We know what they did wrong, but not why: the case for 'frame-based' feedback.
Actionable feedback targeted to the learner's needs is one of the strongest predictors of improved performance in learning. Unfortunately, when a trainee makes an error, although instructors may understand what a trainee has done wrong, they can erroneously assume they know why. There is a growing recognition that cognitive biases impede clinical diagnosis, however, the same biases can also undermine accurate and effective feedback. Instead of focusing primarily on correcting actions, it is often crucial to diagnose trainees' 'frames'-- the thought processes that drive their actions. We offer an efficient three-step algorithm for providing this 'frame-based' feedback: (1) describe how the trainee is doing according to the instructor; (2) diagnose the trainee's immediate learning needs using inquiry to elicit their frame; and (3) direct instruction to those needs. 'Misdiagnosis' of the trainee's actual needs wastes time when instructors teaching unneeded material, diminishes the trainee's faith in the value of instruction and undermines patient safety when incorrect frames about important clinical processes persist.


Lack of microsatellite instability in giant cell tumor of bone.
Microsatellite instability was searched for at six different loci on chromosome arms 5q, 18q, 15q, 17p, 19q, and 11p in 22 patients (12 men and 10 women; average age of 31.8 years, range of 20-55 years) with giant cell tumor of bone (GCT). These loci were chosen because of their use in microsatellite instability studies in other tumors such as colorectal cancer (e.g., 5q, 18q, 17p) or because of the presence of chromosomal abnormalities such as telomeric associations commonly occurring at 19q and 11p termini (thus the reason for including the 19q and 11p termini microsatellites in our study of GCT). No microsatellite instability or loss of heterozygosity were detected when comparing normal and tumor cells from any of the GCT patients. Unlike several other tumors, our study indicates that microsatellite instability does not appear to play a role in the tumorigenesis of GCT although other abnormal cytogenetic, biochemical, and molecular genetics data do exist for this musculoskeletal tumor.


Filling a Protein Scaffold With a Reference.
In mass spectrometry-based de novo protein sequencing, it is hard to complete the sequence of the whole protein. Motivated by this, we study the (one-sided) problem of filling a protein scaffold S with some missing amino acids, given a sequence of contigs none of which is allowed to be altered, with respect to a complete reference protein P of length n , such that the BLOSUM62 score between P and the filled sequence S' is maximized. We show that this problem is polynomial-time solvable in O(n26) time. We also consider the case when the contigs are not of high quality and they are concatenated into an (incomplete) sequence I , where the missing amino acids can be inserted anywhere in I to obtain I' , such that the BLOSUM62 score between P and I' is maximized. We show that this problem is polynomial-time solvable in O(n22) time. Due to the high time complexity, both of these algorithms are impractical, we hence present several algorithms based on greedy and local search, trying to solve the problems practically. The empirical results, based on some antibody and mammalian proteins, show that the algorithms can fill protein scaffolds with high quality, provided that a good pair of scaffold and reference are given.


Age-related changes in the function of the pituitary-gonadal axis in a sterile male rat mutant (hd/hd).
Testicular growth is depressed in the genetically sterile male rat (hd/hd) relative to its LE phenotype littermates (by 50% and 73% at 27 and 90 days of age, respectively). Within the hd/hd testis, both the tubular and seminiferous tubule tissues are affected by the mutation. In addition, there is significantly less germ cell production from the primary spermatocyte stage of spermatogenesis onwards and the total number of Sertoli cells observed is less. In the intertubular tissue, the total volume and the total number of Leydig cells per testis is significantly less, but the mean volume of an average Leydig cell is not modified. The serum gonadotropin levels are higher in the hd/hd rat, whereas from 40 days of age onwards the level of testosterone is lower. The FSH and LH binding affinity constants are unchanged by the mutation; however, the total number of FSH binding sites per 10(6) Sertoli cells is lower while that of LH per 10(6) Leydig cells is greater. Indeed, it is likely that the lesser concentration of serum testosterone in the hd/hd rat is a result of a smaller number of Leydig cells since their individual function is not modified. The testicular androgen binding protein (ABP) content and the ABP output towards the epididymis are lower as a consequence of both a lesser number and an altered function of the Sertoli cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Improved detection of acute myocardial infarction in patients with chest pain and significant left main stem coronary stenosis.
Non-invasive diagnosis of acute myocardial infarction (AMI) associated with significant left main stem (LMS) stenosis remains challenging. Consecutive patients presenting with acute ischaemic-type chest pain from 2000 to 2010 were analysed. Entry criteria: 12-lead ECG and Body Surface Potential Map (BSPM) at presentation, cardiac troponin T (cTnT) ≥12 h and coronary angiography during admission. cTnT ≥0.03 µg/l defined AMI. ECG abnormalities assessed: STEMI by Minnesota criteria; ST elevation (STE) aVR ≥0.5 mm; ST depression (STD) ≥0.5 mm in ≥2 contiguous leads (CL); T-wave inversion (TWI) ≥1 mm in ≥2 CL. BSPM STE was ≥2 mm in anterior, ≥1 mm in lateral, inferior, right ventricular or high right anterior and ≥0.5 mm in posterior territories. Significant LMS stenosis was ≥70%. Enrolled were 2810 patients (aged 60 ± 12 years; 71% male). Of these, 116 (4.1%) had significant LMS stenosis with AMI occurring in 92 (79%). STEMI by Minnesota criteria occurred in 13 (11%) (sensitivity 12%, specificity 92%), STE in lead aVR in 23 (20%) (sensitivity 23%, specificity 92%), TWI in 38 (33%) (sensitivity 34%, specificity 71%) and STD in 51 (44%) (sensitivity 49%, specificity 75%). BSPM STE occurred in 85 (73%): sensitivity 88%, specificity 83%, positive predictive value 95% and negative predictive value 65%. Of those with AMI, 74% had STE in either the high right anterior or right ventricular territories not identified by the 12-lead ECG. C-Statistic for AMI diagnosis using BSPM STE was 0.800 (P < 0.001). In patients with significant LMS stenosis presenting with chest pain, BSPM STE has improved sensitivity (88%), with specificity 83%, over 12-lead ECG in the diagnosis of AMI.


Decontamination of Ti Oxide Surfaces by Using Ultraviolet Light: Hg-Vapor vs. LED-Based Irradiation.
C-range Ultraviolet (UVC) mercury (Hg)-vapor lamps have shown the successful decontamination of hydrocarbons and antimicrobial effects from titanium surfaces. This study focused on surface chemistry modifications of titanium dental implants by using two different light sources, Hg-vapor lamps and Light Emitting Diodes (LEDs), so as to compare the effectivity of both photofunctionalization technologies. Two different devices, a small Hg-vapor lamp (λ = 254 nm) and a pair of closely placed LEDs (λ = 278 nm), were used to irradiate the implants for 12 min. X-ray Photoelectron Spectroscopy (XPS) was employed to characterize the chemical composition of the surfaces, analysing the samples before and after the lighting treatment, performing a wide and narrow scan around the energy peaks of carbon, oxygen and titanium. XPS analysis showed a reduction in the concentration of surface hydrocarbons in both UVC technologies from around 26 to 23.4 C at.% (carbon atomic concentration). Besides, simultaneously, an increase in concentration of oxygen and titanium was observed. LED-based UVC photofunctionalization has been suggested to be as effective a method as Hg-vapor lamps to remove the hydrocarbons from the surface of titanium dental implants. Therefore, due to the increase in worldwide mercury limitations, LED-based technology could be a good alternative decontamination source.


A new device for measuring intrauterine temperature.
We evaluated a new device that uses the intrauterine pressure catheter to measure the maternal temperature in patients who are in labor. The study was conducted at two medical centers, Christiana Hospital in Newark, Delaware, and Saint Louis University/St Mary's Health Center in St Louis, Missouri, from September 1, 1997, to May 2, 1998. An intrauterine pressure catheter with a thermistor sensor in the tip was placed into the uterus after spontaneous rupture of membranes. The intrauterine, oral, and tympanic temperatures were simultaneously obtained immediately after insertion of the intrauterine pressure catheter and then hourly until delivery or the initiation of amnioinfusion. The study comprised 97 patients and 404 temperature readings with a temperature range of 34.7 degrees C to 40.7 degrees C. The normal mean +/- SD for the oral, tympanic, and intrauterine temperatures was 36.7 degrees C +/- 0.5 degrees C, 36.8 degrees C +/- 0.5 degrees C, and 37.3 degrees C +/- 0.4 degrees C, respectively. There was a linear relationship among the oral, tympanic, and intrauterine temperatures. All three methods showed a significant increase in mean body temperature after epidural anesthesia. The new device, the intrauterine pressure-temperature catheter, provides a convenient and accurate means of continuously measuring uterine temperature in patients who are in labor and require intrauterine monitoring.


Morphogenetic processes: application to cambial growth dynamics.
Both the physiological and the pathological morphogenetic processes that we can meet in embryogenesis, neogenesis and degenerative dysgenesis present common features: they are ruled by three different kinds of mechanisms, one related to cell migration, the second to cell differentiation and the third to cell proliferation. We deal here with an application to the cambial growth which essentially involves the third type of mechanism. Woody plants produce secondary tissue (secondary xylem and phloem) from a meristematic tissue called vascular cambium, responsible for the radial growth of a tree. This paper focuses on the formation of secondary xylem, considered in two dimensions in a cross-section framework. A new discrete modelling approach is used, based on the cellular scale, in order to attain a more accurate understanding of how the elementary microscopic behaviour of each cell takes part in the macroscopic morphogenesis. The mathematical model essentially uses an occurrence method simulating the main features of radial growth with simple geometric rules, such as Thom's division rule (Thom,1972)to account for the cell proliferation. The study applies to concrete instances in which the changes made in the geometrical cellular patterns of the vascular cambium clearly affect the shape of the tree, as in Pinus radiata (D. Don.).


