Interaural time discrimination of envelopes carried on high-frequency tones as a function of level and interaural carrier mismatch.
The present study investigated interaural time discrimination for binaurally mismatched carrier frequencies in listeners with normal hearing. One goal of the investigation was to gain insights into binaural hearing in patients with bilateral cochlear implants, where the coding of interaural time differences (ITDs) may be limited by mismatches in the neural populations receiving stimulation on each side. Temporal envelopes were manipulated to present low frequency timing cues to high-frequency auditory channels. Carrier frequencies near 4 kHz were amplitude modulated at 128 Hz via multiplication with a half-wave rectified sinusoid, and that modulation was either in-phase across ears or delayed to one ear. Detection thresholds for nonzero ITDs were measured for a range of stimulus levels and a range of carrier frequency mismatches. Data were also collected under conditions designed to limit cues based on stimulus spectral spread, including masking and truncation of sidebands associated with modulation. Listeners with normal hearing can detect ITDs in the face of substantial mismatches in carrier frequency across ears. The processing of ITDs in listeners with normal hearing is likely based on spread of excitation into binaurally matched auditory channels. Sensitivity to ITDs in listeners with cochlear implants may depend on spread of current that results in the stimulation of neural populations that share common tonotopic space bilaterally.


BTLA, a key regulator of Vγ9Vδ2 T-cell proliferation.
Although in the last few years γδ T lymphocytes have been the subject of growing interest as potential anticancer immunotherapeutics, how the proliferative and effector responses of these cells are regulated remains unclear. We have recently reported that the co-receptor B and T lymphocyte associated (BTLA) inhibits the proliferation of human Vγ9Vδ2 T cells, potentially underpinning a mechanism of immune escape by lymphoma cells.


Central herniation revealed by focal decrease in blood flow without elevation of intracranial pressure: a case report.
Until recently, in standard hospital settings the tissue blood supply could be inferred only from indirect measures such as assessment of the clinical signs and intracranial pressure (ICP) monitoring. This critical parameter can now be imaged directly with stable xenon-enhanced computed tomographic (CT) imaging. The procedure requires only an additional 10 minutes after a standard head study, yet it provides potentially vital information about tissue perfusion. We describe here a patient in whom a frontal lobe hematoma produced a direct mass effect, causing an element of central herniation with relative sparing of lateral and posterior cortical regions. Although the ICP recordings remained unchanged, symptoms of brain stem compression became apparent. Xenon/CT cerebral blood flow (CBF) mapping demonstrated a flow decrease mainly within the left frontal lobe and throughout central ganglionic structures. After removal of the left frontal hematoma, both clinical status and local and central flow improved. Because the xenon/CT method combines direct anatomical information with blood flow information in one examination, it may be a valuable clinical tool in providing a better understanding of pathophysiology in patients with head injuries and other mass lesions.


[Receptor tyrosine kinase KIT may regulate expression of genes involved in spontaneous regression of neuroblastoma].
Hallmark of neuroblastoma is an ability of this malignant tumor to undergo spontaneous regression or differentiation into benign tumor during any stage of the disease, but it is little known about mechanisms of these phenomena. We studied effect of receptor tyrosine kinase receptor KIT on expression of genes, which may be involved in tumor spontaneous regression. Downregulation of KIT expression by RNA interference in SH-SY5Y cells causes suppression of neurotrophin receptor NGFR expression that may promote the loss of sensibility of cells to nerve growth factors, also it causes upregulation of TrkA receptor expression which can stimulate cell differentiation or apoptosis in NGF dependent manner. Furthermore there is an upregulation of genes which stimulate malignant cell detection by immune system, such as genes of major histocompatibility complex HLA class I HLA-B and HLA-C, and interferon-γ receptors IFNGR1 and IFNGR2 genes. Thus KIT can mediate neuroblastoma cell sensibility to neurotrophins and immune system components--two factors directly contributing to spontaneous regression of neuroblastoma.


Neurotoxicity induced by antineoplastic proteasome inhibitors.
In the last ten years, the proteasome has become one of the most attractive targets for the treatment of several cancer malignancies. Like other types of antineoplastic agents, proteasome inhibitors cause toxic peripheral neuropathy, which indeed is one of the limiting side effects of these treatments, and which thus curtails its potential effectiveness. Bortezomib was the first proteasome inhibitor approved for clinical use and is currently the first line treatment for multiple myeloma. The incidence of neuropathy induced by bortezomib is around 30-60%. Although the neurotoxic mechanisms are not completely understood, experimental studies suggest that aggresome formation, endoplasmic reticulum stress, mitotoxicity, inflammatory response, and DNA damage could contribute to this neurotoxicity. Additionally, the second generation of proteasome inhibitors, headed by carfilzomib, is currently being developed in order to reduce the toxic profile, with promising results. However, more extensive clinical experience and further experimental research are needed in order to determine the potential benefits of the second generation over bortezomib. The present review summarizes the main clinical features and mechanistic events related to the neuropathy induced by proteasome-inhibitors.


A fMRI evaluation of lamotrigine for the treatment of trigeminal neuropathic pain: pilot study.
Using functional magnetic resonance imaging (fMRI) methods, we evaluated the effects of lamotrigine vs placebo in a double-blind 1:1 randomized trial. Six patients with neuropathic pain were recruited for the study. All subjects had baseline pain >4/10 on a visual analog scale (VAS) and allodynia to brush as inclusion criteria for the study. Patients underwent two fMRI sessions, with half of the subjects receiving placebo first and half receiving drug first (based on the blinding protocol). Lamotrigine decreased their average pain intensity level from 5.6 to 3.5 on a VAS. All subjects had brush, cold, and heat applied to the affected and mirror-unaffected sides of their face. The results show: 1) in a small cohort, lamotrigine had a significant effect on heat VAS but not on the other stimuli; and 2) contrast analysis of fMRI results for heat stimuli applied to the affected face for lamotrigine vs placebo produced an overall decrease in blood oxygen dependent level signal, suggesting a potential inhibitory effect of the drug on predominantly cortical regions (frontal, parietal, and temporal).


Tricyclic antidepressant drug interactions with histamine and alpha-adrenergic receptors.
Tricyclic antidepressant drugs are remarkable in their therapeutic actions. When given acutely they are generally sedating. Then after a lag of 1-3 weeks, they alleviate depressive symptoms. Besides the delayed psychic energizing properties, the immediate apparent sedative actions may have importance for the relief of psychomotor agitation. This article describes influences of the drugs on histamine H1 and alpha-adrenergic receptors which may be of relevance to the energizing effects and relief of psychomotor agitation.


FGF-FGFR Mediates the Activity-Dependent Dendritogenesis of Layer IV Neurons during Barrel Formation.
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that Fgfr1/2/3 and Fgf7/9/10/22 mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding de novo dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting Fgfr1/2/3 in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several Fgf/Fgfr mRNAs within 2 h. In vivo, within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of Fgf9, Fgf10, Fgfr2c, and Fgfr3b in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting Fgfr1/2/3 abolished kainic acid-induced bSC dendritic overgrowth. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study.SIGNIFICANCE STATEMENT Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core factor in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of Fgfrs and their ligands Fgfs Deleting Fgfr1/2/3 not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic overgrowth. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic outgrowth within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.


Requirement for diverse TCR specificities determines regulatory T cell activity in a mouse model of autoimmune arthritis.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are required to restrain the immune system from mounting an autoaggressive systemic inflammatory response, but why their activity can prevent (or allow) organ-specific autoimmunity remains poorly understood. We have examined how TCR specificity contributes to Treg activity using a mouse model of spontaneous autoimmune arthritis, in which CD4(+) T cells expressing a clonotypic TCR induce disease by an IL-17-dependent mechanism. Administration of polyclonal Tregs suppressed Th17 cell formation and prevented arthritis development; notably, Tregs expressing the clonotypic TCR did not. These clonotypic Tregs exerted Ag-specific suppression of effector CD4(+) T cells using the clonotypic TCR in vivo, but failed to mediate bystander suppression and did not prevent Th17 cells using nonclonotypic TCRs from accumulating in joint-draining lymph nodes of arthritic mice. These studies indicate that the availability of Tregs with diverse TCR specificities can be crucial to their activity in autoimmune arthritis.


Ecological super-spreaders drive host-range oscillations: Omicron and risk space for emerging infectious disease.
The unusual genetic diversity of the Omicron strain has led to speculation about its origin. The mathematical modelling platform developed for the Stockholm Paradigm (SP) indicates strongly that it has retro-colonized humans from an unidentified nonhuman mammal, likely originally infected by humans. The relationship between Omicron and all other SARS-CoV-2 variants indicates oscillations among hosts, a core part of the SP. Such oscillations result from the emergence of novel variants following colonization of new hosts, replenishing and expanding the risk space for disease emergence. The SP predicts that pathogens colonize new hosts using pre-existing capacities. Those events are thus predictable to a certain extent. Novel variants emerge after a colonization and are not predictable. This makes it imperative to take proactive measures for anticipating emerging infectious diseases (EID) and mitigating their impact. The SP suggests a policy protocol, DAMA, to accomplish this goal. DAMA comprises: DOCUMENT to detect pathogens before they emerge in new places or colonize new hosts; ASSESS to determine risk; MONITOR to detect changes in pathogen populations that increase the risk of outbreaks and ACT to prevent outbreaks when possible and minimize their impact when they occur.


