The presence of IFL3/4 rs12979860 C allele influences the in vitro IP-10 production by mononuclear cells from patients with systemic lupus erythematosus.
To explore whether the IFNL3/4 rs12979860 genotype may influence serum levels or production of interferon-inducible protein-10 (IP-10) by peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). Sixty-six patients with SLE and 22 healthy blood donors (controls) were included. The IFNL3/4 rs12979860 polymorphism was genotyped by real-time polymerase chain reaction. IP-10 levels in sera supernatants of IFNα stimulated peripheral blood mononuclear cells were measured by enzime-linked immunosorbent assay. Allelic frequencies were CC (29%), CT (52%) and TT (20%) in SLE, and CC (32%), CT (41%) and TT (27%) in healthy controls. Median serum IP-10 levels were higher in SLE patients than in controls (190.8 versus 118.1 pg/ml; p < 0.001), particularly in those with high disease activity (278.5 versus 177.2 pg/ml; p = 0.037). However, serum IP-10 levels were not influenced by IFNL3/4 genotypes. Higher IP-10 production by peripheral blood mononuclear cells was found in both SLE patients (median 519.3 versus 207.6 pg/ml; p = 0.012) and controls (median 454.0 versus 201.7 pg/ml; p = 0.034) carrying the IFNL3/4 C allele compared with carriers of the T allele. Although IFNL3/4 rs12979860 allele C does not appear to influence serum IP-10 levels in SLE, it plays an important role in the production of IP-10 by peripheral blood mononuclear cells after IFNα stimulation.


Prediction of high-risk patients by genome-wide copy number alterations from remaining cancer after neoadjuvant chemotherapy and surgery.
In breast cancer, changes of gene copy number were analyzed by cDNA microarray-based comparative genome hybridization using post-treatment archived tissues. Genomic DNA was extracted from 45 surgical specimens after chemotherapy. Informative genes were selected by t-test and were statistically validated by prediction analysis using support vector machine in R package. Fluorescence in situ hybridization and quantitative PCR were performed for validation. We developed three clinical models: comparing good vs. poor prognosis (I), comparing good vs. poor prognosis among poor responders (II) and among good responders (III). 158 gene set (I) differentiated high and low risk of relapse group with 92% accuracy. 51 gene set (II) differentiated good and poor prognosis subgroups among poor responders with 99.9% accuracy. 32 gene set (III) differentiated good and poor prognosis subgroups among good responders with 96% accuracy. This approach has potential applications in the identification of high risk of recurrence after neoadjuvant chemotherapy and surgery.


Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig.
To investigate the long-term effect of cigarette smoke on pulmonary structure and function, we exposed groups of guinea pigs to the smoke of 10 cigarettes each day, 5 days per week, for 1, 3, 6, and 12 months. We found that the guinea pigs developed progressive lung destruction (emphysema) and alterations in their pulmonary function tests similar to that seen in humans with cigarette smoke-induced chronic obstructive lung disease. This method of smoke-induced lung destruction should provide a good model for the study of the early changes of emphysema.


Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites.
The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly.


Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing-remitting multiple sclerosis.
The association of white matter (WM) lesions and grey matter (GM) atrophy is a feature in relapsing-remitting multiple sclerosis (RRMS). The spatiotemporal distribution pattern of WM lesions, their relations to regional GM changes and the underlying dynamics are unclear. Here we combined parametric and non-parametric voxel-based morphometry (VBM) to clarify these issues. MRI data from RRMS patients with progressive (PLV, n = 45) and non-progressive WM lesion volumes (NPLV, n = 44) followed up for 12 months were analysed. Cross-sectionally, the spatial WM lesion distribution was compared using lesion probability maps (LPMs). Longitudinally, WM lesions and GM volumes were studied using FSL-VBM and SPM5-VBM, respectively. WM lesions clustered around the lateral ventricles and in the centrum semiovale with a more widespread pattern in the PLV than in the NPLV group. The maximum local probabilities were similar in both groups and higher for T2 lesions (PLV: 27%, NPLV: 25%) than for T1 lesions (PLV: 15%, NPLV 14%). Significant WM lesion changes accompanied by cortical GM volume reductions occurred in the corpus callosum and optic radiations (P = 0.01 corrected), and more liberally tested (uncorrected P < 0.01) in the inferior fronto-occipital and longitudinal fasciculi, and corona radiata in the PLV group. Not any WM or GM changes were found in the NPLV group. In the PLV group, WM lesion distribution and development in fibres, was associated with regional GM volume loss. The different spatiotemporal distribution patterns of patients with progressive compared to patients with non-progressive WM lesions suggest differences in the dynamics of pathogenesis.


Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.
Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized.


Ultrafiltration in heart failure.
Fluid overload is a key pathophysiologic mechanism underlying both the acute decompensation episodes of heart failure and the progression of the syndrome. Moreover, it represents the most important factor responsible for the high readmission rates observed in these patients and is often associated with renal function worsening, which by itself increases mortality risk. In this clinical context, ultrafiltration (UF) has been proposed as an alternative to diuretics to obtain a quicker relief of pulmonary/systemic congestion. This review illustrates technical issues, mechanisms, efficacy, safety, costs, and indications of UF in heart failure. The available evidence does not support the widespread use of UF as a substitute for diuretic therapy. Owing to its operative characteristics, UF cannot be expected to directly influence serum electrolyte levels, azotemia, and acid-base balance, or to remove high-molecular-weight substances (eg, cytokines) in clinically relevant amounts. Ultrafiltration should be used neither as a quicker way to achieve a sort of mechanical diuresis nor as a remedy for an inadequately prescribed and administered diuretic therapy. Instead, it should be reserved to selected patients with advanced heart failure and true diuretic resistance, as part of a more complex strategy aiming at an adequate control of fluid retention.


Degradation of Crude 4-MCHM (4-Methylcyclohexanemethanol) in Sediments from Elk River, West Virginia.
In January 2014, approximately 37 800 L of crude 4-methylcyclohexanemethanol (crude MCHM) spilled into the Elk River, West Virginia. To understand the long-term fate of 4-MCHM, we conducted experiments under environmentally relevant conditions to assess the potential for the 2 primary compounds in crude MCHM (1) to undergo biodegradation and (2) for sediments to serve as a long-term source of 4-MCHM. We developed a solid phase microextraction (SPME) method to quantify the cis- and trans-isomers of 4-MCHM. Autoclaved Elk River sediment slurries sorbed 17.5% of cis-4-MCHM and 31% of trans-4-MCHM from water during the 2-week experiment. Sterilized, impacted, spill-site sediment released minor amounts of cis- and up to 35 μg/L of trans-4-MCHM into water, indicating 4-MCHM was present in sediment collected 10 months post spill. In anoxic microcosms, 300 μg/L cis- and 150 μg/L trans-4-MCHM degraded to nondetectable levels in 8-13 days in both impacted and background sediments. Under aerobic conditions, 4-MCHM isomers degraded to nondetectable levels within 4 days. Microbial communities at impacted sites differed in composition compared to background samples, but communities from both sites shifted in response to crude MCHM amendments. Our results indicate that 4-MCHM is readily biodegradable under environmentally relevant conditions.


Frequency of malignant solid tumors in children.
To find out the frequency of malignant solid tumors in children (< 15 years). All cases of pediatric malignant solid tumors which were diagnosed in the section of histopathology at the Aga Khan University Hospital, Karachi during the period of two years. These tumors were initially evaluated on H&E stained sections and special stains were also performed whenever indicated. The undifferentiated tumors were evaluated immunohistochemically by using a panel of antibodies on sections from routinely processed, formalin fixed, paraffin embedded tissue blocks. Of two hundred and fifty three (253) consecutive cases of paediatric malignant solid tumors, lymphoma (26.1%) was the most common tumor followed by central nervous system tumors (16.6%), osteosarcoma (7.5%), rhabdomyosarcoma (6.7%), neuroblastoma (5.1%), Wilm's tumor (5.1%), Ewing's sarcoma (4.7%), retinoblastoma (4.7%), germ cell tumor (4.4%) and primitive neuroectodermal tumor (4%) in order of frequency. In seven cases (2.8%), the nature of lesion remained undetermined even after immunohistochemical staining. Rest of malignant tumors (12.3%) included the rare entities like synovial sarcoma, nasopharyngeal carcinoma, leiomyosarcoma, malignant schwannoma and thyroid carcinoma, etc. Lymphoma was the most frequent Paediatric tumor. The frequency of childhood central nervous system tumors was quite high as compared to the other series from different regions of Pakistan.


TB treatment: as simple as DOT?
Treatment completion continues to be an unmet challenge in tuberculosis (TB) control worldwide. Since the introduction of DOTS by the World Health Organization in 1993, directly observed therapy (DOT) has been promoted as the centerpiece of the strategy. The results of three randomized controlled studies designed to evaluate the effects of DOT on treatment completion, and carried out in South Africa, Thailand and Pakistan, showed conflicting results. It is doubtful that any of the studies provided valid measures of the effectiveness of DOT. Each study operationalized DOT in ways that did not match the study definition and failed to account for additional study interventions in their analyses. Given the evidence, there is no one factor that is 'the' answer to the challenge of TB treatment completion.


Engagement during reading instruction for students who are deaf or hard of hearing in public schools.
An observational study of reading instruction was conducted in general education, resource, and self-contained classrooms, grades 1-4, in public schools. Participants included students who were deaf or hard of hearing and their reading teachers. Results indicated that time engaged in reading and/or academically responding varied significantly by grade level enrolled, reading curriculum grade level, and instructional setting, but not level of hearing loss or presence or absence of concomitant conditions. Students working with reading curriculum one grade level below spent significantly less time in reading instruction and reading than students working on grade level or two levels below. Students in general education settings spent significantly more time in reading instruction and reading silently than students in self-contained settings. The probability that students would engage in reading was significantly increased by several teacher and ecological conditions more likely to be observed in general education settings.


