Roles of real-time three-dimensional transesophageal echocardiography in peri-operation of transcatheter left atrial appendage closure.
Left atrial appendage (LAA) closure is a new treatment option for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). Conventional 2-dimensional transesophageal echocardiography (2D TEE) has some limitations in the imaging assessment of LAA closure. Real-time 3-dimensional transesophageal echocardiography (RT-3D TEE) allows for detailed morphologic assessment of the LAA. In this study, we aim to determine the clinical values of RT-3D TEE in the periprocedure of LAA closure.Thirty-eight persistent or paroxysmal AF patients with indications for LAA closure were enrolled in this study. RT-3D TEE full volume data of the LAA were recorded before operation to evaluate the anatomic feature, the landing zone dimension, and the depth of the LAA. On this basis, selection of LAA closure device was carried out. During the procedure, RT-3D TEE was applied to guide the interatrial septal puncture, device operation, and evaluate the occlusion effects. The patients were follow-up 1 month and 3 months postclosure.Twenty-eight (73.7%) patients with AF received placement of LAA occlusion device under RT-3D TEE. Eleven cases with single-lobe LAAs were identified using RT-3D TEE, among which 4 showed limited depth. Seventeen cases showed bilobed or multilobed LAA. Seven cases received LAA closure using Lefort and 21 using LAmbre based on the 3D TEE and radiography. The landing zone dimension of the LAA measured by RT-3D TEE Flexi Slice mode was better correlated with the device size used for occlusion (r = 0.90) than 2D TEE (r = 0.88). The interatial septal puncture, the exchange of the sheath, as well as the release of the device were executed under the guidance of RT-3D TEE during the procedure. The average number of closure devices utilized for optimal plugging was (1.11 ± 0.31). There were no clinically unacceptable residual shunts, pericardial effusion, or tamponade right after occlusion. All the patients had the device well-seated and no evidence of closure related complications in the follow-up.Assessment of LAA morphology by RT-3D TEE contributes to the decision of device selection for the closure. 3D TEE is a reliable imaging modality to guide device operation and assess on-site closure.


Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma.
Glioblastoma (GBM) is an incurable brain tumor characterized by the expression of pro-angiogenic cytokines. A recent phase II clinical trial studied VEGF Trap in adult patients with temozolomide-resistant GBM. We sought to explore changes in [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) in trial participants correlating these changes with disease response. FDG-PET and MRI images obtained before and after the first dose of VEGF Trap were spatially co-registered. Regions of interest on each image slice were combined to produce a volume of interest representative of the entire tumor. Percent and absolute changes in maximum FDG-avidity, mean apparent diffusion coefficient (ADC), Ktrans, and Ve were calculated per lesion. Among the 12 participants that underwent dynamic contrast enhanced MRI (DCE-MRI), there were large, statistically significant reductions in Ktrans and Ve (median difference = -41.8 %, p < 0.02 and -42.6 %, p < 0.04, respectively). In contrast, there were no significant reductions in ADC or FDG-PET SUVmax values. DCE-MRI is a useful measure of early pharmacodynamic effects of VEGF Trap on tumor vasculature. The absence of significant changes in FDG-PET and DW-MRI suggest that the early pharmacodynamic effects are specific to tumor perfusion and/or permeability and do not directly inhibit metabolism or induce cell death. DCE-MRI in conjunction with standard imaging may be promising for the identification of anti-angiogenic effects in this patient population with this therapeutic target. Further studies are needed to evaluate the relationship between DCE-MRI response and clinical outcome.


[Morpho-functional endocrine glands changes in male and female rats under deficiency of functional loading].
Histomorphometric and immunocytochemical methods were employed in comparative morphofunctional analysis of the endocrine glands of female and male rats deprived of support loads on the hind limbs by tail suspension. It was shown that pituitary somatotrophs, pancreatic insulocytes and thyroid calcitonin-producing cells in females and males react to deficiency of support loading equally by reducing the functional activity. Blood testosterone decreases in the tail-suspended rats and concurrent hyperplasia of Leydig's cells in testicles are suggestive of an abnormal testosterone synthesis/secretion by these cells in consequence of resticle displacement toward the abdomen. Activation of adenohypophysial gonadotrophs producing the luteinizing hormone that controls the Leydig's cells proliferation appears to be a feedback reaction of gonadotrophs to the low testosterone level in blood.


Long-circulating liposomal contrast agents for magnetic resonance imaging.
Contrast-enhanced magnetic resonance imaging (CE-MRI) is a dynamic technique for imaging vasculature. However, the currently used gadolinium (Gd) chelates, such as Gd-DTPA, restrict the time window for image acquisition due to their rapid elimination from blood and their rapid diffusion into the extravascular space, which prevents their use in steady-state imaging, particularly for MR angiography (MRA). The goal of this study was to prepare long-circulating polyethylene glycol-bearing ((PEG)ylated) liposomes encapsulating Gd chelate, and characterize and demonstrate their utility for MRA. The liposomes were prepared by hydrating a mixture of lipids with gadodiamide (Omniscan). The liposomes were sized down to around 100 nm by extruder and exhaustively dialysed to remove the unencapsulated gadodiamide. The Gd liposomes exhibited a significant sustained (>4 hr) contrast enhancement of the vasculature with improved spatial details in a rat model with little leakage relative to Gd-DTPA controls as shown by MRI. We suggest that such long-circulating liposomal formulations allow for high spatial resolution imaging without the confounding effects of clearance and extravascular diffusion of the agent complicating the data and image analysis.


Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain.
A prospective double-blind randomized trial in 31 patients. To assess the clinical efficacy of percutaneous radiofrequency denervation of the lumbar zygapophysial joints in reducing pain, functional disability, and physical impairment in patients with back pain originating from the lumbar zygapophysial joints. Chronic low back pain is a major health problem in the industrialized world. A treatment option is percutaneous radiofrequency denervation of the lumbar zygapophysial joints. Its clinical efficacy has never been formally tested in a controlled trial. Thirty-one patients with a history of at least 1 year of chronic low back pain were selected on the basis of a positive response to a diagnostic nerve blockade and subsequently randomly assigned to one of two treatment groups. Each patient in the radiofrequency treatment group (15 patients) received an 80 C radiofrequency lesion of the dorsal ramus of the segmental nerve roots L3, L4, and L5. Patients in the control group (n = 16) underwent an the same procedure but without use of a radiofrequency current. Both the treating physician and the patients were blinded to the group assignment. Before treatment, physical impairment, rating of pain, the degree of disability, and quality of life were assessed by a blinded investigator. Eight weeks after treatment, there were 10 success patients in the radiofrequency group (n = 15) and 6 in the sham group (n = 16). The unadjusted odds ratio was 3.3 (P = 0.05, not significant), and the adjusted odds ratio was 4.8 (P < 0.05, significant). The differences in effect on the visual analog scale scores, global perceived effect, and the Oswestry disability scale were statistically significant. Three, 6, and 12 months after treatment, there were significantly more success patients in the radiofrequency group compared with the sham group. Radiofrequency lumbar zygapophysial joint denervation results in a significant alleviation of pain and functional disability in a select group of patients with chronic low back pain, both on a short-term and a long-term basis.


Gammaherpesvirus Readthrough Transcription Generates a Long Non-Coding RNA That Is Regulated by Antisense miRNAs and Correlates with Enhanced Lytic Replication In Vivo.
Gammaherpesviruses, including the human pathogens Epstein⁻Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are oncogenic viruses that establish lifelong infections in hosts and are associated with the development of lymphoproliferative diseases and lymphomas. Recent studies have shown that the majority of the mammalian genome is transcribed and gives rise to numerous long non-coding RNAs (lncRNAs). Likewise, the large double-stranded DNA virus genomes of herpesviruses undergo pervasive transcription, including the expression of many as yet uncharacterized lncRNAs. Murine gammaperherpesvirus 68 (MHV68, MuHV-4, HV68) is a natural pathogen of rodents, and is genetically and pathogenically related to EBV and KSHV, providing a highly tractable model for studies of gammaherpesvirus biology and pathogenesis. Through the integrated use of parallel data sets from multiple sequencing platforms, we previously resolved transcripts throughout the MHV68 genome, including at least 144 novel transcript isoforms. Here, we sought to molecularly validate novel transcripts identified within the M3/M2 locus, which harbors genes that code for the chemokine binding protein M3, the latency B cell signaling protein M2, and 10 microRNAs (miRNAs). Using strand-specific northern blots, we validated the presence of M3-04, a 3.91 kb polyadenylated transcript that initiates at the M3 transcription start site and reads through the M3 open reading frame (ORF), the M3 poly(a) signal sequence, and the M2 ORF. This unexpected transcript was solely localized to the nucleus, strongly suggesting that it is not translated and instead may function as a lncRNA. Use of an MHV68 mutant lacking two M3-04-antisense pre-miRNA stem loops resulted in highly increased expression of M3-04 and increased virus replication in the lungs of infected mice, demonstrating a key role for these RNAs in regulation of lytic infection. Together these findings suggest the possibility of a tripartite regulatory relationship between the lncRNA M3-04, antisense miRNAs, and the latency gene M2.