An in vitro α-neurotoxin-nAChR binding assay correlates with lethality and in vivo neutralization of a large number of elapid neurotoxic snake venoms from four continents.
The aim of this study was to develop an in vitro assay for use in place of in vivo assays of snake venom lethality and antivenom neutralizing potency. A novel in vitro assay has been developed based on the binding of post-synaptically acting α-neurotoxins to nicotinic acetylcholine receptor (nAChR), and the ability of antivenoms to prevent this binding. The assay gave high correlation in previous studies with the in vivo murine lethality tests (Median Lethal Dose, LD50), and the neutralization of lethality assays (Median Effective Dose, ED50) by antisera against Naja kaouthia, Naja naja and Bungarus candidus venoms. Here we show that, for the neurotoxic venoms of 20 elapid snake species from eight genera and four continents, the in vitro median inhibitory concentrations (IC50s) for α-neurotoxin binding to purified nAChR correlated well with the in vivo LD50s of the venoms (R2 = 0.8526, p < 0.001). Furthermore, using this assay, the in vitro ED50s of a horse pan-specific antiserum against these venoms correlated significantly with the corresponding in vivo murine ED50s, with R2 = 0.6896 (p < 0.01). In the case of four elapid venoms devoid or having a very low concentration of α-neurotoxins, no inhibition of nAChR binding was observed. Within the philosophy of 3Rs (Replacement, Reduction and Refinement) in animal testing, the in vitro α-neurotoxin-nAChR binding assay can effectively substitute the mouse lethality test for toxicity and antivenom potency evaluation for neurotoxic venoms in which α-neurotoxins predominate. This will greatly reduce the number of mice used in toxicological research and antivenom production laboratories. The simpler, faster, cheaper and less variable in vitro assay should also expedite the development of pan-specific antivenoms against various medically important snakes in many parts of the world.


[Loose anagen hair syndrome].
In 1984, Zaun described a new type of pilary dysplasia characterized by easily pluckable hair. We were able to observe three patients with this anomaly, and this paper is an attempt at reviewing the subject on the basis of these new cases compared with those previously published. Clinical features. The major sign of the anomaly is that hairs can be pulled off in tufts easily and painlessly, and promptly grow again (our cases). In all cases reported so far the hair was blond or dark-blond; in some patients it is described as scintillating (our cases). The hair shaft is usually thin (one of our cases), but it may be of normal caliber (two of our patients). In the occipital region the hairs are entangled, dry and short (our cases). They are implanted wide apart or at normal intervals (our patients); areas of alopecia are sometimes encountered (our cases). Hair growth may be slow (one of our cases) or of normal speed (two of our cases). The eyelashes and eyebrows, as well as other body hairs, are normal in all patients (fig. 1). Microscopy. The trichogram is exclusively composed of anagenic and dystrophic roots (our cases). Pathological examination by biopsy of the scalp is characteristic: transverse and oblique sections of the follicles show that the hairs are oval, triangular or trapezoidal in shape (fig. 7). Alterations of the inner epithelial sheath are also present, including keratinization and early decomposition (fig. 8), lack of complementation (fig. 7) and fissures between the cuticle of the inner epithelial sheath and of the hair, in the keratogenic area (fig. 9). (ABSTRACT TRUNCATED AT 250 WORDS)


A case-control study of patients readmitted to the intensive care unit.
To determine characteristics of patients requiring readmission to an intensive care unit (ICU). Retrospective case-control chart review. Adult patients in an 8-bed medical and 16-bed surgical ICU in a 650-bed university teaching hospital during an 18-month period. None. Each patient readmitted to either ICU was compared to a single control patient matched for age, sex, unit, and diagnosis. A total of 117 variables were obtained from chart review. The last value for each variable before ICU discharge was used. Chi-square analysis, linear regression factor analysis, correlation, and Student's t-test were used to identify significant factors predicting the patient's return to an ICU. Descriptive statistics were used to describe various subgroups. Mortality rate was 41.5% in the 82 readmitted patients (comprising 4.6% of the total ICU admissions) and only 7.3% in the controls. Mean (+/- SD) hospital length of stay was 47.8 +/- 42.0 days in the study group and 20.8 +/- 14.2 days (p < .0009) in the controls. Initial ICU length of stay was 8.3 +/- 16.1 days in the readmitted group and 4.0 +/- 5.0 days (p = .02) in the controls. Variables that predicted readmission to the ICU were: increased respiratory rate (24.2 vs. 20 breaths/min, p < .002), lower hematocrit value (31.9% vs. 34.4%, p = .01), positive fluid balance (p < .03), and positive blood cultures (six in the readmitted group, none in the controls, p = .002). More than 30% of readmissions were for a recurrence or worsening of the original problem. Fifty-four percent of the patients were readmitted with pulmonary failure. Mortality rate in both groups was related to advanced age, Acute Physiology and Chronic Health Evaluation (APACHE II) scores at ICU discharge, and increased blood urea nitrogen concentrations. Mortality rate in the control group, but not in the readmitted group, correlated with the level of consciousness, serum creatinine concentration, and use of hemodialysis. Readmission to an ICU carries a risk of high mortality rate and increased length of stay and may represent premature discharge in at least 30% of patients. Pulmonary failure is the immediate cause of readmission in more than half of the readmitted patients. Increased respiratory rate correlates with ICU readmission. Intermediate care areas for patients with poor pulmonary function may help to avoid readmission to an ICU, prevent death, and conserve hospital resources.


Existence of cord compression in extramedullary hematopoiesis due to beta thalassemia intermedia.
Extramedullary hematopoiesis (EMH) is a rare disorder, characterized by the appearance of hematopoietic elements outside of the bone marrow, which occurs in patients with chronic myeloproliferative disorders or congenital hemolytic anemias. We report a case with thalassemia intermedia, EMH in spinal cord and a paravertebral mass. We report the case of a 20 year old female who initially presented with back pain and leg weakness was found to have paravertebral mass in the spinal cord.


[Impacts of electroacupuncture on left hippocampus NAA/Cr for patients of Uygur and Han nationality with mild cognitive impairment].
To observe the clinical efficacy of electroacupuncture (EA) on mild cognitive impairment (MCI) for patients of Uygur and Han nationality and explore the national diversity among the patients with MCI. Twenty-five cases were divided into Han nationality group (15 cases) and Uygur nationality group (10 cases) according to patient's nationality. In either group, EA was applied to Baihui (GV 20), Fengchi (GB 20), Xuanzhong (GB 39), Fuliu (KI 7), Sanyinjiao (SP 6) and Taixi (KI 3), once per day, 15 treatments made one session and there were 5 days at the interval among the sessions. Totally, 3 sessions of treatment were required. The proton magnetic resonance spectroscopy (1H-MRS) was used to observe the changes in the ratio of N-acetylaspartate and creatine (NAA/Cr) on the left hippocampus for the patients in two groups before and after treatment as well as the changes in the results of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) separately. NAA/Cr in Uygur nationality group was higher than that in Han nationality group before treatment (1.659 +/- 0.418 vs 1.137 +/- 0.190, P < 0.05). After treatment, MMSE and MoCA scores all increased apparently as compared with those before treatment in two groups (P < 0.05, P < 0.01), and NAA/Cr on the left hippocampus in either group was up-regulated as compared with that before treatment (both P < 0.01). EA can improve the overall cognitive function for the patients with MCI. There is the national diversity in the partial brain metabolite level between Uygur patients and Han patients with MCI.


Wet adhesion of buckypaper produced from oxidized multiwalled carbon nanotubes on soft animal tissue.
Buckypaper (BP) is the general definition of a macroscopic assembly of entangled carbon nanotubes. In this paper, a new property of a BP film produced from oxidized multiwalled carbon nanotubes was investigated. In particular, BP shows to be able to promptly and strongly adhere to animal internal soft and wet tissues, as evaluated by peeling and shear tests. BP adhesion strength is higher than that recorded for a commercial prosthetic fabric (sealed to the tissue by fibrin glue) and comparable with that of other reported optimized nanopatterned surfaces. In order to give an interpretation of the observed behavior, the BP composition, morphology, porosity, water wettability, and mechanical properties were analyzed by AFM, X-ray photoelectron spectroscopy, wicking tests, contact angle, and stress-strain measurements. Although further investigations are needed to assess the biocompatibility and safety of the BP film used in this work, the obtained results pave the way for a possible future use of buckypaper as adhesive tape in abdominal prosthetic surgery. This would allow the substitution of conventional sealants or the reduction in the use of perforating fixation.


Single acetylcholine-activated channel currents in developing muscle cells.
The properties of single acetylcholine-activated ion channels in developing rat myoblasts and myotubes in tissue culture have been investigated using the gigaohm seal patch clamp technique. Two classes of ACh-activated channels were identified. The major class of channels (accounting for greater than 95% of all channel openings) has a conductance of 35 pS and a mean open time of 15 msec (at room temperature and -80 mV). The minor class of channels has a larger conductance (55 pS) and a briefer mean open time (2-3 msec). Functional ACh-activated channels are present in undifferentiated mononucleated myoblasts 1-2 days in culture, although the channel density on such cells is low. Over the next week in culture, as the myoblasts fuse to form multinucleate myotubes, there is a marked increase in channel density and an increase in the proportion of large conductance channels. No significant change, however, occurs in channel conductance or open time (within a given class of channels) during this period. At high concentrations of ACh, channels desensitize and channel openings occur in groups, similar to what has been previously described in adult muscle. The rate of channel opening within a group of openings increases with increasing agonist concentration while mean open time is independent of agonist concentration, as expected from simple models of drug action. During a group of openings, the channel is open for half the time (i.e., channel opening rate is equal to channel closing rate) at a concentration of approximately 6 micron ACh.