Vaccine entrapment in liposomes.
The use of liposomes as carriers of peptide, protein, and DNA vaccines requires simple, easy-to-scale-up technology capable of high-yield vaccine entrapment. Work from this laboratory has led to the development of techniques that can generate liposomes of various sizes, containing soluble antigens such as proteins and particulate antigens (e.g., killed or attenuated bacteria or viruses), as well as antigen-encoding DNA vaccines. Entrapment of vaccines is carried out by the dehydration-rehydration procedure which entails freeze-drying of a mixture of "empty" small unilamellar vesicles and free vaccines. On rehydration, the large multilamellar vesicles formed incorporate up to 90% or more of the vaccine used. When such liposomes are microfluidized in the presence of nonentrapped material, their size is reduced to about 100 nm in diameter, with much of the originally entrapped vaccine still associated with the vesicles. A similar technique applied for the entrapment of particulate antigens (e.g., Bacillus subtilis spores) consists of freeze-drying giant vesicles (4-5 microm in diameter) in the presence of spores. On rehydration and sucrose gradient fractionation of the suspension, up to 30% or more of the spores used are associated with generated giant liposomes of similar mean size.


Impact of the Internet on entomology teaching and research.
The Internet is affecting entomology teaching and research. Internet tools help students communicate and easily find and access information. Entomology instructors who adopt these tools may discover they are surprisingly time consuming to implement. Requiring students to use the Internet teaches them to glean from the glut of available information and to communicate electronically, both vital skills in today's workplace. The Internet helps meet the growing need for distance education by providing a medium that allows students to conveniently access course materials and to communicate with the instructor and other students. Researchers benefit from using the Internet for one-to-one and one-to-many communication and from access to large cooperative databases, for example, in molecular biology and systematics. Perhaps the greatest impact on research will be the migration to the Web of journals and other specialized research literature. This may permit free access and will change the content and format of journal articles. In the online version of this chapter, the hyperlinks in the Literature Cited section are active.


Implicit, predictive timing draws upon the same scalar representation of time as explicit timing.
It is not yet known whether the scalar properties of explicit timing are also displayed by more implicit, predictive forms of timing. We investigated whether performance in both explicit and predictive timing tasks conformed to the two psychophysical properties of scalar timing: the Psychophysical law and Weber's law. Our explicit temporal generalization task required overt estimation of the duration of an empty interval bounded by visual markers, whereas our temporal expectancy task presented visual stimuli at temporally predictable intervals, which facilitated motor preparation thus speeding target detection. The Psychophysical Law and Weber's Law were modeled, respectively, by (1) the functional dependence between mean subjective time and real time (2) the linearity of the relationship between timing variability and duration. Results showed that performance for predictive, as well as explicit, timing conformed to both psychophysical properties of interval timing. Both tasks showed the same linear relationship between subjective and real time, demonstrating that the same representational mechanism is engaged whether it is transferred into an overt estimate of duration or used to optimise sensorimotor behavior. Moreover, variability increased with increasing duration during both tasks, consistent with a scalar representation of time in both predictive and explicit timing. However, timing variability was greater during predictive timing, at least for durations greater than 200 msec, and ascribable to temporal, rather than non-temporal, mechanisms engaged by the task. These results suggest that although the same internal representation of time was used in both tasks, its external manifestation varied as a function of temporal task goals.


Characterization of Novel Cement-Based Carboxymethyl Chitosan/Amorphous Calcium Phosphate.
This study aimed to analyze, evaluate, and characterize novel cement-based carboxymethyl chitosan/amorphous calcium phosphate (CMC/ACP). The three cement groups studied were gypsum (Gyp), and CMC/ACP-gypsum cement-based 5% (5% CAG) and 10% (10% CAG). The groups were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), setting time, and scanning electron microscopy (SEM) data. The characterization results were analyzed qualitatively, but the data for setting time were analyzed using SPSS (p < 0.05). Data were statistically analyzed. One-way analysis of variance was used to compare numerical (parametric) data between more than two separate groups followed by post hoc Tukey. FTIR showed phosphate groups indicate the presence of calcium phosphate in the form of amorphous (ACP) in the CMC/ACP, CMC/ACP post-milled powder, and CMC/ACP cement-based (5% CAG and 10% CAG). XRD showed no difference in the diffraction spectra among the Gyp, 5% CAG, and 10% CAG groups. SEM images revealed that the CMC/ACP cement-based groups (5% CAG and 10% CAG) showed CMC/ACP cluster filled with hollow spaces between the gypsum crystals and aggregations surrounding the gypsum crystals. The CMC/ACP showed envelopes and attached to the crystalline structures of the gypsum. Setting times of 5% CAG and 10% CAG showed significant differences compared with Gyp (p < 0.05). The result of our study showed that CMC/ACP cement-based (5% CAG and 10% CAG) demonstrated amorphous characteristic, which can stabilize calcium ions and phosphate group (ACP). In addition, the modification of gypsum using CMC/ACP as cement-based extended the time of setting.


Influence of Severe Thoracic Trauma on Choosing the Correct Surgical Strategy in Patients with Polytrauma from Kosovo.
BACKGROUND Severe thoracic trauma (TT) has a significant impact on the selection of treatment strategy in patients with polytrauma. Our aim was to assess the impact of severe TT on choosing the optimal surgical procedure to decrease mortality. MATERIAL AND METHODS Overall, 66 patients with polytrauma and significant TT were analyzed. Demographic data, trauma history, admittance imaging, injury details, injury severity scores, conservative treatment, surgical treatment, days of hospital stay, and mortality data were gathered. Frequencies of thoracic surgical procedures and other treatments were collected and compared with those in the literature. RESULTS All patients had Abbreviated Injury Scale (AIS) scores of thorax >3. Injuries to extremities and/or the osseous pelvis accounted for 50% of injuries; 47.0% included the head and/or neck; 45.5% were external injuries; and 27.3% were abdominal injuries or included pelvic organs and/or lumbar spine. Mean prehospital time was 40.3 min. Mean time from trauma occurrence to tertiary treatment was 125 min. Blunt TT (BTT) was recorded in 59 patients (89.4%), and penetrant TT (PTT) was recorded in 7 patients (10.6%). Thoracic drainage, urgent thoracotomy and laparotomy were recorded procedures. The mean Injury Severity Score (ISS) of all patients was 31.17. Nine patients died (13.6%) and had BTT with a mean ISS of 48.44. The Trauma Injury Severity Score for BTT injuries was 77.08% and for PTT, 85.6%. CONCLUSIONS Factors that decreased hospital stay and mortality and increased survival included arriving in time after injury, aggressive reanimation/intensive care, and mandatory thoracic surgical procedure combined with laparotomy.


[Benzo(a)pyrene content in sausage products].
The content of the carcinogenic polycyclic aromatic hydrocarbon, benz(a)pyrene was determined in sausage products (boiled, raw- and semi-smoked) treated both with a smoke-air mixture and with the smoking liquid "Vakhtol". It was found that in raw- and semi-smoked sausage products treated with the smoke-air mixture, the level of benz(a)pyrene was 12-18 times greater than in boiled sausages exposed to the similar treatment. The use of the smoking liquid "Vakhtol" favours the manufacture of the produce not contaminated with carcinogenic substances. This forms basis for "Vakhtol" introduction into food industry.


Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection.
The complement cascade defines an important link between the innate and the specific immune system. Here we show that mice deficient for the third component of complement (C3-/- mice) are highly susceptible to primary infection with influenza virus. C3-/- mice showed delayed viral clearance and increased viral titers in lung, whereas mice deficient for complement receptors CR1 and CR2 (Cr2-/- mice) cleared the infection normally. Priming of T-helper cells and cytotoxic T cells (CTLs) in lung-draining lymph nodes was reduced, and the recruitment into the lung of virus-specific CD4+ and CD8+ effector T cells producing interferon-gamma was severely impaired in C3-/- but not in Cr2-/- mice. Consequently, T-helper cell-dependent IgG responses were reduced in C3-/- mice but remained intact in Cr2-/- mice. These results demonstrate that complement induces specific immunity by promoting T-cell responses.


Trends in reader access and article processing charges among urology journals: A systematic review.
This bibliometric study is designed to investigate the relations of urology journals with access types and article processing charges (APCs) to assess the changing paradigm in urology publishing. The three major databases: The Master Journal List directory by Clavirate Analytics, Scopus® and PubMed were queried for relevant journals in urology and subspecialties. Characterization of urology journals was undertaken, and citation metrics and APCs were compared across access types. A partial sampling was used to investigate the number of open access (OA) articles according to access types and correlations with both APCs and CiteScore. Seventy-seven journals were included into the study. Gold and diamond OA journals comprised 35.4% of urology journals in 2009 and were increased to 49.3% in 2022. No significant difference was found for change in the CiteScore of 2017 and 2021 between the access types, F (2,63) = 0.152, P = 0.859, η2 = 0.005. A moderate positive correlation was found between APCs and CiteScore for both hybrid (rs [27] =0.431, P < 0.0005) and gold OA (rs [27] =0.489, P = 0.007) journals. The authors need to pay $1175 more to publish their articles in OA model in hybrid journals. The number of articles published in OA model by hybrid journals were not correlated with APCs (rs = 0.332, P = 0.078) but correlated with CiteScore (rs = 0.393, P = 0.035). A paradigm shift in urology publishing toward OA model has been occurring. Authors choose prestige, OA model, rapid publication, and less rigorous peer-review to publish their articles. APCs bear only moderate correlation with the citation metrics of the urology journals.