Gene therapy for murine mucopolysaccharidosis type VII.
Mucopolysaccharidosis type VII (MPS VII) is caused by a deficiency in the lysosomal enzyme beta-glucuronidase resulting in the accumulation of undegraded glycosaminoglycans in many tissues. A murine model of MPS VII shares many of the clinical, biochemical and histopathological features of human MPS VII and has provided an opportunity to study novel therapeutic approaches in a system with a uniform genetic background. Retroviral mediated gene therapy directed to the hematopoietic system or to artificial neo-organs resulted in low levels of enzyme in several tissues and reduced lysosomal storage in the liver and spleen. Partial correction of the disease in the eye was observed following an intravitreal injection of recombinant adenovirus. Neither retroviral nor adenoviral mediated gene transfer techniques resulted in a systemic reduction of lysosomal storage. Here we discuss several novel gene transfer approaches designed to increase the systemic levels of beta-glucuronidase in the MPS VII mouse.


Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS.
Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo-Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction.


Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.
Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.


A set of electroencephalographic (EEG) data recorded during amplitude-modulated transcranial alternating current stimulation (AM-tACS) targeting 10-Hz steady-state visually evoked potentials (SSVEP).
Transcranial alternating current stimulation (tACS) can affect perception, learning and cognition, but the underlying mechanisms are not well understood. A promising strategy to elucidate these mechanisms aims at applying tACS while electric or magnetic brain oscillations targeted by stimulation are recorded. However, reconstructing brain oscillations targeted by tACS remains a challenging problem due to stimulation artifacts. Besides lack of an established strategy to effectively supress such stimulation artifacts, there are also no resources available that allow for the development and testing of new and effective tACS artefact suppression algorithms, such as adaptive spatial filtering using beamforming or signal-space projection. Here, we provide a full dataset comprising encephalographic (EEG) recordings across six healthy human volunteers who underwent 10-Hz amplitude-modulated tACS (AM-tACS) during a 10-Hz steady-state visually evoked potential (SSVEP) paradigm. Moreover, data and scripts are provided related to the validation of a novel stimulation artefact suppression strategy, Stimulation Artifact Source Separation (SASS), removing EEG signal components that are maximally different in the presence versus absence of stimulation. Besides including EEG single-trial data and comparisons of 10-Hz brain oscillatory phase and amplitude recorded across three conditions (condition 1: no stimulation, condition 2: stimulation with SASS, condition 3: stimulation without SASS), also power spectra and topographies of SSVEP amplitudes across all three conditions are presented. Moreover, data is provided for assessing nonlinear modulations of the stimulation artifact in both time and frequency domains due to heartbeats. Finally, the dataset includes eigenvalue spectra and spatial patterns of signal components that were identified and removed by SASS for stimulation artefact suppression at the target frequency. Besides providing a valuable resource to assess properties of AM-tACS artifacts in the EEG, this dataset allows for testing different artifact rejection methods and offers in-depth insights into the workings of SASS.


Advancing proactive crash prediction: A discretized duration approach for predicting crashes and severity.
Driven by advancements in data-driven methods, recent developments in proactive crash prediction models have primarily focused on implementing machine learning and artificial intelligence. However, from a causal perspective, statistical models are preferred for their ability to estimate effect sizes using variable coefficients and elasticity effects. Most statistical framework-based crash prediction models adopt a case-control approach, matching crashes to non-crash events. However, accurately defining the crash-to-non-crash ratio and incorporating crash severities pose challenges. Few studies have ventured beyond the case-control approach to develop proactive crash prediction models, such as the duration-based framework. This study extends the duration-based modeling framework to create a novel framework for predicting crashes and their severity. Addressing the increased computational complexity resulting from incorporating crash severities, we explore a tradeoff between model performance and estimation time. Results indicate that a 15 % sample drawn at the epoch level achieves a balanced approach, reducing data size while maintaining reasonable predictive accuracy. Furthermore, stability analysis of predictor variables across different samples reveals that variables such as Time of day (Early afternoon), Weather condition (Clear), Lighting condition (Daytime), Illumination (Illuminated), and Volume require larger samples for more accurate coefficient estimation. Conversely, Daytime (Early morning, Late morning, Late afternoon), Lighting condition (Dark lighted), Terrain (Flat), Land use (Commercial, Rural), Number of lanes, and Speed converge towards true estimates with small incremental increases in sample size. The validation reveals that the model performs better in highway segments experiencing more frequent crashes (segments where the duration between crashes is less than 100 h, or approximately 4 days).


Urine/blood ratios of ethanol in deaths attributed to acute alcohol poisoning and chronic alcoholism.
The concentrations of ethanol were determined in femoral venous blood (BAC) and urine (UAC) and the UAC/BAC ratios were evaluated for a large case series of forensic autopsies in which the primary cause of death was either acute alcohol poisoning (N=628) or chronic alcoholism (N=647). In alcohol poisoning deaths both UAC and BAC were higher by about 2g/l compared with chronic alcoholism deaths. In acute alcohol poisoning deaths the minimum BAC was 0.74 g/l and the distribution of UAC/BAC ratios agreed well with the shape of a Gaussian curve with mean+/-standard deviation (S.D.) and median (2.5th and 97.5th centiles) of 1.18+/-0.182 and 1.18 (0.87 and 1.53), respectively. In alcoholism deaths, when the BAC was above 0.74 g/l (N=457) the mean+/-S.D. and median (2.5th and 97.5th centiles) UAC/BAC ratios were 1.30+/-0.29 and 1.26 (0.87 and 2.1), respectively. When the BAC was below 0.74 g/l (N=190), the mean and median UAC/BAC ratios were considerably higher, being 2.24 and 1.58, respectively. BAC and UAC were highly correlated in acute alcohol poisoning deaths (r=0.84, residual S.D.=0.47 g/l) and in chronic alcoholism deaths (r=0.95, residual S.D.=0.41 g/l). For both causes of death (N=1275), the correlation between BAC and UAC was r=0.95 and the residual S.D. was 0.46 g/l. The lower UAC/BAC ratio observed in acute alcohol poisoning deaths (mean and median 1.18:1) suggests that these individuals died before absorption and distribution of ethanol in all body fluids were complete. The higher UAC/BAC ratio in chronic alcoholism (median 1.30:1) is closer to the value expected for complete absorption and distribution of ethanol in all body fluids.


Enantiomerically Pure [2.2]Paracyclophane-4-thiol: A Planar Chiral Sulfur-Based Building Block Readily Available by Resolution with an Amino Acid Chiral Auxiliary.
Acyl chloride of N-phthaloyl-(S)-isoleucine is an efficient chiral auxiliary for the resolution of (±)-[2.2]paracyclophane-4-thiol. A preparative protocol, based on the conversion into diastereoisomeric thiolesters and separation by two fractional crystallizations and column chromatography, was developed. Deprotection with LiAlH4 allowed isolation of the individual thiol enantiomers in good yield (∼40%) and high enantiomeric purity (ee >93%). The absolute configurations were determined by comparison of the optical rotation value of the products with literature data and were confirmed by X-ray crystallography.


Antimalarial activity of selected aromatic chelators. IV. Cation uptake by Plasmodium falciparum in the presence of oxines and siderochromes.
The growth of Plasmodium falciparum, a human malaria parasite, is sensitive to inhibition by chelators of several types. The alkylthiocarbamates and 8-hydroxyquinoline at pharmacologic doses selectively inhibit glycolysis within 6 hr in parasitized erythrocytes. The mechanism attributed to these agents is through the extracellular formation of lipid-soluble 2:1 metal complexes which enter susceptible cells and liberate a lethal 1:1 complex. This study further supports this mechanism since the uptake of 59Fe:oxine complexes within 6 hr occurs at doses corresponding to, or less than, those producing the lethal effects and metabolic changes. Fifty per cent of the uptake occurs in less than 6 hr. The presence of 8-hydroxyquinoline facilitates entry of the radiolabeled cations and uninfected erythrocytes take up less cation, especially in the absence of chelator. The siderochromes, rhodotorulic acid and mycobactin P, when mixed with 59Fe, result in an insignificant uptake, i.e., none of the former and only 12% of the latter penetrate the parasitized cells in 6 hr. Less than 25% of 59Fe:iodochlorhydroxyquin enters infected cells and 8% enters normal erythrocytes, suggesting that very little antimicrobial activity of the iodinated oxines is due to chelation unlike an agent such as KAN-322. In fact, 30% of the oxine complex and possibly more KAN-322 appears to partition in the intracellular parasite itself.


Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction.
The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases.


Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure.
Although brain natriuretic peptide (BNP) of myocardial origin is important in cardiovascular and renal function and as a marker of cardiac dysfunction, the expression of BNP in atrial and ventricular myocardium remains controversial both under normal conditions and in heart failure. We therefore determined left atrial and left ventricular (LV) gene expression and tissue concentration as well as circulating BNP during the evolution of rapid ventricular pacing-induced congestive heart failure (CHF) in the dog. Early LV dysfunction after 10 days of pacing was characterized by impaired LV function but maintained arterial pressure, and overt CHF after 38 days of pacing was characterized by further impaired LV function and decreased systemic arterial pressure. Under normal conditions, cardiac BNP mRNA and cardiac tissue BNP were of atrial origin. In early LV dysfunction, BNP mRNA and tissue BNP were markedly increased in the left atrium in association with an increase in circulating BNP but remained below or at the limit of detection in the LV. In overt CHF, BNP mRNA was further increased in the left atrium and first increased in the LV, together with an increase in LV tissue BNP and a further increase in circulating BNP. In the progression of CHF, early LV dysfunction is characterized by a selective increase in atrial BNP expression in association with increased circulating BNP. Overt CHF is characterized by an additional recruitment of ventricular BNP expression and a further increase in circulating BNP. These studies provide important new insight into the local and temporal regulation of cardiac BNP gene expression during the progression of heart failure and underscore the predominant endocrine role of atrial myocardium under normal conditions and in early LV dysfunction.


