Gene expression profile of adipocyte differentiation and its regulation by peroxisome proliferator-activated receptor-gamma agonists.
PPAR gamma is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR gamma, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR gamma agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of beta-catenin as a new PPAR gamma target gene. Both mRNA and protein levels for beta-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR gamma agonists. Treatment of db/db mice with a PPAR gamma agonist also resulted in reduction of beta-catenin mRNA levels in adipose tissue. These results suggest that beta-catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR gamma activation.


Benefits of breakfast meals and pattern of consumption on satiety-related sensations in women.
This study evaluated the effects on satiety-related sensations of seven isoenergetic cereal-based breakfasts and two fruit products (salad and juice) consumed within breakfast or as a midmorning snack. Nine healthy women participated to 11 sessions following a randomized repeated-measures design. Subjects were asked to consume seven breakfasts consisting of a standard beverage and a different cereal-based product, and also fruit salad or apricot juice consumed within breakfast or as a midmorning snack. Satiety, desire-to-eat and perceived characteristics of products consumed were monitored on Visual Analog Scales from 8:30 am until lunch. Ratings registered and areas under the curve of sensations were analyzed by repeated-measures ANOVA. All breakfast meals maintained the satiety-related sensations at lunch time higher than basal values. The best satiety control was obtained when the fruit salad was consumed as a midmorning snack. Consequently, regular consumption of breakfast and of whole fruit as midmorning snack may be a valid strategy to achieve appetite control.


[Antenatal screening for Down syndrome: a smattering of epidemiology].
Maternal age per se is not an indication for chorionic villous sampling or amniocentesis anymore. Although the risk for fetal Down syndrome increases with maternal age, it must be adjusted after other screening tests are performed. Current recommendations include ultrasound measurement of the fetal nuchal transluciency, and of maternal PAPP-A and free-b-hCG in addition to maternal age. This strategy has a sensitivity of 80 to 90%, with false positive rate of 5%. The thickness of fetal nuchal transluciency is strongly associated with the risk of Down syndrome, and measurement must be performed by an experie ced sonographer. For women with an intermediate risk (1/380 to 1/1000), a genetic son gram allows a reassessement of the risk and may help couples to make a decision of invasive sampling.


Observation of carrier-density-dependent many-body effects in graphene via tunneling spectroscopy.
We find the scanning tunneling spectra of backgated graphene monolayers to be significantly altered by many-body excitations. Experimental features in the spectra arising from electron-plasmon interactions show carrier density dependence, distinguishing them from density-independent electron-phonon features. Using a straightforward model, we are able to calculate theoretical tunneling spectra that agree well with our data, providing insight into the effects of many-body interactions on the lifetime of graphene quasiparticles.


[Neurological protection effects of "paraplegia-triple-needling method" on rats with incomplete spinal cord injury].
To observe the neurological protection effects of "paraplegia-triple-needling method" on rats with incomplete spinal cord injury (SCI), so as to make a preliminary exploration on its mechanism. A total of 45 SD rats were randomly divided into a paraplegia-triple-needling method group (group A), a regular acupuncture group (group B) and a model group (group C), 15 rats in each one. The rats model of incomplete spinal cord injury was established by modified Allen's method. The acupoints of governor vessel and back-shu points next to the vertebras of upper end and lower end of injured segment as well as motor points in key muscle of lower extremities were treated with acupuncture in the group A; the acupoints of governor vessel and back-shu points next to the vertebras of upper end and lower end of injured segment as well as "Huantiao" (GB 30), "Housanli" (ST 36), "Yanglingquan" (GB 34) and "Genduan"(Extra) were treated with acupuncture in the group B; rats in the group C received no treatment after model establishment but grabbing and immobilization. The needles were retained for 15 min in the group A and group B, once a day for 14 times. 1 d, 7 d and 14 d after model establishment, Basso Beattie Bresnahan (BBB) scores were observed in each group; the morphologic change of injured spinal cord and expression of positive cells of calcitonin gene-related peptide (CGRP) were observed. Results (1) One day after SCI, there was no significant difference of BBB scores among three groups (P> 0. 05); 7 days and 14 days after SCI, BBB scores in the group A and group B were significantly superior to those in the group C (all P<0. 05), and the BBB scores in the group A were superior to those in the group B ( both P<0. 05). (2) There was expression of CGRP positive cells in all three groups, and that in the group A and group B was significantly higher than that in group C (both P<0. 05); 14 days after treatment, the expression in the group A was higher than that in the group B (P<0. 05). The "paraplegia-triple-needling method" could obviously! improve the motor function of rats with SCI, especially the expression of neuroprotective factor CGRP, which is likely to be one of the mechanisms of neurological protection effect.


Protein-Polymer Dynamics as Affected by Polymer Coating and Interactions.
We investigate the relaxation dynamics of protein-polymer conjugates by neutron scattering spectroscopy to understand to which extent the coating of a protein by a polymer can replace water in promoting thermal structural fluctuations. For this purpose, we compare the dynamics of protein-polymer mixtures to that of conjugates with a variable number of polymers covalently attached to the protein. Results show that the flexibility of the protein is larger in protein-polymer mixtures than in native protein or in conjugates, even in the dry state. Upon hydration, both the native protein and the conjugate show equivalent dynamics, suggesting that the polymer grafted on the protein surface adsorbs all water molecules.


Targeted massively parallel sequencing of angiosarcomas reveals frequent activation of the mitogen activated protein kinase pathway.
Angiosarcomas are rare malignant mesenchymal tumors of endothelial differentiation. The clinical behavior is usually aggressive and the prognosis for patients with advanced disease is poor with no effective therapies. The genetic bases of these tumors have been partially revealed in recent studies reporting genetic alterations such as amplifications of MYC (primarily in radiation-associated angiosarcomas), inactivating mutations in PTPRB and R707Q hotspot mutations of PLCG1. Here, we performed a comprehensive genomic analysis of 34 angiosarcomas using a clinically-approved, hybridization-based targeted next-generation sequencing assay for 341 well-established oncogenes and tumor suppressor genes. Over half of the angiosarcomas (n = 18, 53%) harbored genetic alterations affecting the MAPK pathway, involving mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 and NF1, or amplifications in MAPK1/CRKL, CRAF or BRAF. The most frequently detected genetic aberrations were mutations in TP53 in 12 tumors(35%) and losses of CDKN2A in9 tumors (26%). MYC amplifications were generally mutually exclusive of TP53 alterations and CDKN2A loss and were identified in 8 tumors (24%), most of which (n = 7, 88%) arose post-irradiation. Previously reported mutations in PTPRB (n = 10, 29%) and one (3%) PLCG1 R707Q mutation were also identified. Our results demonstrate that angiosarcomas are a genetically heterogeneous group of tumors, harboring a wide range of genetic alterations. The high frequency of genetic events affecting the MAPK pathway suggests that targeted therapies inhibiting MAPK signaling may be promising therapeutic avenues in patients with advanced angiosarcomas.


Epidemiological evidence for associations between variants in CHRNA genes and risk of lung cancer and chronic obstructive pulmonary disease.
Genetic studies have previously reported that single-nucleotide polymorphisms (SNPs) in CHRNA genes (such as CHRNA3, CHRNA4, CHRNA5, or CHRNA3-CHRNA5-CHRNB4 clusters) are linked to the risk of neoplastic and non-neoplastic diseases. However, these conclusions were controversial and no systematic research synopsis has been available. We aimed to synthesize current knowledge of variants in the CHRNA genes on the risk of diseases. We systematically searched for publications using PubMed, Medline, and Web of Science on or before 25 August 2021. A total of 1,818 publications were identified, of which 29 were deemed eligible for inclusion that could be used to perform meta-analysis based on at least three data sources to assess whether the morbidity associated with neoplastic and non-neoplastic diseases can be attributed to SNPs in CHRNA genes. To further evaluate the authenticity of cumulative evidence proving significant associations, the present study covered the Venice criteria and false-positive report probability tests. Through the Encyclopedia of DNA Elements (ENCODE) project, we created functional annotations for strong associations. Meta-analyses were done for nine genetic variants with two diseases {chronic obstructive pulmonary disease (COPD) and lung cancer (LC)}that had at least three data sources. Interestingly, eight polymorphisms were significantly related to changes in the susceptibility COPD and LC (p < 0.05). Of these, strong evidence was assigned to six variants (28 significant associations): CHRNA3 rs1051730, CHRNA3 rs6495309, and CHRNA5 rs16969968 with COPD risk, and CHRNA3 rs1051730, CHRNA3 rs578776, CHRNA3 rs6495309, CHRNA3 rs938682, CHRNA5 rs16969968, and CHRNA5 rs588765 with LC risk; moderate evidence was assigned to five SNPs (12 total associations) with LC or COPD risk. Data from ENCODE and other public databases showed that SNPs with strong evidence may be located in presumptive functional regions. Our study summarized comprehensive evidence showing that common mutations in CHRNA genes are strongly related to LC and COPD risk. The study also elucidated the vital function of CHRNA genes in genetic predispositions to human diseases.


YF3:Ln3+ (Ln = Ce, Tb, Pr) submicrospindles: hydrothermal synthesis and luminescence properties.
YF(3):Ln(3+) (Ln = Ce, Tb, Pr) microspindles were successfully fabricated by a facile hydrothermal method. X-Ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), lifetimes, photoluminescence (PL) and low-voltage cathodoluminescence (CL) were used to characterize the resulting samples. The lengths and diameters of YF(3):0.02Ce(3+) microspindles are around 760 nm and 230 nm, respectively. Adding dilute acid and trisodium citrate (Cit(3-)) are essential for obtaining YF(3) microspindles. A potential formation mechanism for YF(3) microspindles has been presented. PL spectroscopy investigations show that YF(3):Ce(3+) and YF(3):Tb(3+) microcrystals exhibit the characteristic emission of Ce(3+) 5d → 4f and Tb(3+ 5)D(4)→(7)F(J) (J = 6-3) transitions, respectively. In addition, the energy transfer from Ce(3+) to Tb(3+) was investigated in detail for YF(3):Ce(3+), Tb(3+) microspindles. Under the excitation of electron beams, YF(3):Pr(3+) show quantum cutting emission and YF(3):Ce(3+), Tb(3+) phosphors exhibit more intense green emission than the commercial phosphor ZnO:Zn.