Oral contraceptives and reproductive system cancer.
Extensive research during the last 20 years has shown that oral contraceptives are safe. Several recent epidemiological studies have confirmed that combined oral contraceptives (COCs) provide substantial protection against endometrial and ovarian cancer, and this protection is long-lasting and may persist for 15 or more years after termination of OC use. In many studies COCs have been associated with an increased risk of cervical abnormalities and cervical cancer, but there might be alternative explanations for these epidemiological associations (COC users can start having sexual intercourse at an earlier age, they have more sexual partners, and they rarely use barrier methods of contraception), so OCs act as a promoter for HPV-induced carcinogenesis. Finally, women who are currently using COCs or have used them in the past 10 years are at a slightly increased risk of having breast cancer during the next 10 years, although the additional cancers diagnosed tend to be localized to the breast and they are less advanced clinically than the cancers diagnosed in those who have never used COCs.


A Pathophysiological Model-Driven Communication for Dynamic Distributed Medical Best Practice Guidance Systems.
There is a great divide between rural and urban areas, particularly in medical emergency care. Although medical best practice guidelines exist and are in hospital handbooks, they are often lengthy and difficult to apply clinically. The challenges are exaggerated for doctors in rural areas and emergency medical technicians (EMT) during patient transport. In this paper, we propose the concept of distributed executable medical best practice guidance systems to assist adherence to best practice from the time that a patient first presents at a rural hospital, through diagnosis and ambulance transfer to arrival and treatment at a regional tertiary hospital center. We codify complex medical knowledge in the form of simplified distributed executable disease automata, from the thin automata at rural hospitals to the rich automata in the regional center hospitals. However, a main challenge is how to efficiently and safely synchronize distributed best practice models as the communication among medical facilities, devices, and professionals generates a large number of messages. This complex problem of patient diagnosis and transport from rural to center facility is also fraught with many uncertainties and changes resulting in a high degree of dynamism. A critically ill patient's medical conditions can change abruptly in addition to changes in the wireless bandwidth during the ambulance transfer. Such dynamics have yet to be addressed in existing literature on telemedicine. To address this situation, we propose a pathophysiological model-driven message exchange communication architecture that ensures the real-time and dynamic requirements of synchronization among distributed emergency best practice models are met in a reliable and safe manner. Taking the signs, symptoms, and progress of stroke patients transported across a geographically distributed healthcare network as the motivating use case, we implement our communication system and apply it to our developed best practice automata using laboratory simulations. Our proof-of-concept experiments shows there is potential for the use of our system in a wide variety of domains.


Vaginal birth after cesarean delivery in a small rural community with a solo practice.
The objective of this study is to review the safety and success of a trial of labor after cesarean in a group of patients managed by a solo practitioner in a rural community. This was a retrospective review of all deliveries performed over an 11-year period by a single practitioner in a rural community. Standard contraindications for attempt at vaginal birth after cesarean were observed. Between January 1, 1989 and December 31, 1999, there were 5015 total deliveries. Women with at least one previous cesarean delivery accounted for 11.8% (593) of all patients. Trial of labor was attempted in 413 (74.5%) of these patients, and resulted in vaginal delivery in 308 (75%). Maternal complications were similar between the groups. There was no incidence of uterine rupture, maternal deaths, or neonatal deaths. Vaginal birth after cesarean can be performed safely in isolated rural hospitals with a high success rate.


Sociodemographic and Clinical Predictors of Prescription Opioid Use in a Longitudinal Community-Based Cohort Study of Middle-Aged and Older Adults.
Identifying factors associated with opioid use in middle-aged and older adults is a fundamental step in the mitigation of potentially unnecessary opioid consumption and opioid-related harms. Using longitudinal data on a community-based cohort of adults aged 50-90 years residing in Johnston County, North Carolina, we examined sociodemographic and clinical factors in non-opioid users (n = 786) at baseline (2006-2010) as predictors of opioid use at follow-up (2013-2015). Variables included age, sex, race, obesity, educational attainment, employment status, household poverty rate, marital status, depressive symptoms, social support, pain catastrophizing, pain sensitivity, insurance status, polypharmacy, and smoking status. At follow-up, 13% of participants were using prescription opioids. In the multivariable model, high pain catastrophizing (adjusted odds ratio; 95% confidence interval = 2.14; 1.33-3.46), polypharmacy (2.08; 1.23-3.53), and history of depressive symptoms (2.00; 1.19-3.38) were independent markers of opioid use. Findings support the assessment of these modifiable factors during clinical encounters in patients ≥ 50 years old with chronic pain.


Cascaded differential and wavelet compression of chromosome images.
This paper proposes a new method for chromosome image compression based on an important characteristic of these images: the regions of interest (ROIs) to cytogeneticists for evaluation and diagnosis are well determined and segmented. Such information is utilized to advantage in our compression algorithm, which combines lossless compression of chromosome ROIs with lossy-to-lossless coding of the remaining image parts. This is accomplished by first performing a differential operation on chromosome ROIs for decorrelation, followed by critically sampled integer wavelet transforms on these regions and the remaining image parts. The well-known set partitioning in hierarchical trees (SPIHT) (Said and Perlman, 1996) algorithm is modified to generate separate embedded bit streams for both chromosome ROIs and the rest of the image that allow continuous lossy-to-lossless compression of both (although lossless compression of the former is commonly used in practice). Experiments on two sets of sample chromosome spread and karyotype images indicate that the proposed approach significantly outperforms current compression techniques used in commercial karyotyping systems and JPEG-2000 compression, which does not provide the desirable support for lossless compression of arbitrary ROIs.


Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets.
Malonyl-CoA, generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the control of fatty acid synthesis and oxidation in response to dietary changes. ACC2 is associated to the mitochondria, and Acc2-/- mice have a normal lifespan and higher fatty acid oxidation rate and accumulate less fat. Mutant mice fed high-fat/high-carbohydrate diets weighed less than their WT cohorts, accumulated less fat, and maintained normal levels of insulin and glucose, whereas the WT mice became type-2 diabetic with hyperglycemic and hyperinsulinemic status. Fatty acid oxidation rates in the soleus muscle and in hepatocytes of Acc2-/- mice were significantly higher than those of WT cohorts and were not affected by the addition of insulin. mRNA levels of uncoupling proteins (UCPs) were significantly higher in adipose, heart (UCP2), and muscle (UCP3) tissues of mutant mice compared with those of the WT. The increase in the UCP levels along with increased fatty acid oxidation may play an essential role in the regulation of energy expenditure. Lowering intracellular fatty acid accumulation in the mutant relative to that of the WT mice may thus impact glucose transport by higher GLUT4 activity and insulin sensitivity. These results suggest that ACC2 plays an essential role in controlling fatty acid oxidation and is a potential target in therapy against obesity and related diseases.


How to stabilize the level of ionized calcium and citrate during plateletpheresis.
Citrate reactions are uncomfortable and potentially dangerous to apheresis donors. Reduction of citrate increases comfort, but may lead to platelet clumping. We describe a protocol for stepwise reduction of the volume of ACD-A injected during plateletpheresis. This protocol has been carried out in 45 healthy donors with the Cobe 2997 (Cobe) cell separator, and in 35 with the Fenwal-CS 3000 (CS). Using this protocol, during the first hour of platelet collection, ionised calcium decreased on average by 18% for CS and by 18.4% for Cobe. During the second hour, Ca2+ and citrate ion concentration did not change with either Cobe or CS (about 65% of citrate ion load is eliminated). We observed mild signs of neuromuscular hyperexcitability in only 22% and 28% of donors with Cobe and CS, respectively. We also found a significant reduction of phosphate ions (p < 0.0001) at the end of the procedures. With this stepdown citrate reduction protocol, we obtained a significant reduction of injected citrate without the complication of platelet clumps.


Further observations on the corpuscles of Stannius in two Indian hill-stream teleosts.
The corpuscles of Stannius in Glyptothorax pectinopterus and Pseudecheneis sulcatus occur in close proximity to the mesonephros. They are encapsulated structures comprising of secretory cells which make up a homogeneous mass in G. pectinopterus, but are arranged in complete or incomplete lobules in P. sulcatus. Based on their reaction to the aldehyde fuchsin or PAS, two types of corpuscular cells are demonstrable, and the earlier suggestion that CS have a single cell type in these two species is therefore withdrawn. The stainable cells react positively and intensely in contrast to the nonstainable ones which remain more or less colourless. Although a mixture of the two cell types comprise the CS, the stainable cells preponderate.


Functional metabolic mapping during forelimb movement in rat. II. Stimulation of forelimb muscles.
Repetitive electrical stimulation of wrist extensor muscles in rat was combined with quantitative 14C-deoxyglucose autoradiography to study sensory systems functionally activated during forelimb movement. Metabolism increased ipsilaterally in the wrist extensors, the dorsal horn of the cervical spinal cord, the cuneate nucleus and cerebellar hemisphere. The metabolic activation in cerebellum occurred in cortex surrounding the primary fissure anteriorly (lobules simplex and V), and the prepyramidal fissure posteriorly (lobules paramedian and copula pyramis). Metabolism was increased in both granule cell and molecular layers and was uniform throughout the zone of activation. Hindlimb stimulation primarily activated the medial aspect of copula pyramis, demonstrating the somatotopic specificity of changes. Forelimb stimulation also activated contralateral sites in the dorsal accessory nucleus of the inferior olive, ventrobasal thalamus, and SI and SII in cortex. Studies of the relationship between the magnitude of the response and the frequency of the stimulation revealed a positive correlation in muscle, dorsal horn and cuneate nucleus. Other activated sites only showed a significant change at the highest rates of stimulation. Comparison of the pattern of metabolic activation during forelimb movements induced centrally (Collins et al., 1986) with the pattern induced peripherally revealed overlap primarily in the paramedian zone of anterior and posterior cerebellum, and the granular cortex of SI and SII. These studies suggest that forelimb movement initiated centrally would have considerable influence on feedback sensation from the moving limb in these sites.


