Radiation exposure in high resolution computed tomography of the spine.
From all the available radiodiagnostic procedures for diagnosing spinal disorders (conventional tomography, myelography, CT), high-resolution, thin-slice computer tomography presents the highest radiation exposure as represented by the somatic dose index. It allows, however, the retrospective computer reformatting of axial slices into secondary slices of any projection desired. To obtain this extra information with conventional tomography would require further exposures in the desired projections and/or thinner slices. But there is a great amount of important diagnostic information that plays a decisive role in the choice of the form of therapy and the preoperative planning of surgical which cannot be obtained by conventional radiological procedures.


Was there a significant difference in sleep shifts in the high school population due to the COVID-19 pandemic depending on chronotype? A nationwide cross-sectional study.
The aim of this study was to detect whether the COVID-19 pandemic has caused changes in the sleep cycle (subjective sleep shifts) of high school students divided into a sample of young women - W (n = 1999, age = 17.65 ± 2.39 y) and young men - M (n = 1094, age = 17.49 ± 1.74 y) in Slovakia depending on circadian preference in comparison with the term before COVID-19. The present cross-sectional study employed a self-reported standardized questionnaire (Morningness-Eveningness Questionnaire) to study circadian preference, which was complemented by a question focused on subjective sleep shifts before and during the pandemic. The results revealed significant strong dependence between circadian preference and subjective sleep shift in both W (χ2(8) = 153.1, p < .01, Cramer's V = .20, p < .01) and M (χ2(8) = 98.3, p < .01, Cramer's V =.21, p < .01). The delay of the sleep cycle has mainly become apparent in the case of definite evening types (W: 75.7%; M: 71.8%) and moderate evening types (W: 83.1%; M: 70.3%). The delay also prevailed in the intermediate types (W: 61.9%; M: 53.8%). Subjective sleep shifts were not confirmed (W: 93.8%; M: 35.3%) in the definite morning type. The sleep cycle was changed to earlier hours of definite morning types (W: 6.3%; M: 52.9%). It is necessary to focus on definite and moderate evening types and regulate the unsuitable state to time shift of the sleep cycle.


Radiation Dose Optimization in Pediatric Chest CT: Major Indicators of Dose Exposure in 1695 CT Scans over Seven Years.
To analyze possible influencing factors on radiation exposure in pediatric chest CT using different approaches for radiation dose optimization and to determine major indicators for dose development. In this retrospective study at a clinic with maximum care facilities including pediatric radiology, 1695 chest CT examinations in 768 patients (median age: 10 years; range: 2 days to 17.9 years) were analyzed. Volume CT dose indices, effective dose, size-specific dose estimate, automatic dose modulation (AEC), and high-pitch protocols (pitch ≥ 3.0) were evaluated by univariate analysis. The image quality of low-dose examinations was compared to higher dose protocols by non-inferiority testing. Median dose-specific values annually decreased by an average of 12 %. High-pitch mode (n = 414) resulted in lower dose parameters (p < 0.001). In unenhanced CT, AEC delivered higher dose values compared to scans with fixed parameters (p < 0.001). In contrast-enhanced CT, the use of AEC yielded a significantly lower radiation dose only in patients older than 16 years (p = 0.04). In the age group 6 to 15 years, the values were higher (p < 0.001). The diagnostic image quality of low-dose scans was non-inferior to high-dose scans (2.18 vs. 2.14). Radiation dose of chest CT was reduced without loss of image quality in the last decade. High-pitch scanning was an independent factor in this context. Dose reduction by AEC was limited and only relevant for patients over 16 years. · The radiation dose of pediatric chest CT was reduced in the last decade.. · High-pitch scanning is an independent factor of dose optimization.. · Dose reduction by AEC is limited and only relevant for older children.. · Esser M, Hess S, Teufel M et al. Radiation Dose Optimization in Pediatric Chest CT: Major Indicators of Dose Exposure in 1695 CT Scans over Seven Years. Fortschr Röntgenstr 2018; 190: 1131 - 1140.


