Infusion of Valproic Acid Into the Renal Medulla Activates Stem Cell Population and Attenuates Salt-Sensitive Hypertension in Dahl S Rats.
Our previous study has detected a stem cell deficiency in the renal medulla in Dahl salt-sensitive (S) rats. This study determined whether infusion of valproic acid (VA), an agent known to stimulate the stem cell function, attenuated salt-sensitive hypertension in Dahl S rats. Uninephrectomized Dahl S rats were infused with vehicle or VA (50mg/kg/d) into the renal medulla and fed with a low (LS) or high salt diet (HS). Stem cell marker and number were analyzed by immunohistochemistry, Real-time RT-PCR and Western blot. Sodium excretion and blood pressure were measured. VA significantly increased the mRNA and protein levels of FGF2, a stem cell niche factor, and CD133, a stem cell marker. The number of CD133+ cells was significantly increased in the renal medulla in VA-treated rats. Meanwhile, high salt-induced increases in the mRNA level of proinflammatory factors interleukin-1β and interleukin-6 were blocked in VA-treated rats. Functionally, sodium excretion in response to the blood pressure increase and acute sodium loading was significantly enhanced, sodium retention attenuated, high salt-induced increase of blood pressure reduced in VA-treated rats. Activation of stem cell function by VA inhibits the activation of proinflammatory factors and attenuates salt-sensitive hypertension in Dahl S rats.


[On the formulation of TCM foreign exchange policy after the reform and opening-up].
The foreign exchange activities of traditional Chinese medicine are conducted under the guidance of the policy of the CPC and Chinese government. After the carrying out of the reform and opening-up policy, foreign exchange policy of TCM has experienced the process of growing up from nothing, from less to more, and from coarse to fine, which is closely related to our country's foreign policy, the cause of Chinese medicine development, and urgent need of international communication. In the three decades after the reform and opening-up policy, the formulation of foreign exchange policy of TCM can be divided into three stages: viz., inclusion in the framework of national foreign policy (1978-1985), embodiment in the policy of developing TCM cause (1986-1996), and appearance in the special policy of foreign exchange of Chinese medicine (since 1997). From the development process of these policies, the development of each policy gradually complies with the process of the development of the times, with its contents basically in line with the requirements of the times. The implementation of some policies promotes the foreign exchanges and cooperation of Chinese medicine.


DNA structure equilibria in the human c-myc gene.
We have employed analytical S1 nuclease analysis to identify sites with altered DNA secondary structure in the human c-myc gene. We have mapped several sites of that kind in vitro at one-base resolution but have focused our attention on one particularly stable conformational isomer which occurs approximately 270 base pairs upstream from the preferred transcription origin. We have analyzed the kinetics of that conformational equilibrium as a function of supercoil density and enzyme concentration and find that DNA structure in this region is adequately modeled as a two-state equilibrium between an undistorted (S1 nuclease insensitive) and a distorted (S1-sensitive) state. We find that at fixed supercoil density, S1 nuclease cleavage at this DNA segment can be altered in vitro by a DNA sequence change as far away as 1500 bases. We also find that the S1 nuclease cleavage at this site can be dramatically enhanced by the binding of small RNA molecules. On the basis of an analysis of S1 cutting kinetics and an analysis of DNA sequence at the S1 cleavage site, we conclude that RNA may bind directly to DNA, thereby shifting the underlying conformational equilibrium. Together, these data suggest that as a class, short RNA molecules could serve as site-specific regulatory elements in the myc gene and elsewhere.


Multifractal analysis of light scattering-intensity fluctuations.
We provide a simple interpretation of non-Gaussian nature of the light scattering-intensity fluctuations from an aging colloidal suspension of Laponite using the multiplicative cascade model, Markovian method, and volatility correlations. The cascade model and Markovian method enable us to reproduce most of recent empirical findings: long-range volatility correlations and non-Gaussian statistics of intensity fluctuations. We provide evidence that the intensity increments Deltax(tau)=I(t+tau)-I(t), upon different delay time scales tau, can be described as a Markovian process evolving in tau. Thus, the tau dependence of the probability density function p(Deltax,tau) on the delay time scale tau can be described by a Fokker-Planck equation. We also demonstrate how drift and diffusion coefficients in the Fokker-Planck equation can be estimated directly from the data.


Interaction between aluminum and calcium ions in potassium chloride depolarized gastrointestinal smooth muscle.
Aluminum chloride (5 times 10-minus 4 M) abolished the inhibitory effects of papaverine chloride (1.5 times 10- minus 5 M) on contractions of guinea-pig ileum and rat colon evoked by calcium in Tyrode's solution containing high KC1. The inhibitory effects of cocaine hydrochloride (10- minus 3 M) and MgSO4 (2 times 10- minus 2 M) were not antagonized. In isolated rat colon depolarized by partial exchange of NaCl by 40 mM KC1, AlC13 decreased the phasic contractions, slowed the onset of tonic contraction while increasing maximal tone and induced superimposed spontaneous activity during the tonic phase. Similar changes were evoked by increasing the CaCl2 concentration from 1.8 times 10- minus 3 M to 7.2 times 10- minus 3 M. The increase in spontaneous activity was not blocked by atropine sulfate (10- minus 7 minus 10- minus 4 M) but was partially antagonized by 10- minus 3 M caffeine and completely blocked by papaverine chloride (5 times 10- minus 4 M). More than one aluminum site of action is proposed for effects of aluminum on the gastro-intestinal smooth muscle.


Fast Pixelwise Adaptive Visual Tracking of Non-Rigid Objects.
In this paper, we present a new algorithm for real-time single-object tracking in videos in unconstrained environments. The algorithm comprises two different components that are trained "in one shot" at the first video frame: a detector that makes use of the generalized Hough transform with color and gradient descriptors and a probabilistic segmentation method based on global models for foreground and background color distributions. Both components work at pixel level and are used for tracking in a combined way adapting each other in a co-training manner. Moreover, we propose an adaptive shape model as well as a new probabilistic method for updating the scale of the tracker. Through effective model adaptation and segmentation, the algorithm is able to track objects that undergo rigid and non-rigid deformations and considerable shape and appearance variations. The proposed tracking method has been thoroughly evaluated on challenging benchmarks, and outperforms the state-of-the-art tracking methods designed for the same task. Finally, a very efficient implementation of the proposed models allows for extremely fast tracking.


Informed consent in functional endoscopic sinus surgery: the patient's perspective.
Informed consent is essential prior to functional endoscopic sinus surgery (FESS). The content of this discussion is often determined by each surgeon. Many doctors discuss all potential complications. This may provoke anxiety or deter from beneficial surgery. Our goal was to examine the process from the patient's perspective. Study design A list of potential complications was reviewed with FESS patients. Patients were asked questions concerning their consent and the potential complications before and after FESS. Both before and after surgery, patients felt that discussion of most potential complications was important. Vision changes and cerebrospinal fluid leak (CSF) received the highest scores. No significant differences were found between primary and revision cases. Patients wanted most potential FESS complications to be discussed. Even though this triggered anxiety, they felt it was important to have a thorough disclosure. Findings presented may impact how surgeons counsel patients prior to FESS.


Why is glycine not a part of the osmoticum in the urea-rich cells?
Kidney cells of animals including human and marine invertebrates contain high amount of the protein denaturant, urea. Methylamine osmolytes are generally believed to offset the harmful effects of urea on proteins in vitro and in vivo. In this study we have investigated the possibility of glycine to counteract the effects of urea on three proteins by measuring thermodynamic stability, ΔGD° and functional activity parameters (K(m) and k(cat)). We discovered that glycine does not counteract the effects of urea in terms of both protein stability and functional activity. We also observed that the glycine alone is compatible with enzymes function and increases protein stability in terms of T(m) (midpoint of thermal denaturation) to a great extent. Our study indicates that a most probable reason for the absence of a stabilizing osmolyte, glycine in the urea-rich cells is due to the fact that this osmolyte is non-protective to macromolecules against the hostile effects of urea, and hence is not chosen by evolutionary selection pressure.


Ultrasonographic and computed tomographic examinations of the avian eye: physiologic appearance, pathologic findings, and comparative biometric measurement.
Ultrasonography (US) and computed tomography (CT) were performed after routine ophthalmologic and ophthalmoscopic examinations in 190 eyes of six various diurnal (common buzzard [Buteo buteo L., 1758], n = 20; common kestrel [Tinnunculus tinnunculus L., 1758], n = 20) and nocturnal raptor species (barn owl [Tyto alba L., 1758], n = 22; tawny owl [Strix aluco L., 1758], n = 8; long-eared owl [Asio otus L., 1758], n = 5; horned owl [Bubo bubo L., 1758], n = 1); and domestic pigeons (Columba livia, Gmel., 1789; n = 19), with a total of 95 individuals. Pathologic findings such as lens subluxation and luxation, intravitreal hemorrhage, detached retina, post-traumatic partial sequestration, or malformation of the pecten could be demonstrated with diagnostic imaging tools, while opacities of cornea or lens constrained direct ophthalmoscopic examination. The results proved US to be a quick noninvasive imaging technique for detailed ocular diagnoses. CT provided detailed information of the bony skull and bony scleral rings as well as adequate visualization of shape, size, and margination of the eye and lens. Nevertheless, CT was unable to differentiate subtle structures within the vitreous like the pecten oculi or hemorrhage. Biometric measurements were carried out to objectify imaging results. Results showed good correlation of depth and width of the anterior eye chamber, lens and vitreous, length of the bulbus, and the pecten but no correlation of cornea and posterior wall thickness was found.