Evaluation of cuspoid and umbilic diffraction catastrophes of codimension four.
The evaluation of the two diffraction catastrophes of codimension four, namely, the butterfly and the parabolic umbilic, is here proposed by means of a simple computational approach developed in the past to characterize the whole hierarchy of the structurally stable diffraction patterns produced by optical diffraction in three-dimensional space. In particular, after expanding the phase integral representations of butterfly and parabolic umbilic in terms of (slowly) convergent power series, the retrieving action of the Weniger transformation on them is investigated through several numerical experiments. We believe that the methodology and the results presented here could also be of help for the dissemination of catastrophe optics to the widest scientific audience.


Intrinsic prostaglandin release. A mediator of anoxia-induced relaxation in an isolated coronary artery preparation.
Isolated coronary artery strips of the bovine heart in vitro relax in response to decreased bath oxygen tensions (from 515 mm Hg to 112, 53, and 38 mm Hg). In addition, the rate of intrinsic formation and release of prostaglandin is considerably increased under conditions of decreased PO2. The vascular relaxations under reduced PO2 are attenuated and the elevations in prostaglandin output blocked by prostaglandin synthesis inhibitors. It appears that alterations in the output of a PGE with vasodilator activity, probably E1, is a significant factor regulating the compensatory changes in tone of the coronary arteries in response to anoxic conditions.


The role of a 5alpha-hydroxylated intermediate in the formation of the 5, 6-double bond in cholesterol biosynthesis.
If the biological conversion of cholest-7-en-3beta-ol (I) into cholesterol (IV) occurred thorugh the intermediacy of cholest-7-ene-3beta,5alpha-diol (II) then the factor(s) adversely affecting the convwesion of the 5alpha-hydroxy sterol (II) into cholesterol must at least equally adversely affect the formation of cholesterol from cholest-7-en-3beta-ol. By using partial denaturation techniquws and dual-labelled precursors it was shown that the enzyme system responsible for the conversion of the 5alpha-hydroxy sterol (II) into cholesterol denatured faster than that for the corresponding conversion from cholest-7-en-3beta-ol (I).


Solvent-dependent modulation of metal-metal electronic interactions in a dinuclear cyanoruthenate complex: a detailed electrochemical, spectroscopic and computational study.
The dinuclear complex [{Ru(CN)(4)}(2)(μ-bppz)](4-) shows a strongly solvent-dependent metal-metal electronic interaction which allows the mixed-valence state to be switched from class 2 to class 3 by changing solvent from water to CH(2)Cl(2). In CH(2)Cl(2) the separation between the successive Ru(II)/Ru(III) redox couples is 350 mV and the IVCT band (from the UV/Vis/NIR spectroelectrochemistry) is characteristic of a borderline class II/III or class III mixed valence state. In water, the redox separation is only 110 mV and the much broader IVCT transition is characteristic of a class II mixed-valence state. This is consistent with the observation that raising and lowering the energy of the d(π) orbitals in CH(2)Cl(2) or water, respectively, will decrease or increase the energy gap to the LUMO of the bppz bridging ligand, which provides the delocalisation pathway via electron-transfer. IR spectroelectrochemistry could only be carried out successfully in CH(2)Cl(2) and revealed class III mixed-valence behaviour on the fast IR timescale. In contrast to this, time-resolved IR spectroscopy showed that the MLCT excited state, which is formulated as Ru(III)(bppz(˙-))Ru(II) and can therefore be considered as a mixed-valence Ru(II)/Ru(III) complex with an intermediate bridging radical anion ligand, is localised on the IR timescale with spectroscopically distinct Ru(II) and Ru(III) termini. This is because the necessary electron-transfer via the bppz ligand is more difficult because of the additional electron on bppz(˙-) which raises the orbital through which electron exchange occurs in energy. DFT calculations reproduce the electronic spectra of the complex in all three Ru(II)/Ru(II), Ru(II)/Ru(III) and Ru(III)/Ru(III) calculations in both water and CH(2)Cl(2) well as long as an explicit allowance is made for the presence of water molecules hydrogen-bonded to the cyanides in the model used. They also reproduce the excited-state IR spectra of both [Ru(CN)(4)(μ-bppz)](2-) and [{Ru(CN)(4)}(2)(μ-bppz)](4-) very well in both solvents. The reorganization of the water solvent shell indicates a possible dynamical reason for the longer life time of the triplet state in water compared to CH(2)Cl(2).


Regulations on Genome Editing of Human Embryos in Japan: Our Moral Moratorium.
The use of human embryos in genome editing research has recently been approved in China and the United Kingdom. In Japan, the debate on regulations on genome editing research studies using human embryos is underway, but is becoming increasingly entangled, to the point of deadlock. One main reason for this is the misalignment between the Japanese government and the research communities, in their awareness surrounding these regulations. In this article, we report on this ongoing and entangled debate in Japan concerning the regulations on genome editing technology using human embryos. The most critically needed next step is a grassroots level discussion among various experts such as those in the arts and humanities.


Differential Expression of Markers and Activities in a Group of PC12 Nerve Cell Clones.
Sixteen clones, recently isolated from the PC12 nerve cell line, were analysed for a variety of markers and activities. Two endoplasmic reticulum (ER) luminal markers, the chaperone protein BiP and the major Ca2+ storage protein calreticulin, as well as the 40-kD rough ER membrane marker and the plus-end-directed mirotubule motor protein, kinesin, were found to be expressed at similar levels. These results suggest that the size of the ER, the function of microtubules and the capacity of the rapidly exchanging Ca2+ store do not change substantially among the clones. Other proteins expressed at comparable levels were synapsin I and IIa, members of a nerve cell-specific protein family known to bind synaptic vesicles to the cytoskeleton. In contrast, another ER membrane protein, calnexin, and the markers of secretory organelles were found to vary markedly. One clone (clone 27) completely lacked both chromogranin B and secretogranin II, the proteins contained within dense granules, and synaptophysin, a marker of clear vesicles. Other clones expressed these markers to variable and apparently mutually unrelated levels. Marked variability was observed also in the uptake of exogenous catecholamines, in their release both at rest and after stimulation, and in nerve growth factor-induced differentiation. These results provide indirect information about the mechanisms that regulate the expression of structures and activities in PC12 cells. Of particular interest is clone 27, which appears globally incompetent for regulated secretion and might therefore be a valuable tool for the study of this activity in a nerve cell.


Nursing image as reflected in sex role preferences.
This study examined the relationships between sex role preference and image of nursing among 43 female freshman students of nursing. Student nurses who envisioned themselves as fulfilling a more traditional female role saw nursing differently from those who envisioned themselves as more liberal. The Dreyer Sex Role Preference Profile delineated two groups. A two-tailed test of proportions was used to analyze the data with significance determined at the .05 level. The groups differed significantly on nine of the 19 attributes of nursing, and differed in the importance to self on eight of the 19 items. Interestingly, however, none saw themselves as strongly traditional.


Spatial mapping of splicing factor complexes involved in exon and intron definition.
We have analyzed the interaction between serine/arginine-rich (SR) proteins and splicing components that recognize either the 5' or 3' splice site. Previously, these interactions have been extensively characterized biochemically and are critical for both intron and exon definition. We use fluorescence resonance energy transfer (FRET) microscopy to identify interactions of individual SR proteins with the U1 small nuclear ribonucleoprotein (snRNP)-associated 70-kD protein (U1 70K) and with the small subunit of the U2 snRNP auxiliary factor (U2AF35) in live-cell nuclei. We find that these interactions occur in the presence of RNA polymerase II inhibitors, demonstrating that they are not exclusively cotranscriptional. Using FRET imaging by means of fluorescence lifetime imaging microscopy (FLIM), we map these interactions to specific sites in the nucleus. The FLIM data also reveal a previously unknown interaction between HCC1, a factor related to U2AF65, with both subunits of U2AF. Spatial mapping using FLIM-FRET reveals differences in splicing factors interactions within complexes located in separate subnuclear domains.


The role of health technology assessment in coverage decisions on newborn screening.
The role and impact of health technology assessment (HTA) in health policy has been widely discussed. Researchers have started to analyze how decisions on coverage of new technologies are made. Although the involvement of HTA may be an indicator of a well established decision process, this hypothesis requires validation. Also, it is not known whether HTA involvement is associated with other characteristics of decision making like participation or transparency. The primary objective of this study was to develop and test statements on the association between the publication of an HTA and coverage decision making for newborn screening tests in European Union countries. Five statements were defined on the relative role of HTA during the steps of decision processes: trigger, participation, publication, assessment, and appraisal. For this purpose, data on twenty-two decision processes in the area of newborn screening across Europe were analyzed, defined as a coverage decision for a given disorder in a specific country. Decision processes were compared by whether the decision was accompanied by the publication of an HTA report. To test differences, nonparametric statistical tests were used. The decision steps of trigger, participation and publication differed between the HTA and the non-HTA groups. No clear association between HTA and assessment methods in coverage decision making was identified. It appeared that there is an association between HTA and coverage decision processes that are more explicit, inclusive, and transparent. It is unclear whether HTA is associated with formal evidence reviews and economic evaluations.


The Wider Impacts of the Coronavirus Pandemic on the NHS.
The coronavirus pandemic has had huge impacts on the National Health Service (NHS). Patients suffering from the illness have placed unprecedented demands on acute care, particularly on intensive care units (ICUs). This has led to an effort to dramatically increase the resources available to NHS hospitals in treating these patients, involving reorganisation of hospital facilities, redeployment of existing staff and a drive to bring in recently retired and newly graduated staff to fight the pandemic. These increases in demand and changes to supply have had large knock-on effects on the care provided to the wider population. This paper discusses likely implications for healthcare delivery in the short and medium term of the responses to the coronavirus pandemic, focusing primarily on the implications for non-coronavirus patients. Patterns of past care suggest those most likely to be affected by these disruptions will be older individuals and those living in more deprived areas, potentially exacerbating pre-existing health inequalities. Effects are likely to persist into the longer run, with particular challenges around recruitment and ongoing staff shortages.


Emotional Intelligence: An Old Issue and a New Look in Clinical Teaching.
In this paper, a novel model of clinical teachers with social and emotional competency which is emphasized on the importance of clinical teacher's social and emotional competence is presented. In this model, we supposed that a teacher with social and emotional competence can manage her/his emotions and has the ability to personal development and well-being. Such teacher has the competency of empathy, communication with the patients, teamwork, and collaboration to provide successful patient-centered care and relationship-centered care. He/she will be success in clinical supervision, role modeling, and mentoring by providing appropriate relationship with students. This teacher can influence and build bonds that will be effective for clinical management and leadership. In addition, it will affect the hidden and informal curriculum with the awareness of the context. These factors establish an appropriate learning environment to achieve students' academic, professional, social, and emotional outcomes and create an appropriate health care environment that influences the successful care of patient and patient's satisfaction. We reviewed a broad body of research to support our proposed model and finally proposed agendas for future research.


Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations.
Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This "windshield wiper" effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.


Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats.
The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct-ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2. FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis.


Creation of low-copy integrated transgenic lines in Caenorhabditis elegans.
In Caenorhabditis elegans, transgenic lines are typically created by injecting DNA into the hermaphrodite germline to form multicopy extrachromosomal DNA arrays. This technique is a reliable means of expressing transgenes in C. elegans, but its use has limitations. Because extrachromosomal arrays are semistable, only a fraction of the animals in a transgenic extrachromosomal array line are transformed. In addition, because extrachromosomal arrays can contain hundreds of copies of the transforming DNA, transgenes may be overexpressed, misexpressed, or silenced. We have developed an alternative method for C. elegans transformation, using microparticle bombardment, that produces single- and low-copy chromosomal insertions. Using this method, we find that it is possible to create integrated transgenic lines that reproducibly express GFP reporter constructs without the variations in expression level and pattern frequently exhibited by extrachromosomal array lines. In addition, we find that low-copy integrated lines can also be used to express transgenes in the C. elegans germline, where conventional extrachromosomal arrays typically fail to express due to germline silencing.


Immunopathology of Brucella infection.
In spite of the protean nature of the disease, inflammation is a hallmark of brucellosis and affected tissues usually exhibit inflammatory infiltrates. As Brucella lacks exotoxins, exoproteases or cytolysins, pathological findings in brucellosis probably arise from inflammation-driven processes. The cellular and molecular bases of immunopathological phenomena probably involved in Brucella pathogenesis have been unraveled in the last few years. Brucella-infected osteoblasts, either alone or in synergy with infected macrophages, produce cytokines, chemokines and matrixmetalloproteinases (MMPs), and similar phenomena are mounted by fibroblast-like synoviocytes. The released cytokines promote the secretion of MMPs and induce osteoclastogenesis. Altogether, these phenomena may contribute to the bone loss and cartilage degradation usually observed in brucellar arthritis and osteomyelitis. Proinflammatory cytokines may be also involved in the pathogenesis of neurobrucellosis. B. abortus and its lipoproteins elicit an inflammatory response in the CNS of mice, leading to astrogliosis, a characteristic feature of neurobrucellosis. Heat-killed bacteria (HKBA) and the L-Omp19 lipoprotein elicit astrocyte apoptosis and proliferation (two features of astrogliosis), and apoptosis depends on TNF-α signaling. Brucella also infects and replicates in human endothelial cells, inducing the production of chemokines and IL-6, and an increased expression of adhesion molecules. The sustained inflammatory process derived from the longlasting infection of the endothelium may be important for the development of endocarditis. Therefore, while Brucella induces a low grade inflammation as compared to other pathogens, its prolonged intracellular persistence in infected tissues supports a long-lasting inflammatory response that mediates different pathways of tissue damage. In this context, approaches to avoid the invasion of host cells or limit the intracellular survival of the bacterium may be suitable to prevent the pathological consequences of Brucella infections. The article presents some of the recent patents related to such approaches.


Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development.
ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13) is primarily synthesized in liver. The biosynthesis of ADAMTS13 and its physiological role in placenta are not known. We used real-time polymerase chain reaction, immunohistochemistry, and Western blotting analyses, as well as proteolytic cleavage of FRETS (fluorescent resonance energy transfers)-VWF73, to determine ADAMTS13 expression in placenta and trophoblasts obtained from individuals with normal pregnancy and patients with severe preeclampsia. We also determined the role of ADAMTS13 in extravillous trophoblasts using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound scratch assay, transwell migration assay, tube formation assay, and tissue outgrowth assays. We showed that full-length and proteolytically active ADAMTS13 was expressed in normal human placenta, primarily in the trophoblasts and villous core fetal vessel endothelium during pregnancy. Placental expression of ADAMTS13 mRNA, protein, and proteolytic activity was at the highest levels during the first trimester and significantly reduced at the term of gestation. Additionally, significantly reduced levels of placental ADAMTS13 expression was detected under hypoxic conditions and in patients with preeclampsia. In addition, recombinant ADAMTS13 protease stimulated proliferation, migration, invasion, and network formation of trophoblastic cells in culture. Finally, knockdown of ADAMTS13 expression attenuated the ability of tube formation in trophoblast (HTR-8/SVNEO) cells and the extravillous trophoblast outgrowth in placental explants. Our results demonstrate for the first time the expression of ADAMTS13 mRNA and protein in normal and abnormal placental tissues and its role in promoting angiogenesis and trophoblastic cell development. The findings support the potential role of the ADAMTS13-von Willebrand factor pathway in normal pregnancy and pathogenesis of preeclampsia.


Folium mori increases cell proliferation and neuropeptide Y expression in dentate gyrus of streptozotocin-induced diabetic rats.
The possibility has been raised that Folium mori is clinically effective for the treatment and prevention of diabetes. In the present study, the effects of Folium mori on cell proliferation and expression of neuropeptide Y (NPY) in the dentate gyrus of rats with streptozotocin (STZ)-induced diabetes were investigated by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and NPY immunohistochemistry. In rats with STZ-induced diabetes, cell proliferation and NPY expression in the dentate gyrus were suppressed, and treatment with Folium mori was shown to increase new cell formation and NPY expression in the dentate gyrus in both normal rats and those with STZ-induced diabetes. In light of previous studies, this result appears to indicate that increased expression of NPY in the dentate gyrus induced by treatment with Folium mori is associated with the observed effect of Folium mori extract on cell proliferation. Based on the present results, it is suggested that Folium mori treatment may aid in the recovery from the central nervous system complications of diabetes mellitus.


Modeling and computing of stock index forecasting based on neural network and Markov chain.
The stock index reflects the fluctuation of the stock market. For a long time, there have been a lot of researches on the forecast of stock index. However, the traditional method is limited to achieving an ideal precision in the dynamic market due to the influences of many factors such as the economic situation, policy changes, and emergency events. Therefore, the approach based on adaptive modeling and conditional probability transfer causes the new attention of researchers. This paper presents a new forecast method by the combination of improved back-propagation (BP) neural network and Markov chain, as well as its modeling and computing technology. This method includes initial forecasting by improved BP neural network, division of Markov state region, computing of the state transition probability matrix, and the prediction adjustment. Results of the empirical study show that this method can achieve high accuracy in the stock index prediction, and it could provide a good reference for the investment in stock market.


Pharmacokinetics of cefazolin in guinea pigs.
The occurrence of antibiotic-related enterocolitis in guinea pigs restricts the use of many common antibiotics in this species. Cephaloridine, an antibiotic frequently recommended for this species, is no longer available and a substitute has yet to be explored. In this study, the potential therapeutic efficacy of cefazolin, also a first generation cephalosporin, was evaluated in guinea pigs by assessing pharmacokinetics, toxicity and the minimal inhibitory concentration for selected animal pathogens. Pharmacokinetics and toxicity were evaluated in four phases: single intramuscular injections, multiple intramuscular injections over 30 hours, multiple intramuscular injections over 5 days, and serum-protein binding studies. Antibiotic-related enterocolitis and irritation at the injection site occurred following high (100 mg/kg) repeated doses. At all dose levels, blood values exceeded the minimum inhibitory concentration for Bordetella bronchiseptica for only 1 hour postinjection. For Streptococcus and Staphylococcus sp., the drug half-life was 0.5 hours with peak concentrations occurring within 0.25 hours of injection. The volume of distribution of 0.5 l/kg indicated that there was extensive tissue distribution. Serum protein binding was approximately 85%. The short half-life and rapid plasma clearance rate (10.4 ml/min/kg) indicated that cefazolin is eliminated very rapidly from the guinea pig and may be of questionable therapeutic value.


The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy.
To provide updated, evidence-based recommendations for the therapy of hypertension in adults. For patients with hypertension, a number of antihypertensive agents may control blood pressure. Randomized trials evaluating first-line therapy with thiazides, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, alpha-blockers, centrally acting agents or angiotensin II receptor antagonists were reviewed. The health outcomes that were considered were changes in blood pressure, cardiovascular morbidity, and cardiovascular and/or all-cause mortality rates. Economic outcomes were not considered due to insufficient evidence. MEDLINE was searched for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension. Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other published studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. A high value was placed on the avoidance of cardiovascular morbidity and mortality. Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood-pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality. The present document contains detailed recommendations pertaining to treatment thresholds, target blood pressures, and choice of agents in various settings in patients with hypertension. The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus, the amalgamation of the previous sections on treatment of hypertension in the young and old into one section, increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke. Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk, the presence and/or absence of target organ damage, and comorbidities. All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation. Only those recommendations achieving high levels of consensus are reported here. These guidelines will continue to be updated annually.


Assessment of children exposed to adult pulmonary tuberculosis in Cali, Colombia.
There is a lack of uniform criteria for the diagnosis and management of tuberculosis (TB) in children in Cali, Colombia. Addressing TB in children is a challenge in this setting, under both programmatic and research conditions. To facilitate the diagnostic assessment of TB in a paediatric cohort of TB household contacts. A diagnostic and management algorithm (DMA) was used to assess children exposed to adult TB cases, according to clinical and epidemiological findings and under programmatic conditions. On the basis of diagnostic tests, cases were classified as TB exposure, TB infection, suspected TB, possible TB or confirmed TB and then submitted to a management plan. This was a prospective pilot study nested within a national cohort study of the transmission dynamics of Mycobacterium tuberculosis, undertaken in Colombia during 2005-2008. During 24 months of follow-up, 54 of 217 children met the criteria for assessment by DMA, 18 of whom (33%) were considered to be TB incident cases (new TB cases among household contacts). The main clinical findings were failure to thrive and cough lasting >21 days. Only one case was smear-positive and culture-confirmed TB. TB treatment was given to 16 children and they demonstrated clinical and radiographic resolution at follow-up. Conducting the study under programmatic conditions demonstrated barriers to accessing competent radiological evaluation, correct interpretation of the tuberculin skin test, and proper specimen collection. Structured assessment using DMA facilitated the detection of incident TB cases. The study identified potential barriers to addressing childhood TB in Cali.


SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells.
Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8+ T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8+ T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity.


Radicality and safety of mediastinal lymphadenectomy in lung resection: a comparative analysis of uniportal thoracoscopic, multiportal thoracoscopic, and thoracotomy approaches.
Lung cancer poses a significant challenge with high mortality rates. Minimally invasive surgical approaches, including the uniportal thoracoscopic technique, offer potential benefits in terms of recovery and patient compliance. This study focuses on evaluating the radicality of mediastinal lymphadenectomy during uniportal thoracoscopic lung resection, specifically assessing the reachability of established lymphatic stations. A comparative study was conducted at the University Hospital Ostrava from January 2015 to July 2022, focusing on the evaluation of radicality in mediastinal lymphadenectomy across three patient subgroups: uniportal thoracoscopic approach, multiportal thoracoscopic approach, and thoracotomy approach. The study implemented the routine identification and excision of 8 lymph node stations from the respective hemithorax to assess the radicality of lymph node harvesting. A total of 428 patients were enrolled and evaluated. No significant differences were observed in the number of lymph nodes removed between the subgroups. The mean number of lymph nodes removed was 6.50 in the left hemithorax and 6.49 in the right hemithorax. The 30-day postoperative morbidity rate for the entire patient population was 27.3%, with 17.5% experiencing minor complications and 6.5% experiencing major complications. Statistically significant differences were observed in major complications between the uniportal approach and the thoracotomy approach (3.5% vs 12.0%, p = 0.002). The overall mortality rate in the study population was 3%, with a statistically significant difference in mortality between the uniportal and multiportal approaches (1.0% vs 6.4%, p = 0.020). The uniportal approach demonstrated comparable accessibility and lymph node yield to multiportal and thoracotomy techniques. It is equivalent to established methods in terms of postoperative complications, with fewer major complications compared to thoracotomy. While our study indicates a potential for lower mortality following uniportal lung resection in comparison to multiportal lung resection, and demonstrates comparable outcomes to thoracotomy, it is important to approach these findings cautiously and refrain from drawing definitive conclusions.


Men who have sex with men diagnosed with a sexually transmitted infection are significantly more likely to engage in sexualised drug use.
The sexualised use of recreational drugs (Mephedrone, GBL/GHB, Crystal Meth) generally known as 'chemsex' in men who have sex with men (MSM) is thought to be associated with sexually transmitted infection (STI) acquisition; however there is little data showing a direct relationship. We reviewed 130 randomly selected cases of MSM with an STI attending our STI service and 130 controls (MSM attending the STI service who did not have an STI) between 5 May 2015 and 2 November 2015. Reported condomless anal sex was significantly higher in cases 90/121 (74%) compared with controls 65/122 (53%); ( χ2 = 11.71, p < 0.005, OR 2.54). Recreational drug use in the cases 38/122 (31%) was significantly greater than in controls 20/125 (16%); ( χ2 = 7.88, p < 0.005, OR 2.37). This demonstrates a link between STI acquisition and recreational drug use in MSM. Harm reduction initiatives identifying and addressing party drug use can help to improve the sexual health of MSM, including reducing risk-taking behaviours.


Structural Conformation and Activity of Spider-Derived Inhibitory Cystine Knot Peptide Pn3a Are Modulated by pH.
Numerous spider venom-derived gating modifier toxins exhibit conformational heterogeneity during purification by reversed-phase high-performance liquid chromatography (RP-HPLC). This conformational exchange is especially peculiar for peptides containing an inhibitor cystine knot motif, which confers excellent structural stability under conditions that are not conducive to disulfide shuffling. This phenomenon is often attributed to proline cis/trans isomerization but has also been observed in peptides that do not contain a proline residue. Pn3a is one such peptide forming two chromatographically distinguishable peaks that readily interconvert following the purification of either conformer. The nature of this exchange was previously uncharacterized due to the fast rate of conversion in solution, making isolation of the conformers impossible. In the present study, an N-terminal modification of Pn3a enabled the isolation of the individual conformers, allowing activity assays to be conducted on the individual conformers using electrophysiology. The conformers were analyzed separately by nuclear magnetic resonance spectroscopy (NMR) to study their structural differences. RP-HPLC and NMR were used to study the mechanism of exchange. The later-eluting conformer was the active conformer with a rigid structure that corresponds to the published structure of Pn3a, while NMR analysis revealed the earlier-eluting conformer to be inactive and disordered. The exchange was found to be pH-dependent, arising in acidic solutions, possibly due to reversible disruption and formation of intramolecular salt bridges. This study reveals the nature of non-proline conformational exchange observed in Pn3a and possibly other disulfide-rich peptides, highlighting that the structure and activity of some disulfide-stabilized peptides can be dramatically susceptible to disruption.


The arbuscular mycorrhizal status has an impact on the transcriptome profile and amino acid composition of tomato fruit.
Arbuscular mycorrhizal (AM) symbiosis is the most widespread association between plant roots and fungi in natural and agricultural ecosystems. This work investigated the influence of mycorrhization on the economically relevant part of the tomato plant, by analyzing its impact on the physiology of the fruit. To this aim, a combination of phenological observations, transcriptomics (Microarrays and qRT-PCR) and biochemical analyses was used to unravel the changes that occur on fruits from Micro-Tom tomato plants colonized by the AM fungus Glomus mosseae. Mycorrhization accelerated the flowering and fruit development and increased the fruit yield. Eleven transcripts were differentially regulated in the fruit upon mycorrhization, and the mycorrhiza-responsive genes resulted to be involved in nitrogen and carbohydrate metabolism as well as in regulation and signal transduction. Mycorrhization has increased the amino acid abundance in the fruit from mycorrhizal plants, with glutamine and asparagine being the most responsive amino acids. The obtained results offer novel data on the systemic changes that are induced by the establishment of AM symbiosis in the plant, and confirm the work hypothesis that AM fungi may extend their influence from the root to the fruit.


Recovery of somatosensory evoked potential amplitude after movement.
Sensory transmission is known to be impaired during movement of the stimulated body part. The goal of this study was to determine whether sensory gating persists for a measurable time after completion of a voluntary movement. Tactile stimuli were applied to the right index fingertip at intervals ranging from 63 to 1,000 msec after the completion of rapid thumb movement. Somatosensory evoked potentials (SEPs), recorded over the left cerebral hemisphere, were found to be reduced in size for at least 500 msec after the cessation of movement. The prolonged attenuation of SEPs after movement appears to depend on a central process that persists for a measurable time after the movement has ended.


Epidemiological and clinical aspects of oesophageal carcinoma in the USA.
A study was conducted of all primary oesophageal cancer cases hospitalized from 1970 to 1975 in Oklahoma City hospitals. During this 6 year period, 181 cases were identified. The average annual incidence in Oklahoma county was lowest in white females (2 per 100,000 population), and highest in black males (19 per 100,000 population). Some of the descriptive features of oesophageal carcinoma by age, sex and race distribution were largely compatible to those reported in the literature. Cases with carcinoma in which pain was the first symptom to appear, sought medical advice latest compared to cases with dysphagia as the first symptom, the latter group seeking medical advice earliest. Blacks and whites presented dissimilar distribution of tumours by site. Whereas in blacks 58% of carcinomas were located in the middle thoracic and none in the oesophagogastric junction, in whites tumours were more or less equally distributed in various anatomical sites. Black males exhibited higher mean ages at diagnosis in all sites than black females. The whites showed the opposite trend except in the oesophagogastric junction. Squamous cell carcinoma was the most frequent cell type (80%). The absence of adenocarcinoma cell types in blacks except only two male cases was a noteworthy observation. The clinical stage distribution by anatomical site was unusual for middle thoracic and gastric cardia carcinomas with 54% and 46% of tumours localized and in regional stages at diagnosis respectively.


[35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex.
t- Butylbicyclophosphorothionate ( TBPS ), a derivative of potent GABA antagonistic cage convulsants, has recently been introduced ( Squires , R. F., J.E. Casida , M. Richardson, and E. Saederup (1983) Mol. Pharmacol. 13:326-336) as ligand for a GABA-A receptor-linked drug receptor. Using conventionally prepared washed membrane fractions from rat cerebral cortex, we have confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites (Kd 26 +/- 5 nM) and that muscimol inhibits [35S] TBPS binding (IC50 0.32 microM) allosterically. In 200 mM NaCl the apparent affinity of [35S] TBPS binding sites is lower (Kd 60 +/- 5 nM), and muscimol has biphasic effects with stimulation at low concentrations of muscimol (EC50 0.023 microM) followed by inhibition at high concentrations (IC50 0.72 microM). Both base line [35S] TBPS binding (in 200 mM NaCl) and muscimol inhibition of [35S] TBPS binding (in 200 mM NaBr) are bidirectionally modulated by the occupancy of benzodiazepine receptors with its ligands. Benzodiazepine receptor agonists, regardless of their structure, enhance and inverse benzodiazepine receptor agonists inhibit base line [35S] TBPS binding and muscimol inhibition of [35S] TBPS binding. Fourteen ligands for benzodiazepine receptors display a similar in vitro profile as benzodiazepine receptor agonists or inverse benzodiazepine receptor agonists on [35S] TBPS binding as their anti- or proconvulsive effects in vivo suggest (Jensen, L. H., E. N. Petersen, and C. Braestrup (1983) Life Sci. 33: 393-399). That [35S] TBPS binding sites are constituents of a GABA benzodiazepine receptor complex is also suggested by a number of membrane pretreatments.(ABSTRACT TRUNCATED AT 250 WORDS)


Differentiation of mammalian vestibular hair cells from conditionally immortal, postnatal supporting cells.
We provide evidence from a newly established, conditionally immortal cell line (UB/UE-1) that vestibular supporting cells from the mammalian inner ear can differentiate postnatally into more than one variant of hair cell. A clonal supporting cell line was established from pure utricular sensory epithelia of H2k(b)tsA58 transgenic mice 2 d after birth. Cell proliferation was dependent on conditional expression of the immortalizing gene, the "T" antigen from the SV40 virus. Proliferating cells expressed cytokeratins, and patch-clamp recordings revealed that they all expressed small membrane currents with little time-dependence. They stopped dividing within 2 d of being transferred to differentiating conditions, and within a week they formed three defined populations expressing membrane currents characteristic of supporting cells and two kinds of neonatal hair cell. The cells expressed several characteristic features of normal hair cells, including the transcription factor Brn3.1, a functional acetylcholine receptor composed of alpha9 subunits, and the cytoskeletal proteins myosin VI, myosin VIIa, and fimbrin. Immunofluorescence labeling and electron microscopy showed that the cells formed complex cytoskeletal arrays on their upper surfaces with structural features resembling those at the apices of normal hair cells. The cell line UB/UE-1 provides a valuable in vitro preparation in which the expression of numerous structural and physiological components can be initiated or upregulated during early stages of mammalian hair cell commitment and differentiation.


Resuscitation status in psychogeriatric and general medical inpatients aged 65 years and older: a retrospective comparison study.
Objective The aims of the present study were to establish rates of resuscitation order documentation of patients aged ≥65 years from both psychogeriatric and general medical units and to compare patients on predictors of resuscitation status, particularly examining the effect of depression. Methods A retrospective case note audit of psychogeriatric (n=162) and general medical (n=135) unit admissions within a tertiary teaching hospital was performed. Multivariate logistic regression was used to determine significant clinical and demographic predictors of resuscitation status. Results Resuscitation orders were documented in more psychogeriatric (94.4%) than general medical (48.1%) files. Depression did not significantly predict resuscitation status in either group. Having undergone competency assessment significantly predicted resuscitation status for the total sample and separately for psychogeriatric and medical patients. Older age (overall sample), poorer prognosis (overall sample), living in residential care (overall sample and medical group) and self-consenting to resuscitation status (overall sample and medical group) significantly predicted resuscitation status. Conclusions Resuscitation orders were more frequently documented on the psychogeriatric unit. Further prospective analysis is needed of how resuscitation orders are made before depression is discounted as a predictor of end-of-life decision-making. What is known about the topic? Despite increased community, media and research attention to end-of-life decision-making, resuscitation preferences of older patients are often poorly documented. Existing research into patient clinical and demographic factors that influence end-of-life decision-making have largely focused on general medical rather than psychogeriatric settings. There is a need to investigate rates of resuscitation documentation in psychogeriatric and general medical units and specific factors associated with having a 'do not attempt resuscitation' order in place, particularly the effect of current depression on decision-making. What does this paper add? Resuscitation orders were more frequently documented on the psychogeriatric than medical unit. Depression was not a significant predictor of resuscitation status in either group of patients. Although having undergone a competency assessment, older age and poorer prognosis predicted not being for resuscitation for the total sample, living in residential care and self-consenting to resuscitation status predicted not being for resuscitation for the overall sample and the medical group specifically. What are the implications for practitioners? This paper suggests that the need for clinicians to ensure documentation of preferences is a focus of day-to-day work with older patients. Clinicians should consider patient competency in end-of-life decision-making and how factors associated with depression, such as helplessness, may be more closely related to resuscitation decision-making in older patients.


An update on epigenetics and childhood respiratory diseases.
Epigenetic mechanisms, defined as changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence, have been proposed to constitute a link between genetic and environmental factors that affect complex diseases. Recent studies show that DNA methylation, one of the key epigenetic mechanisms, is altered in children exposed to air pollutants and environmental tobacco smoke early in life. Several candidate gene studies on epigenetics have been published to date, but it is only recently that global methylation analyses have been performed for respiratory disorders such as asthma and chronic obstructive pulmonary disease. However, large-scale studies with adequate power are yet to be presented in children, and implications for clinical use remain to be evaluated. In this review, we summarize the recent advances in epigenetics and respiratory disorders in children, with a main focus on methodological challenges and analyses related to phenotype and exposure using global methylation approaches.


Time dependence of lysozyme adsorption on end-grafted polymer layers of variable grafting density and length.
A combined experimental and theoretical approach establishes the long-lived nature of protein adsorption on surfaces coated with chemically grafted macromolecules. Specifically, we monitor the time dependence of adsorption of lysozyme on surfaces comprising polymer assemblies made of poly(2-hydroxyethyl methacrylate) brushes grafted onto flat silica surfaces such that they produce patterns featuring orthogonal and gradual variation of the chain length (N) and grafting density (σ). We show that in the kinetically controlled regime, the amount of adsorbed protein scales universally with the product σN, while at equilibrium the amount of adsorbed protein is governed solely by σ. Surprisingly, for moderate concentrations of protein in solution, adsorption takes more than 72 h to reach an equilibrium, or steady state. Our experimental findings are corroborated with predictions using molecular theory that provides further insight into the protein adsorption phenomenon. The theory predicts that the universal behavior observed experimentally should be applicable to polymers in poor and theta solvents and to a limited extent also to good solvent conditions. Our combined experimental and theoretical findings reveal that protein adsorption is a long-lived phenomenon, much longer than generally assumed. Our studies confirm the previously predicted important differences in behavior for the kinetic versus thermodynamic control of protein adsorption.


Stretching and folding of 2-nanometer hydrocarbon rods.
Linear alkanes CnH2n+2 in vacuum isolation are finite models for an infinite polyethylene chain. Using spontaneous Raman scattering in supersonic jet expansions for n = 13-21 in different spectral ranges, we determine the minimal chain length nh for the cohesion-driven folding of the preferred extended all-trans conformation into a hairpin structure. We treat fully stretched all-trans alkanes as molecular "nanorods" and derive Young's modulus E for the stretching of an isolated single-strand polyethylene fibre by extrapolating the longitudinal acoustic mode to infinite chain length. Two key quality parameters for accurate intra- and intermolecular force fields of hydrocarbons (nh = 18 ± 1, E = 305 ± 5 GPa) are thus derived with high accuracy from experimental spectroscopy.


Pyridine-Embedded Phenothiazinium Dyes as Lysosome-Targeted Photosensitizers for Highly Efficient Photodynamic Antitumor Therapy.
Development of new photosensitizers (PSs) with high photodynamic efficacy and minimal side effects is of great interest in photodynamic therapy (PDT). In this work, we reported several pyridine-embedded phenothiazinium (pyridophenothiazinium) dyes, which could be conveniently synthesized in a few short steps and acted as highly efficient and potent PSs to selectively localize to lysosomes and photosensitively kill cancer cells. Among them, compound 5, which possessed the ability of promoting intracellular reactive oxygen species (ROS) upon light irradiation by almost 40-fold higher than that of methylene blue (MB, a general phenothiazinium-based PS), exhibited a remarkable phototherapeutic index (PI = 53.8) against HT29 cancer cells, leading to eradication of large solid tumors (∼300 mm3) in a xenograft mouse model without apparent side effects. These results suggest that the pyridophenothiazinium dyes developed herein, especially compound 5, may serve as promising lysosome-targeted PSs for efficient photodynamic antitumor therapy.


Despair of Treatment: A Qualitative Study of Cirrhotic Patients' Perception of Treatment.
Cirrhotic patients are exposed to illness progression and life-threatening side effects. The nature of the disease, its incurability, limitations of liver transplantation, and the intensity of threatening conditions lead to psychological distress for the patients and change in their perception of the treatment. To provide holistic care, it is necessary to clarify the patient's perception of the treatment. The aim of this study was to clarify cirrhotic patients' perception of their treatment. This qualitative study was carried out through a content analysis approach. The participants were 15 cirrhotic patients. Data were collected via semistructured, in-depth interviews and analyzed on the basis of the Granheme and Landman method. Despair of treatment was revealed through four categories: (1) disease perception (quiet start and quiet death, living in an aggravating limitation, intensifying threatening conditions), (2) self-perception (living in the shadow of death, loss of self, preferring family to oneself), (3) perception of treatment (difficulty of treatment compliance, believed to be incurable, treatment conditioned to die, treatment limitation), and (4) spirituality-religion (destiny and divine test, asking God instead of doctors). The study shows that despair of treatment is considered as one of the main concerns of cirrhotic patients. Nurses should program their surveillance to support patients effectively based on the study findings.


Epiluminescence microscopy. A new approach to in vivo detection of Sarcoptes scabiei.
The usual methods of scabies diagnosis include microscopic identification of the mites and their eggs and feces in skin scrapings. In many cases, the results of microscopic examination can be negative owing to the low number of parasites present in the cornified layer. Epiluminescence microscopy (ELM) is an in vivo technique that allows a detailed inspection of the skin, from the surface to the superficial papillary dermis. This is where the scabies mite lives. In this study, we evaluate the applicability and the usefulness of ELM for in vivo diagnosis of scabies. Sixty-five (93%) of 70 cases of scabies showed small, dark, triangular structures at the sites examined with ELM. A subtle linear segment seen below the base of the triangle was made visible by the presence of small air bubbles. Together, both structures resembled a jet with contrail. On traditional microscopic examination of the scrapings, we verified that the triangular structure corresponded to the pigmented anterior section of the mite in all cases. The linear segment observed on ELM was thought to be the burrow of the mite along with its eggs and fecal pellets. The cases in which the results of a first ELM examination were negative demonstrated positive results on a second ELM examination carried out 20 days later. Epiluminescence microscopy is a very useful tool for in vivo diagnosis of scabies because it permits Sarcoptes scabiei detection in only a few minutes, with no discomfort to the patient and with a very low number of false-negative results.


Longitudinal aneurysm shrinkage following endovascular aortic aneurysm repair: a source of intermediate and late complications.
To report the incidence of delayed complications following endovascular abdominal aortic aneurysm (AAA) repair and the relationship of these sequelae to morphological changes in the sac and endograft. Twenty-six AAA patients treated with Vanguard endografts had completed > or = 1-year follow-up. Postoperative angiograms and spiral computed tomographic (CT) scans with 3-dimensional reconstruction were compared to the 1-year images to determine morphological changes in the aneurysm sac and the endograft. These changes were then related to complications occurring between 1 and 12 months postoperatively in the study group. Comparison of angiograms uncovered endograft buckling in 18 (69%) patients and acutely angled or kinked endografts in 10 (38%). Measurements from the CT scans found that undistorted endografts had a mean change in sac length of +6.6 mm. Mean sac length change in buckled endografts was -3.1 mm, while kinked endografts displayed a mean change of -6.2 mm (p < 0.002, Student's t-test). Five (19%) patients, all with distorted endografts, demonstrated late (1 to 12 months) complications (4 endoleaks and 1 graft limb thrombosis) owing to component separation, distal stent migration, and acute angulation. No movement in the proximal stent was observed. Elongation of the endograft (flow line measurement) was observed in one tube graft only. In this study, longitudinal shrinkage of the sac following endovascular aortic aneurysm repair led to buckling or kinking of the endograft within 1 year in 69% of patients. This appears to be an important source of delayed complications.


Ultrasonic evaluation of pararenal masses.
The ease of performing ultrasonic examination and its noninvasive nature make it especially useful in seriously ill patients. We present 12 patients with lesions that can be identified by ultrasound, along with a discussion of the differential diagnosis. Ultrasonically guided percutaneous aspiration biopsy can confirm the diagnosis in selected patients.


Preventing preterm birth: the past limitations and new potential of animal models.
The high rate of preterm birth in the USA and many other countries is a potential target for improving children's immediate health and reducing the medical problems they face as adults. The acute complications for infants born prematurely often require intensive care management and are followed by long-lasting cognitive, sensory, motor, and cardiovascular deficits that substantially limit adult capabilities and survival. The inability to effectively reduce preterm birth stems from the failure to understand normal mechanisms of parturition in humans. Although studies from several model organisms help define the physiology of maintenance and termination of pregnancy, there are fundamental differences between species. For example, species regulate their production of progesterone, the crucial hormone in sustaining pregnancy, differently. This limits the extent to which models can provide meaningful information about the physiological mechanisms of human gestation. The growing wealth of sequenced mammalian genomes, computational comparative genomic tools and systems biology approaches provides new potential to utilize the divergence of DNA sequences and physiology between species to understand the genetic underpinnings of preterm birth.


Anterior segment optical coherence tomography meibography compared with keratograph meibography.
The aim of this study was to determine the feasibility of using readily accessible technology, anterior segment optical coherence tomography (AS-OCT), to detect and grade meibomian gland dropout and examine its interchangeability with the Oculus Keratograph 5M (K5M). A total of 30 participants (30 eyes) with a median age of 21 (range = 19-28 years) were recruited. Meibography was performed using two commercially available imaging devices to look at the structure of the meibomian glands and grade them subjectively in real time, and image analysis was used to quantify meibomian gland loss objectively. Gland loss as imaged by the two techniques was graded using the meiboscore grading schema. Test-retest reliability was determined with intraclass correlation coefficients (ICCs). Weighted kappa was used to evaluate agreement between the two imaging devices and four methods of image analysis. Spearman and Pearson correlation coefficients were used to determine the association of structural measurements between each of the techniques. The agreement between the two imaging techniques was determined with the Bland-Altman analysis. Reliability of subjective grading was strong for AS-OCT (ICC: 0.92, 95% CI: 0.83-0.96, p < 0.001) and K5M (ICC: 0.96, 95% CI: 0.96-0.91, p = 0.001). Image analysis with ImageJ reliability was strong between the imaging devices (ICC: 0.84, 95% CI: 0.55-0.94, p < 0.001). Agreement between each subjective technique was fair, κ = 0.45 (95% CI: 0.17-0.73, p < 0.001) and a positive Spearman correlation was also observed (r = 0.52, p < 0.001). There was no significant difference between the mean meibomian gland loss measured with ImageJ between AS-OCT and K5M (0.92 ± 6.28, p = 0.26). The 95% limits of agreement were -12.45% to +14.04%. These findings suggest subjective real-time grading of meibomian gland loss could be performed using readily available AS-OCT technology and that this method was interchangeable with the K5M.


A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model.
Nobiletin and tangeretin are polymethoxy flavonoids (PMFs), found in rich quantities in the peel of citrus fruits. In the present study, we assessed the biological effect of the PMFs on liver damage using a mouse model of binge drinking. First, we extracted PMFs from the peels of Citrus aurantium to make Citrus aurantium extract (CAE). Male C57BL/6 mice were orally treated with silymarin and CAE (50, 100, and 200 mg/kg) for 3 days prior to ethanol (5 g/kg, total of 3 doses) oral gavage. Liver injury was observed in the ethanol alone group, as evidenced by increases in serum hepatic enzymes and histopathologic alteration, as well as by hepatic oxidative status disruption. CAE improved serum marker and hepatic structure and restored oxidative status by enhancing antioxidant enzyme levels and by reducing lipid peroxidation levels. In addition, CAE evidently suppressed inflammation and apoptosis in the livers of mice administered with ethanol, by 85% (tumor necrosis factor-α) and 44% compared to the control group, respectively. Furthermore, CAE activated lipid metabolism related signals and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and nuclear factor E2-related factor 2 (Nrf2) with several cytoprotective proteins including heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrated that, CAE possesses antioxidant, anti-inflammatory, and antiapoptotic activity against ethanol-induced liver injury.


Disparate Impacts of Two Public Reporting Initiatives on Clinical and Perceived Quality in Healthcare.
Transparency is increasingly viewed as a prerequisite for value-based health care that invites quality in the assessment of achieved value. However, nowadays the ability of transparency initiatives to enhance quality of care remains obscure, if not rejected. Thus, this study aims to investigate how transparency initiatives influence two types of quality of care: clinical and perceived quality. First, factor analyses were conducted to construct three dependent variables: healthcare-associated infections (HAIs), 30-day readmission rates, and patient satisfaction. Then, the three quality models were compared by running ordinary least squares multiple regressions using STATA 14.1. The existence of heteroskedasticity was remedied by using robust standard errors. Examining general acute care hospitals in the US, the present study noted that the ability of public reporting to improve quality of care remains inconclusive and that the pursuit of transparency may lead to inadvertent results. The disclosure of all-payer claims data (APCD) was found to have the power to differentiate hospitals' clinical and perceived quality, but it failed to reach the desired outcomes without market pressure. The impact of transparency on quality of care diverges depending on the unique characteristics of each transparency policy, even though they pursue the same ends through information dissemination. Furthermore, the same public policy showed starkly disparate impacts on clinical quality (eg, healthcare-associated infections (HAIs) and 30-day readmission rates) and perceived quality (eg, patient satisfaction). Despite the theoretically acknowledged merits of transparency, the present study noted that its ability to enhance quality of care remains inconclusive, and the pursuit of transparency may even inadvertently harm quality of care. While hospitals may need to finetune their strategies for each quality measurement in order to cope with the new environmental pressure, it is health policymakers' role to coordinate those quality metrics and improve the validity of patient experience measures and surveys.


Renal cell carcinoma in children.
Data from four pediatric hospitals concerning 20 children treated for renal cell carcinoma (RCC) from 1964-1978 were reviewed. Median age of the patients (pts) was 11.8 years (range, 14 months-19 years). Twelve were male and eight female; 17 were white and three black. Most patients presented with pain and hematuria with or without a palpable mass. An intrarenal tumor was detected at IV urography (17 pts), arteriography (2 pts), or at surgery (1 pt). Treatment consisted of nephrectomy in 15 pts, renal biopsy (4 pts), or no surgery (1 pt), followed by chemotherapy (5 pts), radiation therapy (1 pt), or both (7 pts). Ten pts died of distant metastases at a median of one year (range, 0.2 to two years) after diagnosis. The other 10 pts (50%) survive free of relapse at a median of 4 years (range, two to ten years) from diagnosis. Proportions surviving free of recurrent disease two or more years by National Wilms' Tumor Study (NWTS) Group were 5/5 in Group I, 3/7 in Group II, 1/3 in Group III, and 1/5 in Group IV; by age at diagnosis, 6/6 in those under 11 years old and 4/14 in those 11 or older; and by type of surgery, 10/15 who had nephrectomy and 0/5 with limited or no surgery. The data indicate that radiation and chemotherapy had only minor if any influences on relapse-free survival. We conclude that (1) RCC in children is similar to its counterpart in adults; (2) RCC has a worse prognosis than Wilms' tumor except for the earliest stage; (3) nephrectomy alone is adequate treatment for Group I RCC, and (4) young age (less than 11 years old) may be prognostically favorable.


Transapical approach to myectomy for midventricular obstruction in hypertrophic cardiomyopathy.
Midventricular obstruction in hypertrophic cardiomyopathy (HCM) is less common than subaortic obstruction, and there are few data on outcomes after surgical treatment. We reviewed 56 consecutive patients (28 men) with HCM and midventricular obstruction who underwent myectomy between February 1997 and June 2012. Five patients had prior myectomy for subaortic obstruction. Mean age was 42 ± 17 years. Preoperatively, 51% of patients had dyspnea, and the remaining had palpitations (25%), angina (5%), or syncope (9%). Midventricular obstruction was relieved by means of a transaortic myectomy in 5 patients, a transapical approach in 32 patients, and combined transaortic and transapical incisions in 19 patients. In 13 patients, an apical aneurysm or pouch was repaired at the time of midventricular myectomy. There were no early deaths. Intraoperative intraventricular gradients were reduced from 64 ± 32 mm Hg before myectomy to 6 ± 12 mm Hg postoperatively (p ≤ 0.0001). Early complications included atrial arrhythmias in 5 patients and reoperation for bleeding in 4 patients. Fifty patients had follow-up beyond 30 days (median, 1.6 years; range, 33 days to 13 years). Survival at 1 and 5 years was 100% and 95%, and average New York Heart Association class improved from 2.9 ± 0.7 preoperatively to 1.3 ± 0.6 postoperatively (p = 0.0001). There were no aneurysms related to the apical incision; 2 patients had late reoperation, 1 for resection of right atrial mass to prevent embolus. A transapical approach allows excellent exposure for midventricular myectomy and relief of intraventricular gradients and related symptoms. There were no complications unique to the apical incision, and 5-year survival was similar to expected survival (95% versus 97%).


A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer.
Esophagectomy is often considered the standard treatment for resectable esophageal cancer but the rate of cure is low. Combining neoadjuvant chemotherapy with surgery has theoretical appeal and some clinical evidence suggests a benefit. We performed a meta-analysis of randomized controlled trials (RCTs) that compared neoadjuvant chemotherapy and surgery with surgery alone for esophageal cancer. Medline and manual searches were done to identify all published RCTs that compared neoadjuvant chemotherapy and surgery to surgery alone for esophageal cancer. The selection process was inclusive; no trials were excluded. Trial validity assessment was done and a trial quality score was assigned. Outcomes assessed by meta-analysis included 1-, 2-, and 3-year survival, rate of resection, rate of complete resection, operative mortality, anastomotic leaks, postoperative pulmonary complications, all treatment mortality, local-regional cancer recurrence, distant cancer recurrence, and all cancer recurrence. A random-effects model was used and odds ratio was the principal measure of effect. Systematic quantitative review was done for outcomes unique to the neoadjuvant chemotherapy treatment group (clinical response, pathological complete response, and chemotherapy mortality). Eleven RCTs, which included 1,976 patients, were selected with quality scores ranging from 1 to 3 (5-point Jadad scale). Odds ratio (95% confidence interval [CI]; P value), expressed as chemotherapy and surgery versus surgery alone (treatment versus control; values <1 favor chemotherapy-surgery arm), was 1.00 (0.76, 1.30; P = 0.98) for 1-year survival, 0.88 (0.62, 1.24; P = 0.45) for 2-year survival, 0.77 (0.37, 1.59; P = 0.48) for 3-year survival, 1.71 (1.22, 2.40; P = 0.002) for rate of resection, 0.71 (0.58, 0.87; P = 0.001) for rate of complete resection, 0.94 (0.66, 1.35; P = 0.76) for operative mortality, 1.08 (0.45, 2.60; P = 0.87) for anastomotic leaks, 1.31 (0.77, 2.23; P = 0.32) for postoperative pulmonary complications, 1.36 (0.83, 2.25; P = 0.22) for all treatment mortality, 0.71 (0.36, 1.42; P = 0.33) for local-regional cancer recurrence, 0.79 (0.57, 1.10; P = 0.16) for distant cancer recurrence, and 0.63 (0.28, 1.41; P = 0.26) for all cancer recurrence. A clinical response to chemotherapy was observed in 31% of patients and 5% had a complete pathological response. Chemotherapy mortality (before surgery) was 1.6%. Compared with surgery alone, neoadjuvant chemotherapy and surgery is associated with a lower rate of esophageal resection but a higher rate of complete (R0) resection. It does not increase treatment related mortality. This meta-analysis did not demonstrate a survival benefit for the combination of neoadjuvant chemotherapy and surgery.


Amelogenin-guided crystal growth on fluoroapatite glass-ceramics.
The formation of aligned fibrous apatite crystals in enamel is predominantly attributed to the involvement of amelogenin proteins. We developed a model to study interactions of matrix proteins with apatite mineral in vitro and tested the hypothesis that amelogenin solubility affects the ability to induce protein-guided mineralization. Crystal growth experiments were performed on fluoroapatite (FAP) glass-ceramics in mineralizing solutions containing recombinant full-length amelogenin (rH174) at different concentrations. Using atomic force microscopy, we observed that mineral precipitated randomly on the substrate, but also formed thin layers (height, 10 nm) on FAP within 24 hrs. This growth pattern was unaffected when 0.4 mg/mL of rH174 was added. In contrast, crystals grew on FAP at a rate up to 20 times higher, at 1.6 mg/mL protein. Furthermore, nanospheres and mineral bound specifically to FAP and aligned in strings approximately parallel to the c-axis of FAP, leading us to the conclusion that amelogenin proteins indeed control direction and rate of growth of apatite in enamel.