Cost-effectiveness analysis of 3 months of weekly rifapentine and isoniazid compared to isoniazid monotherapy in a Canadian arctic setting.
To assess the cost effectiveness of once weekly rifapentine and isoniazid for 12 weeks (3HP) to the current standard care for latent tuberculosis (TB) infection (LTBI) in Iqaluit, Nunavut. A cost-effectiveness analysis using a Markov model reflecting local practices for LTBI treatment. A remote Canadian arctic community with a high incidence of TB. Hypothetical patients with LTBI. The cost effectiveness of 3HP was compared with the existing standard of care in the study region which consists of 9 months of twice weekly isoniazid (9H) given by directly observed therapy. Effectiveness was measured in quality-adjusted life years (QALYs) with model parameters were derived from historical programmatic data, a local implementation study of 3HP and published literature. Costs from the perspective of the Nunavut healthcare system were measured in 2019 US dollars and were obtained primarily from local, empirically collected data. Secondary health outcomes included estimated TB cases and TB deaths averted using 3HP versus 9H. One way and probabilistic sensitivity analyses were performed. The 3HP regimen was dominant over 9H: costs were lower (US$628 vs US$924/person) and health outcomes slightly improved (20.14 vs 20.13 QALYs/person). In comparison to 9H, 3HP treatment resulted in fewer TB cases (27.89 vs 30.16/1000 persons) and TB deaths (2.29 vs 2.48/1000 persons). 3HP completion, initiation and risk of fatal adverse events were the primary drivers of cost effectiveness. In a remote Canadian arctic setting, using 3HP instead of 9H for LTBI treatment may result in cost savings and similar or improved health outcomes.


Esophageal and gastric motor abnormalities in gastroesophageal reflux during infancy.
Thirty-four infants with symptoms of gastroesophageal reflux were evaluated by esophageal manometry, pH probe, and gastric emptying studies. Infants with failure to thrive (group A) and recurrent pulmonary disease (group B) had more severe reflux by pH probe (41.6% and 36.3% reflux time postprandially, respectively) than the group of infants without serious sequellae of gastroesophageal reflux (group C), who had 19.0% reflux time postprandially, p less than 0.01. Lower esophageal sphincter pressure did not vary significantly between infants with severe reflux and milder disease. Groups A and B had significantly decreased peristaltic amplitude in the distal body of the esophagus (28.3 +/- 4.8 and 23.2 +/- 5.5 mmHg, respectively) when compared to group C (50.2 +/- 3.2 mm Hg, p less than 0.01); in addition to a significantly increased number of nonperistaltic sequences. Gastric emptying of isotope-labeled cow's milk formula after 1 h was 20.9% and 22.8% in groups A and B, respectively; significantly delayed compared to 40.6% of the meal emptied in group C infants. Gastric retention was significantly correlated with impaired distal esophageal peristaltic amplitude (r = 0.68) and increased postprandial pH documented reflux (r = 0.60). Our results provide evidence for the diffuse nature of the upper gastrointestinal motility disorder present in severe gastroesophageal reflux of infancy.


Dopamine modulates diurnal and circadian rhythms of protein phosphorylation in photoreceptor cells of mouse retina.
Many aspects of photoreceptor metabolism are regulated as diurnal or circadian rhythms. The nature of the signals that drive rhythms in mouse photoreceptors is unknown. Dopamine amacrine cells in mouse retina express core circadian clock genes, leading us to test the hypothesis that dopamine regulates rhythms of protein phosphorylation in photoreceptor cells. To this end we investigated the phosphorylation of phosducin, an abundant photoreceptor-specific phosphoprotein. In mice exposed to a daily light-dark cycle, robust daily rhythms of phosducin phosphorylation and retinal dopamine metabolism were observed. Phospho-phosducin levels were low during the daytime and high at night, and correlated negatively with levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid. The effect of light on phospho-phosducin levels was mimicked by pharmacological activation of dopamine D4 receptors. The amplitude of the diurnal rhythm of phospho-phosducin was reduced by > 50% in D4 receptor-knockout mice, due to higher daytime levels of phospho-phosducin. In addition, the daytime level of phospho-phosducin was significantly elevated by L-745,870, a dopamine D4 receptor antagonist. These data indicate that dopamine and other light-dependent processes cooperatively regulate the diurnal rhythm of phosducin phosphorylation. Under conditions of constant darkness a circadian rhythm of phosducin phosphorylation was observed, which correlated negatively with the circadian rhythm of 3,4-dihydroxyphenylacetic acid levels. The circadian fluctuation of phospho-phosducin was completely abolished by constant infusion of L-745,870, indicating that the rhythm of phospho-phosducin level is driven by dopamine. Thus, dopamine release in response to light and circadian clocks drives daily rhythms of protein phosphorylation in photoreceptor cells.


Metabolism of glyphosate in an Arthrobacter sp. GLP-1.
The metabolism of glyphosate [N-(phosphonomethyl)glycine] in a bacterium tentatively identified as an Arthrobacter sp., capable of growth on this herbicide as its sole phosphorus source, has been investigated using solid-state NMR techniques as well as radiotracer analysis. The pathway involves the conversion of glyphosate to glycine, a C1 unit and phosphate. The phosphonomethyl carbon is specifically incorporated into the amino acids serine, cysteine, methionine, and histidine, as well as into purine bases and thymine, indicating the involvement of tetrahydrofolate in single-carbon transfer reactions. Glycine derived from glyphosate is utilized in purine and protein biosynthesis. This pathway for glyphosate degradation in a gram-positive bacterium is similar to that previously reported for Pseudomonas sp. PG2982 [Jacob et al. (1985) J. Biol. Chem. 260, 5899-5905] and is distinct from that reported for soil metabolism of glyphosate where aminomethylphosphonic acid has been shown to be a major metabolite. Preliminary evidence is presented which indicates that the conversion of glyphosate to glycine and the C1 unit involves the intermediate formation of sarcosine. Thus, the primary event in glyphosate degradation by Arthrobacter sp. GLP-1 is the cleavage of its C-P bound. This report constitutes the first demonstration of the metabolism of glyphosate in a gram-positive bacterium.


LINK-B: study protocol of a retrospective and prospective project for identification and linkage to care of people living with hepatitis B in a large health area of Barcelona.
An estimated 290 million people are living with hepatitis B virus (HBV) worldwide; in Spain, the prevalence of hepatitis B virus surface antigen (HBsAg) is 0.4%. In our setting, many HBsAg-positive individuals are not linked to care, which implies a barrier to receiving treatment and controlling the infection. The main objective of this project is to evaluate the performance of a programme designed to achieve appropriate linkage to specialist care of HBsAg-positive individuals, newly tested or previously tested and lost to follow-up. This is a retrospective and prospective study in which all HBsAg-positive cases recorded in the microbiology database will be identified. The retrospective phase will include cases detected between 2018 and 2020, and the prospective phase will run from January 2021 to June 2022. The project will be carried out in a tertiary university hospital covering the northern health area of Barcelona with a catchment population of 450 000 inhabitants and 16 affiliated primary care centres. The central laboratory detects approximately 1200 HBsAg-positive individuals every year; therefore, we expect to identify around 4000 patients over the duration of the project. The medical records of HBsAg-positive individuals will be consulted to identify and retrieve those who have not been appropriately linked to care. Candidates will be contacted to offer specialist disease assessment and follow-up. A website will be created to provide HBV-related information to primary care physicians, and a mobile phone application will be available to patients to improve the linkage circuits and ensure follow-up continuity. The Vall d'Hebrón Hospital Ethics Committee (PR(AG)201/2021) and the Spanish Agency of Medicines and Medical Devices approved this study. The findings will be disseminated through peer-reviewed publications and conference presentations. This programme could increase the number of HBsAg-positive individuals properly linked to care and achieve better HBV monitoring, which will have a positive impact on WHO's viral hepatitis elimination goals.


Randomized, double-blind, placebo-controlled clinical trial for evaluating the efficacy of fractional CO2 laser compared with topical estriol in the treatment of vaginal atrophy in postmenopausal women.
The aim of the study was to evaluate efficacy of fractional CO2 vaginal laser treatment (Laser, L) and compare it to local estrogen therapy (Estriol, E) and the combination of both treatments (Laser + Estriol, LE) in the treatment of vulvovaginal atrophy (VVA). A total of 45 postmenopausal women meeting inclusion criteria were randomized in L, E, or LE groups. Assessments at baseline, 8 and 20 weeks, were conducted using Vaginal Health Index (VHI), Visual Analog Scale for VVA symptoms (dyspareunia, dryness, and burning), Female Sexual Function Index, and maturation value (MV) of Meisels. Forty-five women were included and 3 women were lost to follow-up. VHI average score was significantly higher at weeks 8 and 20 in all study arms. At week 20, the LE arm also showed incremental improvement of VHI score (P = 0.01). L and LE groups showed a significant improvement of dyspareunia, burning, and dryness, and the E arm only of dryness (P < 0.001). LE group presented significant improvement of total Female Sex Function Index (FSFI) score (P = 0.02) and individual domains of pain, desire, and lubrication. In contrast, the L group showed significant worsening of pain domain in FSFI (P = 0.04), but FSFI total scores were comparable in all treatment arms at week 20. CO2 vaginal laser alone or in combination with topical estriol is a good treatment option for VVA symptoms. Sexual-related pain with vaginal laser treatment might be of concern.