Mechanisms of Traditional Chinese Medicine in the Treatment of Mammary Gland Hyperplasia.
Mammary gland hyperplasia (MGH) occurs with high frequency among middle-aged women and is closely related to breast cancer. The treatment of this disease has become a research hotspot. Many patients with MGH are worried about the potential side effects of the synthetic drugs they are on. Thus, they seek alternative therapy, such as traditional Chinese medicine (TCM). In recent years, along with the Chinese herbs and its active ingredients, TCM compounds have been widely accepted and implemented in the treatment of MGH, whose mechanism hitherto is not completely clear. In this paper, we elaborate the mechanism of TCM in the treatment of MGH from the perspectives of sexual hormone levels, the expression of ER and PR, hemorheology, free radical activity and lipid peroxidation, VEGF and BFGF, cell proliferation activities, anti-apoptosis gene BcL-2, promoting apoptosis gene Bax, ERK, and tumor suppressor gene. In conclusion, TCM appears to be promising for MGH treatment. This paper will provide an overview of the mechanism of TCM in the treatment of MGH. In the near term, a better understanding of TCM will be achieved through comprehensive studies of its molecular mechanism.


A knowledge management framework to morph clinical cases with clinical practice guidelines.
In this paper we present a knowledge management framework that allows the automatic linking/mapping of contextually and functionally similar medical knowledge that may originate from different sources and be represented in diverse modalities. Our tacit-explicit knowledge morphing framework supports the extraction of tacit knowledge from past cases stored in a case-base and maps it to corresponding explicit knowledge stored in clinical practice guidelines. The novelty of our approach is inherent in the fact that it allows practitioners to simultaneously refer to explicit knowledge-i.e. clinical practice guidelines-and experiential knowledge-i.e. past clinical cases. Here we present the system design and intended functionality of our knowledge morphing framework.


Opportunistic infections in renal allograft recipients.
The risk of opportunistic infection in the renal transplant patient is due to an interaction between two major factors: the epidemiologic exposures (particularly within the hospital environment) and the net state of immunosuppression. The net state of immunosuppression is determined by the nature, dose, and duration of the immunosuppressive therapy being administered; the presence or absence of granulocytopenia and technical factors that could compromise the primary mucocutaneous barriers to infection; such metabolic factors as uremia, hyperglycemia, and the state of nutrition; and, finally, the immunomodulating effects of such viruses as CMV, the hepatitis viruses, and HIV. The major types of opportunistic infection to which the renal transplant patient is susceptible are the following: the viruses of the herpes group and papovaviruses; bacteria such as L monocytogenes, N asteroides, and Legionella; such fungi as Candida, Aspergillus, C neoformans, and the Mucoraceae; and protozoans such as P carinii, S stercoralis, and T gondii.


Angiogenic microvascular endothelial cells release microparticles rich in tissue factor that promotes postischemic collateral vessel formation.
Therapeutic angiogenesis is a promising strategy for treating ischemia. Our previous work showed that endogenous endothelial tissue factor (TF) expression induces intracrine signaling and switches-on angiogenesis in microvascular endothelial cells (mECs). We have hypothesized that activated mECs could exert a further paracrine regulation through the release of TF-rich microvascular endothelial microparticles (mEMPs) and induce neovascularization of ischemic tissues. Here, we describe for the first time that activated mECs are able to induce reparative neovascularization in ischemic zones by releasing TF-rich microparticles. We show in vitro and in vivo that mEMPs released by both wild-type and TF-upregulated-mECs induce angiogenesis and collateral vessel formation, whereas TF-poor mEMPs derived from TF-silenced mECs are not able to trigger angiogenesis. Isolated TF-bearing mEMPs delivered to nonperfused adductor muscles in a murine hindlimb ischemia model enhance collateral flow and capillary formation evidenced by MRI. TF-bearing mEMPs increase angiogenesis operating via paracrine regulation of neighboring endothelial cells, signaling through the β1-integrin pathway Rac1-ERK1/2-ETS1 and triggering CCL2 (chemokine [C-C motif] ligand 2) production to form new and competent mature neovessels. These findings demonstrate that TF-rich mEMPs released by microvascular endothelial cells can overcome the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization and tissue reperfusion.