Effects of the Wenyang Zhenshuai Granule on the Expression of LncRNA-MiR143HG/miR-143 Regulating ERK5 in H9C2 Cardiomyocytes.
Chronic heart failure (CHF) is a complex clinical syndrome caused by a variety of heart problems, with a high incidence. The 5-year survival rate of patients with clinical symptoms is similar to that of malignant tumors. Wenyang Zhenshuai granules are a safe and effective granule of traditional Chinese medicine components, including aconite, dried ginger, licorice, and red ginseng. In contemporary clinical applications, it is widely used in acute and chronic heart insufficiency, coronary heart disease, and arrhythmia. This research cultured H9C2 cardiomyocytes and divided them into the normal control group, LncRNA-MiR143HG overexpression group, LncRNA-MiR143HG silence group, Adriamycin (ADR) group, ADR + medicated serum group, ADR + LncRNA-MiR143HG overexpression + medicated serogroup, and ADR + LncRNA-MiR143HG silence + medicated serogroup. The cells of each group were treated differently, and the survival rate of each group of cells and the expression levels of LncRNA-MiR143HG/miR-143 and ERK5 were detected at the end of the experiment, and the expression of LncRNA-MiR143HG/miR-143 in H9C2 cardiomyocytes was regulated by Wenyang Zhenshuai granules' impact. The results of this study showed that, in the doxorubicin-induced H9C2 cardiomyocyte injury model, the expression of miR-143 was upregulated, and the expression of LncRNA-MiR143HG and ERK5 was significantly downregulated. Wenyang Zhenshuai granules can downregulate the expression of miR-143 to promote ERK5 protein expression and phosphorylation. The process is regulated by LncRNA-MiR143HG/miR-143, which may be one of its important mechanisms for the treatment of chronic heart failure.


Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: a systematic review.
Cancer cachexia is a devastating syndrome of advanced malignancy which negatively impacts on patients' morbidity, mortality and quality of life. Chronic inflammation is a key characteristic of cancer cachexia. Therefore, non-steroidal anti-inflammatory drugs (NSAIDs) may be able to break the cycle of cachexia. To systematically review the literature on the use of NSAIDs for the treatment of cachexia in advanced cancer patients. All titles retrieved through searching were downloaded to a reference management database, duplicates were removed and the remaining citations were checked for eligibility. Full copies of all eligible articles were obtained and reviewed. Electronic searches (from inception up to 09/2011) included CINAHL, MEDLINE, EMBASE, and Web of Science. Reference lists from reviewed articles, trial registers and abstracts from relevant conferences were searched. Eligibility criteria were (a) Randomised Controlled Trial; (b) participants were adults with cancer with weight loss or a clinical diagnosis of cachexia; (c) administration of oral NSAIDs. Four studies were included. These studies provided some evidence of positive therapeutic effect on quality of life, performance status, inflammatory markers, weight gain and survival, but there was insufficient evidence demonstrated for their widespread use in practice. Insufficient studies have been performed to allow a conclusion to be formed with regard to the effectiveness of NSAIDs in the treatment of cachexia in advanced cancer. Major challenges in this patient cohort include the lack of uniformity of inclusion criteria across studies and the frailty of the patients recruited.


Parallel adaptations to nectarivory in parrots, key innovations and the diversification of the Loriinae.
Specialization to nectarivory is associated with radiations within different bird groups, including parrots. One of them, the Australasian lories, were shown to be unexpectedly species rich. Their shift to nectarivory may have created an ecological opportunity promoting species proliferation. Several morphological specializations of the feeding tract to nectarivory have been described for parrots. However, they have never been assessed in a quantitative framework considering phylogenetic nonindependence. Using a phylogenetic comparative approach with broad taxon sampling and 15 continuous characters of the digestive tract, we demonstrate that nectarivorous parrots differ in several traits from the remaining parrots. These trait-changes indicate phenotype-environment correlations and parallel evolution, and may reflect adaptations to feed effectively on nectar. Moreover, the diet shift was associated with significant trait shifts at the base of the radiation of the lories, as shown by an alternative statistical approach. Their diet shift might be considered as an evolutionary key innovation which promoted significant non-adaptive lineage diversification through allopatric partitioning of the same new niche. The lack of increased rates of cladogenesis in other nectarivorous parrots indicates that evolutionary innovations need not be associated one-to-one with diversification events.


Signal intensity changes of the posterior elements of the lumbar spine in symptomatic adults.
Modic type 1 changes around the vertebral endplate of the lumbar spine are well known to indicate inflammation; however, the clinical significance of similar SCs of the posterior elements has not been elucidated. Six hundred ninety-eight MRIs of patients with complaints of low back/leg pain were retrospectively examined. Target SCs in this study were hypointensity on T1-WI and hyperintensity on T2-WI or short tau inversion recovery sequences showing the same signal patterns seen in Modic type 1 change of the lumbar posterior elements. We analyzed the (1) Prevalence, symptom, and age distribution of SCs, (2) Localization of SCs and their association with Modic type 1 changes, (3) Spinal level distribution of SCs, (4) Association between SCs and disc degeneration of the affected spinal level, and (5) Association between SCs and radiological changes (spondylolisthesis, scoliosis). (1) Among 698 adult patients, 36 (16 men, 20 women) exhibited SCs (5.2%). No SCs were identified in patients age <40 years. (2) Of the 36 SCs, 9 (25%) were localized at a single spinal level, while 27 (75%) were found at neighboring spinal levels across the facet joint. Thirteen SCs (36.1%) had continuity with Modic type 1 changes around the vertebral endplate, while 23 (63.9%) were localized to the posterior elements. (3) SCs were frequently identified in the lower lumbar spine below the L4 level. (4) More than 80% of the SCs involved disc degeneration. (5) Spondylolisthesis was associated with 93% of SCs in double-level, and scoliosis was associated with SCs in unilateral side. The prevalence of SCs in symptomatic adults was 5.2%. On the basis of observed disc degeneration, 75% of SCs were considered to indicate inflammation or bone marrow edema around the facet joint.


Characterization of two dominant alleles of the major rhodopsin-encoding gene ninaE in Drosophila.
In this study we investigated the biochemical and cell biologic characteristics of flies expressing two novel dominant alleles of the major rhodopsin encoding gene neither inactivation nor afterpotential E (ninaE) in a heterozygous background. Presence of the deep pseudopupil in flies was assayed 5 days post eclosion. For structural analysis, 1-μm-retinal cross sections were obtained from fixed and resin-embedded Drosophila heads. Confocal microscopy was performed on dissected retinas stained with antibodies specific for rhodopsin, NinaA, and F-actin. Rhodopsin levels were determined by western and slot blot analysis. Dominant rhodopsin mutants showed progressive age-dependent and light-independent loss of the deep pseudopupil, without any apparent retinal degeneration at the morphological level. Expression of mutant rhodopsin caused rhodopsin to mislocalize to the cell body and the endoplasmic reticulum compartment. Mutant rhodopsin also caused loss of solubility of wild-type rhodopsin and its accumulation presumably as a high molecular mass complex in the photoreceptor cell body. In heterozygous mutant flies, there is loss of wild-type rhodopsin immunoreactivity on a western assay but less reduction using slot blot analysis. This suggests that mutant rhodopsin is likely inducing the misfolding and insolubility of wild-type rhodopsin. Localization of rhodopsin revealed that in mutant flies, wild-type rhodopsin is mislocalized to the cell body and the endoplasmic reticulum.


[Scandinavian guidelines on the pre-hospital management of traumatic brain injury].
Head trauma causes the death of many young persons. The number of fatalities can be reduced through systematic management. Preventing secondary brain injury together with the fastest possible transport to a neurosurgical unit has been shown to be effective in reducing mortality and morbidity. Evidence-based guidelines already exist that focus on all steps in the management. This article, which was written by members of the Scandinavian Neurotrauma Committee, presents recommendations on the pre-hospital management of traumatic brain injury adapted to the infrastructure of Scandinavia.


[Life cycle of the trematode, Crowcrocaecum skrjabini (Iwanitzky, 1928) (Allocreadiata, Opecoelidae)].
Crowcrocaecum skrjabini has an intermediate and additional hosts. The mollusk Lithoglyphus naticoides serves as an intermediate host; the invasion extensity is 43.88% in summer and 28.57% -- in autumn and winter. In the experiment Gammarus (Rivulogammarus) balcanicus has turned to be an additional host and Carassius auratus givelia -- a definitive hot. The descriptions are given of cercaria (which belongs to a cotylocercal type), metacercaria and marita, reared in the experiment.


Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy.
Pylorus-preserving pancreaticoduodenectomy is associated with a high incidence of delayed gastric emptying. The aim of this study was to determine the incidence and risk factors for delayed gastric emptying after this procedure. This retrospective study included 63 consecutive patients who received pylorus-preserving pancreaticoduodenectomy from July 1993 to December 2002. The patients were divided into 2 groups based on the presence of delayed gastric emptying. Preoperative indices, postoperative morbidity, nasogastric intubation, and hospital stay were compared. The risk factors for delayed gastric emptying were analyzed. The postoperative incidence of delayed gastric emptying was 44% (28/63 patients). Multivariate analysis revealed that no preoperative biliary drainage, no cholestatic change in the liver and blood loss > 400 mL were significant risk factors for delayed gastric emptying. Pylorus-preserving pancreaticoduodenectomy is a safe procedure with a high incidence of delayed gastric emptying. Delicate surgical dissection to decrease blood loss and the extent of perigastric inflammation may be the key factor to prevent delayed gastric emptying.


Thermal niches of specialized gut symbionts: the case of social bees.
Responses to climate change are particularly complicated in species that engage in symbioses, as the niche of one partner may be modified by that of the other. We explored thermal traits in gut symbionts of honeybees and bumblebees, which are vulnerable to rising temperatures. In vitro assays of symbiont strains isolated from 16 host species revealed variation in thermal niches. Strains from bumblebees tended to be less heat-tolerant than those from honeybees, possibly due to bumblebees maintaining cooler nests or inhabiting cooler climates. Overall, however, bee symbionts grew at temperatures up to 44°C and withstood temperatures up to 52°C, at or above the upper thermal limits of their hosts. While heat-tolerant, most strains of the symbiont Snodgrassella grew relatively slowly below 35°C, perhaps because of adaptation to the elevated body temperatures that bees maintain through thermoregulation. In a gnotobiotic bumblebee experiment, Snodgrassella was unable to consistently colonize bees reared at 29°C under conditions that limit thermoregulation. Thus, host thermoregulatory behaviour appears important in creating a warm microenvironment for symbiont establishment. Bee-microbiome-temperature interactions could affect host health and pollination services, and inform research on the thermal biology of other specialized gut symbionts.