Outpatient health care utilization in a sample of cognitively impaired veterans receiving care in VHA geriatric evaluation and management clinics.
Within the Veterans Health Administration (VHA), Geriatric Evaluation And Management (GEM) clinics are designed specifically to address the needs of older veterans with complex age-related concerns, including dementia and comorbid medical and mental health conditions. Previous literature describes aging veterans as having greater health care needs compared with age-matched nonveteran samples, and multimorbidity is of particular concern in this population. Using data extracted from electronic medical records (EMRs), the present study describes the demographic characteristics, mental health diagnoses, and health care utilization of a sample of 476 VHA GEM patients with diagnosed cognitive impairment or dementia seen in clinics across Upstate New York. Examination of EMR data demonstrated that in addition to diagnosed cognitive impairment and dementia, over 66% of the sample had at least 1 additional mental health diagnosis coded during the study period. Many were prescribed dementia medications and/or other psychotropic medications, predominantly antidepressants. These veterans utilized a variety of outpatient services, including high rates of mental health consultation subsequent to GEM evaluation, though low rates of mental health follow-up were observed. Results from the current study provide insight into the important role mental health providers such as psychologists and psychiatrists can play as collaborators in interdisciplinary geriatrics care for veterans.


Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK.
Oxidative stress exhibits a central role in the course of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease commonly found to include a copper/zinc superoxide dismutase (SOD1) gene mutation. Fisetin, a natural antioxidant, has shown benefits in varied neurodegenerative diseases. The possible effect of fisetin in ALS has not been clarified as of yet. We investigated whether fisetin affected mutant hSOD1 ALS models. Three different hSOD1-related mutant models were used: Drosophila expressing mutant hSOD1G85R, hSOD1G93A NSC34 cells, and transgenic mice. Fisetin treatment provided neuroprotection as demonstrated by an improved survival rate, attenuated motor impairment, reduced ROS damage and regulated redox homeostasis compared with those in controls. Furthermore, fisetin increased the expression of phosphorylated ERK and upregulated antioxidant factors, which were reversed by MEK/ERK inhibition. Finally, fisetin reduced the levels of both mutant and wild-type hSOD1 in vivo and in vitro, as well as the levels of detergent-insoluble hSOD1 proteins. The results indicate that fisetin protects cells from ROS damage and improves the pathological behaviors caused by oxidative stress in disease models related to SOD1 gene mutations probably by activating ERK, thereby providing a potential treatment for ALS.


Establishment of a maedi-visna-free flock after the purchase of infected sheep.
Maedi-visna (MV) infection was detected in a cohort of 68 purchased ewes, one of several groups of sheep introduced to a farm after the previous stock had been culled with suspected foot-and-mouth disease in 2001. Except for short periods totalling six to seven weeks when the sheep co-grazed with 13 ewe lambs and ram lambs, the infected cohort was kept separate from other sheep on the farm over a total of 21 months. During this period two crops of lambs were reared from the infected ewes. All the lambs were fattened and killed, and all ewes were culled after the second crop of lambs had been weaned. Subsequent serological testing of the remaining sheep on the farm confirmed the elimination of MV infection from the flock, leading to its acceptance in the Maedi Visna Accreditation Scheme of the Scottish Agricultural College's Sheep and Goat Health Schemes.


Probing the axis alignment of an ultracold spin-polarized Rb(2) molecule.
We present a novel method for probing the alignment of the molecular axis of an ultracold, nonpolar dimer. These results are obtained using diatomic ^{87}Rb_{2} molecules in the vibrational ground state of the lowest triplet potential a^{3}Σ_{u}^{+} trapped in a 3D optical lattice. We measure the molecular polarizabilities, which are directly linked to the alignment, along each of the x, y, and z directions of the lab coordinate system. By preparing the molecules in various, precisely defined rotational quantum states we can control the degree of alignment of the molecular axis with high precision over a large range. Furthermore, we derive the dynamical polarizabilities for a laser wavelength of 1064.5 nm parallel and orthogonal to the molecular axis of the dimer, α_{∥}=(8.9±0.9)×10^{3} a.u. and α_{⊥}=(0.9±0.4)×10^{3} a.u., respectively. Our findings highlight that the depth of an optical lattice strongly depends on the rotational state of the molecule, which has to be considered in collision experiments. The present work paves the way for reaction studies between aligned molecules in the ultracold temperature regime.


Rare species of wood-inhabiting fungi are not local.
Wood-inhabiting fungal communities are a diverse and ecologically critical part of forest ecosystems, yet the spatial structure of fungal biodiversity in these ecosystems is largely unknown. Legislation allowed harvesting of deadwood from temperate rainforests on conservation lands in New Zealand following Cyclone Ita in 2014. Harvesting guidelines specified widely spread harvesting, on the assumption that rare fungal species may be highly spatially restricted, but were not based on quantitative assessment. We sampled fungi in and on logs of Dacrydium cupressinum (Podocarpaceae) a long-lived, common, canopy tree in lowland New Zealand forests. DNA was extracted from 81 logs varying in decay state across a 40 km long region of West Coast (South Island) forests, and sequenced using general fungal primers for metabarcoding to identify OTUs (operational taxonomic units). We examined three axes of rarity: occupancy, dominance when present, and niche breadth (as spatial extent and decay state specialization). Low-occupancy fungi were common, including a group of infrequently occurring but dominant when present fungi, the majority of which were Ascomycota. Despite this, there was an overall positive relationship between occupancy and dominance. Widespread, dominant fungi were most commonly Basidiomycota. Testing all fungal OTUs, there were no more fungi with maximum range sizes < 4 km than would be expected at random. Of the 351 low-occupancy OTUs found two to four times, only 12 had maximum range sizes < 900 m, and there was no more spatial restriction at scales < 900 m than would be expected by random chance, although there was some evidence of niche breadth restriction based on decay state similarity. The results show that fungal communities in deadwood are highly diverse, and include many rare taxa. Nonetheless, the lack of fungal OTUs with spatial restriction at scales < 900 m suggests that spatially dispersed timber harvesting will not mitigate risks of harvesting to rare fungal biodiversity.


Genome-Wide Identification and Functional Analysis of the TIFY Family Genes in Response to Abiotic Stresses and Hormone Treatments in Tartary Buckwheat (Fagopyrum tataricum).
TIFY is a plant-specific gene family with four subfamilies: ZML, TIFY, PPD, and JAZ. Recently, this family was found to have regulatory functions in hormone stimulation, environmental response, and development. However, little is known about the roles of the TIFY family in Tartary buckwheat (Fagopyrum tataricum), a significant crop for both food and medicine. In this study, 18 TIFY family genes (FtTIFYs) in Tartary buckwheat were identified. The characteristics, motif compositions, and evolutionary relationships of the TIFY proteins, as well as the gene structures, cis-acting elements, and synteny of the TIFY genes, are discussed in detail. Moreover, we found that most FtTIFYs responded to various abiotic stresses (cold, heat, salt, or drought) and hormone treatments (ABA, MeJA, or SA). Through yeast two-hybrid assays, we revealed that two FtTIFYs, FtTIFY1 and FtJAZ7, interacted with FtABI5, a homolog protein of AtABI5 involved in ABA-mediated germination and stress responses, implying crosstalk between ABA and JA signaling in Tartary buckwheat. Furthermore, the overexpression of FtJAZ10 and FtJAZ12 enhanced the heat stress tolerance of tobacco. Consequently, our study suggests that the FtTIFY family plays important roles in responses to abiotic stress and provides two candidate genes (FtJAZ10 and FtJAZ12) for the cultivation of stress-resistant crops.


UK O&G trainees' attitudes to caesarean delivery for maternal request.
We assessed the attitudes of UK Obstetrics and Gynaecology (O&G) trainees towards a caesarean delivery for maternal request (CDMR); and identified differences in attitude towards patients requesting CDMR and preferences for their own mode of delivery. An internet survey was constructed with questions covering trainees' personal preferences towards and experience of CDMR; attitudes to CDMR; and how they might treat patients making this request. From 02/2013 to 06/2013, the survey was sent electronically via email to all UK Deaneries to be forwarded to O&G trainees. Two hundred and forty O&G trainees participated; 78% female. 6/101 (6%) respondents had opted for CDMR in their first pregnancy. 28/131 (21%) would choose CDMR in their first pregnancy. Reasons for CDMR included concerns about pelvic floor/perineum, safety of the baby and convenience. 105/226 (46.4%) disagreed or strongly disagreed, and 67 (29.6%) agreed or strongly agreed with CDMR. 75/128 (58.6%) of respondents would grant CDMR to a patient; reasons included maternal choice, psychological concerns of the mother, perineal injury, pelvic floor. Our results are encouraging: positive attitudes of trainees towards vaginal delivery may help to reduce the rising caesarean rate. Impact Statement What is already known on this subject: Over the last 30 years, the rate of caesarean section in the UK has trebled and currently accounts for 25% of all deliveries. The rate of caesarean section in the UK has risen to 25% of all deliveries, incurring a financial burden and an excess clinical risk. With pressure to keep the caesarean rates low, understanding the attitudes and experience of obstetricians in training is important. What the results of this study add: Six percent of obstetric trainees, or their partners who had children had chosen a caesarean delivery for maternal request (CDMR), consistent with the population average. Twenty one percent of those who had not had children would choose CDMR. Both groups cited concerns over the pelvic floor as the predominant reason. Fifty nine percent of respondents would grant patients' request for CDMR. 29.6% of respondents agreed, and 46.4% disagreed with CDMR. Trainees' attitude to CDMR does not appear to be associated with whether or not they have had children, but does appear to be associated with whether they had experienced, or were planning to choose CDMR themselves in the future. What the implications are of these findings for clinical practice and/or further research: Training for obstetric trainees regarding the optimum way to manage patients' requests for, and clearer guidance on CDMR may be of benefit. It is important that obstetricians discuss the reasons behind such requests in order to individualise management.


