed to remain for 12 to 24 hours, after which they were washed and wet-ashed with chromic acid. Opaline silica was deposited on inner surfaces of cell walls so that silica replicas of the various types of cell lumens were produced. Entire twigs were not replicated intact, but macroscopic replicas of cell aggregates were common. Carbon replicas of the silica replicas provide an unusual view of cellular spaces in woody tissue. The pits were viewed as projections from cells rather than holes in cell walls. This technique offers a new way of examining woody tissue and a method for deliberate petrification in a relatively short period of time under laboratory conditions.


Impact of Intrauterine Growth Restriction on the Capillarization of the Early Postnatal Rat Heart.
Capillarization plays a key role in the growth of the developing heart. We therefore hypothesized that impaired heart development following intrauterine growth restriction (IUGR) may arise from inadequate myocardial capillary growth. The aims of the study were to examine the effect of IUGR on the growth and diffusion radius of intramyocardial capillaries in rats at postnatal day 1. Uteroplacental insufficiency was induced in rats in late gestation (E18, term = E22) by bilateral uterine artery and vein ligation (restricted offspring N = 12; six males and six females); offspring from sham-operated dams were used as controls (N = 10; five males and five females). At postnatal day 1, the hearts were immersion-fixed and heart volume, capillary length density, capillary diffusion radius, and total capillary length were stereologically determined. Restricted offspring were significantly smaller at birth, with a concomitant reduction in heart volume and total myocardial capillary length compared to controls. Capillary growth was not impaired relative to heart size, with no significant differences in capillary length density or diffusion radius in the myocardium of restricted and control offspring. There were no sex differences in any of the parameters examined. In conclusion, there was no evidence to indicate that microvascular development is compromised in the heart of IUGR offspring at 1 day after birth. Total myocardial capillary length, however, was significantly reduced in the growth restricted offspring and further longitudinal studies are required to elucidate the long-term impact, particularly following hypertrophic cardiac growth. Anat Rec, 302:1580-1586, 2019. © 2018 American Association for Anatomy.


Correlation between magnifying narrow-band imaging endoscopy results and organoid differentiation indicated by cancer cell differentiation and its distribution in depressed- type early gastric carcinoma.
A close association between patterns identified by magnifying narrow-band imaging (M-NBI) and histological type has been described. M-NBI patterns were also recently reported to be related to the mucin phenotype; however, detials remain unclear. We investigated the cellular differentiation of gastric cancer lesions, along with their mucosal distribution observed by M-NBI. Ninety-seven depressed-type early gastric cancer lesions (74 differentiated and 23 undifferentiated adenocarcinomas) were visualized by M-NBI. Findings were divided into 4 patterns based on abnormal microvascular architecture: a chain loop pattern (CLP), a fine network pattern (FNP), a corkscrew pattern (CSP), and an unclassified pattern. Mucin phenotypes were judged as gastric (G-type), intestinal (I-type), mixed gastric and intestinal (M-type), and null (N-type) based on 4 markers (MAC5AC, MUC6, MUC2, and CD10). The relationship of each pattern of microvascular architecture with organoid differentiation indicated by cancer cell differentiation and its distribution in each histological type of early gastric cancer was investigated. All CLP and FNP lesions were differentiated. The cancer cell distribution showed organoid differentiation in 84.2% (16/19) and 61.1% (22/36) of the two types of lesions, respectively, and there was a significant difference from the unclassified pattern with organoid differentiation (p<0.001). Almost all (94.7%; 18/19) CSP lesions were undifferentiated, and organoid differentiation was observed in 72.2% (13/18). There was a significant difference from the unclassified pattern with organoid differentiation (p<0.05). Cellular differentiation and distribution are associated with microvascular architecture observed by M-NBI.


[Spectral characters analysis of ground objects in snowmelt period in the northern slope of Tianshan Mountains].
Urumqi River Basin and Juntanghu Basin, located in the northern slope of Tianshan Mountains in Xinjiang, were selected as typical study areas. With the portable field spectrometer CI700 produced by CID in the United States and from a large number of field investigations and field measurements in the snowmelt period (usually starts in the end of February or the beginning of March, and goes on for many days) from 2006 to 2009, a variety of spectral curves and their variation of typical ground objects in the snowmelt period in the northern slope of Tianshan Mountains, such as snow, ice, water and soil, were obtained, and spectral characters analysis was carried out based on the collected data. The results showed that the classes of ground objects in snowmelt period are quite monotone, however, a great challenge was brought about to the quantitative remote sensing research on surface parameters in snowmelt period because of the interactive effects of the complex systems of snow-ice-water-soil, the spectral properties of typical ground objects, and their complex changes. Reflectance of soil with different moisture conditions is distinct, as well as reflectance of ice and snow under different environment or dissimilar mixtures have obvious development trends. The series of observations and analysis of the typical and complex spectral features in snowmelt period are of great significance for the fundamental study of objects' spectral characteristics, as well as for the application of quantitative remote sensing studies.


The Effects of the Growing Pro-Social Program on Early Maladaptive Schemas and Schema-Related Emotions in Male Young Offenders: A Nonrandomized Trial.
This study aimed to test the effects of a 25-session version of the Growing Pro-Social (GPS-25) program over schemas and schema-related emotions in male young offenders. Participants included 123 youth aged between 14 and 19 years, placed in eight Portuguese detention facilities. Youth were allocated to receive GPS (n = 63) or treatment as usual (n = 60), and answered a self-report measure assessing schemas and schema-related emotions at baseline and posttreatment. Two-factor mixed multivariate analysis of variance (MANOVA; group change) and the Reliable Change Index (individual change) revealed nonsignificant differences between groups for the schema's endorsement. Significant differences between groups were found for the schema-related emotions: Treatment participants presented lower scores and/or higher clinical improvements after GPS, when compared with controls. GPS-25 produced change at an emotional level but not in schema's endorsement, suggesting that longer interventions should be tested in their capability to promote cognitive and emotional change in young offenders.


Targeting netrin-3 in small cell lung cancer and neuroblastoma.
The navigation cue netrin-1 is well-documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin-1. Interestingly, the epitope recognized by NP137 in netrin-1 shares 90% homology with its counterpart in netrin-3, the closest member to netrin-1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin-3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin-3 and netrin-1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL-1 or NeuroD1 transcription factors in SCLC. Netrin-3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin-3 for netrin-1 receptors and we demonstrated that netrin-3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin-3 in NB and SCLC.


Stem cell-mediated development, regeneration, chimerism, and aging in the colonial chordate Botryllus schlosseri.
Stem cells are units of biological organization, responsible for tissue and organ development and regeneration. I study stem cell biology, aging, and the evolution of immunity using the colonial chordate Botryllus schlosseri as a model system. This organism is uniquely suited for this study because it is closely related to vertebrates, undergoes weekly cycles of stem cell mediated regeneration, is long lived and has a recognition system and robust immune system. I have led the Botryllus genome project and developed a novel method to obtain a synthetic long read sequence, identified Botryllus stem cells and stem cell niches, isolated the gene that controls self/non self-recognition and characterized its immune system on the cellular and molecular levels. Recently, I led the Botryllus atlas project to characterize the two developmental pathways, embryogenesis (sexual) and blastogenesis (asexual), revealing the unique molecular landscapes for each developmental mode and investigated the molecular clock and neurodegeneration pathways in young and old colonies and investigated the molecular clock and neurodegeneration pathways in young and old colonies. These results and the resources we developed are used by my lab and others to further study stem cell and immune cell properties during development, regeneration, transplantation, and aging.