Comparative anticancer effects of flavonoids and diazepam in cultured cancer cells.
This study examined the comparative anticancer effects of flavonoids and diazepam in the cultured cancer cells. In the SNU-C4 colorectal and MDA-MB-231 breast adenocarcinoma cells, apigenin and fisetin, flavonoids, and diazepam inhibited cancer cell survival concentration and incubation-time dependently. Diazepam consistently inhibited FAS activity, a known anticancer mechanism of flavonoids, in a concentration dependent manner. Unlike diazepam, in highly aggressive breast MDA-MB-231 cells known to have a nuclear/perinuclear located PBR, PK11195, a specific PBR ligand enhanced the proliferation of cells, and the proliferative effect of PK11195 was reversed by an addition of lovastatin, a HMG-CoA reductase inhibitor. Diazepam- and flavonoids-induced cytotoxic activity in both cancer cell lines was not reduced by the addition of 5-fluorouracil (5-FU), a chemotherapeutic agent. Like flavonoids, diazepam inhibited the release of vascular endothelial growth factor (VEGF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) into supernatants of cultured in the SNU-C4 and MDA-MB-231 cells. In conclusion, this study provided in vitro information on the safe use of sedative in oncologic patients.


A method for biomolecular structural recognition and docking allowing conformational flexibility.
In this work, we present an algorithm developed to handle biomolecular structural recognition problems, as part of an interdisciplinary research endeavor of the Computer Vision and Molecular Biology fields. A key problem in rational drug design and in biomolecular structural recognition is the generation of binding modes between two molecules, also known as molecular docking. Geometrical fitness is a necessary condition for molecular interaction. Hence, docking a ligand (e.g., a drug molecule or a protein molecule), to a protein receptor (e.g., enzyme), involves recognition of molecular surfaces. Conformational transitions by "hinge-bending" involves rotational movements of relatively rigid parts with respect to each other. The generation of docked binding modes between two associating molecules depends on their three dimensional structures (3-D) and their conformational flexibility. In comparison to the particular case of rigid-body docking, the computational difficulty grows considerably when taking into account the additional degrees of freedom intrinsic to the flexible molecular docking problem. Previous docking techniques have enabled hinge movements only within small ligands. Partial flexibility in the receptor molecule is enabled by a few techniques. Hinge-bending motions of protein receptors domains are not addressed by these methods, although these types of transitions are significant, e.g., in enzymes activity. Our approach allows hinge induced motions to exist in either the receptor or the ligand molecules of diverse sizes. We allow domains/subdomains/group of atoms movements in either of the associating molecules. We achieve this by adapting a technique developed in Computer Vision and Robotics for the efficient recognition of partially occluded articulated objects. These types of objects consist of rigid parts which are connected by rotary joints (hinges). Our method is based on an extension and generalization of the Hough transform and the Geometric Hashing paradigms for rigid object recognition. We show experimental results obtained by the successful application of the algorithm to cases of bound and unbound molecular complexes, yielding fast matching times. While the "correct" molecular conformations of the known complexes are obtained with small RMS distances, additional, predictive good-fitting binding modes are generated as well. We conclude by discussing the algorithm's implications and extensions, as well as its application to investigations of protein structures in Molecular Biology and recognition problems in Computer Vision.


Objectively Measured Physical Activity Reduces the Risk of Mortality among Brazilian Older Adults.
Use of objectively measured physical activity (PA) in older adults to assess relationship between PA and risk of all-causes mortality is scarce. This study evaluated the associations of PA based on accelerometry and a questionnaire with the risk of mortality among older adults from a city in Southern Brazil. A cohort study. Urban area of Pelotas, Southern Brazil. A representative sample of older adults (≥60 y) from Pelotas, enrolled in 2014. Overall physical activity (mg), light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were estimated by raw accelerometer data. The International Physical Activity Questionnaire estimated leisure time and commuting PA. Hazard ratios (excluding deaths in the first 6 mo) stratified by sex were estimated by Cox regression analysis considering adjustment for confounders. From the 1451 older adults interviewed in 2014, 145 died (10%) after a follow-up of an average 2.6 years. Men and women in the highest tertile of overall PA had on average a 77% and 92% lower risk of mortality than their less active counterparts (95% confidence interval [CI] = .06-.84 and 95% CI = .01-.65, respectively). The highest tertile of LPA was also related to a lower risk of mortality in individuals of both sexes (74% and 91% lower risk among men and women, respectively). MVPA statistically reduced the risk of mortality only among women (hazard ratio [HR] = .30 and HR = .07 in the second and third tertiles). Self-reported leisure-time PA was statistically associated with a lower risk of mortality only among men. Women in the highest tertiles of commuting PA showed a lower risk of mortality than those in the reference group. Accelerometry-based PA was associated with a lower risk of mortality among Brazilian older adults. Older individuals should practice any type of PA. J Am Geriatr Soc 68:137-146, 2019.


Racial differences in adherence to cardiac medications.
To determine whether there are racial differences in adherence to cardiac medications. Retrospective analysis. African-American and white male veterans aged 45 years or older who had received any of four groups of drugs: angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers (BBs), calcium channel blockers (CCBs,) or HMG CoA (hydroxymethyl glutaryl coenzyme A) reductase inhibitors (statins). Administrative records were used to identify eligible veterans and their demographic characteristics, medical diagnoses, and medication use. We used a standard measure of adherence to medications based on whether the veteran obtained enough drug to take it as prescribed on 80% of the days. We identified 833 eligible African-American and 4436 eligible white veterans. In univariable analysis, African Americans were less likely to be adherent to medications than whites for ACEIs (81.4% versus 87.6%, P = 0.004), CCBs (75.3% versus 81.7%, P = 0.003), and statins (59.9% versus 74.1%, P < 0.001) but not BBs (84.8% versus 83.5%, P = 0.6). In multivariable analysis, racial differences in adherence to medications were found primarily among veterans younger than 55 years old. Younger African Americans were less adherent to medications than whites in a setting where financial barriers are minimized. Although the reason for this finding is unclear, it may contribute to high cardiovascular morbidity among African Americans.


Evidence for a glutamatergic neural pathway in the myenteric plexus.
The objective of this study was to determine whether L-glutamate (L-Glu) may serve as a neurotransmitter candidate in the guinea pig myenteric plexus. We observed that [3H]Glu and gamma-[3H]aminobutyric acid were synthesized from [3H]glutamine and released from neurons of the myenteric plexus during K+ and 1,1-dimethyl-4-phenylpiperazinium-evoked depolarization in a concentration-dependent manner. Muscle tension studies performed on ileal longitudinal muscle-myenteric plexus (LM-MP) preparations revealed that L-Glu [mean effective dose (ED50) 2.5 x 10(-5) M] produced concentration-dependent contractions, which were unaffected by hexamethonium but abolished by tetrodotoxin, atropine, and magnesium, suggesting that L-Glu acts via N-methyl-D-aspartate (NMDA)-type receptors that stimulate a cholinergic neural pathway unaffected by ganglionic blockade. In addition, L-Glu (ED50 4 x 10(-5) M) and NMDA (ED50 2 x 10(-4) M) stimulated concentration-dependent release of [3H]acetylcholine (ACh) from LM-MP sections, which was inhibited by tetrodotoxin, magnesium, and the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (AP-5). L-Glu-mediated release of [3H]ACh was enhanced by theophylline (10-6 M) and 3-isobutyl-1-methylxanthine (1 mM) and was significantly reduced by the adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (10(-4) M) and somatostatin-14 (10(-6) M), which inhibits adenosine 3',5'-cyclic monophosphate (cAMP)-dependent cholinergic transmission in the myenteric plexus. These studies suggest that L-Glu may serve as an excitatory neurotransmitter in the myenteric plexus via its action on NMDA-type receptors, which are coupled to cAMP-dependent release of ACh.


Effect of cigarette smoke on the permeability and IL-1beta and sICAM-1 release from cultured human bronchial epithelial cells of never-smokers, smokers, and patients with chronic obstructive pulmonary disease.
Although cigarette smoking is of paramount importance in the development of chronic obstructive pulmonary disease (COPD), only a small proportion of smokers develop the disease. We tested the hypothesis that the response of the bronchial epithelium to cigarette smoke (CS) differs in patients with COPD. Such a difference might explain in part why only some cigarette smokers develop the disease. We established primary explant cultures of human bronchial epithelial cells (HBEC) from biopsy material obtained from never-smokers who had normal pulmonary function, smokers with normal pulmonary function, and smokers with COPD, and exposed these for 20 min to CS or air. Measurements were subsequently made over a period of 24 h of transepithelial permeability and release of interleukin (IL)-1beta and soluble intercellular adhesion molecule-1 (sICAM-1). In addition, intracellular reduced glutathione (GSH) levels were measured after 24 h incubation. Exposure to CS increased the permeability of these cultures in all study groups, but the most marked effect was observed in cultures from patients with COPD (mean increase, 85.5%). The smallest CS-induced increase in the permeability was observed in HBEC cultured from smokers with normal pulmonary function (mean, 25.0%), and this was significantly lower than that of HBEC from never-smokers (mean, 53.4%) (P<0.001). Compared with exposure to air, exposure to CS led to a significantly increased release of these mediators from cultures of the never-smoker group (mean 250.0% increase in IL-1beta and mean 175.3% increase in sICAM-1 24 h after exposure) and COPD group (mean 383.3% increase in IL-1beta and mean 97.4% increase in sICAM-1 24 h after exposure). In contrast, CS exposure did not influence significantly the release of either mediator from the cells of smokers with normal pulmonary function. Levels of intracellular GSH were significantly higher in cultures of HBEC derived from smokers, both those with normal pulmonary function and those with COPD, compared with cultures from healthy never-smokers. Exposure to CS significantly decreased the concentration of intracellular GSH in all cultures. However, the fall in intracellular GSH was significantly greater in cells from patients with COPD (mean 72.9% decrease) than in cells from never-smokers (mean 61.4% decrease; P = 0.048) or smokers with normal pulmonary function (mean 43.9% decrease; P = 0.02). These results suggest that whereas smokers with or without COPD demonstrate increased levels of GSH within bronchial epithelial cell cultures, those with COPD have a greater susceptibility to the effects of CS in reducing GSH levels and causing increased permeability and release of proinflammatory mediators such as IL-1beta and sICAM-1.