Type VI collagen bound to collagen fibrils by chondroitin/dermatan sulfate glycosaminoglycan in mouse corneal stroma.
We investigated the ultrastructural localization of type VI collagen in mouse corneal stroma and its relationship to striated collagen fibrils and glycosaminoglycans, using chondroitinase ABC digestion and immunoelectron microscopy with colloidal gold particles. After chondroitinase ABC digestion, the arrangement of striated collagen fibrils was disrupted, and large spaces containing widely scattered fibrils appeared. The spaces were filled by filamentous networks that were stained by anti-type VI collagen IgG, which were apparently clumps of beaded filament. Interfibrillar type VI collagen beaded filaments and immunogold particles decreased. Our results indicate that type VI collagen is bound to the striated collagen fibrils by mediation of chrondroitin/dermatan sulfate glycosaminoglycan or proteoglycan. We believe that this interaction is essential to the orderly arrangement of the striated collagen fibrils, which results in corneal transparency.


Phycocyanin enhances secretary IgA antibody response and suppresses allergic IgE antibody response in mice immunized with antigen-entrapped biodegradable microparticles.
In the present study, we have investigated the effects of phycocyanin, a biliprotein of Spirulina platensis, on mucosal and systemic immune responses and allergic inflammation in C3H/HeN and BALB/cA mice. To induce the antigen-specific antibodies in the peripheral lymphoid tissues such as Peyer's patches and mesenteric lymph nodes, biodegradable ovalbumin-entrapped poly (DL-lactide-co-glycolide) particles were used as an antigen. Two weeks after the onset of phycocyanin ingestion, mice were immunized with an aqueous ovalbumin (OVA) solution. Starting at one week after the primary immunization, the mice were subjected to oral immunization with the biodegradable OVA microparticles twice a week. IgA, IgE and IgG1 antibodies were determined by ELISA. The OVA microparticles of 4-microm diameter successfully induced antigen-specific antibodies. In the mice that received phycocyanin treatment for 6 wk, a marked increase in the antigen-specific, as well as the total, IgA antibody level was observed in the Peyer's patches, mesenteric lymph nodes and intestinal mucosa as well as in the spleen cells. Both antigen-specific IgG1 and IgE antibody levels in the serum were suppressed by ingestion of phycocyanin for 8 wk. However, inflammation of the small intestine, monitored as vascular permeability by the Evans blue-leaking method was reduced by phycocyanin at 6 wk, which preceded the suppression of antigen-specific IgG1 and IgE antibody production by 2 wk. These results suggest that phycocyanin enhances biological defense activity against infectious diseases through sustaining functions of the mucosal immune system and reduces allergic inflammation by the suppression of antigen-specific IgE antibody.


Inner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing.
Faithful chromosome segregation during mitosis requires that the kinetochores of all sister chromatids become stably connected to microtubules derived from opposite spindle poles. How stable chromosome bi-orientation is accomplished and coordinated with anaphase onset remains incompletely understood. Here we show that stable chromosome bi-orientation requires inner centromere localization of the non-enzymatic subunits of the chromosomal passenger complex (CPC) to maintain centromeric cohesion. Precise inner centromere localization of the CPC appears less relevant for Aurora B-dependent resolution of erroneous kinetochore-microtubule (KT-MT) attachments and for the stabilization of bi-oriented KT-MT attachments once sister chromatid cohesion is preserved via knock-down of WAPL. However, Aurora B inner centromere localization is essential for mitotic checkpoint silencing to allow spatial separation from its kinetochore substrate KNL1. Our data infer that the CPC is localized at the inner centromere to sustain centromere cohesion on bi-oriented chromosomes and to coordinate mitotic checkpoint silencing with chromosome bi-orientation.


Association of plasma MiR-17-92 with dyslipidemia in patients with coronary artery disease.
Circulating microRNAs (miRNAs) have already been proposed as sensitive and informative biomarkers for the diagnosis of multiple diseases. We investigated the miRNA expression patterns in plasma samples of patients with coronary artery disease (CAD) and explored the potential functions of certain miRNAs.Deep sequencing analysis was performed to determine the miRNA expression profiles using RNA samples isolated from 20 healthy subjects and 20 patients with CAD. Quantitative reverse transcription polymerase chain reaction was applied to confirm the differential expression of the miR-17-92 cluster in 81 patients and 50 healthy volunteers. The association between the miR-17-92 cluster and clinical characteristics of patients with CAD were analyzed using SPSS16.0, SPSS Inc, Chicago, IL.Hundreds of miRNAs were detected and most members from the miR-17-92 cluster and its paralogs, including miR-18a, miR-92a, miR-106b, and miR-17, exhibited differential expression in the plasma of patients with CAD compared with controls. Moreover, these miRNAs were found widely related to the blood lipids in the patients with CAD, as miR-17 was positively correlated with total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B, while miR-92a was found positively related to high-density lipoprotein cholesterol (HDL-C) but negatively related to lipoprotein-a. Additionally, miR-106b was positively related to HDL-C and apolipoprotein A-I.Taken together with existing evidence from mechanistic studies, the current results of our study support a relationship between the miR-17-92 family and lipid metabolism, which merits further study.


Systematic review and meta-analysis of experimental studies: In-hospital mobilization for patients admitted for medical treatment.
To determine the impact of strategies to promote mobilization on physical function in hospitalized adults with medical conditions. Slow progress is noted on the promotion of mobilization during hospitalization for adult patients admitted for medical conditions. This may reflect the limited evidence on the evaluation of the impact of progressive mobilization activities on clinical endpoints in adult patients throughout hospitalization. A systematic review and meta-analysis of published randomized controlled trials in any language. The literature search was performed in the MEDLINE, CINAHL online, HealthStar, EMBASE, the Cochrane Library Controlled Trials Registry and LILACS databases (January 2000-February 2017). Two authors independently identified randomized trials meeting inclusion criteria, assessed their quality and extracted relevant data. Outcomes assessed were the changes in physical function evaluated by scales measuring either the aerobic (metres walked/second) or the balance domain (using the Time Up and Go test, in seconds), length of hospital stay (days), and adverse clinical events. We calculated pooled mean differences or Mantel-Haenszel odds ratios and 95% confidence intervals for continuous or dichotomous outcome data and obtained heterogeneity statistics across studies. Thirteen studies, including in total 2,703 participants, met our eligibility criteria. Patients in the intervention group showed significant improvement in physical function (aerobic domain), reduced length of stay, and a reduction of pulmonary embolism. Patients and health providers should consider a course of therapy that enhances the functional capacity of medical patients during hospitalization.


Corticospinal control of antagonistic muscles in the cat.
We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABA(A) receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors.


[Structure and function of nociceptive neuronal receptors].
It has been well known that pain is caused by nociceptive stimulation such as protons (i.e. acidic solutions), heat and capsaicin, a pungent ingredient of chilli peppers. For a long period, the signal transduction mechanism of pain activated by these nociceptive stimuli has not been clarified. Recent advance, especially the identification of TRPV1 receptor (for which capsaicin, protons and heat are ligands), P2X and P2Y receptor (for which ATP is a ligand) and acid sensing ion channel made a remarkable progress in understanding the mechanism of nociceptive neurons. This article reviews the structures and functions of nociceptive neuronal system particularly in TRPV1 receptor, P2X and P2Y receptors.


Health and Well-Being in the Year before Death: The Association with Quality of Life and Care at the End-of-Life.
Objective: We examined whether older adults' health and well-being during their final year of life predicts end-of-life (EOL) quality of life (QOL) and quality of care (QOC). Methods: Using data from deceased participants (n = 1125) in the 2011-2015 National Health and Aging Trends Study, we performed latent class analysis to identify profiles of health and well-being, and we examined the association between these classes and EOL QOL and QOC. Results: Four classes were identified: healthy/happy (20%), frail/happy (37%), cognitively impaired/moderately distressed (27%), and highly impaired/highly distressed (16%). Persons in the highly impaired/highly distressed class showed a poorer QOL at the EOL, whereas those in the healthy/happy class reported a lower level of QOC at the EOL. Discussion: The benefits of maintaining health and well-being often carry forward to EOL. Older adults with high impairment and distress merit greater attention such as assuring care and advance care plans.


Intravitreal ranibizumab (Lucentis) for the treatment of myopic choroidal neovascularization.
Macular choroidal neovascularization (CNV) is one of the most vision-threatening complications of myopia, which can lead to severe vision loss. The purpose of this study was to evaluate the safety and efficacy of intravitreal ranibizumab in the treatment of myopic CNV. We conducted a prospective, consecutive, interventional study of patients with subfoveal or juxtafoveal CNV secondary to pathologic myopia (PM) treated with intravitreal injection of ranibizumab in the Jules Gonin University Eye Hospital from June 2006 to February 2008. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) were performed at baseline and monthly for all patients. Indications for retreatment were loss in BCVA associated either with persistent leakage from CNV shown on FA, and/or evidence of CNV activity on OCT. The study included 14 eyes of 14 patients. The mean spherical equivalent refractive error was -12.5 (range, -8.0 D to -16.0 D). Mean time of follow-up was 8.4 months (range from 3 to 16 months, SD: 3). The mean number of intravitreal injections administered for each patient was 2.36 (SD 1.5). The mean initial visual acuity (VA) was 0.19 decimal equivalent (log-MAR: 0.71, SD: 0.3). A statistically significant improvement to a mean VA of 0.48 decimal equivalent (log-MAR:0.32, SD: 0.25) was demonstrated at the final follow-up. VA improved by a mean of 3.86 (SD 2.74) lines. Nine patients (64%) demonstrated a gain of 3 or more lines. Mean central macular thickness (CMT) measured with OCT was 304 microm (SD: 39) at the baseline, and was reduced significantly at the final follow-up to 153 microm (SD: 23). Average CMT reduction was 170 microm (SD: 57). No injection complications or drug-related side effects were noted during the follow-up period. In this small series of eyes with limited follow-up, intravitreal ranibizumab was a safe and effective treatment for CNV secondary to PM, resulting in functional and anatomic improvements.