Urolithin A Nanoparticle Therapy for Cisplatin-Induced Acute Kidney Injury.
Cisplatin continues to be one of the frontline cytotoxic drugs. However, cisplatin-induced acute kidney injury (AKI) remains a major unmet medical need without any approved pharmacological interventions. The involvement of reactive oxygen species generation and activation of inflammatory and apoptotic pathways in the pathogenesis of cisplatin-induced AKI prompts the use of natural anti-inflammatory compounds. In this context, resolution of inflammation using natural antioxidant and anti-inflammatory such as urolithin A (UA) could prove beneficial. In the end, testing such combinations in models to eliminate the possibility that UA stimulates tumor growth or compromises the potency of cisplatin could prove useful for clinical translation of adjuvant therapies.


ABIDE: An Accurate Predictive Model of Liver Decompensation in Patients With Nonalcoholic Fatty Liver-Related Cirrhosis.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly important cause of liver cirrhosis and subsequent complications. We retrospectively developed and validated a model to predict hepatic decompensation in patients with NAFLD and cirrhosis and compared this with currently available models. Baseline variables from an international cohort of 299 patients with biopsy-proven NAFLD with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 patients with biopsy-proven NAFLD cirrhosis from the United States. Prognostic accuracy was compared with the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4), Model for End-Stage Liver Disease (MELD), Child-Turcotte-Pugh (CTP), and albumin-bilirubin (ALBI)-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts, respectively. In the derivation cohort, independent predictors of hepatic decompensation (Aspartate aminotransferase/alanine aminotransferase ratio, Bilirubin, International normalized ratio, type 2 Diabetes, and Esophageal varices) were combined into the ABIDE model. Patients with a score ≥4.1 compared with those with a score <4.1 had a higher risk of decompensation (subhazard ratio, 6.7; 95% confidence interval [CI], 4.0-11.2; P < 0.001), a greater 5-year cumulative incidence (37% vs. 6%, P < 0.001), and shorter mean duration to decompensation (3.8 vs 6.7 years, P < 0.001). The accuracy of the ABIDE model at 5 years was good in the derivation (tAUC, 0.80; 95% CI, 0.73-0.84) and validation cohorts (0.78; 95% CI, 0.74-0.81) and was significantly more accurate than the NFS (0.72), FIB-4 (0.74), MELD (0.69), CTP (0.72), and ALBI-FIB-4 (0.73) (all P < 0.001). In patients with NAFLD and compensated cirrhosis, ABIDE, a predictive model of routine clinical measures, predicts future hepatic decompensation.


Chemoprophylaxis of leprosy in the southern Marquesas with a single 25 mg/kg dose of rifampicin. Results after 10 years.
In 1988, a programme of leprosy chemoprophylaxis, employing a supervised, single 25 mg/kg dose of rifampicin, was implemented in the Southern Marquesas Islands. Of the 2786 inhabitants, 2751 (98.7%) were treated. In addition, 3144 South Marquesans living elsewhere in French Polynesia were administered the same chemoprophylaxis. During the following 10 years, seven leprosy patients were detected among those who had been administered chemoprophylaxis. Of these, two were very likely missed cases of leprosy, and cannot be considered a failure of chemoprophylaxis. The epidemiometric projection model, based on cases of leprosy observed in the Southern Marquesas during the 20 years preceding implementation of the programme, predicted that 17 leprosy cases could be expected in the South Marquesan population if no chemoprophylaxis were given. In fact, only five cases were detected in the treated population, a number significantly smaller than 17, suggesting that the chemoprophylaxis was 70% effective, assuming that no change of detection rate would have occurred without chemoprophylaxis. However, during the 10 years following implementation of the chemoprophylaxis programme, the detection rate in the Polynesian population that was not administered chemoprophylaxis declined by about 50%. Therefore, the effectiveness of the chemoprophylaxis was only 35-40%.


Quality of life in Croatian metastatic melanoma patients.
The aim of this study was to examine the quality of life (QoL) in 40 Croatian metastatic melanoma patients who had completed at least first-line treatment and to see if there was a correlation between QoL parameters and serum lactate dehydrogenase (LDH). LDH levels were measured and all patients clinically examined between April and September 2013. Two QoL questionnaires were used for patient self-evaluation: the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC QLQ-C30) and the Dartmouth Primary Care Cooperative Research Network and the World Organization of National Colleges, Academies, and Academic Associations of General Practitioners/Family Physicians (COOP/WONCA) charts. The average EORTC QLQ-C30 score for global health status (GHS) was 41.204. The average scores for functional scales were high, with the exception of emotional functioning (65.02). Blood LDH levels positively correlated with the Eastern Cooperative Oncology Group (ECOG) status (r = 0.415; p < 0.01) and pain (r = 0.345; p < 0.05), but not with any functional or COOP/WONCA scores. Global health status (GHS) positively correlated with patient age at the time of evaluation (r = 0.386; p < 0.05) and age at the time when metastatic disease had been diagnosed (r = 0.366; p < 0.05). Quality of life for the studied group of metastatic melanoma patients in Croatia can be considered generally good, with the exception of emotional functioning and symptoms of fatigue, dispnoea, insomnia, and financial difficulties.


Activation of epidermal growth factor receptor during corneal epithelial migration.
Epidermal growth factor (EGF) and related growth factors: transforming growth factor (TGF)-alpha, heprin-ding (HB)-EGF, and amphiregulin (AR), have been shown to stimulate events associated with epithelial wound repair. These growth factors function by binding to a common EGF receptor (EGFR), tyrosine kinase. We have used in vivo and organ culture wound-healing models to examine the kinetics and extent of EGFR activation during corneal epithelial wound repair and whether the epithelium itself produces EGFR ligands capable of stimulating the healing process. In the in vivo model, 3-mm debridement wounds were made in rat corneas and allowed to heal in situ. Activation of EGFR was analyzed by 1) indirect immunofluorescence microscopy, 2) immunoprecipitation using anti-EGFR and anti-phosphotyrosine (anti-PT), and 3) binding-site localization using EGF-fluorescein isothiocyanate (FITC). Relative levels of mRNA for EGF, TGF-alpha, HB-EGF, and AR were determined using reverse transcription-polymerase chain reaction. To determine whether inhibiting EGFR activation slows epithelial migration, wounded corneas were allowed to heal in organ culture in the presence of tyrphostin AG1478 (0-50 microM), a specific inhibitor of EGFR kinase activity. In unwounded corneas, EGFR was localized in basal cells and appeared to be membranous. Within 1 hour after wounding, EGFR was no longer immunolocalized in the membranes of cells migrating into the wound area. EGF-FITC-binding assays indicated that EGFR ligands could penetrate all the way to the limbus. Immunoprecipitation showed that EGFR was phosphorylated on tyrosine residues within 30 minutes after wounding and that phosphorylation levels increased after wounding. Levels of mRNA for TGF-alpha, HBEGF, and AR all appeared to increase after wounding. In organ culture experiments, tyrphostin AG1478 inhibited migration rates in a dose-dependent manner. These data indicate that EGFR was activated during corneal epithelial wound healing in vivo. Furthermore, this activation appears to be a necessary component of the process, because inhibition of the EGFR signaling cascade significantly slowed migration rates.