Patient non-attendance at urgent referral appointments for suspected cancer and its links to cancer diagnosis and one year mortality: A cohort study of patients referred on the Two Week Wait pathway.
The 'Two Week Wait' policy aims to ensure patients with suspected cancer are seen within two weeks of referral. However, patient non-attendance can result in this target being missed. This study aimed to identify predictors of non-attendance; and analyse the relationship between attendance and outcomes including cancer diagnosis and early mortality. A cohort study of 109,433 adults registered at 105 general practices, referred to a cancer centre within a large NHS hospital trust (April 2009 to December 2016) on the 'Two Week Wait' pathway. 5673 (5.2%) patients did not attend. Non-attendance was largely predicted by patient factors (younger and older age, male gender, greater deprivation, suspected cancer site, earlier year of referral, greater distance to the hospital) over practice factors (greater deprivation, lower Quality and Outcomes Framework score, lower cancer conversion rate, lower cancer detection rate). 10,360 (9.6%) patients were diagnosed with cancer within six months of referral (9.8% attending patients, 5.6% non-attending patients). Among these patients, 2029 (19.6%) died within 12 months of diagnosis: early mortality risk was 31.3% in non-attenders and 19.2% in attending patients. Non-attendance at urgent referral appointments for suspected cancer involves a minority of patients but happens in predictable groups. Cancer diagnosis was less likely in non-attending patients but these patients had worse early mortality outcomes than attending patients. The study findings have implications for cancer services and policy.


ECT use delayed in the presence of comorbid mental retardation: a review of clinical and ethical issues.
The objective is to develop a clinically and ethically supportive literature for the use of electroconvulsive therapy (ECT) in patients with mental retardation who are concurrently experiencing a significant psychiatric illness. A review of both the clinical and ethical literature using traditional, manual library methods and the Medline and Psychlit databases was undertaken. In addition, a record of all patients who had undergone ECT at our facility between 1995 and 2000 was examined for patients with comorbid mental retardation. We found that the use of ECT for people who have both a psychiatric illness and comorbid mental retardation was significantly delayed. However, a rapid response to index, continuation, and maintenance ECT was also noted. Further, this response occurred with routine ECT administered irrespective of age, gender, diagnosis, stimulus parameters, electrode placement, or number of treatments. In addition, the successful use of right-sided unilateral ECT at six times the initial seizure threshold was reported in a patient who had previously responded to bilateral ECT. A cogent ethical justification was developed with the use of the rule of double effect. We concluded that for patients who have mental retardation and who subsequently develop a psychiatric illness, ECT is delayed and left as a treatment of last choice. Although the literature is sparse and uncontrolled, a cogent clinical and ethical justification may help negotiate these and other delays.


Novel Method for Automated Analysis of Retinal Images: Results in Subjects with Hypertensive Retinopathy and CADASIL.
Morphological analysis of the retinal vessels by fundoscopy provides noninvasive means for detecting and staging systemic microvascular damage. However, full exploitation of fundoscopy in clinical settings is limited by paucity of quantitative, objective information obtainable through the observer-driven evaluations currently employed in routine practice. Here, we report on the development of a semiautomated, computer-based method to assess retinal vessel morphology. The method allows simultaneous and operator-independent quantitative assessment of arteriole-to-venule ratio, tortuosity index, and mean fractal dimension. The method was implemented in two conditions known for being associated with retinal vessel changes: hypertensive retinopathy and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The results showed that our approach is effective in detecting and quantifying the retinal vessel abnormalities. Arteriole-to-venule ratio, tortuosity index, and mean fractal dimension were altered in the subjects with hypertensive retinopathy or CADASIL with respect to age- and gender-matched controls. The interrater reliability was excellent for all the three indices (intraclass correlation coefficient ≥ 85%). The method represents simple and highly reproducible means for discriminating pathological conditions characterized by morphological changes of retinal vessels. The advantages of our method include simultaneous and operator-independent assessment of different parameters and improved reliability of the measurements.


Understanding Nonsuicidal Self-Injury.
Nonsuicidal self-injury has existed since biblical times. It is increasing and gaining acceptance particularly among adolescents. Spiritual discontent or doubt is often a component. Therapeutic interventions include cognitive and behavior practices and developing strong, sustained relationships with patients to encourage healthy transformation.


Surgical undercutting prevents receptor redistribution in developing kitten visual cortex.
Recent studies have shown that several receptor populations in cat visual cortex undergo alterations in their laminar distributions during postnatal development (Shaw et al., 1984a,b; 1986b). These redistributions occur during the first few months of postnatal life, coincident with the physiologically defined critical period for cortical plasticity. In the present communication, we demonstrate that receptor redistributions can be prevented from occurring, or progressing once started, by surgically isolating the visual cortex at appropriate postnatal ages. These data suggest that the maturation of the chemical circuitry of the visual cortex is dependent on factors of extrinsic origin.


[Preparation and identification of monoclonal antibody GB2 directed against human breast cancer serum antigen].
Spleen cells from BALB/c mice immunized with human breast cancer serum antigen were fused with murine myeloma SP 2/0 cells. After screening with ELISA and limited-dilution cloning, one hybridoma which could stably secrete specific antibody was obtained and designated McAbGB2. The titer of McAbGB2 was up to 1.2 x 10(6) after purified by ammonium sulfate and DEAE-cellulose. The McAbGB2 was defined as murine IgG1 by agarose double immunodiffusiong. Immunoblotting analysis revealed that the antigens with molecular weights of 116 kd and 45 kd recognized by McAbGB2 were distributed in human breast cancer tissue and serum.


Prediction Medicine: Biomarkers, Risk Calculators and Magnetic Resonance Imaging as Risk Stratification Tools in Prostate Cancer Diagnosis.
This review discusses the most recent evidence for currently available risk stratification tools in the detection of clinically significant prostate cancer (csPCa), and evaluates diagnostic strategies that combine these tools. Novel blood biomarkers, such as the Prostate Health Index (PHI) and 4Kscore, show similar ability to predict csPCa. Prostate cancer antigen 3 (PCA3) is a urinary biomarker that has inferior prediction of csPCa compared to PHI, but may be combined with other markers like TMPRSS2-ERG to improve its performance. Original risk calculators (RCs) have the advantage of incorporating easy to retrieve clinical variables and being freely accessible as a web tool/mobile application. RCs perform similarly well as most novel biomarkers. New promising risk models including novel (genetic) markers are the SelectMDx and Stockholm-3 model (S3M). Prostate magnetic resonance imaging (MRI) has evolved as an appealing tool in the diagnostic arsenal with even stratifying abilities, including in the initial biopsy setting. Merging biomarkers, RCs and MRI results in higher performances than their use as standalone tests. In the current era of prostate MRI, the way forward seems to be multivariable risk assessment based on blood and clinical parameters, potentially extended with information from urine samples, as a triaging test for the selection of candidates for MRI and biopsy.


Introduction: Bringing Institutions Back in the Study of Global Value Chains.
The article introduces and summarizes the key questions and findings of this special issue of Global Policy on the role of domestic and international institutions in the study of Global Value Chains (GVCs). The article starts by briefly introducing the concept of GVCs and the state-of-the-art of the existing literature focusing on the political implications of these landmark changes in the global economy. Then we make a case for grounding this emerging literature more strongly into an "institutionalist" perspective. More specifically, we argue that while a great deal of attention has been paid to intra-chain governance modes - i.e. the different ways in which firms organize their cross-border production arrangements - the role external institutional forces play in structuring chain dynamics remains surprisingly under-researched. These observations invite an analytical perspective that brings institutions back into the study of GVCs. The contributions to the special issue focus on multiple causal pathways linking GVCs and various types of domestic- and international institutions. Altogether, these contributions underscore that the politics engendered by GVCs, as well as how they evolve, can only be fully understood by paying attention to the external institutional context in which they are embedded.


Macular Morpho-Functional and Visual Pathways Functional Assessment in Patients with Spinocerebellar Type 1 Ataxia with or without Neurological Signs.
Spinocerebellar ataxia type 1 (SCA-ATXN1) is an autosomal dominant, neurodegenerative disease, caused by CAG repeat expansion in the ataxin-1 gene (ATXN1). In isolated reports of patients with neurological signs [symptomatic patients (SP)], macular abnormalities have been described. However, no reports exist about macular anomalies in SCA1 subjects carrying the ATXN1 mutation without neurological signs [not symptomatic carriers (NSC)]. Therefore, the main aim of our work was to evaluate whether the macular functional and morphological abnormalities could be detectable in SP, genetically confirmed and with neurological signs, as well as in SCA-ATXN1-NSC, harboring pathogenic CAG expansion in ATXN1. In addition, we investigated whether the macular involvement could be associated or not to an impairment of RGCs and of their fibers and of the neural conduction along the visual pathways. Herein, nine SCA-ATXN1 subjects (6 SP and 3 NSC) underwent the following examinations: visual acuity and chromatic test assessments, fundus oculi (FO) examination, macular and peripapillary retinal nerve fiber layer thickness (RNFL-T) analysis by Spectral domain-Optical Coherence Tomography (Sd-OCT) acquisition, multifocal electroretinogram (mfERG), pattern reversal electroretinogram (PERG) and visual evoked potentials (VEP) recordings. In four eyes of two SP, visual acuity reduction and chromatic abnormalities were observed; in three of them FO changes associated with macular thinning and outer retinal defects were also detected. In three NSC eyes, slight FO abnormalities were associated with qualitative macular morphological changes. By contrast, abnormal mfERG responses (exclusively from foveal and parafoveal areas) were detected in all SP and NSC (18 eyes). No abnormalities of PERG values, RNFL-T, and VEP responses were found, but in one SP, presenting abnormal papillo-macular bundle neural conduction. Results from our SCA-ATXN1 cohort suggest that a macular dysfunction, detectable by mfERG recordings, may occur in the overt disorder, and unexpectedly in the stage of the disease in which there is still an absence of neurological signs. In NSC, an exclusive dysfunction of preganglionic macular elements can be observed, and this is associated with both normal RGCs function and neural conduction along the visual pathways.