Endotoxin-induced inflammation and injury of the guinea pig respiratory airways cause bronchial hyporeactivity.
It was investigated whether an endotoxin-induced airway inflammation and injury correlated with the induction of bronchial hyperreactivity. Guinea pigs were treated with an endotoxin aerosol, and 4 and 24 h later lung lavages were performed and a differential cell count was made. The number of neutrophils and monocytes was significantly increased (p less than 0.005) at these times. After 24 h, the number of eosinophils and lymphocytes was also increased (p less than 0.005). The number of alveolar macrophages remained unchanged. Histologic examination revealed increased intraluminal mucus and an influx of erythrocytes and neutrophils in the tracheal and bronchial lumen at both time points after the endotoxin aerosol. The epithelium was morphologically changed and contained many neutrophils. Focal matting and/or loss of cilia also occurred. Airway smooth muscle responsiveness was measured in vitro on isolated guinea pig tracheal smooth muscle preparations 4 and 24 h after endotoxin aerosol. No differences in the maximal responses or slope factors of the dose-response curves for carbachol, histamine, or isoprenaline were detected between the control and endotoxin-exposed groups. The EC50 value of the histamine dose-response curve 4 h after endotoxin nebulization was slightly but significantly (p less than 0.05) increased, indicating decreased sensitivity. Responsiveness in vivo was measured in anesthetized spontaneously breathing guinea pigs 24 h after the endotoxin aerosol. The histamine-induced increase in pulmonary resistance was reduced by about 35% in the endotoxin-nebulized group (p less than 0.01). It can be concluded that an influx of inflammatory cells accompanied by injury of the airways induces hyporeactivity of the guinea pig respiratory tract.


Restacorin, a new antiarrhythmic drug: a review of its electrophysiologic and hemodynamic properties.
Restacorin is a recently developed effective antiarrhythmic agent with primarily class Ic properties. The present paper reviews the electrophysiologic and hemodynamic effects of this compound. The major electrophysiologic effects are a depression of Vmax and an increase in AH, HV and QRS duration. The administration of restacorin does not induce significant side effects. In subjects with a normal left ventricular function, restacorin does not show negative inotropic effects. However, in patients with a decreased left ventricular function, restocorin produces a moderate negative inotropic effect.


Participation of the AngII/TRPC6/NFAT axis in the pathogenesis of podocyte injury in rats with type 2 diabetes.
The canonical transient receptor potential channel 6 ion channel is expressed in podocytes and is an important component of the glomerular slit diaphragm. Focal segmental glomerulosclerosis is closely associated with TRPC6 gene mutations, and TRPC6 mediates podocyte injury induced by high glucose. Angiotensin II (AngII) has been revealed to enhance TRPC6 currents in certain types of cells, including podocytes and ventricular myocytes. It has been reported that glucose regulated TRPC6 expression in an AngII‑dependent manner in podocytes and that this pathway is critical in diabetic nephropathy. In the present study, the role of TRPC6 detected by western blotting and reverse transcription‑quantitative polymerase chain reaction in AngII‑mediated podocyte injury was evaluated in rats with type 2 diabetes induced by high‑calorie diets and streptozotocin. The results demonstrated that urinary albumin excretion was elevated, and morphological changes, including glomerular basement membrane thickening and podocyte process effacement, were observed. There was increased expression of AngII and TRPC6 in diabetic rats. The angiotensin receptor blocker valsartan significantly reduced TRPC6 and nuclear factor of activated T‑cells (NFAT) overexpression in diabetic rats. These results in vivo were confirmed by studies in vitro, which demonstrated that inhibition of TRPC6 ameliorated high glucose‑induced podocyte injury by decreasing NFAT mRNA levels. Taken together, the present results suggested that the AngII/TRPC6/NFAT axis may be a crucial signaling pathway in podocytes that is necessary for maintaining the integrity of the glomerular filtration barrier. In addition, TRPC6 may represent a potential therapeutic target for diabetic nephropathy.


Barcoding Neotropical birds: assessing the impact of nonmonophyly in a highly diverse group.
In this study, we verified the power of DNA barcodes to discriminate Neotropical birds using Bayesian tree reconstructions of a total of 7404 COI sequences from 1521 species, including 55 Brazilian species with no previous barcode data. We found that 10.4% of species were nonmonophyletic, most likely due to inaccurate taxonomy, incomplete lineage sorting or hybridization. At least 0.5% of the sequences (2.5% of the sampled species) retrieved from GenBank were associated with database errors (poor-quality sequences, NuMTs, misidentification or unnoticed hybridization). Paraphyletic species (5.8% of the total) can be related to rapid speciation events leading to nonreciprocal monophyly between recently diverged sister species, or to absence of synapomorphies in the small COI region analysed. We also performed two series of genetic distance calculations under the K2P model for intraspecific and interspecific comparisons: the first included all COI sequences, and the second included only monophyletic taxa observed in the Bayesian trees. As expected, the mean and median pairwise distances were smaller for intraspecific than for interspecific comparisons. However, there was no precise 'barcode gap', which was shown to be larger in the monophyletic taxon data set than for the data from all species, as expected. Our results indicated that although database errors may explain some of the difficulties in the species discrimination of Neotropical birds, distance-based barcode assignment may also be compromised because of the high diversity of bird species and more complex speciation events in the Neotropics.


Internal Herniation of Small Bowel Underneath Iliac Vascular Axis After Pelvic Surgery: A Systematic Review.
Internal abdominal hernias are rare entities that most commonly present with acute small bowel obstruction. These hernias can be congenital or acquired. While congenital hernias are considered the most common type, acquired hernias are becoming more common. Recently, a rare type of internal herniation has been reported underneath iliac vasculature in patients who have undergone pelvic lymph node dissection in the past. This study was carried out to assess the prevalence of this rare type of internal hernia. Two reviewers searched the literature in three online databases using the Cochrane methodology for systematic reviews. The search of databases yielded 70 articles. The studies which reported internal herniation underneath iliac vasculature were included. Studies that reported herniation underneath other pelvic organs or vasculature were excluded. After screening, 17 articles were deemed suitable and selected. All 17 cases reviewed underwent pelvic lymph node dissection in the past. The median latency period between index surgery and clinical presentation with the incarcerated hernia was 20 months. All 17 cases were managed surgically with small bowel resection carried out in 13 cases. Eleven authors reported closing the hernia defect with various techniques, while five decided not the close it. All 17 cases were alive at the time of discharge from the hospital, with a mean hospital stay of 12.7 days. Given our findings, there should be a high index of suspicion of internal hernia in patients presenting with small bowel obstruction with a history of pelvic lymph node dissection. In our review, internal herniation was always preceded by pelvic lymph node dissection, so the closure of the peritoneum should be considered while pelvic lymph node dissection is carried out.


Prevalence and Risk Factors Associated with Adverse Drug Reactions among Previously Treated Tuberculosis Patients in China.
We assessed the incidence of adverse drug reactions (ADRs) with anti-TB medications and evaluated the risk factors for developing ADRs in previously treated tuberculosis patients in China. All patients received the first-line anti-TB regimen (2HREZS/6HRE) as recommended by the national guidelines. Clinical and laboratory evaluations were performed once a month. Out of the 354 participants, 262 (74.0%) experienced ADRs such as hyperuricemia (65.0%, 230/354), hepatotoxicity (6.2%, 22/354) and hearing disturbances (4.8%, 17/354). ADRs were significantly associated with diabetes mellitus [OR (95% CI): 15.5 (2.07-115.87)]; however, weight more than 50 kg [OR (95% CI): 0.41 (0.22-0.85)] was a protective factor for occurrence of ADRs. Hyperuricemia is the most common adverse event but, most patients with hyperuricemia showed increased tolerance for high uric acid levels. Low body weight and diabetes mellitus increased the risk of the occurrence of ADRs during anti-TB treatment.


Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction.
To test the hypothesis that the heat shock response is associated with myocardial salvage, the heat stress protein (HSP) content of cardiac tissue was increased by either ischemic or thermal stress. Rabbits were divided into four groups. Ischemic pretreatment (n = 15) comprised four 5-minute episodes of coronary ligation separated by 10 minutes of reperfusion. The corresponding control group (n = 21) underwent surgical preparation without coronary ligation. Thermal pretreatment (n = 16) involved whole-body temperature elevation to 42 degrees C for 15 minutes; corresponding controls (n = 15) were treated with anesthetic alone. Twenty-four hours later, hearts were removed for HSP estimation or infarct size assessment after a 30-minute coronary ligation. Myocardial HSP72 content assessed by Western blotting was elevated by both ischemic and thermal pretreatments (2.5 +/- 0.2 units, n = 4, and 2.8 +/- 0.3 units, n = 4, mean +/- SEM; P = NS, respectively) compared with the corresponding control groups (1.0 +/- 0.3, n = 4, P < or = .01 and 0.3 +/- 0.1, n = 4, P < or = .01, respectively). HSP60 was preferentially elevated by ischemic pretreatment. After a 30-minute coronary occlusion and 120 minutes of reperfusion, ischemic and thermal pretreatments limited infarct size as a percentage of the volume at risk by 28.8 +/- 5.2% vs 52.0 +/- 5.2%, P < or = .01 and 32.8 +/- 3.8% vs 56.9 +/- 6.5%, P < or = .01, respectively. Myocardial stress protein induced by either sublethal thermal or ischemic injury is associated with myocardial salvage. Our findings suggest that stress protein elevation, rather than the nonspecific effects of thermal or ischemic stress, may be responsible for the myocardial protection seen in this model. Our observations may have important implications regarding myocardial adaptation to brief periods of ischemia.