Predicting clinical outcome in patients diagnosed with synchronous ovarian and endometrial cancer.
Patients with synchronous ovarian and endometrial cancers may represent cases of a single primary tumor with metastasis (SPM) or dual primary tumors (DP). The diagnosis given will influence the patient's treatment and prognosis. Currently, a diagnosis of SPM or DP is made using histologic criteria, which are frequently unable to make a definitive diagnosis. In this study, we used genetic profiling to make a genetic diagnosis of SPM or DP in 90 patients with synchronous ovarian/endometrial cancers. We compared genetic diagnoses in these patients with the original histologic diagnoses and evaluated the clinical outcome in this series of patients based on their diagnoses. Combining genetic and histologic approaches, we were able make a diagnosis in 88 of 90 cases, whereas histology alone was able to make a diagnosis in only 64 cases. Patients diagnosed with SPM had a significantly worse survival than patients with DP (P = 0.002). Patients in which both tumors were of endometrioid histology survived longer than patients of other histologic subtypes (P = 0.025), and patients diagnosed with SPM had a worse survival if the mode of spread was from ovary to endometrium rather than from endometrium to ovary (P = 0.019). Genetic analysis may represent a powerful tool for use in clinical practice for distinguishing between SPM and DP in patients with synchronous ovarian/endometrial cancer and predicting disease outcome. The data also suggest a hitherto uncharacterized level of heterogeneity in these cases, which, if accurately defined, could lead to improved treatment and survival.


Knowledge of physical activity guidelines among adults in the United States, HealthStyles 2003-2005.
We estimated percentages of US adults (>/=18 years) who knew that prior federal physical activity (PA) guidelines call for a minimum of 30 minutes of moderate-intensity PA most days (>/=5)/week using 2003 to 2005 HealthStyles, an annual mail survey. 10,117 participants identified "the minimum amount of moderate-intensity PA the government recommends to get overall health benefits." Response options included 30/>/=5, 20/>/=3, 30/7, and 60/7 (minutes/days per week), "none of these," and "don't know." The odds of correctly identifying the guideline was modeled by participant sex, age, race/ethnicity, income, education, marital status, body mass index, physical activity level, and survey year using logistic regression. 25.6% of respondents correctly identified the guideline. Women were 30% more likely to identify the guideline than men (Odds Ratio [95% Confidence Limits] (OR) = 1.28 [1.15, 1.44]). Regular PA was positively associated with identifying the guideline versus inactivity (OR = 2.08 [1.73, 2.50]). Blacks and those earning <$15,000 annually were 24% to 32% less likely to identify the guideline than whites and those earning >$60,000, respectively. Most adults did not know the previous moderate-intensity PA recommendation, which indicates a need for effective communication strategies for the new 2008 Physical Activity Guidelines for Adults.


The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line.
While androgens clearly have significant skeletal effects, the paracrine mediators of androgen action on bone are at present unclear. Interleukin-6 (IL-6) is a candidate cytokine that is produced by osteoblastic lineage cells and promotes osteoclastogenesis and bone resorption. Here, we assessed constitutive as well as IL-1beta- and tumor necrosis factor-alpha (TNF-alpha)-stimulated IL-6 mRNA expression by Northern analysis and protein secretion by immunoassay in a human androgen-responsive osteoblastic cell line (hFOB/AR-6) which contains approximately 4000 androgen receptors (ARs)/nucleus. Treatment with 5alpha-dihydrotestosterone (DHT) dose-dependently inhibited constitutive and TNF-alpha/IL-1beta-stimulated IL-6 mRNA steady-state levels in hFOB/AR-6 cells by 70-80% at 10-7 M. In addition, testosterone also suppressed TNF-alpha/IL-1beta-stimulated IL-6 mRNA levels by 57%, while the adrenal androgen dehydroepiandrosterone had no effect. Of note, the specific AR antagonist, hydroxyflutamide, also inhibited IL-6 mRNA levels by 70%. Consistent with the Northern analyses, treatment with 5alpha-DHT, testosterone, and hydroxyflutamide also inhibited IL-6 protein production by 79%, 62%, and 71%, respectively (p < 0.001), while these agents had no effect on IL-6 soluble receptor levels. Finally, we demonstrated that hydroxyflutamide treatment of hFOB/AR-6 cells markedly inhibited the activation and binding of NF-kappaB (a known stimulator of IL-6 gene transcription) to its response element, thus providing a potential mechanism for its effect on IL-6 production by osteoblasts. These data are consistent with the hypothesis that suppression of osteoblast IL-6 production by androgens may mediate, at least in part, the antiresorptive effects of androgens on bone. Moreover, our findings also indicate that hydroxyflutamide, which is a known AR antagonist in most tissues, may function as a selective AR modulator for effects on IL-6 production by osteoblasts.


Residual enzymatic activity of the tetanus toxin light chain present in tetanus toxoid batches used for vaccine production.
The light chain of tetanus neurotoxin (TeNT) is a zinc-dependent metalloprotease which specifically cleaves the synaptic vesicle protein synaptobrevin. This crucial mechanism of tetanus toxicity leads to a blockade of inhibitory neurotransmitter release. We recently reported the development of a highly sensitive endopeptidase assay for the specific in vitro detection of active TeNT based on this proteolytic feature. Using this method, we could show that formaldehyde-inactivated TeNT preparations (toxoids), which are used for the production of tetanus vaccines, contain a high residual synaptobrevin-cleaving activity. Such an activity was detected in numerous tetanus toxoid batches obtained from several vaccine manufacturers which did not display any in vivo toxicity in the obligatory animal tests. The enzymatic activity could be attributed to the presence of free TeNT light chains whose function had not been restrained by the formaldehyde treatment, but which lack the functional heavy chain necessary for entering neurons in vivo. To our knowledge, this is the first report describing a residual proteolytic activity in tetanus toxoids.


Trimester-specific prenatal heavy metal exposures and sex-specific postpartum size and growth.
There has been limited research considering the effects of prenatal exposure to multiple heavy metals on early childhood size and growth. We evaluated prenatal exposures to 15 heavy metals in association with measures of weight, length, and head circumference (HC) measured at birth, and 1, 3 and 6 months of age in a study of 358 mother-child pairs. Urinary concentrations were measured in the first and third trimesters of pregnancy and examined, using sex-stratified general linear models, in association with average standardized size and changes in size (growth) over the first 6 months of life. Confounding effects among metals were explored. Increased first trimester Hg and V were associated with decreased average HC among males and weight among females, respectively. Increased first trimester V was associated with a decline in weight among females over time. Increased third trimester Cs, Rb and Tl were associated with increased average weight and HC among males. Increased third trimester Se was associated with increased HC among females over time. Evidence for confounding was observed between Cs, Rb and Tl in association with weight and HC. We observed multiple biologically plausible associations between prenatal heavy metal exposures and postnatal size and growth. We have taken a comprehensive and novel approach to evaluating the impacts of prenatal heavy metal exposures on size and growth during early childhood. Our detailed analyses consider exposures to 15 different heavy metals at two time points during pregnancy, as well as multiple metrics of size and growth collected at birth and 1, 3 and 6 months of age.


Cutaneous manifestations of Lyme borreliosis.
The dermatological symptoms of Lyme borreliosis present with a typical clinical pattern and characteristic time of appearance. In contrast to other manifestations of Lyme borreliosis they are easily recognizable in most of the cases. In the first stage, erythema migrans arises at the tick bite site. With this symptom the diagnosis of Lyme borreliosis can be established. During all manifestations of Lyme borreliosis the history of erythema migrans is an important parameter to verify the diagnosis. In the early stage of disease a lymphocytic proliferation can appear at the tick bite site, at the ear lobe, or at the mamilla. Borrelia lymphocytoma can be diagnosed when antibodies against Borrelia burgdorferi are positive. Years after infection, acrodermatitis chronica atrophicans arises at distal body sites causing livid swelling and gradually skin atrophy. Skin lesions can be accompanied by neuropathies, mostly of the lower legs, which in contrast to the skin lesions, do not respond well to antibiotic therapy. There is evidence that some cases of Shulman syndrome, morphea and lichen sclerosus et atrophicus might be related to a borrelia infection as indicated by cultivation of B. burgdorferi from skin biopsies of morphea and response to antibiotic treatment in some cases. The classical dermatological symptoms of Lyme borreliosis, erythema migrans, borrelia lymphocytoma and acrodermatitis chronica atrophicans respond to oral antibiotic treatment. In acrodermatitis chronica atrophicans parenteral antibiotic therapy is sometimes necessary.