Force and amount of resin composite paste used in direct and indirect bonding.
To investigate the relationship between the forces applied by the operator and the amount of adhesive used in the direct and indirect bonding methods. A system for measuring the force applied by operator was used to test specimens prepared by 12 orthodontic specialists. To determine the proper amount of adhesive, metal brackets were bonded to transparent resin teeth using composite resin paste and different forces (100, 200, and 300 g); the area of the composite resin paste was then measured using image-analysis software. The mean forces applied in direct and indirect bonding were compared by Student's t-test. Various values for force were obtained for the direct bonding (53-940 g) and indirect bonding (150-870 g) techniques. Although in all cases the area of composite resin paste after the application of constant force was greater than the area of the metal brackets, an insufficient amount of composite resin paste on the bracket base was observed with forces of 100 and 200 g. A force of greater than 200 g might be preferable for obtaining a thin composite resin layer and for achieving sufficient spreading of the composite resin paste.


Pharmacophore-similarity-based QSAR (PS-QSAR) for group-specific biological activity predictions.
Recent technological breakthroughs in medicinal chemistry arena had ameliorated the perspectives of quantitative structure-activity relationship (QSAR) methods. In this direction, we developed a group-based QSAR method based on pharmacophore-similarity concept which takes into account the 2D topological pharmacophoric descriptors and predicts the group-specific biological activities. This activity prediction may assist the contribution of certain pharmacophore features encoded by respective fragments toward activity improvement and/or detrimental effects. We termed this method as pharmacophore-similarity-based QSAR (PS-QSAR) and studied the activity contribution of fragments from 3-hydroxypyridinones derivatives possessing antimalarial activities.


Composite pelvic resection. An approach to advanced pelvic cancer.
The definition of resectability has changed in the management of advanced pelvic malignancy. Most tumors previously considered unresectable can be removed by a function-preserving composite resection of the pelvis. We have performed resection in 55 such patients. Most had posterior pelvic tumors (47 patients), had previously undergone irradiation, and required a combined sacral resection. Included were patients with recurrent or locally advanced rectal cancer (32 patients), epidermoid cancer of the anorectum (seven patients), and primary pelvic malignancies (eight patients). Most had good functional recovery. The five-year actuarial survival rate was 23% (five of 25 patients survived longer than 51 months) in the patients with resected rectal cancer and 14% (one of seven patients) in the patients with resected anorectal carcinoma. Five of eight patients with primary tumors survived longer than 48 months. Lateral pelvic resections were done for five tumors that involved the ileum or ischium, and anterior resection was done in three patients for malignancy that involved the symphysis and rami. Four of these patients were living three to six years after surgery. The overall mortality rate was 7% (four of 55 patients). Composite pelvic resections can provide good local control with preservation of limb function in most patients with primary or secondary tumors of the bony pelvis.


Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful.
Maternal oxygen is often given to laboring women to improve fetal metabolic status or in an attempt to alleviate nonreassuring fetal heart rate patterns. However, the only 2 randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support that such supplementation is likely to be of benefit to the fetus. And by increasing free radical activity, maternal oxygen supplementation may even be harmful. Based on a review of the available literature, we conclude that until it is studied properly in a randomized clinical trial, maternal oxygen supplementation in labor should be reserved for maternal hypoxia, and should not be considered an indicated intervention for nonreassuring fetal status.


Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients.
We explored the relationships between lymphocyte subsets, cytokines, pulmonary inflammation index (PII) and disease evolution in patients with (corona virus disease 2019) COVID-19. A total of 123 patients with COVID-19 were divided into mild and severe groups. Lymphocyte subsets and cytokines were detected on the first day of hospital admission and lung computed tomography results were quantified by PII. Difference analysis and correlation analysis were performed on the two groups. A total of 102 mild and 21 severe patients were included in the analysis. There were significant differences in cluster of differentiation 4 (CD4+ T), cluster of differentiation 8 (CD8+ T), interleukin 6 (IL-6), interleukin 10 (IL-10) and PII between the two groups. There were significant positive correlations between CD4+ T and CD8+ T, IL-6 and IL-10 in the mild group (r2 = 0·694, r 2 = 0·633, respectively; P < 0·01). After 'five-in-one' treatment, all patients were discharged with the exception of the four who died. Higher survival rates occurred in the mild group and in those with IL-6 within normal values. CD4+ T, CD8+ T, IL-6, IL-10 and PII can be used as indicators of disease evolution, and the PII can be used as an independent indicator for disease progression of COVID-19.


[Congenital choledochal cyst and laparoscopic techniques].
The authors present a 5-year-old girl with a congenital choledochal cyst and repeated cholangitis. On laparoscopy, a type I choledochal cyst of Todani classification was confirmed. The cyst was excised laparoscopically. After exteriorization of the small bowel through the umbilical incision, a Roux-en Y anastomosis was performed. Then the bowel was reintroduced into the abdominal cavity and a laparoscopic end-to-side hepaticojejunostomy was carried out. There were not intra or post operative problems. Oral food intake started at 72 hours and the patient was discharged on day 5 without complications and with excellent cosmetic results. We conclude that laparoscopic techniques are an excellent option for the resection of congenital choledochal cyst and hepaticojejunostomy in children.


Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis.
Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer-related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3'-Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAF(V600E), we previously developed a model of PTC. However, as in humans, BRAF(V600E)-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAF(V600E) cooperates with either PIK3CA(H1074R) or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma. This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma.


Intensity and frequency resolution: masking of absolute identification and fixed and roving discrimination.
Auditory intensity and frequency resolution were studied in three paradigms under masking conditions. Absolute identifications of single stimuli (one-interval paradigm) and 2IFC judgments of fixed- and roving-level pairs of stimuli (two-interval paradigm) were obtained from the same experienced observers. Judgments were made under optimal (no mask) conditions, in the presence of a broadband noise mask (simultaneous mask), and when the stimulus(i) to be judged were either preceded (forward mask) or followed (backward mask) by a broadband noise mask. Substantial masking of intensity resolution was found in all mask conditions. Only a simultaneous mask affected frequency resolution. In the no mask condition, performance was best for fixed-level (or frequency) 2IFC discrimination, followed by roving-level (frequency) 2IFC, and finally absolute identification. These differences were maintained under masking for frequency resolution, but not for intensity resolution. The results are discussed in terms of the Braida and Durlach (1988) model of intensity resolution. A similar model is suggested for frequency resolution with differences suggested by the differences in neural coding of sound intensity and frequency.


The many characters of visual alpha oscillations.
A central feature of human brain activity is the alpha rhythm: a 7-13 Hz oscillation observed most notably over occipitoparietal brain regions during periods of eyes-closed rest. Alpha oscillations covary with changes in visual processing and have been associated with a broad range of neurocognitive functions. In this article, we review these associations and suggest that alpha oscillations can be thought to exhibit at least five distinct 'characters': those of the inhibitor, perceiver, predictor, communicator and stabiliser. In short, while alpha oscillations are strongly associated with reductions in visual attention, they also appear to play important roles in regulating the timing and temporal resolution of perception. Furthermore, alpha oscillations are strongly associated with top-down control and may facilitate transmission of predictions to visual cortex. This is in addition to promoting communication between frontal and posterior brain regions more generally, as well as maintaining ongoing perceptual states. We discuss why alpha oscillations might associate with such a broad range of cognitive functions and suggest ways in which these diverse associations can be studied experimentally.