Emergent primary PCI of anomalous LAD.
Approximately 0.3% to 2% of patients may have anomalous origins of the coronary arteries. Anomalous origin of the left coronary artery (LCA) or left anterior descending (LAD) artery from the right sinus has been well described. In persons in whom the course involves an interarterial track between the aorta (Ao) and pulmonary artery (PA), an increased incidence of sudden death has been reported, particularly during or shortly after exercise. This has been felt to be due to transient occlusion of the anomalous LAD from increased blood flow through the Ao and PA as the anomalous LAD courses between them, possibly causing myocardial ischemia. In an elective setting, further anatomic delineation with other methodologies such as cardiac magnetic resonance (MR) imaging is recommended. In this case report we present an emergent percutaneous coronary intervention (PCI) of an anomalous LAD arising from the right sinus of Valsalva and coursing between the Ao and PA in a nonsurgical candidate.


Post-tetanic hyperpolarization evoked by depolarizing pulses in crayfish stretch receptor neurones in tetrodotoxin.
A post-tetanic hyperpolarization (p.t.h.) that is quantitatively identical to that evoked by a train of action potentials in stretch receptor neurones of crayfish Procambarus clarki and Pacifastacus leniculus is evoked when the normal Na+ influx is blocked with tetrodotoxin (TTX) and a train of depolarizing pulses is used to simulate a train of action potentials. The p.t.h. evoked by depolarizing pulses in the presence of TTX is attributable to an electrogenic Na-K pump, because it (a) is abolished by strophanthidin, (b) is abolished by removal of external K+, (c) depends in magnitude on internal Na+ concentration, (d) is not associated with a change in membrane conductance and (e) does not exhibit a reversal potential. When each action potential in the stimulus train is followed by a hyperpolarizing pulse, generation of the p.t.h. is prevented even though the action potentials are unchanged. The time constant for build-up of the p.t.h. is longer than the time constant of decay. Increasing the magnitude of depolarizing pulses increases the magnitude of the p.t.h. response in the presence of TTX and also increases the time constant for its build-up. The suppression of the p.t.h. occurring in low external Na+ appears to represent a response to a change in internal Na+ concentration, characterized by a time constant much longer than the decay of the p.t.h. The activity of the pump appears to be regulated by two mechanisms: a Na+-sensitive mechanism with a time constant of the order of a minute and an apparently voltage-sensitive mechanism with a time constant of about 5 s. The hypothesis is proposed that changes in the transmembrane electric field influence the enzymatic systems of the pump and disrupt the steady-state distribution of conformation states. The decay of the p.t.h. represents a relaxation back to the resting distribution.


UPDOs Protective Styles, a Multilevel Intervention to Improve Pre-exposure Prophylaxis Uptake Among Black Cisgender Women: Pretest-Posttest Evaluation.
In the United States, Black cisgender women account for one in five new HIV infections with Black Americans, accounting for 57% of new diagnoses in the South. Pre-exposure prophylaxis (PrEP) is 99% effective at preventing HIV. Still, Black women's uptake remains at 2% due to multiple documented barriers, including lack of awareness and knowledge, mistrust, stigma, and low perceived risk. Culturally relevant interventions leveraging trusted venues, such as beauty salons, can overcome these barriers. This article reports preliminary results of an intervention to improve PrEP knowledge and awareness, PrEP stigma, PrEP trust, and uptake among Black cisgender women. This multilevel, mixed-methods study used a community-engagement approach to develop and pilot a salon-based intervention, Using PrEP and Doing it for Ourselves (UPDOs) Protective Styles. The intervention improved knowledge, awareness, and trust around PrEP among Black cisgender women. PrEP use stigma within interpersonal relationships decreased, but low perceived risk and social stigma remained constant. Culturally and socially acceptable interventions like UPDOs Protective Styles can model health care delivery to improve trust, thus improving uptake over time for this population.


Internalization of radioiodinated erythropoietin and the ligand-induced modulation of its receptor in murine erythroleukemia cells.
We have studied the internalization of 125I-erythropoietin (Epo) and regulation of Epo receptors by the ligand in a murine erythroleukemia cell clone, TSA8. To determine internalization, a high-salt acid wash was performed. Internalization of 125I-Epo was found in TSA8 cells as well as in fetal mouse liver cells (FMLC), although the percentage of internalized radioactivity reached 40% after incubation at 37 degrees C for 150 min and was lower than that in FMLC. Exposure of TSA8 cells to unlabeled Epo resulted in a rapid, time-dependent reduction in 125I-Epo binding activity. The net loss of the activity was related to the ambient Epo concentration and 5 X 10(-8)M Epo induced approximately 80% loss of total binding capacity. Scatchard analysis of the binding data revealed that the high-affinity receptor number was decreased but the affinity was increased in the Epo-treated cells. In low-affinity receptors, however, the receptor affinity was decreased and the receptor number was not changed much by preincubation with Epo. These results suggest that the decrease in 125I-Epo binding activity after preincubation with unlabeled Epo is mainly accounted for by a decrease in the number of high-affinity receptors, and the high-affinity receptors play an important role in the biological response to Epo.


A Well Doctor's Family: The Struggle for Intimacy.
For married people, mental health depends on a sound marriage and family life. Intimacy is a major requirement for a healthy marriage. One of the biggest problems among physicians is failure to develop intimate relationships within their families. Intimacy may be inhibited because the characteristics of a good physician are not always characteristics of a good spouse and parent. For example, a physician should be able to control feelings, while a spouse and parent should be able to express feelings. Also, the pressure of practice may mean physicians do not spend enough time with their families. Or, confronted by tensions at home, doctors may retreat into their work, where they feel competent and appreciated. However, physicians must realize that self-esteem and intimacy through family relationships are just as important as professional esteem.


Diversion evaluations: a specialized forensic examination.
Diversion programs screen justice-involved individuals for the presence of psychiatric disorders, and after negotiations take place with attorneys and treatment providers, these programs link participants with community-based treatment programs in lieu of incarceration. As the number of diversion programs, including mental health courts, continues to rapidly grow, so does the need for "diversion evaluations". Diversion evaluations are a type of forensic mental health assessment (FMHA) conducted to assist the courts in making decisions regarding diversion eligibility. As a result, they should follow the general principles of FMHA and the American Academy of Psychiatry and Law Practice Guideline for Forensic Assessment. Diversion evaluations also require application of specific areas of knowledge and experience, as court-based diversion is a unique, therapeutically focused context that is purposefully non-adversarial. The diversion evaluator is a role that combines objective decision-making with clinical consultation. The purpose of this article is to apply generally accepted forensic report standards to diversion evaluations, with a particular focus on the unique issues of diversion-specific forensic evaluations.


Efficient oil-water separation coating with robust superhydrophobicity and high transparency.
There has been a growing interest in oil-water separation due to the massive economic and energy loss caused by world-wide oil spill. In the past decades, a new type of superhydrophobic surface has been developed for the efficient oil-water separation, but its large-scale use is significantly limited by its expensive, sophisticated, and fragile roughness structure. Meanwhile, to handle complex operating conditions, the transparency of the superhydrophobic surface has been more attractive due to its potential visual oil-water separation and optical application scenarios. Herein, we showed a simple and versatile strategy to fabricate superhydrophobic coating with robustness and high transparency. Subsequently, this multifunctional superhydrophobic coating was utilized for oil-water separation and indicated excellent separation efficiency. In this strategy, candle soot composed of carbon nanoparticles was deposited onto the substrate and used as a rough surface template. Then, a filmy and hard silica shell was modified onto this template via chemical vapor deposition to reinforce the roughness structure. Following, this soot-silica coated substrate was calcined in air to remove the candle soot template. Finally, based on a rational surface design, this robust silica coating achieved excellent superhydrophobicity thereby showing inherently oil-water separation benefits. This reinforced superhydrophobic coating presented robust superhydrophobicity even after 410 s sand impacting with the height of 40 cm and 20 cycles of sandpaper abrasion. Also, it retained excellent oil-water separation efficiency even after reuses.


Liver function parameters aspartate aminotransferase and total protein predict functional outcome in stroke patients with non-cardioembolism.
Stroke, classified as cardioembolism and non-cardioembolism (non-CE), entails a large socioeconomic burden on the elderly. The morbidity and mortality of non-CE are high, whereas studies concerning prognostic factors impacting function outcome remain underdeveloped and understudied. Liver function parameters are convenient approaches to predicting prognosis in cardiovascular diseases, but their clinical significance has not been well characterized in stroke, especially in non-CE. In our study, a total of 576 patients with non-CE at 1 year of follow-up were enrolled in a cohort from a consecutive hospital-based stroke registry, with randomly 387 patients as the development cohort and 189 patients as the validation cohort. The univariate and multivariate analyses revealed the following novel findings: (i) The incidence of unfavorable functional outcomes after non-CE was significantly greater (p < 0.01) in patients with higher age, aspartate aminotransferase (AST), the National Institutes of Health Stroke Scale (NIHSS) score, and depressed total protein (TP); (ii) We established a novel model and nomogram to predict stroke prognosis, in addition to the known factors (age and the NIHSS score). The levels of AST and TP were independently correlated with the incidence of unfavorable outcomes [AST: odds ratio (OR) = 1.026, 95% CI (1.002-1.050); TP: OR = 0.944, 95% CI (0.899-0.991)]; (iii) The results persisted in further subgroup analysis stratified by age, gender, the NIHSS score, and other prespecified factors, especially in males 60 years or older. Overall, this study demonstrates that hepatic parameters (AST and TP) after non-CE are considered to be associated with functional outcomes at 1-year follow-up, especially in males aged ≥ 60 years.


Impact of Diagnostic Practices on the Self-Reported Health of Mothers of Recently Diagnosed Children with ASD.
Obtaining a diagnosis of an Autism Spectrum Disorder (ASD) for a child is a pivotal point in developing the treatment plan for the child but can also be regarded as highly stressful by parents. The current study examined the impact of different aspects of the diagnosis process on the self-reported mental health of mothers of children undergoing a diagnosis for ASD in a cross-sectional cohort design. One-hundred-fifty-eight mothers of consequently diagnosed children with ASD participated. The severity of the children's ASD and their intellectual functioning was assessed within twelve months of the diagnosis, and the mothers completed a psychometric assessment battery including the Hospital Anxiety and Depression Scale, General Health Questionnaire, and Questionnaire on Resources and Stress. The actual time from first reporting a problem to obtaining a diagnosis, and the speed of the diagnostic process from first to last appointment, were both negatively related to patenting stress. In contrast, mothers' perceptions of the speed and helpfulness of the process were negatively related to levels of anxiety and depression. The number of professionals involved in the process and the perceived coherence of the diagnosis were also negatively related to aspects of mothers' functioning. Care is needed to help mothers through the diagnostic process with regard to their own functioning. Providing information and help sources throughout the process, while keeping the number of professionals involved to a minimum, may improve the parent perception of the process and reduce the negative impacts of the diagnosis on the family as a whole.