Cosmetic surgery procedures as luxury goods: measuring price and demand in facial plastic surgery.
To evaluate the relationship between cosmetic facial plastic surgery procedure price and demand, and to test the hypothesis that these procedures function as luxury goods in the marketplace, with an upward-sloping demand curve. Data were derived from a survey that was sent to every (N = 1727) active fellow, member, or associate of the American Academy of Facial Plastic and Reconstructive Surgery, assessing the costs and frequency of 4 common cosmetic facial plastic surgery procedures (face-lift, brow-lift, blepharoplasty, and rhinoplasty) for 1999 and 1989. An economic analysis was performed to assess the relationship of price and demand for these procedures. A significant association was found between increasing surgeons' fees and total charges for cosmetic facial plastic surgery procedures and increasing demand for these procedures, as measured by their annual frequency (P</=.003). After a multiple regression analysis correcting for confounding variables, this association of increased price with increased demand holds for each of the 4 procedures studied, across all US regions, and for both periods surveyed. Cosmetic facial plastic surgery procedures do appear to function as luxury goods in the marketplace, with an upward-sloping demand curve. This stands in contrast to other, traditional, goods for which demand typically declines as price increases. It appears that economic methods can be used to evaluate cosmetic procedure trends; however, these methods must be founded on the appropriate economic theory.


Stress, the hippocampus, and epilepsy.
Stress is among the most frequently self-reported precipitants of seizures in patients with epilepsy. This review considers how important stress mediators like corticotropin-releasing hormone, corticosteroids, and neurosteroids could contribute to this phenomenon. Cellular effects of stress mediators in the rodent hippocampus are highlighted. Overall, corticosterone--with other stress hormones--rapidly enhances CA1/CA3 hippocampal activity shortly after stress. At the same time, corticosterone starts gene-mediated events, which enhance calcium influx several hours later. This later effect serves to normalize activity but also imposes a risk for neuronal injury if and when neurons are concurrently strongly depolarized, for example, during epileptic activity. In the dentate gyrus, stress-induced elevations in corticosteroid level are less effective in changing membrane properties such as calcium influx; here, enhanced inhibitory tone mediated through neurosteroid effects on gamma-aminobutyric acid (GABA) receptors might dominate. Under conditions of repetitive stress (e.g., caused from experiencing repetitive and unpredictable seizures) and/or early life stress, hormonal influences on the inhibitory tone, however, are diminished; instead, enhanced calcium influx and increased excitation become more important. In agreement, perinatal stress and elevated steroid levels accelerate epileptogenesis and lower seizure threshold in various animal models for epilepsy. It will be interesting to examine how curtailing the effects of stress in adults, for example, by brief treatment with antiglucocorticoids, may be beneficial to the treatment of epilepsy.


GLP-1/glucagon receptor co-agonism for treatment of obesity.
Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.


Metal nitride cluster fullerene M3N@C80 (M=Y, Sc) based dyads: synthesis, and electrochemical, theoretical and photophysical studies.
The first pyrrolidine and cyclopropane derivatives of the trimetallic nitride templated (TNT) endohedral metallofullerenes I(h)-Sc(3)N@C(80) and I(h)-Y(3)N@C(80) connected to an electron-donor unit (i.e., tetrathiafulvalene, phthalocyanine or ferrocene) were successfully prepared by 1,3-dipolar cycloaddition reactions of azomethine ylides and Bingel-Hirsch-type reactions. Electrochemical studies confirmed the formation of the [6,6] regioisomers for the Y(3)N@C(80)-based dyads and the [5,6] regioisomers in the case of Sc(3)N@C(80)-based dyads. Similar to other TNT endohedral metallofullerene systems previously synthesized, irreversible reductive behavior was observed for the [6,6]-Y(3)N@C(80)-based dyads, whereas the [5,6]-Sc(3)N@C(80)-based dyads exhibited reversible reductive electrochemistry. Density functional calculations were also carried out on these dyads confirming the importance of these structures as electron transfer model systems. Furthermore, photophysical investigations on a ferrocenyl-Sc(3)N@C(80)-fulleropyrrolidine dyad demonstrated the existence of a photoinduced electron-transfer process that yields a radical ion pair with a lifetime three times longer than that obtained for the analogous C(60) dyad.


Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ.
Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.


Safety assessment of Vitis vinifera (grape)-derived ingredients as used in cosmetics.
The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 24 Vitis vinifera (grape)-derived ingredients and found them safe in the present practices of use and concentration in cosmetics. These ingredients function in cosmetics mostly as skin-conditioning agents, but some function as antioxidants, flavoring agents, and/or colorants. The Panel reviewed the available animal and clinical data to determine the safety of these ingredients. Additionally, some constituents of grapes have been assessed previously for safety as cosmetic ingredients by the Panel, and others are compounds that have been discussed in previous Panel safety assessments.


Unique antigenic determinants (idiotypes) used as markers in a patient with macroglobulinemia and urticaria. Similar idiotypes demonstrated in the skin and on peripheral blood lymphocytes.
An antiserum was raised against a monoclonal IgMk macroglobulin isolated from serum of a patient with recurrent urticaria. The antiserum was made idiotype-specific through adequate absorptions. The anti-idiotype antiserum reacted only with the immunizing protein and its Fab fragments and not with other monoclonal proteins of IgM and IgA class or pooled IgG as assayed in an enzyme-linked immunosorbent assay. IgM antibodies with the same idiotype as the monoclonal IgM protein were detected in the dermal/epidermal junction area of diseased skin. The similar idiotypic determinants could also be demonstrated on membrane-bound molecules of peripheral blood B and T lymphocytes using the immunofluorescence methods.


Weight loss is still an essential intervention in obesity and its complications: a review.
The prevalence of obesity is more than 20% in many developed countries and it increases in developing countries. Obesity is associated with metabolic disorders, cardiovascular diseases, pulmonary diseases, digestive diseases, and cancers. Although other specific treatments for these complications exist, weight loss is still an essential intervention in obesity and its complications. Therapeutic life change, behavior modification, pharmacotherapy, and surgery are major approaches to weight loss. In addition, medicine used in diabetes such as Glucagon-like peptide-1 analogues may be a new type of medicine for obesity, at least for those obese patients with diabetes.


Perinatal outcomes of congenital heart disease after emergent neonatal cardiac procedures.
We compared outcome of neonates with prenatal and post-natal diagnosis of congenital heart disease presenting in our paediatric heart centre between March 2005 and May 2015 who underwent an emergent intervention within 48 h post-partum. In 52/111 (46.8%) with emergent intervention, congenital heart disease was diagnosed prenatally, in 59/111 (53.2%) with no specialized foetal echocardiography, diagnosis was made post-natally. In 98/111 (88.2%), 30-day outcome was known. Regarding the entire cohort, 30-day survival did not differ significantly in prenatal and post-natal diagnosis group (71.2 vs. 72.9%; p > .1). Infants with prenatal diagnosis were more likely to be born by caesarean section (59.6% vs. 33.9%, p = .01). Those with post-natal diagnosis had a higher need for intubation (32.7% vs. 52.5%; p < .05). Subgroup analysis of HLH/HLHC (hypoplastic left heart/hypoplastic left heart complex) patients revealed higher number of deaths within 30 days of life in the post-natal diagnosis group, although the difference did not reach statistical significance (5/7, 71.4% vs. 5/20, 25.0%; p = .075). For newborns who require emergent neonatal cardiac procedures, our results point towards a lower death rate after prenatal diagnosis of HLH/HLHC.


Mayolenes: labile defensive lipids from the glandular hairs of a caterpillar (Pieris rapae).
Larvae of the European cabbage butterfly, Pieris rapae (Pieridae), are beset with glandular hairs, bearing droplets of a clear oily secretion at their tip. The fluid consists primarily of a series of chemically labile, unsaturated lipids, the mayolenes, which are derived from 11-hydroxylinolenic acid. In bioassays with the ant Crematogaster lineolata, the secretion was shown to be potently deterrent, indicating that the fluid plays a defensive role in nature.


Acute non-Q-wave myocardial infarction: a distinct clinical entity of increasing importance.
Despite the increasing incidence of acute non-Q-wave myocardial infarction, controversy remains regarding its validity as a distinct pathophysiologic physiologic and clinical entity. Review of the data indicates that the controversy is more apparent than real. The pathophysiologic factor discriminating best between non-Q-wave and Q-wave infarction is the incidence rate of total occlusion of the infarct-related artery, approximately 30% in non-Q-wave infarction and 80% in Q-wave infarction. Patients with non-Q-wave infarction have a higher incidence of pre-existing angina than patients with Q-wave infarction; they also have lower peak creatine kinase levels, higher ejection fractions and lower wall-motion abnormality scores, which suggests a smaller area of acute infarction damage. However, patients with non-Q-wave infarction have a significantly shorter time to peak creatine kinase level and more heterogeneous ventriculographic and electrocardiographic infarct patterns. The in-hospital death rate is lower in non-Q-wave than in Q-wave infarction (approximately 12% v. 19%). The long-term death rates are similar for the two groups (27% and 23%), but the incidence of subsequent coronary events is higher among patients with non-Q-wave infarction; in particular, reinfarction is an important predictor of risk of death. Most of the differences in biologic and clinical variables between the two types of acute infarction can be related to a lower incidence of total occlusion, earlier reperfusion or better collateral supply in non-Q-wave infarction. Further study is needed to better characterize the long-term risk and to define the most appropriate therapies.