Cold agglutinin induced autoimmune hemolytic anemia and NK-cell leukemia: a new association.
Cold agglutinin induced autoimmune hemolytic anemia is uncommonly associated with leukemia and lymphomas. We present a case of a young Mexican female presenting with a cold agglutinin hemolytic anemia with expression of a rare Pr antigen specificity and an aggressive NK-cell leukemia. Our patient had a rapid fatal course. To our knowledge this is the first reported case of such an association.


Disease persistence in patients with cervical intraepithelial neoplasia undergoing electrosurgical conization.
Cone margin status has been reported to be the most important predictor of residual disease in patients with cervical intraepithelial neoplasia (CIN) undergoing electrosurgical excisional treatment. The primary aim of this study of patients treated with electrosurgical conization was to evaluate the association of cone margin status and other clinical and pathologic factors with the probability of residual disease. The study population comprised 699 patients with at least one follow-up visit within 12 months of conization. Residual disease was defined as a histology diagnosis of CIN within 3 years of conization. Multivariate associations were evaluated with multiple logistic regression analysis. Attendance to follow-up was 97% for the second visit and 34% for the third visit. Residual disease was detected in a total of 38 patients (5.4%). The detection rate was 3.3% at the first visit, 2.1% at the second visit, and 0.4% at the third visit. An increased probability of residual disease was associated with a referral Pap smear reported as high-grade squamous intraepithelial neoplasia and carcinoma (odds ratio, 2.9; reference category, low-grade squamous intraepithelial neoplasia). A decreased probability was associated with a squamocolumnar junction entirely visible at the first follow-up visit (odds ratio, 0.2; reference category, squamocolumnar junction not visible). Patient age, time period, lesion size, lesion site, grade of CIN, cone width, cone depth, and margin status had no influence. The determinants of residual disease in this study differed from those generally reported so far. Factors associated with effectiveness of electrosurgical treatment of CIN need further research.


[Long-term results of organo-safe operation in obstructive ureterohydronephrosis of terminal stage].
A comparative analysis of efficacy of two methods was the purpose of the research. Politano-Leadbetter technique was applied in 41 cases and nipple way was used in 13 cases. The investigation included 45 patients aged from 2 months till 17 years with congenital obstructive ureterohydronephrosis of terminal stage (the pathology was diagnosed from both sides in 15 children). A follow-up period was from 1 till 6 years. Recurrent intervention was required in 31 cases. An analysis of overall results allowed determining the outcome as positive in 26 cases after Politano-Leadbetter operation. There were a vesicoureteral reflux in 6 cases and signs of obstruction appeared in 9 cases. The application of nipple operation had positive results in 9 cases, at the same time, the complication such as vesicoureteral reflux was noted in 2 cases, the signs of obstruction were in 2 cases. The authors prefer using the nipple method of reimplantation in spite of identical results of two different methods.


Aflatoxin B1 and sterigmatocystin in wheat and wheat products from supermarkets in China.
Wheat is an important cereal but it is often contaminated with mycotoxins. The natural occurrence of aflatoxin B1 (AFB1) and sterigmatocystin (STC) was determined in 178 food samples (32 wheat samples and 146 wheat products) purchased from Chinese supermarkets. The methodology was validated, the wheat and wheat products samples were treated with a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). From these samples 18.8% of wheat and 8.2% of cracker samples were contaminated with AFB1. Mean levels were 0.06 µg/kg and 0.05µg/kg, respectively. There was no AFB1 contamination in white bread or whole meal bread. Meanwhile 53.1% of wheat, 59.2% of crackers, 20.8% of white bread and 16% of whole meal bread samples were contaminated with STC. The mean levels were 0.07, 0.79, 0.12 and 0.12 µg/kg respectively. Although the levels were low, this demonstrates the need for more comprehensive surveys for these two mycotoxins in wheat and wheat products from China.


Towards prenatal biomonitoring in North Carolina: assessing arsenic, cadmium, mercury, and lead levels in pregnant women.
Exposure to toxic metals during the prenatal period carries the potential for adverse developmental effects to the fetus, yet such exposure remains largely unmonitored in the United States. The aim of this study was to assess maternal exposure to four toxic metals (arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb)) in a cohort of pregnant women in North Carolina. We analyzed blood samples submitted to the North Carolina Department of Health and Human Services for blood typing to assess toxic metal levels in pregnant women (n = 211) across six North Carolina counties. Whole blood metal concentrations were measured by inductively coupled plasma mass spectrometry. The association between maternal characteristics, including county of residence, age, and race, and metal exposure was analyzed using multiple linear regression analysis. A large fraction of the blood samples showed detectable levels for each of the four metals. Specifically, As (65.7%), Cd (57.3%), Hg (63.8%), and Pb (100%) were detected in blood samples. Moreover, compared with adult females participating in the Fourth National Report on Human Exposure to Environmental Chemicals and guidelines for pregnant women, some women in the sample population exceeded benchmark levels of Cd, Hg, and Pb. Evidence from this pilot study indicates that pregnant women in North Carolina are exposed to As, Cd, Hg, and Pb and suggests that factors related to maternal county of residence and race may impact maternal exposure levels. As increased levels of one or more of these metals in utero have been associated with detrimental developmental and reproductive outcomes, further study is clearly warranted to establish the impacts to newborns.


Impaired cognitive flexibility during sleep deprivation among carriers of the Brain Derived Neurotrophic Factor (BDNF) Val66Met allele.
Accumulating evidence points to a genetic contribution to explain inter-individual vulnerability to sleep deprivation. A functional polymorphism in the BDNF gene, which causes a valine (Val) to methionine (Met) amino acid substitution at Codon 66, has been associated with cognitive impairment, particularly in populations with impaired frontal functioning. We hypothesised that sleep deprivation, which affects frontal function, may lead to cognitive dysfunction in Met allele carriers. To examine this, we investigated, in different BDNF genotypes, the effects of sleep deprivation on cognitive flexibility, as measured by response inhibition using the Stroop Color Naming Task. Thirty healthy, adults of European ancestry, including 12 heterozygous Met allele carriers and 18 Val/Val homozygotes, underwent 30-h of extended wakefulness under constant routine conditions. A computerised Stroop task was administered every 2h. Error rate and reaction times increased with time awake for all individuals. Participants with the Val/Met genotype made more errors on incongruent trials after 20h awake. While Val/Met participants also took significantly longer to respond when inhibiting a prepotent response irrespective of time awake, this was particularly evident during the biological night. Our study shows that carriers of the BDNF Met allele are more vulnerable to the impact of prolonged wakefulness and the biological night on a critical component of executive function, as measured by response inhibition on the Stroop task.


Infection and the progression of hepatic encephalopathy in acute liver failure.
Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.


CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity.
Autoimmune thyroid diseases (AITDs) frequently occur together with other endocrine autoimmune conditions, denominated as polyglandular autoimmunity (PGA). The cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene was recently associated with AITD and PGA, and the CTLA-4 protein is a strong inhibitor of T-cells.The tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine. This study aimed to analyze the association of the CTLA-4 CT60 and TNF-alpha-863 polymorphisms with PGA. Homogeneous groups of 70 patients with AITD, 70 with type 1 diabetes (T1D), 70 with both AITD and T1D (PGA), and 100 healthy controls were genotyped for the CTLA-4 CT60 and TNF-alpha-863 polymorphisms by minisequencing on an ABI PRISM-3100 genetic analyzer. The CT60 G/G genotype was significantly more common in patients with PGA than in healthy controls (48.6 % vs. 32.0 % , OR = 2.01, 95 % CI = 1.07-3.77, p = 0.038). The CT60 allele frequencies differed as well between PGA patients and controls, with the predisposing G allele being increased in PGA (OR = 1.63, 95 % CI = 1.03-2.55, p = 0.042). Patients with PGA did not differ from those with AITD (p = 0.602) or T1D(p = 0.362). For TNF-alpha-863, carriers of the minor A allele occurred more frequently in the T1D group than in controls (47.1 % vs. 33 % , OR = 1.81, 95 % CI = 0.97-3.39, p = 0.079), but no differences in allele or genotype distribution were noted between PGA patients and controls (p = 0.886 and 0.389, respectively). In conclusion the CTLA-4 CT60 polymorphism is associated with PGA.


Usual suspects: the foreign bodies of the aerodigestive tract.
This case series is about four different foreign bodies lodged in different locations of the aerodigestive tract. All four cases had delayed diagnosis due to inconspicuous history. Radiology in the form of computed tomography aided the appropriate diagnosis in most of these cases. Though all four patients have been successfully managed by removal of foreign body, not all of them have identical outcomes. A brief discussion about predictive factors in the fish bone foreign body has been included. The authors also discuss certain critical aspects of the management, which may aid in reducing the morbidity. We emphasise on the high index of suspicion in peculiar cases and on the low threshold for radiological investigation in doubtful clinical scenarios.