[Circulating opioid peptides in chronic renal failure: acute effect of dialysis treatment].
In 14 patients affected by chronic renal failure (7 males and 7 females) it has been evaluated the secretion of beta LPH, beta EP, ACTH and Cortisol in basal conditions and immediately after a dialytic treatment. For beta LPH and beta EP measurements on each thawed plasma a silic acid extraction and a successive peptides separation by a Sephadex G-75 column chromatography preceeded the two specific RIAs. Basal beta LPH plasma levels resulted significantly higher than in normal controls, while that of beta EP, ACTH and Cortisol were in the normal range. The dialytic treatment was able to increase ACTH and Cortisol plasma levels, without to modified beta LPH and beta EP plasma levels.


Managing older people with atrial fibrillation and preventing stroke: a review of anticoagulation approaches.
Oral anticoagulants (OACs) are the cornerstone of stroke prevention in atrial fibrillation (AF), but prescribing decisions in older people are complicated. Clinicians must assess the net clinical benefit of OAC in the context of multiple chronic conditions, polypharmacy, frailty and life expectancy. The under-representation of high-risk, older adult sub-populations in clinical trials presents the challenge of choosing the right OAC, where a 'one-size-fits-all' approach cannot be taken. This review discusses OAC approaches for stroke prevention in older people with AF and presents a prescribing aid to support clinicians' decision-making. High-risk older adults with multiple chronic conditions, specifically chronic kidney disease, dementia/cognitive impairment, previous stroke/transient ischemic attack or intracranial hemorrhage, polypharmacy, frailty, low body weight, high falls risk, and those aged ≥75 years are considered. Non-vitamin K antagonist OACs are the preferred first-line OAC in older adults with AF, including high-risk subpopulations, after individual assessment of stroke and bleeding risk, except those with mechanical heart valves and moderate-to-severe mitral stenosis. Head-to-head comparisons of NOACs are not available, therefore the choice of drug (and dose) should be based on an individual's risk (stroke and bleeding) and incorporate their treatment preferences. Treatment decisions must be person-centered and principles of shared decision-making applied.


[Immunostimulating and anticoagulating activity of fucoidan from brown algae Fucus evanescens of Okhotskoe sea].
Fucoidan--nontoxic sulfated polysaccharide was isolated from brown algae Fucus evanescens in Okhotskoe Sea. Chemical analysis of the compound was performed, it was shown that fucoidan is freely soluble in water and acid solutions. Immunotropic and anticoagulating properties of the compound were evaluated in comparison with heparin. It was demonstrated that fucoidan in wide range of doses stimulated phagocytic and bactericidic activity at leucocytes of mice peritoneal exudate. Heparin on the contrary demonstrated depressive effect on these functions at high dose. It was shown that fucoidan has dose-dependent anticoagulating activity in vitro and in vivo comparable with heparin activity. The results of investigation demonstrated possibility of fucoidan application as immunomodulating and anticoagulating agent of plant origin.


The effect of hearing aid technologies on listening in an automobile.
Communication while traveling in an automobile often is very difficult for hearing aid users. This is because the automobile/road noise level is usually high, and listeners/drivers often do not have access to visual cues. Since the talker of interest usually is not located in front of the listener/driver, conventional directional processing that places the directivity beam toward the listener's front may not be helpful and, in fact, could have a negative impact on speech recognition (when compared to omnidirectional processing). Recently, technologies have become available in commercial hearing aids that are designed to improve speech recognition and/or listening effort in noisy conditions where talkers are located behind or beside the listener. These technologies include (1) a directional microphone system that uses a backward-facing directivity pattern (Back-DIR processing), (2) a technology that transmits audio signals from the ear with the better signal-to-noise ratio (SNR) to the ear with the poorer SNR (Side-Transmission processing), and (3) a signal processing scheme that suppresses the noise at the ear with the poorer SNR (Side-Suppression processing). The purpose of the current study was to determine the effect of (1) conventional directional microphones and (2) newer signal processing schemes (Back-DIR, Side-Transmission, and Side-Suppression) on listener's speech recognition performance and preference for communication in a traveling automobile. A single-blinded, repeated-measures design was used. Twenty-five adults with bilateral symmetrical sensorineural hearing loss aged 44 through 84 yr participated in the study. The automobile/road noise and sentences of the Connected Speech Test (CST) were recorded through hearing aids in a standard van moving at a speed of 70 mph on a paved highway. The hearing aids were programmed to omnidirectional microphone, conventional adaptive directional microphone, and the three newer schemes. CST sentences were presented from the side and back of the hearing aids, which were placed on the ears of a manikin. The recorded stimuli were presented to listeners via earphones in a sound-treated booth to assess speech recognition performance and preference with each programmed condition. Compared to omnidirectional microphones, conventional adaptive directional processing had a detrimental effect on speech recognition when speech was presented from the back or side of the listener. Back-DIR and Side-Transmission processing improved speech recognition performance (relative to both omnidirectional and adaptive directional processing) when speech was from the back and side, respectively. The performance with Side-Suppression processing was better than with adaptive directional processing when speech was from the side. The participants' preferences for a given processing scheme were generally consistent with speech recognition results. The finding that performance with adaptive directional processing was poorer than with omnidirectional microphones demonstrates the importance of selecting the correct microphone technology for different listening situations. The results also suggest the feasibility of using hearing aid technologies to provide a better listening experience for hearing aid users in automobiles.


The Correlation Between Detection Value of Distortion-Product Otoacoustic Emissions and the Early Prognosis of Sudden Sensorineural Hearing Loss.
To explore the correlation between the detection value of distortion-product otoacoustic emissions and the early prognosis of sudden sensorineural hearing loss. Seventy-eight patients with first-onset sudden sensorineural hearing loss (all frequencies) from April 2018 to July 2019 were included in this study. Distortion-product otoacoustic emissions and pure-tone audiometry tests were performed at days 0, 3, and 6 of admission. Repeated measures analysis of variance was performed to evaluate the changes in the signal-to-noise ratio for different distortion-product otoacoustic emissions frequencies over time and the interaction of grouping factors and time factors. The distortion-product otoacoustic emissions evocation rate in the 4 groups was significantly different starting at day 3 of treatment. It was higher in the cured (35.3%) and obviously effective (20.0%) groups than in the other 2 groups (0%, 0%). At the 6 f2 frequencies of 1105 Hz, 1560 Hz, 2211 Hz, 3125 Hz, 4416 Hz, and 8837 Hz, the signal-to-noise ratio was different among the groups (P < .05) and was notably higher in the cured group. The analysis of the signal-to-noise ratio change before and after treatment at the intermediate f2 frequencies of 1105 Hz, 1560 Hz, and 2211 Hz in all patients indicated a linear correlation between the signal-to-noise ratio change and the pure-tone hearing threshold change, with a correlation coefficient of 0.481. Distortion-product otoacoustic emissions evocation in the early stage (within 3 days of treatment) or the signal-to-noise ratio trend over time at intermediate frequencies may predict the prognosis of sudden sensorineural hearing loss.


Other forms of treatment for anxiety.
Other methods for the treatment of anxiety are discussed--psychotherapeutic, behavioural and pharmacological. Among the psychotherapeutic methods are psychoanalytical and supportive therapy, psycho-education, cognitive therapy and paradoxical intention. Behaviour- modifying methods include systematic desensitization, flooding, thought blocking and biofeedback. However, none of these methods in isolation seems to be effective in the treatment of anxiety disorders. Drugs such as beta-blockers, monoamine oxidase inhibitors, tricyclic antidepressants, antipsychotic drugs and buspirone are reviewed. Buspirone seems to be as effective as the benzodiazepines in the alleviation of anxiety and may have less untoward effects. A few new drugs that are still being evaluated--fenobam, suriclone, synaptamine, fominoben and tracazolate--are mentioned.


Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain.
Toxoplasma gondii is an obligate intracellular protozoan parasite that causes various diseases, including lymphadenitis, congenital infection of fetuses and life-threatening toxoplasmic encephalitis in immunocompromised individuals. Interferon-gamma (IFN-γ)-mediated immune responses are essential for controlling tachyzoite proliferation during both acute acquired infection and reactivation of infection in the brain. Both CD4+ and CD8+ T cells produce this cytokine in response to infection, although the latter has more potent protective activity. IFN-γ can activate microglia, astrocytes and macrophages, and these activated cells control the proliferation of tachyzoites using different molecules, depending on cell type and host species. IFN-γ also has a crucial role in the recruitment of T cells into the brain after infection by inducing expression of the adhesion molecule VCAM-1 on cerebrovascular endothelial cells, and chemokines such as CXCL9, CXCL10 and CCL5. A recent study showed that CD8+ T cells are able to remove T. gondii cysts, which represent the stage of the parasite in chronic infection, from the brain through their perforin-mediated activity. Thus, the resistance to cerebral infection with T. gondii requires a coordinated network using both IFN-γ- and perforin-mediated immune responses. Elucidating how these two protective mechanisms function and collaborate in the brain against T. gondii will be crucial in developing a new method to prevent and eradicate this parasitic infection.


