Distinction between benign and malignant type of Parkinson's disease.
Clinical data demonstrate that there is a significant difference between at least two types of idiopathic Parkinsonian patients; a benign type of Parkinson's disease and a malignant type. They can be distinguished by the time course of a disability-score, independent of the duration of the disease. The benign cases respond very well to L-Dopa (Madopar) treatment and show a long lasting (7 years) drop in the disability, whereas the improvement of disability in the malignant cases is much smaller and lasts for about one year, followed by an increase of disability. The duration of the disease is 12,5 +/- 0,4 years in the benign type but only 4,0 +/- 0,3 years in the malignant type. Akinetic crises, off-phases, hyperkinetic crises and toxic deliria after Madopar treatment can be observed later in the benign than in the malignant cases. These results suggest that the degeneration of the dopaminergic nigrostriatal system occurs much more rapidly in malignant cases than in benign cases of Parkinson's disease.


Changes in aortic rotational flow during cardiopulmonary bypass studied by transesophageal echocardiography and magnetic resonance velocity imaging: a potential mechanism for atheroembolism during cardiopulmonary bypass.
The human aorta is a curved conduit with a complex three-dimensional geometry. The curvature influences axial velocity distribution and introduces transverse velocity components. Rotational flow in the aorta can be demonstrated during normal pulsatile flow using transesophageal echocardiography. Cardiopulmonary bypass may affect the pattern of rotational flow in the aorta and thus influence the generation of atheroemboli. We investigated rotational flow in the descending aorta using color flow mapping and pulse-wave Doppler on transesophageal echocardiography before and during cardiopulmonary bypass. We correlated our findings with magnetic resonance velocity imaging in a model of a human aortic arch connected to a cardiopulmonary bypass circuit. Before cardiopulmonary bypass, rotational flow in the descending aorta was seen in 37 of 40 patients (93%). In the majority of these patients, rotational flow was in the clockwise direction during systole, looking in the direction of flow (30 of 37 patients, 81%, P < 0.01 vs counterclockwise rotation). During cardiopulmonary bypass, there were almost equal numbers of patients with clockwise (18 patients) and counterclockwise rotation (19 patients). Forty-seven percent of patients with clockwise rotation before cardiopulmonary bypass developed reversal in the direction of rotation to counterclockwise during cardiopulmonary bypass. Twenty-nine percent of patients with counterclockwise rotation developed reversal of the direction of rotation during cardiopulmonary bypass. The transverse velocity component increased during cardiopulmonary bypass regardless of the direction of rotation. We also demonstrated clockwise rotation in the descending aorta of a human aortic arch model connected to a cardiopulmonary bypass circuit using magnetic resonance velocity mapping. Before cardiopulmonary bypass, rotation was predominantly clockwise, while during cardiopulmonary bypass, there was no preferred direction of rotation. The geometry of the aorta, which is fairly constant in all patients, imposes handedness to aortic flow before cardiopulmonary bypass. However, during cardiopulmonary bypass, other extrinsic factors such as aortic cannula orientation may influence the direction of rotation. The change in direction of rotational flow and increase in its transverse velocity component during cardiopulmonary bypass may have implications for atheroembolism and arterial branch perfusion during extended periods of non-pulsatile flow.


Beyond Young's experiment: time-domain correlation measurement in a pinhole array.
Time-domain analysis of field correlations provided by the interferogram from a nonredundant pinhole array is performed. It is shown that the described single measurement is identically equal to a series of Young's two-pinhole experiments. Proper postmeasurement analysis, taking into account the finite coherence time of the source, results in a sampling of the spatial-temporal coherence function.


Anti-tumor effects of all-trans retinoic acid are enhanced by genistein.
The effects of all-trans retinoic acid (ATRA) on cancer are complex. ATRA has anti-cancer effects as it promotes cancer cell differentiation. However, ATRA also up-regulates expression of vascular endothelial growth factor (VEGF) in cancer cells, which leads to angiogenesis and can, thus, facilitate cancer growth. Genistein, a crucial non-nutrient component in soybean, exhibits anti-cancer effects by inhibiting protein tyrosine kinase that is involved in up-regulation of VEGF. We hypothesized that genistein, applied simultaneously with ATRA, would counter its undesired angiogenic effects and, thus, enhance the anti-cancer effects of ATRA. The purpose of this study was to document potential synergistic effects of genistein and ATRA in A549 lung adenocarcinoma cells. We further explored the role of genistein on countering the ATRA-induced VEGF expression. We demonstrate that genistein enhances the ATRA-induced growth inhibition of A549 cells by promoting apoptosis. Further, the combined use of ATRA and genistein leads to cancer cell arrest in G0/G1 and G2/M cell cycle phases. Finally, expression of VEGF (both mRNA and protein) was diminished in A549 cells exposed to both ATRA and genistein. In conclusion, our results demonstrate that genistein effectively enhances anti-cancer effects of ATRA, particularly, by countering the ATRA-induced up-regulation of VEGF. Our study provides an experimental basis for combined use of ATRA and genistein in the treatment of lung cancer.


Newly incriminated anopheline vectors of human malaria parasites in Junin Department, Peru.
Sporozoite data from salivary gland dissections are presented that clearly incriminate Anopheles trinkae, An. pseudopunctipennis, An. sp. near fluminensis, An. oswaldoi, An. nuneztovari and An. rangeli as vectors of malaria parasites in the Rio Ene Valley, a hyperendemic malarious area in Junin Department, eastern Peru. Anopheles trinkae is considered the most important vector based on dissections, abundance and man-vector contact. Other notes are presented on the relative abundance, bionomics and previous records of these species in Peru and in the study sites.


Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.
Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log(10) decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir. The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.


Multicultural Developmental Experiences: Implications for Resilience in Transitional Age Youth.
Transitional age youth were born into a world that is becomingly increasingly diverse. Youth who are ethnic or racial minorities encounter cultural stressors, including acculturative stress and discrimination that undermine their health and mental health. Decades of research demonstrate that cultural assets can serve as risk-reducing and resilience-enhancing mechanisms among minority and immigrant youth. Cultural assets include the development of a healthy ethnic-racial identity and maintenance of cultural values. Practitioners should assess for culturally relevant stressors and incorporate cultural assets such as ethnic-racial identity and cultural values to support the mental health of these youth.


Does climate knowledge act as a shield for farm livelihoods? Empirical analysis from the coastal and non-coastal ecosystems of India.
Developing countries with agrarian economy have been facing challenges arising from climate change events and its consequences. Climate knowledge influences the adaptation and mitigation measures shielding farm households in climatically vulnerable regions. Indian states with climatically vulnerable coastal and non-coastal agro-ecosystems have dominantly an agrarian economy; and small and marginal farmers' livelihoods are under focus through implementation of National Innovations in Climate Resilient Agriculture (NICRA) by the Indian Council of Agricultural Research. The present study was undertaken in one such state, Odisha. Climate knowledge test was developed following appropriate methods and administered to 200 farmers, 100 each in coastal and non-coastal NICRA districts to assess the knowledge level of dominant livelihood groups. Farmers' climate knowledge was higher in coastal district as compared to non-coastal district with overall climate knowledge index values of 53.10 and 43.95, respectively. Farmers who engaged in crop + livestock farming have better climate knowledge as compared to crop farmers and livestock farmers. Multiple regression and path analyses revealed social, economic, communication and psychological attributes of the farmers determining their climate knowledge level. Education level, social participation, participation in community initiatives, annual family income and personal cosmopolite information sources use are few such important determinants of climate knowledge. These dimensions require attention for the policy advocacies to improve climate knowledge so as to shield climatically vulnerable farm households.


Augmentation of delayed-type hypersensitivity to high dose sheep erythrocytes by cyclosporin A in the mouse: influence of drug dosage and route of administration and analysis of spleen cell populations.
When administered by various routes 48 h before a high systemic dose (10 degrees) of sheep red blood cells (SRBC), Cyclosporin A (CsA) prevented the suppression of delayed-type hypersensitivity (DTH) reactions elicited 4 days later. Augmentation of DTH was observed over a wide range (5-200 mg/kg) and with circulating CsA levels ranging below 45 ng/ml at the time of immunization or antigen challenge. Splenic lymphocytes from vehicle- and CsA-treated mice exhibited good proliferative responses to mitogen in vitro, but only those from CsA-treated animals responded to antigen. Expression of DTH was associated with a progressive, 2-fold increase in the absolute numbers of splenic L3T4+ cells, whereas no significant alteration in the number of Lyt-2+ lymphocytes was recorded. B cell and macrophage numbers in the spleen were unaffected by CsA. In contrast to its potentiating effects on cell-mediated immunity, CsA caused profound (up to 100%) suppression of the concomitant production of splenic anti-SRBC IgM-secreting plasma cells. Circulating anti-SRBC antibody levels were also markedly reduced. These data show that CsA can permit induction of TDTH, whilst suppressing T-dependent humoral immunity and without significant change in absolute numbers of Lyt-2+ cells.


Imaging of Irreversible Loss of Brain Function.
The updated guidelines for the determination of irreversible loss of brain function include a substantial innovation, i. e., the use of CT angiography as a supplementary technical examination. Adherence to a standardized protocol is the prerequisite for the application of CT angiography. The guidelines for standardized execution of perfusion scintigraphy are unchanged and still valid. Requirements regarding the quality of examining physicians are specified. • The guidelines for determining irreversible loss of brain function were updated.• The approval of CT angiography as a supplementary examination method is a major innovation.• CT angiography is to be performed to determine the cessation of cerebral blood circulation according to a standard protocol.• The guidelines for the standardized implementation of perfusion scintigraphy continue to be valid.• Quality requirements regarding examining physicians were specified.


PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study.
The aim of this study was to evaluate the use of [(18)F]fluorothymidine (FLT) as a positron emission tomography (PET) tracer for the diagnosis of breast cancer. To this end, 12 patients with 14 primary breast cancer lesions (T2-T4) were studied by FLT-PET. For comparison, [(18)F]fluorodeoxyglucose (FDG) PET scans were performed in six patients. Thirteen of the 14 primary tumours demonstrated focally increased FLT uptake (SUV(mean)=3.4+/-1.1). Seven out of eight patients with histologically proven axillary lymph node metastases showed focally increased FLT uptake in the corresponding areas (SUV(mean)=2.4+/-1.2). The lowest SUV (mean =0.7) was observed in one of two inflammatory cancers. The contrast between primary tumours or metastases and surrounding tissue was high in most cases. In direct comparison to FDG-PET, the SUVs of primary tumours (5/6) and axillary lymph node metastases (3/4) were lower in FLT-PET (SUV(FLT): 3.2 vs SUV(FDG): 4.7 in primary tumours and SUV(FLT): 2.9 vs SUV(FDG): 4.6 in lymph node metastases). Since FLT uptake in surrounding breast tissue was also lower, tumour contrast was comparable to that with FDG. It is of note that normal FLT uptake was very low in the mediastinum, resulting in a higher tumour-to-mediastinum ratio as compared to FDG ( P=0.03). FLT-PET is suitable for the diagnosis of primary breast cancer and locoregional metastases. High image contrast may facilitate the detection of small foci, especially in the mediastinum.


Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study.
CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.


Role of melanin in mechanical properties of Glycera jaws.
The remarkable mechanical prowess of the jaws of the bloodworm Glycera dibranchiata appears to be a consequence of a robust cross-linked network of organic molecules, notably melanin and proteins, as well as small amounts of unmineralized Cu and a Cu-based mineral. The present study focuses on the role of melanin. Mechanical properties of untreated jaws and the constituent melanin are probed through nanoindentation, both in air and underwater. Complementary information is obtained from density and porosity measurements and attempts at Cu removal from the jaws using EDTA, an effective metal chelator in most biological systems. In near-tip regions of the jaws, mechanical properties attain the highest values and diminish only slightly when wet (by 15-25%), in contrast to the behavior of other organic biomaterials. The melanin constituent contributes significantly to the mechanical integrity of the jaw; its hardness and elastic modulus are about half those of untreated jaws. Although melanin may be the dominant shape-determining component of the structure, it remains to be shown whether jaw assembly is mediated by protein deposition on a melanin scaffold or, conversely, by melanin deposition on a protein scaffold. The inability of EDTA to chelate Cu from the jaws and the relatively high density of the jaws and the melanin support the notion of a highly cross-linked molecular structure. Finally, based on the metric H(3)/E(2) (H being hardness and E the Young's modulus), the results suggest that the abrasion resistance of the jaws is superior to all engineering polymers and competitive with the hardest metallic alloys.


Defining clusters in APT reconstructions of ODS steels.
Oxide nanoclusters in a consolidated Fe-14Cr-2W-0.3Ti-0.3Y₂O₃ ODS steel and in the alloy powder after mechanical alloying (but before consolidation) are investigated by atom probe tomography (APT). The maximum separation method is a standard method to define and characterise clusters from within APT data, but this work shows that the extent of clustering between the two materials is sufficiently different that the nanoclusters in the mechanically alloyed powder and in the consolidated material cannot be compared directly using the same cluster selection parameters. As the cluster selection parameters influence the size and composition of the clusters significantly, a procedure to optimise the input parameters for the maximum separation method is proposed by sweeping the d(max) and N(min) parameter space. By applying this method of cluster parameter selection combined with a 'matrix correction' to account for trajectory aberrations, differences in the oxide nanoclusters can then be reliably quantified.


Peripheral nerve electrophysiology studies in relation to fatigue in patients with chronic inflammatory demyelinating polyneuropathy.
To explore the relationship between fatigue, standard electrophysiological parameters and number and size of functioning motor units in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Experienced fatigue was assessed using the linearly-weighted, modified Rasch-built fatigue severity scale (R-FSS) and the multidimensional Checklist of Individual Strength (CIS). Averaged electrophysiology values were calculated from multiple nerves. Motor Unit Number Index (MUNIX) technique was utilised to assess motor unit function. Assessments were repeated in 15 patients receiving regular intravenous immunoglobulin therapy, with changes in parameters calculated. R-FSS and CIS scores did not correlate MUNIX or MUSIX sum scores from 3 different muscles. Inverse correlation was observed only between distal CMAP area and R-FSS but not CIS scores. However, changes in distal CMAP area and R-FSS scores on repeat assessment were not correlated. Experienced fatigue does not appear to correlate with loss of functioning motor units in patients with CIDP. Changes in experienced fatigue on repeat assessment did not correlate with changes in any of the electrophysiological parameters, suggesting fatigue experienced in CIDP is not strongly correlated with peripheral nerve dysfunction. Nerve conduction studies and MUNIX values do not appear to be useful surrogate markers for fatigue in CIDP.


Bub1 is not essential for the checkpoint response to unattached kinetochores in diploid human cells.
Error-free chromosome segregation during mitosis depends on a functional spindle assembly checkpoint (SAC). The SAC is a multi-component signalling system that is recruited to unattached or incorrectly attached kinetochores to catalyse the formation of a soluble inhibitor, known as the Mitotic Checkpoint Complex (MCC), which binds and inhibits the anaphase promoting complex (APC/C) [1]. We have previously proposed that two separable pathways, composed of KNL1-Bub3-Bub1 (KBB) and Rod-Zwilch-Zw10 (RZZ), recruit Mad1-Mad2 complexes to human kinetochores to activate the SAC [2]. Although Bub1 is absolutely required for checkpoint signalling in yeast (which lack RZZ), there is conflicting evidence as to whether this is the case in human cells based on siRNA studies [2-5]. Here we show that, while Bub1 is required for recruitment of BubR1, it is not strictly required for the checkpoint response to unattached kinetochores in diploid human cells.


Monozygotic twin pregnancy: diagnostic and Doppler ultrasound studies.
Of 178 consecutive twin pregnancies, 63 were both monozygotic and also studied prenatally by real-time B-scan (and usually Doppler) ultrasound. The 48 pregnancies with monochorionic placentas (in which vascular anastomoses are almost universal) were compared with the 15 monozygotic pregnancies having dichorionic placentas. The type of placenta found at delivery was predicted with substantial accuracy by ultrasound examination in mid-pregnancy. We were unable to identify any inter-group difference in fetal growth rate, discordance of fetal growth between twins or pattern of umbilical artery flow velocity waveform. In the absence of the rare florid twin transfusion syndrome, the vascular anastomoses that have been shown to be common in monochorionic placentas do not exert a strong influence on fetal growth or fetoplacental blood flow.


Incomplete genome doubling enables to consistently enhance plant growth for maximum biomass production by altering multiple transcript co-expression networks in potato.
Cytochimera potato plants, which mixed with diploid and tetraploid cells, could cause the highest and significantly increased biomass yield than the polyploid and diploid potato plants. Polyploidization is an important approach in crop breeding for agronomic trait improvement, especially for biomass production. Cytochimera contains two or more mixed cells with different levels of ploidy, which is considered a failure in whole genome duplication. Using colchicine treatment with diploid (Dip) potato (Solanum chacoense) plantlets, this study generated tetraploid (Tet) and cytochimera (Cyt) lines, which, respectively, contained complete and partial cells with genome duplication. Compared to the Dip potato, we observed remarkably enhanced plant growth and biomass yields in Tet and Cyt lines. Notably, the Cyt potato straw, which was generated from incomplete genome doubling, was of significantly higher biomass yield than that of the Tet with a distinctively altered cell wall composition. Meanwhile, we observed that one layer of the tetraploid cells (about 30%) in Cyt plants was sufficient to trigger a gene expression pattern similar to that of Tet, suggesting that the biomass dominance of Cyt may be related to the proportion of different ploidy cells. Further genome-wide analyses of co-expression networks indicated that down-regulation (against Dip) of spliceosomal-related transcripts might lead to differential alternative splicing for specifically improved agronomic traits such as plant growth, biomass yield, and lignocellulose composition in Tet and Cyt plants. In addition, this work examined that the genome of Cyt line was relatively stable after years of asexual reproduction. Hence, this study has demonstrated that incomplete genome doubling is a promising strategy to maximize biomass production in potatoes and beyond.


Interpretation of the disk diffusion susceptibility test for amikacin: report of a collaborative study.
Because excessively high rates of false resistance have been encountered with the 10-mug amikacin disk in diffusion susceptibility tests, a study was performed to examine existing zone diameter interpretative criteria and to compare the accuracy of 10- and 30-mug amikacin disks by the error rate-bounded classification scheme. Although current zone diameter interpretative criteria eliminate false susceptibles, there is an unacceptably high rate of false resistants. This problem can be resolved in most instances by revising the zone diameter interpretative criteria for the 10-mug disk (resistant, </=9 mm; indeterminate, 10 to 11 mm; susceptible, >/=12 mm) or, preferably, by replacing the 10-mug disk with a 30-mug disk and adopting new interpretative criteria (resistant, </=14 mm; indeterminate, 15 to 16 mm; susceptible, >/=17 mm). Because of significant differences in performance among media, it is necessary to include Pseudomonas aeruginosa ATCC 27853 among controls routinely tested and to exclude from use lots of Mueller-Hinton agar yielding results outside the 75% tolerance (90% confidence) limits for amikacin.