Regulation of cholinergic development by target contact.
Avian ciliary ganglion neurons in cell culture have been used as a model neuronal system to examine the developmental role of direct contact with an appropriate target tissue. Live myotubes, which are immediately innervated, and their membrane remnants, on which neurons form terminal structures, were both found to stimulate or accelerate the acquisition or retention of important parameters of neuronal function. Contact with the target membrane supports survival, aids retention of active nicotinic receptors to acetylcholine, and accelerates the acquisition of adult transmitter synthetic capacity. These results emphasize the multifaceted nature of neurodevelopment, with soluble protein factors, membrane-bound elements, and other functional events all acting in concert in the embryonic nervous system.


Reduced parasympathetic activity during sleep in the symptomatic phase of severe premenstrual syndrome.
Severe premenstrual syndrome (PMS) is a common distressing disorder in women that manifests during the premenstrual (late-luteal) phase of the ovulatory menstrual cycle. There is some evidence that altered autonomic function may be an important component of PMS, but few studies have used heart rate variability (HRV) as a sensitive marker of autonomic activity in severe PMS, and findings are conflicting. We investigated HRV during sleep, a state that is relatively free of external disruptions, in 9 women with severe PMS and 12 controls. The normal-to-normal (NN) RR interval was shorter during the sleep period in women with PMS than in controls in both the follicular and the late-luteal phases of the menstrual cycle. The standard deviation of all NN intervals, a measure of total variability in the interbeat interval, was lower during the sleep period in the late-luteal phase than in the follicular phase in women with PMS. The square root of the mean of the sum of the squares of differences between adjacent NN intervals, a measure reflecting high-frequency (HF) activity, showed a similar pattern. HF power, a marker of parasympathetic activity, was lower during non-rapid eye movement (non-REM) and REM sleep in the late-luteal phase than in the follicular phase in women with severe PMS. Controls had a shorter NN interval, but similar HRV measures, in the late-luteal phase compared with the follicular phase. These results suggest that women with severe PMS have decreased parasympathetic activity during sleep in association with their premenstrual symptoms in the late-luteal phase compared with the follicular phase when they are symptom-free.


Aerobic Capacity in Adults with Congenital Heart Disease: More than VO2peak, a Follow-Up Study.
To control the development of people with congenital heart disease (CHD), it is important to follow their aerobic capacity (AC), especially when they exercise. This research aimed to study the progress of AC during a follow-up of adults with CHD. This is a longitudinal study which involved 127 adults with a mean age of 33.8 (11.1) years (57.5% female; 75 moderate CHD and 52 complex CHD) who had undergone two cardiopulmonary exercise tests (CEPT) in at least one year between the first and the second test. The AC and exercise performance (EP) (duration of exercise time, velocity and percentage of grade) were assessed using a ramp protocol over a treadmill. In a mean of 4.5 (2.0) years of follow-up, there was a significant decrease in AC. The VO2peak at baseline was 27.8 (27.7) mL/kg/min (82.9% (20.3%) predicted) versus 26.6 (7.8) mL/kg/min (79.3% (20.8%) predicted) at the end of follow-up. This decline was independent of the body weight increase. There was no significant difference in HRpeak and EP among periods. These results suggest a sign of favorable evolution of adults with CHD. More research is needed to study different factors that could contribute to AC reduction.


Short-acting nifedipine and risk of stroke in elderly hypertensive patients.
Short-acting nifedipine is frequently prescribed in elderly hypertensive patients, despite warnings of possible harmful cardiovascular effects. We conducted a case-crossover study to estimate the risk of stroke episodes associated with use of short-acting nifedipine in elderly hypertensive patients. We used the Korea Health Insurance Review & Assessment Service database. Cases included elderly hypertensive patients with hospitalization or emergency department visits for first stroke (International Classification of Diseases-10, I60-I64) between July 1, 2005, and June 30, 2006. Patients with prior stroke-related hospital admission or any visit related to TIA were excluded. Exposure to a short-acting nifedipine formulation was assessed within 7 days before the incident stroke episode (case period) and within a 7-day period preceding 60 days before the episode (control period). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by conditional logistic regression, with adjusting for antihypertensives, anticoagulants, antiplatelet agents, and pneumonia. A total of 16,069 stroke patients with a mean (±SD) age of 68.3 (±2.1) years were studied, of whom 8,573 (53.3%) were female. Short-acting nifedipine was prescribed at least once to 301 (1.9%) patients during the case period. An increased risk of stroke associated with use of short-acting nifedipine within 7 days (adjusted OR 2.56; 95% CI 1.96-3.37) was observed. Patients who were newly prescribed nifedipine within the recent 7 days showed an OR of 4.17 (95% CI 2.93-5.93) compared with nonusers. Use of short-acting nifedipine was associated with increased risk of stroke occurrence in elderly hypertensive patients.


[Work in structure of social and psychologic factors in doctors].
The article deals with results obtained through social and hygienic poll among Bashkortostan Republic doctors (6077 questionnaires) on analysis and evaluation of professional activities role in moral values structure. Most of the doctors appeared to work with exceeding their personal abilities, that causes prolonged overstrain in them and remains along with low salary one of the main reasons for anxiety, nervousness or stress at work.


Measurement properties of the Work Limitations Questionnaire were sufficient among cancer survivors.
The purpose of this study was to determine reproducibility, validity, and responsiveness of the Work Limitations Questionnaire (WLQ) among cancer survivors. A cohort of 53 cancer survivors completed the WLQ and other questionnaires at baseline, 4-week, and 6-month follow-up. We assessed internal consistency, intraclass correlation coefficient, standard error of measurement, floor- and ceiling effects and compared the WLQ with other constructs. For responsiveness, we assessed the following anchor-based measures: minimal important change (MIC) versus smallest detectable change (SDC) and area under the curve (AUC) of receiver operation characteristic (ROC). We found sufficient reproducibility at group level but not at individual level as the MIC (4.0) exceeded SDC at group level (3.1) but not at individual level (18.0). There was no indication of systematic bias or proportional bias. The internal consistency and construct validity for the WLQ and its subscales were sufficient or slightly less than sufficient. There was a floor effect for one subscale, but there were no ceiling effects. Responsiveness was sufficient with an AUC of a ROC of 0.65. The WLQ is reproducible, valid, and responsive for use at group level among cancer survivors but not sufficiently reproducible for use at individual level.