Direct association of Csk homologous kinase (CHK) with the diphosphorylated site Tyr568/570 of the activated c-KIT in megakaryocytes.
The Csk homologous kinase (CHK), formerly MATK, has previously been shown to bind to activated c-KIT. In this report, we characterize the binding of SH2(CHK) to specific phosphotyrosine sites on the c-KIT protein sequence. Phosphopeptide inhibition of the in vitro interaction of SH2(CHK)-glutathione S-transferase fusion protein/c-KIT from SCF/KL-treated Mo7e megakaryocytic cells indicated that two sites on c-KIT were able to bind SH2(CHK). These sites were the Tyr568/570 diphosphorylated sequence and the monophosphorylated Tyr721 sequence. To confirm this, we precipitated native CHK from cellular extracts using phosphorylated peptides linked to Affi-Gel 15. In addition, purified SH2(CHK)-glutathione S-transferase fusion protein was precipitated with the same peptide beads. All of the peptide bead-binding studies were consistent with the direct binding of SH2(CHK) to phosphorylated Tyr568/570 and Tyr721 sites. Binding of FYN and SHC to the diphosphorylated Tyr568/570 site was observed, while binding of Csk to this site was not observed. The SH2(CHK) binding to the two sites is direct and not through phosphorylated intermediates such as FYN or SHC. Site-directed mutagenesis of the full-length c-KIT cDNA followed by transient transfection indicated that only the Tyr568/570, and not the Tyr721, is able to bind SH2(CHK). This indicates that CHK binds to the same site on c-KIT to which FYN binds, possibly bringing the two into proximity on associated c-KIT subunits and leading to the down-regulation of FYN by CHK.


A new method for the construction of coarse-grained models of large biomolecules from low-resolution cryo-electron microscopy data.
The rapid development of cryo-electron microscopy (cryo-EM) has led to the generation of significant low-resolution electron density data of biomolecules. However, the atomistic details of huge biomolecules usually cannot be obtained because it is very difficult to construct all-atom models for MD simulations. Thus, it is still a challenge to make use of the rich low-resolution cryo-EM data for computer simulation and functional study. In this study, we proposed a new method called Convolutional and K-means Coarse-Graining (CK-CG) for the efficient coarse-graining of large biological systems. Using the CK-CG method, we could directly map the cryo-EM data into coarse-grained (CG) beads. Furthermore, the CG beads were parameterized with an empirical harmonic potential to construct a new CG model. We subjected the CK-CG models of the fibrillar protein assemblies F-actin and collagen to external forces in pulling dynamic simulations to assess their mechanical response. The agreement between the estimated tensile stiffness between CG models and experiments demonstrates the validity of the CK-CG method. Thus, our method provides a practical strategy for the direct construction of a structural model from low-resolution data for biological function studies.


"OPTImAL": an ontology for patient adherence modeling in physical activity domain.
Maintaining physical fitness is a crucial component of the therapeutic process for patients with cardiovascular disease (CVD). Despite the known importance of being physically active, patient adherence to exercise, both in daily life and during cardiac rehabilitation (CR), is low. Patient adherence is frequently composed of numerous determinants associated with different patient aspects (e.g., psychological, clinical, etc.). Understanding the influence of such determinants is a central component of developing personalized interventions to improve or maintain patient adherence. Medical research produced evidence regarding factors affecting patients' adherence to physical activity regimen. However, the heterogeneity of the available data is a significant challenge for knowledge reusability. Ontologies constitute one of the methods applied for efficient knowledge sharing and reuse. In this paper, we are proposing an ontology called OPTImAL, focusing on CVD patient adherence to physical activity and exercise training. OPTImAL was developed following the Ontology Development 101 methodology and refined based on the NeOn framework. First, we defined the ontology specification (i.e., purpose, scope, target users, etc.). Then, we elicited domain knowledge based on the published studies. Further, the model was conceptualized, formalized and implemented, while the developed ontology was validated for its consistency. An independent cardiologist and three CR trainers evaluated the ontology for its appropriateness and usefulness. We developed a formal model that includes 142 classes, ten object properties, and 371 individuals, that describes the relations of different factors of CVD patient profile to adherence and adherence quality, as well as the associated types and dimensions of physical activity and exercise. 2637 logical axioms were constructed to comprise the overall concepts that the ontology defines. The ontology was successfully validated for its consistency and preliminary evaluated for its appropriateness and usefulness in medical practice. OPTImAL describes relations of 320 factors originated from 60 multidimensional aspects (e.g., social, clinical, psychological, etc.) affecting CVD patient adherence to physical activity and exercise. The formal model is evidence-based and can serve as a knowledge tool in the practice of cardiac rehabilitation experts, supporting the process of activity regimen recommendation for better patient adherence.


Radiographically occult, diffuse intrasinusoidal hepatic metastases from primary breast carcinomas: a clinicopathologic study of 3 autopsy cases.
Liver metastases usually present as radiographically detectable mass lesions that do not significantly compromise liver function. Rarely, metastatic carcinoma can diffusely infiltrate hepatic sinusoids, a pattern of metastasis that may be missed on imaging studies, and can result in liver failure. To describe the clinicopathologic features of 3 cases of diffuse intrasinusoidal hepatic metastases from primary breast carcinomas identified at autopsy. Clinical histories and radiographic, macroscopic, and microscopic appearances of the livers were compared. Sampled liver tissue was stained with antibodies to E-cadherin, smooth muscle actin, and CD44. Two of 3 cases had a history of infiltrating ductal carcinoma of the breast and presented with new-onset liver failure, but no hepatic metastases were identified on radiologic imaging. An additional case had no history of carcinoma, presented with a severe thrombocytopenic thrombotic purpura-like syndrome, and metastatic carcinoma of the breast was diagnosed only at autopsy. The livers in all 3 cases at autopsy were homogeneous, firm, and tan-yellow, and contained no large metastatic lesions. Microscopically, poorly differentiated carcinoma diffusely infiltrated hepatic sinusoids. Antibodies to smooth muscle actin stained activated hepatic stellate cells lining involved sinusoids. Cell surface adhesion molecules, E-cadherin or CD44, were not detected in any hepatic metastases. Diffuse intrasinusoidal hepatic metastases of breast carcinoma can occupy a large percentage of the hepatic volume, yet remain occult both radiographically and macroscopically. This type of metastatic spread can present as cryptogenic liver failure. The 3 cases we studied were associated with an absence of E-cadherin and CD44 expression.


A Decision-Tree Approach to Assist in Forecasting the Outcomes of the Neonatal Brain Injury.
Neonatal brain injury or neonatal encephalopathy (NE) is a significant morbidity and mortality factor in preterm and full-term newborns. NE has an incidence in the range of 2.5 to 3.5 per 1000 live births carrying a considerable burden for neurological outcomes such as epilepsy, cerebral palsy, cognitive impairments, and hydrocephaly. Many scoring systems based on different risk factor combinations in regression models have been proposed to predict abnormal outcomes. Birthweight, gestational age, Apgar scores, pH, ultrasound and MRI biomarkers, seizures onset, EEG pattern, and seizure duration were the most referred predictors in the literature. Our study proposes a decision-tree approach based on clinical risk factors for abnormal outcomes in newborns with the neurological syndrome to assist in neonatal encephalopathy prognosis as a complementary tool to the acknowledged scoring systems. We retrospectively studied 188 newborns with associated encephalopathy and seizures in the perinatal period. Etiology and abnormal outcomes were assessed through correlations with the risk factors. We computed mean, median, odds ratios values for birth weight, gestational age, 1-min Apgar Score, 5-min Apgar score, seizures onset, and seizures duration monitoring, applying standard statistical methods first. Subsequently, CART (classification and regression trees) and cluster analysis were employed, further adjusting the medians. Out of 188 cases, 84 were associated to abnormal outcomes. The hierarchy on etiology frequencies was dominated by cerebrovascular impairments, metabolic anomalies, and infections. Both preterms and full-terms at risk were bundled in specific categories defined as high-risk 75-100%, intermediate risk 52.9%, and low risk 0-25% after CART algorithm implementation. Cluster analysis illustrated the median values, profiling at a glance the preterm model in high-risk groups and a full-term model in the inter-mediate-risk category. Our study illustrates that, in addition to standard statistics methodologies, decision-tree approaches could provide a first-step tool for the prognosis of the abnormal outcome in newborns with encephalopathy.


A yeast transcriptional stimulatory protein similar to human PC4.
A yeast protein has been identified that stimulates basal transcription by RNA polymerase II, binds both single- and double-stranded DNA, and interacts with both a general transcription factor and a transcriptional activator. Phosphorylation appears to regulate these interactions. The gene for the transcriptional stimulatory protein, termed TSP1, was cloned and found to be dispensable for yeast cell viability. The deduced amino acid sequence is similar to that of mammalian coactivator protein PC4.


[Small intestinal leiomyoma causing gastrointestinal hemorrhage].
Leiomyomas are uncommon benign tumors of smooth muscle which may occur wherever smooth muscle is present. The small bowel is the most frequent site. Bleeding is the most common presenting symptom. Other symptoms, nausea, vomiting, abdominal pain are rare. In this article a 44 year-old male, presented, who was admitted with intermittent gastrointestinal bleeding in requence of jejunal leiomyoma with exulceration.


Intermittent plasmapheresis prevents recurrence in neuromyelitis optica.
Neuromyelitis optica (NMO) is a relapsing inflammatory condition characterized by selective involvement of the optic nerves and spinal cord. Humoral immune mechanisms play a role in the pathogenesis of NMO. The therapeutic efficacy of plasmapheresis (PP) has been reported in the cases that were poorly controlled with other treatments. Herein, we report four patients with NMO who underwent PP following intensive intravenous corticosteroid therapy. All patients showed definite functional improvement following one to five plasma exchanges. To prevent relapse, these patients were treated with oral prednisolone in combination with azathioprine or cyclophosphamide. Two of the four patients also underwent intermittent PP because treatment with oral agents was unsuccessful. In conclusion, when treatment with oral immunosuppressants is ineffective in reducing recurrences of NMO, an additional PP session should be attempted.