A Novel Hemostatic Belt Allowing Ambulation Soon After Atrial Fibrillation Ablation.
We aimed to develop a hemostatic device with physiological evidence that allows ambulation soon after atrial fibrillation (AF) ablation. We measured right femoral vein pressure in 57 participants to clarify why groin post-venipuncture rebleeding often occurs during the transition from supine to sitting under compression bandage application and found that it increased more than threefold when raising the upper body (8.6 ± 4.1 to 27.6 ± 6.9 mmHg; P < 0.001). Based on that data, we created a novel hemostatic belt. Its capability test including 25 participants demonstrated that the belt gave much higher compression pressures on the right groin while sitting than the compression bandage (59.5 ± 14.9 vs. 8.1 ± 4 mmHg; P < 0.001), achieving pressures above the maximum femoral vein pressure in 92% of participants. A randomized trial comparing the belt with compression bandage in 74 AF patients demonstrated that the belt reduced time to ambulation without any rebleeding (340 [92.5-360] vs. 360 [360-360] min; P < 0.001) and satisfied more patients. The novel hemostatic belt provided a much higher compression pressure on the right groin during the sitting position than the conventional compression bandage, achieving a pressure above the maximum femoral vein pressure in 92% of the participants.


Morphologic observations on experimental subretinal neovascularization in the monkey.
Subretinal neovascularization is a poorly understood and potentially disastrous feature of many eye diseases. We used light and electron microscopy to study the sequence of events that lead to the formation of new vessels after laser photocoagulation of the retina and choroid of primates. In this animal model there is a rapid development of new blood vessels; one day after photocoagulation, endothelial cell degeneration and thrombus formation were observed in the capillaries, venules and arterioles of the choroid around the center of the lesion. Re-endothelialization began in some thrombosed choroidal vessels, with migration of the activated endothelial cells within the old basement membrane. Two days after photocoagulation, re-endothelialization was observed in almost all thrombosed choroidal vessels, and the initial stage of the endothelial cell budding was observed in the pre-existing choroidal vessels; this was especially prominent in venules with pericytes. Three days after photocoagulation, not only the endothelial cells in pre-existing vessels but also those in re-endothelialized vessels showed budding and lumen formation. The lumen of vessels was formed by the budding of adjacent endothelial cells that were coupled by transient intercellular junctions. Mitotic figures were frequently found in the endothelial cells distal to the growing tip. Five to eight days after photocoagulation, many new vessels extended into the subretinal space.


Initial end-tidal CO2 is markedly elevated during cardiopulmonary resuscitation after asphyxial cardiac arrest.
To compare the initial end-tidal CO2 (PetCO2) during cardiopulmonary resuscitation in asphyxial versus ventricular fibrillatory cardiac arrest. A cohort study. University research laboratory. Forty domestic piglets. Asphyxial cardiac arrest was produced by clamping the endotracheal tube in 20 piglets and was continued for 10 minutes after loss of aortic pulsations occurred. Ventricular fibrillation (VF) was induced by applying 60 Hz of alternating current via a pacing wire to the myocardium of the other 20 piglets, and continued for a 15-minute downtime. Cardiopulmonary resuscitation (CPR) was then provided to each group for two minutes, followed by standard advanced cardiac life support protocols. All piglets were instrumented for continuous monitoring of PetCO2, electrocardiogram, central venous pressure, and aortic pressure. PetCO2 of the first breath of CPR was 91 +/- 20 mmHg in the asphyxial group versus 34 +/- 14 mmHg in the VF group (P < 0.001). The asphyxial group continued to exhibit significantly greater PetCO2 for the first five breaths of resuscitation, after which there were no differences. The coronary perfusion pressures during the first breaths of CPR did not differ between the two groups. High initial PetCO2 did not correlate with return of spontaneous circulation. End-tidal CO2 during the first five breaths of CPR is much higher after an asphyxial cardiac arrest than VF. In each case, the initial PetCO2 appears to reflect alveolar CO2 prior to CPR. After one minute of CPR, PetCO2 is useful in monitoring the effectiveness of CPR.


Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region. Induction by cytokines and phorbol ester.
Human intercellular adhesion molecule-1 (ICAM-1), a specific ligand for the lymphocyte function-associated Ag-1 (LFA-1), plays an important role in leukocyte-endothelial cell interactions. It is induced by proinflammatory cytokines such as IL-1, TNF-alpha, or IFN-gamma. However, little is known concerning the intracellular regulatory mechanisms which trigger ICAM-1 up-regulation. In order to study potential regulatory elements involved in ICAM-1 induction we have cloned the human ICAM-1 gene and 5 kb of its 5'-regulatory region. The sequence of the cDNA was found to be distributed over seven exons separated by six introns, whereby each of the five extracellular Ig-like domains of ICAM-1 is encoded by its own exon. The upstream sequence harbors a number of sequence motifs implicated in the regulation and expression of eukaryotic genes, including binding sites for the transcription factors SP-1, AP-1, and NF-kB. Primer extension and S1 nuclease analysis revealed two transcription initiation sites 319 bp and 41 bp upstream of the translation start site. Consensus TATA boxes were found at the expected positions about 25 bp upstream of both start sites. Reverse transcriptase polymerase chain reaction showed differential use of the two TATA boxes in A549 and HS913T cells. Both RNA seem to code for the same for of ICAM-1 protein. For regulation studies a 1.3-kb EcoRI/SalI fragment of the 5'-flanking region was used to promote transcription of a linked luciferase reporter gene in transient-transfection assays in A549 and HS913T cells. Treatment of A549 cells with IL-1 or TNF-alpha resulted in a two- or fourfold increase in luciferase activity. Furthermore, a sixfold induction could be achieved after treatment with the phorbol ester PMA. In contrast, agents that increase intracellular cAMP levels did not induce luciferase activity. Northern blot analysis was used to investigate the kinetics of ICAM-1 mRNA synthesis upon induction with TNF-alpha and PMA. These data suggest that the up-regulation of ICAM-1 by cytokines occurs at least partly at the transcriptional level. Deletion analysis of the 1.3-kb fragment of the 5'-flanking region revealed sequences responsible for promotion and inhibition of transcription. In particular, two functionally distinct regions have been characterized: a short fragment containing an NF-kB binding site has been shown to function as an activator, followed immediately downstream by a sequence acting as a silencer element. Therefore, ICAM-1 gene expression seems to be modulated by multiple cis-acting elements.


Assessment and treatment of liver disease in Japanese haemophilia patients.
We studied the prevalence of the hepatitis C virus (HCV), human immunodeficiency virus (HIV) and GB virus C or hepatitis G virus (GBV-C/HGV), and characteristics of infections in Japanese haemophilia patients. Haemophilia patients were highly infected with HCV (88.2%) because of frequent use of unheated blood concentrates. Analysis for HCV genotypes revealed characteristics of HCV infection in haemophilia patients. Japanese haemophilia patients were highly infected with rare genotypes in Japan: genotype 1a (26.5%), genotype 3 (14.5%) and genotype 4 (2.4%). HIV infection was observed in 32.3% of haemophilia patients. HCV quasispecies (clones) and direct sequencing were investigated in patients with a single HCV genotype in the hypervariable region 1 of HCV, which resulted in a high degree of diversity. This indicates that even a single genotype of HCV might have multiple origins. GBV-C/HGV infection was noted in 20.9% of Japanese haemophilia patients. Over 40 haemophilia patients with chronic hepatitis C have been treated with interferon alpha for 6 months at total doses of 480-720 million units. About 38% showed clearance of HCV RNA from serum. Six patients with HIV infection were included in the study and they did not show eradication of HCV from the serum. This might derive from that they had high serum HCV RNA titers and genotype 1a or 1b. Histologic assessment was performed in 36 haemophilia patients with HCV. No case showed a histologically normal liver. Hepatic fibrosis in the biopsy specimens was classified into five stages of fibrosis and compared with serum hepatic fibrosis markers. Serum hyaluronic acid mostly correlated with hepatic fibrosis (r = 0.78, P < 0.0001) followed by type IV collagen (r = 0.38, P < 0.05). This suggests that estimation of serum fibrosis markers might be substituted for liver biopsy in haemophilia patients.


HIV infection: pre-highly active antiretroviral therapy IL-7 plasma levels correlate with long-term CD4 cell count increase after treatment.
Highly active antiretroviral therapy (HAART) in HIV patients generally increases the CD4 cell count, but the level of CD4 cell restoration remains very heterogeneous. IL-7 is the main cytokine controlling the size of the T-cell pool. We assessed the hypothesis that pre-HAART IL-7 plasma levels may affect CD4 cell restoration after treatment. A positive correlation was found in a cohort of 18 patients between pre-HAART IL-7 plasma levels and CD4 cell increases after 20 +/- 7.8 months of HAART.


The Emergence of Discrete Perceptual-Motor Units in a Production Model That Assumes Holistic Phonological Representations.
Intelligible speakers achieve specific vocal tract constrictions in rapid sequence. These constrictions are associated in theory with speech motor goals. Adult-focused models of speech production assume that discrete phonological representations, sequenced into word-length plans for output, define these goals. This assumption introduces a serial order problem for speech. It is also at odds with children's speech. In particular, child phonology and timing control suggest holistic speech plans, and so the hypothesis of whole word production. This hypothesis solves the serial order problem by avoiding it. When the same solution is applied to adult speech the problem becomes how to explain the development of highly intelligible speech. This is the problem addressed here. A modeling approach is used to demonstrate how perceptual-motor units of production emerge over developmental time with the perceptual-motor integration of holistic speech plans that are also phonological representations; the specific argument is that perceptual-motor units are a product of trajectories (nearly) crossing in motor space. The model, which focuses on the integration process, defines the perceptual-motor map as a set of linked pairs of experienced perceptual and motor trajectories. The trajectories are time-based excursions through speaker-defined perceptual and motor spaces. By hypothesis, junctures appear where motor trajectories near or overlap one another in motor space when the shared (or extremely similar) articulatory configurations in these regions are exploited to combine perceptually-linked motor paths along different trajectories. Junctures form in clusters in motor space. These clusters, along with their corresponding (linked) perceptual points, represent perceptual-motor units of production, albeit at the level of speech motor control only. The units serve as pivots in motor space during speaking; they are points of transition from one motor trajectory to another along perceptually-linked paths that are selected to produce best approximations of whole word targets.