Hepatic metabolism of glucagon in the dog: contribution of the liver to overall metabolic disposal of glucagon.
The hepatic extraction (HE) of glucagon (G) and insulin (I) was measured in 27 dogs, using peripheral infusion of the hormones following elimination of endogenous secretion by pancreatectomy (Px) or somatostatin (S) infusion. HE(G) was 22.5 +/- 1.7%, and HE(I) was 45.1 +/- 3%. HE(G) in seven Px dogs was 27.9 +/- 4.2%, not significantly different from the value of 20.6 +/- 1.6% in 20 S-infused dogs, with corresponding values for HE(I) being 44.9 +/- 6 and 46.0 +/- 3.6%, respectively, suggesting that S does not affect HE of either hormone. HE of endogenous G (22.1 +/- 2.8%) was similar to that of exogenously infused G (19.1 +/- 1.9). HE(G) was nonsaturable in the physiologic and pathophysiologic range of plasma G levels, but there was evidence of saturability in the pharmacologic range. Comparison of simultaneously measured parameters of I and G metabolism indicated independence of the metabolic processes of these two islet hormones, despite distinct similarities in their overall patterns of metabolic disposal. Metabolic clearance rates (MCR) for G and I were 12.6 +/- 0.8 and 19.5 +/- 1.0 ml . kg-1 . min-1, while simultaneously measured hepatic HE rates were 4.2 +/- 0.3 and 8.1 +/- 0.6 ml . kg-1 . min-1, respectively. MCR(G) was independent of arterial G levels. Half-life of infused G and I was 5.5 +/- 0.5 and 4.1 +/- 0.3 min, respectively. The liver accounted for 34.7 +/- 2.4% of the MCR(G) and 42.0 +/- 2.9% of MCR(I). The liver is thus an important site for G removal. However, HE(G) varies widely in different animals, and it is therefore not possible to predict portal vein G concentrations or G secretion rates from G levels in peripheral vessels.


High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia.
Standard doses of alkylating agents or purine analogues effect response rates of up to 50% in Waldenström's macroglobulinaemia (WM); however, complete responses are infrequent and there are no cures. We have evaluated the feasibility, safety and efficacy of high-dose chemotherapy with peripheral blood stem cell support in six patients aged 45-69 years (median 51.5) with WM; four patients relapsed after prior therapy inclusive of purine analogues and two patients proceeded with transplant after minimal therapy. Four patients mobilized adequate numbers of stem cells; however, two patients with more extensive fludarabine therapy failed to mobilize and required a second attempt at stem cell collection. Five patients were treated with melphalan 200 mg/m2, including one patient who received tandem transplants and one patient who received melphalan 140 mg/m2 with added total body irradiation (TBI). There was no treatment-related mortality and non-haematological toxicities were manageable. Engraftment was prompt except in one patient with extensive prior use of fludarabine. All the six patients achieved at least partial response (PR), including one who achieved complete response (CR). Five patients are alive and four are event-free at 52+, 15+, 12+ and 2+ months post transplant. This pilot study suggests safety and efficacy of high-dose therapy in WM and suggests that the peripheral blood stem cells should preferably be procured prior to extensive use of purine analogues.


The transpiration of water at negative pressures in a synthetic tree.
Plant scientists believe that transpiration-the motion of water from the soil, through a vascular plant, and into the air-occurs by a passive, wicking mechanism. This mechanism is described by the cohesion-tension theory: loss of water by evaporation reduces the pressure of the liquid water within the leaf relative to atmospheric pressure; this reduced pressure pulls liquid water out of the soil and up the xylem to maintain hydration. Strikingly, the absolute pressure of the water within the xylem is often negative, such that the liquid is under tension and is thermodynamically metastable with respect to the vapour phase. Qualitatively, this mechanism is the same as that which drives fluid through the synthetic wicks that are key elements in technologies for heat transfer, fuel cells and portable chemical systems. Quantitatively, the differences in pressure generated in plants to drive flow can be more than a hundredfold larger than those generated in synthetic wicks. Here we present the design and operation of a microfluidic system formed in a synthetic hydrogel. This synthetic 'tree' captures the main attributes of transpiration in plants: transduction of subsaturation in the vapour phase of water into negative pressures in the liquid phase, stabilization and flow of liquid water at large negative pressures (-1.0 MPa or lower), continuous heat transfer with the evaporation of liquid water at negative pressure, and continuous extraction of liquid water from subsaturated sources. This development opens the opportunity for technological uses of water under tension and for new experimental studies of the liquid state of water.


Panel of synaptic protein ELISAs for evaluating neurological phenotype.
The purpose of this study was to develop ELISAs for key neural proteins, three synaptic and one glial, that exist in different intracellular compartments, which would be used as a measure of synaptic phenotype. These assays would be valuable to neurologically phenotype transgenic mouse models of human disease and also human disease itself using minimal amounts of post-mortem tissue. We showed that supernatant from crude brain tissue homogenates extracted in RIPA buffer containing 0.1% SDS bind to synaptophysin, synaptosome-associated protein of 25 kDa (SNAP-25), post-synaptic density-95 (PSD-95), and glial fibrillary acidic protein (GFAP) antibody pairs with high affinity and selectivity. Overall, RIPA + 0.1% SDS were more efficient than RIPA + 2% SDS or a buffer containing only 1% Triton-X-100. Diluting the brain extracts resulted in dose-dependent binding to the antibody pairs for each neural protein, with EC50s that varied from 8.6 microg protein for PSD-95 to 0.23 microg for GFAP. The assays were used to measure synaptic marker protein levels at various times during mouse development and GFAP in a model of disease accompanied by neuroinflammation. Comparison of ELISAs with Western blots by measuring marker levels in brain extract from developing mice showed a greater relative difference in values derived from ELISA. These ELISAs should be valuable to phenotype the synapse in neurological disease and their rodent models.


[Parapharyngeal space tumors. Presentation of three cases and literature review].
Tumors originating in the parapharyngeal space are rare. Eighty percent of the parapharyngeal space neoplasms are benign, and 20% are malignant. The most frequent tumours of this localization are those of salivary origin followed by neurogenic tumor and in third place the paragangliomas. This paper presents three representative cases of parapharyngeal space neoplasms. The literature is reviewed.


Analysis of metacarpophalangeal pattern profiles.
The analysis of measurements of phalangeal lengths with the metacarpophalangeal pattern profile plots (MCPPP), has been further extended. I suggest to correlate these measurements to the total length of the phalanges in order to obtain only one mean and standard deviation table for all ages from 3 years to adults. The technique described has proved very useful for comparing published pictures with actual x-ray images. The technique also yields an enhancement of small peculiarities in the plots of a given malformation. As an example the plots of the tricho-rhino-phalangeal syndromes type 1 and 2 (Langer-Giedion syndrome) are presented and compared with the literature.


Lichenysin, a cyclooctapeptide occurring in Chinese liquor jiannanchun reduced the headspace concentration of phenolic off-flavors via hydrogen-bond interactions.
Nonvolatile compounds play important roles in the quality of alcoholic beverages. In our previous work, a type of cyclooctapeptide lichenysin was newly identified in Chinese strong-aroma type liquor. In this work, it was found that lichenysin could selectively affect aroma volatility in strong-aroma type (Jiannanchun) liquor. Interaction of lichenysin and volatile phenolic compounds (off-odors in strong-aroma type liquor) was characterized using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS). HS-SPME results indicated that lichenysin very efficiently suppressed the volatility of phenolic compounds by 36-48% (P < 0.05). Thermodynamic analysis showed that the binding process was mainly mediated by hydrogen bonding. Furthermore, the mixture of lichenysin and 4-ethylguaiacol revealed intermolecular cross peaks between the aH (Val) of lichenysin and the 1H of 4-ethylguaiacol, by using nuclear Overhauser effect spectroscopy. This study will help to further understand the interaction mechanisms between flavor and nonvolatile matrix components in Chinese liquors.