Decontamination method using heat and relative humidity for radish seeds achieves a 7-log reduction of Escherichia coli O157:H7 without affecting product quality.
We developed a novel decontamination method to inactivate Escherichia coli O157:H7 on radish seeds without adversely affecting seed germination or product quality. The use of heat (55, 60, and 65 °C) combined with relative humidity (RH; 25, 45, 65, 85, and 100%) for 24h was evaluated for effective microbial reduction and preservation of seed germination rates. A significant two-way interaction of heat and RH was observed for both microbial reduction and germination rate (P<0.0001). Increases in heat and RH were associated with corresponding reductions in E. coli O157:H7 and in germination rate (P<0.05). The order of lethality for the different treatments was generally as follows: no treatment <55 °C/25-65% RH ≒60 °C/25-45% RH ≒65 °C/25% RH <55 °C/85% RH =60 °C/65% RH <55 °C/100% RH =60 °C/85-100% RH =65 °C/45-100% RH. The most effective condition, 65 °C/45% RH, completely inactivated E. coli O157:H7 on the seeds (7.0 log CFU/g reduction) and had no significant effect on the germination rate (85.4%; P>0.05) or product quality. The method uses only heat and relative humidity without chemicals, and is thus applicable as a general decontamination procedure in spout producing plants where the use of growth chambers is the norm.


Immunotherapy for malignant glioma.
Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.


[Experimental-psychological study in the late period of closed wartime craniocerebral injuries].
An experimental psychological study covered 70 patients with a long-term progressive course of a closed craniocerebral injury (CCCI) sustained during the war. The traumatological symptomatology was characterized by unstable working capacity, exhaustibility, deteriorated memory, inconsistent thinking, low self-esteem and a lower level of aspirations, weakening of incentives, the presence of residual disorders of speech and visual-spatial orientation. Patients with a predominant cerebrovascular disease, along with exhaustibility characteristic of traumatic pathology, showed general inhibition, inertia, rigid processes, memory deterioration, as well as poor ability for generalization and abstract thinking, lack of interests and uncritical perception of information. The results obtained should be considered in the differential diagnosis of the clinical variant of the progressive time-course at a long-term period of a CCCI as well as in the assessment of the patient's working ability and the causes of disability.


Plasmonic nanoparticle amyloid corona for screening Aβ oligomeric aggregate-degrading drugs.
The generation of toxic amyloid β (Aβ) oligomers is a central feature of the onset and progression of Alzheimer's disease (AD). Drug discoveries for Aβ oligomer degradation have been hampered by the difficulty of Aβ oligomer purification and a lack of screening tools. Here, we report a plasmonic nanoparticle amyloid corona (PNAC) for quantifying the efficacy of Aβ oligomeric aggregate-degrading drugs. Our strategy is to monitor the drug-induced degradation of oligomeric aggregates by analyzing the colorimetric responses of PNACs. To test our strategy, we use Aβ-degrading proteases (protease XIV and MMP-9) and subsequently various small-molecule substances that have shown benefits in the treatment of AD. We demonstrate that this strategy with PNAC can identify effective drugs for eliminating oligomeric aggregates. Thus, this approach presents an appealing opportunity to reduce attrition problems in drug discovery for AD treatment.


Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group.
To determine the site and bacterial epidemiology of nosocomial infections (NIs) in children. 6-month prospective study with periodic chart review during hospitalization using a uniform prospective questionnaire in each unit, analyzed at a coordinating center. 20 units in eight European countries: 5 pediatric intensive care units (PICUs), 7 neonatal units, 2 hematology-oncology units, 8 general pediatric units. All children hospitalized during the study period with an NI according to Centers for Disease Control and Prevention criteria. The overall incidence of NI was 2.5%, ranging from 1% in general pediatric units to 23.6% in PICUs. Bacteria were responsible for 68% (gram-negative bacilli, 37%; gram-positive cocci, 31%), Candida for 9%, and viruses for 22% of cases. The proportion of lower respiratory tract infections was 13% in general pediatric units and 53% in PICUs. Bloodstream infections were most frequent in neonatal units (71% of NIs) and were associated with a central venous catheter in 66% of cases. Coagulase-negative Staphylococcus (CNS) was the main pathogen. Eleven percent of NI were urinary tract infections. Gastrointestinal infections were most commonly viral and accounted for 76% of NIs in general pediatric units. The prevalence of antimicrobial resistance depended on the type of unit. The highest rates were observed in PICUs: 26.3% of Staphylococcus aureus and 89% of CNS were methicillin-resistant, and 37.5% of Klebsiella pneumoniae had an extended-spectrum beta-lactamase. Mortality due to NI was 10% in PICUs and 17% in neonatal units. We found large differences in NI frequency and microbial epidemiology in this European study. Viruses were the main pathogens in general pediatrics units. Catheter-related sepsis and CNS were frequent in newborns. A high frequency of multiresistant bacteria was observed in some units. Clinical monitoring of NIs and bacterial resistance profiles are required in all pediatric units.


Dendritic cell-targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation.
Dendritic cell (DC) activation and antigen presentation are critical for efficient priming of T cell responses. Here, we study how lentiviral vectors (LVs) deliver antigen and activate DCs to generate T cell immunization in vivo. We report that antigenic proteins delivered in vector particles via pseudotransduction were sufficient to stimulate an antigen-specific immune response. The delivery of the viral genome encoding the antigen increased the magnitude of this response in vivo but was irrelevant in vitro. Activation of DCs by LVs was independent of MyD88, TRIF, and MAVS, ruling out an involvement of Toll-like receptor or RIG-I-like receptor signaling. Cellular DNA packaged in LV preparations induced DC activation by the host STING (stimulator of interferon genes) and cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase) pathway. Envelope-mediated viral fusion also activated DCs in a phosphoinositide 3-kinase-dependent but STING-independent process. Pseudotransduction, transduction, viral fusion, and delivery of cellular DNA collaborate to make the DC-targeted LV preparation an effective immunogen.


Computerisation of accident and emergency departments in Hong Kong.
This article reviews the history and progress of the computerisation of accident and emergency departments in Hong Kong. The Hospital Information System was the first computerisation project to be launched in a public hospital in Hong Kong, when the Princess Margaret Hospital was selected as a pilot site in April 1991. The network infrastructure comprised a central processor that linked to all workstations in the hospital in an integrated network. With the introduction of bar-coding technology and the implementation of an interfaced network, the Accident and Emergency Information System version 1.0 was launched at the Prince of Wales Hospital in March 1993. A Clinical Management System was then piloted at the Accident and Emergency Department of the Alice Ho Miu Ling Nethersole Hospital in December 1997; it contained clinical data of individual patients, including diagnoses, drug treatments, discharge summaries, allergies, and medical histories. Laboratory, diagnostic radiology, and electrocardiography results were also available in this system. With the extensive development of Internet technology within the Hospital Authority, clinical information can now be retrieved in any hospital in a couple of minutes. The availability of important clinical information will be of great help to emergency physicians in the delivery of quality care to patients.


Presence of a D8/17 B lymphocyte marker and HLA-DR subgroups in patients with rheumatic heart disease.
The aim of our study was to investigate the association of HLA antigens and a non-HLA protein D8/17 with rheumatic heart disease and its pattern of cardiac involvement. This cross- sectional observational study included 35 children and 12 adult patients who have rheumatic heart disease and 35 healthy children and 12 healthy adult controls. After physical examination, all patients and control group members were evaluated with 2D and color-coded echocardiography. B- lymphocyte D8/17 expression was tested by a flow cytometry assay. HLA genotyping was performed using polymerase chain reaction sequence-specific primers. In statistical analysis, Chi-square, unpaired t and Mann-Whitney U tests were used for comparison groups. The percentage of the D8/17-expressing B lymphocytes of the patient group was significantly higher than of the control group (77.3±15.6% vs. 67.7±20.0%, p=0.013). When compared with the control group, the HLA DRB5 (38.6% vs. 13.6%, p=0.007) and HLA DRB1*15 (31.8% vs. 9.0%, p=0.008) expression levels of the patient group were significantly higher and the DRB4 expression of the patient group was significantly lower (29.5% vs. 50.0%, p=0.049). Our findings support the association between HLA Class 2 subgroups and rheumatic heart disease, and an association between D8/17 expression and rheumatic heart disease. Further studies including higher number of patients and control group members should be performed for the confirmation of our results.


Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins.
Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.


ZIP kinase is responsible for the phosphorylation of myosin II and necessary for cell motility in mammalian fibroblasts.
Reorganization of actomyosin is an essential process for cell migration and myosin regulatory light chain (MLC20) phosphorylation plays a key role in this process. Here, we found that zipper-interacting protein (ZIP) kinase plays a predominant role in myosin II phosphorylation in mammalian fibroblasts. Using two phosphorylation site-specific antibodies, we demonstrated that a significant portion of the phosphorylated MLC20 is diphosphorylated and that the localization of mono- and diphosphorylated myosin is different from each other. The kinase responsible for the phosphorylation was ZIP kinase because (a) the kinase in the cell extracts phosphorylated Ser19 and Thr18 of MLC20 with similar potency; (b) immunodepletion of ZIP kinase from the cell extracts markedly diminished its myosin II kinase activity; and (c) disruption of ZIP kinase expression by RNA interference diminished myosin phosphorylation, and resulted in the defect of cell polarity and migration efficiency. These results suggest that ZIP kinase is critical for myosin phosphorylation and necessary for cell motile processes in mammalian fibroblasts.


[Guided bone regeneration for single tooth replacements by oral implants].
Single tooth replacement is a good indication for an oral implant. However, bone regeneration, is often required to improve the bone quantity and the contour of the overlying soft tissues. Guided Bone Regeneration (GBR) using membranes is a good technique to restore local bone defects within a six months period. With this technique it is crucial that a membrane properly separates the bony and soft tissues and creates a space around a bony defect for bone ingrowth. This article describes the indications and contra-indications for GBR, the technique and the possible complications.