[Morphological study of capsules formed around various breast endoprostheses].
Silicone implants used in mammaplasty are often associated with constrictive capsule fibrosis, leading to induration and deformation of the prosthetic organs. In connection with this, there has been developed and is currently successfully applied in the clinical practice of the A. V. Vishnevsky Institute of Surgery an original method of mammary gland endoprosthesis with oily implants. The objective of this work was to make a comparative study of the late results of mammaplasty based upon the morphologic study of capsules formed around silicone and oily implants, removed during secondary surgical interventions. The dynamics of capsule formation around temporary organic glass endoprostheses has also been studied. The results showed that implantation of silicone prostheses results in a formation of a rough thick capsule, an active inflammatory reaction in the surrounding tissues and the development of constrictive fibrosis. Implantation of a temporary organic glass endoprosthesis that is filled with oil at the second stage of the operation, is followed by a thin capsule formation without signs of inflammation. The stability of the capsule structure up to 3 years has been noted. On the whole, this prosthesis provides a good cosmetic effect during long time after mammaplasty.


A neurocomputational method for fully automated 3D dendritic spine detection and segmentation of medium-sized spiny neurons.
Acquisition and quantitative analysis of high resolution images of dendritic spines are challenging tasks but are necessary for the study of animal models of neurological and psychiatric diseases. Currently available methods for automated dendritic spine detection are for the most part customized for 2D image slices, not volumetric 3D images. In this work, a fully automated method is proposed to detect and segment dendritic spines from 3D confocal microscopy images of medium-sized spiny neurons (MSNs). MSNs constitute a major neuronal population in striatum, and abnormalities in their function are associated with several neurological and psychiatric diseases. Such automated detection is critical for the development of new 3D neuronal assays which can be used for the screening of drugs and the studies of their therapeutic effects. The proposed method utilizes a generalized gradient vector flow (GGVF) with a new smoothing constraint and then detects feature points near the central regions of dendrites and spines. Then, the central regions are refined and separated based on eigen-analysis and multiple shape measurements. Finally, the spines are segmented in 3D space using the fast marching algorithm, taking the detected central regions of spines as initial points. The proposed method is compared with three popular existing methods for centerline extraction and also with manual results for dendritic spine detection in 3D space. The experimental results and comparisons show that the proposed method is able to automatically and accurately detect, segment, and quantitate dendritic spines in 3D images of MSNs.


Is It Possible to Directly Determine the Radius of a Spherical Indenter Using Force Indentation Data on Soft Samples?
An important factor affecting the accuracy of Young's modulus calculation in Atomic Force Microscopy (AFM) indentation experiments is the determination of the dimensions of the indenter. This procedure is usually performed using AFM calibration gratings or Scanning Electron Microscopy (SEM) imaging. However, the aforementioned procedure is frequently omitted because it requires additional equipment. In this paper, a new approach is presented that focused on the calibration of spherical indenters without the need of special equipment but instead using force indentation data on soft samples. Firstly, the question whether it is mathematically possible to simultaneously calculate the indenter's radius and the Young's modulus of the tested sample (under the restriction that the sample presents a linear elastic response) using the same force indentation data is discussed. Using a simple mathematical approach, it was proved that the aforementioned procedure is theoretically valid. In addition, to test this method in real indentation experiments agarose gels were used. Multiple measurements on different agarose gels showed that the calibration of a spherical indenter is possible and can be accurately performed. Thus, the indenter's radius and the soft sample's Young's modulus can be determined using the same force indentation data. It is also important to note that the provided accuracy is similar to the accuracy obtained when using AFM calibration gratings. The major advantage of this paper is that it provides a method for the simultaneous determination of the indenter's radius and the sample's Young's modulus without requiring any additional equipment.


Cancer Occurrence as the Upcoming Complications of COVID-19.
Previous studies suggested that patients with comorbidities including cancer had a higher risk of mortality or developing more severe forms of COVID-19. The interaction of cancer and COVID-19 is unrecognized and potential long-term effects of COVID-19 on cancer outcome remain to be explored. Furthermore, whether COVID-19 increases the risk of cancer in those without previous history of malignancies, has not yet been studied. Cancer progression, recurrence and metastasis depend on the complex interaction between the tumor and the host inflammatory response. Extreme proinflammatory cytokine release (cytokine storm) and multi-organ failure are hallmarks of severe COVID-19. Besides impaired T-Cell response, elevated levels of cytokines, growth factors and also chemokines in the plasma of patients in the acute phase of COVID-19 as well as tissue damage and chronic low-grade inflammation in "long COVID-19" syndrome may facilitate cancer progression and recurrence. Following a systemic inflammatory response syndrome, some counterbalancing compensatory anti-inflammatory mechanisms will be activated to restore immune homeostasis. On the other hand, there remains the possibility of the integration of SARS- CoV-2 into the host genome, which potentially may cause cancer. These mechanisms have also been shown to be implicated in both tumorigenesis and metastasis. In this review, we are going to focus on potential mechanisms and the molecular interplay, which connect COVID-19, inflammation, and immune-mediated tumor progression that may propose a framework to understand the possible role of COVID-19 infection in tumorgenesis and cancer progression.


Is Halcyon feasible for single thoracic or lumbar vertebral segment SBRT?
Halcyon linear accelerators employ intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) techniques. The Halcyon offers translational, but not rotational, couch correction, which only allows a 3 degrees of freedom (3-DOF) correction. In contrast, the TrueBeam (TB) linear accelerator offers full 6-DOF corrections. This study aims to evaluate the difference in treatment plan quality for single thoracic or lumbar vertebral segment SBRT between the Halcyon and TB linear accelerators. In addition, this study will also investigate the effect of patient rotational setup errors on the final plan quality. We analyzed 20 patients with a single-level spine metastasis located between the T7 and L5 vertebrae near the spinal canal. The median planning target volume was 52.0 cm3 (17.9-138.7 cm3 ). The median tumor diameter in the axial plane was 4.6 cm (range 1.7-6.8 cm), in the sagittal plane was 3.3 cm (range 2-5 cm). The prescription doses were either 12-16 Gy in 1 fraction or 18-24 Gy in 3 fractions. All patients were treated on the TB linear accelerator with a 2.5 mm Multi-Leaf Collimator (MLC) leaf width. Treatment plans were retrospectively created for the Halcyon, which has a 5 mm effective MLC leaf width. The 20 patients had a total of 50 treatments. Analysis of the 50 cone beam computed tomography (CBCT) scans showed average rotational setup errors of 0.6°, 1.2°, and 0.8° in pitch, yaw, and roll, respectively. Rotational error in roll was not considered in this study, as the original TB plans used a coplanar volumetric modulated arc therapy (VMAT) technique, and each 1° of roll will contribute an error of 1/360. If a plan has 3 arcs, the contribution from errors in roll will be < 0.1%. To simulate different patient setup errors, for each patient, 12 CT image datasets were generated in Velocity AI with different rotational combinations at a pitch and yaw of 1°, 2°, and 3°, respectively. We recalculated both the TB and Halcyon plans on these rotated images. The dosimetric plan quality was evaluated based on the percent tumor coverage, the Conformity Index (CI), Gradient Index (GI), Homogeneity index (HI), the maximum dose to the cord/cauda, and the volume of the cord/cauda receiving 8, 10, and 12 Gy (V8Gy, V10Gy and V12Gy). Paired t-tests were performed between the original and rotated plans with a significance level of 0.05. The Eclipse based VMAT plans on Halcyon achieved a similar target coverage (92.3 ± 3.0% vs. 92.4 ± 3.3%, p = 0.82) and CI (1.0 ± 0.1 vs. 1.1 ± 0.2, p = 0.12) compared to the TB plans. The Gradient index of Halcyon is higher (3.96 ±0.8) than TB (3.85 ±0.7), but not statistically significant. The maximum dose to the spinal cord/cauda was comparable (11.1 ± 2.8 Gy vs. 11.4 ± 3.6 Gy, p = 0.39), as were the V8Gy, V10Gy and V12Gy to the cord/cauda. The dosimetric influence of patient rotational setup error was statistically insignificant for rotations of up to 1° pitch/yaw (with similar target coverage, CI, max cord/cauda dose and V8Gy, V10Gy, V12Gy for cord/cauda). The total number of monitor units (MUs) for Halcyon (4998 ± 1688) was comparable to that of TB (5463 ± 2155) (p = 0.09). The Halcyon VMAT plans for a single thoracic or lumbar spine metastasis were dosimetrically comparable to the TB plans. Patient rotation within 1° in the pitch and yaw directions, if corrected by translation, resulted in insignificant dosimetric effects. The Halcyon linear accelerator is an acceptable alternative to TB for the treatment of single thoracic or lumbar spinal level metastasis, but users need to be cautious about the patient rotational setup error. It is advisable to select patients appropriately, including only those with the thoracic or lumbar spine involvement and keeping at least 2 mm separation between the target and the cord/cauda. More margin is needed if the distance between the isocenter and cord/cauda is larger. It is advisable to place the planning isocenter close to the spinal canal to further mitigate the rotational error. We simulated various scenarios of patient setup errors with different rotational combinations of pitch and yaw with 1°, 2°, and 3°, respectively. Rotation was corrected with translation only to mimic the Halcyon treatment scenario. Using the Halcyon for treating a tumor in a single thoracic or lumbar vertebral segment is feasible, but caution should be noted in patients requiring rotational corrections of > 1° in the absence of 6-DOF correction capabilities.


