Forgive or complain: Interpersonal distance modulates reactive attitudes and neural responses toward wrongdoers.
While the effect of interpersonal distance on forgiveness has been investigated over the past few years, it remains unclear whether this facilitating effect holds even when measured implicitly. Meanwhile, though cognitive control and the corresponding prefrontal cortex play a prominent role in forgiveness processing, the neural mechanism underlying forgiveness toward varied wrongdoers is largely unexplored. Here, forty-two participants initially underwent noise offense either from their friend or stranger, followed by a word identification test to examine their implicit attitude, during which they were presented with word-name combinations and required to categorize forgive- or complain-label words while ignoring the names of their friends or strangers below. A shorter reaction time reflects more congruence with one's implicit attitude. Electroencephalogram was recorded during the word identification test. Behaviorally, while individuals reacted faster to forgive-friend relative to complain-friend pairings, no such reaction bias was found for the stranger-wrongdoer, which suggests that individuals were more inclined to forgive someone close. Regarding the EEG/ERP results, forgive-friend elicited lower alpha oscillation and more negative frontal alpha asymmetry (FAA) value than complain-friend combinations, suggesting increased and dominant activity in the right prefrontal network during forgiveness toward friends. Whereas complain- relative to forgive-stranger combinations elicited larger P3 amplitudes, suggesting a neural encoding bias to information associated with complaints about stranger-wrongdoer. These multimodal findings provide evidence for the benefits of closeness in forgiveness and shed light on the neural mechanisms underlying forgiveness toward different types of wrongdoers.


Atorvastatin calcium alleviates 5-fluorouracil-induced intestinal damage by inhibiting cellular senescence and significantly enhances its antitumor efficacy.
5-Fluorouracil (5-Fu) is the preferred drug in colorectal cancer treatment. Although 5-Fu treatment contributes to the increase in survival rates, long-term use of 5-Fu causes severe intestinal damage, eventually decreasing long-term survival. There is no standardtreatmentfor intestinal damage induced by 5-Fu. Our previous study found that 5-Fu-induced intestinal damage was connected to an increase in senescent cells, and antiaging drugs could relieve some adverse side effects caused by 5-Fu. Hence, it is essential to discover novel, potential antiaging therapeutic drugs for 5-Fu side effect treatment. According to the current study, Atorvastatincalcium (Ator) alleviated cellular senescence in human intestinal epithelial cells (HUVECs) and human umbilical vein endothelial cells (HIECs) caused by oxidative stress and 5-Fu. 5-Fu resulted in an increase in SA-β-Gal-positive cells, synchronously increased expression of aging-related proteins (p16), aging-related genes (p53, p21), and the senescence-associated secretory phenotype (SASP: IL-1β, IL-6, TNF-α), while Atorvastatincalcium (Ator) reversed the increase in these indicators. In the BALB/c mouse model, we confirmed that intestinal damage caused by 5-Fu is related to the increase in senescent cells and drug-induced inflammation, with the therapeutic effects of Ator. In addition, Ator increased the sensitivity of 5-Fu to chemotherapy in vitro and in vivo. Combination therapy significantly reduced HCT116 cell viability. Furthermore, Ator and 5-Fu present a cooperative effect on preventing the growth of tumors in CRC xenograft nude mice. In conclusion, our study demonstrates the value of Ator for treating intestinal damage. Moreover, Ator combined with 5-Fu increased the antitumor ability in CRC cells. Additionally, we provide a novel therapeutic protocol for CRC.


Assay of factor VIII antigen (VIII:CAg) in 294 haemophilia A patients by a new commercial ELISA using monoclonal antibodies.
Monoclonal antibodies (MoAbs 833 and D4H1) directed against human factor VIII (FVIII) have been produced on a large scale to measure VIII:CAg by two-site ELISA (Asserachrom VIII:CAg, Diagnostica Stago). F(ab')2 from MoAb 833 were used for coating and bound VIII:CAg was revealed with MoAb D4H1 coupled to peroxidase. Control plasma (100 VIII:CAg U dL-1 by comparing with the International Standard) was used as reference. The assay sensitivity was 0.1 U dL-1 VIII:CAg. No apparent effect of the plasma proteins was observed provided plasma dilution was > or = 5. Thus this ELISA allowed us to estimate VIII:CAg levels of 0.5 U dL-1 in plasma. Levels of VIII:CAg were similar to those of VIII:C (correlation coefficient r = 0.87) in plasma from normal individuals (32 cases) and in patients with von Willebrand disease of various types (30 cases). Among 294 patients with haemophilia A (HA), 161 had severe HA (VIII:C < 1 U dL-1). Among those patients, 124 were cross-reacting material (CRM) negative with undetectable VIII:CAg and 37 were CRM+ (VIII:CAg 1-31 U dL-1). In 42 patients with moderate HA (VIII:C 1-5 U dL-1), 33 were CRM reduced (VIII:CAg 0.5-8 U dL-1) and nine were CRM+ with a VIII:CAg/VIII:C ratio of 6-91 (mean 34.3). In mild HA (91 cases with VIII:C > or = 6 U dL-1), 29 patients were classified as CRM+ (VIII:C 6-57 U dL-1, VIII:CAg 17-130 U dL-1 and VIII:CAg/VIII:C ratio 1.8-13.7 (mean 4.51)). In 62 CRM reduced patients there was a linear correlation between VIII:C (6-39 U dL-1) and VIII:CAg (2-36 U dL-1) levels (r = 0.88). In conclusion, this sensitive assay allows us to distinguish the quantitative CRM reduced and negative from the qualitative (CRM+) abnormalities in haemophilia A.


Antioxidant effects of ginsenoside Re in cardiomyocytes.
We have previously demonstrated that American ginseng berry extract exhibited significant protection against oxidant-mediated injury in cardiomyocytes. To extend this work, we sought to investigate the antioxidant effects of Re, a protopanaxatriols-type and single chemical integrant present in American ginseng berry extract, using the same chick cardiomyocyte model of oxidant injury as well as ESR spectroscopy in a cell-free chemical system. In cells exposed to 2 h of H2O2 (0.5 mM), pretreatment with Re (0.05, 0.1, or 0.5 mg/ml for 2 h) significantly attenuated 2',7'-dichlorofluorescein (DCF) fluorescence by 51% (from 1345+/-67 to 658+/-46 a.u., P<0.001), and remarkably reduced cell death (from 51.5+/-3.0% to 11.8+/-1.5%, P<0.001, compared to the control). Similar results were also observed in cells exposed to antimycin A (100 microM), a mitochondrial electron transport chain site III inhibitor which increases endogenous oxidative stress. In the ESR study, however, Re failed to reduce the formation of the superoxide/DMPO adduct and DPPH radicals. These results suggest that ginsenoside Re functions as an antioxidant, protecting cardiomyocytes from oxidant injury induced by both exogenous and endogenous oxidants, and that its protective effects may be mostly attributed to scavenging H2O2 and hydroxyl radicals.


Auditory physiology and anatomy of octavolateral efferent neurons in a teleost fish.
Vertebrate hair cell systems receive innervation from efferent neurons in the brain. Here we report the responses of octavolateral efferent neurons that innervate the inner ear and lateral lines in a teleost fish, Dormitator latifrons, to directional linear accelerations, and compare them with the afferent responses from the saccule, the main auditory organ in the inner ear of this species. Efferent neurons responded to acoustic stimuli, but had significantly different response properties than saccular afferents. The efferents produced uniform, omnidirectional responses with no phase-locking. Evoked spike rates increased monotonically with stimulus intensity. Efferents were more broadly tuned and responsive to lower frequencies than saccular afferents, and efferent modulation of the otolithic organs and lateral lines is likely more pronounced at lower frequencies. The efferents had wide dynamic ranges, shallow rate-level function slopes, and low maximum discharge rates. These findings support the role of the efferent innervation of the otolithic organs as part of a general arousal system that modulates overall sensitivity of the peripheral octavolateral organs. In addition, efferent feedback may help unmask biologically relevant directional stimuli, such as those emitted by a predator, prey, or conspecific, by reducing sensitivity of the auditory system to omnidirectional ambient noise.


Efficacy and safety of moxibustion on cancer-related fatigue: a systematic review and meta-analysis of randomized controlled trials.
The goal of this research was to review the literature from randomized controlled trials (RCTs) on the impacts of moxibustion on cancer-related fatigue (CRF) as well as provide credible evidence to guide clinical practice. Three English electronic medical databases (PubMed, Embase, and the Cochrane Library) and two Chinese databases (China National Knowledge Infrastructure and Wanfang) were searched. Only randomized controlled trials on the effect of moxibustion on CRF were included in this systematic review. Study selection, data extraction, and validation were all carried out independently by two reviewers. The revised Cochrane Risk of Bias tool was used to assess the quality of the RCTs (RoB 2.0). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to assess effect sizes in individual RCTs and pooled effect sizes in meta-analyses. Data were meta-analyzed using Stata (version 14.0). In a random-effects meta-analysis of 24 RCTs with 1894 participants, the aggregated standardized mean difference (SMD) revealed a statistically significant association between moxibustion and alleviation from cancer-related fatigue (SMD = - 1.66, 95% CI = - 2.05, - 1.28, p = 0.000). Pooled results, however, show significant heterogeneity (I2 = 92.5%), and the evidence is insufficient to determine whether this association varies systematically by measuring tools and moxibustion modalities. Furthermore, evidence ranging from very low to low showed that moxibustion had an immediate positive effect on patients with CRF. Moxibustion may have a therapeutic effect on cancer-related fatigue. However, further large-scale, multicenter, high-quality RCTs on moxibustion for fatigue relief and safety are still needed because of the handful of studies included and the low methodological quality.


Surgical correction of atrioventricular canal during the first year of life.
Eight infants less than 1 year of age with an atrioventricular (A-V) canal defect (five with the complete form and three with the partial form) had definitive surgical correction performed because of intractable congestive heart failure. At operation, the infants weighed 2.9 to 6.5 kg. There was one operative death and one late death. The six surviving children were all doing well when followed up 10 months to more than 4 years postoperatively. This small series demonstrates that complete connection of A-V canal is possible even in very small infants and that chances of success are excellent. The infant with this defect who is not progressing with medical management should undergo definitive surgical correction, and a strong argument can be made for elective complete repair in all patients with this lesion, who have severe pulmonary hypertension, during the first 1 or 2 years of life.