Estimating the occupancy rate of spatially rare or hard to detect species: a conditional approach.
We consider the problem of estimating the occupancy rate of a target species in a region divided in spatial units (called quadrats); this quantity being defined as the proportion of quadrats occupied by this species. We mainly focus on spatially rare or hard to detect species that are typically detected in very few quadrats, and for which estimating the occupancy rate (with an acceptable precision) is problematic. We develop a conditional approach for estimating the quantity of interest; we condition on the presence of the target species in the region of study. We show that conditioning makes identifiable the occurrence and detectability parameters, regardless of the number of visits made in the sampled quadrats. Compared with an unconditional approach, it proves to be complementary, in that this allows us to deal with biological questions that cannot be addressed by the former. Two Bayesian analyses of the data are performed: one is noninformative, and the other takes advantage of the fact that some prior information on detectability is available. It emerges that taking such a prior into account significantly improves the precision of the estimate when the target species has been detected in few quadrats and is known to be easily detectable.


Contemporary Outcomes in Patients With Long QT Syndrome.
Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope, aborted cardiac arrest, or sudden cardiac death. This study sought to evaluate LQTS outcomes from a single center in the contemporary era. The authors conducted a retrospective study comprising the 606 patients with LQTS (LQT1 in 47%, LQT2 in 34%, and LQT3 in 9%) who were evaluated in Mayo Clinic's Genetic Heart Rhythm Clinic from January 1999 to December 2015. Breakthrough cardiac events (BCEs) were defined as LQTS-attributable syncope or seizures, aborted cardiac arrest, appropriate ventricular fibrillation-terminating implantable cardioverter-defibrillator shocks, and sudden cardiac death. There were 166 (27%) patients who were symptomatic prior to their first Mayo Clinic evaluation. Median age at first symptom was 12 years. Treatment strategies included no active therapy in 47 (8%) patients, beta-blockers alone in 350 (58%) patients, implantable cardioverter-defibrillators alone in 25 (4%) patients, left cardiac sympathetic denervation alone in 18 (3%) patients, and combination therapy in 166 (27%) patients. Over a median follow-up of 6.7 (IQR: 3.9 to 9.8) years, 556 (92%) patients have not experienced an LQTS-triggered BCE. Only 8 of 440 (2%) previously asymptomatic patients have experienced a single BCE. In contrast, 42 of 166 (25%) previously symptomatic patients have experienced ≥1 BCE. Among the 30 patients with ≥2 BCEs, 2 patients have died and 3 LQT3 patients underwent cardiac transplantation. Although outcomes have improved markedly, further optimization of treatment strategies is still needed given that 1 in 4 previously symptomatic patients experienced at least 1 subsequent, albeit nonlethal, LQTS-triggered cardiac event.


Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae.
Frataxin is a nuclear-encoded mitochondrial protein widely conserved among eukaryotes. Human frataxin (fxn) is severely reduced in Friedreich ataxia (FRDA), a frequent autosomal recessive neuro- and cardio-degenerative disease. Whereas the function of fxn is unknown, the yeast frataxin homolog (Yfh1p) has been shown to be involved in mitochondrial iron homeostasis and protection from free radical toxicity. Evidence of iron accumulation and oxidative damage in cardiac tissue from FRDA patients suggests that fxn may have a similar function, but whether yeast and human frataxin actually have interchangeable roles in mitochondrial iron homeostasis is unknown. We show that a wild-type FRDA cDNA can complement Yfh1p-deficient yeast (yfh1 delta) by preventing the mitochondrial iron accumulation and oxidative damage associated with loss of Yfh1p. We analyze the functional effects of two FRDA point mutations, G130V and W173G, associated with a mild and a severe clinical presentation, respectively. The G130V mutation affects protein stability and results in low levels of mature (m) fxn, which are nevertheless sufficient to rescue yfh1 delta yeast. The W173G mutation affects protein processing and stability and results in severe m-fxn deficiency. Expression of the FRDA (W173G) cDNA in yfh1 delta yeast leads to increased levels of mitochondrial iron which are not as elevated as in Yfh1p-deficient cells but are above the threshold for oxidative damage of mitochondrial DNA and iron-sulfur centers, causing a typical yfh1 delta phenotype. These results demonstrate that fxn functions like Yfh1p, providing experimental support to the hypothesis that FRDA is a disorder of mitochondrial iron homeostasis.


Cardioprotection of controlled and cardiac-specific over-expression of A(2A)-adenosine receptor in the pressure overload.
Adenosine binds to three G protein-coupled receptors (R) located on the cardiomyocyte (A(1)-R, A(2A)-R and A(3)-R) and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. Because of its ability to increase cardiac contractility and heart rate, we hypothesized that enhanced signaling through A(2A)-R would protect the heart during the stress of transverse aortic constriction (TAC). Using a cardiac-specific and inducible promoter, we selectively over-expressed A(2A)-R in FVB mice. Echocardiograms were obtained at baseline, 2, 4, 8, 12, 14 weeks and hearts were harvested at 14 weeks, when WT mice developed a significant decrease in cardiac function, an increase in end systolic and diastolic dimensions, a higher heart weight to body weight ratio (HW/BW), and marked fibrosis when compared with sham-operated WT. More importantly, these changes were significantly attenuated by over expression of the A(2A)-R. Furthermore, WT mice also demonstrated marked increases in the hypertrophic genes β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF)--changes that are mediated by activation of the transcription factor GATA-4. Levels of the mRNAs encoding β-MHC, ANP, and GATA-4 were significantly lower in myocardium from A(2A)-R TG mice after TAC when compared with WT and sham-operated controls. In addition, three inflammatory factors genes encoding cysteine dioxygenase, complement component 3, and serine peptidase inhibitor, member 3N, were enhanced in WT TAC mice, but their expression was suppressed in A(2A)-R TG mice. A(2A)-R over-expression is protective against pressure-induced heart failure secondary to TAC. These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A(2A)-R may provide a novel new target for pharmacologic therapy in patients with cardiovascular disease.


Variation in performance of the tree fern Cyathea caracasana (Cyatheaceae) across a successional mosaic in an Andean cloud forest.
In Andean forests, Cyathea caracasana grows across a range of successional habitats. This study documents variation in several measures of plant performance (stem growth, leaf production, leaf longevity, and spore production) in C. caracasana growing in open habitat, low-canopy secondary forest, and high-canopy secondary forest, based on 33 mo of observation. In open habitat, C. caracasana displayed significantly higher growth rates, leaf production rates, and leaf turnover than in either of the forested habitats. The highest rates of spore production were also observed in open-habitat individuals, with only one plant in the forest understory producing spores during the study. Despite low growth and no reproduction, I observed no mortality among ferns in the forest understory. These data show that C. caracasana performs best under conditions of full sun but can persist under the closed canopy. This suggests a life history in which periods of rapid growth, spore production, and recruitment in forest gaps alternate with low growth rate and persistence in the understory. A phylogenetic perspective suggests that the habitat flexibility, which might conventionally mark C. caracasana as a habitat generalist, is better interpreted as specialization for the dynamic forest in which it grows.