Psychological morbidity and caregiver burden in parents of children with Tourette's disorder and psychiatric comorbidity.
To investigate the mental health and caregiver burden in parents of children with Tourette's disorder (TD) compared with parents of children with asthma. A cross-sectional cohort survey was conducted at TD and pediatric asthma hospital outpatient clinics over a 6-month period. Main outcome measures were parent mental health (General Health Questionnaire [GHQ]-28) and caregiver burden (Child and Adolescent Impact Assessment) scores. The response rate achieved was 89.7%. Of the parents of children with TD, 76.9% achieved caseness on the GHQ-28 compared with 34.6% of the parents of children with asthma; this effect remained significant after controlling for demographic variables. Parents of children with TD also experienced greater caregiver burden, and this burden was significantly correlated with GHQ caseness. Parents of children with TD are at risk of psychiatric morbidity; an intervention targeting caregiver burden might be helpful in reducing this.


Depth profiling of calcifications in breast tissue using picosecond Kerr-gated Raman spectroscopy.
Breast calcifications are found in both benign and malignant lesions and their composition can indicate the disease state. Calcium oxalate (dihydrate) (COD) is associated with benign lesions, however calcium hydroxyapatite (HAP) is found mainly in proliferative lesions including carcinoma. The diagnostic practices of mammography and histopathology examine the morphology of the specimen. They can not reliably distinguish between the two types of calcification, which may indicate the presence of a cancerous lesion during mammography. We demonstrate for the first time that Kerr-gated Raman spectroscopy is capable of non-destructive probing of sufficient biochemical information from calcifications buried within tissue, and this information can potentially be used as a first step in identifying the type of lesion. The method uses a picosecond pulsed laser combined with fast temporal gating of Raman scattered light to enable spectra to be collected from a specific depth within scattering media by collecting signals emerging from the sample at a given time delay following the laser pulse. Spectra characteristic of both HAP and COD were obtained at depths of up to 0.96 mm, in both chicken breast and fatty tissue; and normal and cancerous human breast by utilising different time delays. This presents great potential for the use of Raman spectroscopy as an adjunct to mammography in the early diagnosis of breast cancer.


Mitochondria, oxidative stress and neurodegeneration.
Mitochondria are involved in ATP supply to cells through oxidative phosphorylation (OXPHOS), synthesis of key molecules and response to oxidative stress, as well as in apoptosis. They contain many redox enzymes and naturally occurring inefficiencies of oxidative phosphorylation generate reactive oxygen species (ROS). CNS functions depend heavily on efficient mitochondrial function, since brain tissue has a high energy demand. Mutations in mitochondrial DNA (mtDNA), generation and presence of ROS and environmental factors may contribute to energy failure and lead to neurodegenerative diseases. Many rare metabolic disorders have been associated with mitochondrial dysfunction. More than 300 pathogenic mtDNA mutations involve proteins that regulate OXPHOS and mitochondrial structural integrity, and have also been described in neurodegenerative diseases with autosomal inheritance. Mitochondria may have an important role in ageing-related neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In primary mitochondrial and neurodegenerative disorders, there is strong evidence that mitochondrial dysfunction occurs early and has a primary role in pathogenesis. In the present review, we discuss several mitochondrial diseases as models of neurodegeneration.


Cutaneous manifestations in a series of 417 patients with SARS-CoV-2 infection: epidemiological and clinical correlates of chilblain like lesions.
A variety of dermatological lesions have been described in COVID-19, although the prevalence and pathogenic relationship remain unclear particularly for chilblain-like lesions. Dermatological examination was performed in a prospective cohort of consecutive patients seen at the service for SARS-CoV-2 infection. Out of 417 patients with confirmed SARS-CoV-2 infection [median age 29.5 years (range 15-65); 62.5% males], dermatological lesions were detected in 7 (1.7%). Three patients had acral lesions; their age (range) was 15-29 years; all had a negative nasopharyngeal swab and developed IgG and/or IgM-specific antibodies; all presented none or mild symptoms. A fourth patient remained negative at repeated testing; mother, father and sister had a documented mild COVID-19. Non-acral lesions were observed in four older patients, with severe COVID-19. Chilblain-like lesions may be the sole manifestation of SARS-CoV-2 infection; their presence in asymptomatic school children and adolescents should be considered a potential signal of familial or community spread of the virus.


A myelin sheath protein forming its lattice.
The formation of a mature, multilayered myelin sheath requires the compaction of lipid bilayers, but the molecular mechanism by which these bilayers condense is an open question. In this issue, Ruskamo et al. find that peripheral myelin protein P2 forms an ordered three-dimensional lattice within model membranes using Escherichia coli polar lipid liposomes. These data will help to understand the assembly, function, and structure of the myelin sheath.