Effects of variable docking conditions and scoring functions on corresponding protein-aligned comparative molecular field analysis models constructed from diverse human protein tyrosine phosphatase 1B inhibitors.
The effects of variable docking conditions and scoring functions on corresponding protein-aligned comparative molecular field analysis (CoMFA) models have been assessed. To this end, a group of diverse inhibitors were docked into the active site of human protein tyrosine phosphatase 1B (h-PTP 1B). The docked structures were utilized to construct corresponding protein-aligned CoMFA models by employing probe-based (H+, OH, CH3) energy grids and genetic partial least squares (G/PLS) statistical analysis. A total of 48 different docking configurations were evaluated, of which some succeeded in producing self-consistent and predictive CoMFA models. However, the best CoMFA model coincided with docking the un-ionized ligands into the hydrated form of the binding site via the PLP1 scoring function and restricted docking settings (r2(LOO) = 0.647, r2(PRESS) against 27 test compounds = 0.617). Interestingly, the most significant CoMFA models were orthogonal and corresponded to significantly different docked conformers/poses. To utilize the predictive potentials of the best CoMFA models collectively, it was decided to combine them in a single quantitative structure-activity relationship (QSAR) model. The combination model illustrated excellent statistical properties (r2(LOO) = 0.890, r2(PRESS) against 27 test compounds = 0.750).


Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil.
Fasudil, a Rho-kinase inhibitor, is a promising neuroprotectant against ischemic stroke; however, its low bioavailability is an obstacle to be overcome. Our previous study revealed that the liposomal drug delivery system is a hopeful strategy to increase the therapeutic efficacy of neuroprotectants. In the present study, the usefulness of intravenously administered liposomal fasudil for cerebral ischemia/reperfusion (I/R) injury treatment was examined in transient middle cerebral artery occlusion (t-MCAO) rats. The results showed that PEGylated liposomes of approximately 100nm in diameter accumulated more extensively in the I/R region compared with those of over 200nm. Confocal images showed that fluorescence-labeled liposomal fasudil was widely distributed in the I/R region, and was not noticeably taken up by microglia, which are well-known resident macrophages in the brain, and neuronal cells. These data indicated that liposomal fasudil mainly exerted its pharmacological activity by releasing fasudil from the liposomes in the I/R region. Moreover, liposomal fasudil effectively suppressed neutrophil invasion and brain cell damage in the t-MCAO rats, resulting in amelioration of their motor function deficits. These findings demonstrated both the importance of particle size for neuroprotectant delivery and the effectiveness of liposomal fasudil for the treatment of cerebral I/R injury.


Cs2GeB4O9: a new second-order nonlinear-optical crystal.
A new alkali-metal borogermanate with noncentrosymmetric structure, namely, Cs2GeB4O9, has been discovered, and a large crystal with dimensions of 20 × 16 × 8 mm(3) has been grown by a high-temperature top-seeded solution method using Cs2O-B2O3 as a flux. The compound crystallizes in the tetragonal space group I4 with a = b = 6.8063(2) Å, c = 9.9523(7) Å, V = 461.05(4) Å(3), and Z = 2. It features a three-dimensional anionic open framework based on GeO4 tetrahedra and B4O9 clusters that are interconnected via corner-sharing, forming one-dimensional channels of nine-/ten-membered rings along the a and b axes, which are occupied by Cs(+) cations. Cs2GeB4O9 exhibits a very high thermal stability with a melting point of 849 °C, and it possesses a short-wavelength absorption edge onset at 198 nm determined by UV-vis transmission spectroscopy measurements on a slab of polished crystal. Powder second-harmonic generation (SHG) measurement on sieved crystals reveals that Cs2GeB4O9 is a type I phase-matchable material with a strong SHG response of about 2.8 × KH2PO4. The preliminary investigation indicates that Cs2GeB4O9 is a new promising second-order nonlinear-optical crystalline material.


Boundary lubrication properties of materials with expansive freezing.
We have performed molecular dynamics simulations of solid-solid contacts lubricated by a model fluid displaying many of the properties of water, particularly its expansive freezing. Near the region where expansive freezing occurs, the lubricating film remains fluid, and the friction force decreases linearly as the shear velocity is reduced. No sign of stick-slip motion is observed, even at the lowest velocities. We give a simple interpretation of these results, and suggest that, in general, good boundary lubrication properties will be found in the family of materials with expansive freezing.


[Large uterine leiomyoma in pregnancy--case report].
This is a case report of a successful pregnancy outcome in a 36-year-old primigravida with an enormous leiomyoma. Potential pregnancy complications and pain treatment during pregnancy are discussed in the following work.


Outcomes and Processes in the Meyerhoff Scholars Program: STEM PhD Completion, Sense of Community, Perceived Program Benefit, Science Identity, and Research Self-Efficacy.
Previous research has shown that the Meyerhoff Scholars Program at the University of Maryland, Baltimore County, is an effective intervention for high-achieving underrepresented minority (URM) students; African-American Meyerhoff students are significantly more likely to enter science, technology, engineering, and mathematics (STEM) PhD programs than comparison students. The first of two studies in this report extends the prior research by examining levels of PhD completion for Meyerhoff (N = 479) versus comparison sample (N = 249) students among the first 16 cohorts. Entering African-American Meyerhoff students were 4.8 times more likely to complete STEM PhDs than comparison sample students. To enhance understanding of potential mechanisms of influence, the second study used data from the 22nd (Fall 2010) to 25th (Fall 2013) cohorts (N = 109) to test the hypothesis that perceived program benefit at the end of freshman year would mediate the relationship between sense of community at the end of Summer Bridge and science identity and research self-efficacy at the end of sophomore year. Study 2 results indicated that perceived program benefit fully mediated the relationship between sense of community and both criterion measures. The findings underscore the potential of comprehensive STEM intervention programs to enhance PhD completion, and suggest mechanisms of influence.


Beyond the somatopause: growth hormone deficiency in adults over the age of 60 years.
GH secretion declines by 14% decade of adult life, leading to the suggestion that people over the age of 60 yr are functionally GH deficient. If this is the case, one might not be able to detect a difference in GH secretion between the elderly with documented hypothalamic-pituitary disease and an age-matched control group. We studied GH secretion in 24 patients with hypothalamic-pituitary disease and 24 controls matched for body mass index and age using 24-h GH profiles, arginine stimulation tests, and serum insulin-like growth factor I (IGF-I) levels. The median (range) area under the curve of the GH profile [< 9.6 (< 9.6-20) vs. 18.5 (10.7-74.4) micrograms/L.24 h; P < 0.0001], the median stimulated peak GH response to arginine [< 0.4 (< 0.4-7.7) vs. 8.0 (1.6-37.0) micrograms/L; P < 0.0001], and the median serum IGF-I concentration [102 (< 14-162) vs. 147 (65-255) ng/mL; P = 0.0002] were significantly lower in the patients than in the controls. Fifteen patients showed no evidence of spontaneous or stimulated GH secretion, whereas all controls had evidence of both. The area under the GH curve in the 33 subjects with demonstrable GH secretion correlated significantly with the peak GH response to arginine (r = 0.71; P < 0.0001), but not with serum IGF-I concentration. This study suggests that organic GH deficiency in the elderly is distinct from the decline in GH secretion associated with the aging process. These patients may benefit from GH replacement therapy.


Cyclic tetramers composed of rhodium(III), iridium(III), or ruthenium(II) half-sandwich and 6-purinethiones.
Six new cyclic tetranuclear complexes [[M(Cp*)(L)](4)](4+) and [[Ru(II)(L)(cymene)](4)](4+) [Cp* = eta(5)-C(5)Me(5), cymene = eta(6)-p-MeC(6)H(4)Pr(i); M = Rh(III) and Ir(III); HL = 6-purinethione (H(2)put) and 2-amino-6-purinethione (H(2)aput)] were prepared in a self-assembly manner and characterized by NMR spectroscopy, electrospray ionization mass spectrometry, and X-ray crystal structure analysis. The two crystal structures of [[Rh(Cp*)(H(0.5)put)](4)](CF(3)SO(3))(2) and [[Ir(Cp*)(Haput)](4)](CF(3)SO(3))(4) revealed that they have similar S(4) structures with an alternate chirality array of CACA, and all ligands adopt a mu-1kappaN(9):2kappa(2)S(6),N(7) coordination mode. The orientations of the four bridging ligands are alternately up and down, and they form a central square cavity. Interestingly, the cationic tetramers of the former are stacked up along the c axis, resulting in an infinite channel-like cavity. The driving force of this stacking is due to intermolecular double hydrogen bonds [N(1)-H...N(21) = 2.752(4) A] at both sides of the cavity. In the two Rh(III)- and Ru(II)-H(2)aput systems, it turned out that the dimeric species are dominantly formed in the reaction solutions but finally convert into the tetrameric species.


Engineering the atomic arrangement of bimetallic catalysts for electrochemical CO2 reduction.
The electrochemical CO2 reduction reaction (CO2RR) to form highly valued chemicals is a sustainable solution to address the environmental issues caused by excessive CO2 emissions. Generally, it is challenging to achieve high efficiency and selectivity simultaneously in the CO2RR due to multi-proton/electron transfer processes and complex reaction intermediates. Among the studied formulations, bimetallic catalysts have attracted significant attention with promising activity, selectivity, and stability. Engineering the atomic arrangement of bimetallic nanocatalysts is a promising strategy for the rational design of structures (intermetallic, core/shell, and phase-separated structures) to improve catalytic performance. This review summarizes the recent advances, challenges, and opportunities in developing bimetallic catalysts for the CO2RR. In particular, we firstly introduce the possible reaction pathways on bimetallic catalysts concerning the geometric and electronic properties of intermetallic, core/shell, and phase-separated structures at the atomic level. Then, we critically examine recent advances in crystalline structure engineering for bimetallic catalysts, aiming to establish the correlations between structures and catalytic properties. Finally, we provide a perspective on future research directions, emphasizing current challenges and opportunities.