Identification of a tripartite interaction between the N-terminus of HIV-1 Vif and CBFβ that is critical for Vif function.
HIV-1 Vif interacts with the cellular core-binding factor β (CBFβ) and counteracts the protective roles of certain human APOBEC3 (A3) proteins by targeting them for proteasomal degradation. Previous studies have identified some amino acids important for Vif-CBFβ interactions, and recently a co-crystal structure of a pentameric complex of HIV-1 Vif, CBFβ, Cul5, EloB, and EloC was resolved. However, a comprehensive analysis of Vif-CBFβ interactions that are important for Vif function has not been performed. Here, we carried out double-alanine scanning mutagenesis of the first 60 amino acids of Vif and determined their effects on interaction with CBFβ and their ability to induce A3G degradation as well as rescue HIV-1 replication in the presence of A3G. We found that multiple Vif residues are involved in the extensive N-terminal Vif-CBFβ interaction and that the 5WQVMIVW11 region of Vif is the major determinant. A minimum of three alanine substitutions are required to completely abrogate the Vif-CBFβ interaction and Vif's ability to rescue HIV-1 infectivity in the presence of A3G. Mutational analysis of CBFβ revealed that F68 and I55 residues are important and participate in a tripartite hydrophobic interaction with W5 of Vif to maintain a stable and functional Vif-CBFβ complex. We also determined that CBFβ amino acids 73WQGEQR78, which are not resolved in the structure of the pentameric complex, are not involved in interaction with HIV-1 Vif. Our results provide detailed insight into the Vif-CBFβ interactions that are critical for Vif function and may contribute to the rational design of HIV-1 inhibitors that block Vif-mediated degradation of A3 proteins.


Symptom clusters in women with breast cancer: an analysis of data from social media and a research study.
User-generated content on social media sites, such as health-related online forums, offers researchers a tantalizing amount of information, but concerns regarding scientific application of such data remain. This paper compares and contrasts symptom cluster patterns derived from messages on a breast cancer forum with those from a symptom checklist completed by breast cancer survivors participating in a research study. Over 50,000 messages generated by 12,991 users of the breast cancer forum on MedHelp.org were transformed into a standard form and examined for the co-occurrence of 25 symptoms. The k-medoid clustering method was used to determine appropriate placement of symptoms within clusters. Findings were compared with a similar analysis of a symptom checklist administered to 653 breast cancer survivors participating in a research study. The following clusters were identified using forum data: menopausal/psychological, pain/fatigue, gastrointestinal, and miscellaneous. Study data generated the clusters: menopausal, pain, fatigue/sleep/gastrointestinal, psychological, and increased weight/appetite. Although the clusters are somewhat different, many symptoms that clustered together in the social media analysis remained together in the analysis of the study participants. Density of connections between symptoms, as reflected by rates of co-occurrence and similarity, was higher in the study data. The copious amount of data generated by social media outlets can augment findings from traditional data sources. When different sources of information are combined, areas of overlap and discrepancy can be detected, perhaps giving researchers a more accurate picture of reality. However, data derived from social media must be used carefully and with understanding of its limitations.


Initiation of DNA double strand break repair: signaling and single-stranded resection dictate the choice between homologous recombination, non-homologous end-joining and alternative end-joining.
A DNA double strand break (DSB) is a highly toxic lesion, which can generate genetic instability and profound genome rearrangements. However, DSBs are required to generate diversity during physiological processes such as meiosis or the establishment of the immune repertoire. Thus, the precise regulation of a complex network of processes is necessary for the maintenance of genomic stability, allowing genetic diversity but protecting against genetic instability and its consequences on oncogenesis. Two main strategies are employed for DSB repair: homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is initiated by single-stranded DNA (ssDNA) resection and requires sequence homology with an intact partner, while NHEJ requires neither resection at initiation nor a homologous partner. Thus, resection is an pivotal step at DSB repair initiation, driving the choice of the DSB repair pathway employed. However, an alternative end-joining (A-EJ) pathway, which is highly mutagenic, has recently been described; A-EJ is initiated by ssDNA resection but does not require a homologous partner. The choice of the appropriate DSB repair system, for instance according the cell cycle stage, is essential for genome stability maintenance. In this context, controlling the initial events of DSB repair is thus an essential step that may be irreversible, and the wrong decision should lead to dramatic consequences. Here, we first present the main DSB repair mechanisms and then discuss the importance of the choice of the appropriate DSB repair pathway according to the cell cycle phase. In a third section, we present the early steps of DSB repair i.e., DSB signaling, chromatin remodeling, and the regulation of ssDNA resection. In the last part, we discuss the competition between the different DSB repair mechanisms. Finally, we conclude with the importance of the fine tuning of this network for genome stability maintenance and for tumor protection in fine.


Impact of alignment to gravito-inertial force on motion sickness and cardiopulmonary variables.
In tilting trains partial alignment to the gravito-inertial force (GIF) in the curves seems to be the best tilt compensation to reduce the incidence of motion sickness. We investigated the effect of alignment to the GIF on the development of motion sickness during low-frequency horizontal motion. There were 12 healthy subjects who participated. The design was a three-period, single-blind, crossover trial, counterbalanced for order. Cardiopulmonary measurements, Misery SCores (MISC), and questionnaire data (Motion Sickness Susceptibility Questionnaire, Nijmegen Questionnaire for Hyperventilation) were obtained. The stimulus was a sinusoidal movement (0.176 Hz, 0.2 g peak acceleration) on the ESA-sled. The cabin was compensated for 0% (A-0), 50% (A-50), and 100% (A-100) to the GIF. Runs were 1 wk apart. The A-50 condition may delay the development of motion sickness. Based on the survival curves the possible effect seems temporary. However, MISC 2 early in the runs resulted in high positive and negative predictive values for dropout and survival during the runs. No synchronization of the respiratory frequency with the sled motion was observed. There was a significant (P = 0.002) drop in relative end-tidal CO2 levels. There seems to be a rationale for partially compensating to the GIF while trying to prevent motion sickness in tilting trains. Sitting comfort is just better than without compensation at all and Coriolis effects are not as nauseating as with complete tilt compensation. Also, a drop in end-tidal CO2 levels might be a sign of pulmonary compensation for the nauseating stimulus.


FRET and ligand related NON-FRET processes in single quantum dot-perylene bisimide assemblies.
Nanoassemblies are formed via self-assembly of ZnS capped CdSe quantum dots (QD) and perylene bisimide dyes (PBI). Upon assembly formation with functionalized dye molecules the QD photoluminescence (PL) is quenched. Quenching has been assigned partly to FRET (fluorescence resonance energy transfer) and NON-FRET processes. By means of time resolved single particle spectroscopy of immobilized QD-dye assemblies, it is demonstrated that NON-FRET processes are due to new non-radiative decay channels caused by the assembly formation process itself. Immobilized (single) assemblies exhibit the same processes as ensembles of assemblies in toluene solution. Only one dye molecule on a QD quenches the PL up to 50%, which is much stronger than is expected when replacing a volume related number of ligands. NON-FRET processes are distinct from photoinduced charge and/or energy transfer. A combination of a Stern-Volmer and FRET analysis of ensemble experiments supports the investigation of the dynamics of assembly formation at extremely low concentration ratios of PBI to QD. This allows us to distinguish between the effects of PBI and ligands on PL quenching on a single molecule level which is not possible in conventional ligand dynamic experiments.


The influence of distal colon irritation on the changes of cystometry parameters to esophagus and colon distentions.
The co-occurrence of multiple pathologies in the pelvic viscera in the same patient, such as, irritable bowel syndrome and interstitial cystitis, indicates the complexity of viscero-visceral interactions and the necessity to study these interactions under multiple pathological conditions. In the present study, the effect of distal colon irritation (DCI) on the urinary bladder interaction with distal esophagus distention (DED), distal colon distention (DCD), and electrical stimulation of the abdominal branches of vagus nerve (abd-vagus) were investigated using cystometry parameters. The DCI significantly decreased the intercontraction time (ICT) by decreasing the storage time (ST); nonetheless, DED and Abd-vagus were still able to significantly decrease the ICT and ST following DCI. However, DCD had no effect on ICT following the DCI. The DCI, also, significantly decreased the Intravesical pressure amplitude (P-amplitude) by increasing the resting pressure (RP). Although DED has no effect on the P-amplitude, both in the intact and the irritated animals, the abd-vagus significantly increased the P-amplitude following DCI by increasing the maximum pressure (MP). In the contrary, 3mL DCD significantly increased the P-amplitude by increasing the MP and lost that effect following the DCI. Concerning the pressure threshold (PT), none of the stimuli had any significant changes in the intact animals. However, DCI significantly decreased the PT, also, the abd-vagus and 3mL DCD significantly decreased the PT. The results of this study indicate that chemical irritation of colon complicates the effects of mechanical irritation of esophagus and colon on urinary bladder function.


Induction of tolerance to intrathecal butorphanol in rats.
Butorphanol, an opioid agonist/antagonist, has been administered spinally and epidurally in humans for moderate to severe pain. However, unlike intrathecal (i.t.) morphine, virtually no information is available regarding butorphanol's ability to induce analgesic tolerance at the spinal cord level upon chronic i.t. administration. Continuous infusion of i.t. butorphanol was given via an osmotic minipump. Rats were randomly assigned to four groups (n = 7 each) to receive i.t. infusion (1 microliter/h) consisting of saline, or butorphanol (13, 26, or 52 nmol/h) for 96 h. Tail-flick (TF) latencies were measured during the period of i.t. infusion. A dose-dependent antinociceptive effect, as measured by TF latency, was demonstrated in the groups receiving i.t. butorphanol as compared to the saline group. The overall antinociceptive effects calculated from the areas under the curve (AUC's) were 372 +/- 3.0, 394 +/- 7.5, and 433 +/- 20 for the 13, 26, and 52 nmol/h butorphanol-infused groups, respectively; the AUC's of the 26 and 52 nmol/h groups were significantly different from the AUC of 356 +/- 3.4 for the saline-infused group (p < 0.01, one way ANOVA; p < 0.05, post hoc Dunnett's test). The TF latencies of the 26 and 52 nmol/h groups were 3.77 +/- 0.05 and 3.73 +/- 0.03 s at the baseline (before the i.t. infusion), respectively; and gradually increased significantly (p < 0.01, two way repeated measure ANOVA; p < 0.05, post hoc Student-Newman-Keuls or SNK test) to the peak values of 4.31 +/- 0.14 and 4.90 +/- 0.28 s, respectively; then decreased significantly from the peaks (p < 0.05, post hoc SNK test) to the final values of 3.87 +/- 0.06 and 4.10 +/- 0.13 s at the end of the 96-h infusion, respectively. The TF values of the saline and the 13 nmol/h groups did not show statistically significant differences throughout the 96-h infusion period. Therefore, continuous infusion of i.t. butorphanol at the rate of 26 and 52 nmol/h induced tolerance to tail-flick analgesia within 96 h.