ABO-incompatible heart transplantation: crossing the immunological barrier.
Due to the shortage of organ donors, heart transplantation cannot be offered to many infants with end-stage heart failure; this issue leads to mortality rates of 30-50% in patients in the paediatric age group awaiting operation. ABO-incompatible heart transplantation has been performed safely with no particular or invasive preparatory procedures other than plasma exchange during cardiopulmonary bypass for removing preformed antibodies, with no reports of hyperacute rejection. We report our first clinical experience of heart transplantation on a 2-month-old-infant (blood group O), diagnosed with intracardiac tumour, in which the donor was a 19-day-old newborn of blood group A. Sharing the know-how about ABO-incompatible heart transplantation in newborns and infants awaiting transplantation will help in decreasing mortality among this group of patients.


Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis.
The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-gamma production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.


Laparoscopic Ventral Mesh Rectopexy (LVMR) for Internal and External Rectal Prolapse: An Analysis of 122 Consecutive Patients.
Even though several reports have been published on the results of laparoscopic ventral mesh rectopexy (LVMR) in Asia, there are few mid-term or long-term results of LVMR. The authors aimed to evaluate the results of LVMR in patients with internal rectal prolapse (IRP) external rectal prolapse (ERP). From September 2013 to January 2019, 122 patients with IRP (n=48) or ERP (n=74) underwent LVMR. Constipation and fecal incontinence (FI) scores were evaluated using the Cleveland Clinic Florida score preoperatively and postoperatively. The questionnaire for the change of obstructed defecation or FI symptoms after surgery was also administered to grade the results as cured, improved, unchanged, or worsened for each survey. The mean age of the patients was 61.9 years. The mean operation time was 116.5 minutes, and the mean hospital stay was 5.1 days. The mean follow-up was 42.1 months. There were no mesh-related complications. Eight patients (10.7%) among the ERP group required additional surgery for recurrent full-thickness prolapse. Eleven patients (14.7%) who had mucosal prolapse within 2 cm underwent stapled hemorrhoidopexy after LVMR. In the postoperative 6-month period, the overall constipation score (7.12) significantly improved compared with the preoperative score (13.03) (P<0.001), whereas the FI score significantly improved after surgery (12.16 to 8.92; P<0.001). LVMR is a feasible and safe technique and favorable recurrence for ERP. Functional outcomes of obstructed defecation and FI were improved and the satisfaction of LVMR was high after the surgery. LVMR can be considered a recommended surgical option to treat ERP and IRP.


Value of the ERG in congenital nystagmus.
A group of 64 children with poor vision and early onset nystagmus were investigated retrospectively by the electroretinogram (ERG). Fifty-eight of these children also underwent analysis of the visual evoked potential (VEP), and 40 underwent colour vision analysis. Seventeen children were found to have complete congenital achromatopsia (rod monochromatism), being identified by their total colour blindness, reduced visual acuity, and reduced or absent photopic and flicker (30 Hz) ERGs. Two children with incomplete X-linked congenital achromatopsia were also found. This study identified the need to investigate children with nystagmus by means of the ERG and suggested that the ERG was useful where the diagnosis was uncertain, particularly at early school age. The incidence of congenital achromatopsia in a group of otherwise undiagnosed children with early onset nystagmus was high (29%), with 40% being classified as having congenital idiopathic nystagmus.


The epidemiology of atherosclerosis in 1987: unraveling a common-source epidemic.
Epidemiologists studying the risk factors of coronary heart disease, as indicated by a heart attack, often presume that these risk factors combine in a susceptible host to increase the risk of the heart attack. The "biological" basis for the interaction of the key risk factors is often not considered in the analysis. A more rational model for the study of clinical heart disease, stroke, and peripheral vascular disease would be to separate the epidemiology of atherosclerosis from that of the clinical event. In the past, this has been extremely difficult because of the absence of techniques for the measurement of atherosclerosis in vivo, especially in well-defined populations. However, in recent years, greater emphasis on the quantification of atherosclerosis and its relationship to specific risk factors has improved our ability to study the underlying pathology that is atherosclerosis. Atherosclerosis is an example of a common-source epidemic. The environmental agent is the intake of cholesterol and saturated fat. The interaction of specific dietary factors and genetic determinants is the key to the evolution of atherosclerosis. There are marked variations in the evolution of the disease in different vascular beds as well as among individuals exposed to similar environmental factors. In the future, we will probably be able to study atherosclerosis as a continuous variable in populations and to relate the rate of progression, the extent of disease at any point in time, and topical distribution of atherosclerosis within individual vascular beds to specific genetic and environmental determinants.