Development and validation of an LC-MS/MS assay for the quantification of the trans-methylation pathway intermediates S-adenosylmethionine and S-adenosylhomocysteine in human plasma.
Although increased levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) have been implicated as markers for renal and vascular dysfunction, until now there have been no studies investigating their association with clinical post-transplant events such as organ rejection and immunosuppressant nephrotoxicity. A newly developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of SAM and SAH in human EDTA plasma was used for a clinical proof-of-concept pilot study. Retrospective analysis was performed using samples from a longitudinal clinical study following de novo kidney transplant patients for the first year (n=16). The ranges of reliable response were 8 to 1024 nmol/l for SAM and 16 to 1024 nmol/l for SAH. The inter-day accuracies were 96.7-103.9% and 97.9-99.3% for SAM and SAH, respectively. Inter-day imprecisions were 8.1-9.1% and 8.4-9.8%. The total assay run time was 5 min. SAM and SAH concentrations were significantly elevated in renal transplant patients preceding documented acute rejection and nephrotoxicity events when compared to healthy controls (n=8) as well as transplant patients void of allograft dysfunction (n=8). The LC-MS/MS assay will provide the basis for further large-scale clinical studies to explore these thiol metabolites as molecular markers for the management of renal transplant patients.


Neuropharmacological Effects of the Dichloromethane Extract from the Stems of Argemone ochroleuca Sweet (Papaveraceae) and Its Active Compound Dihydrosanguinarine.
Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography-mass spectrometry (GC-MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1-50 mg/kg p.o.) and DHS (0.1-10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED50) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED50 = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED50 = 3 mg/kg) and the tail suspension test (ED50 = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED50 = 2 mg/kg) in the hole board test. The AOE (1-50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABAA receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS.


Cost-Effectiveness of Surveillance after Metastasectomy of Stage IV Colorectal Cancer.
Surveillance of stage IV colorectal cancer (CRC) after curative-intent metastasectomy can be effective for detecting asymptomatic recurrence. Guidelines for various forms of surveillance exist but are supported by limited evidence. We aimed to determine the most cost-effective strategy for surveillance following curative-intent metastasectomy of stage IV CRC. We performed a decision analysis to compare four active surveillance strategies involving clinic visits and investigations elicited from National Comprehensive Cancer Network (NCCN) recommendations. Markov model inputs included data from a population-based cohort and literature-derived costs, utilities, and probabilities. The primary outcomes were costs (2021 Canadian dollars) and quality-adjusted life years (QALYs) gained. Over a 10-year base-case time horizon, surveillance with follow-ups every 12 months for 5 years was most economically favourable at a willingness-to-pay threshold of CAD 50,000 per QALY. These patterns were generally robust in the sensitivity analysis. A more intensive surveillance strategy was only favourable with a much higher willingness-to-pay threshold of approximately CAD 425,000 per QALY, with follow-ups every 3 months for 2 years then every 12 months for 3 additional years. Our findings are consistent with NCCN guidelines and justify the need for additional research to determine the impact of surveillance on CRC outcomes.


Impact of surgical approach on the management of macroscopic early ovarian borderline tumors.
The aim of this study was to evaluate the impact of the surgical approach on the management and outcomes of patients with early borderline ovarian tumors (BOTs). We retrospectively reviewed the medical charts of patients with stage Ia to Ic BOT treated surgically between January 1, 1985, and December 31, 2001. We compared patients initially managed by laparoscopy vs. laparotomy in terms of potentially harmful procedures and quality of staging. Of the 118 included patients, 48 (41%) had laparoscopy for initial surgery, 54 (45%) had laparotomy, and 16 (14%) had conversion from laparoscopy to laparotomy. Conservative treatment (57% of patients) was more common with laparoscopy (vs. laparotomy, P < 0.05) and in women older than 44 years (vs. younger than 44 years, P < 0.001). Intraoperative tumor rupture occurred in 9% of patients and was not associated with the surgical approach (P = 0.1). Bag extraction was used in 19 (40%) of the 48 laparoscopy patients. Staging was incomplete in 73% of patients overall. By univariate analysis, better quality of staging was associated with bilateral adnexectomy, age >44 years, laparotomy, hysterectomy, and treatment after 1995. By multivariate analysis, bilateral adnexectomy or hysterectomy was associated with better staging. Mean follow-up was 40 months, during which recurrence and survival rates were similar in the laparoscopy and laparotomy groups. Staging of macroscopic early stage BOTs was better in patients requiring radical surgery. After adjustment on disease severity, type of surgical access was not related to staging quality.


About thiol derivatization and resolution of basic proteins in two-dimensional electrophoresis.
The influence of thiol blocking on the resolution of basic proteins by two-dimensional electrophoresis was investigated. Cysteine blocking greatly increased resolution and decreased streaking, especially in the basic region of the gels. Two strategies for cysteine blocking were found to be efficient: classical alkylation with maleimide derivatives and mixed disulfide exchange with an excess of a low molecular weight disulfide. The effect on resolution was significant enough to allow correct resolution of basic proteins with in-gel rehydration on wide gradients (e.g. 3-10 and 4-12), but anodic cup-loading was still required for basic gradients (e.g. 6-12 or 8-12). These results demonstrate that thiol-related problems are not solely responsible for streaking of basic proteins on two-dimensional gels.


Yacon-based product improves intestinal hypertrophy and modulates the production of glucagon-like peptide-1 in postmenopausal experimental model.
The progressive decline in estrogen level puts postmenopausal women at a higher risk of developing cardiometabolic diseases. Thus, we evaluated the potential beneficial effects of yacon-based product (YBP) on glycemic profile and intestinal health of postmenopausal rats. Eighty Wistar rats were randomized into 4 ovariectomized (OVX) groups or 4 celiotomized groups treated with a standard diet (SD) or diet supplemented with YBP at 6% of fructooligosaccharide (FOS)/inulin. The continued consumption of YBP at 6% of FOS/inulin did not generate liver damage and gastrointestinal disorders. Rats fed with YBP displayed higher food consumption, but this did not increase the body weight gain, abdominal circumference and body fat percentual of OVX rats. Furthermore, we also found that the FOS/inulin fermentation present in the YBP resulted in cecum, ileum and colon crypts hypertrophy and increased the lactic acid levels in the cecal content. We observed an increase of glucagon-like peptide-1 (GLP-1) immunoreactive cells and there was no change in the glucose and insulin plasma levels of YBP-fed OVX rats. Our findings indicated that YBP when consumed previously and after the menopausal period has important effects on the morphology and function of intestinal mucous of rats and has potential to modulate indirectly the glycemic and insulinemic profiles, weight gain and body fat percentual in the hypoestrogenic period through metabolites produced in the fermentation process.


Recurrent abdominal pain in children.
Functional abdominal pain can occur in a well-defined clinical entity (e.g., IBS) or as a part of a poorly defined clinical syndrome. Although the clinician may feel compelled to exclude disease in all cases, the authors suggest that it is more appropriate to take a biopsychosocial approach. In so doing, there can be an appreciation of the close interaction of the gut and the brain, allowing the child, family, and physician the opportunity to address the pain on many levels. Although the parameters set forth by the pediatric ROME II committee have facilitated the authors' description of these disorders greatly, basic research likely will further delineate biochemical processes in the enteric and central nervous systems that will expand therapeutic horizons.


Ligand-induced functions of the epidermal growth factor receptor require the positively charged region asymmetrically distributed across plasma membrane.
Many plasma membrane proteins, including the epidermal growth factor (EGF) receptor, possess basic regions on the cytoplasmic surface of the membrane. To examine the function of these positively charged regions, we constructed mutated EGF receptor genes lacking this region by substitution of the basic amino acid residues with 3 approximately 8 neutral Asn residues, or by their complete deletion. There was no significant difference in the affinities for EGF of the wild-type and mutant receptors which are produced in rodent fibroblasts through transfection. However, EGF-induced tyrosine phosphorylation of the receptor was strongly inhibited by removal of the 3 approximately 8 positively charged residues. On addition of EGF, cells expressing the mutant EGF receptors did not show morphological changes, whereas cells expressing the wild-type receptor did. These findings suggest that the positively charged regions of membrane proteins that are asymmetrically distributed on the cytoplasmic surface of the membrane may be required for the functions of membrane proteins in general.


Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608).
The stress-induced hyperthermia test is a paradigm developed several years ago to model the expression of autonomic hyperactivity in anxiety. Whereas in the classical stress-induced hyperthermia, cohort removal was used, in a recently described modification of the stress-induced hyperthermia model singly housed mice rather than groups of mice were used. The modification of this model can be summarized as follows: rectal temperature is recorded in singly housed animals at two consecutive time-points (T1 and T2) which are interspaced by a defined time-interval (15 min). Since the value at the second temperature-recording exceeds the value of the initial measure it is the difference between these two core-temperatures which reflects stress-induced hyperthermia. In the present study, the stress-induced hyperthermia paradigm, in its modified design, was evaluated in OF1/IC mice. By comparing the effect of various compounds in both the modified as well as the classical (cohort removal) stress-induced hyperthermia paradigm, a very high correlation was found for the pharmacological sensitivity of the two paradigms. Furthermore, it was demonstrated that other anxiolytics, all known to be active in the classical stress-induced hyperthermia paradigm, such as the benzodiazepines chlordiazepoxide (0.3, 1, 3, 10 mg/kg, p.o.), diazepam (0.1, 0.3, 1, 3 mg/kg, p.o.), clobazam (5 or 10 mg/kg, p.o.) and oxazepam (5 or 10 mg/kg, p.o.) as well as the non-benzodiazepines buspirone (7.5 or 15 mg/kg, p.o.) and ethanol (15% or 30%, 10 ml/kg, p.o.), showed a marked reduction in stress-induced hyperthermia in the modified design. New candidate anxiolytics, i.e. the metabotropic glutamate (mGlu) receptor group 2 agonist LY314582 (1 or 10 mg/kg, p.o.; racemic mixture of LY354740 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid), the metabotropic glutamate 5 receptor antagonist MPEP (1, 7.5, 15 or 30 mg/kg, p.o.; 2-methyl-6-(phenylethynyl)pyridine) and the neurokinin 1 (NK1) receptor antagonist NKP608 (0.01 or 0.1 mg/kg, p.o.; quinoline-4-carboxylic acid [trans-(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amide) also reduced stress-induced hyperthermia in the modified paradigm clearly indicating anxiolytic-like activity for these compounds. Finally, the effects of the classical benzodiazepine chlordiazepoxide (10 mg/kg, p.o.), in parallel with its effect on stress-induced hyperthermia, were also investigated for its effect on plasma concentrations of the two stress hormones, adrenocorticotropin (ACTH) and corticosterone. It was shown that all three parameters were significantly increased 15 min after T1 in vehicle-treated mice whereas the increase was significantly attenuated following pre-treatment with chlordiazepoxide. In conclusion, all the data presented here indicate that the modified version of the stress-induced hyperthermia-paradigm is a valid and interesting alternative to the classical stress-induced hyperthermia test.