Fertility Preservation in Breast Cancer.
As more young women survive breast cancer, fertility preservation (FP) is an important component of care. This review highlights the importance of early pretreatment referral, reviews the risks of infertility associated with breast cancer treatment, and defines existing and emerging techniques for FP. The techniques reviewed include ovarian suppression, embryo cryopreservation, oocyte cryopreservation, and ovarian tissue cryopreservation and transplantation. The barriers women face, such as not being appropriately referred and the costs of treatment, also are addressed. Multidisciplinary, patient-centered care is essential to discussing FP with patients with breast cancer and ensuring appropriate care that includes quality of life in survivorship.


In vitro effects of a high-molecular-weight heat-labile enterotoxin from enteroaggregative Escherichia coli.
The pathogenic mechanisms of enteroaggregative Escherichia coli (EAggEC) infection are not fully elucidated. In this work we show that an ammonium sulfate precipitate of culture supernatant of EAggEC strain 049766 increased the potential difference (PD) and the short-circuit current (Isc) in rat jejunal preparations mounted in Ussing chambers. The precipitate contained two major proteins of 108 and 116 kDa, which were partially copurified by chromatography in DEAE-cellulose. This chromatographic fraction (peak I) increased jejunal PD and Isc in a dose-dependent manner, accompanied by a decrease in tissue electrical resistance. These effects were inhibited by incubation of peak I at 75 degreesC for 15 min or for 1 h with proteinase K at 37 degreesC. Rabbit polyclonal antibodies against peak I containing both the 108- and 116-kDa proteins inhibited the enterotoxic effect. Specific polyclonal antibodies raised against the 108-kDa but not against the 116-kDa protein inhibited the enterotoxic effect, suggesting that the 108-kDa protein is the active toxic species. Moreover, another EAggEC strain (065126) producing the 116-kDa protein but not the 108-kDa protein had no effect on rat jejunal mucosa in the Ussing chamber. The >100-kDa fraction derived from prototype EAggEC strain 042, which also expressed both 108- and 116-kDa proteins, also produced an enterotoxic effect on rat jejunal preparations in Ussing chambers; however, the same strain cured of its 65-MDa adherence plasmid did not. A subclone derived from the 65-MDa plasmid expressing the 108-kDa toxin (and not the 116-kDa protein) elicited rises in Isc. Tissue exposed to any preparation containing the 108-kDa toxin exhibited similar histopathologic changes, characterized by increased mucus release, exfoliation of cells, and development of crypt abscesses. Our data suggest that some EAggEC strains produce a ca. 108-kDa enterotoxin/cytotoxin which is encoded on the large virulence plasmid.


Probability rather than logic as the basis of perception.
Formal logic may be an inappropriate framework for understanding perception. The responses of neurons at various levels of the sensory hierarchy may be better described in terms of probability than logic. Analysis and modeling of the multisensory responses of neurons in the midbrain provide a case study.


mecA Gene Dissemination Among Staphylococcal and Non-staphylococcal Isolates Shed in Surface Waters.
Aquatic ecosystems represent important vehicles for the dissemination of antibiotic resistant bacteria and antibiotic resistance genes. Of particular interest are methicillin-resistant staphylococci (MRS) harboring mecA gene that confers their resistance to β-lactams. Therefore, in this study, water samples collected from different locations of a river impacted by surrounding facilities and domestic effluents were analyzed to learn more about the occurrence of MRS and mecA gene. Out of 290, 12 surface water isolates displayed resistance to both cefoxitin and oxacillin antibiotics. Resistant staphylococcal and non-staphylococcal isolates, identified by 16S rRNA sequencing, were found to harbor mecA gene. The phylogenetic tree of partial mecA sequences obtained from staphylococcal and non-staphylococcal isolates showed sequence similarity values of 8 %-100 %. Surface water bodies receive contaminated waters via runoff, effluents from industrial, agricultural, and municipal discharges. Therefore, surface waters are not only hot spots for mecA harboring staphylococcal isolates but also non-staphylococcal isolates and require special scientific consideration.


Memory Consolidation Is Linked to Spindle-Mediated Information Processing during Sleep.
How are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation [1-4]. In related work, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of auditory cues [5-10], a procedure known as targeted memory reactivation (TMR). It has remained unclear, however, whether TMR triggers the brain's endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of mnemonic information. We devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilizing next-day retention relative to non-cued memories. First, we found that, compared to novel control adjectives, memory cues evoked an increase in fast spindles. Critically, during the time window of cue-induced spindle activity, the memory category linked to the verbal cue (object or scene) could be reliably decoded, with the fidelity of this decoding predicting the behavioral consolidation benefits of TMR. These results provide correlative evidence for an information processing role of sleep spindles in service of memory consolidation.


[Early stages of myocardial infarct studied by opitcal methods].
The hearts of 45 dogs were investigated at times from 10 minutes to 24 hours following ligation of the anterior interventricular branch of the left coronary artery. The material was fixed in formalin and embedded in parafin. It was established that at early stages of experimental myocardial infarction in the zone of eschemia there took place eschemic zone various foms of contactural damages, lumpy decmposition, relaxation and sarcoplasmic matrix. By the polarizing microscope method in the peripheral area of the eshemic zone various forms of contractural damages, lumpy decomposition, relaxation and desaggregation of myofibrills, were noted. Phaso-contrast and interference microscopy investigations revealed in the damaged cells an induration of the sarcoplasmic matrix due to an increase in the dry matter concentration. The studies conducted with the help of polarizing, phaso-contrast, and interference microscopy methods showed that by using these methods it is possible at early periods to reveal the zone of myocardial infarction on stained and unstained preparations prepared by conventional methods.


An extracellular matrix molecule of newt and axolotl regenerating limb blastemas and embryonic limb buds: immunological relationship of MT1 antigen with tenascin.
Several well-characterized extracellular matrix (ECM) components have been localized to the amphibian limb regenerate, but the identification and characterization of novel ECM molecules have received little attention. Here we describe, using mAb MT1 and immunocytochemistry, an ECM molecule expressed during limb regeneration and limb development. In limb stumps, mAb MT1 reactivity was restricted to tendons, myotendinous junctions, granules in the basal layers of epidermis, periosteum (newts) and perichondrium (axolotls). In regenerating limbs, reactivity in the distal limb stump was first detected 5 days and 1 day after amputation of newt and axolotl limbs, respectively. In both species, mAb MT1 recognized what appeared to be an abundant blastema matrix antigen, localized in both thin and thick cords between and sometimes closely associated with blastema cells. Reactivity was generally uniform throughout the blastema except for a particularly thick layer that was present immediately beneath the wound epithelium. During redifferentiation stages, mAb MT1 reactivity persisted among blastema cells and redifferentiating cartilage but was lost proximally in areas of muscle and connective tissue differentiation. During the entire period of embryonic limb development, mAb MT1 reactivity was seen in the ECM of the mesenchyme and in a layer beneath the limb bud ectoderm, similar to its distribution during regeneration. Considerable mAb MT1 reactivity was also associated with the developing somites. The reactivity of mAb MT1 in blastema and limb bud was similar if not identical to that of a polyclonal Ab against tenascin (pAbTN), a large, extracellular matrix glycoprotein implicated in growth control, inductive interactions, and other developmental events. This pAbTN effectively competed against mAb MT1 binding on blastema sections. In immunoblots, both mAb MT1 and pAbTN recognized a very high molecular weight (approximately Mr 1000 x 10(3)) protein in blastema extracts of both newts and axolotls. mAb MT1 immunoprecipitated a protein of Mr 1000K size which reacted to both mAb MT1 and pAbTN in immunoblots. These data show that tenascin is in the matrix of the urodele blastema and limb bud, and suggest that mAb MT1 identifies urodele tenascin.


Why is it difficult to accurately predict the COVID-19 epidemic?
Since the COVID-19 outbreak in Wuhan City in December of 2019, numerous model predictions on the COVID-19 epidemics in Wuhan and other parts of China have been reported. These model predictions have shown a wide range of variations. In our study, we demonstrate that nonidentifiability in model calibrations using the confirmed-case data is the main reason for such wide variations. Using the Akaike Information Criterion (AIC) for model selection, we show that an SIR model performs much better than an SEIR model in representing the information contained in the confirmed-case data. This indicates that predictions using more complex models may not be more reliable compared to using a simpler model. We present our model predictions for the COVID-19 epidemic in Wuhan after the lockdown and quarantine of the city on January 23, 2020. We also report our results of modeling the impacts of the strict quarantine measures undertaken in the city after February 7 on the time course of the epidemic, and modeling the potential of a second outbreak after the return-to-work in the city.


Interferometric broadband Fourier spectroscopy with a partially coherent gas-discharge extreme ultraviolet light source.
Extreme ultraviolet (EUV) spectroscopy is a powerful tool for studying fundamental processes in plasmas as well as for spectral characterization of EUV light sources and EUV optics. However, a simultaneous measurement covering a broadband spectral range is difficult to realize. Here, we propose a method for interferometric broadband Fourier spectroscopy connecting soft x ray and visible spectral ranges with moderate spectral resolution. We present an analytical model to recover the spectrum from a double-slit interferogram. We apply our model for spectral characterization of a partially coherent gas-discharge EUV light source operated with different gases in the spectral range between 10 and 110 nm wavelengths. Our approach allows a simple and fast broadband spectroscopy with fully or partially spatially coherent light sources, for instance, to characterize out-of-band radiation in EUV lithography applications.