Respiratory symptoms as initial manifestations of interstitial lung disease in clinically amyopathic juvenile dermatomyositis: a case report with literature review.
Clinically amyopathic juvenile dermatomyositis (CAJDM) is a clinical subgroup of juvenile dermatomyositis (JDM), characterized by JDM rashes with little or no clinically evident muscle weakness. Interstitial lung disease (ILD) is an uncommon but potentially fatal complication of juvenile dermatomyositis (JDM). While adults with dermatomyositis-associated ILD usually present respiratory symptoms before or at the same time as skin muscle manifestations, only a few studies have covered the onset of respiratory symptoms of ILD in JDM patients, especially CAJDM. There is currently no clear effective treatment regime or any prognostic factors for CAJDM-associated ILD. Here, we report the first case of a CAJDM patient who presented with respiratory symptoms as the initial manifestation. A 10-year-old male patient presented to the hospital with a complaint of progressive cough and chest pain. Violaceous macule and papules appeared a few days later and he was positive for anti-Ro-52 antibodies. Imaging showed diffuse interstitial infiltration in both lungs and lung function tests showed restrictive and obstructive ventilatory dysfunction. Muscular abnormalities were excluded by thigh magnetic resonance imaging (MRI) and electromyography. Skin biopsy showed pathognomonic findings consistent with DM. Lung biopsy indicated chronic inflammation of the mucosa. This patient was finally diagnosed with CAJDM complicated by ILD and prescribed methylprednisolone, immunoglobulin, prednisolone and mycophenolate mofetil (MMF) for treatment. The patient's cutaneous and respiratory manifestations were largely improved. We retrospectively reviewed this and another six cases with CAJDM-associated ILD reported previously to better understand its clinical characteristics and effective management. Initial respiratory symptoms with rapid progression in patients presenting Gottron papules should be considered manifestations of CAJDM-associated ILD. We also found a combination of corticosteroids, IVIG and MMF to be an effective method of arresting the progress of CAJDM-associated ILD and improving the prognosis of the patients.


Job performance failure and occupational carpal tunnel claims.
Using a sample of one job type from one firm (to hold job tasks and sick leave/disability policy constant), we estimate the effect of demographic variables, job performance warnings, and workers' compensation benefits on the propensity to file a carpal tunnel syndrome (CTS) loss work-time claim. We find that disciplinary notices increase the employees' propensity to file a CTS claim. State maximum workers' compensation benefits are also positively related to CTS claim frequency, however, the relationship is not statistically significant. CTS claimants respond differently than other sprain/strain claimants to benefits and to gender. In particularly, women have relatively more CTS claims, while men have relatively more other sprain/strain claims in our sample. The estimates here underscore the importance of psychosocial factors in the filing of occupational CTS and sprain injuries claims.


Why are we weighting? The role of importance ratings in quality of life measurement.
Many Quality of Life (QoL) instruments ask respondents to rate a number of life domains in terms of satisfaction and personal importance, and derive weighted satisfaction scores by multiplying the two ratings. This paper demonstrates that this practice is both undesirable and unnecessary. QoL domains are selected on the basis of their inherent importance, rendering separate importance rating partially redundant. Weighted scores present difficulties in interpretation. Further, we show that multiplicative composites have undesirable psychometric properties. There is evidence that multiplicative composites have little or no advantage over unweighted ratings in correlational or predictive studies. Apart from the face validity and the intuitive appeal of multiplying satisfaction ratings by importance ratings, there appear to be no sound reasons for doing so, and several good reasons not to do so.


Microplastics ingestion induces plasticity in digestive morphology in larvae of Xenopus laevis.
Global changes in temperature, predator introductions, and pollution might challenge animals by altering food conditions. A fast-growing source of environmental pollution are microplastics. If ingested with the natural food source, microplastics act as artificial fibers that reduce food quality by decreasing nutrient and energy density with possible ramifications for growth and development. Animals might cope with altered food conditions with digestive plasticity. We examined experimentally whether larvae of the African clawed frog (Xenopus laevis) exhibit digestive morphology plasticity (i.e., gut length, mass, and diameter) in response to microplastics ingestion. As natural systems contain non-digestible particles similar in size and shape to microplastics, we included cellulose as a natural fiber control group. Gut length and mass increased in response to microplastics and cellulose ingestion indicating that both types of fibers induced digestive plasticity. Body mass and body condition were similar across experimental groups, indicating that larvae fully compensated for low nutrient and energy density by developing longer intestines. The ability of a species to respond plastically to environmental variation, as X. laevis responded, indicates that this species might have the potential to cope with new conditions during global change, although it is uncertain whether this potential may be reduced in a multi-stressor environment.


Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls.
HCC is a common cancer and HBV and AFB(1) are well-documented, major risk factors. Epidemiologic studies have documented that cigarette smoking also contributes to the development of HCC. PAHs are ubiquitous environmental pollutants and products of incomplete combustion. They are present in both mainstream and sidestream cigarette smoke. PAHs are metabolically activated by phase I enzymes, including CYP1A1, into electrophilic reactants (diol epoxides), which covalently bind to DNA to form adducts. Diol epoxides are also substrates for phase II detoxifying enzymes, including GSTM and GSTP. To examine the association between PAH-DNA adducts and HCC, adduct levels were determined in liver tissue by relative staining intensity with an immunoperoxidase method using a polyclonal antiserum against BPDE-modified DNA. Subjects were also genotyped for polymorphism in several genes involved in the metabolism of PAH, including GSTM1 and GSTP1. Liver tissue was collected from patients with histologically confirmed HCC (n = 105) and from non-HCC controls (n = 37). There was a significant positive correlation (r = 0.3, p < 0.01) between adducts in tumor and adjacent nontumor tissues among HCC cases. The risk of HCC was higher after adjustment for age, sex and HBsAg in the group with the highest tertile tissue levels of PAH-DNA adducts (mean relative nuclear staining intensity of tumor and nontumor tissue > 344) than in the group with the lowest tertile (staining < 241, OR = 3.9, 95% CI = 1.0-14.9). Among non-HCC controls, there were no significant associations between adduct levels and cigarette smoking, GSTM1 null genotype and HBsAg positivity. A strikingly increased HCC risk was observed (OR = 20.3, 95% CI = 5.0-81.8) among HBsAg-positive subjects whose PAH-DNA adduct levels were high (mean relative nuclear staining intensity of tumor and nontumor tissue > 301, median of control tissues) compared to HBsAg-negative subjects who had low PAH-DNA adduct levels. 4-ABP- and AFB(1)-DNA adducts had been measured previously in these same tissues. Subjects with elevated DNA adduct levels of PAH, 4-ABP and AFB(1) had a significantly higher HCC risk with an OR of 36.7 (95% CI 7.2-187.2) compared to those who had low DNA adduct levels. These results suggest that PAHs may play a role in human hepatocarcinogenesis in conjunction with HBsAg carrier status, GSTM1 and GSTP1 genotypes and exposure to 4-ABP and AFB(1).


Tomographic reconstruction of neopterous carboniferous insect nymphs.
Two new polyneopteran insect nymphs from the Montceau-les-Mines Lagerstätte of France are presented. Both are preserved in three dimensions, and are imaged with the aid of X-ray micro-tomography, allowing their morphology to be recovered in unprecedented detail. One-Anebos phrixos gen. et sp. nov.-is of uncertain affinities, and preserves portions of the antennae and eyes, coupled with a heavily spined habitus. The other is a roachoid with long antennae and chewing mouthparts very similar in form to the most generalized mandibulate mouthparts of extant orthopteroid insects. Computer reconstructions reveal limbs in both specimens, allowing identification of the segments and annulation in the tarsus, while poorly developed thoracic wing pads suggest both are young instars. This work describes the morphologically best-known Palaeozoic insect nymphs, allowing a better understanding of the juveniles' palaeobiology and palaeoecology. We also consider the validity of evidence from Palaeozoic juvenile insects in wing origin theories. The study of juvenile Palaeozoic insects is currently a neglected field, yet these fossils provide direct evidence on the evolution of insect development. It is hoped this study will stimulate a renewed interest in such work.


[Tuberculosis of the breast].
Tuberculosis of the breast is a rare modern disease or a forgotten diagnosis. During the last 15 years (1982-1996), 28 cases of mammary tuberculosis were reported in Japan. The initial diagnosis of almost all were carcinoma. Physical sign, mammography and USG are not so usefull for the diagnosis. It is important for the early and certain diagnosis to detect acid-fast bacilli on smear or culture and to perform pathological examination on biopsied specimen.


Changing trends of speech outcomes after total laryngectomy in the 21st century: a single-center study.
To describe the speech rehabilitation outcomes of patients undergoing total laryngectomy (TL) in the 21st century. Retrospective chart review. Tertiary academic center Retrospective review of 167 patients who underwent TL from June 2000 to February 2012. Demographics, disease variables, and surgical factors were reviewed. Primary alaryngeal speech modality, speech outcome, and tracheoesophageal puncture (TEP) complication rates were assessed. Overall TEP speech success rate (primary or secondary) was 72%. Overall TEP speech success rate was 76% for those with primary TEP and was 68% for those with secondary TEP. TEP speech success rates at first, second, and beyond second year were 75%, 72%, and 70%, respectively. Success rates for primary TL, salvage TL, primary TL with pharyngeal reconstruction, or salvage TL with pharyngeal reconstruction groups were 71%, 72%, 73%, and 71%, respectively. TEP-related complications occurred in 43% of patients, with no difference in complication rates between primary versus salvage TL or primary versus secondary TEP. For those with complications, TEP success rate was 65%. This study showed TEP speech-outcome success rates lower than what has been historically reported. There was no significant difference in TEP speech outcome between primary versus salvage TL or primary versus secondary TEP. Patients with TEP-related complications had TEP speech-outcome success rates comparable to those without any complication. TEP may continue to be a superior option as a mode of speech in patients with TL, including those undergoing salvage TL. 4.