In situ measurement of absorption in high-power interferometers by using beam diameter measurements.
We present a simple technique to make in situ measurements of the absorption in the optics of high-power laser interferometers. The measurement is particularly useful to those commissioning large-scale high power optical systems.


Selective laser trabeculoplasty.
Selective laser trabeculoplasty (SLT) has been shown to be safe, well tolerated, and effective in intraocular pressure (IOP) reduction as therapy in several forms of open-angle glaucoma. The preservation of trabecular meshwork (TM) architecture and the demonstrated efficacy in lowering IOP make SLT a reasonable and safe alternative to argon laser trabeculoplasty (ALT). SLT may also be effective for cases of failed ALT and is a procedure that may also be repeatable, unlike ALT. SLT is also a simple technique for an ophthalmologist to learn as the large spot size eliminates the need to locate a particular zone of treatment on the TM. SLT has been demonstrated to be effective as primary treatment for open angle glaucoma and can be an effective adjunct in the early treatment of glaucoma. Furthermore, SLT can be considered as a primary treatment option in patients who cannot tolerate or who are noncompliant with their glaucoma medications, without interfering with the success of future surgery.


Exercise snacking to improve physical function in pre-frail older adult memory clinic patients: a 28-day pilot study.
Finding innovative yet feasible ways of preventing physical and cognitive decline in those at risk is a critical global challenge, with exercise being championed as a key precursor to robust health in later life. Exercise snacking, here defined as short bouts of sporadic [muscle-strengthening] exercise, is one such strategy designed to overcome typical participation barriers observed in older adults. This study examined the acceptability of exercise snacking amongst pre-frail older adults and explored the efficacy of this approach in improving physical function. In this single group design, 21 pre-frail outpatients with mild-cognitive impairment were recruited from a UK memory clinic. To be eligible, participants were aged ≥ 65-years who scored 3-8 (inclusive) on the short physical performance battery (SPPB) and were not regularly engaging in sport or exercise. Participants completed a 28-day, twice daily, exercise snacking intervention, consisting of five muscle-strengthening exercises, with the aim being to complete as many repetitions as possible of each exercise in a minute. Acceptability of the intervention was measured quantitatively and qualitatively using a survey and topic guide informed by the Theoretical Framework of Acceptability. Pre- and post-intervention physical function was measured using the SPPB, timed up-and-go (TUG), and 60s standing balance and sit-to-stand tests. Eighteen participants provided follow-up data and showed 85% adherence to the exercise snacking intervention, measured as the proportion of all sessions completed out of a possible 56. Participants rated the intervention as highly acceptable (4.6/5) suggesting it supported their self-efficacy (4.3/5) was enjoyable (4.1/5) and had a low burden (2.1/5). Qualitative findings suggested the ease of use, flexibility of the programme, and perceived effectiveness was important, and particularly useful for non-exercisers. Changes in SPPB score (8(1) vs. 9(3), p < 0.01), TUG (11.32(4.02) vs. 9.18(5.25) seconds, p < 0.01) and in the 60-second sit-to-stand test (17 ± 5 vs. 23 ± 7 repetitions, p < 0.01) were seen between baseline and follow-up. Exercise snacking is an acceptable and potentially efficacious format of exercise for pre-frail memory clinic attendees who are at heightened risk of falling and frailty. Large scale randomised controlled trials are required to confirm whether exercise snacking is effective in the short and long term. NCT05439252 (30/06/2022).


Onco-Nephrology in the Critical Care Setting: Recognizing and Treating Renal Manifestations of Cancer and Oncological Emergencies.
Onco-nephrology focuses on the care of patients with cancer and kidney disease. Patients with acute kidney injury, tumor lysis syndrome, and malignancy-associated hypercalcemia are frequently treated in a critical care setting. Oncological emergencies can have a high mortality rate when not promptly recognized and appropriately treated. The critical care nurse should be knowledgeable regarding the risk factors, clinical manifestations, and laboratory abnormalities of common renal manifestations of malignancy and oncological emergencies to optimize care and improve patient outcomes.


Biosynthesis of low molecular weight RNA in mouse myeloma cells.
The low molecular weight RNAs in the nucleus and cytoplasm of mouse myeloma cells have been characterized. There are major nuclear species (other than 5-S and tRNA), four of which contain 'capped' 5' termini. There are three major small cytoplasmic RNAs none of which contain 'caps'. The biosynthesis of the nuclear species when studied using [3H]adenosine as an RNA precursor is characterized by a rapid, transient appearance in the cytoplasm, followed by fixation in the nucleus. Within 15 min, the amount in the cytoplasm has reached a steady-state level maintained for 60 min, while the accumulation in nuclei is linear after a short lag (less than 5 min). When biosynthesis is studied using [Me-3H]methionine as a precursor, much less labeled RNA is present in the cytoplasm, suggesting that methylation may immediately precede fixation into the nucleus.


Structural insights on physiological functions and pathological effects of alpha-synuclein.
Alpha-synuclein is an intrinsically unfolded protein that can adopt a partially helical structure when it interacts with different lipid membranes. Its pathological relevance is linked to its involvement in several neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, and dementia with Lewy bodies. Typical of such ailments is the presence of alpha-synuclein aggregates in a beta-structure that can be soluble or precipitate. This review focuses on the structural knowledge acquired in recent years on the various conformations accessible to alpha-synuclein and to its pathologically relevant mutants. Furthermore, the role of the different variables of the chemical environments that govern the equilibria among the accessible conformations is also reviewed. The hypotheses that rationalize the relevance of the individual structural features and conformations for the physiological function of the protein or for its purported pathological role are described and compared.


Multidisciplinary collaborative care for depressive disorder in the occupational health setting: design of a randomised controlled trial and cost-effectiveness study.
Major depressive disorder (MDD) has major consequences for both patients and society, particularly in terms of needlessly long sick leave and reduced functioning. Although evidence-based treatments for MDD are available, they show disappointing results when implemented in daily practice. A focus on work is also lacking in the treatment of depressive disorder as well as communication of general practitioners (GPs) and other health care professionals with occupational physicians (OPs). The OP may play a more important role in the recovery of patients with MDD. Purpose of the present study is to tackle these obstacles by applying a collaborative care model, which has proven to be effective in the USA, with a focus on return to work (RTW). From a societal perspective, the (cost)effectiveness of this collaborative care treatment, as a way of transmural care, will be evaluated in depressed patients on sick leave in the occupational health setting. A randomised controlled trial in which the treatment of MDD in the occupational health setting will be evaluated in the Netherlands. A transmural collaborative care model, including Problem Solving Treatment (PST), a workplace intervention, antidepressant medication and manual guided self-help will be compared with care as usual (CAU). 126 Patients with MDD on sick leave between 4 and 12 weeks will be included in the study. Care in the intervention group will be provided by a multidisciplinary team of a trained OP-care manager and a consultant psychiatrist. The treatment is separated from the sickness certification. Data will be collected by means of questionnaires at baseline and at 3, 6, 9 and 12 months after baseline. Primary outcome measure is reduction of depressive symptoms, secondary outcome measure is time to RTW, tertiary outcome measure is the cost effectiveness. The high burden of MDD and the high level of sickness absence among people with MDD contribute to the relevance of this study. The intervention is an innovative approach, with trained OPs in a new role as care managers in the treatment of MDD. If this intervention proves to be cost-effective, implementation will be very relevant for individual patients as well as for society. ISRCTN78462860.


Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study.
Trastuzumab (T) combined with chemotherapy has been recently shown to improve outcome in HER2-positive breast cancer (BC). The aim of this study was to evaluate the toxic effects of concurrent radiation therapy (RT) and T administration in the adjuvant setting. Data of 146 patients with stages II-III HER2-positive BC were recorded. Median age was 46 years. In all, 32 (23%) and 114 (77%) patients received a weekly and a 3-week T schedule, respectively. A median dose of 50 Gy was delivered after surgery. Internal mammary chain (IMC) was irradiated in 103 (71%) patients. Grade >2 dermatitis and esophagitis were noted in 51% and 12%, respectively. According to the Common Toxicity Criteria v3.0 scale and HERA (HERceptin Adjuvant) trial criteria, respectively, 10% and 6% of the patients had a grade >/=2 of left ventricular ejection fraction (LVEF) decrease after RT. Multivariate analyses revealed two independent prognostic factors: weekly T administration (for LVEF decrease) and menopausal status (for dermatitis). Higher level of T cumulative dose (>1600 mg) was only borderline of statistical significance for acute esophagitis toxicity. We showed that weekly concurrent T and RT are feasible in daily clinical practice with, however, a decrease of LVEF. Cardiac volume sparing and patient selections for IMC irradiation are highly recommended. Longer follow-up is warranted to evaluate late toxic effects.