Interleukin (IL)-13 is the predominant Th2 cytokine in localized cutaneous leishmaniasis lesions and renders specific CD4+ T cells unresponsive to IL-12.
Semiquantitative reverse transcription-polymerase chain reaction analysis of leishmania lesion cytokine profile showed a Th2 cytokine expression pattern, as reflected by interleukin (IL)-4 and IL-13 mRNA expression. There was a predominance of IL-13 in most lesions from patients with American localized cutaneous leishmaniasis caused by Leishmania guyanensis. IL-13 production by peripheral blood mononuclear cells in response to specific leishmania antigens was confirmed in these patients. The absence of the second chain of the IL-12 receptor (IL-12Rbeta2) mRNA expression in lesions and the presence of specific IgE and IgG4 in some serum samples demonstrated the functional role of these Th2 cytokines. IL-13, unlike IL-4, rendered specific T cells unresponsive to IL-12 by inhibiting the expression of the IL-12Rbeta2 chain. These data establish the crucial role of IL-13 in human cutaneous leishmaniasis.


Phospholipid secretions of organ cultured ciliary body.
Homeostasis of intraocular pressure (IOP) is important for the maintenance of anterior eye anatomic integrity, minimizing pressure-associated damage to the optic nerve, and maintaining a pressure gradient for blood flow to the eye. IOP is regulated by equilibrium between aqueous humor (AH) production and its outflow. The ciliary body (CB) is thought to actively secrete AH. However, whether AH composition and in particular, its phospholipids are entirely due to CB secretion remains uncertain. Comparison of phospholipids released by cultured CB, phospholipids present within CB tissue, within AH, and within blood and serum are consistent with release of most phospholipids into the AH by the CB. Treatment of CB in culture with timolol, a non-specific beta-adrenergic antagonist, alters the release of phospholipids by CB into the media. However, dorzalamide, a carbonic anhydrase inhibitor that reduces production of AH, does not affect phospholipid release thereby suggesting timolol, which also decreases IOP through decreased AH outflow, affects other physiological homeostatic mechanisms regulating aqueous outflow. These outflow changes also affect the composition of secreted phospholipids. We present evidence that release of lipids by the CB has a prolonged survival effect on cultured primary TM cells and TM tissue.


Menstrual characteristics and night work among nurses.
Night work has been associated with adverse effects in terms of reproductive health. Specifically, menstruation has been suggested to be negatively impacted by night work, which again may influence fertility. This study investigated whether working nights is related to menstrual characteristics and if there is a relationship between shift work disorder (SWD) and menstruation. The study was cross-sectional, response rate 38%. The sample comprised female nurses who were members of the Norwegian Nurses Association; below 50 yr of age, who were not pregnant, did not use hormonal pills or intrauterine devices and who had not reached menopause (n=766). The nurses answered a postal survey including questions about night work and menstrual characteristics. Fifteen per cent reported to have irregular menstruations. Thirty-nine per cent of the nurses were classified as having SWD. Logistic regression analyses concerning the relationship between irregular menstruations and night work did not show any associations. Furthermore, no associations were found between cycle length or bleeding period and night work parameters. No associations were found between menstrual characteristics and SWD.


Regulation of the enzymes converting L-mandelate into benzoate in bacterium N.C.I.B. 8250.
l-Mandelate is oxidized to benzoate by the enzymes l-mandelate dehydrogenase, phenylglyoxylate carboxy-lyase and benzaldehyde dehydrogenase I. Conditions have been established for measuring these three enzymes as well as benzyl alcohol dehydrogenase, benzaldehyde dehydrogenase II and catechol 1,2-oxygenase in a single cell-free extract prepared from bacterium N.C.I.B. 8250. The kinetics of induction of all these enzymes have been measured under a variety of conditions. l-Mandelate dehydrogenase, phenylglyoxylate carboxy-lyase and benzaldehyde dehydrogenase I appear to be co-ordinately regulated because (a) their differential rates of synthesis are proportional to one another under various conditions of induction and repression, (b) they are specifically and gratuitously induced by thiophenoxyacetate and a number of other compounds, and (c) mutant strains have been isolated that lack all three enzymes. Phenylglyoxylate is the primary inducer of the regulon as mutant strains lacking phenylglyoxylate carboxy-lyase form the other two enzymes in the presence of l-mandelate or phenylglyoxylate, whereas in mutant strains devoid of l-mandelate dehydrogenase activity only phenylglyoxylate induces phenylglyoxylate carboxy-lyase and benzaldehyde dehydrogenase I.


Difference of genomic copy numbers alterations between hairy cell leukemia-variant and classical hairy cell leukemia: a pilot retrospective study in Chinese.
Background: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder. It has two pathological subtypes: classical HCL (HCL-C) and HCL-variant (HCL-V). HCL-C and HCL-V are distinct in morphology and immunophenotype. Their differentiation is important for patient management and clinical outcome, with HCL-V responding poorly to conventional HCL treatments. Recently, whole genomic sequencing has been used to identify the difference between HCL-C and HCL-V and mutation of BRAFV600E has been proved to be a molecular hallmark of HCL-C. However, BRAF inhibitors were not effective in all HCL-C cases and HCL-V seems be lack of the high-frequency mutations. Therefore, it is necessary to compare the genomic changes between HCL-C and HCL-V by high-resolution studies, especially in Chinese population, the genomic alterations of HCL have rarely be reported. Methods: In this study, the clinical features of a total of 18 Chinese HCL patients were described. Single nucleotide polymorphism (SNP) array analysis was performed to evaluate the genomic copy number alterations (CNA) and copy neutral loss of heterozygosity (CN-LOH) on six HCL-Vs with CD25-/BRAFV600E- and four HCL-Cs with CD25+/BRAFV600E+. Results: A total of 24 CNAs including seven chromosomal gains and 17 chromosomal losses, and 22 CN-LOHs were revealed. Five of the six cases of HCL-V showed 15 CNAs including four cryptic chromosomal gains and 11 chromosomal losses. Overlapping regions involving micro-deletion of chromosome 2q13 and large chromosomal loss of 14q were showed in HCL-V. In HCL-C, a total of nine CNAs were revealed in three of the four cases including three chromosomal gains and six chromosomal losses. No overlapping area was observed among the CNVs. 15 CN-LOHs were showed in five of the six cases of HCL-V and seven CN-LOHs was demonstrated in all of the four HCL-Cs. Conclusions: Comparing to Westerners, a relatively higher proportion of HCL-V in all HCL is observed in this study. CNAs and CN-LOHs were common in both HCL-V and HCL-C but the CNAs were different in them. HCL-C was characterized with the higher ratio of large chromosomal changes but lacked of recurrent CNAs, while HCL-V was presented with the higher incidence of cryptic CNAs and recurrent CNAs involving tumor-associated genes. It is necessary to further investigate the association of the genes, such as NPHP1 and TRAF3 genes, and HCL-V in the future study.


[Aspects of the development in dysphagia and its functional dynamics].
100 patients (88 women, 12 men) of 16-64 years of age with functional dysphagia were examined. In all the cases the disease develops under the influence of stress in individuals with high anxiety, easy formation of dysthymic, obsessive-phobic reactions in the situation of frustration. Functional dysphagia arises most frequently at the age of 20-40 years. 4 stages pass in the course of the disease: a stage of reactive (neurotic) depression; psychosomatic reactions; psychosomatic cycles (mono- and polysomic); psychopathization. Psychopathization manifests pathologic (psychosomatic) development of personality observed usually in long-term course of dysphagia.


Comparison of palonosetron and ondansetron in preventing postoperative nausea and vomiting in renal transplantation recipients: a randomized clinical trial.
End-stage renal diseases patients have a high risk of postoperative nausea and vomiting (PONV), which is multifactorial and need acute attention after renal transplantation for a successful outcome in term of an uneventful postoperative period. The study was done to compare the efficacy of palonosetron and ondansetron in preventing early and late-onset PONV in live donor renal transplantation recipients (LDRT). The prospective randomized double-blinded study was done on 112 consecutive patients planned for live donor renal transplantation. Patients of both sexes in the age group of 18-60 years were randomly divided into two groups: Group O (Ondansetron) and Group P (Palonosetron) with 56 patients in each group by computer-generated randomization. The study drug was administered intravenously (IV) slowly over 30 seconds, one hour before extubation. Postoperatively, the patients were accessed for PONV at 6, 24, and 72 hours using the Visual Analogue Scale (VAS) nausea score and PONV intensity scale. The incidence of PONV in the study was found to be 30.35%. There was significant difference in incidence of PONV between Group P and Group O at 6 hours (12.5% vs. 32.1%, p = 0.013) and 72 hours (1.8% vs. 33.9%, p < 0.001), but insignificant difference at 24 hours (1.8% vs. 10.7%, p = 0.113). VAS-nausea score was significantly lower in Group P as compared to Group O at a time point of 24 hours (45.54 ± 12.64 vs. 51.96 ± 14.70, p = 0.015) and 72 hours (39.11 ± 10.32 vs. 45.7 ± 15.12, p = 0.015). Palonosetron is clinically superior to ondansetron in preventing early and delayed onset postoperative nausea and vomiting in live-related renal transplant recipients.