Sources and holes in a one-dimensional traveling-wave convection experiment.
We study dynamical behavior of local structures, such as sources and holes, in traveling-wave patterns in a very long (2 m) heated wire convection experiment. The sources undergo a transition from stable coherent behavior to erratic behavior when the driving parameter epsilon is decreased. This transition, as well as the scaling of the average source width in the erratic regime are both qualitatively and quantitatively in accord with earlier theoretical predictions. We also present results for the holes sent out by the erratic sources.


Differential induction of CD38 expression by TNF-{alpha} in asthmatic airway smooth muscle cells.
The ADP-ribosyl cyclase activity of CD38, a membrane protein expressed in human airway smooth muscle (ASM) cells, generates cyclic ADP-ribose (cADPR), a Ca²(+)-mobilizing agent. cADPR-mediated Ca²(+) responses to agonists are augmented in human ASM cells by TNF-α. CD38-deficient mice fail to develop airway hyperresponsiveness following intranasal TNF-α or IL-13 challenge, suggesting a role in asthma. The role of CD38 in human asthma remains unknown. We hypothesized that CD38 expression will be elevated in ASM cells from asthmatic donors (ASMA cells). CD38 mRNA and ADP-ribosyl cyclase activity were measured in cells maintained in growth-arrested conditions and exposed to vehicle or TNF-α (10-40 ng/ml). TNF-α-induced induction of CD38 expression was greater in ASMA than in ASM cells from nonasthmatic donors (ASMNA). In four of the six donors, basal and TNF-α-induced ERK and p38 MAPK activation were higher in ASMA than ASMNA cells. JNK MAPK activation was lower in ASMA than ASMNA cells. Nuclear NF-κB (p50 subunit) and phosphorylated c-Jun were comparable in cells from both groups, although nuclear c-Fos (part of the AP-1 complex) levels were lower in ASMA than ASMNA cells. NF-κB or AP-1 binding to their consensus sequences was comparable in ASMNA and ASMA cells, as are the decay kinetics of CD38 mRNA. The findings suggest that the differential induction of CD38 by TNF-α in ASMA cells is due to increased transcriptional regulation involving ERK and p38 MAPK activation and is independent of changes in NF-κB or AP-1 activation. The findings suggest a potential role for CD38 in the pathophysiology of asthma.


Quantitative Estimation of Protein in Sprouts of Vigna radiate (Mung Beans), Lens culinaris (Lentils), and Cicer arietinum (Chickpeas) by Kjeldahl and Lowry Methods.
Protein scarcity is the most vital cause of long-lasting diseases and even untimely deaths in some developing nations. The application of protein in food is advantageous from the point of view of non-toxicity, biocompatibility, and dietary benefits. This study aimed to determine the protein contents of the sprouts of Vigna radiates (mung beans), Lens culinaris (lentils), and Cicer arietinum (chickpeas) using the Kjeldahl and Lowry methods. The results obtained from the Kjeldahl method identified protein concentrations of 2.54, 2.63, and 2.19%, whereas the Lowry method results identified protein concentrations of 2.96%, 4.10%, and 1.6% in mung beans, lentils, and chickpeas, respectively. In both the methods, lentils were found to have the highest amount of protein followed by mung beans and chickpeas. Both the Kjeldahl and Lowry methods demonstrated good protein values and low variation in the protein amount in the analyzed samples. Furthermore, the methods had greater sensitivity and comparable experimental variability. The outcomes revealed that assays can be applied for protein analysis in legumes. In the context of a lack of suitable standard procedures for evaluating legumes' compositions, the present study is suitable for food control laboratories. In addition, the studied samples represent a significant source of protein and can be used to fulfil the daily requirements for protein intake and other food applications.


An integrative approach to the biomechanical function and neuromuscular control of the fingers.
The exquisite mechanical functionality and versatility of the human hand emerges from complex neuro-musculo-skeletal interactions that are not completely understood. I have found it useful to work within a theoretical/experimental paradigm that outlines the fundamental neuro-musculo-skeletal components and their interactions. In this integrative paradigm, the laws of mechanics, the specifications of the manipulation task, and the sensorimotor signals define the interactions among hand anatomy, the nervous system, and manipulation function. Thus, our collaborative research activities emphasize a firm grounding in the mechanics of finger function, insistence on anatomical detail, and meticulous characterization of muscle activity. This overview of our work on precision pinch (i.e., the ability to produce and control fingertip forces) presents some of our findings around three Research Themes: Mechanics-based quantification of manipulation ability; Anatomically realistic musculoskeletal finger models; and Neural control of finger muscles. I conclude that (i) driving the fingers to some limit of sensorimotor performance is instrumental to elucidating motor control strategies; (ii) that the cross-over of tendons from flexors to extensors in the extensor mechanism is needed to produce force in every direction, and (iii) the anatomical routing of multiarticular muscles makes co-contraction unavoidable for many tasks. Moreover, creating realistic and clinically useful finger models still requires developing new computational means to simulate the viscoelastic tendinous networks of the extensor mechanism, and the muscle-bone-ligament interactions in complex articulations. Building upon this neuromuscular biomechanics paradigm is of immense clinical relevance: it will be instrumental to the development of clinical treatments to preserve and restore manual ability in people suffering from neurological and orthopedic conditions. This understanding will also advance the design and control of robotic hands whose performance lags far behind that of their biological counterparts.


Methylation of an intronic region regulates miR-199a in testicular tumor malignancy.
In the testicular cancer cell line, NT2, we previously demonstrated that differentially methylated regions were located in introns or intergenic regions, and postulated these might regulate non-coding RNAs. Three microRNAs and three small nucleolar RNAs were differentially methylated; one, miR-199a, was associated with the progression and prognosis of gastric and ovarian cancers. In this report we document, by epigenomic profiling of testicular tissue, that miR-199a is transcribed as antisense of dynamin 3 (chromosome 1q24.3), and hypermethylation of this region is correlated with miR-199a-5p/3p repression and tumor malignancy. Re-expression of miR-199a in testicular cancer cells led to suppression of cell growth, cancer migration, invasion and metastasis. The miR-199a-5p, one of two mature miRNA species derived from miR-199a, is associated with tumor malignancy. We further identified the embryonal carcinoma antigen podocalyxin-like protein 1 (PODXL), an anti-adhesive protein expressed in aggressive tumors, as a target of miR-199a-5p. We demonstrated PODXL is overexpressed in malignant testicular tumor, and cellular depletion of PODXL resulted in suppression of cancer invasion. The inverse relationship between PODXL and miR-199a-5p expression suggests PODXL is a downstream effector mediating the action of miR199a-5p. This report identifies DNA methylation, miR-199a dysregulation and PODXL as critical factors in tumor malignancy.


Development and tracking in fitness components: Leuven longtudinal study on lifestyle, fitness and health.
In the Leuven Growth Study of Belgian Boys the growth and physical performance of Belgian boys followed longitudinally between 12 and 19 years were studied. Subsequently, a subsample (n = 240) of Flemish-speaking males were reexamined at 30 and 35 years. A first question relates to the individual growth patterns in a variety of physical fitness characteristics. The three strength tests (static, functional, explosive) show curves that are qualitatively similar to those for height and weight. Their adolescent spurts occur after the height spurt. Flexibility and the two speed tests appear to reach maximum velocities prior to the height and weight spurts. Longitudinal principal component analysis was applied to the study of growth patterns of several somatic and motor characteristics. The results for height show three components sufficient to provide an adequate representation of the original information. The first component characterizes the general position of an individual growth curve. Components 2 and 3 reflect fluctuation in percentile level during the age period studied and can be conceived as indices of stability and are related to age at peak height velocity (APHV) and peak height velocity (PHV), respectively. Relationships between somatic characteristics, physical performance, and APHV have been studied in a sample of 173 Flemish boys, measured yearly between +/- 13 and +/- 18 years and again as adults at 30 years of age. The sample was divided into three contrasting maturity categories based on the APHV. There are consistent differences among boys of contrasting maturity status during adolescence in body weight, skeletal lengths and breadths, circumferences, and skinfolds on the trunk. There are no differences in skinfolds on the extremities. None of the differences in somatic dimensions and ratios among the three contrasting maturity groups are significant at 30 years of age except those for subscapular skinfold and the trunk/extremity skinfold ratio. During adolescence, speed of limb movement, explosive strength and static strength are negatively related to APHV; thus, early maturers performed better than late maturers. However, between late adolescence and adulthood (30 years), the late maturers not only caught up to the early maturers, but there were significant differences for explosive strength and functional strength in favor of late maturers. Finally, age-specific tracking, using inter-age correlations, of adult health- and performance-related fitness scores were investigated. In addition, the independent contribution of adolescent physical characteristics to the explanation of adult fitness scores was also studied. Tracking between age 13 and age 30 years was moderately high (46% of variance explained) for flexibility, low to moderate (between 19% and 27% of variance explained) for the other fitness parameters and low for pulse recovery and static strength (7% to 11% of variance explained). Between age 18 and age 30 years the tracking was high for flexibility, moderately high for explosive and static strength, and moderate for the other fitness parameters except for pulse recovery. The amount of variance of adult fitness levels explained increased significantly when other characteristics observed during adolescence entered the regressions or discriminant functions.


Coping behaviors as predictors of the course of clinical depression.
We assessed a large sample of nonmelancholic, depressed subjects, using a self-report measure we developed, to determine behavioral coping dimensions and the predictive validity of the measure. A principal-components analysis of measure scores suggested dimensions of distraction, support seeking, self-consolation, recklessness, affect reduction, and help seeking, largely replicating findings in nonclinical groups. Factor scores on each dimension were calculated for the subsample of depressive subjects consulting a psychiatrist. Those baseline scores were examined against subsequent improvement in depression levels at six and 20 weeks. A significant and consistent predictor of a poor outcome was a higher initial score on the self-consolation dimension. A better outcome was weakly associated at six and 20 weeks with higher scores on affect reduction, whereas higher distraction scores were weakly associated with a poorer outcome at 20 weeks. The study thus confirmed the relevance of coping behaviors in a clinically depressed group and demonstrated the predictive strength of the measure.


Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. The SWIss Venous ThromboEmbolism Registry (SWIVTER) II.
In patients with acute cancer-associated thrombosis, current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Among 1,247 patients with acute venous thromboembolism (VTE) enrolled in the prospective Swiss Venous Thromboembolism Registry (SWIVTER) II from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, 83 (26%) prior cancer surgery, and 63 (20%) recurrent VTE. Long-term anticoagulation treatment for >12 months was more often planned in patients with versus without cancer (47% vs. 19%; p<0.001), with recurrent cancer-associated versus first cancer-associated VTE (70% vs. 41%; p<0.001), and with metastatic versus non-metastatic cancer (59% vs. 31%; p<0.001). In patients with cancer, recurrent VTE (OR 3.46; 95%CI 1.83-6.53), metastatic disease (OR 3.04; 95%CI 1.86-4.97), and the absence of an acute infection (OR 3.55; 95%CI 1.65-7.65) were independently associated with the intention to maintain anticoagulation for >12 months. In conclusion, long-term anticoagulation treatment for more than 12 months was planned in less than half of the cancer patients with acute VTE. The low rates of long-term anticoagulation in cancer patients with a first episode of VTE and in patients with non-metastatic cancer require particular attention.


Comparisons of Stereological and Other Approaches for Quantifying Macrophage Aggregates in Piscine Spleens.
Macrophage aggregates (MAs) are focal accumulations of pigmented macrophages in the spleen and other tissues of fish. A central role of MAs is the clearance and destruction of degenerating cells and recycling of some cellular components. Macrophage aggregates also respond to chemical contaminants and infectious agents and may play a role in the adaptive immune response. Tissue damage or physiological stress can result in increased MA accumulation. As a result, MAs may be sensitive biomarkers of environmental stress in fish. Abundance of MAs in tissues has been reported in a variety of ways-most commonly as density, mean size, and relative area-but the utility of these estimates has not been compared. In this study, four different types of splenic MA abundance estimates (abundance score, density, relative area, and total volume) were compared in two fish populations (Striped Bass Morone saxatilis and White Perch M. americana) with a wide range in ages. Stereological estimates of total volume indicated an increase in MA abundance with spleen volume, which generally corresponded to fish age, and with splenic infections (mycobacteria or trematode parasites). Abundance scores were generally limited in the ability to detect changes in MA abundance by these factors, whereas density estimates were greatly influenced by changes in spleen volume. In some instances, densities declined while the total volume of MAs and spleen volume increased. Experimentally induced acute stress resulted in a decrease in spleen volume and an increase in MA density, although the total volume of MAs remained unchanged. Relative area estimates accounted for the size and number of MAs but not for changes in organ volume. Total volume is an absolute measure of MA abundance irrespective of changes in organ volume or patterns of accumulation and may provide an improved means of quantifying MAs in the spleens of fish.


Genomics evolution of Jingmen viruses associated with ticks and vertebrates.
Jingmen virus (JMV) associated with ticks and vertebrates have been found to be related to human disease. We obtained the genome of a Jingmen tick virus (JMTV) strain from Rhipicephalus microplus in Guizhou province and compared the genomes of seven JMV species associated with ticks and vertebrates to understand the evolutionary relationships. The topology of the phylogenetic tree of segment 1 and segment 3 is similar, and segment 2 and segment 4 formed two different topologies, with the main differences being between Alongshan virus (ALSV), Takachi virus, Yanggou tick virus and Pteropus lylei jingmen virus (PLJV), and the possibility of genetic reassortment among these viruses. Moreover, we detected recombination within JMTV and between PLJV and ALSV. The genetic reassortment and recombination that occurs during cross-species transmission of these JMV associated with ticks and vertebrates not only complicates their evolutionary relationships, but also raises the risk of these viruses to humans.


Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway.
Stroke, characterized by a disruption of blood supply to the brain, is a major cause of morbidity and mortality worldwide. Although humanin, a 24-amino acid polypeptide, has been identified to have multiple neuroprotective functions, the level of humanin in plasma has been demonstrated to decrease with age, which likely limits the effects against stroke injury. A potent humanin analogue, S14G-humanin (HNG), generated by replacement of Ser14 with glycine, has been demonstrated to have 1,000-fold stronger biological activity than humanin. The present study established an in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model using SH-SY5Y neuroblastoma cells to mimic the in vivo ischemia/reperfusion injury in stroke. Adding HNG (0-10 µg/l) to SH-SY5Y cells to different extents blocked OGD/R-induced reduction of cell viability and antioxidative capacity, as well as decreased the elevated apoptosis rate induced by OGD/R, with the most evident effects at 1 µg/l HNG. Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) signaling was attenuated in OGD/R processes, yet reactivated with HNG treatment. FLLL32 (5 µM), a specific inhibitor of the signal, abolished effects of HNG on anti-apoptosis and antioxidation in OGD/R processes. Co-treatment with HNG and FLLL32 failed to interrupt upregulation of cytochrome c, B-cell lymphoma 2-associated X protein and cleaved caspase-3 provoked by OGD/R. Similar to FLLL32, Jak2/Stat3 signaling activated by HNG was also repressed by inhibitor of phosphoinositide 3-kinase (PI3K; 10 µM LY294002) or protein kinase B (AKT; 5 µM MK-2206 2HCl). These data collectively indicated that HNG has neuroprotective effects against OGD/R by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway, suggesting that HNG may be a promising agent in the management of stroke.


The control of glucose 1,6-bisphosphatase by Ca2+ and calmodulin.
1. The control of glucose 1,6-bisphosphatase activity, the enzyme that degrades glucose 1,6-bisphosphate, a metabolite that regulates hexose phosphate metabolism, has been examined in a rat muscle extract. 2. The enzyme has been found to be activated by physiological Ca2+ concentrations. Ca2+ can be replaced by Sr2+ and Mn2+, but the effects are not so pronounced. 3. The Ca2+ effect is inhibited by EGTA. Trifluoperazine also inhibits enzyme activity. This effect can be reversed by adding exogenous calmodulin.


Carbon-14 in methane sources and in atmospheric methane: the contribution from fossil carbon.
Measurements of carbon-14 in small samples of methane from major biogenic sources, from biomass burning, and in "clean air" samples from both the Northern and Southern hemispheres reveal that methane from ruminants contains contemporary carbon, whereas that from wetlands, pat bogs, rice fields, and tundra is somewhat, depleted in carbon-14. Atmospheric (14)GH(4) seems to have increased from 1986 to 1987, and levels at the end of 1987 were 123.3 +/- 0.8 percent modern carbon (pMC) in the Northern Hemisphere and 120.0 +/- 0.7 pMC in the Southern Hemisphere. Model calculations of source partitioning based on the carbon-14 data, CH(4) concentrations, and delta(13)C in CH(4) indicate that 21 +/- 3% of atmospheric CH(4) was derived from fossil carbon at the end of 1987. The data also indicate that pressurized water reactors are an increasingly important source of (14)CH(4).


Mechanisms of the formation of the peritoneal dissemination in gastric cancer.
To clarify the mechanisms of the formation of peritoneal dissemination, a new animal model by the i.p. inoculation of highly metastatic gastric cancer cell line MKN-45-P was developed. Peritoneal dissemination with bloody ascites was found in 100% of nude mice, injected 1x10(7) MKN-45-P cells in suspension into the peritoneal cavity. By a highly sensitive method for specific detection of metastasized human tumor cells in nude mice using polymerase chain reaction, a human beta-globin-related sequence in the DNA from various parts of the peritoneum was specifically amplified and detected by gel electrophoresis and by a specific oligonucleotide probe. Greater omentum showed a strong signal of the amplified fragments of human beta-globin gene from the 1st day and the signals gradually increased. The signals in the gonadal fat, mesentery and ovarium could be weakly detected on the Ist day, transiently decreased on the 3rd day, and then increased from the 7th day. In the diaphragm, and abdominal wall, signals could be detected from the 7th day. In contrast, small intestine and colon did not show any human beta-globin signals. In greater omentum and gonadal fat, cancer cells were selectively detected in the milky spots stained by activated carbon on the 3rd day. In the diaphragm, cancer cells adhered to the small pores termed stomata, and invaded into the subdiaphragmatic lymphatic lacunae connected with stomata. From the 3rd day, mesothelial cells of the abdominal cavity became round and separated, resulting in the exposure of the underlying connective tissue. MKN-45-P cells were found to adhere to the naked areas of the submesothelial connective tissue. From these results, we conclude that the major metastatic route of the peritoneum may be firstly through milky spots, secondly through the diaphragmatic stomata, and thirdly by the adhesion to the naked connective tissue exposed after shrinkage of the mesothelial cells. The third process may be related to the interaction between some adhesion molecules and their ligands.


The Effect of Yoga on Menstrual Disorders: A Systematic Review.
To summarize and evaluate evidence for the effect of yoga on menstrual disorders. PubMed, CINAHL/MEDLINE, Web of Science, AMED, and Scopus were searched for English-language literature relevant to the review question. All primary research studies were included. Fifteen studies described in 18 papers were included in the review. A range of yoga interventions were used. Some studies used a combination of Asana, Pranayama, and other yogic relaxation or meditation techniques. All included studies reported some change in their outcome measures, suggesting reduced symptoms of menstrual distress following a yoga intervention; however, the heterogeneity and intensity of the interventions and outcome measures meant that findings have limited generalizability and applicability in practice settings. Further research on the relationship between yoga practice and menstrual disorders is warranted, but there must be both consistency in the methods, measures, and quality of studies and a shift toward research on yoga practices that are replicable outside of the clinical trial setting.