Breathing on chip: Dynamic flow and stretch accelerate mucociliary maturation of airway epithelium in vitro.
Human lung function is intricately linked to blood flow and breathing cycles, but it remains unknown how these dynamic cues shape human airway epithelial biology. Here we report a state-of-the-art protocol for studying the effects of dynamic medium and airflow as well as stretch on human primary airway epithelial cell differentiation and maturation, including mucociliary clearance, using an organ-on-chip device. Perfused epithelial cell cultures displayed accelerated maturation and polarization of mucociliary clearance, and changes in specific cell-types when compared to traditional (static) culture methods. Additional application of airflow and stretch to the airway chip resulted in an increase in polarization of mucociliary clearance towards the applied flow, reduced baseline secretion of interleukin-8 and other inflammatory proteins, and reduced gene expression of matrix metalloproteinase (MMP) 9, fibronectin, and other extracellular matrix factors. These results indicate that breathing-like mechanical stimuli are important modulators of airway epithelial cell differentiation and maturation and that their fine-tuned application could generate models of specific epithelial pathologies, including mucociliary (dys)function.


[Evaluation of antioxidant activity of Radix Linderae and other two Chinese drugs using TLC-bioautography].
To evaluate the antioxidant capacity and quality of traditional Chinese medicines using TLC-bioautography. Two chromatograms of each crude drug sample were obtained, after developing, by spraying with 1,1-diphenyl-2-picrylhydrazyl (DPPH) solution in ethanol and classical stained reagents, separately. The images sprayed with DPPH solution were captured under light after the plates were heated at 40 degrees C for 30 min, and scanned using video scan software to get peak areas of active compounds. Total peak areas of the spots on TLC were calculated to evaluate the antioxidant capacity of the tested crude drugs from different habitats and sources. The results indicated that Radix Linderae cultivated in Tiantai (Zhejiang province), Cortex Magnoliae Officinalis cultivated in Liangshan (Sichuan province), and Fructus Perillae acquired in Shanghai have the highest scavenging properties towards DPPH in their respective TLC-autographic assays. Norisoboldine, magnolol and honokiol, luteolin, apigenin and an unknown compound "U" proved to be the major antioxidant components in the corresponding crude drugs as they contribute the dominating peak areas to the total ones. TLC-bioautography can not only be used for screening of the components with antioxidant potency but also for the purpose of quality evaluation of traditional Chinese medicines at the same time, and the method proved to be selective, simple and reproducible.


Low-dose lipopolysaccharide protects nerve cells against spinal cord injury via regulating the PI3K-AKT-Nrf2 signaling pathway.
This study explored the molecular mechanism behind the protective effects from low-dose lipopolysaccharide (LPS) on an in-vitro model of spinal cord injury (SCI). For this, PC12 cells were treated with different concentrations of LPS and the cell counting kit-8 assay was used to measure the toxicity of LPS to the cells. Next, we used immunofluorescence to measure nuclear translocation of Nrf2 in PC12 cells. PC12 cells were then treated with IGF-1 (PI3K agonist) and LY294002 (PI3K inhibitor). An in-vitro model of SCI was then established via oxygen-glucose deprivation/reoxygenation. Rates of apoptosis were measured using flow cytometry and the TUNEL assay. Low-dose LPS increased the expression levels of Nrf2, p-PI3K/PI3K, and p-AKT/AKT, and facilitated nuclear translocation of Nrf2. The activation of PI3K-AKT signaling by IGF-1 significantly increased the expression of Nrf2, whereas inhibition of PI3K-AKT signaling significantly decreased the expression of Nrf2. Low-dose LPS reduced the apoptotic ratio of PC12 cells, decreased the expression levels of caspase 3 and caspase 9, and increased the expression levels of HO-1, NQO1, and γ-GCS. Low-dose LPS also reduced the rate of apoptosis and oxidative stress by activating the PI3K-AKT-Nrf2 signaling pathway. Collectively, the results indicate that PI3K-AKT-Nrf2 signaling participates in the protective effects from low-dose LPS in an in-vitro PC12 cell model of SCI.