[The combined treatment of venereal diseases and alcoholism].
Combined therapy for a sexually transmitted disease and chronic alcoholism or alcohol abuse has been administered in a hospital for sexually transmitted diseases. No side effects were recorded. Late results have been followed up in 111 patients; a stable remission has been achieved in 40%.


Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?
Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques - immunotherapy and SABR - in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments.


HSP90 inhibitors 17-AAG and VER-82576 inhibit porcine deltacoronavirus replication in vitro.
Porcine deltacoronavirus (PDCoV) is highly pathogenic to piglets, and no specific drugs or vaccines are available for the prevention and treatment of PDCoV infection, the need for antiviral therapies is pressing. HSP90 inhibitors have potent inhibitory effects against the replication of numerous viruses, hence we evaluated three HSP90 inhibitors, 17-AAG, VER-82576, and KW-2478, for their effects on PDCoV infection in vitro. We evaluated their effectivenesses at suppressing PDCoV by qRT-PCR, western blot, and TCID50 assay, and found that 17-AAG and VER-82576 inhibited PDCoV at the early stage of replication, while KW-2478 showed no significant antiviral activity at any stage of infection. These results indicated that the PDCoV-inhibitory effects of 17-AAG and VER-82576 might be exerted by targeting host cell factor HSP90AB1 but not HSP90AA1. Further study showed that HSP90AB1 mRNA and protein levels were not significantly different in 17-AAG and VER-82576-treated cells versus control cells. 17-AAG and VER-82576 were also evaluated for their effects on the expressions of TNF-α, IL-6, and IL-12, which are PDCoV-induced proinflammatory cytokines. We found that both 17-AAG and VER-82576 inhibited the expressions of TNF-α, IL-6, and IL-12 to varying degrees, but in a dose dependent manner. From our data we can conclude that the HSP90 inhibitors 17-AAG and VER-82576 are promising candidates for the treatment of PDCoV infection.


Treating the symptoms of osteoarthritis-oral treatments.
In 2004-2005, 15% of Australians reported having arthritis.1 Osteoarthritis (OA) is by far the most common form, and is a leading cause of pain and disability among people over 65 years of age.


Tumor cell motility and metastasis : Autocrine motility factor as an example of ecto/exoenzyme cytokines.
Cellular locomotion plays a critical role in such normal processes as embryonic development, tissue segregation, as well as the infiltration of fibroblasts and vascular cells during wound repair and the inflammatory responses of the adult immune system. During tumor invasion and metastasis the processes of cell migration achieve dire significance. Disruption of normal homeostatic mechanisms to benefit the survival of the individual tumor cell is a common theme discovered during the characterization of factors once thought to be tumor-specific. One such molecule, tumor cell autocrine motility factor, was so described and has only recently been identified as a normal protein involved in intracellular glycolysis as well as implicated as an extracellular effector of normal cell functions including survival of certain populations of neurons. This molecule represents a member of the newly emerging family of intracellular enzymes whose disparate functions as extracellular mediators of cellular responses defines a new class of ecto/exoenzymes which play a role in normal cellular processes and are inappropriately utilized by tumor cells to elicit new survival strategies.


Short group psychoeducation followed by daily electronic self-monitoring in the long-term treatment of bipolar disorders: a multicenter, rater-blind, randomized controlled trial.
Despite various pharmacological and psychological treatment interventions, bipolar disorders rank among the leading causes of global disease burden. Group psychoeducation has been demonstrated an effective add-on to pharmacotherapy, but it may be difficult to implement in practice depending on the clinical setting and available human resources. Multicenter, rater-blind, randomized controlled trial to investigate the efficacy of a new intervention program consisting of an initial 6-week psychoeducation protocol plus a subsequent structured daily computer-based self-charting program (ChronoRecord) over 54 weeks in remitted patients with bipolar disorders. The control condition included non-structured group sessions followed by daily computer-based self-reports (unstructured like a diary). Both groups received treatment-as-usual. Over 2 years, 41 mood episodes occurred in the experimental group (n = 39) compared to 27 in the control group (n = 34), without reaching statistical significance. Time to recurrence did not significantly differ between the experimental and control group (25% relapsed after 112 and 273 days, respectively). There were no significant group-by-time interactions in mood symptoms, quality of life, self-efficacy expectations or perceived involvement in care. Six weekly psychoeducational group sessions followed by daily self-monitoring via ChronoRecord for 54 weeks may not be superior to non-structured group meetings followed by unstructured self-reporting. Other psychotherapeutic interventions may be needed to optimize the treatment of patients with bipolar disorders, especially for those at later disease stages. Trial registration Retrospectively registered at German Clinical Trials Register on May 24, 2019; DRKS00017319.


Latitudinal variation in intertidal algal community structure: the influence of grazing and vegetative propagation.
The hypothesis that sea urchin grazing and interactions with turf-forming red algae prevent large brown algae from forming an extensive canopy in the low intertidal zone of southern California was tested with field experiments at two study sites. Experimental removal of sea urchins resulted in rapid algal recruitment. Crustose coralline algae which typically dominate the substratum in areas with dense urchin populations were quickly overgrown by several species of short-lived green, brown and red algae. The removal of urchins also significantly increased the recruitment of two long-lived species of large brown algae (Egregia laevigata and Cystoseira osmundacea at one study site and E. laevigata and Halidrys dioica at the other). The experimental plots at both sites were eventually dominated by perennial red algae.A two-factorial experiment demonstrated that sea urchin grazing and preemption of space by red algae in areas where urchins are less abundant are responsible for the rarity of large brown algae in the low intertidal of southern California. The three dominant perennial red algae, Gigartina canaliculata, Laurencia pacifica and Gastroclonium coulteri, recruit seasonally from settled spores but can rapidly fill open space with vigorous vegetative growth throughout the year. These species encroach laterally into space created by the deaths of large brown algae or by other disturbances. Once extensive turfs of these red algae are established further invasion is inhibited. This interaction of algae which proliferate vegetatively with algae which recruit only from settled spores is analogous to those which occur between solitary and colonial marine invertebrates and between solitary and cloning terrestrial plants.It is suggested that a north-south gradient in the abundance of vegetatively propagating species, in grazing intensity and in the frequency of space-clearing disturbances, may account for latitudinal variation in intertidal algal community structure along the Pacific coast of North America.


Febrifugine dihydrochloride as a new oral chemotherapeutic agent against visceral leishmaniasis infection.
Visceral leishmaniasis (VL) is the deadliest form of leishmaniasis without a safer treatment option. This study implies drug repurposing to find a novel antileishmanial compound, namely febrifugine dihydrochloride (FFG) targeting Leishmania antioxidant system. Starting with virtual screening revealed the high binding affinity and lead likeness of FFG against the trypanothione reductase (TR) enzyme of Leishmania donovani, followed by experimental validation. The promastigotes inhibition assay gave the IC50 concentration of FFG and Miltefosine (positive control) as 7.16 ± 1.39 nM and 11.41 ± 0.29 μM, respectively. Their CC50 was found as 451 ± 12.73 nM and 135.9 ± 5.94 μM, respectively. FFG has been shown to increase the reactive oxygen species (ROS), leading to apoptosis-like cell death among L. donovani promastigotes. Spleen touch biopsy resulted in 62% and 55% decreased parasite load with FFG and miltefosine treatment, respectively. Cytokine profiling has shown an increased proinflammatory cytokine response post-FFG treatment. Moreover, FFG is safe on the liver toxicity parameter in mice post-treatment.


A feasible method for independently evaluating the mechanical properties of glial LC and RGC axons by combining atomic force microscopy measurement with image segmentation.
The deformation of lamina cribrosa (LC) under the elevated intraocular pressure (IOP) might squeeze the retinal ganglion cell (RGC) axons and impair the visual function. Mechanical behaviors of LC and RGC axons are supposed to be related to the optic nerve damage of glaucoma patients. However, they cannot be independently studied with the existing methods because the LC and RGC axons intertwine in the LC area. This study proposed a feasible method to evaluate the respective mechanical properties of glial LC and RGC axons of rats. The atomic force microscope (AFM) nano-indentation experiment was performed on unfixed cryosection samples acquired from the glial LC tissues of eight eyes from four rats. For each sample, three regions of interests (ROIs) with sizes of 20 × 20 μm2 were selected from the ventral, central and dorsal regions of the sample, respectively, and the nano-indentation was performed on 128 × 128 points within each ROI to obtain a Young's modulus image. The glial LC and RGC axons were segmented on each modulus images using Otsu thresholding segmentation method, and their respective Young's modulus was further extracted for statistical analysis. Young's modulus of glial LC and RGC axons are 297 ± 98 kPa and 76 ± 36 kPa in ventral regions, 342 ± 84 kPa and 84 ± 32 kPa in central regions, 280 ± 104 kPa and 75 ± 30 kPa in dorsal regions, respectively. No significant differences are found among the Young's modulus of different regions, both for glial LC and RGC axons. This study takes the nature property of the LC area as a composite material into consideration, and proposes a feasible method to distinguish between the glial LC and RGC axons and measure their respective Young's modulus. These findings may provide useful information for establishing finite element models of the optic nerve head and promote the study on the deformation of the optic nerve under high intraocular pressure, and finally contribute to the early diagnosis of glaucoma.


Effect of body mass index on N-terminal pro-brain natriuretic peptide values in patients with heart failure.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker used for the diagnosis of heart failure. There is a relationship between NT-proBNP levels and body mass index (BMI). The study aimed to explore the impact of BMI on NT-proBNP concentrations and to examine whether other factors independent of or combined with BMI affect NT-proBNP values in patients with heart failure. A total of 293 participants were recruited. The mean age was 68.9 ± 13.2 years, males accounted for 46.4% of the total cohort, the mean BMI was 23.1 ± 4.0 kg/m2, and the median NT-proBNP level was 3776 (1672-8806) pg/ml. There was an inverse relationship between BMI and log NT-proBNP (r = - 0.29; p < 0.001, Spearman correlation). Each standard deviation increase in BMI (4 kg/m2) was associated with a 7% decrease in NT-proBNP values in the total cohort. The independent inverse determinants of NT-proBNP other than BMI were male gender and eGFR, while the variables directly correlated to NT-proBNP were LVEF ≤ 40% and NYHA class III-IV heart failure. There is an inverse association between BMI and NT-proBNP levels. However, the correlation is weak, and there are other variables that have a significant impact on the NT-proBNP values as well. The NT-proBNP levels are still valuable in the diagnosis of heart failure regardless of BMI status.