Topology of chaotic mixing patterns.
A stirring device consisting of a periodic motion of rods induces a mapping of the fluid domain to itself, which can be regarded as a homeomorphism of a punctured surface. Having the rods undergo a topologically complex motion guarantees at least a minimal amount of stretching of material lines, which is important for chaotic mixing. We use topological considerations to describe the nature of the injection of unmixed material into a central mixing region, which takes place at injection cusps. A topological index formula allow us to predict the possible types of unstable foliations that can arise for a fixed number of rods.


Electron acceptor-dependent respiratory and physiological stratifications in biofilms.
Bacterial respiration is an essential driving force in biogeochemical cycling and bioremediation processes. Electron acceptors respired by bacteria often have solid and soluble forms that typically coexist in the environment. It is important to understand how sessile bacteria attached to solid electron acceptors respond to ambient soluble alternative electron acceptors. Microbial fuel cells (MFCs) provide a useful tool to investigate this interaction. In MFCs with Shewanella decolorationis, azo dye was used as an alternative electron acceptor in the anode chamber. Different respiration patterns were observed for biofilm and planktonic cells, with planktonic cells preferred to respire with azo dye while biofilm cells respired with both the anode and azo dye. The additional azo respiration dissipated the proton accumulation within the anode biofilm. There was a large redox potential gap between the biofilms and anode surface. Changing cathodic conditions caused immediate effects on the anode potential but not on the biofilm potential. Biofilm viability showed an inverse and respiration-dependent profile when respiring with only the anode or azo dye and was enhanced when respiring with both simultaneously. These results provide new insights into the bacterial respiration strategies in environments containing multiple electron acceptors and support an electron-hopping mechanism within Shewanella electrode-respiring biofilms.


Parkinson's disease monotherapy with controlled-release MK-458 (PHNO): double-blind study and comparison to carbidopa/levodopa.
The potent and selective dopamine D-2 agonist, MK-458 [PHNO; (+)-4-propyl-9-hydroxynaphthoxazine] was administered as monotherapy to nine patients with Parkinson's disease in a double-blind, placebo-controlled 12-week investigation; ten other patients were randomized to placebo. MK-458 was formulated as a controlled-release preparation, using a hydroxypropyl methylcellulose-lactase (HPMC) matrix. Patients receiving MK-458/HPMC improved on a variety of measures of parkinsonism, compared to their baseline scores; in contrast, only trivial improvement was seen within the placebo group. We subsequently compared the anti-Parkinson response to MK-458/HPMC with the response to chronic carbidopa/levodopa monotherapy in an open label trial. Carbidopa/levodopa improved parkinsonism to a significantly greater degree than MK-458/HPMC. Doses of MK-458 used in these studies (up to 60 mg per day) were substantially higher than those in previously reported preliminary studies of this medication. We conclude that monotherapy with MK-458/HPMC results in a significant anti-Parkinson effect; however, the response falls short of that seen with carbidopa/levodopa.


An Abnormal Tibial Position Is Associated With Alterations in the Meniscal Matrix: A 3-Year Longitudinal Study After Anterior Cruciate Ligament Reconstruction.
An altered tibial position is still present despite anterior cruciate ligament (ACL) reconstruction. It has been demonstrated that an abnormal tibial position after an ACL injury may play a role in subsequent injuries to the meniscus, which can lead to early cartilage degeneration. To determine changes in both the tibial position and the meniscal matrix present before and after ACL reconstruction as well as to evaluate the association between these 2 variables in ACL-injured knees 3 years after reconstruction. Cohort study; Level of evidence, 2. Bilateral knee magnetic resonance imaging (MRI) of 32 patients with unilateral ACL injuries was performed before reconstruction; 13 control participants also underwent MRI. Follow-up MRI was performed up to 3 years after surgery. Tibial position, internal tibial rotation, and T1ρ and T2 values of the menisci were calculated using an in-house MATLAB program. Student t tests and multiple linear regression were used to compare differences between injured, uninjured, and control knees as well as to assess correlations between the tibial position at 3 years and 3-year changes in quantitative MRI meniscal relaxation values. The tibial position of injured knees was more anterior than that of uninjured knees at baseline, 6 months, and 1, 2, and 3 years (P < .05 for all). The T1ρ and T2 values of the menisci of injured knees were greater than those of uninjured and control knees in the posterior lateral and posterior medial horns up to 1 and 2 years after surgery, respectively (P < .05 for all). The tibial position at 3 years was associated with increased T2 values from baseline to 3 years in the posterior medial horn (β = 0.397; P = .031) and anterior medial horn (β = 0.360; P = .040). Results of the current study indicate that there is a persistently altered tibial position after ACL reconstruction. Initial preoperative meniscal abnormalities show prolonged but gradual improvement. Additionally, correlations between the tibial position and changes in the medial meniscal matrix suggest that the tibial position may play a role in the increased susceptibility to medial meniscal tears seen after reconstruction. The development of newer surgical techniques must address a persistently altered tibial position. Quantitative MRI is an effective instrument to evaluate meniscal matrix changes and can serve as an early radiological tool for meniscal injuries.


Pseudomelanosis duodeni.
Pseudomelanosis duodeni, speckled black pigmentation of the duodenal mucosa, presents a striking appearance at endoscopy. Among the 14 reported cases there is a predominance of black women greater than 40 years old, but it can occur in any race and age group. There is no known association with pigmentation elsewhere in the gastrointestinal tract or with the use of laxatives. However, most reported patients were hypertensive (many treated with hydralazine and propranolol) and significant numbers suffered from upper gastrointestinal bleeding, chronic renal failure, or diabetes mellitus. The pigment is usually located in mucosal macrophages, in lysosomes. Histochemical studies and electron probe microanalysis suggest that several pigments may result in this endoscopic appearance, including lipomelanin, ceroid, iron sulfide, and hemosiderin. Additional studies, possibly using tissue from surgical resections or autopsies, are needed to determine the etiology and clinical significance of this heterogeneous entity.


Origin of Subgap States in Normal-Insulator-Superconductor van der Waals Heterostructures.
Superconductivity in van der Waals materials, such as NbSe2 and TaS2, is fundamentally novel due to the effects of dimensionality, crystal symmetries, and strong spin-orbit coupling. In this work, we perform tunnel spectroscopy on NbSe2 by utilizing MoS2 or hexagonal boron nitride (hBN) as a tunnel barrier. We observe subgap excitations and probe their origin by studying various heterostructure designs. We show that the edge of NbSe2 hosts many defect states, which strongly couple to the superconductor and form Andreev bound states. Furthermore, by isolating the NbSe2 edge we show that the subgap states are ubiquitous in MoS2 tunnel barriers but absent in hBN tunnel barriers, suggesting defects in MoS2 as their origin. Their magnetic nature reveals a singlet- or a doublet-type ground state, and based on nearly vanishing g factors or avoided crossings of subgap excitations, we highlight the role of strong spin-orbit coupling.


Dim light at night increases body mass of female mice.
During the past century, the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16 h light at ∼150 lux/8 h dark at ∼0 lux) cycle or to light/dim light at night (dLAN; 16 h light at ∼150 lux/8 h dim light at ∼5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism.


Local steroid injection in severe idiopathic granulomatous mastitis as a new first-line treatment modality with promising therapeutic efficacy.
Intralesional steroid injection has recently evolved as a novel treatment modality for localized idiopathic granulomatous mastitis (= IGM). We aimed to explore the therapeutic efficacy of local steroid injections (LSI) in patients with severe IGM. Fifty-one patients diagnosed with severe IGM were included in the study and treated with either local steroid injection (LSI) alone (n = 25) or combined LSI with systemic oral steroid treatment (OST) (n = 26). The local steroid injection protocol included an intralesional triamcinolone acetonide injection into the palpable granulomas every 4-week, and topical administration of steroid-containing pomades twice a day on the affected surface of the breast. Patients with a combined LSI and OST received low-dose oral methylprednisolone (<16 mg). Patients with LSI alone required more LSI applications than those in the combined LSI with OST group (LSI: 5 ± 2.9; vs. LSI/OST: 3.5 ± 2.5; p = 0.080) to obtain an effective optimum therapeutic response. At a median of 12 months (range, 4-42), no difference was found in complete response rates between patients in the LSI group and the combined LSI group with OST (52 vs. 53.9%, p = 0.999). However, steroid-related systemic side effects were lower in the LSI alone group (p < 0.008). Local steroid injection could be considered as the first-line treatment in patients with severe IGM until a therapeutic response has been obtained either as the sole treatment modality or combined with oral steroids. Compared with systemic oral steroid therapy, local steroid administration can be considered a new treatment modality with fewer side effects.