Cryobacterium ruanii sp. nov. and Cryobacterium breve sp. nov., isolated from glaciers.
Strains Sr36T and TMT4-23T were isolated from No. 1 glacier in Xinjiang Uygur Autonomous Region and Toumingmengke glacier in Gansu Province, PR China, respectively. They were Gram-stain-positive and rod-shaped micro-organisms. The optimum growth temperature of the two strains was 10-14 °C. Phylogenetic analysis showed that the two strains were related to members of the genus Cryobacterium. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain Sr36T and its close relatives Cryobacterium luteum Hh15T, Cryobacterium aureum Hh31T, Cryobacterium levicorallinum Hh34T and Cryobacterium flavum Hh8T were 81.16-87.24 and 28.0-32.5 %, respectively. The ANI and dDDH values between strain TMT4-23T and its close relative Cryobacterium psychrotolerans 0549T were 81.16 and 22.3 %. The polar lipids of strain Sr36T were diphosphatidylglycerol, phosphatidylglycerol, one unidentified glycolipid and three unidentified lipids. The polar lipids of strain TMT4-23T were diphosphatidylglycerol, phosphatidylglycerol, one unidentified glycolipid, one unidentified phospholipid and six unidentified lipids. The major fatty acids of strain Sr36T were anteiso-C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 1. The major fatty acids of strain TMT4-23T were anteiso-C15 : 0, anteiso-C17 : 0, iso-C16 : 0, anteiso-C15 : 1 and iso-C15 : 1. Both strains contained 2,4-diaminobutyric acid and their predominant menaquinone was MK-10. On the basis of the phenotypic, phylogenetic and genotypic data, two novel species Cryobacterium ruanii sp. nov. (type strain = Sr36T=CGMCC 1.9275T=NBRC 113797T) and Cryobacterium breve sp. nov. (type strain =TMT4-23T=CGMCC 1.9556T=NBRC 113800T) are proposed.


Is autism spectrum disorder an inflammation?

In our study, we aimed to evaluate inflammation by measuring serum Adenosine deaminase and dipeptidyl peptidase IV levels of individuals diagnosed with autism spectrum disorder and to determine its relationship with the Childhood Autism Rating Scale.
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37 children aged 2-12 years with a diagnosis of autism spectrum disorder and 27 children aged 2-12 years without any psychiatric disease were included in the study. Psychiatric examination and clinical evaluation according to DSM-5 diagnostic criteria for the diagnosis of autism spectrum disorder were performed on the children included in the study. The Childhood Autism Rating Scale was filled in by the researcher by interviewing the parents of the children diagnosed with autism spectrum disorder. 5 ml of venous blood samples were taken from the children in both groups in the morning on a full stomach.
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There was no statistically significant difference between the groups in terms of age, gender, and sociodemographic data. While serum adenosine deaminase levels were found to be statistically significantly higher in the group with autism spectrum disorder, serum dipeptidyl peptidase IV levels were found to be significantly lower. A positive correlation was found between dipeptidyl peptidase IV and Childhood Autism Rating Scale.
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We think that inflammation may play a role in the etiology of autism spectrum disorder due to altered adenosine deaminase and dipeptidyl peptidase IV levels in children with autism spectrum disorder.
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Attitude and Perception of Medical Students Towards Histology Subject at Wollo University, Ethiopia.
Students' perceptions and feedback have a significant impact on academic progress. To assess the attitude and perception of medical students towards histology subject at Wollo University, Northern Ethiopia. An institution-based cross-sectional study design was carried out in Wollo University from January, 2021 to February, 2021. A pre-tested and structured self-administered questionnaire was used for data collection. All opinions were rated using a positive-point Likert scale, which ranges from "strongly disagree" to "strongly agree." The data were entered and analyzed using SPSS version 20. A total of 184 students participated in this study, with a 100% response rate. Of the respondents, 84.24% of them were very much interested in histology subject. However, only 31 (16.85%) thought of histology as a career choice. The two major reason for not joining histology was less chance of promotion (65, 35.33%) and financial growth (41, 22.28%) followed by difficulty of the subject (23, 12.5%). Most of the respondents (155, 84.24%) agreed or strongly agreed that histology knowledge will help them a lot in their future clinical practice. Regarding different methods of teaching histology, our study reveals that there were 82.61% of participants who agreed with the proposed integration of histology and pathology. Moreover, system approach in teaching pathology with other disciplines was preferred by 70.1% and was comparable to several studies. Overall, the study findings indicate that medical students have a favorable attitude toward histology courses. But, they are unable to join the field due to the lower chance of promotion and financial growth. The curricular integration of histology and pathology in the first year needs to be continued, and much effort is needed to increase students' affinity for microscopic anatomy. This evidence serves as an additional motive for the development of histology courses focusing on practical application of knowledge in a clinically oriented setting.


Participation following knee replacement: the MOST cohort study.
Participation is an important, yet seldom studied, outcome after total knee replacement (TKR). The purpose of this study was to investigate the extent and predictors of participation and participation restriction among people after TKR. This study investigated the changes in pain, function, and participation scores (measured using a subscale of the Late-Life Function and Disability Instrument) from pre-TKR to ≥1 year post-TKR among a subsample of participants from the Multicenter Osteoarthritis Study (MOST) longitudinal cohort (MOST is funded by the National Institutes of Health). The proportions of individuals with participation restriction pre-TKR and ≥1 and ≥2 years post-TKR were calculated for all participants and for important demographic subgroups. The association between demographic and clinical factors and participation was estimated using linear regression. The association between demographic and clinical factors and participation restriction was estimated using logistic regression. There were 292 individuals with outcome data ≥1 year post-TKR. Of these, 218 (75%) had data pre-TKR and ≥1 year post-TKR and 160 (55%) had data ≥2 years post-TKR. There were mean improvements in pain, function, and participation at ≥1 and 2 years. However, approximately 30% of the study sample had participation restriction pre-TKR and post-TKR, and the proportion decreased significantly only for those <65 years old. Non-whites had a higher proportion of participation restriction than any other subgroup (41% ≥1 year, 48% ≥2 years). Female sex and non-white race were associated with a worse participation score, and several demographic and modifiable factors were associated with participation restriction following TKR. The time between pre-TKR and post-TKR assessment varied across study participants, and data were not available on their rehabilitation utilization. Although there was a mean increase in participation ≥1 year following TKR, participation restriction was common. The likelihood of low participation was increased among women, non-whites, and those with depressive symptoms, severe pain in either knee, or worse pre-TKR function.