Treatment effects of blood pressure targets and hemodynamics according to initial blood lactate levels in comatose out-of-hospital cardiac arrest patients - A sub study of the BOX trial.
Out-of-hospital cardiac arrest (OHCA) survivors remaining comatose are often circulatory unstable with high mortality in the first days following resuscitation. Elevated lactate will reflect the severity and duration of hypoperfusion in cardiac arrest. Further, the severity of hypoperfusion could modify the effect on survival of different mean arterial blood pressure (MAP) targets. In this sub-study of the BOX trial, adult successfully resuscitated comatose OHCA patients (n = 789) with a presumed cardiac cause were randomized to a MAP target of 63 mmHg vs. 77 mmHg. Patients were arbitrarily grouped in low-lactate: <25% of sample, medium-lactate: 25%-75%, and high >75 percentile according to blood lactate levels at hospital arrival as a surrogate of the severity of hypoperfusion. Invasive hemodynamic evaluations were performed using an arterial catheter and pulmonary artery catheter (PAC), and data from admission to 48 hours (h) were recorded. Logistic regression analysis evaluated whether lactate levels (as continuous and categorical) modify the effect of MAP targets on mortality at 365 days. The three lactate groups had initial lactate levels of low-lactate: <2.9 mmol/L, medium-lactate: 2.9-7.9 mmol/L, and high-lactate > 7.9 mmol/L. All patients were randomized to a 63 mmHg or 77 mmHg MAP target. The proportion of patients in the high-MAP target group was 100/201 (50%), 178/388 (46%), and 114/197 (58%) for low, medium, and high-lactate groups respectively. At admission, the high-lactate groups had a lower MAP compared to the medium-lactate (2.6 mmHg (95% CI: 0.1-5.0 mmHg, p = 0.02), and the low-lactate group, (3.6 mmHg (95% CI: 0.8-6.5 mmHg, p < 0.01). Accordingly, the vasoactive inotropic score was 79% (95%CI: 42%-124%%) higher with increasing initial lactate level (High-lactate vs. low-lactate) with the largest difference at 6 hours (110.6% (95%CI: 54.4%-187.2%) higher in high-lactate patients). No difference in the cardiac index or systemic vascular resistance was observed between lactate groups. The initial lactate level (continuous) modified the effect of the two MAP targets (p = 0.04). In the highest lactate group, the mortality was 100/197 (51%), and with an odds ratio (OR): 1.7 (95%CI: 0.9-3.0) if randomized to MAP 77 mmHg compared to MAP 63 mmHg. In the lowest lactate group, the mortality was 35/201(17%) and similar if randomized to a MAP target of 77 mmHg (OR: 1.1 (95% CI: 0.5-2.3)). Comatose OHCA patients with high initial lactate levels required more vasoactive drugs on the first two days of ICU admission to meet the blood pressure target and had a poorer prognosis. No indication that aiming for a higher MAP target is beneficial in patients with an initial high lactate level was found, however, given the post-hoc nature of this study, these results should be considered hypothesis-generating.


Increased gastric acid secretion after massive small bowel resection is related to a decrease in enterogastrones.
The reported increase of gastric secretion after small bowel (SB) resection is controversial. To determine the effect of SB resection on gastric acid secretion we studied basal and dose step pentagastrin-stimulated gastric acid secretion as well as basal serum gastrin, secretin, neurotensin and postprandial gastrin levels in 12 dogs, before and after resection of 60% of the intestine representing both proximal (n = 6) and distal (n = 6) SB. Rat bioassay was also performed to rule out the presence of unknown gastric secretagogues in the blood. Proximal SB resection produced a significant increase in basal and low dose (100 ng/kg/h) pentagastrin-stimulated gastric acid secretion (ED50 = 1,110 vs. 720 ng/kg/h after resection). However, no significant changes in gastric secretion were observed after distal SB resections. Neither proximal nor distal SB resection altered basal or postprandial serum gastrin levels. Proximal SB resection reduced serum secretin levels (229 +/- 38 vs. 134 +/- 16 pg/ml, p < 0.05) but did not alter neurotensin levels. Rat bioassay failed to reveal a circulating secretagogue after SB resections. We conclude that proximal but not distal SB resection increases basal and submaximally stimulated gastric acid secretion. Such an effect may be due to the observed decrease in circulating secretin levels.


Multicenter outbreak of infections by Saprochaete clavata, an unrecognized opportunistic fungal pathogen.
Rapidly fatal cases of invasive fungal infections due to a fungus later identified as Saprochaete clavata were reported in France in May 2012. The objectives of this study were to determine the clonal relatedness of the isolates and to investigate possible sources of contamination. A nationwide alert was launched to collect cases. Molecular identification methods, whole-genome sequencing (WGS), and clone-specific genotyping were used to analyze recent and historical isolates, and a case-case study was performed. Isolates from thirty cases (26 fungemias, 22 associated deaths at day 30) were collected between September 2011 and October 2012. Eighteen cases occurred within 8 weeks (outbreak) in 10 health care facilities, suggesting a common source of contamination, with potential secondary cases. Phylogenetic analysis identified one clade (clade A), which accounted for 16/18 outbreak cases. Results of microbiological investigations of environmental, drug, or food sources were negative. Analysis of exposures pointed to a medical device used for storage and infusion of blood products, but no fungal contamination was detected in the unused devices. Molecular identification of isolates from previous studies demonstrated that S. clavata can be found in dairy products and has already been involved in monocentric outbreaks in hematology wards. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen. This report also underlines further the potential of WGS for investigation of outbreaks due to uncommon fungal pathogens. Several cases of rapidly fatal infections due to the fungus Saprochaete clavata were reported in France within a short period of time in three health care facilities, suggesting a common source of contamination. A nationwide alert collected 30 cases over 1 year, including an outbreak of 18 cases over 8 weeks. Whole-genome sequencing (WGS) was used to analyze recent and historical isolates and to design a clade-specific genotyping method that uncovered a clone associated with the outbreak, thus allowing a case-case study to analyze the risk factors associated with infection by the clone. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen.


Calcium transport and local pool regulate polycystin-2 (TRPP2) function in human syncytiotrophoblast.
Polycystin-2 (PC2, TRPP2) is a Ca(2+)-permeable, nonselective cation channel implicated in Ca(2+) transport and epithelial cell signaling. Although PC2 may contribute to Ca(2+) transport in human term placenta, the regulatory mechanisms associated with Ca(2+) handling in this tissue are largely unknown. In this work we assessed the regulation by Ca(2+) of PC2 channel function from a preparation of apical membranes of human syncytiotrophoblast (PC2hst) reconstituted in a lipid bilayer system. Addition of either EGTA or BAPTA to the cis hemi-chamber, representing the cytoplasmic domain of the channel, and lowering Ca(2+) to ∼0.6-0.8 nM, inhibited spontaneous PC2hst channel activity, with a time response dependent on the chelator tested. EGTA reduced PC2hst channel currents by 86%, with a t1/2 = 3.6 min, whereas BAPTA rapidly and completely (100%) eliminated channel activity with a t1/2 = 0.8 min. Subsequent titration with Ca(2+) reversed the inhibition, which followed a Hill-type function with apparent dissociation constants of 1-5 nM, and 4 Ca(2+) binding sites. The degree of inhibition by the cis Ca(2+) chelator largely depended on increasing trans Ca(2+). This was consistent with measurable Ca(2+) transport through the channel, feeding the regulatory sites in the cytoplasmic domain. Interestingly, the reconstituted in vitro translated PC2 (PC2iv) was completely insensitive to Ca(2+) regulation, suggesting that the regulatory sites are not intrinsic to the channel protein. Our findings demonstrate the presence of a Ca(2+) microdomain largely accessible through the channel that controls PC2 function in human syncytiotrophoblast of term placenta.


The Association of IL-12b Polymorphisms with Systemic Lupus Erythematosus in Chinese Han Population.
Background. Systemic lupus erythematosus (SLE) is a complex immune disease. The genetic variation in the IL-12b gene was found to associate with SLE in Caucasian population. In this study, we examined this association in Chinese Han population by a recently developed method, unlabeled probe-based high resolution melting analysis. Methods. A total of 297 SLE patients and 351 controls were recruited. Unlabeled probe-based high resolution melting analysis (HRMA) was used in genotyping. Results. Statistically significant differences were observed in both genotype and allele frequencies for rs6887695 in the SLE patients as compared with the controls. Minor allele (C) of rs6887695 (P = 0.031, OR 0.78, [95% CI 0.63-0.98]) was found to be protective against SLE. The association of SNP rs6887695 with the diagnostic criteria of SLE was also examined. Minor allele (C) exerts protective effect on the incidence of arthritis (P = 0.013, OR = 0.65, 95% CI = 0.47-0.92) and abnormalities of antinuclear antibody (P = 0.022, OR = 0.68, 95% CI = 0.49-0.95). IL-12b SNPs were irrelevant to other diagnostic criteria of SLE. Summary. Polymorphisms of rs6887695 in IL-12b gene were associated with disease risk, as well as arthritis and antinuclear antibody synthesis, of systemic lupus erythematosus in Chinese population.


Intratesticular injection of a balanced zinc solution for permanent sterilization of dogs.
Five male mature dogs with normal sex organs and normal pre-study semen evaluation received intratesticular injections of a sterile solution of balanced zinc gluconate. Semen without sperm could be collected on days 26, 30, 35 and 51 from 4 dogs. The dogs achieved penile erection but no ejaculation before these days. There were no significant adverse effects and no change in the dog behavior during the time that they were observed. Histopathological findings documented virtually complete fibrosis of seminiferous tubules and Leydig cells on days 60 and 75. This preliminary study concludes that balanced zinc gluconate may be used to sterilize dogs.


Association of epilepsy and burns - a case control study.
General practitioners play a vital role in reducing risk for people with epilepsy through pharmacological prevention of seizures. Burns are the most common injury sustained during epileptic seizure. This article examines the risk of burns among patients with epilepsy in Victoria. A case control study was conducted using the Victorian Admitted Episodes Dataset (VAED) from 2000-2005. Odds ratios were adjusted for potential confounders and 95% confidence intervals were calculated comparing burns among epilepsy versus nonepilepsy patients using multivariate logistic regression. Epilepsy was three times more likely to be associated with burns, with women being five times more likely to be burned. Hot drinks, food, fats, cooking oils, steam and household appliances, hot tap water, hot fluids other than water, and hot heating appliances were all significant causes. The strength of association between epilepsy and burns for these types of causes was consistently higher for women compared with men. This study has shown a strong association between epilepsy and burns in hospital admissions, and identifies the importance of using routine databases for contributing to the limited knowledge about seizure related burns in epileptic patients.


The dose makes the poison: Non-linear behavioural response to CO2-induced aquatic acidification in zebrafish (Danio rerio).
CO2-induced aquatic acidification is predicted to affect fish neuronal GABAA receptors leading to widespread behavioural alterations. However, the large variability in the magnitude and direction of behavioural responses suggests substantial species-specific CO2 threshold differences, life history and parental acclimation effects, experimental artifacts, or a combination of these factors. As an established model organism, zebrafish (Danio rerio) can be reared under stable conditions for multiple generations, which may help control for some of the variability observed in wild-caught fishes. Here, we used two standardized tests to investigate the effect of 1-week acclimatization to four pCO2 levels on zebrafish anxiety-like behaviour, exploratory behaviour, and locomotion. Fish acclimatized to 900 μatm CO2 demonstrated increased anxiety-like behaviour compared to control fish (~480 μatm), however, the behaviour of fish exposed to 2200 μatm CO2 was indistinguishable from that of controls. In addition, fish acclimatized to 4200 μatm CO2 had decreased anxiety-like behaviour; i.e. the opposite response than the 900 μatm CO2 treatment. On the other hand, exploratory behaviour did not differ among any of the pCO2 exposures that were tested. Thus, zebrafish behavioural responses to elevated pCO2 are not linear; with potential important implications for physiological, environmental, and aquatic acidification studies.


Stimulus-response-outcome coding in the pigeon nidopallium caudolaterale.
A prerequisite for adaptive goal-directed behavior is that animals constantly evaluate action outcomes and relate them to both their antecedent behavior and to stimuli predictive of reward or non-reward. Here, we investigate whether single neurons in the avian nidopallium caudolaterale (NCL), a multimodal associative forebrain structure and a presumed analogue of mammalian prefrontal cortex, represent information useful for goal-directed behavior. We subjected pigeons to a go-nogo task, in which responding to one visual stimulus (S+) was partially reinforced, responding to another stimulus (S-) was punished, and responding to test stimuli from the same physical dimension (spatial frequency) was inconsequential. The birds responded most intensely to S+, and their response rates decreased monotonically as stimuli became progressively dissimilar to S+; thereby, response rates provided a behavioral index of reward expectancy. We found that many NCL neurons' responses were modulated in the stimulus discrimination phase, the outcome phase, or both. A substantial fraction of neurons increased firing for cues predicting non-reward or decreased firing for cues predicting reward. Interestingly, the same neurons also responded when reward was expected but not delivered, and could thus provide a negative reward prediction error or, alternatively, signal negative value. In addition, many cells showed motor-related response modulation. In summary, NCL neurons represent information about the reward value of specific stimuli, instrumental actions as well as action outcomes, and therefore provide signals useful for adaptive behavior in dynamically changing environments.


Negative feedback neuroendocrine control of inflammatory response in the rat is dependent on the sympathetic postganglionic neuron.
Negative feedback control of inflammation is mediated by activation of nociceptive afferents that in turn activates the hypothalamic-pituitary-adrenal axis to release corticosteroids. Plasma extravasation (PE) produced by the potent inflammatory mediator, bradykinin (BK), but not that induced by another potent inflammatory mediator, platelet-activating factor (PAF), is inhibited by released corticosterone. Because bradykinin, but not PAF, produces PE by a mechanism that is, in part, dependent on the sympathetic postganglionic neuron (SPGN) terminal, we tested the hypothesis that the negative feedback control of inflammation is dependent on the SPGN terminal in the inflamed tissue. In sympathectomized rats, the residual (i.e., SPGN-independent) PE in the knee joint produced by BK was not inhibited by noxious electrical stimulation. Furthermore, intravenous administration of corticosterone potently inhibited, with a similar time-course, the SPGN-dependent, but not the SPGN-independent, component of BK-induced PE. Neither electrical stimulation nor corticosterone inhibited PAF-induced PE. Finally, corticosterone's actions do not appear to be mediated by release of norepinephrine from the SPGN terminal, because neither the alpha-adrenergic receptor antagonist phentolamine nor the beta2-adrenergic receptor antagonist ICI 118, 551 antagonized the inhibition of BK-induced PE by corticosterone. We conclude that in the rat knee joint, negative feedback control of the inflammatory response is dependent on the presence of the SPGN terminal. Further, our data suggest that a significant component of corticosteroid-induced inhibition of PE produced by inflammatory mediators is SPGN-dependent.


[Etiopathogenesis of insudative vasculopathy in transplanted kidneys].
In 99 renal allograft recipients with insudative vasculopathy of graft, mean serum cholesterol levels, prevalence of subjects with hypercholesterolaemia, mean cumulative doses of methylprednisolone, prevalence of subjects with methylprednisolone doses > or = 6,000 mg and prevalence of patients with hypertension, all in the period between transplantation and the first diagnostic biopsy, were compared between 51 those with conventional and 48 with cyclosporine maintenance immunosuppression. In subjects treated with cyclosporine the lesion was found in biopsies performed sooner and was present more frequently, prevalence of hypercholesterolaemia and of hypertension was similar and that of subjects with both hypercholesterolaemia and hypertension lower than in subjects treated with azathioprine. A positive correlation was present between high doses of methylprednisolone and prevalence of hypertension, regardless of the type of immunosuppression and of severity of vasculopathy. In etiopathogenesis of insudative vasculopathy atherogenic factors are most probably involved, more markedly when azathioprine is used for maintenance immunosuppression. With cyclosporine, changes of graft haemodynamics and possibly also toxic damage to the vessels involved seem to be more important.


Sex differences in neural and behavioral signatures of cooperation revealed by fNIRS hyperscanning.
Researchers from multiple fields have sought to understand how sex moderates human social behavior. While over 50 years of research has revealed differences in cooperation behavior of males and females, the underlying neural correlates of these sex differences have not been explained. A missing and fundamental element of this puzzle is an understanding of how the sex composition of an interacting dyad influences the brain and behavior during cooperation. Using fNIRS-based hyperscanning in 111 same- and mixed-sex dyads, we identified significant behavioral and neural sex-related differences in association with a computer-based cooperation task. Dyads containing at least one male demonstrated significantly higher behavioral performance than female/female dyads. Individual males and females showed significant activation in the right frontopolar and right inferior prefrontal cortices, although this activation was greater in females compared to males. Female/female dyad's exhibited significant inter-brain coherence within the right temporal cortex, while significant coherence in male/male dyads occurred in the right inferior prefrontal cortex. Significant coherence was not observed in mixed-sex dyads. Finally, for same-sex dyads only, task-related inter-brain coherence was positively correlated with cooperation task performance. Our results highlight multiple important and previously undetected influences of sex on concurrent neural and behavioral signatures of cooperation.


Efficacy of bevacizumab versus epidermal growth factor receptor inhibitors for wild-type RAS metastatic colorectal cancer: a meta-analysis.
Results from several prospective clinical trials comparing anti-epidermal growth factor receptor (EGFR) therapy and anti-vascular endothelial growth factor (VEGF) therapy plus chemotherapy for wild-type RAS metastatic colorectal cancer (mCRC) have been inconsistent. This meta-analysis aims to investigate the optimal choice for these target agents. We searched for clinical trials in both electronic databases from inception until January 2018 and recent conference abstracts to identify prospective clinical studies comparing the efficacy of a VEGF inhibitor (bevacizumab) versus EGFR inhibitors (cetuximab or panitumumab) on wild-type RAS (including its subset KRAS) mCRC. All analyses were conducted using RevMan 5.3 software. A total of 5 studies were included. EGFR inhibitors were associated with a significant benefit in terms of overall survival (OS) compared with VEGF inhibitors in wild-type KRAS or wild-type RAS populations, with hazard ratios (HRs) equal to 0.86 (95% CI: 0.78, 0.95; p=0.003) and 0.83 (95% CI: 0.72, 0.95; p=0.007), respectively. This survival benefit was limited to the first-line setting. No difference was found for progression-free survival (PFS), whereas the objective response rate (ORR) was significantly increased in the wild-type RAS population (OR: 0.64; 95% CI: 0.50, 0.82; p=0.0004). No difference in OS was noted between EGFR inhibitors versus a VEGF inhibitor plus the FOLFIRI regimen, whereas superior survival was noted for EGFR inhibitors plus the mFOLFOX6 regimen versus a VEGF inhibitor (HR: 0.75; 95% CI: 0.57, 0.98; p=0.04). PFS was significantly prolonged (HR: 1.48; 95% CI: 1.14, 1.92; p=0.003), whereas a trend favoring OS (HR: 1.23; 95% CI: 0.93, 1.63; p=0.14) was noted for a VEGF inhibitor in patients with right-sided tumors, with no difference in the ORR (OR: 0.85; 95% CI: 0.52, 1.38; p=0.51). However, left-sided tumors exhibited superior OS (HR: 0.71; 95% CI: 0.59, 0.85; p=0.0002), PFS (HR: 0.84; 95% CI: 0.72, 0.98; p=0.03), and ORR (OR: 0.66; 95% CI: 0.48, 0.92; p=0.01) for EGFR inhibitors. This meta-analysis suggests the superiority of anti-EGFR therapy compared with anti-VEGF therapy for mCRC with wild-type RAS. Primary tumor location should be taken into account in target drug selection. Further research is still needed to confirm which inhibitor may be a better choice when combined with different chemotherapy regimens.


Near-Infrared Spectroscopy Reveals Abnormal Hemodynamics in the Left Dorsolateral Prefrontal Cortex of Menopausal Depression Patients.
Background/Objective. Menopausal depression (MD) is characterized by depressive symptoms along with hormonal fluctuations. We investigate brain function alteration between major depressive disorder (MDD) and MD. Methods. The difference in oxygenated hemoglobin (Oxy-Hb) for the prefrontal cortex (PFC) was compared retrospectively among 90 females presented with 30 MDD, 30 MD, and 30 healthy controls (HCs) using verbal fluency task (VFT) with near-infrared spectroscopy (NIRS). Results. We observed a significant difference in Oxy-Hb alteration in the left dorsolateral PFC (DLPFC) using VFT with NIRS (channel 18, P = 0.007) between the MD and MDD groups. A significant difference in Oxy-Hb levels was observed among the three groups in the bilateral DLPFC (channels 18, 27, 33, 39, 41, and 45; P < 0.05). Compared to the HCs, the MD group presented lower Oxy-Hb activation in the right DLPFC (channel 41; P = 0.048) and the left DLPFC (channels 18, 39, and 45; P < 0.05), and the MDD group presented lower Oxy-Hb activation in the right DLPFC (channels 27, 33, and 41; P < 0.05) and the left DLPFC (channels 39 and 45; P < 0.05). Conclusion. Abnormal hemodynamics of the left DLPFC can differentiate MD from MDD by NIRS.


The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration.
In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n=36) were divided into three groups and administered either saline, GHB 50mg/kg or GHB 300mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.


Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth.
Acute myelogenous leukemia (AML) is often associated with activating mutations in the receptor tyrosine kinase, Flt3, including internal tandem duplications (ITDs) within the regulatory juxtamembrane region. Previous studies have linked Flt3-ITD to the activation of the Fes protein tyrosine kinase in AML, and RNAi-knockdown studies suggest that Fes may be required for Flt3 function. In this study, we tested Fes inhibitors from three different chemical classes for their growth-suppressive activity against Flt3-ITD+ myeloid leukemia cell lines (MV4-11, MOLM-13 and MOLM-14) vs. myeloid cells with wild-type Flt3 (THP-1). All Fes inhibitors selectively inhibited the growth of Flt3-ITD+ AML cells, with IC50 values for diaminopyrimidine and pyrrolopyridine inhibitors ranging from 19 to 166 nM. In contrast, a pyrazolopyrimidine inhibitor was less potent in Flt3-ITD+ AML cells, with IC50 values in the 1.0 μM range. In vitro kinase assays showed that the most potent inhibitors of Flt3-ITD+ AML cell proliferation blocked both Fes and Flt3-ITD kinase activity, while the pyrazolopyrimidine was more selective for Fes vs. Flt3-ITD. All three inhibitors induced significant apoptosis in Flt3-ITD+ AML cells, with potency equivalent to or greater than the established Flt3-ITD inhibitor, tandutinib. Transformation of TF-1 cells with Flt3-ITD resulted in constitutive activation of endogenous Fes, and rendered the cells highly sensitive to all three Fes inhibitors with IC50 values in the 30-500 nM range. The pyrrolopyridine compound also induced apoptotic responses in patient-derived Flt3-ITD+ AML bone marrow cells but not in normal bone marrow mononuclear cells. These results demonstrate that Fes kinase activity contributes to Flt3-ITD signaling in AML, and suggests that dual inhibition of both Flt3 and Fes may provide a therapeutic advantage for the treatment of Flt3-ITD+ AML.


Development of acetylcholinesterase (AChE) staining in human fetal auditory cortex.
In this study acetylcholinesterase (AChE) staining methods have been used to demonstrate the development of the prospective afferent fibres of auditory cortex in human fetuses ranging between 8 and 28 weeks of gestation. Earliest AChE positive staining was found in fetuses at 20--24 weeks in the neuropil of the marginal zone and throughout subplate layer of the auditory cortex. On the basis of this characteristic AChE staining pattern, the auditory cortex may be delineated from surrounding cortical areas. At 24--26 weeks, during intensive lamination of the cortical plate, AchE-positive reaction appears in the deep part of the cortical plate. In the oldest fetuses (28 weeks) a columnar pattern of vertical, darkly stained zones was seen in the middle third of the cortical plate. We conclude that AChE staining is characteristically distributed within cytoarchitectonic compartments and 'synaptic' layers of the developing auditory cortex. The AChE-positive layers coincide with the laminar pattern of synpatogeneis. Thus, AChE-positive reaction during development may serve as a parameter of cortical afferent (thalamic?) innervation of the auditory cortex. In addition, AChE reactivity may indicate the specific transmitter nature of the afferent fibres in the auditory cortex.


Effects of climate and fine particulate matter on hospitalizations and deaths for heart failure in elderly: A population-based cohort study.
There are limited data on the effects of climate and air pollutant exposure on heart failure (HF) within taking into account individual and contextual variables. We measured the lag effects of temperature, relative humidity, atmospheric pressure and fine particulate matter (PM2.5) on hospitalizations and deaths for HF in elderly diagnosed with this disease on a 10-year period in the province of Quebec, Canada. Our population-based cohort study included 112,793 elderly diagnosed with HF between 2001 and 2011. Time dependent Cox regression models approximated with pooled logistic regressions were used to evaluate the 3- and 7-day lag effects of daily temperature, relative humidity, atmospheric pressure and PM2.5 exposure on HF morbidity and mortality controlling for several individual and contextual covariates. Overall, 18,309 elderly were hospitalized and 4297 died for the main cause of HF. We observed an increased risk of hospitalizations and deaths for HF with a decrease in the average temperature of the 3 and 7days before the event. An increase in atmospheric pressure in the previous 7days was also associated with a higher risk of having a HF negative outcome, but no effect was observed in the 3-day lag model. No association was found with relative humidity and with PM2.5 regardless of the lag period. Lag effects of temperature and other meteorological parameters on HF events were limited but present. Nonetheless, preventive measures should be issued for elderly diagnosed with HF considering the burden and the expensive costs associated with the management of this disease.


[Effect of dihydroartemisinin combined irradiation on the apoptosis of human lung cancer GLC-82 cells and its mechanism study].
To study the effect of dihydroartemisinin (DHA) combined irradiation on the apoptosis of human lung cancer GLC-82 cells and to study its mechanism. The growth inhibition rate of GLC-82 cells acted by different concentrations DHA was detected using MTT assay at 24, 48, and 72 h, respectively. Clone forming test was used. With multi-target single-hit model, the radiosensitization effect was assessed by calculating sensitizing enhancement ratio (SER).The effect of DHA combined irradiation on the apoptosis of GLC-82 cell cycle distribution and apoptosis were measured by flow cytometry. The protein expression of p53, p21, Bcl-2, and Bax were detected by Western blot. Different concentrations DHA (4, 8, 16, 32, 64, and 128 μg/mL) had cytotoxicity on GLC-82 cells. The IC50 for 24, 48, and 72 h was 38.25,20.58, and 10.36 μg/mL, respectively, in obvious dose- and time-dependent manner. The growth inhibition rate was more significantly increased than that of the blank control group (P < 0.01, P<0.05). DHA had sensitization enhancement effect on GLC-82 cells, with SER of 1.4. DHA combined irradiation could obviously change the structure of GLC-82 cells cell cycle and induce apoptosis (with the apoptosis rate of 21.5%), which was significantly different from that of the blank control group (P < 0.05). Western blot showed the expression of p53 and p21 protein could be increased by DHA combined irradiation, and the expression of Bcl-2 protein down-regulated (P <0.01, P <0. 05). DHA had stronger cytotoxicity and radiosensitization on GLC-82 cells. Its mechanisms might lie in making the arrest of GLC-82 cells' growth at G0/G1 phase, decreasing the ratio of cells at S phase, restoring the function of p53, decreasing the expression of Bcl-2 protein, and inducing apoptosis in GLC-82 cells.


A case report of cryoballoon-based pulmonary vein isolation in a patient with situs inversus abdominalis and levocardia.
Cryoballoon-based pulmonary vein isolation (cbPVI) is a standardized treatment of atrial fibrillation. In complex anatomies, radiofrequency ablation (rfPVI) is usually preferred. We describe the first cbPVI in a rare patient with SI and levocardia. A 41-year-old male patient with paroxysmal atrial fibrillation was referred to our clinic after a previous, unsuccessful cbPVI procedure. Observation of an atypical lead-wire position due to an abnormal anatomy of the inferior vena cava led to its initial termination. A subsequent thoraco-abdominal computed tomography revealed situs inversus abdominalis and levocardia and the procedure was re-attempted in our clinic. Transseptal puncture (TSP) was guided via transoesophageal echocardiography and fluoroscopy, using a SL0-Sheath and a standard BRK-needle. Advancement of the sheath initially failed but after additional dilatation with an Inoue® dilator, transseptal passage of the sheath was successful. Due to the unusual antero-cranial TSP, the septal pulmonary veins (PV) contrasted poorly. After repeat TSP, a steerable FlexCath Advance® sheath was introduced into the left atrium using an Amplatz Super Stiff® guidewire. Subsequently, all PV were intubated with the Achieve® catheter, over which a 2nd generation cryoballoon was introduced. Despite the practical challenges in this case, all PV were isolated. The main challenges include the achievement of transseptal access and manipulation of the cryoballoon to achieve a patent seal of the pulmonary veins. cbPVI eliminates the need for constant re-positioning of the ablation catheter and might facilitate the creation of durable lesions under such difficult anatomical conditions.


Computational Study on the Photolysis of BrHgONO and the Reactions of BrHgO• with CH4, C2H6, NO, and NO2: Implications for Formation of Hg(II) Compounds in the Atmosphere.
Global models suggest BrHgONO to be the major Hg(II) species initially formed in atmospheric oxidation of Hg(0) in most of the atmosphere, but its atmospheric fate has not been previously investigated. In the present work, we use quantum chemistry to predict that BrHgONO photolysis produces the thermally stable radical BrHgO•. Subsequently, BrHgO• may react with NO2 to form thermally stable BrHgONO2, or with NO to re-form BrHgONO. Additionally, BrHgO• abstracts hydrogen atoms from CH4 and C2H6 with higher rate constants than does •OH, producing a stable BrHgOH molecule. Because BrHgO• can abstract hydrogen atoms from sp3-hybridized carbons on many organic compounds, we expect production of BrHgOH to dominate globally, although formation of BrHgONO and BrHgONO2 may compete in urban regions. In the absence of experimental data on the kinetics and fate of BrHgONO and BrHgO•, we aim to guide modelers and other scientists in their search for Hg(II) compounds in the atmosphere.


PM0.1 emissions during diesel trap regeneration.
A nanostructured spinel-type oxide catalyst (CoCr2O4) prepared by solution combustion synthesis was developed and deposited over a SiC wall-flow trap for diesel particulate removal. Bench tests proved that, after soot loading, the developed trap enables a faster and more complete regeneration at 550 degrees C than a commercial Pt-catalyst based trap or a noncatalyzed trap. On the other hand, secondary nanoparticle emission occurs during the fast regeneration promoted by the CoCr2O4-catalyzed trap. This is a likely consequence of oxidative fragmentation of the trapped soot agglomerates. This problem can be resolved by performing a "mild" regeneration at lower temperatures (e.g., 450 degrees C).


Clonal Hematopoiesis and Liquid Biopsy in Gastrointestinal Cancers.
The use of blood liquid biopsy is increasingly being incorporated into the clinical setting of gastrointestinal cancers care. Clonal hematopoiesis (CH) occurs naturally as a result of the accumulation of somatic mutations and the clonal proliferation of hematopoietic stem cells with normal aging. The identification of CH-mutations has been described as a source of biological noise in blood liquid biopsy. Incorrect interpretation of CH events as cancer related can have a direct impact on cancer diagnosis and treatment. This review summarizes the current understanding of CH as a form of biological noise in blood liquid biopsy and the reported clinical significance of CH in patients with GI cancers.


Unilateral multinodular toxic goiter: scintiscan mimicking solitary toxic nodule.
A 58-year-old man presented with hyperthyroidism. By palpation, the left lobe of the thyroid was diffusely enlarged, and the right lobe was normal. Radioactive iodide scintiscan demonstrated homogeneous uptake that was localized to the enlarged left lobe, with near total suppression of uptake on the right. TSH stimulation led to clear visualization of a normal appearing right lobe, findings most consistent with an autonomously functioning solitary nodule on the left. Left hemithyroidectomy cured the hyperthyroidism. However, no single dominant nodule was found in the left lobe. Rather, there was diffuse thyroidal hyperplasia of the micronodular variety, consistent with multinodular toxic goiter. Thus, in this patient with a usually diffuse form of thyroid disease, the autonomously functioning hyperactive follicles were localized predominantly to one thyroid lobe. This variant expands the clinical spectrum of multinodular toxic goiter, and further emphasizes the extent of asymmetry in the distribution of hyperactive follicles than can occur in this disorder.


Synthetic biological approaches to optogenetically control cell signaling.
Precise spatial and temporal control of cellular processes is in life sciences a highly sought-after capability. In the recent years, this goal has become progressively achievable through the field of optogenetics, which utilizes light as a non-invasive means to control genetically encoded light-responsive proteins. The latest optogenetic systems, such as those for control of subcellular localization or cellular decision-making and tissue morphogenesis provide us with insights to gain a deeper understanding of the cellular inner workings. Besides, they hold a potential for further development into biomedical applications, from in vitro optogenetics-assisted drug candidate screenings to light-controlled gene therapy and tissue engineering.


Ultraconserved elements (UCEs) illuminate the population genomics of a recent, high-latitude avian speciation event.
Using a large, consistent set of loci shared by descent (orthologous) to study relationships among taxa would revolutionize among-lineage comparisons of divergence and speciation processes. Ultraconserved elements (UCEs), highly conserved regions of the genome, offer such genomic markers. The utility of UCEs for deep phylogenetics is clearly established and there are mature analytical frameworks available, but fewer studies apply UCEs to recent evolutionary events, creating a need for additional example datasets and analytical approaches. We used UCEs to study population genomics in snow and McKay's buntings (Plectrophenax nivalis and P. hyperboreus). Prior work suggested divergence of these sister species during the last glacial maximum (∼18-74 Kya). With a sequencing depth of ∼30× from four individuals of each species, we used a series of analysis tools to genotype both alleles, obtaining a complete dataset of 2,635 variable loci (∼3.6 single nucleotide polymorphisms/locus) and 796 invariable loci. We found no fixed allelic differences between the lineages, and few loci had large allele frequency differences. Nevertheless, individuals were 100% diagnosable to species, and the two taxa were different genetically (F ST = 0.034; P = 0.03). The demographic model best fitting the data was one of divergence with gene flow. Estimates of demographic parameters differed from published mtDNA research, with UCE data suggesting lower effective population sizes (∼92,500-240,500 individuals), a deeper divergence time (∼241,000 years), and lower gene flow (2.8-5.2 individuals per generation). Our methods provide a framework for future population studies using UCEs, and our results provide additional evidence that UCEs are useful for answering questions at shallow evolutionary depths.


Morality in flux: medical ethics dilemmas in the People's Republic of China.
The bioethical dilemmas receiving the most attention in China now relate to the two ends of life: birth and death. On one end are issues relating to reproductive technology, especially birth control and family planning; at the other end is euthanasia... More research and discussion among people from various fields is needed. Progress will be made one step at a time, and I recommend that we proceed now to win acceptance of brain death criteria; to make clear the distinctions between passive and active euthanasia,...to encourage the use of living wills; and to protect the interests of newborns who are not terminally ill, including those with mild defects. In the changing context of modernization, in which different and even incompatible value systems must coexist, it is best for us to approach the ethical dilemmas facing us with mutual respect and understanding.


[Percutaneus coronary interventions for ostial lesions].
An ostial lesion is defined as a lesion near to the ostium (≤3 mm) and is characterized by a rigid fibrotic texture with pronounced sclerosis associated with a very high tendency to recoil. Under certain circumstances this may lead to a modest primary interventional result accompanied by a higher complication rate and in particular a higher rate of restenosis. Ostial lesions of the right coronary artery in particular represent a greater challenge for percutaneous interventions with a higher rate of restenosis despite the introduction of various new techniques. In contrast ostial stenosis of the left main trunk shows very good results after percutaneous interventions and implantation of drug-eluting stents. The indications for percutaneous transluminal coronary angioplasty (PTCA) of an ostial lesion correspond to the indications for treatment of all other lesions. The article gives an overview of the experiences and recommendations with respect to the diagnostics and interventional therapy of ostial lesions.


Innovative solid-state microelectrode for nitrite determination in a nitrifying granule.
Nitrite is an intermediate of both nitrification and denitrification in biological removal of nitrogen from wastewater, and in situ measurement of nitrite concentration in a biofilm or microbial granules is highly desirable. However, a solid-state microelectrode for nitrite determination is not available yet In this work, a solid-state microelectrode was manufactured through electrochemical codeposition of Pt--Fe nanoparticles on a gold microelectrode fabricated using photolithography for in situ nitrite determination. This gold-based microelectrode could be used as a more cost-effective, efficient, and reliable alternative to the liquid membrane microelectrode. Nanoparticles with an average diameter of 50 nm were observed on the surface of the chemically modified electrode. A sigmoid peak at ca. 0.7 V (vs Ag/AgCl) was found on the linear sweep voltammogram in nitrite solutions by using the fabricated microelectrode. The peak height of the first-order derivative of the sigmoid peak was proportional to the nitrite concentration of 0.001--0.05 M and could be used for quantitative determination of nitrite. The detection limits (S/N = 3) were approximately 3 x 10(-5) M. The nitrite microprofiles of aerobic granules from a nitrifying reactor were measured with the microelectrode to demonstrate its potential applications with high spatial resolution.


A differential neural response in obsessive-compulsive disorder patients with washing compared with checking symptoms to disgust.
Patients with obsessive-compulsive disorder (OCD) have symptoms that predominantly concern washing (washers) or checking (checkers), or both. Functional neuroimaging has been used to identify the neural correlates of the urge to ritualize but has not distinguished between washing and checking symptoms in OCD. We used functional magnetic resonance imaging to compare the neural response to emotive pictures in washers and checkers. In one of two 5-minute experiments, washers (N = 7), checkers (N = 7) and age-matched normal controls (N = 14) were scanned while viewing alternating blocks of normally disgusting (rated as disgusting by all subjects) and neutral pictures. In the other experiment, all patients and a normal subgroup (N = 8) viewed alternating blocks of washer-relevant (rated as more disgusting by washers than normal controls or checkers) and neutral pictures. In all subjects, normally disgusting pictures activated visual regions implicated in perception of aversive stimuli and the insula, important in disgust perception. Only in washers were similar regions activated by washer-relevant pictures. In checkers, these pictures activated fronto-striatal regions associated with the urge to ritualize in OCD. Normal controls were more similar in neural response to checkers than washers to these pictures. Both normal controls and checkers had frontal regions activated significantly more by washer-relevant than normally disgusting pictures, and had these regions activated significantly more than washers by washer-relevant pictures. We demonstrate a differential neural response to washer-relevant disgust in washers and checkers: only washers demonstrate a neural response to washer-relevant disgust associated with emotion perception rather than attention to non-emotive visual detail.


Comparing Associations Between Puberty, Ethnic-Racial Identity, Self-Concept, and Depressive Symptoms Among African American and Caribbean Black Boys.
Research on pubertal development among Black boys is limited. Addressing this gap, we examined associations between three pubertal domains (e.g., voice change, hair growth, and perceived relative timing), depressive symptoms, self-esteem, and self-efficacy, among a nationally representative sample of 395 African American and 164 Caribbean Black boys (Mage = 15 years). Moderation by ethnic-racial identity (e.g., racial centrality, racial regard) was also explored. Results indicated that for both ethnic subgroups early voice change increased self-esteem; whereas early voice change increased depressive symptoms among boys who felt society views Blacks more negatively. Buffering effects of ethnic-racial identity also varied significantly between the two groups. Findings suggest that the meaning Black boys ascribe to their ethnic-racial group may explain puberty-linked outcomes.


[The preparation and bioactivities of chiral analogs of baogongteng A].
Eight chiral analogs of baogongteng A were prepared from (+/-)-3 alpha-hydroxy-6 beta-acetoxytropane by chemical resolution. In myotic or mydriatic tests in rabbits, (-)-3 alpha-paramethyl benzenesulfonyloxy-6 beta-acetoxytropane showed cholinergic activities, while (+)-3 alpha-benzoyloxy-6 beta-acetoxytropane and (+)-3 alpha-parachloro benzoyloxy-6 beta-acetoxytropane showed anticholinergic activities.


Correlation of pathological and cytological-cytometric grading of transitional cell carcinoma of the urinary tract.
Cystoscopy and cytology are standard procedures for diagnosis and follow-up of patients with bladder cancer. Urinary cytodiagnosis is a descriptive method for tumor characterization. We correlated histopathologic diagnosis of noninvasive urothelial carcinomas with cytological evaluation and, furthermore, we validated cytology by cytometric analysis. 94 patients with a history of bladder cancer were included in the study. 25 patients were negative for tumors, 22 showed pTa G1 carcinomas, 25 had pTaG2 and 22 patients had G3 carcinomas. All patients underwent cytological and cytometric evaluation. Nuclear diameter and circumference were measured for 15 representative nuclei per specimen. Statistical evaluation was performed using Graph Pad Software. Cytology showed excellent tumor detection for G2 and G3 carcinomas, with a sensitivity of 100% combined with a specificity of 100%. Using cytometry, we can significantly distinguish between unsuspicious patients and G1 carcinomas on the one hand and high-grade carcinomas on the other. Furthermore, in 6 of 25 patients (24%) with noninvasive G2 carcinomas, but G3 cytological evaluation, tumor progression occurred. Urinary cytology is an excellent instrument for detection of clinically relevant high-grade bladder cancer. Descriptive alterations of the cytopathology can be validated by objective data using cytometric analysis.


A new transfectant panel cell line-based MoAb-independent antigen capture assay system for detection of CD36 antibody.
CD36 antibody (Ab) causes several disorders: neonatal alloimmune thrombocytopenia, platelet transfusion refractoriness and non-haemolytic transfusion reactions. However, there is no gold-standard test for CD36 Ab. We developed a transfectant panel cell line-based MoAb-independent antigen capture assay system for detection of CD36 Ab and compared it with the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) system in terms of sensitivity and specificity. Our new system was characterized by (1) gene-transfected cell lines, but not panel platelets; (2) not being hampered by HLA Abs; and (3) no need to use CD36 MoAbs to ensure the antigen specificity of this detection system. In addition, it showed a much better receiver operating characteristic curve than the MAIPA system. The present results indicate that our new system permits highly sensitive and specific detection of CD36 Ab.


An Empirical Study on Traditional, Complementary and Alternative Medicine Usage among Malaysian Cancer Patients.
Usage of traditional, complementary and alternative medicine (TCAM) has gained popularity over the past few years. However, very little is known about TCAM use among Malaysian cancer patients. This study aimed to identify the determinants of TCAM usage among cancer patients with determination of relationships between demographic factors, patient satisfaction with conventional treatment, knowledge on TCAM and healthcare professional influence. Patient's perceptions towards TCAM were also determined. A simple random convenient sampling method was used to recruit 354 patients from Hospital Kuala Lumpur between February to April 2013. All were directly interviewed with a structured questionnaire. In this study, 172 respondents were TCAM users. There was no significant differences between demographic background of respondents in the usage of TCAM. Minimal correlation was found between patient satisfaction with the conventional treatment and usage of TCAM (r=0.091). A poor correlation was found between healthcare professional's influence and TCAM usage (r=-0.213) but the results suggested that increase in influence would decrease TCAM usage. Patient TCAM knowledge correlated negatively with the TCAM usage (r=-0.555) indicated that cancer patients are less likely to use TCAM when they have more TCAM knowledge. Healthcare professionals should be fully equipped with the necessary TCAM knowledge while maintaining patient satisfaction with the conventional treatment. They should also intervene on patient TCAM usage where a potential drug interaction or a harmful adverse event can occur.


Radiotherapy for maxillo-facial hemangiomas in children. Dental and periodontal long term effects.
Vascular maxillo-facial malformations, common pathologies in children, represent 7% of all benign tumors. They are divided into vascular malformations and hemangiomas. In the 70s-80s radiotherapy was the most applied technique, but because of its misuse or overdose, it could lead to relevant and hard consequences for the impact on the salivar glands, periodontium and growing maxillo-facial nuclei. The authors describe the case of a 38-year-old man, who, during infancy, was submitted to radiotherapy for a hemangioma to his chin and cheek. He was under observation for an agressive periodontitis, followed by a serious facial asimmetry, located in his irradiated side. They describe the therapy and the results obtained, underlying the particular difficulties detected in operating on tissues hardly and often irreversibly injured by radiotherapy. On the basis of this clinical case and of the most up-dated knowledge, therapeutical alternatives such as embolization, cryotherapy, cortisonic systemic and intralesional therapy, the use of interferon gamma 2 and the use of the most recent laser, are analyzed, and advantages and disadvantages and the most appropriate indications are underlined.


Chain Mediation Analysis of the Effects of Nutrition and Cognition on the Association of Apolipoprotein E ɛ4 with Neuropsychiatric Symptoms in Alzheimer's Disease.
Apolipoprotein E (APOE) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer's disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. To investigate the association of APOE ɛ4 with NPSs and explore nutritional status and cognition as joint mediators of this association. Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ɛ4 and specific neuropsychiatric symptom. Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ɛ4. Patients with APOE ɛ4 were more likely to have hallucinations (p = 0.014), apathy (p = 0.008), and aberrant motor activity (p = 0.018). MNA and MMSE scores mediated the association between APOE ɛ4 and hallucinations (17.97% and 37.13%, respectively), APOE ɛ4 and apathy (30.73% and 57.72%, respectively), and APOE ɛ4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ɛ4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. Nutritional status and cognition jointly mediate the association between APOE ɛ4 and neuropsychiatric symptoms in patients with aMCI or AD.


The "Emotional Side" of Entrepreneurship: A Meta-Analysis of the Relation between Positive and Negative Affect and Entrepreneurial Performance.
The experience of work in an entrepreneurial context is saturated with emotional experiences. While the literature on the relation between affect and entrepreneurial performance (EP) is growing, there was no quantitative integration of the results so far. This study addresses this gap and meta-analytically integrates the results from 17 studies (N = 3810) in order to estimate the effect size for the relation between positive (PA) and negative affect (NA), on the one hand, and EP, on the other hand. The meta-analysis includes studies in English language, published until August 2016. The results indicate a significant positive relation between PA and EP, r = 0.18. The overall NA - EP relation was not significant, r = -0.12. Only state NA has a significant negative relation with EP (r = -0.16). The moderating role of several conceptual (i.e., emotion duration, integrality etc.), sample (i.e., gender, age, education) and methodological characteristics of the studies (i.e., type of measurements etc.) are explored and implications for future research are discussed.


Role of vegetation in enhancing radon concentration and ion production in the atmosphere.
The role of ions in the production of atmospheric particles has gained wide interest due to their profound impact on climate. Away from anthropogenic sources, molecules are ionized by alpha radiation from radon exhaled from the ground and cosmic γ radiation from space. These molecular ions quickly form into "cluster ions", typically smaller than about 1.5 nm. Using our measurements and the published literature, we present evidence to show that cluster ion concentrations in forest areas are consistently higher than outside. Owing to the low range of alpha particles, radon present deep in the ground cannot directly contribute to the measured cluster ion concentrations. We propose an additional mechanism whereby radon, which is water-soluble, is brought up by trees and plants through the uptake of groundwater and released into the atmosphere by transpiration. We estimate that, in a forest comprising eucalyptus trees spaced 4 m apart, trees may account for up to 37% of the radon that is released from the ground during the middle of the day when transpiration rates are high. The corresponding percentage on an annual basis is 4.1%. Considering that 24% of the earth's land area is still covered in forests; these findings have potentially important implications for atmospheric aerosol formation and climate.


[The influence of multiple sclerosis-related symptoms on health-related quality of life].
Multiple sclerosis (MS) is a chronic disease that is associated with a variety of MS-specific symptoms. Many of these symptoms have a negative impact on health-related quality of life (HRQoL). Until now it is unclear which MS-specific symptoms have the highest impact on the HRQoL. The study is based on the data of a member survey of the German MS Society (DMSG) in 2015 (n = 424). Considering socio-demographic variables and general medical variables, the influence of MS-specific symptoms on HRQoL was examined. The HRQoL was collected using the Multiple Sclerosis Quality of Life-54 (MSQOL-54) instrument. In a pretest, all influencing variables were tested for a significant mean difference (p = 0.05), or a mean correlation (Pearson's r ≥ 0.3). Subsequently, the influence of the variables identified in the pretest on the HRQoL was investigated by multiple linear regression analysis. We calculated a mean physical health composite score (PHCS) of 48.3 (sd = 17.7) and a mean mental health composite score (MHCS) of 56.0 (sd = 20.1). The most fundamental factors influencing HRQoL were the MS-specific symptoms of depression, pain and cognitive impairment. MS-related symptoms with a mobility context showed declining PHCS. Speech disorder and dizziness were associated with a decreasing MHCS. Employment status was the only socio-economic factor that significantly affected HRQoL in multiple regression. The general medical factors showed no significant influence on HRQoL. MS-specific symptoms have a major impact on the HRQoL of people with MS. Our study show that especially the so-called 'hidden symptoms' such as the symptoms of depression, pain and cognitive impairment have a significant influence on the HRQoL. Greater attention should be paid to these in the care of people with MS.


Calciphylaxis in a dialysis patient successfully treated with high-dose vitamin K supplementation.
Calciphylaxis has high mortality. Vitamin K deficiency is common in haemodialysis patients and may be a trigger for calciphylaxis due to its role in activating matrix Gla protein (a tissue inhibitor of calcification). We report the case of a 43-year-old female haemodialysis patient who developed calciphylaxis. Two months prior to the diagnosis she was found to have an undetectable plasma vitamin K concentration. The calciphylaxis completely resolved with vitamin K supplementation and an increase in haemodialysis frequency. She did not receive sodium thiosulphate or bisphosphonates. Supplementation of vitamin K in deficient patients may improve the outcome of this condition.


Physiotherapy students' experiences of bullying on clinical internships: an exploratory study.
To consider the prevalence and type of bullying behaviours experienced whilst on clinical placement in a cohort of final-year BSc undergraduate students. Cross-sectional survey. University in the West Midlands, UK. Fifty-two final-year undergraduate students. Prevalence of incivility and bullying behaviours. Twenty-five percent of students reported at least one incident of bullying behaviour. The perpetrator of the bullying behaviour was most often the clinical educator (8/13, 62%). Despite the negative effects caused, the majority of students (11/13, 84%) did not report this experience to the university. Bullying behaviour may take many forms and can have a negative effect on the well-being of students. It should be addressed by all stakeholders including universities, National Health Service trusts and researchers. Possible strategies to move forwards and better protect the future of the physiotherapy profession are briefly considered.


The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein.
Triosephosphate isomerase of Trichomonas vaginalis (TvTIM) is a 27-kDa cytoplasmic protein encoded by two genes, tvtim1 and tvtim2, that participates in glucose metabolism. TvTIM is also localized to the parasite surface. Thus, the goal of this study was to identify the novel functions of the surface-associated TvTIM in T. vaginalis and to assess the effect of glucose as an environmental factor that regulates its expression and localization. Reverse transcription-PCR (RT-PCR) showed that the tvtim genes were differentially expressed in response to glucose concentration. tvtim1 was overexpressed under glucose-restricted (GR) conditions, whereas tvtim2 was overexpressed under glucose-rich, or high-glucose (HG), conditions. Western blot and indirect immunofluorescence assays also showed that glucose positively affected the amount and surface localization of TvTIM in T. vaginalis Affinity ligand assays demonstrated that the recombinant TvTIM1 and TvTIM2 proteins bound to laminin (Lm) and fibronectin (Fn) but not to plasminogen. Moreover, higher levels of adherence to Lm and Fn were detected in parasites grown under HG conditions than in those grown under GR conditions. Furthermore, pretreatment of trichomonads with an anti-TvTIMr polyclonal antibody or pretreatment of Lm- or Fn-coated wells with both recombinant proteins (TvTIM1r and TvTIM2r) specifically reduced the binding of live parasites to Lm and Fn in a concentration-dependent manner. Moreover, T. vaginalis was exposed to different glucose concentrations during vaginal infection of women with trichomoniasis. Our data indicate that TvTIM is a surface-associated protein under HG conditions that mediates specific binding to Lm and Fn as a novel virulence factor of T. vaginalis.


Establishment of a diazepam preference in human volunteers following a differential-conditioning history of placebo versus diazepam choice.
This study examined whether preference for a drug (diazepam or placebo) could be switched using conditioning procedures. During the first 4 sessions of Phase 1, 6 participants received 5 mg of diazepam or placebo under double-blind conditions. During the remaining 5 sessions of Phase 1, participants selected the drug they wished to receive. The first 4 sessions of Phase 2 were a replication of Phase 1, except that following ingestion of the drug, participants completed a computer task for which they could earn money. Payment for the computer task was lowest following ingestion of the drug they preferred in Phase I and highest following the drug they had avoided. Preference was reassessed during the last 5 sessions of Phase 2. Five of the participants preferred placebo in Phase 1 but diazepam in Phase 2. Subjective responses to the drugs also changed across the 2 phases.


Care of Metabolic and Endocrine Conditions in the Observation Unit.
Accelerated therapeutic protocols targeting metabolic conditions are ideal for observation unit care. Because many conditions, such as hypokalemia and hyperglycemia, have little to no diagnostic uncertainty, the care in the unit is often straightforward. Additionally, some components of care for the endocrine condition may exhaust services, such as phlebotomy. Hence, this discussion focuses resource utilization and management considerations for the purposes of matching the level of care to the severity of the conditions. When carefully selected candidates are cared for in the observation unit, hospital resources can enable a safe, efficient hospital stay.


Counting and Sequential Information Processing in Mechanical Metamaterials.
Materials with an irreversible response to cyclic driving exhibit an evolving internal state which, in principle, encodes information on the driving history. Here we realize irreversible metamaterials that count mechanical driving cycles and store the result into easily interpretable internal states. We extend these designs to aperiodic metamaterials that are sensitive to the order of different driving magnitudes, and realize "lock and key" metamaterials that only reach a specific state for a given target driving sequence. Our metamaterials are robust, scalable, and extendable, give insight into the transient memories of complex media, and open new routes towards smart sensing, soft robotics, and mechanical information processing.


White-coat hypertension is a risk factor for cardiovascular diseases and total mortality.
Whether white-coat hypertension (WCH) is an innocent phenomenon is controversial. In this study, we evaluated the association of WCH and the risk of cardiovascular diseases (CVDs) and mortality, stratified by baseline antihypertensive treatment status. Databases (PubMed, EMBASE, CINAHL Plus, Scopus, and Google Scholar) were searched for prospective studies with data on CVD and total mortality associated with WCH. The primary outcomes were the risk of CVD and total mortality associated with WCH stratified by antihypertensive treatment status. The relative risks of events compared with normotension were calculated. A total of 23 cohorts (20 445 individuals), 11 cohorts (8656 individuals), and 12 cohorts (21 336 individuals) were included for analysis of cardiovascular risk associated with WCH in patients without baseline antihypertensive treatment (untreated), or under antihypertensive treatment (treated) or mixed population (including both untreated and treated patients), respectively. In untreated cohorts, WCH was associated with a 38 and 20% increased risk of CVD and total mortality compared with normotension, respectively. In the mixed population, WCH was associated with a 19 and 50% increased risk of CVD and total mortality. However, in the treated patients, neither the risk of CVD, nor total mortality was increased in WCH. Meta-regression analyses indicated that neither differences of clinic blood pressure, nor out-of-office blood pressure variables were correlated with risk of CVD in WCH. We concluded that WCH is associated with long-term risk of CVD and total mortality in patients without antihypertensive treatment. Close follow-up should be performed in WCH patients.


Editor's Choice-Sex differences in young patients with acute myocardial infarction: A VIRGO study analysis.
Young women with acute myocardial infarction (AMI) have a higher risk of adverse outcomes than men. However, it is unclear how young women with AMI are different from young men across a spectrum of characteristics. We sought to compare young women and men at the time of AMI on six domains of demographic and clinical factors in order to determine whether they have distinct profiles. Using data from Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO), a prospective cohort study of women and men aged ⩽55 years hospitalized for AMI ( n = 3501) in the United States and Spain, we evaluated sex differences in demographics, healthcare access, cardiovascular risk and psychosocial factors, symptoms and pre-hospital delay, clinical presentation, and hospital management for AMI. The study sample included 2349 (67%) women and 1152 (33%) men with a mean age of 47 years. Young women with AMI had higher rates of cardiovascular risk factors and comorbidities than men, including diabetes, congestive heart failure, chronic obstructive pulmonary disease, renal failure, and morbid obesity. They also exhibited higher levels of depression and stress, poorer physical and mental health status, and lower quality of life at baseline. Women had more delays in presentation and presented with higher clinical risk scores on average than men; however, men presented with higher levels of cardiac biomarkers and more classic electrocardiogram findings. Women were less likely to undergo revascularization procedures during hospitalization, and women with ST segment elevation myocardial infarction were less likely to receive timely primary reperfusion. Young women with AMI represent a distinct, higher-risk population that is different from young men.


Hemostasis of left atrial appendage bleed with lariat device.
New devices designed for minimally invasive closure of the left atrial appendage (LAA) may be a viable alternative for patients in whom anticoagulation is considered high risk. The Lariat (Sentreheart, Redwood City, CA), which is currently FDA-approved for percutaneous closure of tissue, requires both trans-septal puncture and epicardial access. However it requires no anticoagulation after the procedure. Here we describe a case of effusion and tamponade during a Lariat procedure with successful completion of the case and resolution of the effusion.


Geniculate Artery Embolization in Patients With Recurrent Hemarthrosis After Knee Arthroplasty: A Retrospective Study.
Recurrent hemarthrosis after knee arthroplasty is an uncommon and disabling complication of this frequently performed procedure. Selective endovascular embolization of the geniculate arteries is one of the therapeutic options to manage this complication. The purpose of this study is to analyze the effectiveness of this treatment in patients suffering from recurrent hemarthrosis after knee arthroplasty. We performed a retrospective study of 31 patients (39 embolization procedures) with recurrent hemarthrosis after knee arthroplasty. There were 17 men and 14 women with a median age of 67 years (range 48-90). All patients were referred for geniculate artery embolization between January 2007 and November 2016. Twenty-seven procedures were executed on the right side and 12 on the left side. Total knee arthroplasty was performed on 29 patients, only 2 patients underwent unicompartmental knee arthroplasty. Embolization of the superior geniculate arteries was achieved in all patients. In 12 of 39 procedures (31%), at least 1 of the inferior geniculate arteries could not be catheterized, therefore embolization was achieved through collaterals. Symptomatic improvement was observed in 26 of 31 patients (84%). Discomfort or mild postprocedural pain was observed in most patients, needing only minor pain medication, mostly resolving within 24 hours. Two patients presented with a severe complication: a 48-year-old male patient developed septic arthritis and an 85-year-old hypertensive female patient treated with anticoagulants showed aseptic necrosis of the femoral condyles. Embolization of geniculate arteries is a safe and effective treatment in recurrent hemarthrosis post knee arthroplasty. Clinical improvement was seen in most patients.


Using Systems Thinking to train future leaders in global health.
Systems Thinking provides a useful set of concepts and tools that can be used to train students to be effective and innovative global health leaders in an ever-changing and often chaotic world. This paper describes an experiential, multi-disciplinary curriculum that uses Systems Thinking to frame and analyse global health policies and practices. The curriculum uses case studies and hands-on activities to deepen students' understanding of the following concepts: complex adaptive systems, dynamic complexity, inter-relationships, feedback loops, policy resistance, mental models, boundary critique, leverage points, and multi-disciplinary, multi-sectoral, and multi-stakeholder thinking and action. A sample of Systems Thinking tools for analysing global health policies and practices are also introduced.


A rare case of primary ovarian carcinoid.
We present a rare case in an elderly Caucasian lady of primary ovarian carcinoid tumor, causing symptoms of the carcinoid syndrome and severe carcinoid heart disease. Carcinoid tumors are the commonest neuroendocrine tumors, the majority of which are found in the gastrointestinal tract and lungs. Ovarian carcinoids represent only 0.1% of all ovarian neoplasms and 1% of all carcinoid tumors. Carcinoid syndrome can present with flushing, diffuse watery diarrhea, wheezing and breathlessness and in advanced cases lead to carcinoid heart disease. This involves damage to the right heart structures and pulmonary hypertension, which can cause significant breathlessness and peripheral edema, and is associated with a worse prognosis. Diagnosis involves multi-modality radiological imaging and biochemical analysis of neuroendocrine tumor markers, and the first line treatment should always be resection of the tumor where possible. Prognosis is generally favorable, except in some cases with metastasis.


Inhibition of attachment of Escherichia coli RDEC-1 to intestinal microvillus membranes by rabbit ileal mucus and mucin in vitro.
Intestinal mucus is postulated to play a role in preventing colonization of the gastrointestinal tract by microbial pathogens. To evaluate the ability of both crude mucus and purified mucin, a glycoprotein of goblet cell origin, to inhibit mucosal adherence of enteric pathogens, we examined whether mucus and mucin derived from rabbit ileum interact with the rabbit enteropathogen Escherichia coli RDEC-1. We examined the manner in which mucus and mucin inhibited adherence of bacteria to rabbit ileal microvillus membranes (MVMs) in vitro. The purity of the mucin preparation was demonstrated by polyacrylamide gel electrophoresis before and after reduction and by showing that an antiserum raised to the mucin localized to goblet cells in rabbit intestine. Using radioactive labeling of bacteria, we quantitated attachment of RDEC-1 to MVMs, mucus, and mucin that had been immobilized on polystyrene microtiter wells. Binding of RDEC-1 to MVMs was also determined after preincubation of organisms with crude ileal mucus and purified mucin. RDEC-1 bound to both crude mucus and purified mucin when they expressed lectinlike adhesions, previously designated attachment factor rabbit 1 pili. Adherence of piliated RDEC-1 to MVMs, mucus, and mucin was significantly greater than when the bacteria were nonpiliated. Binding of piliated RDEC-1 to MVMs was decreased by preincubation of bacteria with both crude mucus (45.6 +/- 4.2% of control) and purified mucin (50.2 +/- 5.8%). These data indicate that the E. coli enteropathogen RDEC-1 can bind to purified glycoproteins of goblet cell origin and that adherence of these bacteria to mucin is mediated by expression of pili. The findings also support a role for intestinal mucus and its principal organic constituent, mucin, in preventing adherence of a known E. coli enteric pathogen to apical MVMs of enterocytes.


[Terminal ballistics. 1].
We have chosen to conceive of terminal ballistics as a violent and extremely rapid confrontation between two forms of resistance before the final state of rest is reached. This definition, which cannot help but don the admittedly loud and outlandish garb of physics, is the most promising for the purposes of biological interpretation. The main characters on this stage are two, but only one of these really plays the lead, namely the human target, which acts out the basic roles inherent in its physical make-up; the other, the bullet, remains a background figure, frozen in its walk-on part, and ready for the next performance. This modus operandi, which is no simplification, but rather an academic necessity, enables us to focus on images which stand out more clearly as a result of an intensive macroscopic spotlight which brings out the features of the individual phenomena, broken down into a succession of close-ups, and subtracts them from the cold physical nature of this or that form of inert matter, which here is merely an occasional, disagreeable witness, or even more, a standing from time to time for but one of the infinite facets of the biological composite being. Here, then, faced with a kind of exploded macrophotograph of a complex kaleidoscope, we see the animal universe, of which we capture so far the plasticity, the subdivisibility, the anisotropy and the cavitation.


Semiotic transformations in psychoanalysis with infants and adults.
The author addresses issues that emerge when we compare psychoanalytic experiences with adults and with infants. Two analyses-one with a 35 year-old woman and one with a 2 week-old boy and his mother-illustrate that infant psychoanalytic experiences help us understand and handle adult transference. However, we cannot extrapolate infant experiences to adult work. Truly, witnessing the baby's communication widens our sensitivity to non-verbal layers of the adult's communication. Infant work also offers a direct encounter with the container and the contained personified by a mother with her baby. But we need to conceptualize carefully the links between clinical experiences with babies and adults. When we call an adult transference pattern 'infantile', we imply that primeval experience has been transformed into present behaviour. However, if we view the analytical situation as one in which infantile invariants have transformed into adult symptoms, we face the impossible task of indicating the roots of the present symptoms. The author rather suggests that what is transformed is not an invariant infantile essence but signs denoting the patient's inner reality. He proposes we define transformation as a semiotic process instead of building it on an essentialist grounding. If we view the analytic situation as a map of signs that we translate during our psychoanalytic work, we can proceed into defining containment as a semiotic process. This idea will be linked with a conceptualization of the mother-infant relation in semiotic terms.


Poly[[tetra-kis-(μ-1,2-di-4-pyridyl-ethyl-ene-κN:N')tetra-kis-(seleno-cyanato-κN)dimanganese(II)] 1,2-di-4-pyridyl-ethyl-ene disolvate].
The crystal structure of the title compound, {[Mn(NCSe)(2)(C(12)H(10)N(2))(2)]·C(12)H(10)N(2)}(2n), consists of two crystallographically independent Mn cations, four seleno-cyanate anions, four 1,2-di-pyridylethylene (bpe) ligands (two of which are located on centers of inversion) and two bpe solvent molecules. Each manganese(II) cation is coordinated by two terminally N-bonded seleno-cyanate anions and four bpe ligands within a slightly distorted octa-hedron. The manganese(II) cations are linked by the bpe ligands into chains that are further connected by these ligands into layers. These layers are stacked, forming cavities in which additional bpe solvent molecules are embedded.


Density Functional Theory Mechanistic Study of Boron-Catalyzed N-Alkylation of Amines with Formic Acid: Formic Acid Activation by Silylation Reaction.
New methodology for the alkylation of amines is an intriguing issue in both academia and industry. Recently, several groups reported the metal-free B(C6 F5 )3 -catalyzed N-alkylation of amines, but the mechanistic details of these important reactions are unclear. Herein, a computational study was performed to elucidate the mechanism of the N-alkylation of amines with formic acid catalyzed by the Lewis acid B(C6 F5 )3 in the presence of hydrosilane. We found that the reaction started with the activation of formic acid through a novel model. Then, the high electrophilicity of the C center of the formic acid unit and the nucleophilic character of the amine resulted in a C-N coupling reaction. Finally, two sequential silyl-group and H- transfer steps occurred to generate the final product. Upon comparing the reaction barrier and the hydrogenation of indole, our mechanism is more favorable than that proposed by the group of Yu and Fu.


Effect of cholesterol on the dimerization of C99-A molecular modeling perspective.
C99, a naturally occurring peptide, is a precursor of the amyloid β-peptide (Aβ) and plays an important role in the so-called amyloidogenic pathway of degradation of amyloid precursor protein. While the effect of C99's dimerization is not clearly determined, it has been hypothesized that the dimerization protects C99 from being cleaved further. Cholesterol (CHOL) is known to interact with C99 and its presence in high concentrations has been linked to an increase in the production of Aβ; however, to what extent this is correlated, and how, has not yet been determined. In this study, we systematically examine the effect of increasing cholesterol concentration on the homodimerization propensity of C99, combining unbiased atomistic molecular dynamics simulations with biased simulations using a coarse grained resolution. Through the use of umbrella sampling, we show how the presence of high levels of CHOL destabilizes the interaction between two C99 monomers. The interaction pattern between the two C99s has shifted several residues, from the N-terminal end of the transmembrane region toward the corresponding C-terminal in the presence of CHOL. The umbrella sampling shows that the presence of high levels of CHOL led to a decrease of the disassociation energy by approximately 3 kJ/mol. In conclusion, this suggests that increasing CHOL destabilizes the interaction between the two C99 monomers, which may possibly cause an increase in the production of Aβ42.


Being bullied by same- versus other-sex peers: does it matter for adolescent victims?
The negative consequences of peer victimization on psychosocial adjustment are well documented. The consequences, however, may depend on who the bullies are. In this study, we examined the consequences of same- versus other-sex victimization. The sample consisted of 4,941 Finnish adolescents (ages 14-15; 47.7% boys). We used structural equation modeling to examine both concurrent and longitudinal associations of same- and other-sex victimization with depression, negative perception of peers, and social self-esteem. Both same- and other-sex victimization were related to psychosocial adjustment. Concurrently, the victimization experiences with same-sex peers in particular were associated with generalized cognitions about peers, whereas being bullied by other-sex peers was related to adolescents' social self-esteem more strongly than victimization by same-sex peers. The longitudinal associations, in turn, showed that only being bullied by boys had carry-over effects on girls' adjustment. Other-sex victimization can have serious consequences especially on girls' psychosocial adjustment.


Interactions between antimigraine drugs and a high affinity uptake and storage mechanism for 5-hydroxytryptamine.
Rabbit hearts removed 3H-5-hydroxytryptamine (3H-5-HT) from a perfusion concentration of 2.6 X 10(-9) g/ml. 15.8% of the extractable cardiac total radioactivity consisted of metabolites, mainly 5-hydroxyindoleacetic acid, and metabolism appeared in the perfusion fluid during the course of the perfusion. Ergotamine tartrate (1.0 X 10(-6) g/ml) caused a small increase in 3H-5-HT uptake by the heart. Methysergide bimaleate (1.0 X 10(-6) g/ml) slowed the appearance of metabolites in the perfusion fluid. Because of the high concentrations required, neither observation seems likely to be of clinical significance to migraine. The results do, however, suggest that the frequently observed sensitisation of tissues to 5-HT by ergotamine and methysergide is not the result of inhibition of its tissue uptake.


Dramatic Responses Seen with TRK Inhibitor.
Presenting data on 50 of 55 patients with advanced TRK fusion-positive tumors, researchers reported that 76% of patients responded to the selective pan-TRK inhibitor larotrectinib, and 12% of patients experienced complete responses; 93% of responders remain on therapy. The targeted therapy was well tolerated, with just 13% of patients requiring a dose modification. None of the patients discontinued treatment due to adverse events.


Synthesis and cytogenetic effects of aminoquinone derivatives with a di- and a tripeptide.
Quinones are of significant interest due to their important role in specific cellular functions. Quinoproteins are a big class of oxyreductive agents occurring in bacteria and other organisms. In this investigation derivatives of 2-amino-1,4-benzoquinone, 2-amino-1,4-naphthoquinone and 2-amino-5,8-dihydroxy-1,4-naphthoquinone with a di- and a tripeptide were prepared for first time. The effect of the synthesized compounds on sister chomatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Among these coupled products the most effective in inducing SCEs and depressing proliferation rate indices is the coupling product of 2-amino-1,4-naphthoquinone with the tripeptide GHK (10). Next in order of magnitude in inducing cytogenetic effects is 2-amino-1,4-naphthoquinone (2) and its coupling products with glycine and serine (4 and 5), while the rest displayed marginal activity.