Acute acalculous cholecystitis.
Sixty-eight patients with acute acalculous cholecystitis were reviewed. The results of history and physical examinations were usually nondiagnostic. IDA cholescintigraphy (93 per cent accuracy rate) was the only reliable diagnostic modality. The results of oral cholecystography, intravenous cholangiography and ultrasonography were considerably less reliable. One-half of the patients had gangrenous cholecystitis. Cholecystectomy was the preferred operation with an over-all mortality of 9 per cent. IDA cholescintigraphy is an important new modality for the diagnosis of acute acalculous cholecystitis which, in the past, has often been difficult to diagnose.


Catalytic Enantioselective Birch-Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters.
A new enantioselective desymmetrizing Mizoroki-Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synthesized from Birch reduction-alkylation of benzoic acid and benzoate esters.


Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies.
Tumor cells evade immune destruction, at least partially, by upregulating inhibitory signals to limit effector T cell activation. Programmed death 1 (PD-1) is one of the most critical co-inhibitory molecules limiting the T-cell antitumor response. PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed by various types of tumors as well as reactive cells in the tumor microenvironment. A growing body of evidence has shown the clinical efficiency and minimal toxicity of PD-1 pathway inhibitors in patients with solid tumors, but the role of these inhibitors in lymphoid malignancies is much less well studied. In this review, we analyze the pathologic role of the PD-1 pathway in most common lymphoid malignancies and we organize the clinical data from clinical trials of PD-1 pathway inhibitors. Several anti-PD-1 regimens have shown encouraging therapeutic effects in patients with relapsed or refractory Hodgkin lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. Additional progress is needed to foster an improved understanding of the role of anti-PD-1 therapy in reconstituting antitumor immunity in patients with lymphoid malignancies. Upcoming trials will explore the clinical efficiency of combining PD-1 pathway inhibitors and various agents with diverse mechanisms of action and create more therapeutic possibilities for afflicted patients.


Structurally and Morphologically Distinct Pathological Tau Assemblies Differentially Affect GVB Accumulation.
Tau aggregation is central to the pathogenesis of a large group of neurodegenerative diseases termed tauopathies, but it is still unclear in which way neurons respond to tau pathology and how tau accumulation leads to neurodegeneration. A striking neuron-specific response to tau pathology is presented by granulovacuolar degeneration bodies (GVBs), lysosomal structures that accumulate specific cargo in a dense core. Here we employed different tau aggregation models in primary neurons to investigate which properties of pathological tau assemblies affect GVB accumulation using a combination of confocal microscopy, transmission electron microscopy, and quantitative automated high-content microscopy. Employing GFP-tagged and untagged tau variants that spontaneously form intraneuronal aggregates, we induced pathological tau assemblies with a distinct subcellular localization, morphology, and ultrastructure depending on the presence or absence of the GFP tag. The quantification of the GVB load in the different models showed that an increased GVB accumulation is associated with the untagged tau aggregation model, characterized by shorter and more randomly distributed tau filaments in the neuronal soma. Our data indicate that tau aggregate structure and/or subcellular localization may be key determinants of GVB accumulation.


The health state of the eel swimbladder as a measure of parasite pressure by Anguillicola crassus.
We have developed an index based on macroscopic criteria to easily assess the health state of the eel swimbladder as a result of infection by the nematode Anguillicola crassus. In the sampling area (brackish lagoons of the French Mediterranean coast), 92% of the host sample (1,251 eels covering all size classes) showed pathological signs of infection. The general trend was for increasing damage as eel size increased, thus suggesting accumulation of pathological effects. We also revealed a non-linear relationship between the swimbladder index and the abundance of living worms. In particular, we showed that severely damaged swimbladders harboured very few living nematodes. We argue that the swimbladder degenerative index more closely reflects the parasite pressure than does classic parasite count. We found seasonal variation in the swimbladder index, with maximum damage occurring in July and thereafter a trend for healthy individuals. We discuss the possibility that the seasonal decrease in the swimbladder index could reflect the death of the more severely affected individuals during the warmest months.


[Pneumococcal vaccination: expected benefits in adults].
Streptococcus pneumoniae is one of the leading causes of bacterial pneumonia, meningitis and acute otitis media in children and adults worldwide. Polysaccharide pneumococcal vaccines have been available for approximately 50 years and conjugate vaccines, which generate immunological memory even at an early age but have limited serotype coverage, have recently been developed. Although the polysaccharide vaccine is considered effective in preventing invasive pneumococcal disease (IPD) in adults, its efficacy against pneumonia and among older or immunocompromised individuals is still controversial. On the other hand, the conjugate vaccine for children allows a large reduction in the incidence of IPD and in the rate of pneumococcal colonization in the general population through herd immunity, but its serotype coverage remains low in adults and serotype replacement may be expected in the long-term. In the present context of widespread antibiotic resistance, it is of the utmost importance to assess the expected benefits of pneumococcal vaccination, in order to be able to use it optimally in all population parts.


Deformation of helix C in the low temperature L-intermediate of bacteriorhodopsin.
X-ray and electron diffraction studies of specific reaction intermediates, or reaction intermediate analogues, have produced a consistent picture of the structural mechanism of light-driven proton pumping by bacteriorhodopsin. Of central importance within this picture is the structure of the L-intermediate, which follows the retinal all-trans to 13-cis photoisomerization step of the K-intermediate and sets the stage for the primary proton transfer event from the positively charged Schiff base to the negatively charged Asp-85. Here we report the structural changes in bacteriorhodopsin following red light illumination at 150 K. Single crystal microspectrophotometry showed that only the L-intermediate is populated in three-dimensional crystals under these conditions. The experimental difference Fourier electron density map and refined crystallographic structure were consistent with those previously presented (Royant, A., Edman, K., Ursby, T., Pebay-Peyroula, E., Landau, E. M., and Neutze, R. (2000) Nature 406, 645-648; Royant, A., Edman, K., Ursby, T., Pebay-Peyroula, E., Landau, E. M., and Neutze, R. (2001) Photochem. Photobiol. 74, 794-804). Based on the refined crystallographic structures, molecular dynamic simulations were used to examine the influence of the conformational change of the protein that is associated with the K-to-L transition on retinal dynamics. Implications regarding the structural mechanism for proton pumping by bacteriorhodopsin are discussed.


Immunological response in chronic hepatitis C virus infection during interferon alpha therapy.
Chronic hepatitis C infection is a serious therapeutic problem. Interferon therapy is one of the possible methods leading to HCV infection elimination in some patients. The aim of the study was the estimation of administration of interferon alpha 2a and its effect on the lymphocyte subpopulations in peripheral blood in patients with chronic hepatitis C. A cytometric analysis was completed concerning the level of CD19+, CD3+, CD4+, CD8+, CD4+ + HLA DR+, CD16+ + 56+ in 21 patients in the 0, 4, 24, 48 weeks of interferon alpha 2a treatment, with the dose of 18 MU/week/48 weeks. Virus elimination was obtained in 26% of patients (responders, R) and a higher CD8+ level and a decrease in CD4+ was observed during interferon administration in those patients. A slight increased NK cell level was noticed mainly in patients who did not eliminate HCV (non-responders, NR). In R patients, lower lymphocyte values of CD19+, NK, CD3+ + HLA DR+, and CD4+ were observed in comparison to NR, which could suggest that they play a role in the process of HCV elimination. Significant immunological changes in peripheral blood were observed mainly in the first 4 weeks of interferon alpha therapy. Our studies did not reveal whether any of examined lymphocyte subpopulations in peripheral blood could be considered as a predictive factor of a positive reaction to interferon alpha treatment. However, there are significant differences in the levels of lymphocytes in R and NR.


A narrow internal auditory canal with duplication in a patient with congenital sensorineural hearing loss.
A narrow internal auditory canal (IAC) with duplication is a rare anomaly of the temporal bone. It is associated with congenital sensorineural hearing loss. Aplasia or hypoplasia of the vestibulocochlear nerve may cause the hearing loss. We present an unusual case of an isolated narrow IAC with duplication that was detected by a CT scan. In this case, the IAC was divided by a bony septum into an empty stenotic inferoposterior portion and a large anterosuperior portion containing the facial nerve that was clearly delineated on MRI.


Genetic determinants of the stress response in cardiovascular disease.
Originating from Hans Selye's general concept, the biological notion of the stress response implicates neuroendocrine and endocrine pathways as well as their cellular mediators as components of the general adaptation syndrome and its consequences. A highly variable degree of response to psychological and physical stresses has been noted in experimental animals and in human populations. Some stressors, such as the "cold pressor test," have been developed as tools for disease prediction. They apply to variable conditions, from hypertension to insulin resistance, but mostly in relation to cardiovascular outcomes. Other environmental factors, including the degree of salt intake, potentiate the stress response in animals and humans. Our group has undertaken to explore the genetic determinants of the stress response in inbred strains, recombinant congenic and congenic strains, as well as founder human populations. We have succeeded, initially, in linking increased body temperature, a major phenotypic response to stress, to the quantitative trait loci (QTL), one at myh3 on chromosome (Chr) 10, one at hsp27 on Chr 12, and one on Chr Y in the rat. The expression of several stress proteins is under the dominant influence of hstf1 at the rat Chr 7 locus (Mit3). The high prevalence of cardiovascular diseases with traits of enhanced stress responsiveness is discussed here in the context of a paradigm, such as hypertension, in the general population.


The missing tracheoesophageal puncture prosthesis: evaluation and management.
Placement of a tracheoesophageal puncture prosthesis in the post-laryngectomy patient has significantly improved voice rehabilitation in this population. Rarely, the prosthesis may become dislodged, necessitating medical evaluation. We present the case of a 61-year-old man who presented to our Emergency Department with a missing prosthesis. We describe the evaluation and management of this patient and review the relevant literature. We conclude with the following algorithm: When a patient presents with a missing prosthesis, evaluation of the tracheobronchial tree must be performed. Once the pulmonary system is cleared, the prosthesis can be presumed in the gastrointestinal tract and allowed to pass. A new prosthesis or catheter should be placed in the tract to prevent aspiration.