Cash transfers for HIV prevention: considering their potential.
Cash payments to vulnerable households and/or individuals have increasingly garnered attention as a means to reduce poverty, improve health and achieve other development-related outcomes. Recent evidence from Malawi and Tanzania suggests that cash transfers can impact HIV-related behaviours and outcomes and, therefore, could serve as an important addition to HIV prevention efforts. This article reviews the current evidence on cash transfers for HIV prevention and suggests unresolved questions for further research. Gaps include (1) understanding more about the mechanisms and pathways through which cash transfers affect HIV-related outcomes; (2) addressing key operational questions, including the potential feasibility and the costs and benefits of different models of transfers and conditionality; and (3) evaluating and enhancing the wider impacts of cash transfers on health and development. Ongoing and future studies should build on current findings to unpack unresolved questions and to collect additional evidence on the multiple impacts of transfers in different settings. Furthermore, in order to address questions on sustainability, cash transfer programmes need to be integrated with other sectors and programmes that address structural factors such as education and programming to promote gender equality and address HIV.


Structure and torsional dynamics of the water octamer from THz laser spectroscopy near 215 μm.
Clusters of eight water molecules play an important role in theoretical analysis of aqueous structure and dynamics but have proven to be challenging experimental targets. Here we report the high-resolution spectroscopic characterization of the water octamer. Terahertz (THz) vibration-rotation-tunneling (VRT) spectroscopy resolved 99 transitions with 1 part per million precision in a narrow range near 46.5 wave numbers, which were assigned to the h16 octamer via detailed isotope dilution experiments. Fitting to a semi-rigid symmetric top model supports predictions of two coexisting cuboidal structures and provides precise values for the changes in their rotational constants. Comparison with theory and previous spectroscopic data provides a characterization of the two structures and the observed torsional vibration and supports the prediction that the D2d symmetry structure is lower in energy than the S4 isomer.


Divergence analysis of failed and successful unanticipated single-leg landings reveals the importance of the flight phase and upper body biomechanics.
The purpose of this study was to describe neuromuscular and kinematic differences during failed and successful drop-vertical jumps in a pediatric population. Healthy young athletes (n = 32) completed single-leg drop vertical jump landings where the required landing leg was unanticipated. Trials were categorized as failed if the participant shifted their base of support during the landing. Joint kinematics and muscle activation amplitudes were time normalized over the flight and landing phases. Statistical parametric mapping (SPM) was used to compare landings and a moving average convergence divergence oscillator was then calculated to determine where failed and successful waveforms began to diverge prior to reaching statistical significance. SPM determined that participants performed the failed trials with reduced pelvic tilt towards the landing limb during 41-69% of the flight phase, greater trunk flexion angle during 31-100% of the landing phase and greater trunk tilt away from the landing limb during 3-13% and 21-90% of the landing phase. Greater rectus femoris activation during the failed trials was identified during 88-100% of the flight phase, as well as 1-4% and 71-97% of the landing phase. Greater gluteus medius and biceps femoris activation was also identified in the failed trials during 54-72% and 76-89% of the landing phase respectively. These findings indicate that the control of proximal joints has an important role in determining if a participant will fail a landing; and that how athletes prepare for a landing may be more relevant than the kinematics following ground contact.


Ectopic salivary gland tissue in the palatine and lingual tonsil.
A case is reported of a child born with a developmental field defect of the first branchial arch in whom there was partial obstruction of the oropharynx by a horseshoe-shaped mass of what was thought to be tonsillar tissue. 'Tonsillectomy' was performed but histopathological examination of the excised specimens showed them to be almost entirely made up of salivary gland tissue.


Inhibition of in vitro RNA synthesis by hycanthone, oxamniquine and praziquantel.
The schistosomicides, hycanthone, oxamniquine and praziquantel, were found to inhibit the in vitro RNA synthesis using isolated hamster liver nuclei. Preincubation of the nuclei with these drugs revealed that the inhibitory effect of oxamniquine was irreversible and progressed with time, whereas that of hycanthone and praziquantel was reversible. On the other hand, hycanthone and praziquantel have a high affinity for DNA but oxamniquine does not. The data indicate that the mechanism of inhibition by oxamniquine is different from that of hycanthone and praziquantel.


Assessment of cardiovascular risk of patients with arterial hypertension of a public health unit.
To assess the cardiovascular risk, using the Framingham risk score, in a sample of hypertensive individuals coming from a public primary care unit. The caseload comprised hypertensive individuals according to criteria established by the JNC VII, 2003, of 2003, among 1601 patients followed up in 1999, at the Cardiology and Arterial Hypertension Outpatients Clinic of the Teaching Primary Care Unit, at the Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. The patients were selected by draw, aged over 20 years, both genders, excluding pregnant women. It was a descriptive, cross-sectional, observational study. The Framingham risk score was used to stratify cardiovascular risk of developing coronary artery disease (death or non-fatal acute myocardial infarction). Age range of 27-79 years (x = 63.2 +/- 9.58). Out of 382 individuals studied, 270 (70.7%) were female and 139 (36.4%) were characterized as high cardiovascular risk for presenting diabetes mellitus, atherosclerosis documented by event or procedure. Out of 243 stratified patients, 127 (52.3%) had HDL-C < 50 mg/dL; 210 (86.4%) had systolic blood pressure > or = 120 mmHg; 46 (18.9%) were smokers; 33 (13.6%) had a high cardiovascular risk. Those added to 139 enrolled directly as high cardiovascular risk, totaled up 172 (45%); 77 (20.2%) of medium cardiovascular risk and 133 (34.8%) of low risk. The highest percentage of high cardiovascular risk individuals was aged over 70 years; those of medium risk were aged over 60 years; and the low risk patients were aged 50 to 69 years. The significant number of high and medium cardiovascular risk individuals indicates the need to closely follow them up.


No evidence for bioenergetic interaction between digestion and thermoregulation in Steller sea lions Eumetopias jubatus.
The increase in metabolism during digestion--the heat increment of feeding--is often regarded as an energetic waste product. However, it has been suggested that this energy could offset thermoregulatory costs in cold environments. We investigated this possibility by measuring the rate of oxygen consumption of four juvenile Steller sea lions (Eumetopias jubatus) before and after they ingested a meal in water temperatures of 2 degrees-8 degrees C. Rates of oxygen consumption of fasted and fed animals increased in parallel with decreasing water temperature, such that the apparent heat increment of feeding did not change with water temperature. These results suggest that Steller sea lions did not use the heat released during digestion to offset thermoregulatory costs.


Structural and functional aspects of intercellular junctions in vascular endothelium.
Cell-to-cell-junctions of endothelial cells are specialized and differentiated areas of the plasma membrane. The main functions include the separation of the intravascular and extravascular compartments, the mechanical connection of the cells, and the maintenance of the cell polarity. Although a wide heterogeneity of endothelial cell-to-cell junctions exists in situ, they should be considered in general as adherens type junctions in which gap and tight junctions are morphologically inserted. Under certain pathological conditions, such as wound healing, angiogenesis and many types of inflammation, the interendothelial junctions have to be dissociated and reorganized in which proteins of the junctions are crucially involved. These important mechanisms predict a sophisticated regulation of junctional proteins. The present paper describes the organization and functional aspects of the occludin/ZO-1 complex typically found in tight junctions, the cadherin/catenin complex of the adherens junctions and the connection of these protein complexes to the dense peripheral band via actin filaments. In addition, special attention has been drawn on the function of junction-associated proteins with respect to their role under fluid shear stress and interendothelial gap formation during inflammation.


Genomics applications to biotech traits: a revolution in progress?
Twenty years since the inception of the agricultural biotechnology era, only two products have had a significant impact in the market place: herbicide-resistant and insect-resistant crops. Additional products have been pursued but little success has been achieved, principally because of limited understanding of key genetic intervention points. Genomics tools have fueled a new strategy for identifying candidate genes. Primarily thanks to the application of functional genomics in Arabidopsis and other plants, the industry is now overwhelmed with candidate genes for transgenic intervention points. This success necessitates the application of genomics to the rapid validation of gene function and mode of action. As one example, the development of C-box binding factors (CBFs) for enhanced freezing and drought tolerance has been rapidly advanced because of the improved understanding generated by genomics technologies.


Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity.
Metaphocytes are tissue-resident macrophage (TRM)/dendritic cell (DC)-like cells of non-hematopoietic origin in zebrafish barrier tissues. One remarkable property of metaphocytes is their ability to capture soluble antigens from the external environment via transepithelial protrusions, a unique function manifested by specialized subpopulations of the TRMs/DCs in mammal barrier tissues. Yet, how metaphocytes acquire myeloid-like cell properties from non-hematopoietic precursors and how they regulate barrier immunity remains unknown. Here, we show that metaphocytes are in situ generated from local progenitors guided by the ETS transcription factor Spic, the deficiency of which results in the absence of metaphocytes. We further document that metaphocytes are the major IL-22BP-producing cells, and the depletion of metaphocytes causes dysregulated barrier immunity that resembles the phenotype of IL-22BP-deficient mice. These findings reveal the ontogeny, development, and function of metaphocytes in zebrafish, which facilitates our understanding of the nature and function of the mammalian TRM/DC counterparts.