The orientation of melittin in lipid membranes. A polarized infrared spectroscopy study.
Polarized infrared spectra of melittin incorporated into macroscopically oriented lipid membranes are reported. From the linear dichroism of the amide I and amide II vibrational bands, the spatial orientation of the melittin helices was determined as being preferentially parallel to the membrane normal, under our experimental condition of low water content and an ordered lipid phase. Considering the various models for the orientation of melittin in lipid membranes proposed in the literature, we conclude that our data are in accord with an arrangement whereby the hydrophobic part of the polypeptide either spans the bilayer in the form of two bent helix segments, or is folded back within one monolayer in the form of a wedge.


Correction: Fanelli Kuczmarski, M.; et al. Aspects of Dietary Diversity Differ in Their Association with Atherosclerotic Cardiovascular Risk in a Racially Diverse US Adult Population. Nutrients 2019, 11, 1034.
The authors wish to make a correction to Table 2 in the published version of their paper [...].


Eradication of persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in individuals with cystic fibrosis (CF) has increased significantly. While studies demonstrate that persistent MRSA infection in CF is associated with poor clinical outcomes, there are no randomized controlled studies informing management. The Persistent MRSA Eradication Protocol was a double-blind, randomized, placebo-controlled study investigating a comprehensive 28-day treatment regimen with or without inhaled vancomycin for eradication of MRSA. Eligible participants had CF and documented persistent MRSA infection. All participants received oral antibiotics, topical decontamination, and environmental cleaning and were randomized to receive inhaled vancomycin or inhaled placebo. The primary outcome was the difference in MRSA eradication rates one month after completion of the treatment protocol. 29 participants were randomized. Four subjects in the inhaled vancomycin group required withdrawal from the study for bronchospasm before outcome data were collected and were excluded from analysis. There was no difference in the primary outcome: 2/10 (20%) of subjects in the intervention group and 3/15 (20%) in the placebo group had a MRSA negative sputum culture one month after treatment. There were no statistically significant differences in the rates of MRSA eradication at the end of treatment or three months after treatment completion. This study suggests that persistent MRSA infection is difficult to eradicate, even with multimodal antibiotics. The use of a single course of inhaled vancomycin may not lead to higher rates of MRSA eradication in individuals with CF and may be associated with bronchospasm. FUND: This trial was financially supported by the Cystic Fibrosis Foundation.


Evolutionary rate variation among vertebrate beta globin genes: implications for dating gene family duplication events.
A comprehensive dataset of 62 beta globin gene sequences from various vertebrates was compiled to test the molecular clock and to estimate dates of gene duplications. We found that evolution of the beta globin family of genes is not clock-like, a result that is at odds with the common use of this family as an example of a constant rate of evolution over time. Divergence dates were estimated either with or without assuming the molecular clock, and both analyses produced similar date estimates, which are also in general agreement with estimates reported previously. In addition we report date estimates for seven previously unexamined duplication events within the beta globin family. Despite multiple sources of rate variation, the average rate across the beta globin phylogeny yielded reasonable estimates of divergence dates in most cases. Exceptions were cases of gene conversion, where it appears to have led to underestimates of divergence dates. Our results suggest (i) the major duplications giving rise to the paralogous beta globin genes are associated with significant evolutionary rate variation among gene lineages; and (ii) genes arising from more recent gene duplications (e.g., tandem duplications within lineages) do not appear to differ greatly in rate. We believe this pattern reflects a complex interplay of evolutionary forces where natural selection for diversifying paralogous functions and lineage-specific effects contribute to rate variation on a long-term basis, while gene conversion tends to increase sequence similarity. Gene conversion effects appear to be stronger on recent gene duplicates, as their sequences are highly similar. Lastly, phylogenetic analyses do not support a previous report that avian globins are members of a relic lineage of omega globins.


[Pneumococcal infections: Appraisal and perspectives in terms of adult vaccination].
Pneumococcal diseases are the first cause of bacterial infections in adult and in the aged adult. While its considerable morbi-mortality is potentially preventable through vaccination, the interest of anti-pneumococcal vaccination in these populations is still debated. Effectiveness appraisal of current anti-pneumococcal vaccines and the perspectives in terms of preventive strategies against Streptococcus pneumoniae infections in the adult population are presented.


[The hygienic characteristics of the medical technology accompaniment to the development, creation and operation of installations equipped with video display terminals].
Radiation measuring on the work places of operators in command and control installations proved that environment parameters depending on electronic display functioning are in line with the regulations' requirements. Nevertheless the operator health estimates show that the problem of personnel security still exists. The authors recommend some measures to improve the situation.


Dating violence and sexually transmitted disease/HIV testing and diagnosis among adolescent females.
Previous studies demonstrate significant associations between dating-violence victimization and sexual risk behaviors among adolescent girls; however, a relationship between dating violence and actual sexually transmitted disease (STD)/HIV testing and diagnosis has yet to be investigated among a representative sample. The present study assesses associations between dating violence and STD/HIV testing and diagnosis among a representative sample of sexually active adolescent girls. Data from 9th- to 12th-grade female students completing the 1999 and 2001 Massachusetts Youth Risk Behavior Surveys and reporting having ever had sexual intercourse (N = 1641) were examined. Odds ratios for STD/HIV testing and diagnosis that were based on experiences of dating violence and adjusted for STD/HIV risk behaviors and demographics were calculated. More than one third (38.8%) of adolescent girls tested for STD or HIV and more than half (51.6%) of girls diagnosed with STD/HIV reported experiencing dating violence. Compared with nonabused girls, girls who experienced both physical and sexual dating violence were 3.0 times more likely to have been tested for STD and HIV, and 2.6 times more likely to report an STD diagnosis. After adjusting for STD/HIV risk behaviors, dating violence remains significantly associated with STD/HIV testing and diagnosis among sexually active adolescent girls.


Guanosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)]thiophosphate and adenosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)]thiophosphate. New nucleotide affinity labels which react with rabbit muscle pyruvate kinase.
Three new reactive nucleotide analogues with bromo-keto substituents adjacent to a thiophosphate have been synthesized. Guanosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)]thiophosphate (GMPS-BDB), reacts covalently with rabbit muscle pyruvate kinase with complete inactivation and incorporation of 1.8 mol of reagent/mol of enzyme subunit. By contrast, the mono-keto compound, guanosine 5'-O-[S-(3-bromo-2-oxopropyl)]thiophosphate (GMPS-BOP), causes no loss of pyruvate kinase activity. When the analogous adenosyl nucleotide derivatives are incubated with pyruvate kinase, the di-keto compound, adenosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)]thiophosphate (AMPS-BDB), rapidly effects inactivation, whereas the mono-keto compound, adenosine 5'-O-[S-(3-bromo-2-oxopropyl)]thiophosphate (AMPS-BOP), causes no loss of activity. Complete protection against inactivation by GMPS-BDB is provided by phosphoenolpyruvate in the presence of K+ and Mn2+ and the amount of reagent incorporated (0.9 mol/reagent/mol subunit) is reduced to half that observed in the absence of protectants. Gas-phase sequencing of the tryptic peptides purified from inactive GMPS-BDB or AMPS-BDB-modified enzyme gave the cysteine-labeled peptides: C151DENILWLDYK161, and N162IC164K165 as the two major peptide products, with a smaller amount of N43TGIIC48TIGPASR55. Reaction in the presence of the protectants PEP, K+, and Mn2+ yielded Cys164 as the only labeled residue, indicating that inactivation is primarily due to modification of Cys151. We propose that GMPS-BDB (or AMPS-BDB), which may exist in enolized form in aqueous solution, functions as a reactive analogue of phosphoenolpyruvate and GDP (ADP) to target Cys151 in the active site of pyruvate kinase.


Coadsorption of Cu and sulfamethoxazole on hydroxylized and graphitized carbon nanotubes.
Because of their various functional groups, antibiotics may complex with heavy metals and thus the environmental behaviors of both antibiotics and heavy metals may be altered. Noticing the experimental flaws of the previous studies, this study used Cu(2+) and sulfamethoxazole (SMX) as model sorbates and carbon nanotubes (CNTs) as model sorbents to investigate the coadsorption of Cu and SMX. Combining the results of binary interaction experiments, we concluded that Cu and SMX preferentially occupy different types of CNT sorption sites at pHs 1.0 and 3.5, showing no apparent sorption change with the presence of coadsorbates. However, at pH 6.5, ternary complexes of Cu-SMX-CNTs and SMX-Cu-CNTs may be formed depending on Cu(2+) concentrations. XPS data provided further support for the adsorption of both Cu and SMX on CNTs. These results indicated that the environmental behavior of antibiotics should be evaluated with careful consideration of the rule of metal ions.


Genome sequencing of 18 francisella strains to aid in assay development and testing.
Francisella tularensis is a highly infectious bacterium with the potential to cause high fatality rates if infections are untreated. To aid in the development of rapid and accurate detection assays, we have sequenced and annotated the genomes of 18 F. tularensis and Francisella philomiragia strains.