Sterile pyuria in patients admitted to the hospital with infections outside of the urinary tract.
The objective of this study was to determine the incidence, associations, evaluation, and management of pyuria in patients admitted to the hospital with nonurinary infections. This study abstracted inpatient records of consecutive patients hospitalized for pneumonia, intra-abdominal infections, female genital tract infections (GYN infections), bacterial septicemia, and enteritis in the pediatric and adult medical and surgical units at an academic medical center. The study population included 210 patients (66 children; 144 adults). Nearly one-third had ≥5 white blood cells (WBCs) per high-power field (pyuria). Pyuria was more common in women (P < .001) and in patients with GYN infections (P = .001) and less common in patients with pneumonia (P < .001). Cultures were performed on 18 of 19 children (94.7%) and 26 of 43 adults (60.5%) with pyuria. Of those, 11.1% of children and 42.1% of adults had a positive culture, and all but one of those met criteria for a urinary tract infection. Excluding patients with GYN infections, only 18.8% of patients with pyuria had a positive culture. Of the 44 patients with pyuria who were cultured, a positive culture was associated with having a GYN infection (P = .01), moderate or large amounts of bacteria in the urine (P = .005), and a positive urine nitrite (P = .004). The absolute number of WBCs or red blood cells in the urine and the presence of casts, proteinuria, and leukocyte esterase were not associated with positive culture or urinary tract infection. Neither pyuria nor a positive culture was related to temperature, systemic WBC count, or serum albumin, blood urea nitrogen, or creatinine. Sterile pyuria of uncertain cause is common in patients admitted to the hospital with acute nonurinary infections.


Recommended Protocol for Round Robin Studies in Additive Manufacturing.
One way to improve confidence and encourage proliferation of additive manufacturing (AM) technologies and parts is by generating more high quality data describing the performance of AM processes and parts. Many in the AM community see round robin studies as a way to generate large data sets while distributing the cost among the participants, thereby reducing the cost to individual users. The National Institute of Standards and Technology (NIST) has conducted and participated in several of these AM round robin studies. While the results of these studies are interesting and informative, many of the lessons learned in conducting these studies concern the logistics and methods of the study and unique issues presented by AM. Existing standards for conducting interlaboratory studies of measurement methods, along with NIST's experience, form the basis for recommended protocols for conducting AM round robin studies. The role of round robin studies in AM qualification, some of the limitations of round robin studies, and the potential benefit of less formal collaborative experiments where multiple factors, AM machine being only one, are varied simultaneously are also discussed.


[Prediction of the maintenance dose of vecuronium for continuous infusion].
The purpose of this study is to examine how to predict the optimal maintenance dose of vecuronium for continuous infusion, knowing the recovery time from the block induced by the first bolus injection. All patients studied were undergoing surgical procedures and were anesthetized using thiopental, vecuronium, 50% nitrous oxide and 2% enflurane in oxygen. Mechanical twitch responses of adductor pollicis muscle caused by the stimulation of the ulnar nerve supramaximally were monitored. Vecuronium concentrations in the plasma were measured using high performance liquid chromatography. The experiments consisted of two phases. Phase 1.: To demonstrate the relationship between the recovery time (T0-T25) and the maintenance dose. Thirty patients were studied in this phase. A bolus injection was given as the first dose (1.5 mg.kg-1). During the recovery from the first block, recovery time (T1) was measured and the second dose (2 mg) was injected at the T25 (25% control twitch height). After waiting the recovery until the T25, the third dose (2 mg) was injected. The duration (T2) (min) between the second and the third injection was measured. The maintenance dose-recovery time curve was obtained. Y = 52.70.exp (-17.50 X) + 1224.53.exp (-224.27X), X = recovery time (min), Y = maintenance dose (mg.hr-1). Phase 2.: Thirty patients were studied in this phase. Patients received infusions after the bolus injection. The infusion rates were obtained from the maintenance dose-recovery time curve.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of Mixture of Recombinant Human Bone Morphogenic Protein-2 and demineralized Bone Matrix in Lateral Lumbar Interbody Fusion.
This study aims to determine the optimal dose of recombinant-human Bone Morphogenic Protein-2 (rhBMP-2) for successful bone fusion in minimally invasive Lateral Lumbar Interbody Fusion (MIS LLIF). Previous studies show that rh-BMP is an effective alternative to autologous iliac crest bone graft, but the optimal dose remains uncertain. The study analyzes the fusion rates associated with different rh-BMP doses to provide a recommendation for the optimal dose in MIS LLIF. 93 patients underwent MIS LLIF using demineralized bone matrix (DBM) or a mixture of rhBMP-2 and DBM as fusion material. The group was divided into the following three groups according to the rhBMP-2 usage. Group A (only DBM was used, n: 27). Group B (1mg of rhBMP-2 per 5cc of DBM paste, n: 41). Group C (2mg of rhBMP-2 per 5cc of DBM paste, n: 25). Demographic data, clinical outcomes, postoperative complication and fusion were assessed. At 12 months post-surgery, the overall fusion rate was 92.3% according to Bridwell fusion grading system. Group B and C, who received rhBMP-2, had significantly higher fusion rates than group A, who received only DBM. However, there was no significant increase in fusion rate when the rhBMP-2 dosage was increased from group B to group C. The group B and C showed significant improvement in back pain and ODI compared to the group A. The incidence of screw loosening was decreased in group B and C, but there was no significant difference in the occurrence of other complications. Usage of rhBMP-2 in LLIF surgery leads to early and increased final fusion rates, which can result in faster pain relief and return to daily activities for patients. The benefits of using rhBMP-2 were not significantly different between the groups that received 1mg/5cc and 2mg/5cc of rhBMP-2. Therefore, it is recommended to use 1mg of rhBMP-2 with 5cc of DBM, taking both economic and clinical aspects into consideration.