Segmental bioimpedance for measuring amlodipine-induced pedal edema: a placebo-controlled study.
The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema in short-term (<4-week) clinical trials have not been reported in the literature. The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives. The efficacy of segmental bioimpedance in the detection of increased pedal edema was compared with that of clinical pitting assessment, ankle circumference, and water displacement volumetry. The study population consisted of male and female healthy subjects and patients with stage 1 or 2 hypertension who were otherwise healthy. Participants were randomly assigned to receive amlodipine 10 mg or placebo once daily in this 6-week, double-blind, parallel-group study. Amlodipine was used as a means of inducing ankle edema, and not for the treatment of hypertension. Patients with hypertension were required to undergo a washout of antihypertensive therapies. Edema was evaluated using segmental bioimpedance at 10 kHz, clinical pitting assessment, ankle circumference, and water displacement at weeks 2, 4, and 6. The ANOVA model used included treatment and baseline values as covariates, with treatment pairs compared via t tests derived from the model. A total of 47 individuals were randomized (49% male; 29 [62%] with hypertension; mean [SD] age, 59 [5.9] years; baseline body mass index, 28.6 kg/m(2) [2.8]; blood pressure 146.6 [10.7]/93.5 [6.5] and 139.3 [8.3]/89.5 [4.5] in individuals with and without hypertension, respectively; amlodipine 10 mg, n = 24; placebo, n = 23). At weeks 2, 4, and 6, statistically significant treatment differences in changes from baseline were detected using water displacement (mean [90% CI] treatment differences, +39.0 g [+17.9 to +60.1], +61.9 g [+36.1 to +87.6], and +72.2 g [+42.3 to +102.1], respectively; all, P ≤ 0.001), ankle circumference (+4.74 mm [+2.38 to +7.11; P < 0.001], +2.92 mm [+0.33 to +5.49; P = 0.032], and +5.16 mm [+2.21 to +8.11; P = 0.002]), and bioimpedance (-11.7 Ω [-18.1 to -5.4], -18.3 Ω [-26.2 to -10.4], and -20.9 Ω [-29.7 to -12.0]; all, P≤0.001), but no significant differences were detected using clinical assessment of pitting. In this population of healthy subjects and patients with hypertension, segmental bioimpedance was comparable to water displacement and ankle circumference and outperformed clinical assessment of pitting for the detection of ankle edema, supporting the use of segmental bioimpedance as a drug-development tool to objectively quantify amlodipine-induced pedal edema.


Industry sponsorship and authorship of clinical trials over 20 years.
The pharmaceutical industry has become a major source of funding for biomedical research. Our general observation is that pharmaceutical industry employees are appearing with increasing frequency as coauthors of clinical trial publications. To characterize clinical trial funding, reporting, and sources; investigate author-industry affiliation; and describe clinical outcome trends over time. We reviewed 500 randomly selected clinical trials published in 5 influential medical journals over a 20-year period (1981-2000). Of the 500 clinical trials reviewed, 181 (36%) involved pharmaceutical industry as an independent (n = 104) or joint (n = 77) sponsor and 180 (36%) involved a peer-review funding source; the balance (139; 28%) lacked any declared sponsorship. The percentage of industry-sponsored clinical trials increased to 62% during 1997-2000. The percentage of nonprofit sponsored clinical trials remained constant over time, while the percentage of those without funding declaration declined. Reported author affiliation with industry increased to 66% of clinical trials sponsored only by industry. An increase in the percentage of clinical trials with reported author-industry affiliation was observed for all journals. Regardless of funding source, the majority of clinical trials reported clinical outcomes that favored the study drug. Pharmaceutical industry-sponsored and mixed-funding clinical trials are common, and the relative incidence of published trials with these declared funding sources in the 5 journals reviewed has increased. Industry employees are appearing as coauthors of clinical trial publications with increasing frequency.


Differential expression of the Ca2+-binding protein parvalbumin during myogenesis in Xenopus laevis.
We have used immunocytological techniques to examine the developmental expression of the Ca2+-binding protein parvalbumin in Xenopus laevis embryos. Western blot experiments show that at least three different forms of parvalbumin are expressed during embryogenesis; the tadpole tail expresses one form, adult brain expresses another, mylohyoid muscle expresses both, and gastrocnemius and sartorius muscles express these two plus a third form. Parvalbumin (PV) is first detectable by immunofluorescence at stages 24-25 of development, a time when myotomal muscles are differentiating and contractile activity occurs spontaneously in embryos. At metamorphosis, PV is expressed in developing limb muscles. While the majority of skeletal muscle fibers express high levels of PV in both embryos and adults, a second fiber type has no detectable PV. The arrangement of PV-containing fibers is stereotyped in each muscle group examined. Histochemical staining of tadpole muscles indicate that PV-containing fibers correspond to fast-twitch skeletal muscles, whereas those without PV correspond to slow-twitch muscles. During tail resorption at metamorphosis, PV appears to be extruded from dying tail muscle cells and taken up by phagocytic cells.


Dynamic contrast-enhanced (DCE) imaging: state of the art and applications in whole-body imaging.
Dynamic contrast-enhanced (DCE) imaging is a non-invasive technique used for the evaluation of tissue vascularity features through imaging series acquisition after contrast medium administration. Over the years, the study technique and protocols have evolved, seeing a growing application of this method across different imaging modalities for the study of almost all body districts. The main and most consolidated current applications concern MRI imaging for the study of tumors, but an increasing number of studies are evaluating the use of this technique also for inflammatory pathologies and functional studies. Furthermore, the recent advent of artificial intelligence techniques is opening up a vast scenario for the analysis of quantitative information deriving from DCE. The purpose of this article is to provide a comprehensive update on the techniques, protocols, and clinical applications - both established and emerging - of DCE in whole-body imaging.


Formation of sulphmyoglobin during expression of horse heart myoglobin in Escherichia coli.
Expression of recombinant horse heart myoglobin in Escherichia coli has been found to result in the production of both native and variable amounts (approximately 16-17% total) of two sulphmyoglobin isomers. The recombinant sulphmyoglobin produced consists primarily of the A and B isomers as identified by 1H NMR spectroscopy with no evidence for production of the C isomer. Conversion of recombinant sulphmyoglobin to the native protein can be achieved by reconstitution with protohaem IX. The possible relationship of this observation to recombinant expression of other heme proteins is discussed.


Phacomatosis pigmentovascularis type IIb associated with Sturge-Weber syndrome and pyogenic granuloma.
A case of phacomatosis pigmentovascularis (PPV) in a 6-year-old girl with Sturge-Weber syndrome, pyogenic granuloma, and other complications is described. It is relatively rare that a complete form of Sturge-Weber syndrome was associated with PPV. A review of the literature on PPV, focusing on total number of reported cases and etiological speculations, is presented. To our knowledge, a total of 118 cases of PPV, including the present one, have been reported to date. Regardless of many speculations, the true etiology remains unknown. The average "density" of mast cells (MCs) per mm2 appearing in the central region of the pyogenic granuloma was calculated to be 86.3/mm2 and that in the adjacent nevus flammeus was 37.9/mm2. The "density" of mast cells in pyogenic granuloma separately calculated from ten other cases was 105.5 +/- 28.6/mm2 (mean +/- SD), compared with that in normal skin, 6.85 +/- 4.9/mm2 (n = 20). There was a significant difference between the two, indicating that MCs are closely associated with angiogenesis in pyogenic granuloma.


UV irradiation activates JNK and increases alphaI(I) collagen gene expression in rat hepatic stellate cells.
Hepatic stellate cells (HSCs) become activated into myofibroblast-like cells during the early stages of hepatic injury associated with fibrogenesis. The subsequent dysregulation of alphaI(I) collagen gene expression is a central pathogenetic step during the development of cirrhosis. Our recent study in rat HSCs (Davis, B. H., Chen, A., and Beno, D. (1996) J. Biol. Chem. 271, 11039-11042) found that ERK1,2 activation might be required for maximal alphaI(I) collagen gene expression. However, the role of the parallel JNK cascade in regulating alphaI(I) collagen gene expression was unknown. In this study, we initially found that UV irradiation of HSCs activated JNK but not ERK1,2. Furthermore, UV irradiation increased endogenous alpha I(I) collagen mRNA abundance and stimulated alpha I(I) collagen gene transcription in HSCs. The effect of the activation of JNK and Jun on alpha I(I) collagen gene expression was further evaluated via transfection of chloramphenicol acetyltransferase reporter plasmids with various sizes of truncated 5' upstream promoter sequence (UPS) of the alphaI(I) collagen gene. This revealed that dominant negative transcription factor JUN suppressed alpha I(I) collagen gene transcription in HSCs maintained in media with 20% serum and constitutively activated JUN increased alphaI(I) collagen gene transcription in HSCs cultured in media with 0.4% serum. UV activated JNK utilized a distal GC box in the 5'-UPS of the collagen gene to regulate gene transcription. This observation was confirmed by site-directed mutagenesis. In co-transfection experiments, the col-chloramphenicol acetyltransferase reporter with a mutagenized GC box was not suppressed by dn-JUN and was not stimulated by activated JUN or by UV irradiation. Southwestern blotting analyses and gel shift assays with basic transcription element-binding protein antiserum suggested that the GC box was bound by basic transcription element-binding protein, a recently described DNA-binding protein. In conclusion, the current study combined with our previous report suggests that ERK1,2 and JNK cascades regulate alphaI(I) collagen expression in HSCs through different regions of the 5'-UPS of the gene. The distal GC box in the 5'-UPS of the alphaI(I) collagen gene may play a central role in receiving extracellular signals through the JNK pathway.


The development of essentialist, ethnic, and civic intuitions about national categories.
Given current global migration patterns, understanding of children's intuitions about nationality and national categories is an important and emerging focus for developmental psychologists. We review theoretical and empirical work on three different types of intuition: (1) that nationality is primarily determined by ancestry (an ethnic intuition); (2) that nationality is determined by commitment to national institutions (a civic intuition); and (3) that membership in a national category is determined by possession of an invisible essence which explains the similarities between members of that category. We examine assumptions about the relations which hold between all three intuitions and derive a series of questions about how these intuitions develop, how they relate to each other, and how they might be affected by children's experience. We describe a study (N=196) suggesting that (1) most children, regardless of experience, possess elements of both ethnic and civic intuitions, and (2) essentialist intuitions about national categories decrease with age and are not associated with ethnic intuitions. We conclude by outlining the implications of these results and a number of important questions which they raise.


The association between triglycerides and incident cardiovascular disease: What is "optimal"?
Elevated triglycerides (TGs) are associated with increased risk of cardiovascular disease (CVD), but the best way to both measure TGs and assess TG-related risk remains unknown. The objective of the study was to evaluate the association between TGs and CVD and determine whether the average of a series of TG measurements is more predictive of CVD risk than a single TG measurement. We examined 15,792 study participants, aged 40-65 years, free of CVD from the Atherosclerosis Risk in Communities and Framingham Offspring studies, using fasting TG measurements across multiple examinations over time. With up to 10 years of follow-up, we assessed time-to-first CVD event, as well as a composite of myocardial infarction, stroke, or cardiovascular death. Compared with a single TG measurement, average TGs over time had greater discrimination for CVD risk (C-statistic, 0.60 vs 0.57). Risk for CVD increased as average TGs rose until an inflection point of ~100 mg/dL in men and ~200 mg/dL in women, above which this risk association plateaued. The relationship between average TGs and CVD remained statistically significant in multivariable modeling adjusting for low-density lipoprotein cholesterol, and interactions were found by sex and high-density lipoprotein cholesterol level. The average of several TG readings provides incremental improvements for the prediction of CVD relative to a single TG measurement. Regardless of the method of measurement, higher TGs were associated with increased CVD risk, even at levels previously considered "optimal" (<150 mg/dL).


Reduced readmission rate for alternating diagnoses of heart failure and pulmonary disease after implementation of B-type natriuretic peptide testing.
Patients with heart failure (HF) or pulmonary diseases (PD) present with similar symptoms. Effective disease management requires an accurate diagnosis. B-type natriuretic peptide (BNP) is increased in patients with HF and is normal in PD patients without cardiac involvement. To determine if the readmission rate for patients with either HF or PD who later present with the alternate diagnosis (PD or HF) is decreased with the implementation of BNP testing at one hospital. We retrospectively determined the impact of BNP testing on reducing diagnostic ambiguities for patients admitted to an emergency department (ED) with these diseases. We compared a HF DRG (Diagnostic Related Group) (#428) and PD DRGs (#480-496) before vs. 1 and 2 y after implementation of BNP testing. In a 12-month period before BNP, there were 42 total visits (15 cases) where a patient presented with a HF DRG and returned within 6 months with a PD DRG, and 41 visits (14 cases) where there was a PD-->HF readmission. One year after BNP implementation, the corresponding number of visits decreased 52% to 20 visits (15 cases) for HF-->PD, and 73% to 11 visits (8 cases) for PD-->HF readmissions. A similar reduction in readmissions was observed in the second year after BNP testing. The total number of HF and PD cases in 1999 (1029 patients) was similar to 2001 (985), and was higher in 2002 (1350) during these time intervals. The ED length-of-stay (LOS) was slightly higher for the HF-->PD cases with BNP testing, whereas there was no change in LOS for the PD-->HF cases. We hypothesize that prior to BNP implementation, there may have been diagnostic ambiguities in the initial diagnosis of HF or PD, which contributed to a repeat visit for the alternate diagnosis (PD or HF). With BNP testing, the apparent number of inappropriate visits decreased. Reducing unnecessary ED admissions helps justify the costs for implementing BNP testing in the hospital.


[Relationship between EGFR Promoter Region Methylation and Secondary Resistance Which may be Induced by Gefitinib].
Nowadays the secondary resistance of gefitinib in the treatment of lung adenocarcinoma is an outstanding problem. This research is to explore whether the gefitinib secondary resistance can be induced by gefitinib, to explore whether epidermal growth factor receptor (EGFR) promotor methylation correlate with the gefitinib-resistance in PC9/GR cell lines and to find a new therapeutic target to overcome the gefitinib secondary resistance in lung adenocarcinoma. In vitro cultivation of lung adenocarcinoma PC9 cell lines, apply gefitinib on lung adenocarcinoma PC9 cell lines, and improve drug concentration. MTT for test of gefitinib resistance index in PC9 cell and PC9/GR cell. Bisulfite sequencing polymerase chain reaction (BSP) and Reverse transcription-polymerase chain reaction (RT-PCR) for detection of EGFR promoter methylation status and mRNA expression. In vitro cultivation of lung adenocarcinoma PC9 cell lines, apply 1 μmol/L 5-Aza-dc on lung adenocarcinoma PC9/GR cell lines for 72 h. MTT method for test of gefitinib resistance index in PC9/GR cell. After improving the gefitinib concentration, MTT results showed that half maximal inhibitory concentration (IC50) of PC9 cell lines increase from (0.01 ± 0.002) μmol/L to (3.95 ± 0.23) μmol/L (P<0.05). BSP results showed that abnormal methylation sites compared the degree of methylation change: PC9: 59%; PC9/GR: 74% (P<0.05). RT-PCR results showed in PC9/GR cell lines, EGFR mRNA expression quantity increased (P<0.05). After applying 5-Aza-dc on PC9 cell lines, IC50 of PC9/GR decrease from (3.87 ± 0.034) μmol/L to (2.55 ± 0.14) μmol/L. The PC9 cell line which is induced by improving gefitinib concentration will be resistant to gefitinib, and the gefitinib-resistant cell line PC9/GR could be built. EGFR gene promoter methylation may be one of the mechanisms for the secondary resistance to gefitinib.


lncRNA SNHG8 promotes aggressive behaviors of nasopharyngeal carcinoma via regulating miR-656-3p/SATB1 axis.
Long non-coding RNA (lncRNA) has been proposed to regulate tumorigenesis, however, the role of small nucleolar RNA host gene 8 (SNHG8) in nasopharyngeal carcinoma (NPC) remains unclear. Levels of SNHG8 in NPC tissues and cells were analyzed with real-time quantitative PCR method. Cell counting kit-8 assay, colony formation assay, wound-healing assay, and transwell invasion assay were performed to detect cell viability, migration, and invasion. Luciferase activity assay and RIP assay were performed to explore relationships among SNHG8, microRNA-656-3p (miR-656-3p), and special AT-rich sequence-binding protein 1 (SATB1). We found SNHG8 level was increased expression in NPC tissues and cells.In vitro assays revealed that SNHG8 stimulates NPC cell proliferation, colony formation, cell migration, and cell invasion. In vivo assay confirmed knockdown of SNHG8 could hamper tumor growth. Furthermore, we showed SNHG8 serves as a sponge for miR-656-3p to regulate SATB1 expression, and participated in NPC progression. In summary, our work indicated the importance of SNHG8 in NPC progression, which provided novel treatment methods for NPC.


Identification and characterization of mouse Gas6 promoter.
In this study, we identify and characterize the promoter of the mouse Gas6 gene, a negative regulator of chondrogenic differentiation. We identified two highly conserved regions within the core Gas6 promoter, which are conserved among mouse, human, and rat Gas6 genes, named A-BOX and B-BOX. Basal transcriptional activity was significantly reduced after deletion of either the A-BOX or the latter half of the B-BOX. After treatment with BMP-2 for 3 days, putative A-BOX Binding Factor(s) B (ABFB) and B-BOX Binding Factor(s) (BBF) were unable to bind to their specific motifs in C3H10T1/2 cells, compared with untreated control cells. In addition, we confirmed binding of an NF-Y site within the core promoter region of mouse Gas6 gene. Taken together, these observations provide insight into the mechanism by which Gas6 is downregulated during mesenchymal stem cells differentiation into chondrocytes.


Peptides as modulators of enzymes and regulatory proteins.
There is currently great interest in the development of methods to modulate the function of diverse classes of target proteins with chemicals (agonists or antagonists). These would be valuable reagents for biomedical research and some might serve as potential drug leads. Traditionally, most chemicals that modulate protein function have been enzyme inhibitors isolated in functional screens specific for the enzyme of interest. However, recent efforts from many laboratories have suggested that relatively simple binding assays may provide a more convenient and general route to chemical modulators. We review here this work with a particular emphasis on peptide modulators.


Neural processing correlates of assaultive violence exposure and PTSD symptoms during implicit threat processing: a network-level analysis among adolescent girls.
Assaultive violence exposure during childhood is a significant risk factor for posttraumatic stress disorder (PTSD). The purpose of the present study was to characterize the relationships of assault and PTSD severity with the organization of large-scale networks identified during emotion processing. Adolescent girls aged 12-16 with (N=15) and without (N=15) histories of assault underwent functional magnetic resonance imaging (fMRI) while engaged in a task that presented images of fearful or neutral facial expressions. Independent component analysis (ICA) identified a frontocingulate network, a frontoparietal network, and a default mode network. Assault exposure was associated with significantly greater activation of the frontocingulate network for fear versus neutral faces. Within the frontocingulate network, Posttraumatic stress disorder (PTSD) severity was associated with weakened functional connectivity between the left amygdala and the perigenual anterior cingulate. Within the frontoparietal network, assaulted girls demonstrated weakened connectivity of the premotor cortex with the right middle frontal gyrus. Within the default mode network, assault exposure and PTSD severity were associated with strengthening functional connectivity of the parahippocampus with the medial and lateral prefrontal cortex, respectively. Individual differences in functional connections within the frontocingulate network and frontoparietal network among the assaulted group were strongly associated with caregiver-rated family disengagement. These results demonstrate associations between assault and PTSD symptoms with the functional organization of large-scale frontoparietal, frontocingulate, and default mode networks during emotion processing. The relationship with caregiver-rated family disengagement suggests the impact of family support on the neural processing correlates of assault and PTSD symptoms.


[The role of metabolic and regulatory factors in the mutagenic activity of purine derivatives in microorganisms].
The results concerning analysis of the mutagenic activity of analogues of nitrogen bases are given for Saccharomyces cerevisiae, Streptomyces antibioticus, Bacillus subtilis. The mutagenic activity of purine derivatives depends on their metabolic transformations in cell and on the activity of enzyme systems, involved in regulation of purine biosynthesis. The criterion of selection of purine analogues with genetic activity is proposed for yeasts, based on retroinhibitory ability of analogues of nitrogen bases.