The Brain Tumor Segmentation (BraTS) Challenge 2023: Focus on Pediatrics (CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs).
Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. The MICCAI Brain Tumor Segmentation (BraTS) Challenge is a landmark community benchmark event with a successful history of 12 years of resource creation for the segmentation and analysis of adult glioma. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge, which represents the first BraTS challenge focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The BraTS-PEDs 2023 challenge focuses on benchmarking the development of volumentric segmentation algorithms for pediatric brain glioma through standardized quantitative performance evaluation metrics utilized across the BraTS 2023 cluster of challenges. Models gaining knowledge from the BraTS-PEDs multi-parametric structural MRI (mpMRI) training data will be evaluated on separate validation and unseen test mpMRI dataof high-grade pediatric glioma. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.


Netrin-1: a novel universal biomarker of human kidney injury.
Currently available diagnostic markers representing kidney injury or function such as serum creatinine and blood urea nitrogen are insensitive and often increased late in the disease process. Netrin-1 protein, a laminin-related secreted molecule, is minimally or not expressed in tubular epithelial cells of normal kidneys. However, it is highly expressed in injured kidneys. Netrin-1 protein has been shown to be detected in urine from mice with acute kidney injury. The current study was carried out to evaluate whether netrin-1 is also induced in human acute kidney injury (AKI) and can serve as a urinary biomarker of the condition. We analyzed netrin-1 levels by sandwich enzyme-linked immunosorbent assay in urine samples from 10 healthy controls, 22 recipients of a renal allograft, 11 patients with ischemic AKI, 13 with AKI associated with sepsis, 9 with radiocontrast-induced AKI, and 8 with drug-induced AKI. Urinary netrin-1 levels normalized for urinary creatinine were significantly higher in all subject groups. The highest values were observed in patients with sepsis and in transplant patients immediately postoperatively. The level of NGAL was similarly increased in transplant patients. In conclusion, urinary netrin-1 levels are increased in patients with various forms of AKI/ATN and may serve as a universal biomarker for AKI.


Cyclosporin A--a chemoprotectant against microcystin-LR toxicity.
Microcystin-LR (MCLR) is a potent hepatotoxin that rapidly produces death in experimental animals. We have shown that cyclosporin A (CsA) can prevent the toxic and lethal effects of MCLR in mice. The LD50 of MCLR in mice is approximately 61 micrograms/kg, and 100 micrograms/kg produces death in 100% of treated mice. The minimum dose of CsA which prevented lethality in mice given 100 micrograms MCLR/kg i.p. was 10 mg/kg. This dose of CsA did not protect mice against higher doses of MCLR. Survival of all mice given 100 micrograms MCLR/kg was achieved if 10 mg CsA/kg was given 0.5-3 h prior to the MCLR but not if the CsA was co-administered or given after the MCLR. The results indicate that CsA effectively protects mice against a lethal dose of MCLR, but that the time of administration and the dose of CsA are critical determinants of the chemoprotective effects.


[Low molecular weight heparin in pregnancy. Report of three cases with pure mitral stenosis].
Three pregnant women with 5 +/- 1.7 weeks of pregnancy and mitral stenosis are described. Their valve area were < 1.0 cm2. They received medical treatment with little improvement and were included in our valvotomy percutaneous mitral (VPM) program with Inoue technique before their 30th week of pregnancy. Before they were treated with low molecular weight heparin (LMWH), Enoxiparin) as prophylaxis of intracavitary thrombus formation transthoracic and transesophageal echocardiogram demonstrated the absence of thrombus. We used 40 mgs. subcutaneous injection once a day during 16 weeks. Repeated transthoracic and transesophageal echocardiogram during VPM showed no evidence of intracavitary thrombus. Complete blood count and coagulation parameters remained within normal limits. The three cases delivered a healthy products. In conclusion, although this series is small, we show that the LMWH can be used in the first trimester of pregnancy as prophylactic treatment instead of oral anticoagulant treatment.


Response of Primary Renal Cell Carcinoma to Systemic Therapy.
Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox's models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16-23) in patients treated with first-line therapy (any type), 28% (22-33) in those treated with first-line VEGF-targeted therapy, and 23% (19-28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5-13) and 20% (15-27) in IMDC poor- and intermediate-risk patients, respectively. Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.


The effect of treatment on pregnancy among couples with unexplained infertility.
Our objective was to determine the effect of treatment on the likelihood of pregnancy among couples with unexplained infertility. We used a nonrandomized, prospective, multicentered cohort analytic study, with mean follow-up time of 14.5 months (range, 0.5-46 months). The subjects were 470 couples who attended infertility clinics affiliated with medical schools in Canada, in whom no abnormality was found after investigation. They were drawn from a total of 2,106 couples registered from April 1, 1984 to March 31, 1987. Of these, 130 couples were selected for treatment at the discretion of the care givers; 340 couples were not treated. Selection for treatment resulted in imbalance between the groups: the treated couples had a longer mean duration of infertility (48 vs. 36 months), and were more likely to have had a laparoscopy as part of the investigation (72% vs. 48%). No specific protocol of treatment was used. Treatments most commonly used were clomiphene (87); gonadotropins (31); intrauterine insemination (20); IVF or GIFT (16); bromocriptine (12); 43 couples had two treatments, and 11 had three treatments. The only important determinants of treatment (logistic regression) were time under observation and laparoscopy status. Duration of infertility was only a minor determinant of treatment. Crude, unadjusted pregnancy rates were 25% for the treated group and 34% for the untreated group. The early occurrence of pregnancy in the untreated couples accounted for much of this difference. After adjustment for baseline differences between the groups and times to and under treatment with proportional hazards analysis, the cumulative probability of pregnancy is 2.0 (95% CI 1.3 to 3.1) times as high with treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Behavioral and electrophysiological responses of Aphids to host and nonhost plant volatiles.
Alate and apterous virginoparae ofAphis fabae Scop, and alate virginoparae ofBrevicoryne brassicae (L.), walking in a linear track olfactometer, were attracted by odor from leaves of their host plants.A. fabae responded to odor from undamaged but not damaged bean leaves. Gynoparae (autumn migrants) ofA. fabae, however, did not respond to their host plant (spindle,Euonymus europaeus) odor. Odors of certain nonhost plants masked the attractiveness of the host plant leaves, but tansy (Tanacetum vulgare) and summer savory (Satureja hortensis) volatiles repelledB. brassicae andA. fabae, respectively. 3-Butenyl isothiocyanate attractedB. brassicae andLipaphis erysimi (Kalt.), the latter species being more sensitive in both behavioral and electrophysiological studies. Isothiocyanate receptors were found on the antennae ofA. fabae, which was repelled by these compounds, 4-pentenyl isothiocyanate being the most active.


Advancing minimally invasive surgery: A cutting-edge cable-actuated conveying mechanism for reliable tissue transportation.
Tissue extraction plays a crucial role in various medical disciplines, with aspiration catheters serving as the prevailing method. Unfortunately, these catheters face limitations such as clogging and dependence on tissue properties and device dimensions. Therefore, there is a pressing need for an improved tissue extraction device that enables efficient and reliable tissue removal during Minimally Invasive Surgery (MIS). In this study, we present a novel tissue transport system that utilizes a cylindrical conveyor belt mechanism for reliable tissue transportation. We conducted experiments using a proof-of-principle prototype to explore the influence of tissue elasticity, rotational velocity, instrument orientation, and tissue shape on the transportation rate, efficiency, and reliability. Tissue phantoms with gelatine concentrations of 3, 9, and 12 wt% were employed to simulate a range of Young's moduli from 1 to 110 kPa. The mean transportation rates for these phantoms were 7.75±0.48, 8.43±1.50, and 8.90±0.56 g/min, respectively. Notably, all phantoms were transported successfully. The perfect reliability exhibited underscores the potential of our instrument as an alternative to aspiration catheters. CONCLUSION: This research presents a significant step forward in the field of tissue extraction, offering a promising approach for MIS with enhanced efficiency and reliability.


A novel optical imaging method for the early detection, quantitative grading, and mapping of cancerous and precancerous lesions of cervix.
This paper describes a novel optical imaging method for the in vivo early detection, quantitative staging, and mapping of cervical cancer and precancer. A multispectral imaging system was developed, which is capable of performing time-resolved imaging spectroscopy. The system was used in order to assess quantitatively the alterations in the light scattering properties of the cervix, induced selectively and reversibly in cervical neoplasias, after the application of acetic acid solution. Spectral imaging and analysis of cervix show that the maximum contrast between acetic acid responsive and nonresponsive areas is obtained at 525 +/- 15 nm, which is further enhanced by cutting off the regular component of tissue reflection, with the aid of two linear cross polarizers. Successive snapshot imaging at this spectral band enables the quantitative assessment of the temporal alterations in the intensity of the backscattered light, in any spatial location of the examined area. Initial clinical trials show that optical contrast enhancement results in a notable improvement of the sensitivity in detecting incipient lesions. It was also shown that the measured temporal characteristics of the phenomenon contain specific information, which enables the differentiation between neoplastic and nonneoplastic lesions, as well as between neoplasias of different grade. The demonstrated improved sensitivity and specificity highlight the potential of the method in both clinical research and noninvasive diagnosis.


Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches.
Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure-activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models' predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.


A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.
Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by an abnormality of the peripheral retina. Both autosomal dominant (adFEVR) and X-linked (XLFEVR) forms have been described, but the biochemical defect(s) underlying the symptoms are unknown. Molecular analysis of the Norrie gene locus (NDP) in a four generation FEVR family (shown previously to exhibit linkage to the X-chromosome markers DXS228 and MAOA (Xp11.4-p11.3)) reveals a missense mutation in the highly conserved region of the NDP gene, which caused a neutral amino acid substitution (Leu124Phe), was detected in all of the affected males, but not in the unaffected family members, nor in normal controls. The observations suggest that phenotypes of both XLFEVR and Norrie disease can result from mutations in the same gene.