The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators.
To investigate the association between control of intraocular pressure after surgical intervention for glaucoma and visual field deterioration. In the Advanced Glaucoma Intervention Study, eyes were randomly assigned to one of two sequences of glaucoma surgery, one beginning with argon laser trabeculoplasty and the other trabeculectomy. In the present article we examine the relationship between intraocular pressure and progression of visual field damage over 6 or more years of follow-up. In the first analysis, designated Predictive Analysis, we categorize 738 eyes into three groups based on intraocular pressure determinations over the first three 6-month follow-up visits. In the second analysis, designated Associative Analysis, we categorize 586 eyes into four groups based on the percent of 6-month visits over the first 6 follow-up years in which eyes presented with intraocular pressure less than 18 mm Hg. The outcome measure in both analyses is change from baseline in follow-up visual field defect score (range, 0 to 20 units). In the Predictive Analysis, eyes with early average intraocular pressure greater than 17.5 mm Hg had an estimated worsening during subsequent follow-up that was 1 unit of visual field defect score greater than eyes with average intraocular pressure less than 14 mm Hg (P =.002). This amount of worsening was greater at 7 years (1.89 units; P <.001) than at 2 years (0.64 units; P =.071). In the Associative Analysis, eyes with 100% of visits with intraocular pressure less than 18 mm Hg over 6 years had mean changes from baseline in visual field defect score close to zero during follow-up, whereas eyes with less than 50% of visits with intraocular pressure less than 18 mm Hg had an estimated worsening over follow-up of 0.63 units of visual field defect score (P =.083). This amount of worsening was greater at 7 years (1.93 units; P <.001) than at 2 years (0.25 units; P =.572). In both analyses low intraocular pressure is associated with reduced progression of visual field defect, supporting evidence from earlier studies of a protective role for low intraocular pressure in visual field deterioration.


Bioadhesive tablets containing cyclodextrin complex of itraconazole for the treatment of vaginal candidiasis.
Itraconazole (ITR) is commonly used in the treatment of Candida infections. It has a nephrotoxic effect and low bioavailability in patients who suffer from renal insufficiency, and its poor solubility in water makes ITR largely unavailable. Cyclodextrins (CyDs) are used to form inclusion complexes with drugs to improve their aqueous solubility and to reduce their side effects. In this study, ITR was complexed with γ-cyclodextrin (γ-CyD), hydroxypropyl-β-cyclodextrin (HP-β-CyD), methyl-β-cyclodextrin (Met-β-CyD) and sulphobutyl ether-β-cyclodextrin (SBE7-β-CyD) to increase its water solubility and to reduce the side effects of the drug without decreasing antifungal activity. Complex formation between ITR and CyDs was evaluated using SEM, (1)H NMR and XRD studies. The antifungal activity of the complexes was analyzed on Candida albicans strains, and the susceptibility of the strains was found to be higher for the ITR-SBE7-β-CyD complex than for the complexes that were prepared with other CyDs. Vaginal bioadhesive sustained release tablet formulations were developed using the ITR-SBE7-β-CyD inclusion complex to increase the residence time of ITR in the vagina, thereby boosting the efficacy of the treatment. The swelling, matrix erosion and bioadhesion properties of formulations and the drug release rate of these tablets were analyzed, and the most therapeutically effective vaginal formulation was determined.


68Ga-Based radiopharmaceuticals: production and application relationship.
The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.


Spontaneous pneumothorax, with or without pulmonary cysts, in patients with COVID-19 pneumonia.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) affects mainly the lungs causing pneumonia and complications like acute respiratory distress syndrome. Pneumothorax is a rare manifestation of the disease. This report is a description of a series of patients with COVID-19 and spontaneous pneumothorax, some of them with associated pulmonary cysts. Cases were collected retrospectively. We included clinical data from medical records and described radiologic findings. Patients that developed pneumothorax during mechanical ventilation were excluded. Ten cases were included in this report, nine of them were male. The median age of our series was 62 years (IQR = 57-68). The median days since the onset of symptoms until the development of pneumothorax was 27 (IQR = 17-31), most cases developed after the second week of the diagnosis of pneumonia. Two cases required invasive mechanical ventilation, but pneumothorax occurred after ventilator weaning. Three cases showed subpleural pulmonary cysts. Cysts and pneumothorax are rare manifestations of SARS-CoV-2 pneumonia with mechanisms not completely understood. This report highlights the role of CT scan in diagnosis of COVID-19 complications.


Extracellular matrix production by osteoblasts on bioactive substrata in vitro.
Some bone-substitute biomaterials have been classified as bioactive since they allow direct biological bonding to their surface in vivo. Using in vitro techniques, we have re-created the first stages of this biological bonding phenomenon and compared the initial, fibrillar, extracellular matrices produced by migrated primary osteoblast cell populations in contact with both dense and macroporous calcium phosphate substrata, apatite/bioactive glass composite (ABC) and 45S5 bioactive glass (BAG). The first formed fibrils in contact with these materials may be identified as collagen from their morphology as observed by scanning electron microscopy (SEM). However, the organization of this fibrillar material is significantly different on the five bioactive substrata examined. These in vitro findings may not only be related to both the surface morphology and surface chemistry of the substrata, but also correlated with their levels of in vivo bioactivity.


Propane oxidation and steam reforming over Pd/LaFe(0.8) Co(0.2) O3 catalyst: effects of the reactant composition and steam.
The effects of reactant composition and steam on propane combustion over Pd/LaFe(0.8) Co(0.2) O3 catalyst were investigated. Propane conversion and the oxidation state of palladium were strongly affected by the redox ratio of reactants. Higher propane conversion could be obtained under rich conditions and explained as a complex balance between oxidation and steam reforming. Water produced in the oxidation could promote the propane conversion by steam reforming. However, the presence excess steam would bring about inhibition.


Second cancer following lymphatic and hematopoietic cancers in Connecticut, 1935-82.
The risk of developing a second primary cancer was evaluated in approximately 19,000 persons with initial cancers of the lymphatic and hematopoietic system in Connecticut between 1935 and 1982. Significant excesses for all second cancers were observed among patients with leukemia (34%), Hodgkin's disease (70%), non-Hodgkin's lymphoma (25%), and multiple myeloma (24%). In general, the risk of second cancers was greater in males than in females, even for cohorts not showing an excess of surveillance-related prostate cancer. Among patients with leukemia, significant excesses of cancers of the lung, kidney/ureter, and prostate were noted; cutaneous melanoma was elevated only in males. These excesses did not persist in the small number of long-term survivors. Possible etiologic factors included tobacco smoking for lung and kidney cancers, medical surveillance artifact for prostate cancer, and immunosuppression for malignant melanoma and lung cancer. The large number and good prognoses of patients with chronic lymphocytic leukemia strongly influenced the pattern of second cancers when all leukemias were analyzed together; no evidence was found for an increased risk of second cancer in patients with acute lymphocytic leukemia. A disproportionate number of subsequent cancers, particularly those of the kidney and ureter, were diagnosed incidentally at autopsy. Patients with Hodgkin's disease displayed significant excesses of cancers of the buccal cavity and pharynx, lung, female breast, and thyroid. The latter 3 sites remained significantly elevated in long-term survivors (10 yr or more postdiagnosis), so that radiation therapy may have contributed to their development. Among persons with non-Hodgkin's lymphoma, cancers of the stomach, lung, brain, and connective tissue occurred excessively. The first 3 sites, plus cancers of the urinary bladder, remained elevated among long-term survivors. The brain cancer excess, not previously reported, may represent misclassification of central nervous system lymphoma. The risk of gastric cancer is reminiscent of similar findings in patients with both acquired and genetically determined immunodeficiency disorders. The alkylating agent, cyclophosphamide, used extensively in the treatment of non-Hodgkin's lymphoma, is known to cause bladder cancer in man.(ABSTRACT TRUNCATED AT 400 WORDS)


Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data.
The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies.