Complications in the treatment of prosthetic joint infection.
Two-stage exchange arthroplasty is the most common definitive treatment for prosthetic joint infection (PJI) in the USA. Complications that occur during treatment are often not considered. The purpose of this study was to analyze complications in patients undergoing two-stage exchange for infected total knee arthroplasty (TKA) and determine when they occur. We analyzed all patients that underwent two-stage exchange arthroplasty for treatment of PJI of the knee from January 2010 to December 2018 at a single institution. We categorized complications as medical versus surgical. The intervals for complications were divided into: interstage; early post-reimplantation (three months); and late post-reimplantation (three months to minimum one year). Minimum follow-up was one year. In total, 134 patients underwent a first stage of a two-stage exchange. There were 69 males and 65 females with an mean age at first stage surgery of 67 years (37 to 89). Success was based on the new Musculoskeletal Infection Society (MSIS) definition of success reporting. Overall, 70 (52%) patients experienced a complication during the planned two-stage treatment, 36 patients (27%) experienced a medical complication and 47 (41%) patients experienced a surgical complication. There was an 18% mortality rate (24/134) at a mean of 3.7 years (0.09 to 8.3). During the inter-stage period, 28% (37/134) of patients experienced a total of 50 complications at a median of 47 days (interquartile range (IQR) 18 to 139). Of these 50 complications, 22 were medical and 28 required surgery. During this inter-stage period, four patients died (3%) and an additional five patients (4%) failed to progress to the second stage. While 93% of patients (125/134) were reimplanted, only 56% (77/134) of the patients were successfully treated without antibiotic suppression (36%, 28/77) or with antibiotic suppression (19%, 15/77) at one year. Reported rates of success of two stage exchanges for PJI have not traditionally considered complications in the definition of success. In our series, significant numbers of patients experienced complications, more often after reimplantation, highlighting the morbidity of this method of treatment. Cite this article: Bone Joint J 2020;102-B(6 Supple A):145-150.


Experimental modification of morphology reveals the effects of the zygosphene-zygantrum joint on the range of motion of snake vertebrae.
Variation in joint shape and soft tissue can alter range of motion (ROM) and create trade-offs between stability and flexibility. The shape of the distinctive zygosphene-zygantrum joint of snake vertebrae has been hypothesized to prevent axial torsion (twisting), but its function has never been tested experimentally. We used experimental manipulation of morphology to determine the role of the zygosphene-zygantrum articulation by micro-computed tomography (μCT) scanning and 3D printing two mid-body vertebrae with unaltered shape and with the zygosphene digitally removed for four species of phylogenetically diverse snakes. We recorded the angular ROM while manipulating the models in yaw (lateral bending), pitch (dorsoventral bending) and roll (axial torsion). Removing the zygosphene typically increased yaw and dorsal pitch ROM. In the normal vertebrae, roll was <2.5 deg for all combinations of pitch and yaw. Roll increased in altered vertebrae but only for combinations of high yaw and ventral pitch that were near or beyond the limits of normal vertebra ROM. In the prairie rattlesnake and brown tree snake, roll in the altered vertebrae was always limited by bony processes other than the zygosphene, whereas in the altered vertebrae of the corn snake and boa constrictor, roll ROM was unconstrained when the pre- and post-zygapophyses no longer overlapped. The zygosphene acts as a bony limit for yaw and dorsal pitch, indirectly preventing roll by precluding most pitch and yaw combinations where roll could occur and potentially allowing greater forces to be applied across the vertebral column than would be possible with only soft-tissue constraints.


Lysophosphatidylcholine promotes cholesterol efflux from mouse macrophage foam cells.
We examined the effects of lysophosphatidylcholine (lyso-PC) on promoting cholesterol efflux from macrophage foam cells. Mouse peritoneal macrophages were converted to foam cells by incubation with [3H]cholesteryl linoleate-labeled or unlabeled acetyl-LDL. When these cells were incubated with lyso-PC, [3H]cholesterol release was promoted in relation to both dose and time, and cellular cholesterol mass was decreased, while medium cholesterol mass was increased. These cholesterol efflux-promotive effects of lyso-PC were confirmed by the fact that the lyso-PC-treated cells showed less oil red O staining than the control cells. ApoE secretion, estimated by Western blotting of the medium, was also augmented by lyso-PC. Both the cholesterol and apoE released by lyso-PC treatment were floated by ultracentrifugation of the medium after its density had been adjusted to 1.210 g/mL. By electron microscopic analysis, vesicular lipoproteins were observed in ultracentrifugally concentrated conditioned medium of lyso-PC. Monensin, a protein secretion inhibitor, effectively inhibited [3H]cholesterol release induced by lyso-PC but not by apoA-I. These results suggest that lyso-PC may inhibit the development of atherosclerosis or enhance its regression by stimulating cholesterol efflux from macrophage foam cells.


Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies.
Venetoclax is a strongly effective B-cell lymphoma-2 inhibitor (BCL-2) with an ability to selectively restore the apoptotic potential of cancerous cells. It has been proven that in combination with immunotherapy, targeted therapies, and lower-intensity therapies such as hypomethylating agents (HMAs) or low-dose cytarabine (LDAC), the drug can improve overall outcomes for adult patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), amongst other hematological malignancies, but its benefit in pediatric hematology remains unclear. With a number of preclinical and clinical trials emerging, the newest findings suggest that in many cases of younger patients, venetoclax combination treatment can be well-tolerated, with a safety profile similar to that in adults, despite often leading to severe infections. Studies aim to determine the activity of BCL-2 inhibitor in the treatment of both primary and refractory acute leukemias in combination with standard and high-dose chemotherapy. Although more research is required to identify the optimal venetoclax-based regimen for the pediatric population and its long-term effects on patients' outcomes, it can become a potential therapeutic agent for pediatric oncology.


End-of-life decisions in neonatal intensive care: physicians' self-reported practices in seven European countries. EURONIC Study Group.
The ethical issue of foregoing life-sustaining treatment for newborn infants at high risk of death or severe disability is extensively debated, but there is little information on how physicians in different countries actually confront this issue to reach end-of-life decisions. The EURONIC project aimed to investigate practices as reported by physicians themselves. The study recruited a large, representative sample of 122 neonatal intensive-care units (NICUs) by census (in Luxembourg, the Netherlands, and Sweden) or stratified random sampling (in France, Germany, the UK, Italy, and Spain) with an overall response rate of 86%. Physicians' practices of end-of-life decision-making were investigated through an anonymous, self-administered questionnaire. 1235 completed questionnaires were returned (response rate 89%). In all countries, most physicians reported having been involved at least once in setting limits to intensive care because of incurable conditions (61-96%); smaller proportions reported such involvement because of a baby's poor neurological prognosis (46-90%). Practices such as continuation of current treatment without intensification and withholding of emergency manoeuvres were widespread, but withdrawal of mechanical ventilation was reported by variable proportions (28-90%). Only in France (73%) and the Netherlands (47%) was the administration of drugs with the aim of ending life reported with substantial frequency. Age, length of professional experience, and the importance of religion in the physician's life affected the likelihood of reporting of non-treatment decisions. A vast majority of neonatologists in European NICUs have been involved in end-of-life limitation of treatments, but type of decision-making varies among countries. Culture-related and other country-specific factors are more relevant than characteristics of individual physicians or units in explaining such variability.


Transition metal-coordinated graphitic carbon nitride dots as a sensitive and facile fluorescent probe for β-amyloid peptide detection.
Herein, we developed a sensitive graphitic carbon nitride quantum dot (gCNQD)-based fluorescent strategy for β-amyloid peptide monomer (Aβ) determination down to the ng mL-1 level for the first time. To realize this goal, the nanostructured gCNQDs were firstly coordinated with four transition metal ions (Cu2+, Cu+, Fe3+, Zn2+). Our findings showed that the fluorescence (FL) intensity of gCNQDs was quenched in the presence of these metal ions possibly due to the effective chelation with the nitrogen element in gCNQDs and subsequent photoinduced electron transfer (PET) of gCNQDs. The degree of fluorescence quenching was found to be the most intense with the addition of Cu2+ and therefore, we selected Cu2+ as the quencher for the following Aβ determination. Through binding to Cu2+, the introduction of Aβ unexpectedly induced a further decline of FL intensity. Importantly, on account of different peptide sequences coexisting in the same cerebral system, including Aβ1-11, Aβ1-16, Aβ1-38, Aβ1-40 and Aβ1-42, their affinities to Cu2+ could be reflected by the distinguished declining extent of FL intensity. The possible mechanism of Aβ sensing by the probe was clarified by TEM characterization. The developed fluorescent biosensor was demonstrated to give a wide linear range from 1 to 700 ng mL-1 and a low detection limit of 0.18 ng mL-1 for Aβ1-42. In the end, the proposed fluorescence approach was successfully applied to monitoring of Aβ1-42 variations in the cortex and hippocampus of AD rats.


Serological responses to Cryptosporidium antigens among women using riverbank-filtered water, conventionally filtered surface water and groundwater in Hungary.
We compared serological responses to Cryptosporidium parvum antigens using surplus sera from females undergoing routine screening for pregnancy from three counties in Hungary where bank-filtered surface water, conventionally filtered and disinfected surface water, and groundwater from either a karst or confined aquifer are commonly used for drinking water. The primary purpose was to determine whether the prevalence and intensity of serological responses, indicators of prior Cryptosporidium infection were similar for these populations. Women using groundwater from a confined aquifer had significantly lower mean serological responses for both the 15/17-kDa and 27-kDa (p < 0.0001) antigen groups than women using conventionally filtered and disinfected surface water or karst well water. This is suggestive of less frequent infections. Women using bank-filtered water also had lower mean responses for both antigen groups. Among women using bank-filtered water, the mean intensity of response for both antigen groups was almost one-third of the mean response observed for women using conventionally filtered and disinfected surface water. These findings suggest that riverbank filtration may be an effective alternative to conventional treatment for reducing Cryptosporidium exposures and infection from surface drinking water sources.