Reversibility of Schistosoma mansoni-associated morbidity after yearly mass praziquantel therapy: ultrasonographic assessment.
A parasitological, clinical and ultrasonographic longitudinal study was undertaken in 1993 in a focus hyperendemic for Schistosoma mansoni infection in the central highlands of Madagascar. All the inhabitants were systematically treated with praziquantel. A complete examination and treatment were repeated each year. Among the 289 villagers who underwent the complete 3 years' follow up, 65.9% excreted eggs at the initial survey and the mean egg count of infected individuals was 202 eggs/g. In 1996, the prevalence of infection was 19.3% with a mean egg count of 27 eggs/g and, among inhabitants aged > 44 years, only one was found to be infected. The proportion of individuals complaining of bloody stool decreased from 24.9% in 1993 to 8.4% in 1996. Compared to the initial clinical examination, the age-adjusted prevalence of splenomegaly was significantly lower in 1996, but remained high: 62% in the 10-14 years age group and 59% in individuals aged > 24 years. Ultrasonographic examination after 3 years of praziquantel therapy showed a marked decrease of the overall prevalence of schistosomal hepatic fibrosis, from 28% in 1993 to 10.3% in 1996. This improvement had already been achieved during the second year of follow-up for most subjects. Usually, the reversal of morbidity affected individuals classified as stage 1 at the beginning of the study. Stage 3 was not observed in the last 2 surveys. One patient's ascites disappeared during the follow-up, associated with a significant reversal of periportal fibrosis. Our results indicate that repeated praziquantel therapy can lead to improvement of liver morbidity and the prevention of the development of schistosomal hepatic fibrosis, even in an old-established hyperendemic focus.


Studies on the total synthesis of bisindole alkaloids in the vinblastine-vincristine series.
A series of investigations involving the total syntheses of a variety of indole and dihydroindole alkaloids in the Aspidosperma, Iboga and Vinca families are discussed. In this lecture particular emphasis is placed on studies relating to the synthesis of the clinically important bisindole or "dimeric" alkaloids of the vinblastine-vincristine family. Apart from the activity demonstrated by the natural alkaloids, it is shown that closely related synthetic derivatives can possess interesting anti-tumor activity as well.


Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo.
To investigate whether ketone bodies are directly anticonvulsant. We tested the effects of acetoacetate (ACA), acetone, and both stereoisomers, D-(-)- and L-(+), of beta-hydroxybutyrate (BHB) on sensory-evoked seizures in Frings audiogenic seizure-susceptible mice. We found that these ketone bodies, with the exception of the D-(-)-isomer of BHB, were anticonvulsant in this model. Furthermore, with gas chromatography-mass spectrometry, we confirmed that the activity of L-(+)-BHB was due to dibenzylamine, a chemical contaminant. Our data indicate that the anticonvulsant efficacy of the ketogenic diet may be due in part to the direct actions of ACA and acetone.


Machine learning in the prediction of cardiac epicardial and mediastinal fat volumes.
We propose a methodology to predict the cardiac epicardial and mediastinal fat volumes in computed tomography images using regression algorithms. The obtained results indicate that it is feasible to predict these fats with a high degree of correlation, thus alleviating the requirement for manual or automatic segmentation of both fat volumes. Instead, segmenting just one of them suffices, while the volume of the other may be predicted fairly precisely. The correlation coefficient obtained by the Rotation Forest algorithm using MLP Regressor for predicting the mediastinal fat based on the epicardial fat was 0.9876, with a relative absolute error of 14.4% and a root relative squared error of 15.7%. The best correlation coefficient obtained in the prediction of the epicardial fat based on the mediastinal was 0.9683 with a relative absolute error of 19.6% and a relative squared error of 24.9%. Moreover, we analysed the feasibility of using linear regressors, which provide an intuitive interpretation of the underlying approximations. In this case, the obtained correlation coefficient was 0.9534 for predicting the mediastinal fat based on the epicardial, with a relative absolute error of 31.6% and a root relative squared error of 30.1%. On the prediction of the epicardial fat based on the mediastinal fat, the correlation coefficient was 0.8531, with a relative absolute error of 50.43% and a root relative squared error of 52.06%. In summary, it is possible to speed up general medical analyses and some segmentation and quantification methods that are currently employed in the state-of-the-art by using this prediction approach, which consequently reduces costs and therefore enables preventive treatments that may lead to a reduction of health problems.


DNA methylation landscapes: provocative insights from epigenomics.
The genomes of many animals, plants and fungi are tagged by methylation of DNA cytosine. To understand the biological significance of this epigenetic mark it is essential to know where in the genome it is located. New techniques are making it easier to map DNA methylation patterns on a large scale and the results have already provided surprises. In particular, the conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged. Not only is promoter methylation often highly dynamic during development, but many organisms also seem to target DNA methylation specifically to the bodies of active genes.


Staphylococcus aureus induces TGF-β1 and bFGF expression through the activation of AP-1 and NF-κB transcription factors in bovine mammary gland fibroblasts.
Staphylococcus aureus is a common Gram-positive pathogen that causes bovine mastitis, a persistent infection of the bovine mammary gland. To better understand the importance of bovine mammary fibroblasts (BMFBs) and the roles of the TLR-NF-κB and TLR-AP-1 signaling pathways in the regulation of S. aureus-associated mastitis and mammary fibosis, BMFBs cultured in vitro were stimulated with different concentrations of heat-inactivated S. aureus to analyze the gene and protein expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) as well as the protein expression of nuclear factor-kappa B (NF-κB) and activation protein-1 (AP-1) by means of quantitative polymerase chain reaction (qPCR) and western blotting, respectively. Specific NF-κB and AP-1 inhibitors were also used to investigate their effects on the regulation of TGF-β1 and bFGF expression. The results indicated that, in addition to increasing mRNA and protein expression of TLR2 and TLR4, S. aureus could also upregulate TGF-β1 and bFGF mRNA expression and secretion through the activation of NF-κB and AP-1. The increase in TGF-β1 and bFGF expression was shown to be inhibited by AP-1- and NF-κB-specific inhibitors. Taken together, S. aureus induces TGF-β1 and bFGF expression through the activation of AP-1 and NF-κB in BMFBs. This information offers new potential targets for the treatment of bovine mammary fibrosis.


Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-β (1-42) and NF-κB pathway.
Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by a gradual decline in cognitive and memory functions of the aged peoples. Long-term exposure to heavy metals (aluminium and iron) cause neurotoxicity by amyloid plaques accumulation, tau phosphorylation, increased oxidative stress, neuroinflammation, and cholinergic neurons degeneration, contributes to the development of AD-like symptoms. The present research work is designed to investigate the neuroprotective effect of spermine in aluminium chloride (AlCl3), and iron (Fe) induced AD-like symptoms in rats. Rats were administered of AlCl3 (100 mg/kg p.o.) alone and in combination with iron (120 μg/g, p.o.) for 28 days. Spermine (5 and 10 mg/kg) through intraperitoneal (i.p.) route was given for 14 days. The recognition and spatial memory impairment were tasted using Morris water maze (MWM), actophotometer, and Novel Object Recognition test (NORT). All the rats were sacrificed on day 29, brains were isolated, and tissue homogenate was used for neuroinflammatory, biochemical, neurotransmitters, metals concentration, and nuclear factor-kappa B (NF-κB) analysis. In the present study, AlCl3 and iron administration elevated oxidative stress, cytokines release, dysbalanced neurotransmitters concentration, and biochemical changes. Rats treated with spermine dose-dependently improved the recognition and spatial memory, attenuated proinflammatory cytokine release, and restored neurotransmitters concentration and antioxidant enzymes. Spermine also mitigated the increased beta-amyloid (Aβ42), with downregulation of tau phosphorylation. Furthermore, spermine augmented the hippocampal levels of B cell leukaemia/lymphoma-2 (Bcl-2), diminished nuclear factor-kappa B (NF-κB) and caspase-3 (casp-3) expression. Moreover, spermine exhibited the neuroprotective effect through anti-inflammatory, antioxidant, neurotransmitters restoration, anti-apoptotic Aβ42 concentration.


Enhancing electronic metal support interaction (EMSI) over Pt/TiO2 for efficient catalytic wet air oxidation of phenol in wastewater.
Phenol is one of the major hazardous organic compounds in industrial wastewater. In this work, a highly active Pt/TiO2 catalyst for catalytic wet air oxidation (CWAO) of phenol was obtained by supporting pre-synthesized Pt on TiO2. During the followed hydrogen reduction, strong hydrogen spillover occurred without the migration of TiO2 onto Pt. The reduced support then enhanced the electron transfer from TiO2 to Pt, increasing the percentage of partially negative Pt (Ptδ-), which has been confirmed by XPS. The strong EMSI made the obtained catalyst far more active than Pt/TiO2 prepared by impregnation method. The electron-enriched Pt/TiO2 achieved total organic carbon (TOC) conversion of 88.8% and TOF 149 h-1 at 100 °C and 2 MPa O2, while conventional Pt/TiO2 gave TOC conversion of 39.5% and TOF 41 h-1 for CWAO of phenol. Our work indicates that the enhancement of EMSI between metal and support can be an effective approach to develop highly active catalysts for phenol treatment.


Serial case report of high seizure threshold patients that responded to the lengthening of pulse width in ECT.
Electroconvulsive therapy (ECT) has been used as an effective treatment modality for psychiatric disorders. In patients with high seizure thresholds, augmentation strategies are considered such as changing anesthetic agents, hyperventilation, and premedication with theophylline. We tried to switch to "long (1.5 ms)" brief pulse ECT in all six patients from October 2020. The successful induction of effective seizures with "long" brief pulse stimulation in five of six patients who could not be treated adequately with standard ECT. In the current situation in cases in which brief pulse ECT, with the maximum dose did not lead to effective seizures, "long" brief pulse waves may be a promising option.