The Association Between Phosphodiesterase-5 Inhibitors and Colorectal Cancer in a National Cohort of Patients.
To examine the association between phosphodiesterase-5 (PDE-5) inhibitor use and incidence of colorectal cancer among patients with erectile dysfunction treated in the Veterans Affairs (VA) Healthcare System. A retrospective cohort study using the Veterans Affairs Informatics and Computing Infrastructure was conducted, with data spanning January 2001-December 2016. Patients were followed up from index until (i) the first diagnosis of colorectal cancer, (ii) death, or (iii) the end of study period. Statistical analyses evaluated demographics and baseline characteristics between cohorts (PDE-5 exposed or not) and the effect of additional dosages of each specific PDE-5 inhibitor using adjusted multivariate Cox proportional hazards models. A total of 221,538 patients met the study inclusion criteria, 192,691 patients in the PDE-5 cohort and 29,227 patients in the never use PDE-5 cohort. The multivariate Cox proportional hazards model results revealed that the those who had any exposure to a PDE-5 inhibitor have an 18% lower hazard of colorectal cancer (adjusted hazard ratio [HR] = 0.816, 95% confidence interval [CI] = 0.754-0.882). For each additional 100-mg dosage of sildenafil and 10-mg dosage of tadalafil, the hazard of colorectal cancer is reduced by 2.4% (adjusted HR = 0.976, 95% CI = 0.973-0.979) and 1.7% (adjusted HR = 0.983, 95% CI = 0.972-0.996), respectively. PDE-5 inhibitor usage in patients with erectile dysfunction is associated with a lower hazard of colorectal cancer compared with patients not exposed to PDE-5 inhibitors.


Anorectal angle at rest predicting successful sacral nerve stimulation in idiopathic fecal incontinence-a cohort analysis.
Sacral nerve stimulation is an effective treatment for patients suffering from fecal incontinence. However, less is known about predictors of success before stimulation. The purpose of this study was to identify predictors of successful sacral nerve stimulation in patients with idiopathic fecal incontinence. Consecutive female patients, receiving peripheral nerve evaluation and sacral nerve stimulation between September 2008 and October 2014, suffering from idiopathic fecal incontinence were included in this study. Preoperative patient's characteristics, anal manometry, and defecography results were collected prospectively and investigated by retrospective analysis. Main outcome measures were independent predictors of treatment success after sacral nerve stimulation. From, all in all, 54 patients suffering from idiopathic fecal incontinence receiving peripheral nerve evaluation, favorable outcome was achieved in 23 of 30 patients after sacral nerve stimulation (per protocol 76.7%; intention to treat 42.6%). From all analyzed characteristics, wide anorectal angle at rest in preoperative defecography was the only independent predictor of favorable outcome in multivariate analysis (favorable 134.1 ± 13.9° versus unfavorable 118.6 ± 17.1°). Anorectal angle at rest in preoperative defecography might present a predictor of outcome after sacral nerve stimulation in patients with idiopathic fecal incontinence.


Investigation of the hypothalamic defensive system in the mouse.
The hypothalamus plays especially important roles in various endocrine, autonomic, and behavioral responses that guarantee the survival of both the individual and the species. In the rat, a distinct hypothalamic defensive circuit has been defined as critical for integrating predatory threats, raising an important question as to whether this concept could be applied to other prey species. To start addressing this matter, in the present study, we investigated, in another prey species (the mouse), the pattern of hypothalamic Fos immunoreactivity in response to exposure to a predator (a rat, using the Rat Exposure Test). During rat exposure, mice remained concealed in the home chamber for a longer period of time and increased freezing and risk assessment activity. We were able to show that the mouse and the rat present a similar pattern of hypothalamic activation in response to a predator. Of particular note, similar to what has been described for the rat, we observed in the mouse that predator exposure induces a striking activation in the elements of the medial hypothalamic defensive system, namely, the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial hypothalamic nucleus and the dorsal premammillary nucleus. Moreover, as described for the rat, predator-exposed mice also presented increased Fos levels in the autonomic and parvicellular parts of the paraventricular hypothalamic nucleus, lateral preoptic area and subfornical region of the lateral hypothalamic area. In conclusion, the present data give further support to the concept that a specific hypothalamic defensive circuit should be preserved across different prey species.


Evaluation of Regenerative Potential of Locally Delivered Vitamin C along with Microneedling in the Treatment of Deficient Interdental Papilla: A Clinical Study.
To evaluate the efficacy of intrapapillary injections of vitamin C along with microneedling (MN) in enhancing deficient interdental papilla (IDP) in esthetic zones clinically. Fifteen patients diagnosed with black triangles according to Norland classification system for loss of papillary height were selected. After oral prophylaxis and baseline measurements of insufficient interdental papilla, the vitamin C injection was loaded in disposable syringe 30G × 1/2" needle. The needle was inserted at 45° angle, 2-3-mm apical to the involved papilla and all surrounding areas. Each involved papilla was injected with an amount till blanching was visible. After that, MN was done in the required area. This method was repeated for 5 times at 7 days intervals consecutively. The final clinical photographs and measurements were recorded after 7 days of last dose administered. There was a statistically significant difference in the mean IDP height observed over the time period (p = 0.002). An overall healthy appearance of gingiva with a remarkable increase in papilla growth was observed. Vitamin C injection along with MN can be considered as an alternative to invasive surgical procedures in reconstruction or regeneration of the missing IDP.


Rapid transport of foreign particles microinjected into crab axons.
The rapid transport of optically detectable organelles in axons has been well documented, although its molecular mechanism remains unknown. Here we report that synthetic particles microinjected into the giant axons of the shore crab, Carcinus maenas, are also transported, moving as though they were endogenous organelles. Polystyrene beads, polyacrolein beads, paraffin droplets and glass fragments, of sizes up to 0.5 micron in diameter, have been tested. Many of these foreign particles move rapidly and for long distances along the axon in the anterograde direction, travelling in a saltatory fashion, within a well defined velocity range. In many respects the movements are indistinguishable from those of anterogradely moving endogenous organelles seen by phase-contrast in these axons. Our results indicate that there is a transport system in axons capable of carrying almost any particle of suitable physical properties in an anterograde direction.


Determination of mitragynine in urine matrices by bar adsorptive microextraction and HPLC analysis.
Bar adsorptive microextraction combined with liquid desorption followed by high performance liquid chromatography with diode array detection (BAµE-LD/HPLC-DAD) is proposed for the determination of the psychoactive alkaloid mitragynine (MG) in human urine matrices. By using a modified N-vinylpyrrolidone polymer (P2) sorbent phase, high selectivity and efficiency is achieved. Assays performed by BAµE(P2)-LD/HPLC-DAD on 25 mL water samples spiked at the 8.0 µg L(-1) level yielded average recoveries around 100% of MG, under optimized experimental conditions. The analytical performance showed good precision (RSD<15%), appropriated detection limits of 0.10 µg L(-1) and linear dynamic ranges (0.6-24.0 μg L(-1)) with convenient determination coefficients of 0.9924. By using the standard addition method, the application of the present methodology for the determination of MG in human urine matrices after Kratom consumer, allowed very good performances. The proposed methodology proved to be a suitable alternative to monitor MG in biological fluid matrices, showing to be easy to implement, reliable, sensitive and requiring low sample volumes, when compared with other sorbent-based methods.


Expression of human intestinal dipeptide transporter in Xenopus laevis oocytes.
The human colon adenocarcinoma cell line Caco-2 retains the H+/dipeptide cotransporter. To identify the structure of the human dipeptide transporter, we have examined the expression of the transporter in Xenopus laevis oocytes injected with Caco-2 poly(A)+RNA, by monitoring the uptake of bestatin, a dipeptide-like anticancer agent. The bestatin uptake in the poly(A)+RNA-injected oocytes was inhibited by excess glycyl-L-leucine, and showed pH dependence (optimal pH of 5.5-6.0). These observations suggest that the human intestinal dipeptide transporter can be expressed functionally in Xenopus oocytes.


A Case of Persistent Fifth Aortic Arch With an Interrupted Fourth Aortic Arch.
We report the case of a 4-year-old boy with coarctation of the aorta resulting from persistent fifth aortic arch, a rare abnormality, along with an interrupted fourth aortic arch. When he visited a general practitioner with an upper respiratory infection, a heart murmur was noted. Computed tomography findings led to the diagnosis of persistent fifth aortic arch with an interrupted fourth aortic arch. He underwent aortic arch repair, excision of the fifth aortic arch, and anastomosis of the original arch with the descending aorta. Pathologically, the tissue of the fifth aortic arch was different from that of the normal aortic arch.


Somatic and visceral inputs to the thoracic spinal cord of the cat: effects of noxious stimulation of the biliary system.
1. Single unit electrical activity has been recorded extracellularly from 133 neurones in the grey matter of the 8th and 9th thoracic segments of the spinal cord in chloralose anaesthetized cats. The responses of these neurones to electrical stimulation of the ipsilateral splanchnic nerve, to natural stimulation of the skin and to distension of the biliary system have been studied.2. Of the neurones studied, 75% responded to electrical stimulation of the splanchnic nerve and had a cutaneous receptive field in the costal region (viscero-somatic neurones). Twenty-three per cent of the neurones had a cutaneous receptive field but no visceral input (somatic neurones) and 2% had a visceral input but no cutaneous field.3. Somatic neurones had well-localized receptive fields from which they could be driven by innocuous stimulation of the skin (52%), by noxious (7%) or by both forms of stimulation (41%). No somatic neurones projected to supraspinal levels via the contralateral ventro-lateral funiculus.4. Viscero-somatic neurones were excited by small myelinated and non-myelinated afferent fibres in the splanchnic nerve. Most viscero-somatic neurones had cutaneous inputs from nociceptors either exclusively (38%) or in addition to non-noxious inputs (53%).5. The recording sites of somatic neurones were located almost exclusively in laminae II and IV and dorsal V of the dorsal horn. In contrast, viscero-somatic neurones were located in lamina I and in laminae V-IX of the grey matter. No differential distribution of recording sites according to type of cutaneous receptive field has been found within the viscero-somatic group of neurones.6. About one-third of all viscero-somatic neurones could be excited by distensions of the biliary system. In all cases, intensities of visceral stimulation above physiological levels were necessary to activate the neurones. Most units driven by biliary afferents were located in or ventral to lamina V of the dorsal horn. The excitation of these units by biliary distension was found to be specifically mediated by receptors in the biliary system.7. Sixteen per cent of the neurones were found to project to supraspinal levels via crossed ventro-lateral pathways. All of these neurones were viscero-somatic with axonal conduction velocities between 12 and 68 m sec(-1).8. These results are discussed in relation to the postulates of the ;Convergence-projection' theory of referred pain.