Eyelid disorders: recognizing pathologic changes in the older patient.
The eyelids provide a vital function in protecting and cleansing the eye but are also the source of numerous disorders and complaints in your older patients. Clinically, the most important of these problems are suspicious lid lesions that may harbor malignancy, neurologic disorders, and structural malpositions that cause poor lid function and may damage the globe. Many of these disorders require prompt evaluation and often referral to an ophthalmologist for surgical management. Less serious problems such as blepharitis can often be treated in the primary care office setting.


The Use of Operational Excellence Principles in a University Hospital.
The introduction of Operational Excellence in the Maastricht University Medical Center (MUMC+) has been the first of its kind and scale for a university hospital. The policy makers of the MUMC+ have combined different elements from various other business, management, and healthcare philosophies and frameworks into a unique mix. This paper summarizes the journey of developing this system and its most important aspects. Special attention is paid to the role of the operating rooms and the improvements that have taken place there, because of their central role in the working of the hospital. The MUMC+ is the leading tertiary healthcare center for the South-East region of The Netherlands and beyond. Regional, national, and international developments encouraged the MUMC+ to start significantly reorganizing its care processes from 2009 onward. First experiments with Lean Six Sigma and Business Modeling were combined with lessons learned from other centers around the world to form the MUMC+'s own type of Operational Excellence. At the time of writing, many improvement projects of different types have been successfully completed. Every single department in the hospital now uses Operational Excellence and design thinking in general as a method to develop new models of care. An evaluation in 2014 revealed several opportunities for improvement. A large number of projects were in progress, but 75% of all projects had not been completed, despite the first projects being initiated back in 2012. This led to a number of policy changes, mainly focusing on more intensive monitoring of projects and trying to do more improvement projects directly under the responsibility of the line manager. Focusing on patient value, continuous improvement, and the reduction of waste have proven to be very fitting principles for healthcare in general and specifically for application in a university hospital. Approaching improvement at a systems level while directly involving the people on the work floor in observing opportunities for improvement and realizing these has shown itself to be essential.


[High-frequency generator for the electrocoagulation of the brain tissue].
The authors present a wiring diagram of a high frequency generator intended for coagulation of animal tissue. Stabilization of output current and automatic formation of gradual increase, time delay and decrease of load current permits its employment for stereotaxic decerebration of animals with a good recurrence of the results of coagulation and least traumatic effect.


Investigation of guanine-nucleotide-binding protein involvement and regulation of cyclic AMP metabolism in interleukin 1 signal transduction.
The involvement of guanine-nucleotide-binding proteins (G-proteins) and regulation of cyclic AMP (cAMP) in interleukin 1 (IL1) signal transduction has been investigated in EL4 and 7OZ/3 cells expressing Type 1 and Type 2 IL1 receptors respectively. Results show that in both cell types IL1 alone failed to induce changes in cellular cAMP levels, and in membrane preparations the cytokine had no significant effect on adenylate cyclase activity. In contrast, forskolin stimulated cAMP levels in cells and membranes. IL1 did not significantly alter GTPase activity or rate of guanosine 5'-[gamma-[35S]thio]triphosphate binding measured in membrane preparations from the EL4 and 7OZ/3 cells. In EL4-cell membrane preparations the kinetics of 125I-IL1 binding were altered in the presence of guanosine 5'-[beta gamma-imido]triphosphate, resulting in the formation of a higher-affinity state for IL1 binding. Adenosine 5'-[beta gamma-imido]triphosphate at the same concentration was without effect. These results suggest that IL1 receptor function may be regulated by guanine nucleotides; however, the mechanism appears to differ from that exhibited by conventional G-protein-linked receptors. The lack of significant effects of IL1 on cAMP metabolism in these cells suggests that alternative pathways must exist to mediate the intracellular responses to stimulation via both types of the IL1 receptor.


Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway.
Biotin (vitamin B7) is essential for human health because of its involvement, as a cofactor, in a variety of critical cellular metabolic reactions. Previous studies have shown that biotin deficiency enhances inflammation, and certain chronic inflammatory diseases are associated with biotin deficiency; however, the mechanisms that mediate the association between biotin status and inflammation are not well understood. In this study, we examined the effect of biotin deficiency on human CD4+ T cell responses to determine their role in biotin deficiency-associated inflammation. Our investigations revealed that anti-CD3/CD28-stimulated CD4+ T cells cultured in biotin-deficient medium secreted significantly enhanced levels of the proinflammatory cytokines IFN-γ, TNF, and IL-17. Expression of the transcription factors T-bet and RORγt was increased, whereas Foxp3 expression was decreased, in biotin-deficient CD4+ T cells. The percentage of T regulatory cells was also decreased under biotin-deficient condition. A similar increase in T-bet, RORγt, and proinflammatory cytokine levels, as well as a decrease in Foxp3, was observed in inguinal lymph nodes of mice fed a biotin-deficient diet relative to pair-fed controls. Furthermore, differentiation of CD4+ T cells toward Th1 and Th17 cells was also enhanced. In vitro and in vivo investigations indicated that the increased inflammatory response was due to enhanced activation of the mammalian target of rapamycin signaling pathway in biotin-deficient CD4+ T cells. In summary, these results demonstrate that biotin deficiency enhances the inflammatory responses in CD4+ T cells, which may contribute to inflammation associated with biotin deficiency.


Intractable muscle pain syndrome, osteomalacia, and axonopathy in long-term use of phenytoin.
Muscle pain syndrome is a complicated situation in that even an extensive work-up may overlook the primary etiology. A patient with multiple medical problems, including a history of partial gastrectomy due to trauma, a below-knee amputation from arteriosclerotic disease, and chronic phenytoin therapy for a seizure disorder, developed intractable, generalized muscle pain, with total dependency in mobility and self care. He was admitted to an acute care hospital and was eventually discharged with a diagnosis of occult malignancy. After being referred to our amputee clinic for prosthetic management, the patient was admitted for inpatient rehabilitation. Electrodiagnostic studies and muscle biopsy revealed typical neuropathic findings and nonspecific myopathic changes. Laboratory studies showed a vitamin D deficiency with secondary hyperparathyroidism. Discontinuation of phenytoin and treatment with calcium and vitamin D resulted in rapid relief of muscle pain and marked improvement in mobility and self care. This case illustrates an unusual combination of phenytoin-induced axonopathy and osteomalacia that incapacitated an otherwise functional person with below-knee amputation.


How a better understanding of transformational leadership can help improve your practice as a nurse administrator.
Nursing administrators of today find themselves practising in an environment of permanent whitewater--an environment of chaotic change. Not only is the environment changing, so too are our employees: their needs, motives and priorities are vastly different than those we knew 20 years ago. The challenges of permanent whitewater cannot be overcome without effective leadership. Theorists agree that most North American organizations are currently overmanaged and underled. Certainly the leadership record of Canadian health care institutions has not been impressive. This paper will examine a selected set of concepts which the author believes are essential for nursing administrators who wish to provide real leadership to their departments and organizations: transformational (as compared to transactional) leadership; feminine (as compared to masculine) leadership; and empowerment. The literature review draws out both theory and practical applications.


Acute brucellosis presenting as leukocytoclastic vasculitis.
We present the case of a 64 year-old-male fur trader from Lerida (Spain), who consulted us because of a 2-week history of night fever and the presence of non-pruritic purpuric lesions on the distal third of the lower limbs. Laboratory findings demonstrated positive serology for brucellosis and cutaneous biopsy showed leukocytoclastic vasculitis. The pathogenesis of the cutaneous process is discussed. We also suggest that brucellosis should be included among the infections taken into account in patients suffering from leukocytoclastic vasculitis coming from brucella-endemic areas.


[Color flow duplex ultrasonography is an effective alternative method].
Increasing use of percutaneous interventional cardiac and peripheral arterial procedures has resulted in high incidence of femoral pseudoaneurysms. This case report presents a 68 year-old male with a femoral pseudoaneurysms after percutaneous iliac transluminal angioplasty, who was treated with ultrasound guided compression successfully. Although surgical procedures are widely performed in Turkey, it should be kept in mind that compression therapy is effective and may present as an initial step in the management of femoral pseudoaneurysms.


Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist.
In contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides (Bicycles). Phage libraries displaying Bicycles were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40 Bicycles were chemically conjugated to tumor antigen Bicycles with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW <8 kDa). The TICAs were evaluated in a suite of in vitro and in vivo assays to characterize their pharmacology and mechanism of action. Linking Bicycles against costimulatory receptors (e.g., CD137) to Bicycles against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presence of tumor cells expressing these antigens. An EphA2/CD137 TICA (BCY12491) efficiently costimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2 expressing tumor cell lines as measured by the increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice transgenic for the human CD137 extracellular domain (huCD137) bearing EphA2-expressing MC38 tumors with BCY12491 resulted in the infiltration of CD8+ T cells, elimination of tumors and generation of immunological memory. BCY12491 was cleared quickly from the circulation (plasma t1/2 in mice of 1-2 hr), yet intermittent dosing proved effective. Tumor target-dependent CD137 agonism using a novel chemical approach (TICAs) afforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.