Microscale polymer-nanotube composites.
Polymer colloids with an interfacial coating of purified single-wall carbon nanotubes (SWCNTs) are synthesized from length- and type-sorted SWCNTs. Aqueous nanotube suspensions sorted through density-gradient ultracentrifugation are used to emulsify spherical polymer colloids of microscale dimensions that are characterized through a combination of optical microscopy, transmission electron microscopy, and impedance spectroscopy. The SWCNT-polymer composite particles exhibit electrical conductivities comparable to or better than those of bulk SWCNT-polymer composites at nanotube loadings of more than 1 order of magnitude lower. The composite particles retain the unique electronic and optical characteristics of the parent SWCNT solution with potential applications as microelectronic and microoptical components.


Experimental verification of the Acuros XB and AAA dose calculation adjacent to heterogeneous media for IMRT and RapidArc of nasopharygeal carcinoma.
To compare the doses calculated by the Acuros XB (AXB) algorithm and analytical anisotropic algorithm (AAA) with experimentally measured data adjacent to and within heterogeneous medium using intensity modulated radiation therapy (IMRT) and RapidArc(®) (RA) volumetric arc therapy plans for nasopharygeal carcinoma (NPC). Two-dimensional dose distribution immediately adjacent to both air and bone inserts of a rectangular tissue equivalent phantom irradiated using IMRT and RA plans for NPC cases were measured with GafChromic(®) EBT3 films. Doses near and within the nasopharygeal (NP) region of an anthropomorphic phantom containing heterogeneous medium were also measured with thermoluminescent dosimeters (TLD) and EBT3 films. The measured data were then compared with the data calculated by AAA and AXB. For AXB, dose calculations were performed using both dose-to-medium (AXB_Dm) and dose-to-water (AXB_Dw) options. Furthermore, target dose differences between AAA and AXB were analyzed for the corresponding real patients. The comparison of real patient plans was performed by stratifying the targets into components of different densities, including tissue, bone, and air. For the verification of planar dose distribution adjacent to air and bone using the rectangular phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 98.7%, 99.5%, and 97.7% on the axial plane for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans, while they were 97.6%, 98.2%, and 97.7%, respectively, on the coronal plane. For the verification of planar dose distribution within the NP region of the anthropomorphic phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 95.1%, 91.3%, and 99.0% for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans. Within the NP region where air and bone were present, the film measurements represented the dose close to unit density water in a heterogeneous medium, produced the best agreement with the AXB_Dw. For the verification of point doses within the target using TLD in the anthropomorphic phantom, the absolute percentage deviations between the calculated and measured data when averaged over all IMRT and RA plans were 1.8%, 1.7%, and 1.8% for AAA, AXB_Dm and AXB_Dw, respectively. From all the verification results, no significant difference was found between the IMRT and RA plans. The target dose analysis of the real patient plans showed that the discrepancies in mean doses to the PTV component in tissue among the three dose calculation options were within 2%, but up to about 4% in the bone content, with AXB_Dm giving the lowest values and AXB_Dw giving the highest values. In general, the verification measurements demonstrated that both algorithms produced acceptable accuracy when compared to the measured data. GafChromic(®) film results indicated that AXB produced slightly better accuracy compared to AAA for dose calculation adjacent to and within the heterogeneous media. Users should be aware of the differences in calculated target doses between options AXB_Dm and AXB_Dw, especially in bone, for IMRT and RA in NPC cases.