Pigmented epidermotropic breast cancer metastases: A rare variant with a particularly unusual feature.
Pigmented epidermotropic breast cancer metastases are a rarity, often clinically misdiagnosed as melanocytic lesions. Histopathologically, they show a dermal proliferation of neoplastic metastatic cells that extend to the overlying epidermis in a pattern identical to that seen in primary Paget disease (PD). Differential diagnosis should be established with entities with a similar presentation, such as pigmented mammary PD and malignant melanoma. Immunohistochemistry may be useful for this purpose. We present a new case of pigmented epidermotropic breast cancer metastases with a particularly unusual feature: the absence of dermal infiltration by neoplastic cells, thus considered as pure epidermotropic metastatic involvement.


Glutamate decarboxylase immunoreactivity and gamma-[3H] aminobutyric acid accumulation within the same neurons in dissociated cell cultures of cerebral cortex.
In order to evaluate the reliability of high affinity [3H]GABA accumulation as a marker for GABAergic neurons, murine cerebral cortical neurons were studied in dissociated cell culture. Cultures which had been incubated in [3H]GABA were stained immunohistochemically for the GABA-synthesizing enzyme, glutamate decarboxylase, fixed with paraformaldehyde, and subsequently processed for radioautography. In mature cultures, there was an 84 to 94% correlation between the presence of the enzyme and [3H]GABA uptake within the same cortical neurons. These data provide direct evidence that those neurons which synthesize GABA are the same neurons which are labeled by high affinity [3H]GABA uptake.


Lobular neoplasia of the breast revisited with emphasis on the role of E-cadherin immunohistochemistry.
Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.


Impaired diastolic function in active rheumatoid arthritis. Relationship with disease duration.
Using digitized M-mode and Doppler echocardiography, we evaluated left ventricular (LV) function in 54 patients (43 women and 11 men; mean age 50 years) suffering from active rheumatoid arthritis (RA) without obvious cardiovascular disease, and compared them with 54 age- and sex-matched normal subjects. No differences were found in LV end-diastolic diameter, systolic function and parietal thickness between the patients and controls. However, a significant reduction in various indexes of LV diastolic function was found, including E/A (ratio of early to late filling waves of mitral inflow Doppler) and the peak lengthening rate of the LV diameter (an index of LV relaxation evaluated by M-mode echocardiography). The former was correlated with patient age and was independent of disease duration, while the latter was more markedly correlated with disease duration than with patient age. The relationship between diastolic impairment and disease duration in active RA may open new perspectives in the study of RA-associated cardiovascular disease.


The drug industry and clinical research in interwar America: three types of physician collaborator.
This essay describes collaborations between American pharmaceutical companies and clinical investigators, mainly in academic medical centers and other research institutions, during the interwar period. I argue that efforts on the part of early twentieth-century "scientific medicine" reformers to impose higher standards on the testing and promotion of pharmaceuticals led both to the intended disciplining of the drug industry and also, as a reciprocal but unintended consequence, to a deep involvement with industry among medical scientists. Three basic patterns of collaboration between clinical trialists and sponsoring drugs firms are described. These patterns may help illuminate the mutual accommodation between ethical drug firms and academic clinical researchers (and institutions) that still prevails today.


A preliminary report on the effect of measured strength training in adolescent idiopathic scoliosis.
The authors studied 12 adolescent patients with scoliosis (10 girls and 2 boys) who were 11 to 16 years old and had curvatures ranging from 20 degrees to 60 degrees. Seven were right thoracic curves and five were thoracolumbar with double curves. When tested on the MedX Torso Rotation Machine, both sides were unequal in their torso rotation strength all patients. Myoelectric activity was asymmetric in both sides and in abdominal and paraspinal muscles of all patients. These asymmetries were corrected completely with torso rotation, which was associated with significant strength gains. Strength gains ranged from 12% to 40%. A 16-year-old girl with a 60 degree lumbar curve progressed and had surgery. None of the remaining patients progressed, and 4 of the 12 had decreases in their curvatures from 20 degrees to 28 degrees. None of the patients used braces during this study.


[Effect of synthetic polyribonucleotides on the immunological and colony-forming activity of irradiated bone marrow cells].
The experimental data are presented concerning the effect of polyribonucleotides on the immunologic and colony forming ability of bone marrow or irradiated mice. All the compounds under study exhibited a pronounced, but to a different degree, colony-forming and immunostimulating action. The comparative study of the influence of polyribonucleotides on the number of endogenous colonies and antibody-forming cells showed an inverse relationship between these parameters: The preparations exerting the most pronounced immunostimulating effect had an insignificant colony-forming action and vice versa. This is evidently indicative of the capacity of these preparations to turn the differentiation of haemopoietic stem cells towards the immunopoiesis.


Vaccination against bovine schistosomiasis japonica with highly X-irradiated schistosomula.
Cercariae of the Chinese mainland strain of Schistosoma japonicum were used. Eighteen cattle, divided into six groups of three each, were immunized with schistosomula transformed from cercariae exposed to three different doses of X-irradiation (24, 36, and 48 kR). The immunization was given either once, twice, or thrice, and the number of immunizing schistosomula was 10,000 or more in each immunization. The immunized cattle were challenged with 500 normal cercariae. Five native cattle were similarly infected with normal cercariae as controls. All cattle were killed 32-33 days after challenge or infection, and the worms were obtained by perfusion. The mean worm reduction in the 18 experimental animals varied from 42.1 to 96.0%. The mean percent worm reduction of the six experimental groups varied from 54.8 to 87.1. The reduction was greater with increasing numbers of immunizations, and was higher in the groups immunized with schistosomula exposed to 36 kR than in those exposed to 24 or 48 kR. Statistical analyses showed that all immunized groups yielded significantly fewer worms than controls. However, the three doses of X-irradiation (24, 36, and 48 kR) had no significant effect for a fixed number of immunizations (1, 2, or 3). The means for both two and three immunizations were significantly different from the mean for one immunization, although they were not significantly different from each other.


[The mechanisms of speech recovery following revascularization surgery in patients having had an ischemic stroke].
A study is presented of 20 patients with ischemic stroke showing speech disorders. After the surgically performed extra-intracranial microanastomosis of the superficial temporal artery with branches of the middle cerebral artery there always followed an improvement of the aphasic defect. During control angiographic examination a 2% solution of novocaine was introduced into the carotid artery. Injection of the preparation into the left carotid artery produced a short-term cessation of speech while administration of novocaine into the right carotid artery did not effect the speech function. It is concluded that speech restoration occurs due to rehabilitation processes in the dominant hemisphere of the brain.


Gastrointestinal Dysmotility in the Elderly.
The number of persons 60 years and older has increased 3-fold between 1950 and 2000. Aging alone does not greatly impact the gastrointestinal (GI) tract. Digestive dysfunction, including esophageal reflux, achalasia, dysphagia, dyspepsia, delayed gastric emptying, constipation, fecal incontinence, and fecal impaction, is a result of the highly prevalent comorbid conditions and the medications with which those conditions are treated. A multidisciplinary approach with the expertise of a geriatrician, gastroenterologist, neurologist, speech pathologist, and physical therapist ensures a comprehensive functional and neurological assessment of the older patient. Radiographic and endoscopic evaluation may be warranted in the evaluation of the symptomatic older patient with consideration given to the risks and benefits of the test being used. Treatment of the digestive dysfunction is aimed at improving health-related quality of life if cure cannot be achieved. Promotion of healthy aging, treatment of comorbid conditions, and avoidance of polypharmacy may prevent some of these digestive disorders. The age-related changes in GI motility, clinical presentation of GI dysmotility, and therapeutic principles in the symptomatic older patient are reviewed here.


Dirty Work in Medicine: Understanding U.S. Physicians' Agency in Contested Medical Practices.
Physicians who participate in abortion and medically assisted death in the United States work at the margins of institutionalized medicine. What motivates them to engage in such "dirty work"? This article uses ethnographic materials from two recent projects to analyze physicians' roles as gatekeepers to contested medical services. Abortion and medically assisted death share many similarities: They are both deeply stigmatized practices that are heavily restricted in many U.S. jurisdictions, and which many physicians are reluctant to participate in for moral, religious, or professional reasons. They both also confer medicine with the power to govern life and death decisions through the apparatus of state law. However, state laws operate quite differently on physicians in these two cases, with different outcomes. This comparative analysis demonstrates how dirty work in medicine enrolls the agency and subjectivity of physicians in distinctive ways that may be eclipsed by totalizing biopolitical frameworks. [abortion, medical aid in dying, physicians, agency, biopolitics, United States].


A chemometric approach for the sensitization procedure of ZnO flowerlike microstructures for dye-sensitized solar cells.
In this paper, a methodology for the streamlining of the sensitization procedure of flowerlike ZnO nanostructures for dye-sensitized solar cells (DSCs) is reported. The sensitization of ZnO surface with ruthenium-based complexes is a particularly critical process, since one has to minimize the dissolution of surface Zn atoms by the protons released from the dye molecules, leading to the formation of Zn(2+)/dye complexes. The fine-tuning of the experimental parameters, such as the dye loading time, the dye concentration, and the pH of the sensitizing solution, performed through a multivariate optimization by means of a chemometric approach, is here reported. The dye loading procedure was optimized using ZnO microparticles with nanostructured protrusions, synthesized by a simple and low-cost hydrothermal process. Mild reaction conditions were used, and wurtzite-like crystalline structure with a relatively high surface area was obtained once the reaction process was completed. After dispersion of ZnO flowerlike particles in an acetic acid-based solution, a 14 μm-thick ZnO layer acting as DSC photoanode was fabricated. The optimized sensitization procedure allowed minimizing the instability of ZnO surface in contact with acidic dyes, avoiding the formation of molecular agglomerates unable to inject electrons in the ZnO conduction band, achieving good results in the photoconversion efficiency. Moreover, the photoharvesting properties were further enhanced by adding N-methylbenzimidazole into the iodine-based liquid electrolyte. Such an additive was proposed here for the first time in combination with a ZnO photoelectrode, helping to reduce an undesired recombination between the photoinjected electrons and the oxidized redox mediator.