Cardiovascular effects of enflurane and asphyxia during long-term beta 1-adrenoceptor blockade.
The haemodynamic effects of enflurane (1.7% and 3.4% expiratory concentrations) were investigated in sheep (n = 6) pretreated with an infusion of metoprolol (0.2 mg X kg-1 X h-1 for 5 days) and in control animals (n = 6). Chloralose was used as basal anaesthetic. A 90 s apnoea period was included in the experiment to evaluate further the possible side-effects of long-term metoprolol treatment in combination with enflurane anaesthesia. MAC 1.0 for enflurane in the sheep was found at 1.45% end-tidal concentration by separate measurements. Before enflurane administration, the only significant differences between the two groups of animals were a lower systemic vascular resistance and a higher stroke volume during metoprolol treatment. Enflurane abolished these discrepancies in a dose-dependent fashion and similar cardiovascular depression was observed in both groups of animals at 3.4% expiratory concentration of enflurane. Metoprolol did not significantly affect the hypertensive response to apnoea during chloralose anaesthesia alone. At enflurane 1.7% expiratory concentration the apnoea response was small and only the metoprolol-treated animals showed a significant increase in left ventricular end-diastolic pressure. We conclude that 5 days of pretreatment with metoprolol in the sheep model does not significantly impair cardiovascular performance during enflurane anaesthesia.


Anemia in rural China's elementary schools: prevalence and correlates in Shaanxi province's poor counties.
Despite growing wealth in China, a significant share of children across rural China still have no access to iron-rich foods, vitamins, and other micronutrients. Such poor diets may result in high incidences of nutritional problems, including anemia. The objective of the study was to increase understanding of the extent of anemia, and identify structural correlates of anemia in poor Shaanxi province's primary schools. The article shows that the overall anemia rate is 21.5 percent when using a blood hemoglobin cutoff of 115 g/L (39 percent with a cutoff of 120 g/L). We find that those students that are boarding at school and eat lunch away from home are more likely to be anemic. Children with anemia are found to have lower height for age (HAZ) scores. If this part of Shaanxi province is representative of all poor counties in China, these findings mean millions of children in poor rural China may be anemic.


Proteome profile of swine testicular cells infected with porcine transmissible gastroenteritis coronavirus.
The interactions occurring between a virus and a host cell during a viral infection are complex. The purpose of this paper was to analyze altered cellular protein levels in porcine transmissible gastroenteritis coronavirus (TGEV)-infected swine testicular (ST) cells in order to determine potential virus-host interactions. A proteomic approach using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled two-dimensional liquid chromatography-tandem mass spectrometry identification was conducted on the TGEV-infected ST cells. The results showed that the 4-plex iTRAQ-based quantitative approach identified 4,112 proteins, 146 of which showed significant changes in expression 48 h after infection. At 64 h post infection, 219 of these proteins showed significant change, further indicating that a larger number of proteomic changes appear to occur during the later stages of infection. Gene ontology analysis of the altered proteins showed enrichment in multiple biological processes, including cell adhesion, response to stress, generation of precursor metabolites and energy, cell motility, protein complex assembly, growth, developmental maturation, immune system process, extracellular matrix organization, locomotion, cell-cell signaling, neurological system process, and cell junction organization. Changes in the expression levels of transforming growth factor beta 1 (TGF-β1), caspase-8, and heat shock protein 90 alpha (HSP90α) were also verified by western blot analysis. To our knowledge, this study is the first time the response profile of ST host cells following TGEV infection has been analyzed using iTRAQ technology, and our description of the late proteomic changes that are occurring after the time of vigorous viral production are novel. Therefore, this study provides a solid foundation for further investigation, and will likely help us to better understand the mechanisms of TGEV infection and pathogenesis.


Empagliflozin/metformin fixed-dose combination: a review in patients with type 2 diabetes.
Most patients with type 2 diabetes, who receive monotherapy, are unable to maintain glucose levels with the progress of disease. Therefore, combination therapy with two or more anti-diabetic agents of different classes is highly desired. Sodium glucose co-transporter 2 (SGLT2) inhibitors improve glycemic control through increasing urinary glucose excretion, which is independent of β-cell function. In addition, they are generally well tolerated and associated with a low risk of hypoglycaemia. SGLT2 inhibitors as add-on therapy to metformin have an additive effect on glycemic control in patients with type 2 diabetes, and fixed-dose tablet is likely to reduce pill burden and then improve patients' adherence. Areas covered: This article reviews empagliflozin/metformin combination therapy for the treatment of type 2 diabetes. The clinical efficacy and tolerability of empagliflozin/metformin in patients with type 2 diabetes are discussed based on the available literature. Expert opinion: It was found that empagliflozin/metformin combination therapy could significantly improve glycemic control, body weight and blood pressure with a low risk of hypoglycaemia. In addition, the empagliflozin/metformin fixed-dose tablets, supported by bioequivalence studies, could reduce pill burden to further achieve the improved patients' adherence, better glycemic control and optimized cost-effectiveness.


The Absence of Protochlorophyll(ide) Accumulation in Algae with Inhibited Chlorophyll Synthesis.
Golenkinia, Chlorella protothecoides, and mutant C-2A' of Scenedesmus were grown in darkness and on media in which chlorophyll synthesis is reduced significantly. The pigments were analyzed by spectrophotometry or by paper chromatography and compared with similar extracts from light-grown algae and dark-grown beans. No protochlorophyll(ide) was present in the dark-grown algae indicating that chlorophyll synthesis is blocked by a mechanism other than feedback regulation of aminolevulinic acid synthesis by protochlorophyll(ide) which has been proposed for flowering plants.


Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies.
The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus-tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range.


The role of oral health-related quality of life in the association between dental caries and height, weight and BMI among children in Bangladesh.
To examine whether oral health-related quality of life (OHRQoL) explained the negative associations between dental caries and anthropometric measures of child growth among a sample of 5- to 9-year-old children in Dhaka, Bangladesh, while taking potential confounding factors (maternal education, family income, study setting, child's birth weight and childhood diseases) into account. In addition, to test whether specific oral impacts had a role in explaining these associations. Data collection was conducted via a cross-sectional survey among children and their parents from both hospital and school settings in Dhaka. Dental caries and severe consequences of dental caries (defined here as dental sepsis) were the exposure variables, and age- and sex-adjusted height-z-scores (HAZ), weight-z-scores (WAZ) and BMI-z-scores (BAZ) were the outcome variables. OHRQoL was measured using the Bengali version of the Scale of Oral Health Outcomes for 5-year-old children (SOHO-5). First, associations between oral impacts (prevalence of overall impacts and specific items of the SOHO-5) and outcome measures were assessed. Multiple linear regression was used to assess associations between caries and anthropometric measures, adjusted for potential confounders. Oral impacts were then added to test whether their inclusion attenuated the associations between exposures and outcomes. To further investigate potential mediating role of oral impacts, structural equation modelling (SEM) was used to test the hypothesis that dental caries and sepsis were associated with the outcomes directly and also indirectly via oral impacts in general. A similar approach was used to investigate mediation by specific SOHO-5 items. The sample consisted of 715 children, 73.1% of whom had dental caries, 37.5% presented with sepsis, and 57.3% reported at least one oral impact (SOHO-5 score ≥1). Prevalence of overall oral impacts and also the impact on 'eating difficulty' (a specific item of SOHO-5) were negatively associated with all three outcomes. Dental caries and sepsis was associated with lower HAZ, WAZ and BAZ, and adjustment for overall oral impacts considerably attenuated the associations between 'severe dental caries' and outcomes, and dental sepsis and outcomes. Using SEM, we found significant indirect associations between caries and sepsis and anthropometric measures via oral impacts (except for dental caries and HAZ). Considering specific oral impacts, eating difficulties explained about 44% and 65% of the associations between caries and anthropometric outcomes, and dental sepsis and anthropometric outcomes, respectively. Oral impacts, in particular eating difficulties, appear to mediate associations between caries and markers of child growth among this population.


Bayesian Networks for Risk Prediction Using Real-World Data: A Tool for Precision Medicine.
The fields of medicine and public health are undergoing a data revolution. An increasing availability of data has brought about a growing interest in machine-learning algorithms. Our objective is to present the reader with an introduction to a knowledge representation and machine-learning tool for risk estimation in medical science known as Bayesian networks (BNs). In this article we review how BNs are compact and intuitive graphical representations of joint probability distributions (JPDs) that can be used to conduct causal reasoning and risk estimation analysis and offer several advantages over regression-based methods. We discuss how BNs represent a different approach to risk estimation in that they are graphical representations of JPDs that take the form of a network representing model random variables and the influences between them, respectively. We explore some of the challenges associated with traditional risk prediction methods and then describe BNs, their construction, application, and advantages in risk prediction based on examples in cancer and heart disease. Risk modeling with BNs has advantages over regression-based approaches, and in this article we focus on three that are relevant to health outcomes research: (1) the generation of network structures in which relationships between variables can be easily communicated; (2) their ability to apply Bayes's theorem to conduct individual-level risk estimation; and (3) their easy transformation into decision models. Bayesian networks represent a powerful and flexible tool for the analysis of health economics and outcomes research data in the era of precision medicine.


Migration of the uncemented CLS acetabular component.
The migration of uncemented press-fit CLS (Cementless Total Hip Replacement System) acetabular cups was measured retrospectively from standard anteroposterior pelvic radiographs using a digitizer and software specifically developed for this study. A radiographic and clinical review also were undertaken. There were 96 patients in the study group. The mean follow-up for radiographic review was 2.23 years, and the mean follow-up for clinical review was 3 years. Migration was measured in the cranial and medial directions. Mean migration of the cup at 2 years was 1.35 mm in the cranial direction and 2.15 mm in the medial direction. Radiographic appearances altered little over the study period. Fifty-five (57.3%) patients demonstrated bone ingrowth onto the prosthesis, predominantly in DeLee and Charnley zone 1. Twenty-one patients demonstrated nonprogressive sclerotic lines; no lucent lines were encountered. Statistical analysis showed a significant correlation between acetabular ingrowth and reduced cup migration in the medial direction (P = .011 at 5 years). There was no statistical relationship between migration of the cup and radiographic features or clinical outcome.