In vivo angiogenic activity of urokinase: role of endogenous fibroblast growth factor-2.
In vitro experimental evidences suggest that the proteolytic degradation of the extracellular matrix (ECM) by activation of the urokinase-type plasminogen activator (uPA)/plasmin system may affect growth factor activity and bioavailability. However, no direct in vivo observations were available to support this hypothesis. Here we demonstrate that endothelial GM 7373 cells overexpressing human uPA (uPA-R5 cells) cause the release of (125)I-labeled fibroblast growth factor-2 (FGF2) from endothelial ECM in a plasmin-dependent manner. Accordingly, uPA-R5 cells are angiogenic in vivo when applied on the top of the chorioallantoic membrane (CAM) of the chick embryo. In contrast, mock-transfected Neo2 cells are unable to release ECM-bound (125)I-FGF2 and are poorly angiogenic. Neovascularization elicited by uPA-R5 cells is significantly reduced by neutralizing anti-FGF2 antibodies to values similar to those observed in Neo2 cell-treated CAMs. Accordingly, purified human uPA stimulates neovascularization of the CAM in the absence of an inflammatory response. The angiogenic activity of uPA is significantly inhibited by neutralizing anti-FGF2 antibodies or by pretreatment with phenylmethylsulfonyl fluoride. The non-catalytic, receptor-binding amino-terminal fragment of uPA is instead non angiogenic. Taken together, the data indicate that uPA is able to induce angiogenesis in vivo via a plasmin-dependent degradation of ECM that causes the mobilization of stored endogenous FGF2.


Extraction, Characterization, Stability and Biological Activity of Flavonoids Isolated from Chamomile Flowers.
Dried flowers of Chamomile (Matricaria chamomilla) are largely used for their medicinal properties. In the present study, we examined the pharmacological properties of aqueous and methanolic fraction isolated from two varieties of German chamomile. HPLC-MS analysis of chamomile extract confirmed apigenin-7-O-glucoside as the major constituent of chamomile; some minor glycoside components were observed along with essential oils. These glucosides are highly stable in solution at different temperature range and their degradation occurs after long-term storage and extraction conditions at different pH and solvent. Methanolic fraction isolated from chamomile flowers demonstrated higher biologic response in inhibiting cell growth and causing induction of apoptosis in various human cancer cell lines compared to aqueous chamomile fraction. Apigenin glucosides inhibited cancer cell growth through deconjugation of glycosides that occurs in the cellular compartment to produce aglycone, apigenin. Taken together, the pharmacological profile of chamomile extract was dependent upon extraction process, storage conditions which affected the biological activity.


[Detecting suicide risk at psychiatric emergency services].
Guide the health professional to identify risk factors and forms of protection, together with handling such patient throughout a clinical interview within the emergency service context. Selected literature revision so as to identify relevant and illustrative key cases. The clinical interview is the best method to evaluate the suicidal risk and has two different aims: 1) emotional support and creation of a bond; 2) collecting information. There is a substantial amount of information to be collected during the clinical interview, such as: risk factors and protection, epidemiologic data, act characterization, psychical dynamics aspects, personal and familial historic patterns, identification models, data on physical wealth and social net support. Difficulties are to emerge throughout the clinical interview, but a trained and informed professional will be able to approach and adequately add the patient. Although several scales have been proposed, none of them have been efficient to deter the suicidal risk. There is no method to predict who is to commit suicide, nevertheless, it is possible to evaluate the individual risk of each patient with regards to a detailed and empathic clinical interview. Prevent the patient to commit suicide is the preliminary and fundamental rule.


[Recent advances in the study of Vitreoscilla hemoglobin(VHb) and related proteins - cloning, expression and physiological actions in heterologons hosts and in transgenic tobacco plants].
The first bacterial hemoglobin(VHb) was found in a strictly aerobic bacterium, Vitreoscilla strain C1, occurring in marshes low in oxygen, but rich in organic matter. The hemoglobin gene is induced under low oxygen tension and may amount to 20 times as high. The expression of VHb promotes cell growth, protein biosynthesis and primary and secondary metabolism of the host cells, because the increased intracellular oxygen accelerates both the function of respiratory chain and terminal oxidases. The serial action of increased oxygen concentration is elucidated through yeast two hybrid system and a model is proposed. In addition, novel globin proteins known as flavohemoglobins have been isolated from various procaryotes and eucaryotes, with a N-terminal similar to VHb and C-terminal with reductase activity. Primary study shows that flavohemoglobin proteins exhibit similar function as VHb and also protection effect to nitrosative stress. Further work is needed to learn more about the physiology of these flavohemoglobins. The most remarkable physiological effects of VHb are exihibited in transgenic tobacco plants, including accelerated seed germination and growth in plant, increased synthesis of chlorophyll and dry weight. Without doubt, these effects are brought about through the increased oxygen supply to plant cells. It is deemed that VHb transgenic tobacco is a forerunner for transgenic crops and VHb may be a valuable route for staple seed crops.


Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study.
It is not known whether the currently available treatment regimen of interferon beta-1b (IFNbeta-1b) 250 microg provides the maximum benefit possible in the treatment of relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFNbeta-1b will prove to be more beneficial. The objective of the present study was to evaluate the tolerability and safety profile of IFNbeta-1b 500 microg compared with the currently approved 250-microg dose. A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFNbeta-1b 250 microg with IFNbeta-1b 500 microg, both self-administered SC QOD for >or=12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 microg or 500 microg) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of >1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd)-diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms. Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38-250 and 33-500 microg IFNbeta-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-microg group (withdrawal of consent) and 1 in the 500-microg group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-microg (n=38; mean [SD] age, 37.9 [8.3] years; weight, 83.5 [19.0] kg; height, 168.4 [9.3] cm) and 500-microg (n=33; mean [SD] age, 37.8 [7.7] years; weight, 82.3 [19.5] kg; height, 169.9 [10.5] cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean [SD] score, 2.8 [1.4] vs 2.0 [1.4], respectively). In the IFN(2)-1b 250-microg group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-microg group (P=NS). A dose-response effect was observed in some of the more frequent AEs (no. [%]) that included influenza-like syndrome (250-microg group, 13 [34] vs 500-microg group, 16 [48]), asthenia (13 [34] vs 16 [48], respectively), headache (12 [32] vs 12 [36]), myalgia (10 [26] vs 13 [39]), hypesthesia (10 [26] vs 11 [33]), nausea (6 [16] vs 8 [24]), paresthesia (6 [16] vs 8 [24]), myasthenia (4 [11] vs 8 [24]), chills (3 [8] vs 6 [18]), depression (3 [8] vs 5 [15]), back pain (2 [5] vs 5 [15]), increased liver enzymes (4 [11] vs 6 [18]), lymphopenia (4 [11] vs 3 [9]), fever (2 [5] vs 4 [12]), and pain in extremities (1 [3] vs 4 [12]). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhanced lesion volume, median Gd-enhanced lesion number, and mean number of newly active lesions. IFNbeta-1b 500 microg administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-microg doses.


Effectiveness of Nivolumab in Second-Line and Later in Patients with Advanced Non-Small Cell Lung Cancer in Real-Life Practice in France and Germany: Analysis of the ESME-AMLC and CRISP Cohorts.
This study reports characteristics and outcomes in patients with locally advanced or metastatic non-small cell lung cancer (aNSCLC) receiving nivolumab in second-line or later (2L+) in France and Germany between 2015 and 2020. Patients with aNSCLC (stage IIIB-C/IV) receiving nivolumab in 2L+ were included from the retrospective Epidemiological Strategy and Medical Economics of Advanced and Metastatic Lung Cancer cohort (ESME-AMLC, France; 2015-2019) and Clinical Research platform Into molecular testing, treatment and outcome of non-Small cell lung carcinoma Patients (CRISP, Germany; 2016-2020). Overall, 2262 ESME-AMLC and 522 CRISP patients were included. Median treatment duration (95% confidence intervals) was 2.8 months (2.5-3.2) in squamous and 2.5 months (2.3-2.8) in non-squamous/others patients in ESME-AMLC, and 2.3 months (1.4-3.1) and 2.3 months (2.0-2.8), respectively in CRISP. One-year and two-year overall survival (OS) were 47.2% and 26.7% in squamous and 50.8% and 32.8% in non-squamous/others patients in ESME-AMLC, and 43.1% and 20.9%, and 37.7% and 18.9%, respectively in CRISP. Poorer performance score and shorter time from start of previous line of therapy initiation were significantly associated with shorter treatment duration and OS. This study confirms, in real-world clinical databases, the efficacy of nivolumab previously observed in clinical trials.


Lipid droplets as a novel cargo of tunnelling nanotubes in endothelial cells.
Intercellular communication is a fundamental process in the development and functioning of multicellular organisms. Recently, an essentially new type of intercellular communication, based on thin membrane channels between cells, has been reported. These structures, termed intercellular or tunnelling nanotubes (TNTs), permit the direct exchange of various components or signals (e.g., ions, proteins, or organelles) between non-adjacent cells at distances over 100 μm. Our studies revealed the presence of tunnelling nanotubes in microvascular endothelial cells (HMEC-1). The TNTs were studied with live cell imaging, environmental scanning electron microscopy (ESEM), and coherent anti-Stokes Raman scattering spectroscopy (CARS). Tunneling nanotubes showed marked persistence: the TNTs could connect cells over long distances (up to 150 μm) for several hours. Several cellular organelles were present in TNTs, such as lysosomes and mitochondria. Moreover, we could identify lipid droplets as a novel type of cargo in the TNTs. Under angiogenic conditions (VEGF treatment) the number of lipid droplets increased significantly. Arachidonic acid application not only increased the number of lipid droplets but also tripled the extent of TNT formation. Taken together, our results provide the first demonstration of lipid droplets as a cargo of TNTs and thereby open a new field in intercellular communication research.