A case of 55-year-old man with first-ever generalized seizure diagnosed with Sturge-Weber syndrome type III by characteristic MRI findings.
A 55-year-old man with no mental retardation had presented a history of frequent transient clumsiness of his right upper and lower extremities for about 20 years. He was admitted to a general hospital with weakness of right side of the body, and first-ever generalized seizure attack occurred the next day. Brain CT showed calcification in the left cerebral cortices. So he was referred to our hospital. On neurological examination, he had mild clumsiness of his right upper limb and right pyramidal tract sign. He had neither facial port-wine stain nor glaucoma. The blood test and cerebrospinal fluid analysis were unremarkable. Electroencephalogram showed slowing and reduction of activity at the left frontal and parietal areas with no epileptic activities. Brain CT showed "tram-track calcification" and lobar atrophy in the left fronto-parietal cortices. Susceptibility weighted imaging (SWI) on MRI revealed enlarged transmedullary veins in the left periventricular white matter and low intensity lesions along the cortical gyri. Post gadolinium fluid-attenuated inversion recovery imaging (FLAIR-Gd) showed leptomeningeal enhancement in the left fronto-parietal lobes more extensively than those by post gadolinium T1-weighted image. Brain perfusion single photon emission computed tomography with a technetium-99m-ethyl cysteinate dimer (99mTc-ECD SPECT) revealed hypoperfusion in the fronto-parietal lobes. These clinical and neuroimaging findings were compatible with type III Sturge-Weber syndrome (SWS). His condition was improved after treatment with oral levetiracetam (1,000 mg daily). Although adult-onset type III SWS is very rare, it is important to perform SWI and post-contrast FLAIR for assessing leptomeningeal angioma in patients with seizure with focal cortical calcification even if they have no facial nevus.


Membrane dynamics and the regulation of epithelial cell polarity.
Plasma membranes of epithelial cells consist of two domains, an apical and a basolateral domain, the surfaces of which differ in composition. The separation of these domains by a tight junction and the fact that specific transport pathways exist for intracellular communication between these domains and distinct intracellular compartments relevant to cell polarity development, have triggered extensive research on issues that focus on how the polarity is generated and maintained. Apart from proper assembly of tight junctions, their potential functioning as landmark for the transport machinery, cell-cell adhesion is obviously instrumental in barrier formation. In recent years, distinct endocytic compartments, defined as subapical compartment or common endosome, were shown to play a prominent role in regulating membrane trafficking to and from polarized membrane domains. Sorting devices remain to be determined but likely include distinct rab proteins, and evidence is accumulating to indicate that signaling events may direct intracellular membrane transport, intimately involved in the biogenesis and maintenance of polarized membrane domains and hence the development of cell polarity.


Inguinal hernia detected using radiography.
There are various clinical presentations of inguinal hernia. Computed tomography is a well-known tool to help diagnose inguinal hernia; however, radiographs are rarely reported to be useful in this aspect. We present a rare case wherein radiographs helped in the diagnosis of inguinal hernia.


Halo score (temporal artery, its branches and axillary artery) as a diagnostic, prognostic and disease monitoring tool for Giant Cell Arteritis (GCA).
Giant cell arteritis (GCA) is a common large vessel vasculitis of the elderly, often associated with sight loss. Glucocorticoids (GC remain the mainstay of treatment, although biologic treatments have been approved. Biomarkers predicting disease severity, relapse rates and damage are lacking in GCA.EULAR recommends ultrasound (US) as the first investigation for suspected GCA. The cardinal US finding, a non-compressible halo, is currently categorised as either negative or positive. However, the extent and severity of this finding may vary.In this study, we hypothesise whether the extent and severity of the halo sign [calculated as a single composite Halo score (HS)] of temporal and axillary arteries may be of diagnostic, prognostic and monitoring importance; whether baseline HS is linked to disease outcomes, relapses and damage; whether HS can stratify GCA patients for individual treatment needs; whether HS can function as an objective monitoring tool during follow up. This is a prospective, observational study. Suspected GCA Participants will be selected from the GCA FTC at the participating centres in the UK. Informed consent will be obtained, and patients managed as part of standard care. Patients with GCA will have HS (temporal and axillary arteries) measured at baseline and months 1,3,6 and 12 long with routine clinical assessments, blood sampling and patient-reported outcomes (EQ5D). Non-GCA patients will be discharged back to the referral team and will have a telephone interview in 6 months.We aim to recruit 272 suspected GCA referrals which should yield 68 patients (25% of referrals) with confirmed GCA. The recruitment will be completed in 1 year with an estimated total study period of 24 months. The identification of prognostic factors in GCA is both timely and needed. A prognostic marker, such as the HS, could help to stratify GCA patients for an appropriate treatment regimen. Tocilizumab, an IL-6R blocking agent, switches off the acute phase response (C-Reactive Protein), making it difficult to measure the disease activity. Therefore, an independent HS, and changes in that score during treatment and follow-up, maybe a more objective measure of response compare to patient-reported symptoms and clinical assessment alone.


Confronting online social aggression in Hong Kong: A wake-up call.
Online bullying as a form of online aggression is an increasingly growing phenomenon that is experienced by all age groups. Apart from the use of technology, online bullying shares the same attributes as conventional bullying. This includes a power imbalance vis-a-vis the bully and the victim and the victims' feeling of helplessness. Its impact however, is greater resulting in severe psychological, social and mental health problems. Because online bullying presents a new type of challenge for lawmakers, educators and parents, there may not be a single solution to this social problem. The paper examines the existing laws in Hong Kong that may apply to online bullying, assessing its effectiveness as a means in redressing the power imbalance. It also looks at non-legal measures that can be adopted in Hong Kong to tackle the problem.


Correlation between degree of neointimal hyperplasia and incidence and characteristics of neoatherosclerosis as assessed by optical coherence tomography.
Emerging evidence suggests that neointimal degenerative changes with development of neoatherosclerosis (NA) may represent an important mechanism for late stent failure. The aim of the present study was to investigate the relation between degree of neointimal hyperplasia and incidence and characteristics of NA using optical coherence tomography. We identified a total of 252 stents with mean neointimal thickness (NIT) >100 μm in 212 patients: 100 bare metal stents (BMSs) and 152 drug-eluting stents (DESs). Based on the values of mean NIT, we divided stents into tertiles and compared neointimal characteristics among the 3 groups. NA was defined as the presence of lipid-laden intima and/or calcification inside the stent. In both BMS and DES, there was a difference in the prevalence of lipid-laden intima among the tertiles (18.2% vs 36.4% vs 47.1%, p = 0.042 [BMS]; 19.6% vs 56.9% vs 88.0%, p <0.001 [DES]). However, no difference in the prevalence of in-stent calcification was observed (21.2% vs 21.2% vs 2.9%, p = 0.053 [BMS]; 5.9% vs 9.8% vs 2.0%, p = 0.252 [DES]). In a multivariate model adjusting for stent type, follow-up duration, conventional coronary risk factors, statin, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blockade use, mean NIT was independently associated with the presence of NA (odds ratio 2.53, 95% confidence interval 1.96 to 3.27, p <0.001). This study demonstrates the presence of a positive correlation between degree of neointimal hyperplasia after stent implantation and presence of lipid-laden intima. This association is independent from stent type and time from implantation and suggests a possible pathogenic link between the two processes.


Fabrication of ordered catalytically active nanoparticles derived from block copolymer micelle templates for controllable synthesis of single-walled carbon nanotubes.
We report the use of the block copolymer micelle approach to produce various transition metal nanoparticles such as iron, cobalt, and nickel with precisely controlled size and spacing. These uniformly sized catalyst nanoparticles derived from the block copolymer micelle approach have enabled the synthesis of carbon nanotubes (CNTs) with narrow size distribution. Because of the excellent film forming ability of the polymeric material, metal-bearing surface micelles produced from the solution micelles can be distributed uniformly on a surface, resulting in evenly dispersed catalyst nanoparticles. As a result, high quality and uniformly distributed CNTs have been synthesized. Spatially selective growth of CNTs from a lithographically patterned metal-bearing micelle film has been achieved. The polymer template approach can potentially be extended to synthesize single-metallic and bimetallic catalytically active nanoparticles with uniform size and spacing and is fully compatible with conventional lithographic process. Additionally, catalyst nanoparticles produced from this method do not coalesce at high growth temperature. All these attributes make this approach a promising fabrication pathway for controllable synthesis of CNTs.


[Surgical treatment of anterior instability of the shoulder joint].
In the article are presented data on the operative treatment of 52 patients (54 operations) with anterior instability of the arm joints. Patients have been distributed into 4 groups depending upon the character of intra-articular damages, revealed in the process of arthrotomy. Each group of patients was subjected to adequate operative intervention, based upon Bankart's method. The authors proceeded from the principle that the arm joint instability treatment should be aimed at removal of intra-articular damages. There have been restored integrity of the damaged cartilage cushion and the joint capsule, the capsule plasty and blocking of the anteroinferior joint sinus. The treatment tactics of the kind allowed to achieve the maximum stability of the arm joint and prevent postoperative recurrencies. Long-term results have been studied with 41 patient, no recurrencies have been noted. The operated limb function has been restored with the majority of the patients.


The role of attention in priming for left-right reflections of object images: evidence for a dual representation of object shape.
Three experiments investigated the role of visual attention in priming for object images and their left-right reflections. Objects to which participants attended were visually primed in both the same view and in the left-right reflected view; ignored objects were primed only in the same view. The effects of attention (attended vs. ignored) and view (same vs. reflected) were strictly additive. These results suggest that 2 separate representations mediate human object recognition (J.E. Hummel & B.J. Stankiewicz, 1996): One requires attention but is invariant with left-right reflection, whereas the other can be activated automatically but is sensitive to left-right reflection. Both representations appear to be invariant with translation across the visual field.