New tools show promise for tackling paper mills.
Fake papers-a symptom of academia's "publish or perish" pressure-are alarmingly common, new findings suggest.


Cilia-Derived Extracellular Vesicles in Caenorhabditis Elegans: In Vivo Imaging and Quantification of Extracellular Vesicle Release and Capture.
Caenorhabditis elegans is a microscopic model nematode characterized by body transparency and ease of genetic manipulation. Release of extracellular vesicles (EVs) is observed from different tissues; of particular interest are the EVs released by the cilia of sensory neurons. C. elegans ciliated sensory neurons produce EVs that are environmentally released and/or captured by neighboring glial cells. In this chapter, we describe a methodological approach to image the biogenesis, release, and capture of EVs by glial cells in anesthetized animals. This method will allow the experimenter to visualize and quantify the release of ciliary-derived EVs.


Purification of soluble murine transplantation antigens by isoelectric focusing.
Hydrosoluble transplantation antigens were prepared from membranes and microsomes of C(3)H mice (BP8 tumoral cells) and purified by isoelectric focusing. A biologically active fraction which seems homogenous by acrylamide gel electrophoresis was characterized: it specifically inhibits anti C(3)H hemagglutinin antibodies and provokes a highly significant prolongation of skin graft.


Difference in patterns of prescribing antidepressants known for their weight-modulating and cardiovascular side effects for patients with obesity compared to patients with normal weight.
Patients with depression and comorbid obesity may be more prone to weight modulating and cardiovascular side effects of selected antidepressants (AD). It is important to ascertain whether these AD prescriptions differ by patient weight status. Canadian Primary Care Sentinel Surveillance Network (CPCSSN) electronic medical records were used. Participants were adults with depression prescribed an AD in 2000-2016, with weight categories established before the first prescription. Logistic regression and mixed effects models were applied to examine associations between obesity and AD prescribing, adjusted for sex, age, and comorbidities. Machine learning algorithm random forest (RF) was used to evaluate the importance of weight in predicting prescribing patterns. Of 26,571 participants, 72.4% were women, mean age was 38.9 years (standard deviation (SD)=14.2) and mean BMI 27.0 kg/m2 (SD = 6.5); 9.5% had ≥ 1 comorbidity. Patients with obesity, compared to normal weight patients, were more likely to receive bupropion (adjusted odds ratio (aOR) 1.24, 95%CI: 1.09,1.42), fluoxetine (aOR 1.14, 95%CI: 0.97,1.34), and amitriptyline (aOR 1.13, 95%CI: 0.93,1.36), and less likely to receive mirtazapine (aOR 0.55, 95%CI: 0.44,0.68) and escitalopram (aOR 0.88, 95%CI: 0.80, 0.97). RF analysis showed that weight was among the most important predictors of prescribing patterns, equivalent to age and more important than sex. AD prescribing patterns for patients with obesity appear to be different for selected AD types, including AD known for their weight-modulating and cardiovascular side effects. Longitudinal studies are needed to examine whether these prescribing patterns are associated with significant health outcomes.


Metabolic control analysis of mammalian serine metabolism.
(1) Mammalian serine metabolism is discussed in relation to its synthesis and utilization in proliferating cells, particularly during the nonmalignant proliferation of lymphocytes. (2) An analysis of the control of serine biosynthesis de novo under conditions of high pathway flux has been carried out using metabolic control theory. (3) The important and novel conclusions are that control of pathway flux is localized exclusively at the final step of this biosynthetic pathway, phosphoserine phosphatase. This conclusion challenges the frequently stated maxim that control of biosynthetic pathways is always directed at the first pathway enzyme in a sequence. In the case of phosphoserine phosphatase, the enzyme is inhibited uncompetitively by its product serine, and this feedback control mechanism has the most significant controlling influence on overall pathway flux. Thus, the serine biosynthesis pathway, under these conditions, is controlled by product demand (serine utilization) and not by substrate supply (glycolytic provision of 3-phosphoglycerate), despite the high rate of glycolysis associated with cell proliferation. (4) The control structure of the pathway is not immutable. As has been observed with other pathways analyzed by metabolic control theory, the key points of control in the pathway can shift according to physiological circumstances. At low pathway flux, the control of serine biosynthesis is shared between all the component enzymes of the pathway, and the responsiveness of flux shifts from product demand to substrate supply. (5) Serine utilization has been studied in mitogenically-stimulated human peripheral lymphocytes. Cell proliferation and serine utilization for nucleic acid synthesis have been shown to be responsive to serine concentrations in the normal plasma range. (6) It is concluded that the maintenance of normal plasma serine concentrations is an important factor in the rate of lymphocyte proliferation and hence the effectiveness with which the body can mount an immune response to an antigenic challenge, such as in infection.


Enterobacteria-mediated nitrogen fixation in natural populations of the fruit fly Ceratitis capitata.
Nitrogen, although abundant in the atmosphere, is paradoxically a limited resource for multicellular organisms. In the Animalia, biological nitrogen fixation has solely been demonstrated in termites. We found that all individuals of field-collected Mediterranean fruit flies (Ceratitis capitata) harbour large diazotrophic enterobacterial populations that express dinitrogen reductase in the gut. Moreover, nitrogen fixation was demonstrated in isolated guts and in live flies and may significantly contribute to the fly's nitrogen intake. The presence of similar bacterial consortia in additional insect orders suggests that nitrogen fixation occurs in vast pools of terrestrial insects. On such a large scale, this phenomenon may have a considerable impact on the nitrogen cycle.


A large cardiac hydatid cyst in the interventricular septum: A case report.
Isolated cardiac location is an uncommon presentation of echinococcosis (0.5-2%), and involvement of the interventricular septum is even rarer. It may lead to various complications because of rupture and embolization. We report the case of a 26 - year- old man who was diagnosed to have a large inter-ventricular hydatid cyst complicated by both cerebral and coronary embolism. Presentation, management and follow-up of the patient is discussed. This case is of particular interest because of the rarity of septal localization of a hydatid cyst, and the conflict between the severity of the complications that occurred and the absence of correlated symptoms.


Implantable cardioverter defibrillator therapy in patients with prior coronary revascularization in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
We conducted this study to examine the effect of the ICD on the outcomes of patients with prior coronary revascularization enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and to assess the association of time from coronary revascularization to enrollment with death and sudden cardiac death (SCD). We included in this analysis patients with ischemic heart disease not randomized to the amiodarone arm. Cox proportional hazards models were used to examine the association of prior CABG and of prior PCI with each outcome. Interactions between randomized treatment and each revascularization type and time were tested in each model. Of the 882 patients who met these inclusion criteria, 255 (29%) had no prior revascularization, 178 (20%) had prior PCI only, 284 (32%) had prior CABG only, and 165 (19%) had prior PCI and CABG. There was no significant difference in ICD benefit across the revascularization subgroups (all P > 0.1). There was a trend toward improved survival with an ICD in patients who had their CABG > 2 years before randomization (HR [CI] = 0.71 [0.49, 1.04]) that was not observed in patients who had their CABG < or = 2 years before randomization (HR [CI] = 1.40 [0.61, 3.24]). In SCD-HeFT, there was no significant difference in ICD benefit across the revascularization subgroups. Patients who had their CABG > 2 years before randomization showed a trend toward improved survival with an ICD that was not observed in patients who had their CABG < or = 2 years before randomization.


Aromatic fluorocopolymers based on α-(difluoromethyl)styrene and styrene: synthesis, characterization, and thermal and surface properties.
A study on the α-(difluoromethyl)styrene (DFMST) reactivity under conventional radical copolymerization conditions is presented. Although the homopolymerization of DFMST failed, its radical bulk copolymerization with styrene (ST) led to the synthesis of fluorinated aromatic polymers (FAPs). The resulting novel poly(DFMST-co-ST) copolymers were characterized by 1H, 19F and 13C NMR spectroscopies that evidenced the successful incorporation of DFMST units into copolymers and enabled the assessment of their respective molar percentages (10.4-48.2 mol%). The molar masses were in the range of 1900-17 200 g mol-1. The bulkier CF2H group in the α-position induced the lower reactivity of the DFMST comonomer. ST and DFMST monomer reactivity ratios (r DFMST = 0.0 and r ST = 0.70 ± 0.05 at 70 °C) were determined based on linear least-square methods. These values indicate that DFMST monomer is less reactive than ST, retards the polymerization rate, and thus reduces the molar masses. Moreover, the thermal properties (T g, T d) of the resulting copolymers indicate that the presence of DFMST units incorporated into poly(ST) structure promotes an increase of the T g values up to 109 °C and a slightly better thermal stability than that of poly(ST). Additionally, the thermal decomposition of poly(DFMST-co-ST) copolymer (10.4/89.6) was assessed by simultaneous thermal analysis coupled with Fourier-transform infrared spectroscopy and thermogravimetric analysis coupled with mass spectrometry showing that H2O, CO2, CO and styrene were released. The surface analysis was focused on the effects of the -CF2H group at the α-position of styrene comonomers on surface free energy of the copolymer films. Water and diiodomethane contact angle (CA) measurements confirmed that these copolymers (M n = 2300-17 200 g mol-1) are not exactly the same as polystyrenes (M n = 2100-21 600 g mol-1) in the solid state. The CA hysteresis for poly(ST) (6-8°) and poly(DFMST-co-ST) copolymers (3-5°) reflected these differences even more accurately.


Serial analysis of gene expression in renal carcinoma cells reveals VHL-dependent sensitivity to TNFalpha cytotoxicity.
We have used serial analysis of gene expression (SAGE) to investigate the influence of the von Hippel-Lindau (VHL) gene on global gene expression profiles. SAGE libraries were prepared from renal cell carcinoma (RCC) lines that either lack (parental) or express wild-type VHL (wtVHL). Comparison of these libraries revealed some differentially expressed genes (Glut-1, for example) that were known to be influenced by VHL, but the majority of genes had not previously been reported to be affected by the cell's VHL status. The identification of several genes involved in TNFalpha-mediated events prompted us to compare the sensitivity of cells with different VHL status in TNFalpha cytotoxicity assays. Strikingly, VHL-deficient cells were much more resistant to the toxic influence of TNFalpha. We propose that VHL-dependent sensitization of RCC cells to TNFalpha-mediated killing may contribute to VHL's growth suppressive function.


Selection of reliable reference genes for the normalisation of gene expression levels following time course LPS stimulation of murine bone marrow derived macrophages.
Macrophages are key players in the initiation, perpetuation and regulation of both innate and adaptive immune responses. They largely perform these roles through modulation of the expression of genes, especially those encoding cytokines. Murine bone marrow derived macrophages (BMDMs) are commonly used as a model macrophage population for the study of immune responses to pro-inflammatory stimuli, notably lipopolysaccharide (LPS), which may be pertinent to the human situation. Evaluation of the temporal responses of LPS stimulated macrophages is widely conducted via the measurement of gene expression levels by RT-qPCR. While providing a robust and sensitive measure of gene expression levels, RT-qPCR relies on the normalisation of gene expression data to a stably expressed reference gene. Generally, a normalisation gene(s) is selected from a list of "traditional" reference genes without validation of expression stability under the specific experimental conditions of the study. In the absence of such validation, and given that many studies use only a single reference gene, the reliability of data is questionable. The stability of expression levels of eight commonly used reference genes was assessed during the peak (6 h) and resolution (24 h) phases of the BMDM response to LPS. Further, this study identified two additional genes, which have not previously been described as reference genes, and the stability of their expression levels during the same phases of the inflammatory response were validated. Importantly, this study demonstrates that certain "traditional" reference genes are in fact regulated by LPS exposure, and, therefore, are not reliable candidates as their inclusion may compromise the accuracy of data interpretation. Testament to this, this study shows that the normalisation of gene expression data using an unstable reference gene greatly affects the experimental data obtained, and, therefore, the ultimate biological conclusions drawn. This study reaffirms the importance of validating reference gene stability for individual experimental conditions. Given that gene expression levels in LPS stimulated macrophages is routinely used to infer biological phenomena that are of relevance to human conditions, verification of reference gene expression stability is crucial.


The role of pharmacotherapy in assisting smoking cessation.
Tobacco use represents the single most important preventable health hazard world-wide. Its consumption confers substantially increased mortality and morbidity due to cardiovascular, cerebrovascular and respiratory disease, and malignancy in a number of sites. A key goal towards improving public health in developing and developed countries alike is to reduce tobacco use across populations. Despite this, current data suggest that global tobacco use is increasing. There have been recent pharmacological advances that offer the hope of achieving more effective tobacco cessation and reduced consumption among established tobacco users. These are discussed in further detail, with reference to evidence supporting their use in clinical practice.


Tissue iron loading and histopathological changes in hypotransferrinaemic mice.
Tissue iron loading in hypotransferrinaemic (hpx/hpx) mice was investigated as a model for genetic (primary) haemochromatosis. Iron loading of liver preceded that in the pancreas and heart. One-year-old hpx/hpx mice showed iron staining in exocrine pancreas, liver parenchymal cells, and cardiac and intestinal smooth muscle cells. Iron-loaded macrophages were observed in all these tissues. Islets of Langerhans, biliary epithelial cells, and spleen were iron-free. The pancreas was fibrotic with massive macrophage infiltration and loss of secretory epithelium. Liver showed evidence of chronic inflammatory infiltration with increased collagen fibres in the parenchymal region but no cirrhosis. Serum aspartate aminotransferase activity and plasma glucose were increased in hpx/hpx compared with wild-type mice. Heavy iron loading with haemosiderin deposition in the liver could be demonstrated in hpx/hpx mice from 6 weeks of age. Heterozygous hypotransferrinaemic mice showed minor increases in liver iron stores at 6-12 weeks, but not at 1 year of age. Serum ferritin levels in heterozygous mice were also increased at 6-8 weeks of age. It was concluded that 1-year-old hpx/hpx mice showed evidence of liver and pancreatic damage secondary to tissue iron overload. The iron loading pattern and tissue damage showed some features which were distinct from those observed in haemochromatosis.


The differential role of spinal MHC class II and cellular adhesion molecules in peripheral inflammatory versus neuropathic pain in rodents.
The present study was designed to determine the role of central expression of immunoregulatory molecules in the development and maintenance of allodynia following a peripheral inflammatory insult or nerve transection. Differential spinal expression of major histocompatibility complex (MHC) class II, platelet-endothelial cellular adhesion molecule (PECAM), intercellular adhesion molecule (ICAM) and CD4 was observed in the two injury models. Intraplantar zymosan produced transient allodynia and only PECAM and ICAM immunoreactivity. In contrast, persistent mechanical allodynia and enhanced spinal PECAM, ICAM, MHC class II and CD4 immunoreactivity was observed following peripheral nerve transection. MHC class II knockout mice exhibited attenuated allodynia following spinal nerve transection as compared to wild-type control mice. These findings suggest that central neuroimmune activation may contribute to the maintenance of neuropathic pain following peripheral L5 spinal nerve transection but not following a peripheral inflammatory insult.


[Chronic renal insufficiency and cardiovascular disease].
Renal insufficiency is frequently seen in patients with cardiovascular disease. In contrast, coronary artery disease is the leading cause of death in patients with renal impairment. The recognition of renal insufficiency is essential in these patients and preventive measures must be put in place to prevent the progression or onset of cardiovascular disease. In this article, we explain the methods to assess kidney function, the epidemiology of coronary heart disease in patients with renal impairment, risk factors conventional and non-conventional found in these patients and the main recommendations for their therapeutic care.


Achieving consensus on the language of obesity: a modified Delphi study.
Obesity is recognized by the World Health Organization as a chronic disease. As such, it should be referred to using the language of chronic diseases, with correct and established terminology and definitions. This study was designed to map the current language used to discuss obesity and to compare this with the standard language used for chronic disease. We performed a modified Delphi study to identify the language of chronic disease that is being used in the context of obesity, and to identify discrepancies and potential use of inadequate language with respect to the standard language used for chronic diseases. Participants (n = 24) were identified from relevant stakeholder groups and desk research, and included patients, healthcare professionals, policymakers, researchers, industry, and payers (social insurers) of 18 nationalities/regions in Europe, North/South America, and South Africa. Participants were enrolled between 20.10.2020 and 30.10.2020. The study comprised two rounds of qualitative surveys. In Round 1, participants responded to six open-ended questions. Round 2 comprised 38 statements based on key terms/themes identified in Round 1 and covered the definition, causes, progression, treatment, management, and complications of obesity. Consensus was defined as ≥70% participant agreement on a statement. All participants completed Round 1 and 23 participants completed Round 2. In Round 2, consensus was reached for 28 of the 38 statements. Participants reached a consensus regarding the use of statements that acknowledge the heterogeneous nature of obesity, but not on the use of statements that: defined obesity based on body mass index; regarded psychological, physical, or physiological factors among the main causes of obesity; or implied that weight loss should be the aim of obesity treatment. This study uses expert consensus to provide insight into the language used to describe obesity as a chronic disease, and forms the basis for a unified language of obesity. Innovative Medicines Initiative, Novo Nordisk A/S.


The NMR structure of the inhibited catalytic domain of human stromelysin-1.
The three-dimensional structure of the catalytic domain of stromelysin-1 complexed with an N-carboxyl alkyl inhibitor has been determined by NMR methods. The global fold consists of three helices, a five stranded beta-sheet and a methionine located in a turn near the catalytic histidines, classifying stromelysin-1 as a metzincin. Stromelysin-1 is unique in having two independent zinc binding sites: a catalytic site and a structural site. The inhibitor binds in an extended conformation. The S1' subsite is a deep hydrophobic pocket, whereas S2' appears shallow and S3' open.


The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study.
To study the incidence, clinical features, etiologic distribution, and day of seizure onset by etiology in neonates with seizures. Prospective, population-based study involving all the obstetric and neonatal units across the province of Newfoundland, Canada. All units were given educational sessions on neonatal seizure symptomatology. Detailed questionnaires were prospectively collected for all infants with probable neonatal seizures for a period of 5 years. The incidence rate was 2. 6 per 1000 live births, 2.00 for term neonates, 11.1 for preterm neonates, and 13.5 for infants weighing <2500 g at birth. Seizures lasting 30 minutes or longer were present in 5%, and the neonatal death rate among infants with seizures was 9%. Hypoxic-ischemic encephalopathy was the presumed cause in 40%, infections in 20%, and metabolic abnormalities in 19%. Clinical neonatal seizures occur 6 times more often in preterm infants than in term infants. Hypoxic-ischemic encephalopathy continues to be a major marker of the likelihood of seizures.


A case of caecal "PECOMA": An uncommon entity.
World Health Organization (WHO) defines PEComa as a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The symptoms and clinical signs of PEComa patients are nonspecific. Hence, diagnosis is usually difficult. Since it's a rare diagnosis, further research might help in understanding the disease better. The patient in this study was an asymptomatic patient, who did colonoscopy as part of a regular check-up. A submucosal cecal tumor was detected in colonoscopy, and apart from that, all other investigative parameters were within normal limits. Laparoscopic Ileocecectomy was performed, and the histopathology report was suggestive of Pecomatosis (PEComa - Perivascular epithelioid cell tumor). The PEComas, neoplasms with perivascular epithelioid cell differentiation, are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells (PEC). The characteristic features of PEC are the positivity of melanocytic markers and smooth muscle markers. Perivascular epithelioid tumors are mostly rare in the gastrointestinal tract, and even more unusual to be detected in Cecum. Surgery is the mainstay of the treatment, although, adjuvant therapy has been tried in recent times. The patients have to be kept in close follow-up, as there are reported cases of recurrences and distant metastasis.


Determination of mutation trend in proteins by means of translation probability between RNA codes and mutated amino acids.
In this study, we estimate the translation probability to amino acid from RNA codon. With the determined 183 translation probabilities and amino-acid composition of eight highly mutated proteins, we construct the theoretical distributions of mutated amino acids in these proteins and then compare them with their actual distributions affected by mutations. Thereafter we trace the pattern of translation probabilities from RNA codons to mutated amino acids of 1053 point missense mutations. Finally, we statistically conclude that the natural mutation trend goes along the theoretical translation probability.