Evidence of two differentially regulated elongasomes in Salmonella.
Cell shape is genetically inherited by all forms of life. Some unicellular microbes increase niche adaptation altering shape whereas most show invariant morphology. A universal system of peptidoglycan synthases guided by cytoskeletal scaffolds defines bacterial shape. In rod-shaped bacteria, this system consists of two supramolecular complexes, the elongasome and divisome, which insert cell wall material along major and minor axes. Microbes with invariant shape are thought to use a single morphogenetic system irrespective of the occupied niche. Here, we provide evidence for two elongasomes that generate (rod) shape in the same bacterium. This phenomenon was unveiled in Salmonella, a pathogen that switches between extra- and intracellular lifestyles. The two elongasomes can be purified independently, respond to different environmental cues, and are directed by distinct peptidoglycan synthases: the canonical PBP2 and the pathogen-specific homologue PBP2SAL. The PBP2-elongasome responds to neutral pH whereas that directed by PBP2SAL assembles in acidic conditions. Moreover, the PBP2SAL-elongasome moves at a lower speed. Besides Salmonella, other human, animal, and plant pathogens encode alternative PBPs with predicted morphogenetic functions. Therefore, contrasting the view of morphological plasticity facilitating niche adaptation, some pathogens may have acquired alternative systems to preserve their shape in the host.


Diagnosis and rehabilitation of the shoulder impingement syndrome in the overhand and throwing athlete.
The shoulder apparatus is of elegant structural design, affording great ROM with substantial power in many planes of movement. It is the underlying anatomic relationships that allow great mobility that also render the shoulder susceptible to injury. Injury in repetitive overhand activities is usually in the form of impingement, which may result from many factors, including multidirectional instability, anterior subluxation, and imbalanced force couple mechanisms, among others. Diagnosis requires a thorough history and physical examination. The impingement sign and test are among the most useful diagnostic maneuvers available. Rehabilitation is individualized, depending upon the cause of impingement, severity of injury, and response to therapy. Overuse syndromes mandate rest and control of inflammation through the use of ice, NSAIDs, and local injections of steroids followed by passive, active-assist, and active ROM; stretching; and mobilization exercises. As pain and inflammation subside, isometric or isotonic exercises are prescribed initially to strengthen the rotator cuff musculature and, therefore, the caudal glide mechanism. Subsequent strengthening exercises then are performed in other planes of movement to strengthen the remaining shoulder-complex muscles. The patient is then advanced to isokinetic training. Stretching is emphasized as an essential preparatory activity for all types of exercise. Maintaining contralateral and lower-limb strength, and cardiovascular conditioning is necessary if athletic activities are to be resumed at the previous level of performance. Following return to athletic performance, an analysis of training habits should be made and a prescription for exercise issued based on the avoidance of aggravating factors and cultivation of activities that enhance existing static and dynamic shoulder stabilizers. Any return of symptoms should prompt an immediate reappraisal with the proper intervention, including adjustment of activity level and exercises as deemed appropriate. With proper conservative therapy, relatively few athletes should require surgical treatment.


Secondary Metabolites in Xylella fastidiosa-Plant Interaction.
During their evolutionary history, plants have evolved the ability to synthesize and accumulate small molecules known as secondary metabolites. These compounds are not essential in the primary cell functions but play a significant role in the plants' adaptation to environmental changes and in overcoming stress. Their high concentrations may contribute to the resistance of the plants to the bacterium Xylella fastidiosa, which has recently re-emerged as a plant pathogen of global importance. Although it is established in several areas globally and is considered one of the most dangerous plant pathogens, no cure has been developed due to the lack of effective bactericides and the difficulties in accessing the xylem vessels where the pathogen grows and produces cell aggregates and biofilm. This review highlights the role of secondary metabolites in the defense of the main economic hosts of X. fastidiosa and identifies how knowledge about biosynthetic pathways could improve our understanding of disease resistance. In addition, current developments in non-invasive techniques and strategies of combining molecular and physiological techniques are examined, in an attempt to identify new metabolic engineering options for plant defense.


Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34(+) cells.
Two HIV-1-infected children on antiretroviral therapy were enrolled into a clinical study of retroviral-mediated transfer of a gene that inhibits replication of HIV-1, targeting bone marrow CD34+ hematopoietic stem/progenitor cells. Two retroviral vectors were used, one encoding a "humanized" dominant-negative REV protein (huM10) that is a potent inhibitor of HIV-1 replication and one encoding a nontranslated marker gene (FX) to serve as an internal control for the level of gene marking. Peripheral blood mononuclear cells (PBMC) containing the huM10 gene or FX gene were detected by quantitative PCR at frequencies of approximately 1/10,000 in both subjects for the first 1-3 months following re-infusion of the gene-transduced bone marrow, but then were at or below the limits of detection (<1/1,000,000) at most times over 2 years. In one patient, a reappearance of PBMC containing the huM10 gene, but not the FX gene, occurred concomitant with a rise in the HIV-1 viral load during a period of nonadherence to the antiretroviral regimen. Unique clones of gene-marked PBMC were detected by LAM-PCR during the time of elevated HIV-1 levels. These findings indicate that there was a selective survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load.


Apathy alters emotional arousal in chronic schizophrenia
Within the heterogeneity of schizophrenia, apathy constitutes an independent cluster of negative symptoms associated with poor outcomes. Attempts to identify an emotional deficit in patients who have schizophrenia with negative symptoms have yielded mixed results, and studies that focus on the relationship between apathy and emotional disorders are lacking. We set out to remedy this shortcoming using a validated battery of film excerpts to induce positive and negative emotions in patients with chronic schizophrenia with (n = 20) or without (n = 20) apathy, and in controls (n = 20) comparable for age, sex and socioeconomic status. We assessed emotions using an innovative but validated technique to evaluate tonic and phasic electrodermal activity and subjective feelings using a standardized visual analogue scale. Using a qualitative measure of apathy, we did not find a specific decrease in tonic activity during the induction of positive emotions. However, we did observe that patients with apathy showed reduced tonic activity independent of valence (i.e., for both positive and negative emotions) compared with controls and patients without apathy. Moreover, the quantitative measure of apathy (Apathy Evaluation Scale) was the only significant factor, explaining 24% of the variance in tonic activity during induction of positive emotions after controlling for confounding factors. Electrodermal activity was the only physiologic measure we acquired. We induced several emotions sequentially that might have overlapped with each other, but we added an emotional "washout" period and randomized the order of each film excerpt to limit this possibility. Taken together, these results suggest that apathy in schizophrenia could impair tonic activity during positive emotions. Treatments aimed at enhancing positive emotions may help alleviate apathy in schizophrenia.


Restorative Possibilities Using Zirconia Ceramics for Single Crowns.
Two clinical cases are presented to explore technical differences and discusses the advantages and disadvantages of using veneered or monolithic zirconia to manufacture posterior single crowns. The first case describes the clinical steps in manufacturing a monolithic crown on a mandibular left second premolar using high translucency zirconia. It shows the use of a conservative tooth preparation based on the superior mechanical properties that this material presents as well as the final optical characteristics achieved by shading and staining. In the second case, a conventional bilayer restorative treatment was made using zirconia framework followed by veneering with feldspar ceramic on a mandibular left first molar. Recent literature indicates that each of these restorative alternatives presents specific advantages and disadvantages. Factors such as mechanical performance, fracture, esthetic characteristics, clinical success, complication rates, adhesion and antagonist wear performance are discussed comparing the two restorative assemblies. The data highlight that monolithic crowns prevent a major problem reported on bilayer restorations: the chipping of veneering ceramic. Monolithic crowns also allow minimally invasive tooth preparations, thus increasing tooth remnant preservation. However, data that support esthetic performance similarity between monolithic and bilayer assemblies are lacking, thus the predictability of use is restricted for the posterior region, as cases demanding high esthetic appeal continue to fundamentally use bilayer restorations. Failures were not found, and patient satisfaction was reported in both techniques after the 12-month follow up.


Ecological causes of morphological evolution in the three-spined stickleback.
The central assumption of evolutionary theory is that natural selection drives the adaptation of populations to local environmental conditions, resulting in the evolution of adaptive phenotypes. The three-spined stickleback (Gasterosteus aculeatus) displays remarkable phenotypic variation, offering an unusually tractable model for understanding the ecological mechanisms underpinning adaptive evolutionary change. Using populations on North Uist, Scotland we investigated the role of predation pressure and calcium limitation on the adaptive evolution of stickleback morphology and behavior. Dissolved calcium was a significant predictor of plate and spine morph, while predator abundance was not. Stickleback latency to emerge from a refuge varied with morph, with populations with highly reduced plates and spines and high predation risk less bold. Our findings support strong directional selection in three-spined stickleback evolution, driven by multiple selective agents.


Functional role of phosphatidylinositol 3-kinase in direct tumor lysis by human natural killer cells.
Cytotoxicity is a key function of natural killer (NK) and T cells; yet the molecular mechanism is unclear. We have biological, biochemical and molecular evidence to demonstrate that phosphatidyl-inositol (PI) 3-kinase is critical for direct NK lysis of tumor cells, via control of intracellular granule movement. Tumor cell engagement rapidly activated PI 3-kinase in NK cells within 5 min, as demonstrated by p85 subunit tyrosine phosphorylation and its ability to generate phosphatidylinositol 3-phosphate, PI(3)P, from PI. Wortmannin and LY294002 effectively inhibited NK cells to lyse 51Cr-labeled tumor cells at the same doses that blocked PI-phosphorylating function in tumor-activated NK cells. Immunostaining demonstrated that tumor engagement for only 5 min mobilized perforin and granzyme B from NK cells unidirectionally towards the target, and prior treatment of NK cells with either PI 3-kinase inhibitor effectively stopped this intracellular polarization. Lastly, ectopic expression of dominant-negative p85 or p110 mutant markedly suppressed NK lytic capacity. These results taken together demonstrate that PI 3-kinase may control NK lytic function via granule polarization towards the contacted target cell.


Studies on the singlet oxygen scavenging mechanism of human macular pigment.
It is thought that direct quenching of singlet oxygen and scavenging free radicals by macular pigment carotenoids is a major mechanism for their beneficial effects against light-induced oxidative stress. Corresponding data from human tissue remains unavailable, however. In the studies reported here, electron paramagnetic resonance (EPR) spectroscopy was used to measure light-induced singlet oxygen generation in post-mortem human macula and retinal pigment epithelium/choroid (RPE/choroid). Under white-light illumination, production of singlet oxygen was detected in RPE/choroid but not in macular tissue, and we show that exogenously added macular carotenoids can quench RPE/choroid singlet oxygen. When the singlet oxygen quenching ability of the macular carotenoids was investigated in solution, it was shown that a mixture of meso-zeaxanthin, zeaxanthin, and lutein in a ratio of 1:1:1 can quench more singlet oxygen than the individual carotenoids at the same total concentration.


Rapid and sensitive screening of N-glycans as 9-fluorenylmethyl derivatives by high-performance liquid chromatography: a method which can recover free oligosaccharides after analysis.
There are a large number of labeling methods for asparagine-type oligosaccharides with fluorogenic and chromophoric reagents. We have to choose the most appropriate labeling method based on the purposes such as mass spectrometry, high-performance liquid chromatography and capillary electrophoresis. Asparagine-type glycans are released from core proteins as N-glycosylamine at the initial step of the releasing reaction when glycoamidase F is employed as the enzyme. The N-glycosylamine-type oligosaccharides thus released by the enzyme are subjected to hydrolysis or mutarotation to form free-form oligosaccharides. In the detailed studies on the enzyme reaction, we found a condition in which the released N-glycosylamine-type oligosaccharides were exclusively present at least during the course of enzyme reaction, and developed a method for in situ derivatization of the glycosylamine-type oligosaccharides with 9-fluorenylmethyl chloroformate (Fmoc-Cl). The Fmoc labeled sialo- and asialo- (or high-mannose and hybrid) oligosaccharides were successfully analyzed on an amine-bonded polymer column and amide-silica column, respectively. The present method showed approximately 5 times higher sensitivities than that using 2-aminobenzoic acid (2-AA). The separation profile was similar to that observed using 2-AA method as examined by the analyses of carbohydrate chains derived from several glycoproteins including complex-type, high-mannose type and hybrid type of N-linked oligosaccharides. The labeled oligosaccharides were stable at least for several months when stored at -20 degrees C. Furthermore, it should be emphasized that the Fmoc-derivatized oligosaccharides could be easily recovered as free reducing oligosaccharides simply by incubation with morpholine in dimethylformamide solution. We obtained a pure triantennary oligosaccharide with 3 sialic acid residues as a free reducing form from fetuin in good yield after isolation of the corresponding Fmoc oligosaccharide followed by removing reaction of the Fmoc group. The proposed method will be useful for preparation of free oligosaccharides as standard samples at pmol-nmol scale from commercially available glycoproteins.


Defending explicability as a principle for the ethics of artificial intelligence in medicine.
The difficulty of explaining the outputs of artificial intelligence (AI) models and what has led to them is a notorious ethical problem wherever these technologies are applied, including in the medical domain, and one that has no obvious solution. This paper examines the proposal, made by Luciano Floridi and colleagues, to include a new 'principle of explicability' alongside the traditional four principles of bioethics that make up the theory of 'principlism'. It specifically responds to a recent set of criticisms that challenge the supposed need for such a principle to perform an enabling role in relation to the traditional four principles and therefore suggest that these four are sufficient without the addition of explicability. The paper challenges the critics' premise that explicability cannot be an ethical principle like the classic four because it is explicitly subordinate to them. It argues instead that principlism in its original formulation locates the justification for ethical principles in a midlevel position such that they mediate between the most general moral norms and the contextual requirements of medicine. This conception of an ethical principle then provides a mold for an approach to explicability on which it functions as an enabling principle that unifies technical/epistemic demands on AI and the requirements of high-level ethical theories. The paper finishes by anticipating an objection that decision-making by clinicians and AI fall equally, but implausibly, under the principle of explicability's scope, which it rejects on the grounds that human decisions, unlike AI's, can be explained by their social environments.


Factor structure of cognition and functional capacity in two studies of schizophrenia and bipolar disorder: Implications for genomic studies.
Impairments in cognition and everyday functioning are common in schizophrenia and bipolar disorder (BPD). In this article, we present factor analyses of cognitive and functional capacity (FC) measures based on 2 studies of schizophrenia (SCZ) and bipolar I disorder (BPI) using similar methods. The overall goal of these analyses was to determine whether performance-based assessments should be examined individually, or aggregated on the basis of the correlational structure of the tests, as well as to evaluate the similarity of factor structures of SCZ and BPI. Veterans Affairs Cooperative Studies Program Study #572 (Harvey et al., 2014) evaluated cognitive and FC measures among 5,414 BPI and 3,942 SCZ patients. A 2nd study evaluated similar neuropsychological (NP) and FC measures among 368 BPI and 436 SCZ patients. Principal components analysis, as well as exploratory and CFAs, were used to examine the data. Analyses in both datasets suggested that NP and FC measures were explained by a single underlying factor in BPI and SCZ patients, both when analyzed separately or as in a combined sample. The factor structure in both studies was similar, with or without inclusion of FC measures; homogeneous loadings were observed for that single factor across cognitive and FC domains across the samples. The empirically derived factor model suggests that NP performance and FC are best explained as a single latent trait applicable to people with SCZ and BPD. This single measure may enhance the robustness of the analyses relating genomic data to performance-based phenotypes.


Uridine reduces rotation induced by L-dopa and methamphetamine in 6-OHDA-treated rats.
The pyrimidine nucleoside uridine may reduce side effects associated with antipsychotic medication by interacting with dopamine or GABA neurotransmission. Male Sprague-Dawley rats were used to investigate coadministration of uridine with agents that alter food intake (amphetamine, haloperidol, and chlordiazepoxide) and locomotor activity (methamphetamine and L-dopa). Results indicated that chronic uridine [32.0 mg/kg, intraperitoneally (IP)] alone did not alter milk intake or reduction of milk intake induced by amphetamine (dose range 0.5-2.0 mg/kg, IP) or haloperidol (0.125-1.0 mg/kg, IP), nor did it alter the biphasic response induced by chlordiazepoxide (5.0-40.0 mg/kg, IP). However, uridine-treated animals with unilateral striatal lesions exhibited no rotational behavior in the absence of drug challenge, but showed decreased rotation induced by the dopamine agonist, L-dopa (50.0-200.0 mg/kg, IP) compared with controls. In addition, uridine-treated rats exhibited reduced rotation after repeated injections of methamphetamine (4.0 mg/kg, IP) in contrast to increasingly greater rotation observed in control animals. These results are further evidence that chronic uridine may alter drug-induced dopaminergic activity without exerting effects itself.


Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review).
Connexin (Cx)43 is a multifunction protein which forms gap junction channels and hemi‑channels. It also contains abundant binding domains which possess the ability to interact with certain Cx43‑associated proteins and therefore serve a fundamental role in various physiological and pathological functions. However, the understanding of the association between cancer and Cx43 along with Cx43‑gap junctions (GJ) remains unclear. All available data illustrate that Cx43 and its associated GJ serve important functions in cancers. The expression levels of Cx43 demonstrate a downward trend and an increase in the levels of malignancy, particularly in astrocytomas. The GJ intercellular communication activity in glioma cells can be adjusted via Cx43 phosphorylation and through the combination of Cx43 and its associated protein. Available evidence reveals Cx43 as a tumor‑inhibiting factor that suppresses glioma growth and proliferation. However, its mechanism is also regarded as complicated and ambiguous. Furthermore, it is apparent that Cx43‑GJ and the carboxyl tail may contribute to glioma growth and proliferation too. However, this valuable role could be weakened by its effects on migration and invasiveness. The detailed mechanism remains unclear and full of controversies. Cx43 can enhance the motor ability and invasiveness of astrocytic glioma cells. It is also able to influence glioma cells to detach from the tumor core to the peritumoral neocortex. This peritumoral region has recently been regarded as the basic focus of glioma‑associated seizure. Thus, Cx43 may take part in the onset and development of glioma‑associated epileptic discharge. In addition, change and increase of Cx43 expression in GJs has been observed in seizure perilesional tissue, which is associated with brain tumors. Cx43 or GJ/hemi‑channels exert enduring effects in the promotion of glioma‑associated epileptic release through direct mass effects and change of the tumor microenvironment. However, there are still a number of issues concerning this aspect that require further exploration. Cx43, as a potential treatment target against this incurable disease and its common symptom of epilepsy, requires further investigation.


Inflammation Triggers Liver X Receptor-Dependent Lipogenesis.
Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.


Effects of Two Different Training Periodization Models on Physical and Physiological Aspects of Elite Female Team Handball Players.
Manchado, C, Cortell-Tormo, JM, and Tortosa-Martínez, J. Effects of two different training periodization models on physical and physiological aspects of elite female team handball players. J Strength Cond Res 32(1): 280-287, 2018-The aim of this study was to compare training-induced changes in selected physiological and physical team handball performance factors after 2 training periodization models: traditional periodization (TP) vs. block periodization (BP). Eleven female team handball players who played over 2 consecutive seasons for a Spanish first league team were assessed twice per season during a training cycle. On each occasion, participants completed anthropometric, maximal strength, and lower-body power assessments. In addition, incremental tests to determine maximum oxygen uptake (V[Combining Dot Above]O2max), sprint- and sport-specific throwing velocity tests were performed. Block periodization group experienced significantly greater improvements than TP on squat jump (5.97%; p < 0.001), countermovement jump (8.76%; p = 0.011), hand-grip strength (8.22%; p = 0.029), bench press 1 repetition maximum (1RM) (5.14%; p = 0.049), 10-m sprint (-6.19%; p < 0.001), and 20-m sprint (2.95%; p = 0.008). Greater changes in BP group (p ≤ 0.05) were also found for the throwing velocities in sport-specific tests compared with the TP group. No significant difference between the groups were detected for the half-squat 1RM (p = 0.15) and the V[Combining Dot Above]O2max (p = 0.44). These findings suggest that BP may be more effective than TP for improving important physiological and physical team handball performance factors in high level female handball players.


IL-2-inducible T cell kinase tunes T regulatory cell development and is required for suppressive function.
IL-2-inducible T cell kinase (ITK) is a key signaling mediator downstream of TCR, mediating T cell positive selection, as well as innate T cell and CD4(+) Th2/Th17 differentiation. In this article, we show that ITK also negatively tunes IL-2-induced expansion of conventional Foxp3-expressing regulatory T cells (Tregs). In vivo, Treg abundance is inversely correlated with ITK expression, and inducible Treg development is inversely dependent on ITK kinase activity. While Treg development normally requires both hematopoietic and thymic MHC class 2 (MHC2) expression, the absence of ITK allows Treg development with MHC2 expression in either compartment, with preference for selection by thymic MHC2, suggesting a gatekeeper role for ITK in ensuring that only Tregs selected by both thymic and hematopoietic MHC2 survive selection. Although ITK suppresses Treg development and is not required for maintenance of neuropilin-1-positive natural Tregs in the periphery, it is indispensable for Treg functional suppression of naive CD4(+) T cell-induced colitis in Rag(-/-) recipients. ITK thus regulates the development and function of Tregs.


Hematin: unique effects of hemostasis.
Hematin is clinically useful in the treatment of acute intermittent porphyria. Recently, hematin-induced coagulopathy has been reported, and a patient we treated bled during hematin therapy. On 3 separate occasions, infusions of hematin (4 mg/kg) induced thrombocytopenia, prolongation of the prothrombin time, partial thromboplastin time. Reptilase time, and apparent decreases in fibrinogen and increases in fibrin(ogen) degradation products (FDP). However, fibrinogen assayed by heat precipitation was unchanged, the protamine paracoagulation test was negative, there was no red blood cell fragmentation, and plasminogen and antithrombin III remained normal, excluding the presence of disseminated intravascular coagulation. Furthermore, premedication with heparin, 5000 U i.v., failed to prevent the lengthening of the Reptilase time and exacerbated the thrombocytopenia. In vitro studies revealed that hematin, 0.1 mg/ml, aggregated platelets and induced the release of 14C-serotonin and adenosine triphosphate (ATP). Hematin also aggregated washed or gel-filtered platelets but had no effect on formalin-fixed platelets. Aggregation was inhibited by aspirin (0.12 mg/ml), adenosine triphosphate, and apyrase, suggesting that hematin aggregated platelets by inducing adenosine diphosphate (ADP) release. Hematin (0.07 mg/ml) progressively inactivated thrombin and 0.1 mg/ml prolonged the Reptilase time. Thus, hematin is unique in that it both induces platelet aggregation and inhibits coagulation.


Reliability and Validity Study of the Finnish Adaptation of Scoliosis Research Society Questionnaire Version SRS-30.
A prospective clinical study to test and adapt a Finnish version of the Scoliosis Research Society 30 (SRS-30) questionnaire. The aim of this study was to perform cross-cultural adaptation and evaluate the validity of the adapted Finnish version of the SRS-30 questionnaire. The SRS-30 questionnaire has proved to be a valid instrument in evaluating health-related quality of life (HRQoL) in adolescent and adult population with spine deformities in the United States. Multinational availability requires cross-cultural and linguistic adaptation and validation of the instrument. The SRS-30 was translated into Finnish using accepted methods for translation of quality-of-life questionnaires. A total of 274 adult patients with degenerative radiographic sagittal spinal disorder answered the questionnaire with sociodemographic data, RAND 36-item health survey questionnaire (RAND Corp. Health, Santa Monica, CA, US), Oswestry disability index, DEPS depression scale, and Visual Analog Scale (VAS) back and leg pain scales within 2 weeks' interval. The cohort included patients with and without previous spine surgery. Internal consistency and validity were tested with Cronbach α, intraclass correlation (ICC), standard error of measurement, and Spearman correlation coefficient with 95% confidence intervals (CIs). The internal consistency of SRS-30 was good in both surgery and nonsurgery groups, with Cronbach α 0.853 (95% CI, 0.670 to 0.960) and 0.885 (95% CI, 0.854 to 0.911), respectively. The test-retest reproducibility ICC of the SRS-30 total and subscore domains of patients with stable symptoms was 0.905 (95% CI, 0.870-0.930) and 0.904 (95% CI, 0.871-0.929), respectively. The questionnaire had discriminative validity in the pain, self-image, and satisfaction with management domains compared with other questionnaires. The SRS-30 questionnaire proved to be valid and applicable in evaluating HRQoL in Finnish adult spinal deformity patients. It has two domains related to deformity that are not covered by other generally used questionnaires. 3.


Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes.
Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands and the type 2 IPNBs consist of complex branching glands, seldom with foci of solid-tubular components. However, clinicopathological and molecular characteristics of these types of IPNBs are yet to be identified. We aimed to uncover clinicopathological and molecular characteristics of the types of IPNBs. Thirty-six IPNBs were studied retrospectively. Clinicopathological features as well as molecular alterations of 31 genes were evaluated by means of targeted next-generation sequencing and immunohistochemical examination of expression of mucin and cancer-associated molecules. The 36 IPNBs were classified into 22 of type 1 and 14 of type 2. The type 1 IPNBs were associated with a non-invasive phenotype, intestinal and oncocytic subtypes, development in the intrahepatic bile duct, overt mucin production, and a relatively good prognosis. The type 2 IPNBs were associated with an invasive phenotype, the pancreatobiliary subtype, development within the extrahepatic bile duct, and worse prognosis compared with the type 1 IPNBs. In the molecular analysis, recurrent mutations were found in TP53 (34.3%), KRAS (31.4%), STK11 (25.7%), CTNNB1 (17.1%), APC (14.3%), SMAD4 (14.3%), GNAS (11.4%), PBRM1 (11.4%), ELF3 (8.6%), KMT2C (8.6%), NF1 (8.6%), PIK3CA (8.6%), ARID1A (5.7%), ARID2 (5.7%), BAP1 (5.7%), BRAF (5.7%), EPHA6 (5.7%), ERBB2 (5.7%), ERBB3 (5.7%), KMT2D (5.7%), and RNF43 (5.7%). Mutations in KRAS and GNAS were enriched in the type 1 IPNBs, whereas mutations in TP53, SMAD4, and KMT2C were enriched in the type 2 IPNBs. These results indicate that IPNBs consist of two distinct types of neoplasms specifically associated with clinicopathological features and molecular phenotypes. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Emergence of posttetanic potentiation as a distinct phase in the differentiation of an identified synapse in Aplysia.
The developmental time course of posttetanic potentiation was studied at an identified chemical synapse. In stage 11 juveniles (3 weeks after metamorphosis), the synaptic connections made by cholinergic neuron L10 onto postsynaptic neurons L2 to L6 were present but showed no posttetanic potentiation. In stage 13 adults (12 weeks after metamorphosis), the same tetanus resulted in an increase of 300 percent in the synaptic potential. A similar pattern was observed at two other identified synapses in the abdominal ganglion. Thus, the initial steps in synapse formation do not include the expression of this plastic capability. Rather, at least 10 weeks is required between the onset of synaptic function and the final expression of mature synaptic properties.


A randomised trial of the analgesic efficacy of ultrasound-guided transversus abdominis plane block after caesarean delivery under general anaesthesia.
Previous studies examining the efficacy of transversus abdominis plane block after caesarean section have mostly been in parturients under spinal anaesthesia. We postulated that the advantage of performing transversus abdominis plane block after caesarean section might be even more obvious after general anaesthesia, resulting in reduced 24-h consumption of morphine. DESIGN, SETTING, PATIENTS AND INTERVENTIONS: In this single centre, randomised double-blind controlled trial, 40 women who underwent caesarean delivery under general anaesthesia were allocated randomly to receive a transversus abdominis plane block or no block. In those who received the block, 20 ml of levobupivacaine 2.5 mg ml was deposited bilaterally into the transversus abdominis plane under ultrasound guidance using a Sonosite Titan (SonoSite, Bothell, Washington, USA) 7-13 MHz linear transducer at the end of surgery when the patient was still anaesthetised. We recorded patient-controlled intravenous morphine use for 24 h, pain scores at rest and activity, sedation, nausea and vomiting, use of antiemetic medication and overall maternal satisfaction. The primary outcome was 24-h morphine consumption. Patients who received the transversus abdominis plane block used significantly less morphine in 24 h than those in the control group [12.3 (2.6) vs. 31.4 mg (3.1), P<0.001) and had higher satisfaction scores [16 (80%) vs. 5 (25%), P = 0.012). There were no differences between groups in the visual analogue pain scores, sedation level, nausea and vomiting or the use of antiemetic medication. Ultrasound-guided transversus abdominis plane block reduced morphine consumption following caesarean section under general anaesthesia, with increased maternal satisfaction.


Biomechanical analysis of the rigid fixation of zygoma fractures: an experimental study.
In this experimental study, the goal was to test the sufficiency of actual fixation plates in zygomatic complex fractures and the efficiency of a modified plate at the zygomaticofrontal suture in a suitable model, which was designed for biomechanical study. To address this issue, a zygomatic fracture model produced by using a cadaveric cranium was simulated and the fractures were fixed by the actual and modified fixation materials. The force simulating masseter muscle pull was applied with the Lloyd material testing apparatus, and the rotation of the zygoma was determined using displacement transducers. In this study, there were three different experimental groups. Although miniplates at the zygomaticomaxillary buttress and microplates at the infraorbital rim were used in all three groups, three different plates (miniplate, microplate, and modified plate) were used at the frontozygomatic suture in these groups. Rotational displacement of the zygoma with the effects of simulated masseter muscle force was determined. According to the results obtained, microplates are not effective in stabilizing the frontozygomatic suture when the masseter muscle forces are within physiological range. Although miniplates stabilize zygomatic complex fractures, it was shown that modified microplates, which have no ondulation along the plate border, have a higher resistance to rotation than that of the conventional plates. The rotation angle at the instant of fracture with microplates was 4.59 degrees, and that with miniplates was 1.26 degrees. The maximum rotation angle with modified microplates was 0.32 degrees. Modified microplates designed for the fixation of fractures in the zygomatico-orbital region have been shown to be suitable in a well-designed experimental model and might be appropriate for clinical use.


Common major gene inheritance of extreme overweight.
We studied 3925 individuals in 961 families to determine the mode of inheritance of overweight. As an index of overweight, we examined body mass index. Our analyses indicate that the most likely genetic model for susceptibility to overweight included moderate polygenic inheritance (34% of variance resulting from many genes with small effects) and common (21% frequency) recessively expressed major genes (a few genes with large effects on the individuals who possess them). Standard statistical criteria for accepting both polygenic and major gene inheritance were met, including tests of Mendelian transmission. These results suggest that recessive major gene inheritance of overweight may be common and that homozygosity for overweight susceptibility alleles often results in overweight. Clinical, biologic, and empirical observations all suggest genetic heterogeneity, that is, more than one predisposing gene.


Short-term heritable variation overwhelms 200 generations of mutational variance for metabolic traits in Caenorhabditis elegans.
Metabolic disorders have a large heritable component, and have increased markedly in human populations over the past few generations. Genome-wide association studies of metabolic traits typically find a substantial unexplained fraction of total heritability, suggesting an important role of spontaneous mutation. An alternative explanation is that epigenetic effects contribute significantly to the heritable variation. Here, we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematode Caenorhabditis elegans, including both the activity and concentration of two metabolic enzymes and the standing pools of their associated metabolites. The only prior studies on the effects of mutation on metabolic enzyme activity, in Drosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life-history traits. However, those studies were not designed to account for short-term heritable effects. We find that the short-term heritable variance for most traits is of similar magnitude as the variance among MA lines. This result suggests that the potential heritable effects of epigenetic variation in metabolic disease warrant additional scrutiny.


Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum.
The principal modulators of the hypothalamic-pituitary-adrenal (HPA) axis are corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). Corticotropin-releasing hormone is not exclusively produced in the hypothalamus. Its presence has been demonstrated at peripheral inflammatory sites. Ovulation and luteolysis bear characteristics of an aseptic inflammation. CRH was found in the theca and stromal cells as well as in cells of the corpora lutea of human and rat ovaries. The cytoplasm of the glandular epithelial cells of the endometrium has been shown to contain CRH and the myometrium contains specific CRH receptors. It has been suggested that CRH of fetal and maternal origin regulates FasL production, thus affecting the invasion (implantation) process through a local auto-paracrine regulatory loop involving the cytotrophoblast cells. Thus, the latter may regulate their own apoptosis. During pregnancy, the plasma level of circulating maternal immunoreactive CRH increases exponentially from the first trimester of gestation due to the CRH production in the placenta, decidua, and fetal membranes. The presence in plasma and amniotic fluid of a CRH-binding protein (CRHbp) that reduces the bioactivity of circulating CRH by binding is unique to humans. Maternal pituitary ACTH secretion and plasma ACTH levels rise during pregnancy-though remaining within normal limits-paralleling the rise of plasma cortisol levels. The maternal adrenal glands during pregnancy gradually become hypertrophic. Pregnancy is a transient, but physiologic, period of hypercortisolism. The diurnal variation of plasma cortisol levels is maintained in pregnancy, probably due to the secretion of AVP from the parvicellular paraventricular nuclei. CRH is detected in the fetal hypothalamus as early as the 12th week of gestation. CRH levels in fetal plasma are 50% less than in maternal plasma. The circulating fetal CRH is almost exclusively of placental origin. The placenta secretes CRH at a slower rate in the fetal compartment. AVP is detected in some neurons of the fetal hypothalamus together with CRH. AVP is usually detectable in the human fetal neurohypophysis at 11 to 12 weeks gestation and increases over 1000-fold over the next 12 to 16 weeks. The role of fetal AVP is unclear. Labor appears to be a stimulus for AVP release by the fetus. The processing of POMC differs in the anterior and intermediate lobes of the fetal pituitary gland. Corticotropin (ACTH) is detectable by radioimmunoassay in fetal plasma at 12 weeks gestation. Concentrations are higher before 34 weeks gestation, with a significant fall in late gestation. The human fetal adrenal is enormous relative to that of the adult organ. Adrenal steroid synthesis is increased in the fetus. The major steroid produced by the fetal adrenal zone is sulfoconjugated dehydroepiandrosterone (DHEAS). The majority of cortisol present in the fetal circulation appears to be of maternal origin, at least in the nonhuman primate. The fetal adrenal uses the large amounts of progesterone supplied by the placenta to make cortisol. Another source of cortisol for the fetus is the amniotic fluid where cortisol converted from cortisone by the choriodecidua, is found. In humans, maternal plasma CRH, ACTH, and cortisol levels increase during normal labor and drop at about four days postpartum; however, maternal ACTH and cortisol levels at this stage are not correlated. In sheep, placental CRH stimulates the fetal production of ACTH, which in turn leads to a surge of fetal cortisol secretion that precipitates parturition. The 10-day-long intravenous administration of antalarmin, a CRH receptor antagonist, significantly prolonged gestation compared to the control group of animals. Thus, CRH receptor antagonism in the fetus can also delay parturition. The HPA axis during the postpartum period gradually recovers from its activated state during pregnancy. The adrenals are mildly suppressed in a way analogous to postcure Cushing's syndrome. Provocation testing has shown that hypothalamic CRH secretion is transiently suppriently suppressed at three and six weeks postpartum, normalizing at 12 weeks.


Efficient co-expression of a recombinant staphopain A and its inhibitor staphostatin A in Escherichia coli.
Staphopain A is a staphylococcal cysteine protease. Genes encoding staphopain A and its specific inhibitor, staphostatin A, are localized in an operon. Staphopain A is an important staphylococcal virulence factor. It is difficult to perform studies on its interaction with other proteins due to problems in obtaining a sufficient amount of the enzyme from natural sources. Therefore efforts were made to produce a recombinant staphopain A. Sequences encoding the mature form of staphopain A and staphostatin A were PCR-amplified from Staphylococcus aureus genomic DNA and cloned into different compatible expression vectors. Production of staphopain A was observed only when the enzyme was co-expressed together with its specific inhibitor, staphostatin A. Loss of the function mutations introduced within the active site of staphopain A causes the expression of the inactive enzyme. Mutations within the reactive centre of staphostatin A result in abrogation of production of both the co-expressed proteins. These results support the thesis that the toxicity of recombinant staphopain A to the host is due to its proteolytic activity. The coexpressed proteins are located in the insoluble fraction. Ni2+-nitrilotriacetate immobilized metal-affinity chromatography allows for an efficient and easy purification of staphopain A. Our optimized refolding parameters allow restoration of the native conformation of the enzyme, with yields over 10-fold higher when compared with isolation from natural sources.


PATIENT EXPOSURE OPTIMISATION THROUGH TASK-BASED ASSESSMENT OF A NEW MODEL-BASED ITERATIVE RECONSTRUCTION TECHNIQUE.
The goal of the present work was to report and investigate the performances of a new iterative reconstruction algorithm, using a model observer. For that, a dedicated low-contrast phantom containing different targets was scanned at four volume computed tomography dose index (CTDIvol) levels on a Siemens SOMATOM Force computed tomography (CT). The acquired images were reconstructed using the ADMIRE algorithm and were then assessed by three human observers who performed alternative forced choice experiments. Next, a channelised hotelling observer model was applied on the same set of images. The comparison between the two was performed using the percentage correct as a figure of merit. The results indicated a strong agreement between human and model observer as well as an improvement in the low-contrast detection when switching from an ADMIRE strength of 1-3. Good results were also observed even in situations where the target was hard to detect, suggesting that patient dose could be further reduced and optimised.


Arthroscopic autogenous osteochondral mosaicplasty for the treatment of femoral condylar articular defects. A preliminary report.
An arthroscopic technique for the use of mosaicplasty osteochondral grafting in the treatment of femoral condylar articular defects is described. During the procedure, small cylindrical grafts are harvested from the nonweightbearing periphery of the patellofemoral joint and implanted in mosaiclike fashion into the focal cartilage defect of the weightbearing condylar surface. This report describes the arthroscopic technique using newly designed instruments and the early results of 44 patients treated by this method. Good to excellent results have been obtained based on follow-up ranging from 1 to 5 years. The modified HSS scores are compared with a control group consisting of patients treated by abrasion arthroplasty. Evaluation was done clinically and, in some cases, by ultrasound, magnetic resonance imaging, 3-dimensional computed tomography. The results of 10 control arthroscopies and the histological evaluations of 6 biopsies demonstrated the hyalinelike cartilage surface at the recipient area and the fibrocartilage formation at the surface of the donor holes.


Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE-/- mice.
Hypercholesterolemia and hypertension are two major risk factors for coronary artery diseases, which remain the major cause of mortality in the industrialized world. Current animal models of atherosclerosis do not recapitulate coronary plaque disruption, thrombosis, and myocardial infarction occurring in humans. Recently, we demonstrated that exposure of the heart to high pressure, by transverse aortic constriction (TAC), induced coronary lesions in ApoE-/- mice on chow diet. The aim of this study was to characterize the magnitude and location of coronary lesions in ApoE-/- mice after TAC and to assess the susceptibility of coronary plaque to disruption, leading to myocardial events. Here, we describe a reliable pathological condition in mice characterized by the development of coronary lesions and its progression, leading to myocardial infarction; this model better recapitulates human disease. Following TAC surgery, about 90% of ApoE-/- mice developed coronary lesions, especially in the left anterior descending artery, with 59% of the mice manifesting a different magnitude of LAD stenosis. Myocardial events, identified in 74% of the mice, were mainly due to coronary plaque thrombosis and occlusion. That TAC-induced development and progression of coronary lesions in ApoE-/- mice, leading to myocardial events, represents a potentially novel and important tool to investigate the development of coronary lesions and its sequelae in a setting that better resemble human conditions.


Preening cups increase apparent wet preening behaviors, but have no impact on other behaviors, body condition, growth, or body morphometrics of grow-out Pekin ducks.
Preening cups may be a form of open water that would allow ducks to express preening behaviors. We set out to test the hypothesis that preening cups would not have detrimental effects on ducks or their environment. Control pens (N = 6, 65 ducks/pen) had nipple lines while experimental pens (N = 6, 65 ducks/pen) had the same nipple line plus one preening cup (PC). Body weights of 30 ducks per pen, and body condition scores on 50 ducks per pen were recorded weekly. On d 18 and 43, 5 ducks per pen were euthanized and their spleens, Bursas, liver, and uropygial glands were weighed. Behavior data were collected using scan sampling with video being recorded for 72 continuous hours at 4 different ages: 25 d, 30 d, 36 d, and 40 d. Body morphometrics were analyzed by 2-way ANOVA with repeated measures. Body condition scoring was analyzed by Pearson's chi-square. The GLIMMIX procedure (SAS 9.4) was used for behavioral analyses to examine treatment differences in the proportion of ducks performing dry preening, wet preening, eating, drinking, standing, and laying down. Feather pecking, feather picking, preening conspecifics (also known as allopreening), dunking head, and drinking from preening cup were analyzed using PROC LOGISTIC with the Firth bias correction for quasi-complete separation and odds ratios were calculated. More PC ducks housed with PC performed wet preening compared to control ducks (25 d: F1,26 = 6.90, P = 0.0143; 30, 36, and 40 d; F1,78 = 24.53, P < 0.0001). Ducks in the PC group were also more likely to lay down compared to controls (25 d: F1,33 = 4.95, P = 0.0330). No differences were observed for any other behavior, body condition score, body weight or morphometrics at any age. Although ducks in the preening cup group showed an increase in wet preening, our data suggest that open water is not necessary to maintain feather condition or uropygial gland size.


[Experimental peroxide atherosclerosis in rabbits].
The paper describes a procedure for reproduction of experimental peroxide atheroarteriosclerosis in rabbits by means of keeping the animals on a semi-natural antioxidant-free diet (casein, coconut oil, starch, sugar. extracted oats, dry yeast, straw, vitamins A and D, a mixture of salts). After 100 days of experimentation the mean area of the involved aorta constituted 72.9 +/- 6.1 %. The biochemical characteristics of experimental peroxide atheroarteriosclerosis is presented. The advantages of this model comparatively to the cholesterol and triglyceride-induced diseases are as follows: the similarity of the atherogenous diet to alimentary factors promoting atherosclerosis in man, endogenous nature of hypercholesterolemia and its moderate grade; development of destructive changes and calcinosis in the arteries in addition to lipidosis and fibrosis.


Renal chymase-dependent pathway for angiotensin II formation mediated acute kidney injury in a mouse model of aristolochic acid I-induced acute nephropathy.
Angiotensin-converting enzyme (ACE) is the primary enzyme that converts angiotensin I (Ang I) to angiotensin II (Ang II) in the renin-angiotensin system (RAS). However, chymase hydrates Ang I to Ang II independently of ACE in some kidney diseases, and it may play an important role. The present study investigated whether chymase played a crucial role in aristolochic acid I (AAI)-induced nephropathy. C57BL/6 mice were treated with AAI via intraperitoneal injection for an accumulated AAI dosage of 45 mg/kg body weight (BW) (15 mg/kg BW per day for 3 days). The animals were sacrificed after acute kidney injury development, and blood, urine and kidneys were harvested for biochemical and molecular assays. Mice exhibited increased serum creatinine, BUN and urinary protein after the AAI challenge. Significant infiltrating inflammatory cells and tubular atrophy were observed in the kidneys, and high immunocytokine levels were detected. Renal RAS-related enzyme activities were measured, and a significantly increased chymase activity and slightly decreased ACE activity were observed in the AAI-treated mice. The renal Ang II level reflected the altered profile of RAS enzymes and was significantly increased in AAI-treated mice. Treatment of AAI-induced nephropathic mice with an ACE inhibitor (ACEI) or chymase inhibitor (CI; chymostatin) reduced renal Ang II levels. The combination of ACEI and CI (ACEI+CI) treatment significantly reversed the AAI-induced changes of Ang II levels and kidney inflammation and injuries. AAI treatment significantly increased renal p-MEK without increasing p-STAT3 and p-Smad3 levels, and p-MEK/p-ERK1/2 signalling pathway was significantly activated. CI and ACEI+CI treatments reduced this AAI-activated signaling pathway. AAI-induced nephropathy progression was significantly mitigated with CI and ACEI+CI treatment. This study elucidates the role of RAS in the pathogenesis of AAI-induced nephropathy.


The Muscle Morphology of Elite Female Sprint Running.
A paucity of research exists examining the importance of muscle morphological and functional characteristics for elite female sprint performance. This study aimed to compare lower body muscle volumes and vertical jumping power between elite and subelite female sprinters and assess the relationships of these characteristics with sprint race and acceleration performance. Five elite (100 m seasons best [SBE 100 ], 11.16 ± 0.06 s) and 17 subelite (SBE 100 , 11.84 ± 0.42 s) female sprinters underwent: 3T magnetic resonance imaging to determine the volume of 23 individual leg muscles/compartments and five functional muscle groups; countermovement jump and 30 m acceleration tests. Total absolute lower body muscle volume was higher in elite versus subelite sprinters (+15%). Elite females exhibited greater muscle volume of the hip flexors (absolute, +28%; relative [to body mass], +19%), hip extensors (absolute, +22%; relative, +14%), and knee extensors (absolute, +21%), demonstrating pronounced anatomically specific muscularity, with relative hip flexor volume alone explaining 48% of sprint performance variability. The relative volume of five individual muscles (sartorius, gluteus maximus, adductor magnus, vastus lateralis, illiopsoas) were both distinct between groups (elite > subelite) and related to SBE 100 ( r = 0.553-0.639), with the combination of the sartorius (41%) and the adductor magnus (17%) explaining 58% of the variance in SBE 100 . Elite female sprinters demonstrated greater absolute countermovement jump power versus subelite, and absolute and relative power were related to both SBE 100 ( r = -0.520 to -0.741) and acceleration performance ( r = 0.569 to 0.808). This investigation illustrates the distinctive, anatomically specific muscle volume distribution that facilitates elite sprint running in females, and emphasizes the importance of hip flexor and extensor relative muscle volume.


[Comparative effectiveness hepatotropic activity remaxol and Essentiale N in chronic viral hepatitis].
Studied hepatotropic activity remaxol and Essentiale N with chronic viral hepatitis (hug) and: 45 patients received the drug remaxol (intravenous drip, 400 ml per day, 10 days), 45 patients Essentiale N (intravenous bolus, 5 ml per day, 10 days). The efficacy was assessed by clinical symptoms, activity ofAlt, AST, bilirubin, alkaline phosphatase, molecules of average weight (MSM), and total effective concentration of albumin (ECA). Remaxol when hug had a hepatotropic effect comparable with Essentiale N, but more effectively cut short asteno vegetative, dyspeptic, cholestatic and intoxication syndrome, which was confirmed by the significantly low values of MSM and high rates of ECA. The inclusion remaxol in the treatment of patients hug should be considered pathogenetically justified, clinically justified and promising.


Wavelet based multi-scale shape features on arbitrary surfaces for cortical thickness discrimination.
Hypothesis testing on signals defined on surfaces (such as the cortical surface) is a fundamental component of a variety of studies in Neuroscience. The goal here is to identify regions that exhibit changes as a function of the clinical condition under study. As the clinical questions of interest move towards identifying very early signs of diseases, the corresponding statistical differences at the group level invariably become weaker and increasingly hard to identify. Indeed, after a multiple comparisons correction is adopted (to account for correlated statistical tests over all surface points), very few regions may survive. In contrast to hypothesis tests on point-wise measurements, in this paper, we make the case for performing statistical analysis on multi-scale shape descriptors that characterize the local topological context of the signal around each surface vertex. Our descriptors are based on recent results from harmonic analysis, that show how wavelet theory extends to non-Euclidean settings (i.e., irregular weighted graphs). We provide strong evidence that these descriptors successfully pick up group-wise differences, where traditional methods either fail or yield unsatisfactory results. Other than this primary application, we show how the framework allows performing cortical surface smoothing in the native space without mappint to a unit sphere.


Radioenzymatic assay for direct measurement of plasma pyridoxal 5'-phosphate.
A radioenzymatic assay for measurement of pyridoxal 5'-phosphate (PLP) is described, based on the incubation of L-[3H]tyrosine (10(6) cpm, spec. acty. 1.88 Ci/mol) in the presence of the apoenzyme tyrosine decarboxylase (EC 22.214.171.124) from Streptococcus faecalis and PLP in phosphate buffer (0.1 mol/L, pH 5.5) at 37 degrees C for 60 min. The decarboxylated metabolite formed, [3H]tyramine, was selectively extracted into ethyl acetate, and the tritium radioactivity in the sample was determined by liquid scintillation counting. As little as 0.5 nmol of PLP can be detected per liter. The assay is specific, no cross reactivity having been noted for several compounds closely related to PLP. With this we could directly measure the concentrations of PLP in plasma without prior deproteinization and ether washing of the samples. Using the assay to determine plasma concentrations of PLP in healthy adult populations, we found results that were comparable with previously reported data.


Incentives and barriers to retinopathy screening among African-Americans with diabetes.
Diabetes-related ophthalmic complications are the leading cause of newly diagnosed blindness among adults. These eye complications are often asymptomatic in the early stages, yet the majority of diabetes patients are not screened yearly. To develop a health promotion intervention to increase the rate of screening for diabetic retinopathy by dilated fundus exam (DFE), we assessed the knowledge and health beliefs related to preventing diabetic eye complications among a sample of African-Americans with diabetes. The study design was cross-sectional, using a telephone interview to collect data. From a random sample of 104 African-Americans with diabetes, 67 (64%) were completed: 54 women; mean age of 58 years. The telephone interview schedule contained items grouped into subscales for Perceived Incentives, Perceived Barriers to getting a DFE, Causes of Eye Problems, Risk of Eye Problems, and Effective Treatments for Eye Problems. Descriptive statistics were used to analyze the quantitative data. Transcribed qualitative responses to the open-ended questions were analyzed for themes. The incentives "having eye problems" and "doctor said it was important to go" each had 91% responding it was an incentive to go for a DFE. Only about one-third agreed that any particular item was a barrier to receiving a DFE (e.g., economic factors). In the subscale for Risk of Eye Problems, "retinopathy" had the lowest level of perceived risk (30%). Only 21% of the sample reported there were effective treatments for retinopathy. Eighty-seven percent reported the faulty belief that "diabetic eye problems have symptoms." Only 36% of the sample said they had heard of retinopathy and of those, only 8% could describe it correctly. Among general response themes were: fear, spirituality (faith and hope), priorities, economic or logistical factors, and external/internal motivation. Perceived incentives for receiving a DFE were acknowledged at far greater rates than perceived barriers. Having a yearly DFE in the absence of symptoms must be emphasized in health promotion materials. There are effective, early treatments for diabetic eye problems, and this information should be used to counter the fear of a dreaded diagnosis with the hope of treatment and cure. Ways of coping with fear of having the exam should be included in health education. DFEs must become a routine yearly exam and not just a reaction to recognized problems. Health education must address the specific needs of high-risk minority populations.


Triage Performance in Emergency Medicine: A Systematic Review.
Rapid growth in emergency department (ED) triage literature has been accompanied by diversity in study design, methodology, and outcome assessment. We aim to synthesize existing ED triage literature by using a framework that enables performance comparisons and benchmarking across triage systems, with respect to clinical outcomes and reliability. PubMed, EMBASE, Scopus, and Web of Science were systematically searched for studies of adult ED triage systems through 2016. Studies evaluating triage systems with evidence of widespread adoption (Australian Triage Scale, Canadian Triage and Acuity Scale, Emergency Severity Index, Manchester Triage Scale, and South African Triage Scale) were cataloged and compared for performance in identifying patients at risk for mortality, critical illness and hospitalization, and interrater reliability. This study was performed and reported in adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 6,160 publications were identified, with 182 meeting eligibility criteria and 50 with sufficient data for inclusion in comparative analysis. The Canadian Triage and Acuity Scale (32 studies), Emergency Severity Index (43), and Manchester Triage Scale (38) were the most frequently studied triage scales, and all demonstrated similar performance. Most studies (6 of 8) reported high sensitivity (>90%) of triage scales for identifying patients with ED mortality as high acuity at triage. However, sensitivity was low (<80%) for identification of patients who had critical illness outcomes and those who died within days of the ED visit or during the index hospitalization. Sensitivity varied by critical illness and was lower for severe sepsis (36% to 74%), pulmonary embolism (54%), and non-ST-segment elevation myocardial infarction (44% to 85%) compared with ST-segment elevation myocardial infarction (56% to 92%) and general outcomes of ICU admission (58% to 100%) and lifesaving intervention (77% to 98%). Some proportion of hospitalized patients (3% to 45%) were triaged to low acuity (level 4 to 5) in all studies. Reliability measures (κ) were variable across evaluations, with only a minority (11 of 42) reporting κ above 0.8. We found that a substantial proportion of ED patients who die postencounter or are critically ill are not designated as high acuity at triage. Opportunity to improve interrater reliability and triage performance in identifying patients at risk of adverse outcome exists.


Three-dimensional hydrogen microscopy in diamond.
A microprobe of protons with an energy of 17 million electron volts is used to quantitatively image three-dimensional hydrogen distributions at a lateral resolution better than 1 micrometer with high sensitivity. Hydrogen images of a <110>-textured undoped polycrystalline diamond film show that most of the hydrogen is located at grain boundaries. The average amount of hydrogen atoms along the grain boundaries is (8.1 +/- 1.5) x 10(14) per square centimeter, corresponding to about a third of a monolayer. The hydrogen content within the grain is below the experimental sensitivity of 1.4 x 10(16) atoms per cubic centimeter (0.08 atomic parts per million). The data prove a low hydrogen content within chemical vapor deposition-grown diamond and the importance of hydrogen at grain boundaries, for example, with respect to electronic properties of polycrystalline diamond.


Fungal peritonitis caused by Lecythophora mutabilis.
Fungal peritonitis caused by Lecythophora mutabilis, a mold rarely isolated from humans, is described. A patient on continuous peritoneal dialysis developed clinical, microbiological, and serological evidence for peritonitis due to this fungus. In vitro susceptibility testing of the fungus revealed marked differences in the activities of various antifungal agents. Although initially responding to treatment with oral ketoconazole, intraperitoneal miconazole, and catheter replacement, the patient had a documented relapse. The patient was eventually cured following the removal of a second catheter in association with prolonged imidazole treatment.


Accreditation of the PGD laboratory.
Accreditation according to an internationally recognized standard is increasingly acknowledged as the single most effective route to comprehensive laboratory quality assurance, and many countries are progressively moving towards compulsory accreditation of medical testing laboratories. The ESHRE PGD Consortium and some regulatory bodies recommend that all PGD laboratories should be accredited or working actively towards accreditation, according to the internationally recognized standard ISO 15189, 'Medical laboratories-Particular requirements for quality and competence'. ISO 15189 requires comprehensive quality assurance. Detailed management and technical requirements are defined in the two major chapters. The management requirements address quality management including the quality policy and manual, document control, non-conformities and corrective actions, continual improvement, auditing, management review, contracts, referrals and resolution of complaints. Technical requirements include personnel competence (both technical and medical), equipment, accommodation and environment, and pre-analytical, analytical and post-analytical processes. Emphasis is placed on the particular requirements of patient care: notably sample identification and traceability, test validation and interpretation and reporting of results. Quality indicators must be developed to monitor contributions to patient care and continual improvement. We discuss the implementation of ISO 15189 with a specific emphasis on the PGD laboratory, highlight elements of particular importance or difficulty and provide suggestions of effective and efficient ways to obtain accreditation. The focus is on the European environment although the principles are globally applicable.


Incorporating Flexibility Effects into Metal-Organic Framework Adsorption Simulations Using Different Models.
High-throughput calculations based on molecular simulations to predict the adsorption of molecules inside metal-organic frameworks (MOFs) have become a useful complement to experimental efforts to identify promising adsorbents for chemical separations and storage. For computational convenience, all existing efforts of this kind have relied on simulations in which the MOF is approximated as rigid. In this paper, we use extensive adsorption-relaxation simulations that fully include MOF flexibility effects to explore the validity of the rigid framework approximation. We also examine the accuracy of several approximate methods to incorporate framework flexibility that are more computationally efficient than adsorption-relaxation calculations. We first benchmark various models of MOF flexibility for four MOFs with well-established CO2 experimental consensus isotherms. We then consider a range of adsorption properties, including Henry's constants, nondilute loadings, and adsorption selectivity, for seven adsorbates in 15 MOFs randomly selected from the CoRE MOF database. Our results indicate that in many MOFs adsorption-relaxation simulations are necessary to make quantitative predictions of adsorption, particularly for adsorption at dilute concentrations, although more standard calculations based on rigid structures can provide useful information. Finally, we investigate whether a correlation exists between the elastic properties of empty MOFs and the importance of including framework flexibility in making accurate predictions of molecular adsorption. Our results did not identify a simple correlation of this type.


Two-Color Pump-Probe Measurement of Photonic Quantum Correlations Mediated by a Single Phonon.
We propose and demonstrate a versatile technique to measure the lifetime of the one-phonon Fock state using two-color pump-probe Raman scattering and spectrally resolved, time-correlated photon counting. Following pulsed laser excitation, the n=1 phonon Fock state is probabilistically prepared by projective measurement of a single Stokes photon. The detection of an anti-Stokes photon generated by a second, time-delayed laser pulse probes the phonon population with subpicosecond time resolution. We observe strongly nonclassical Stokes-anti-Stokes correlations, whose decay maps the single phonon dynamics. Our scheme can be applied to any Raman-active vibrational mode. It can be modified to measure the lifetime of n≥1 Fock states or the phonon quantum coherences through the preparation and detection of two-mode entangled vibrational states.


Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.
Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.


The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase.
Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.


Risk factors for depressive symptom changes in Indonesian geriatric outpatient.
to determine risk factors for depressive symptom changes in geriatric outpatients. a prospective cohort study was conducted on 106 geriatric outpatients at Integrated Geriatric Clinic Cipto Mangunkusumo Hospital, Jakarta in 2010. A structured questionnaire was applied to obtain independent variable such as age, sex, educational level, chronic diseases (diabetes mellitus, chronic kidney diseases, hypertension, dyslipidemia, and osteoarthritis), functional status (WHO-Unescap score), nutritional status (body mass index), health related quality of life (Eq5D score), hospitalization within 6 months, and total calorie intake. Depressive symptom as dependent variable was assessed using Geriatric Depression Scale. The association between aforementioned various factors with depressive symptom changes were analyzed using multiple logistic regression analysis. most of subjects were women (63.2%), aged 70 years old and older (71.0%) and had hypertension (82.1%). There were 22.6% subjects with increase in GDS score during 6-month follow-up. Bivariable analysis showed that diabetes mellitus and chronic kidney diseases were significantly associated with depressive symptom changes. Multiple logistic regression showed that variable which independently associated with depressive symptom changes was uncontrolled chronic kidney disease (OR 3.390; 95% CI 1.07-10.76. uncontrolled chronic kidney disease is risk factor for depressive symptom changes in geriatric outpatients.


Identification, characterization and application of a new peptide against anterior gradient homolog 2 (AGR2).
The cancer-associated protein Anterior Gradient 2 (AGR2) has been described, predominantly in adenocarcinomas. Increased levels of extracellular AGR2 (eAGR2) have been correlated with poor prognosis in cancer patients, making it a potential biomarker. Additionally, neutralizing AGR2 antibodies showed preclinical effectiveness in murine cancer models suggesting eAGR2 may be a therapeutic target. We set out to identify a peptide by mRNA display that would serve as a theranostic tool targeting AGR2. This method enables the selection of peptides from a complex (>1011) library and incorporates a protease incubation step that filters the selection for serum stable peptides. We performed six successive rounds of enrichment using a 10-amino acid mRNA display library and identified several AGR2 binding peptides. One of these peptides (H10), demonstrated high affinity binding to AGR2 with a binding constant (KD) of 6.4 nM. We developed an AGR2 ELISA with the H10 peptide as the capture reagent. Our H10-based ELISA detected eAGR2 from cancer cell spent media with a detection limit of (20-50 ng/ml). Furthermore, we investigated the therapeutic utility of H10 and discovered that it inhibited cell viability at IC50 (9-12 μmoles/L) in cancer cell lines. We also determined that 10 μg/ml of H10 was sufficient to inhibit cancer cell migration in breast and prostate cancer cell lines. A control peptide did not show any appreciable activity in these cells. The H10 peptide showed promise as both a novel diagnostic and a potential therapeutic peptide.


Evidence from 3-month-old infants shows that a combination of postnatal feeding and exposures in utero shape lipid metabolism.
We tested the hypothesis that both postnatal feeding and conditions in utero affect lipid metabolism in infants. Infants who experienced restrictive growth conditions in utero and others exposed to maternal hyperglycaemia were compared to a control group with respect to feeding mode. Dried blood spots were collected from a pilot subset of infant participants of the Cambridge Baby Growth Study at 3mo. Groups: (a) a normal gestation (control, n = 40), (b) small for gestational age (SGA, n = 34) and (c) whose mothers developed hyperglycaemia (n = 59). These groups were further stratified by feeding mode; breastfed, formula-fed or received a mixed intake. Their phospholipid, glyceride and sterol fractions were profiled using direct infusion mass spectrometry. Statistical tests were used to identify molecular species that indicated differences in lipid metabolism. The abundance of several phospholipids identified by multivariate analysis, PC(34:1), PC(34:2) and PC-O(34:1), was 30-100% higher across all experimental groups. SM(39:1) was around half as abundant in in utero groups among breastfed infants only. The evidence from this pilot study shows that phospholipid metabolism is modulated by both conditions in utero and postnatal feeding in a cohort of 133 Caucasian infants, three months post partum.


Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies.
Pioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta-analysis to evaluate the magnitude of this association and the quality of the supporting evidence. Electronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer. Six studies involving 215 142 patients using pioglitazone were included, with a median period of follow-up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09-1.39; I² = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years. Patients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti-hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer.


Zerumbone Suppresses Enterotoxigenic Bacteroides fragilis Infection-Induced Colonic Inflammation through Inhibition of NF-κΒ.
Enterotoxigenic Bacteroides fragilis (ETBF) is human intestinal commensal bacterium and a potent initiator of colitis through secretion of the metalloprotease Bacteroides fragilis toxin (BFT). BFT induces cleavage of E-cadherin in colon cells, which subsequently leads to NF-κB activation. Zerumbone is a key component of the Zingiber zerumbet (L.) Smith plant and can exhibit anti-bacterial and anti-inflammatory effects. However, whether zerumbone has anti-inflammatory effects in ETBF-induced colitis remains unknown. The aim of this study was to determine the anti-inflammatory effect of orally administered zerumbone in a murine model of ETBF infection. Wild-type C57BL/6 mice were infected with ETBF and orally administered zerumbone (30 or 60 mg/kg) once a day for 7 days. Treatment of ETBF-infected mice with zerumbone prevented weight loss and splenomegaly and reduced colonic inflammation with decreased macrophage infiltration. Zerumbone treatment significantly decreased expression of IL-17A, TNF-α, KC, and inducible nitric oxide synthase (iNOS) in colonic tissues of ETBF-infected mice. In addition, serum levels of KC and nitrite was also diminished. Zerumbone-treated ETBF-infected mice also showed decreased NF-κB signaling in the colon. HT29/C1 colonic epithelial cells treated with zerumbone suppressed BFT-induced NF-κB signaling and IL-8 secretion. However, BFT-mediated E-cadherin cleavage was unaffected. Furthermore, zerumbone did not affect ETBF colonization in mice. In conclusion, zerumbone decreased ETBF-induced colitis through inhibition of NF-κB signaling.


The involvement of vimentin in copper-induced regression of cardiomyocyte hypertrophy.
Dietary copper supplementation reverses the pressure overload-induced cardiac hypertrophy. Activation of vascular endothelial growth factor receptor-1 (VEGFR-1) and cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1 (PKG-1) is required for the regression. The present study was undertaken to determine the link between VEGFR-1 and PKG-1 in copper regression of cardiomyocyte hypertrophy. Human cardiac myocytes (HCM) or primary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 μM for 48 h to induce cell hypertrophy. Copper sulfite was added to cultures of hypertrophic cardiomyocytes at a final concentration of 5 μM elemental copper and incubated for 24 h to reverse cell hypertrophy. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified a 56 kDa copper-binding protein, vimentin, which was co-immunoprecipitated with VEGFR-1 and PKG-1. Copper supplementation increased vimentin levels and enhanced PKG-1 activity. Gene silencing using siRNA targeting vimentin prevented copper-induced elevation of vimentin, depressed the activity of PKG-1, and blocked the copper-induced regression of cardiomyocyte hypertrophy. This study demonstrates that vimentin is critically involved in the VEGFR-1 mediated activation of the PKG-1 signaling pathway, leading to regression of cardiomyocyte hypertrophy.


Time structure analysis of leg movements during sleep in REM sleep behavior disorder.
To compare the time structure of leg movements (LM) during sleep of patients with rapid eye movement (REM) sleep behavior disorder (RBD) with that of patients with restless legs syndrome (RLS) or control subjects. The polysomnographically recorded tibialis anterior activity during sleep was analyzed by means of a new approach able to consider duration, intermovement interval, sleep stage and time of night distribution, and periodicity. Twenty patients with idiopathic RBD, 37 with idiopathic RLS and 14 age-matched control subjects were consecutively recruited. Most patients with RBD (85%) presented periodic leg movements during sleep (PLMS). PLMS occurred more frequently during non-REM sleep in patients with RLS and during REM sleep in patients with RBD. PLMS were shorter in duration, less often bilateral, and with a higher intermovement interval in patients with RBD compared to those with RLS. The number of PLMS decreased across the night in patients with RBD and in those with RLS, but not in control subjects. In all subjects, LM periodicity clearly depended on sleep state, with higher values during non-REM than during REM sleep. Patients with RBD showed a lower LM periodicity, compared with patients with RLS, in each of the sleep states. Significant differences, together with some similarities in LM time structure, were observed between patients with RBD and those with RLS; for this reason, our approach seems to indicate that their phenotype might be dependent on 2 factors: disease and sleep stage.