Integrated analysis of the miRNA, gene and pathway regulatory network in gastric cancer.
Gastric cancer is one of the most common malignant tumors worldwide; however, the efficacy of clinical treatment is limited. MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been reported to play a key role in the development of cancer. They also provide novel candidates for targeted therapy. To date, in-depth studies on the molecular mechanisms of gastric cancer involving miRNAs are still absent. We previously reported that 5 miRNAs were identified as being significantly increased in gastric cancer, and the role of these miRNAs was investigated in the present study. By using bioinformatics tools, we found that more than 4,000 unique genes are potential downstream targets of gastric cancer miRNAs, and these targets belong to the protein class of nucleic acid binding, transcription factor, enzyme modulator, transferase and receptor. Pathway mapping showed that the targets of gastric cancer miRNAs are involved in the MAPK signaling pathway, pathways in cancer, the PI3K-Akt signaling pathway, the HTLV-1 signaling pathway and Ras signaling pathway, thus regulating cell growth, differentiation, apoptosis and metastasis. Analysis of the pathways related to miRNAs may provides potential drug targets for future therapy of gastric cancer.


Comprehensive cell-specific protein analysis in early and late pollen development from diploid microsporocytes to pollen tube growth.
Pollen development in angiosperms is one of the most important processes controlling plant reproduction and thus productivity. At the same time, pollen development is highly sensitive to environmental fluctuations, including temperature, drought, and nutrition. Therefore, pollen biology is a major focus in applied studies and breeding approaches for improving plant productivity in a globally changing climate. The most accessible developmental stages of pollen are the mature pollen and the pollen tubes, and these are thus most frequently analyzed. To reveal a complete quantitative proteome map, we additionally addressed the very early stages, analyzing eight stages of tobacco pollen development: diploid microsporocytes, meiosis, tetrads, microspores, polarized microspores, bipolar pollen, desiccated pollen, and pollen tubes. A protocol for the isolation of the early stages was established. Proteins were extracted and analyzed by means of a new gel LC-MS fractionation protocol. In total, 3817 protein groups were identified. Quantitative analysis was performed based on peptide count. Exceedingly stage-specific differential protein regulation was observed during the conversion from the sporophytic to the gametophytic proteome. A map of highly specialized functionality for the different stages could be revealed from the metabolic activity and pronounced differentiation of proteasomal and ribosomal protein complex composition up to protective mechanisms such as high levels of heat shock proteins in the very early stages of development.


Effects of varying levels of duodenal or midjejunal glucose and 2-deoxyglucose infusion on small intestinal disappearance and net portal glucose flux in steers.
Six crossbred steers (261 +/- 18 kg BW) fitted with hepatic portal, mesenteric venous and arterial catheters, and duodenal, midjejunal, and ileal cannulas were used in a replicated 3 x 3 Latin square design to determine the effect of varying levels and site of glucose plus 2-deoxyglucose (2DG) infusion on net portal-drained visceral flux. Steers were fed chopped alfalfa in six equal portions daily at 1.5% of BW. Glucose (0, 9, or 18 g/h) and 2DG (0, 1, or 2 g/h) were infused continuously through the duodenal or midjejunal cannula (two infusion sites) at total glucose plus 2DG infusion rates of 0, 10, or 20 g/h. Arterial and portal blood samples were taken simultaneously at 20-min intervals from 5 to 9 h of infusion. Portal blood flow was determined by continuous infusion of p-aminohippurate and net flux was calculated as venous-arterial concentration (PA) difference times blood flow. Arterial concentration of glucose was not affected (P > .10) by glucose plus 2DG infusion, whereas arterial concentration of 2DG was greater (P < .05) when glucose plus 2DG was infused into the duodenum and increased (linear, P < .10) as amount of glucose plus 2DG infused into both the duodenum and midjejunum increased. Net portal flux and PA difference of glucose and 2DG were greater (P < .05) when glucose plus 2DG was infused into the duodenum. Although 2DG was infused at 10% of the total glucose plus 2DG infusion, it accounted for only 1.7 and .7% of the glucose plus 2DG appearing in portal blood when glucose plus 2DG was infused at 10 and 20 g/h, respectively. We conclude that glucose is more readily absorbed across the proximal-half than the distal-half of the small intestine, and that passive diffusion is a minor route of glucose absorption.


Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche.
Early menarche has been linked to risk of several chronic diseases. Prospective research on whether the intake of soft drinks containing caffeine, a modulator of the female reproductive axis, is associated with risk of early menarche is sparse. We examined the hypothesis that consumption of caffeinated soft drinks in childhood is associated with higher risk of early menarche. The National Heart, Lung, and Blood Institute Growth and Health Study recruited and enrolled 2379 (1213 African American, 1166 Caucasian) girls aged 9-10 y (from Richmond, CA; Cincinnati, OH; and Washington, DC) and followed them for 10 y. After exclusions were made, there were 1988 girls in whom we examined prospective associations between consumption of caffeinated and noncaffeinated sugar- and artificially sweetened soft drinks and early menarche (defined as menarche age <11 y). We also examined associations between intakes of caffeine, sucrose, fructose, and aspartame and early menarche. Incident early menarche occurred in 165 (8.3%) of the girls. After adjustment for confounders and premenarcheal percentage body fat, greater consumption of caffeinated soft drinks was associated with a higher risk of early menarche (RR for 1 serving/d increment: 1.47; 95% CI: 1.22, 1.79). Consumption of artificially sweetened soft drinks was also positively associated with risk of early menarche (RR for 1 serving/d increment: 1.43; 95% CI: 1.08, 1.88). Consumption of noncaffeinated soft drinks was not significantly associated with early menarche (RR for 1 serving/d increment: 0.88; 95% CI: 0.62, 1.25); nor was consumption of sugar-sweetened soft drinks (RR for 1 serving/d increment: 1.15; 95% CI: 0.95, 1.39). Consistent with the beverage findings, intakes of caffeine (RR for 1-SD increment: 1.22; 95% CI: 1.08, 1.37) and aspartame (RR for 1-SD increment: 1.20; 95% CI: 1.10, 1.31) were positively associated with risk of early menarche. Consumption of caffeinated and artificially sweetened soft drinks was positively associated with risk of early menarche in a US cohort of African American and Caucasian girls.


Effect of Ring Strain on the Charge Transport of a Robust Norbornadiene-Quadricyclane-Based Molecular Photoswitch.
Integrating functional molecules into single-molecule devices is a key step toward the realization of future computing machines based on the smallest possible components. In this context, photoswitching molecules that can make a transition between high and low conductivity in response to light are attractive candidates. Here we present the synthesis and conductance properties of a new type of robust molecular photothermal switch based on the norbornadiene (NB)-quadricyclane (QC) system. The transport through the molecule in the ON state is dominated by a pathway through the π-conjugated system, which is no longer available when the system is switched to the OFF state. Interestingly, in the OFF state we find that the same pathway contributes only 12% to the transport properties. We attribute this observation to the strained tetrahedral geometry of the QC. These results challenge the prevailing assumption that current will simply flow through the shortest through-bond path in a molecule.


Ratio of geometric means to analyze continuous outcomes in meta-analysis: comparison to mean differences and ratio of arithmetic means using empiric data and simulation.
Meta-analyses pooling continuous outcomes can use mean differences (MD), standardized MD (MD in pooled standard deviation units, SMD), or ratio of arithmetic means (RoM). Recently, ratio of geometric means using ad hoc (RoGM (ad hoc) ) or Taylor series (RoGM (Taylor) ) methods for estimating variances have been proposed as alternative effect measures for skewed continuous data. Skewed data are suggested for summary measures of clinical parameters restricted to positive values which have large coefficients of variation (CV). Our objective was to compare performance characteristics of RoGM (ad hoc) and RoGM (Taylor) to MD, SMD, and RoM. We used empiric data from systematic reviews reporting continuous outcomes and selected from each the meta-analysis with the most and at least 5 trials (Cochrane Database [2008, Issue 1]). We supplemented this with simulations conducted with representative parameters. Pooled results were calculated using each effect measure. Of the reviews, 232/5053 met the inclusion criteria. Empiric data and simulation showed that RoGM (ad hoc) exhibits more extreme treatment effects and greater heterogeneity than all other effect measures. Compared with MD, SMD, and RoM, RoGM (Taylor) exhibits similar treatment effects, more heterogeneity when CV ≤0.7, and less heterogeneity when CV > 0.7. In conclusion, RoGM (Taylor) may be considered for pooling continuous outcomes in meta-analysis when data are skewed, but RoGM (ad hoc) should not be used. However, clinicians' lack of familiarity with geometric means combined with acceptable performance characteristics of RoM in most situations suggests that RoM may be the preferable ratio method for pooling continuous outcomes in meta-analysis.


Effect of recombinant activin-A on gonadotropin secretion in the female rat.
Repeated injections of recombinant human (rh) activin-A over a 2- to 3-day period are reportedly needed to stimulate the in vivo secretion of FSH. In this paper we present results showing that acute treatment with rh-activin-A caused marked and dose-dependent increases in plasma FSH, but not LH, levels in adult female rats. After one injection, maximum FSH release was observed 4 h after the administration of activin, while two injections of 100 micrograms activin/kg, 5 h apart, maintained elevated FSH levels for more than 10 h in intact diestrous day 1 females. Removal of the GnRH drive by pretreatment of ovariectomized animals with the GnRH antagonist ([Ac-D2Nal1,DCpa2,D3Pal3,Arg5,D-p-methoxyphenyl) 5- oxo-2-amino-pentanoic acid6, DAla10]GnRH; 100 micrograms/kg;) or repeated injections of the GnRH agonist ([DTrp6,Pro9,NEt,NH2]GnRH; 1 microgram/h for 5 days) did not prevent the stimulatory action of activin. Concomitant treatment with rh-inhibin-A (30 micrograms/kg], on the other hand, completely blocked FSH secretion induced by 100 micrograms activin/kg. These results indicate that activin-A is a powerful stimulus for FSH secretion in the female rat and exerts this effect independently of GnRH.