Clinical management of dentin hypersensitivity using cathode and anode iontophoresis.
A clinical study was undertaken to study the desensitising effect of Anode and Cathode iontophoresis using solutions and gels. A total number of sixty patients were selected, divided into four groups and subjected to the following methods of treatment. a) Anode Iontophoresis using strontium Chloride Solution (9%) b) Anode Iontophoresis using Strontium Chloride gel (9%) c) Cathode Iontophoresis using Sodium Fluoride solution (2%) d) Cathode Iontophoresis using Sodium Fluoride gel (2%) Distilled water was used as the control Sensitivity was evaluated objectively with the help of specially designed apparatus which delivered measurable electrical stimuli. The results showed a statistically significant difference in the reduction of tooth sensitivity using Strontium Chloride (9%) both as a gel and solution as compared to Sodium Fluoride (2%) gel and solution.


Our experience in emergency treatment of renal haemorrhage.
Renal haemorrhage is a potentially life-threatening event requiring emergency surgery. Endovascular therapy is currently the first-line treatment option. Review patients with renal haemorrhage who required emergency endovascular therapy at our center. Evaluate the causes of the bleeding, the treatment performed and the clinical outcomes. We performed a retrospective analysis of consecutive patients with renal bleeding who underwent endovascular therapy from June 2012 to June 2017 at Hospital Universitari Joan XXIII (Tarragona, Spain). Demographic data (age, gender and comorbidity) and other related variables were collected (mechanism of injury, haemodynamic stability and anticoagulant therapy). We also studied the CT angiography findings, time from diagnosis to surgery, endovascular technique and materials used, extent of tissue embolised and outcomes. Twenty-two (22) patients were included with a mean age of 63 (range 19-85). The aetiology of injuries included: renal biopsy (n=7, 31.8%), bleeding from malignant kidney tumour (n=5, 22.7%), trauma (n=4, 18.2%), angiomyolipoma (n=2, 9.1%), spontaneous bleeding (n=2, 9.1%) and surgical complications (n=2, 9.1%). The endovascular therapy technique was embolisation in all cases. The following materials were used: spheres (9.1%); coils (63.6%); spheres + coils (18.2%); and spheres + plug (9.1%). In 17 cases (77.3%), selective embolisation was performed and in five cases (22.7%), embolisation of the whole kidney. Clinical and technical success rates of 100% were recorded. The 30-day mortality rate was 9.1%. We believe that endovascular therapy is an effective modality for the management of renal bleeding which, in many cases, enables a large part of the renal tissue to be preserved.


Dimorphism in Ceratocystis minor var. barrasii.
Ceratocystis minor var. barrasii, a fungus associated with the southern pine beetle, Dendroctonus frontalis, exhibits dimorphism which is influenced by the concentration of both carbon dioxide and phosphate. The mycelium produces blastospores from the tips and sides of its hyphae when the concentration of carbon dioxide is high, and these blastospores germinate if the concentration of phosphate is above about 10(-2) mM, whereas below this concentration they bud.


Frutalin, a galactose-binding lectin, induces chemotaxis and rearrangement of actin cytoskeleton in human neutrophils: involvement of tyrosine kinase and phosphoinositide 3-kinase.
Several lectin-like molecules have been shown as potent activators of leukocytes. Galactose-binding lectins are of special interest since they could interact with several endogenous molecules involved in the innate and specific immune responses. The effects of Frutalin (FTL), an alpha-D-galactose (Gal)-binding plant lectin, on the modulation of neutrophil (PMN) functions were investigated. FTL induced a dose-dependent PMN migration in mice pleural cavity. Moreover, FTL was also a potent direct chemotactic for human PMN, in vitro, and triggered oxidative burst in these cells. These effects were accompanied by a rearrangement of the actin cytoskeleton dynamic, activation of tyrosine kinase (TK) pathways, increase in focal adhesion kinase (FAK) phosphorylation, and its subsequent association to phosphoinositide3-kinase (PI3K). All those effects were inhibited in the presence of Gal, suggesting specific carbohydrate recognition for FTL effects. The activations of TK and PI3K pathways are essential events for FTL-induced chemotaxis, since inhibitors of these pathways, genistein and LY294002, inhibited neutrophil migration in vitro. The data indicate that sugar-protein interactions between a soluble lectin and galacto-components on neutrophil surface trigger the TK pathway, inducing FAK and PI3K activation, interfering with cell motility and oxidative response.


Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum.
We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.


Obsessive fears about harm to self or others and overt aggressive behaviors in youth diagnosed with juvenile-onset bipolar disorder.
Obsessive fear-of-harm, either fear of doing harm or fear of harm coming to self, may be closely associated with aggressive behaviors in juvenile-onset bipolar disorder. We analyzed parent-report data on the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Overt Aggression Scale (OAS) for 1601 children/adolescents with a clinician-assigned diagnosis of bipolar disorder. The summing of 6 YBOCS items rated "often" or "very often or almost constant" yielded a biphasic distribution of scores. Median-split was used to define meaningful subgroups contrasting high vs. low "fear-of-harm", which were then compared on parent-reported severe injury to self and others and on parent-reported suicide threats. High fear-of-harm was strongly associated with parent-reported severe injury to self and others. For self-injury, the estimated risk ratio for high vs. low fear-of-harm subgroups was 2.68 (95% confidence interval 1.87-3.86), indicating greater than doubling of risk associated with high fear-of-harm. For severe injury to others, the estimated risk ratio was 7.97 (95% confidence interval 4.19-15.2), suggesting a nearly eight-fold increased risk associated with high fear-of-harm. High fear-of-harm subjects were reported to make serious suicide threats much more frequently than low fear-of-harm subjects (odds ratio, estimated by ordinal logistic regression modeling methods, was 2.42 (95% CI 2.00 to 2.92; z=9.12, p<0.001). Child report data was not obtained; clinician diagnosis was not validated via research interview. Obsessive fears about harm to self or others in a sample of children with a clinician-assigned diagnosis of bipolar disorder were found to be positively related to increased behavioral aggression towards self and others, as well as to frequent suicide threats.


Attributed strings for recognition of epileptic transients in EEG.
This paper presents a structural pattern recognition system for signals interpreted and described by a human expert. For each pattern to be recognized, the signal is represented by a sequence of local information ('types of primitives') which is syntactically correct if some 'structural attributes' are satisfied. Types of primitives and structural attributes are defined. This representation method takes a priori knowledge of the expert's descriptions into account. Our system is concerned with EEG's analysis. Detection of transient events, spikes and spike-and-wave complexes helps the electroencephalographist by rejecting parts of the EEG trace which certainly do not contain these patterns. The transient events detection keeps a 16% average of the initial trace for pathological EEG's and 8.3% for non-pathological EEG's. Only 3.3% of pathological EEG's are not rejected after spikes and spike-and-wave complexes detection. The results of this parse are compared with human interpretations.


Regulatory mechanisms of Gentiopicroside on human diseases: a brief review.
Gentiopicroside (GPS), a single compound isolated from Gentiana lutea L. and the crucial representative of secoiridoid constituent, has been permitted for centuries in traditional Chinese medicine. GPS and its metabolites have been increasingly used in the search for clinical management with therapeutic properties and fewer side effects. The objective of this review was to provide a comprehensive overview of the involvement of molecular pathways in the therapeutic effects of GPS on human diseases and chronic conditions. This study presents a meticulously conducted comprehensive search of the PubMed and Google Scholar databases (from 1983 to 2023), aimed at identifying articles relating to regulatory mechanisms of GPS on human diseases and the pharmacokinetics of GPS. The inclusion criteria were meticulously and precisely defined to encompass original research papers that explicitly focused on elucidating the regulatory mechanisms of GPS in various human diseases through in vitro and animal studies. Notably, these studies were mandated to integrate specific genetic markers or pathways as essential components of their research inquiries. The evaluated pharmacokinetic parameters included maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the curve (AUC), clearance, and plasma half-life (t1/2). Subsequently, through a rigorous screening process of titles and abstracts, studies conducted in vitro or on animals, as well as those reporting pharmacokinetic data related to drugs other than GPS or language barriers, were systematically excluded. Drawing from the data and studies pertaining to this review, we conducted a thorough and informative analysis of the pharmacological characteristics and biological functions of GPS. These encompassed a wide range of effects, including hepatoprotective, anti-inflammatory, antifibrotic, antioxidant, analgesic, antitumor, and immunomodulatory properties. The analysis provided a comprehensive and insightful understanding of GPS's pharmacological profile and its diverse activities. Enhancing theoretical and experimental methodologies could prove advantageous in expanding the clinical applications of GPS. This could involve optimizing the bioavailability and pharmacokinetics of GPS, uncovering additional biomarkers and potential biotransformation pathways, and investigating its combined effects with standard-of-care medications.


Improving the Overall Properties of Circularly Polarized Luminescent Materials Through Arene-Perfluoroarene Interactions.
A major trade-off in the field of circularly polarized luminescence (CPL) of pure organic materials is that the large luminescence dissymmetry factor (glum ) usually gives rise to the suppression of luminescence efficiency (ΦPL ). Here, a supramolecular self-assembled system, driven by arene-perfluoroarene (AP) interactions of chiral polycyclic aromatic hydrocarbons (PAHs) and octafluoronaphthalene (OFN), is reported to provide a solution to this problem. Two kinds of chiral PAHs based on pyrene and anthracene could co-assemble with OFN in hybrid solvents to form long-range-ordered AP assemblies. The detailed process of AP interaction driving self-assembly was verified by morphological measurements and fluorescence spectra. The AP assemblies exhibited chirality amplification not only in the excited state but also in the ground state. In addition, the AP assemblies showed an enhanced luminescence efficiency compared with the individual chiral PAHs due to the energy-barrier effect of OFN. The present strategy based on AP interactions could be applied to boost the development of highly efficient CPL-active materials.