Microscopic localisation of protoporphyrin IX in normal mouse skin after topical application of 5-aminolevulinic acid or methyl 5-aminolevulinate.
Light fractionation does not enhance the response to photodynamic therapy (PDT) after topical methyl-aminolevulinate (MAL) application, whereas it is after topical 5-aminolevulinic acid (ALA). The differences in biophysical and biochemical characteristics between MAL and ALA may result in differences in localisation that cause the differences in response to PDT. We therefore investigated the spatial distribution of protoporphyrin IX (PpIX) fluorescence in normal mouse skin using fluorescence microscopy and correlated that with the PDT response histologically observed at 2.5, 24 and 48 h after PDT. As expected high fluorescence intensities were observed in the epidermis and pilosebaceous units and no fluorescence in the cutaneous musculature after both MAL and ALA application. The dermis showed localised fluorescence that corresponds to the cytoplasma of dermal cells like fibroblast and mast cells. Spectral analysis showed a typical PpIX fluorescence spectrum confirming that it is PpIX fluorescence. There was no clear difference in the depth and spatial distribution of PpIX fluorescence between the two precursors in these normal mouse skin samples. This result combined with the conclusion of Moan et al. that ALA but not MAL is systemically distributed after topical application on mouse skin [Moan et al., Pharmacology of protoporphyrin IX in nude mice after application of ALA and ALA esters, Int. J. Cancer 103 (2003) 132-135] suggests that endothelial cells are involved in increased response of tissues to ALA-PDT using light fractionation. Histological analysis 2.5h after PDT showed more edema formation after ALA-PDT compared to MAL-PDT that was not accompanied by a difference in the inflammatory response. This suggests that endothelial cells respond differently to ALA and MAL-PDT. Further investigation is needed to determine the role of endothelial cells in ALA-PDT and the underlying mechanism behind the increased effectiveness of light fractionation using a dark interval of 2h found after ALA but not after MAL-PDT.


Dupuytren's disease or Cooper's contracture?: Kenneth Fitzpatrick Russell Memorial Lecture.
In his position as curator of the Cowlishaw collection of historical medical books in the Library of the College, Kenneth Russell prepared the definitive catalogue of the collection. This catalogue is comprehensive and for almost all entries there is an annotation that demonstrates his meticulous attention to detail and the love of the book collection that he managed to secure for the College. It is from this catalogue that I have chosen two books in particular that bring together two great surgeons of the turn of the 19th century. Although he was a pupil of the great John Hunter, the young Astley Cooper possessed good manners and a gift of oratory of which the Scot, his teacher, was devoid. After his apprenticeship with Henry Cline senior, Cooper came to share the podium with Cline at Guy's and St Thomas' hospitals and the two dominated surgical teaching in London for some 22 years, until Cline's retirement in 1811. It was the latter who was first to recognize the true nature of the condition now known as Dupuytren's disease. Later, in 1822, Cooper wrote a detailed description of the contracture of the palmar aponeurosis and recommended fasciotomy as being curative. His book A Treatise on Dislocations and Fractures of the Joints, which contains this description of Dupuytren's contracture, is held in the Cowlishaw Collection. On the other side of the English Channel, M. le Baron Dupuytren repeatedly misquoted Cooper and stated that Cooper believed that the disease was incurable. In his famous lecture given to the staff of the Hôtel Dieu in Paris on 5th December 1931, he admitted to having seen 30 or 40 cases over 20 years of practice. It seems likely that he was not aware of the true cause of the condition before 1831 when he treated his first case. This lecture, along with others, are recorded in his Leçons Orales de Clinique Chirurgicale, a copy of which is also to be found in the Cowlishaw Collection.


The emergence of primary care in Latin America: reflections from the field.
A U.S. family physician educator working in El Salvador, recently returned from the WONCA Fourth Regional Congress of the Ibero American Confederation of Family Medicine, reflects on the state of primary care in Latin America. Progress in primary health care and family medicine is occurring in several countries in the region as many countries are coming to accept that primary care is a systematic solution to their structural problems. The author discusses reasons for this progress in the context of political, economic, medical, and cultural dynamics. He notes several key points of comparing this development with the health care system in the United States and suggests that there is much to learn from those systems that are making their way on the path toward primary care.


Cross-reactive lysis of trinitrophenyl (TNP)-derivatized H-2 incompatible target cells by cytolytic T lymphocytes generated against syngeneic TNP spleen cells.
Normal spleen cells, when cultured with irradiated trinitrophenyl (TNP)-derivatized syngeneic spleen cells, develop cytotoxic effectors that lyse most effectiviely a TNP-derivatized target that is H-2 compatible with the effector. However, these effectors also lyse to a lesser extent TNP tumor and TNP spleen targets that are H-2 incompatible. This cross-reactive lysis correlates with the degree of cytolysis seen on the TNP-derivatized syngeneic target; it appears to be medicated by Thy 1.2-bearing cells and is inhibited by antisera to the K and/or D loci of the target cell and not by antisera to non-K or non-D surface antigens. Nonradiolabeled TNP-derivatized lymphoid cells syngeneic to either the stimulator or the target are able to competitively inhibit cross-reactive lysis, while TNP chicken red blood cells are unable to specifically inhibit lysis. These data on cross-reactive lysis of TNP-conjugated targets are most consistent with the altered-self hypothesis.


Sudden Fall in the Lipid-Lowering Effect of Evolocumab: The Butler Is Not Always Guilty.
A 78-year-old man came to our attention after undergoing coronary computed tomography angiography documenting multivessel coronary artery disease. He was started on treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab 140 mg subcutaneously every 2 weeks. Treatment-emergent changes in lipids and lipoproteins were long-lasting, and the medication was well tolerated by the patient in the long-term. Unexpectedly, after 2 years of continuous treatment with evolocumab, serum lipids increased, apparently without any reasonable explanation. During the follow-up visit, the patient was found to have habitually injected evolocumab into his right thumb instead of into the appropriate injection sites (i.e., abdomen, thighs or upper arms) after turning the injector upside down.


Quantum Spin Liquid Intertwining Nematic and Superconducting Order in Fese.
Despite its seemingly simple composition and structure, the pairing mechanism of FeSe remains an open problem due to several striking phenomena. Among them are nematic order without magnetic order, nodeless gap and unusual inelastic neutron spectra with a broad continuum, and gap anisotropy consistent with orbital selection of unknown origin. Here we propose a microscopic description of a nematic quantum spin liquid that reproduces key features of neutron spectra. We then study how the spin fluctuations of the local moments lead to pairing within a spin-fermion model. We find the resulting superconducting order parameter to be nodeless s±d wave within each domain. Further we show that orbital dependent Kondo-like coupling can readily capture observed gap anisotropy. Our prediction calls for inelastic neutron scattering in a detwinned sample.


Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation.
"Escape" variants of hepatitis B virus (HBV) can cause infection despite previous immunization. These viruses show alterations of the immunogenic major hydrophilic loop of the HBV small surface protein (s-protein). We studied whether HBV "escape" variants were selected in patients with graft infection after liver transplantation for HBV-related diseases who received passive immunoprophylaxis with high-dose polyclonal hepatitis B hyperimmune globulin (HBIG). For that, pre- and posttransplantation sera of 34 patients were analyzed for the occurence of HBV S-gene variants. In addition, binding of in vitro-translated variant s-proteins to HBIG was studied. Variants with exchanges of amino acid (aa) 144 (s144) in HBV genotype A and 145 in genotype D (s145) were found to emerge, persist, and predominate during HBIG, and thus fulfilled criteria of "escape" variants selected. In addition to already-known variants sG145R/K/E, we could demonstrate that newly described variants sX144G and sG145A were antigenically altered and showed impaired recognition by polyclonal HBIG in vitro. Diminished recognition of variant s-proteins correlated with the failure of HBIG to prevent infection of the liver graft with antigenically altered variant HBV Patients infected with "escape" variants s144 or s145 showed a worse clinical outcome compared with the other patients on high-dose, long-term HBIG prophylaxis (44% vs. 23% graft failure caused by HBV infection). Our results suggest that antigenically altered HBV variants s144 and s145 can be selected by HBIG and can influence clinical outcome after liver transplantation.


Reproducible model development in the cardiac electrophysiology Web Lab.
The modelling of the electrophysiology of cardiac cells is one of the most mature areas of systems biology. This extended concentration of research effort brings with it new challenges, foremost among which is that of choosing which of these models is most suitable for addressing a particular scientific question. In a previous paper, we presented our initial work in developing an online resource for the characterisation and comparison of electrophysiological cell models in a wide range of experimental scenarios. In that work, we described how we had developed a novel protocol language that allowed us to separate the details of the mathematical model (the majority of cardiac cell models take the form of ordinary differential equations) from the experimental protocol being simulated. We developed a fully-open online repository (which we termed the Cardiac Electrophysiology Web Lab) which allows users to store and compare the results of applying the same experimental protocol to competing models. In the current paper we describe the most recent and planned extensions of this work, focused on supporting the process of model building from experimental data. We outline the necessary work to develop a machine-readable language to describe the process of inferring parameters from wet lab datasets, and illustrate our approach through a detailed example of fitting a model of the hERG channel using experimental data. We conclude by discussing the future challenges in making further progress in this domain towards our goal of facilitating a fully reproducible approach to the development of cardiac cell models.


Phyto-constituents and anti-oxidant activity of the pulp of snake tomato (Trichosanthes cucumerina L.).
The phyto-constituents and antioxidant activity of the fruit pulp of Trichosanthes cucumerina L. have not been reported in literature and were therefore studied. Two identified morphotypes of this plant (Morphotype I [V1] having long fruit with deep green background and white stripes; and Morphotype II [V2] having light green coloured long fruit) were used for the studies. The dry matter contents of the pulp of the V1 and V2 were 10.9 and 9.6 g/100 g fresh weight (FW), while the ascorbic acid contents were 25.7 and 24.8 mg/100 g fresh weight (FW), and lycopene contents were 18.0 and 16.1 mg/100 g FW, respectively. The total phenolics, total flavonoids and total ferric reducing antioxidant power (FRAP) of V2 were significantly higher (P< 0.05) than that of V1 by 46.8%, 78.0% and 26.2%, respectively. Bulk of the carotenoids is made up of lutein in the concentration of 15.6 and 18.4 mg/100 g FW, for V1 and V2, respectively. The alpha-carotene contents were 10.3 and 10.7 mg/100 g FW while the beta-carotene contents were 2.4 and 2.8 mg/100 g FW for V1 and V2, respectively. It is concluded from the results of this study that the two morphotypes of T. cucumerina possess valuable nutraceutical properties that can qualify them as viable substitute to the Solanaceous tomato.