[Intervention in autistic disorders: status quo, evidence-based, questionable and doubtful techniques].
We describe and critically discuss intervention methods that have been used to modify autistic behaviors. Early intervention methods, training of social skills, pharmacological treatment and alternative approaches are reviewed in the light of the empirical evidence. Autism is a persistent and phenotypically heterogeneous disorder for which no cure has been found to date. However, individually composed care and therapies can lead to remarkable quantitative improvement. Further research is needed to evaluate the true impact of psychological and biological intervention techniques in autistic disorders. Among other things, the therapy studies carried out up to now often lack an adequate diagnostic assessment.


Comparative patterns of postcranial ontogeny in therian mammals: an analysis of relative timing of ossification events.
Data on the relative sequence of ossification of postcranial elements for eight therian mammals (Myotis lucifugus, Homo sapiens, Rattus norvegicus, Mus musculus, Mesocricetus auratus, Cavia porcellus, Didelphis albiventris, and Sminthopsis macroura) and three outgroups (Chelydra serpentina, Alligator mississippiensis, and Lacerta vivipara) were taken from the literature. For each species, a matrix was constructed in which the relative timing of the onset of ossification in 24 elements was summarized. This resulted in 276 event pairs (characters) for each species. Thirty-three (33.3)% of the characters examined are uniform across all taxa, 16.3% are variable but uninformative in the phylogeny, and 50.4% potentially deliver diagnostic features for clades of two or more taxa. In all species examined, the clavicle is the first bone to appear. Placentalia is not unequivocally diagnosed by the state of any event pair, while Marsupialia has the largest amount of autapomorphies with 18. The acceleration in the timing of ossification of the scapula in relation to the hindlimb in marsupials is most probably causally correlated to movements after birth and during early phases of pre-weaning life. Marsupials are almost unique among amniotes in that the earliest onset of ossification of at least one element among carpals and among tarsals is simultaneous. Three parsimony analyses, each one with a different reptilian taxon as outgroup, were performed using event pairs as characters. In all cases, results were incongruent with the phylogeny of the studied taxa.


Protein glycation, insulin sensitivity and pancreatic beta cell function in high-risk, non-diabetic, first degree relatives of patients with type 2 diabetes.
Insulin resistance and impaired beta cell function are widely recognized as features of type 2 diabetes. But it is still debated whether insulin resistance or beta cell dysfunction constitutes the primary abnormality. This study was done to evaluate the impact of family history of type 2 diabetes on insulin resistance, beta cell function and glycation of proteins. A total of 30 healthy subjects with a positive family history of type 2 diabetes and thirty two healthy age-matched subjects without any family history of type 2 diabetes were enrolled in this study. Fasting glucose, post prandial glucose, fasting plasma insulin, fructosamine and glycated hemoglobin were evaluated in both the study groups. The mean fasting glucose, fasting Insulin and HOMA-IR were significantly higher among the first-degree relatives of type 2 diabetics, but there was no alteration in HOMA-B. The levels of both glycated hemoglobin and fructosamine were significantly increased in the test group when compared with controls. In conclusion the results from the present study suggest that Indian subjects with family history of type 2 diabetes are associated with insulin resistance and enhanced glycation of proteins, but with no evidence of beta cell defect.


Pretreatment with Rho-kinase inhibitor ameliorates lethal endotoxemia-induced liver injury by improving mitochondrial function.
Rho kinase (ROCK) inhibition has been reported to improve various inflammatory diseases including endotoxemia. Mitochondrial dysfunction might be the key to the pathophysiology of sepsis-induced organ failure. Therefore, this study aimed to explore whether ROCK inhibition protects against the liver injury by regulating mitochondrial function in endotoxemia model mice. The mice were randomly divided into four groups (N=6-8 per group): control, LPS, LPS+Y-27632 (LPS+Y), and LPS+Mito-TEMPO (LPS+M). For induction of endotoxin-induced acute liver injury, the mice were intraperitoneally administered lipopolysaccharide (LPS, 20mg/kg). The ROCK inhibitor Y-27632 (or mitochondrial antioxidant Mito-TEMPO) was intraperitoneally administered at 18 and 1h before injection of LPS. The mice were euthanized 8h after LPS administration. The liver and blood samples were taken and preserved for analysis. Results of this study showed that pretreatment with Y-27632 or Mito-TEMPO significantly attenuated the liver injury as compared to the LPS group. This was confirmed by decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and by reduced hepatocellular apoptosis and histologic damage. Pretreatment with Y-27632 or Mito-TEMPO markedly reduced the LPS-induced inflammatory response and oxidative stress the in liver. Furthermore, it showed similar protective effects on the hepatic mitochondrial function, including an increased activity of complexes I and IV and mitochondrial superoxide dismutase (MnSOD), and an upregulated expression of mtDNA-encoded genes. Taken together, these data demonstrate that Mito-TEMPO can potently inhibit the endotoxin-induced mitochondrial and hepatic abnormalities and indicate that mitochondrial dysfunction might play a key role in the endotoxemia-induced acute liver injury. Moreover, our study shows that ROCK inhibition protects against the endotoxemia-induced liver injury by improving the mitochondrial function.


Philippines to seek Thai assistance in fighting AIDS.
A group of Philippine officials left for Thailand to learn from the Thai government's experience in fighting AIDS. Thailand has one of the highest AIDS levels in Asia and has instituted a variety of public and private programs to deal with the disease. Health Undersecretary Carmencita Reodica, who is leading the delegation, said the Philippines does not expect as many AIDS cases as Thailand. "But if the Philippines does not improve its planning and surveillance system, we could face the same threat in the future," she said. Thailand has a good surveillance program, valuable support services such as mobile clinics, and active private groups fighting AIDS, she said. The group is to meet with Prime Minister Banharn Silpa-archa, who heads the Thai National AIDS Council, and other officials involved in Thailand's anti-AIDS campaign. Thailand has recorded 22,135 AIDS cases and 750,000 people with HIV. In comparison, the Philippine government has documented only 234 AIDS cases in the Philippines and 704 people with HIV. Health officials estimate that as many as 35,000 people in the country are infected with HIV. While Thailand monitors the number of AIDS cases in the general population, the Philippines only monitors the disease among so-called high-risk groups such as prostitutes, homosexuals, and intravenous drug users. Reodica said legislation is needed in the Philippines to support the country's AIDS program, as well as to answer ethical and legal issues concerning AIDS cases.


Mental health and physical activity in the European Union.
This article is the 3rd in a series of four that present data about physical activity in 15 member states of the European Union collected by the Eurobarometer 58.2. On a descriptive level it investigates the relationships between physical activity (MET-h/week) and mental health. Data were collected in 2002 as part of the Eurobarometer by face-to-face interviews. A total of 16,230 respondents age 15 years and older were interviewed. Sample sizes were about 1,000 respondents in most nations. Mental health was assessed with the Mental Health Inventory (MHI-5) and the Energy and Vitality Scale (EVI-scale). Physical activity was assessed with the last 7-days short version of the International Physical Activity Questionnaire (IPAQ). Across sociodemographic subgroups of the populations investigated (age, gender, marital status, gross household income, educational status) it was found, that those being more physically active had in general a better mental health. In some of the 15 nations evidence for a dose-response relationship between physical activity and mental health was found, while in others this was not the case. Results seem to indicate a positive relationship between physical activity level and mental health for population subgroups. However, analysis found no evidence that this relationship can be characterized as being dose-response in all nations.


Potential Role of Hyperglycemia in Fetoplacental Endothelial Dysfunction in Gestational Diabetes Mellitus.
Gestational diabetes mellitus (GDM) is associated with structural and functional alterations in various tissues including endothelial dysfunction. The aim of this study was to explore the effects of hyperglycemia on fibroblast growth factor 2 (FGF2)- and vascular endothelial growth factor (VEGF)-stimulated placental angiogenesis and the underlying molecular signaling mechanisms. The density of fetal placental capillaries was examined using immunohistochemistry. Human umbilical vein endothelial cells (HUVECs) derived from GDM (dHUVECs) and normal healthy patients (nHUVECs) were used as cell models in this study. Cell proliferation, migration and tube formation were measured with an MTS assay, a transwell system and a matrigel assay, respectively. The activation of ERK1/2 was analyzed with Western blot. The specific inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) PD98059 was used to elucidate the involved signaling pathway. GDM did not alter the capillary density of the fetus-placenta. Both the GDM and hyperglycemic conditions inhibited the proliferation of the FGF2- but not the VEGF-stimulated HUVECs and the basal migratory capacity. Hyperglycemic condition significantly inhibited tube formation and ex vivo angiogenesis. Moreover, hyperglycemia inhibited the FGF2- but not the VEGF-induced activation of ERK1/2. PD98059 significantly inhibited the FGF2-activated ERK1/2 phosphorylation and the FGF2-stimulated cell proliferation in HUVECs. Both GDM and hyperglycemia may impair placental angiogenesis by reducing HUVEC proliferation, migration and tube formation. Hyperglycemia-inhibited cell proliferation stimulated by FGF2 probably contributed to the suppression of the MEK1/2/ERK1/2 pathways in the HUVECs.


Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma.
Multiple myeloma (MM), the second most common haematological malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compound, has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compound selectivity towards selenol- and thiol-containing proteins, such as TrxR. In this study, we show that [Au(d2pype)2]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant reduction in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)2]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)2]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)2]Cl. This study highlights the "proof of concept" that improved gold(I)-based compounds could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.


[Determination of free light chains in biological fluids by a latex test].
A novel latex test for the detection and characterization of free light chains in different biological fluids is presented. Accuracy, reliability and sensitivity of the method are evaluated, by comparing experimental results with reference techniques for light chain detection. The assay is tested for quickness and easiness, in order to be routinely used in laboratories of Clinical Chemistry, Haematology, Nephrology and Radiology.