Alteration of testicular response to long photoperiod by transient exposure to short photoperiod in collared lemmings (Dicrostonyx groenlandicus).
The reproductive response of collared lemmings (Dicrostonyx groenlandicus) to photoperiod is unique for rodents. Whereas most reproductively photoresponsive rodents show maximal gonadal growth when exposed to long photoperiod (long day), collared lemmings show delayed maturation when born and maintained under this condition. However, transfer of lemmings from short photoperiod (short day) to long day results in maximal gonadal growth, indicating that the response to long day depends upon photoperiod history. We hypothesized that the slowing of maturation observed in animals born and maintained on long day reflects an inability to respond fully to long day, resulting from the absence of previous exposure to short day. To determine whether young lemmings born in long day are capable of being stimulated by long day, we exposed them at weaning (19 days of age) to 1, 6 or 10 weeks of short day, and then challenged them with a second exposure to long day. Relative to animals transferred permanently to short day at weaning, lemmings exposed to 6 weeks of short day showed accelerated gonadal growth after both 5 and 10 weeks of subsequent exposure to long day, and those exposed to 10 weeks of short day had larger testes after 6 weeks of long day. Thus, during transient exposure to short day, the animals acquired sensitivity to the stimulatory effects of long day. The responses of body mass, bifid claw width and pelage colour to the photoperiod manipulations did not parallel that of the gonads, indicating independent regulation of somatic and reproductive parameters. The unique way in which the reproductive system of collared lemmings responds to photoperiod may reflect evolution in an environment where the production of offspring during periods of unchanging long day (for example, the Arctic summer) is not selectively advantageous.


Switching diseased cells from cytosolic aerobic glycolysis to mitochondrial oxidative phosphorylation: A metabolic rhythm regulated by melatonin?
This commentary reviews the concept of the circadian melatonin rhythm playing an essential role in reducing the development of diseases such as solid tumors which adopt cytosolic aerobic glycolysis (Warburg effect) to support their enhanced metabolism. Experimental data show that solid mammary tumors depend on aerobic glycolysis during the day but likely revert to mitochondrial oxidative phosphorylation at night for ATP production. This conversion of diseased cells during the day to a healthier phenotype at night occurs under control of the circulating melatonin rhythm. When the nocturnal melatonin rise is inhibited by light exposure at night, cancer cells function in the diseased state 24/7. The ability of melatonin to switch cancer cells as well as other diseased cells, for example, Alzheimer disease, fibrosis, hyperactivation of macrophages, etc, from aerobic glycolysis to mitochondrial oxidative phosphorylation may be a basic protective mechanism to reduce pathologies.


Characteristics of physician addicts.
This article attempts to characterize the physician addict and to challenge the usual sociological or psychological explanations of differences and similarities among addicts. Using available data on Quebec physicians, two types of physician addicts are described according to the "two diseases model." In its first form the disease is characterized by the search of euphoria, and as such is considered to be highly contagious and pernicious, while the other is rarely contagious and relatively less pernicious.


Fluctuating odontometric asymmetry in an urban South African black population.
The magnitude of fluctuating odontometric asymmetry is reported for a group of 106 urban South African Blacks by use of re-scaled asymmetry values and Euclidean map analyses. When these results were contrasted with those reported for South African Caucasoids and Paraguayan Lengua Indians, Blacks were found to be significantly more asymmetric. It is suggested that the disproportionately high levels of dental asymmetry may be ascribed to the high disease and malnutrition burden of South African Blacks and to decreased individual buffering ability. The present study failed to support Garn's model of x-chromosomal odontogenetic buffering in females, and also failed to confirm significant arcadal differences in the magnitude of fluctuating odontometric asymmetry.


The 2005 Annual Report of the Regional Infant and Child Mortality Review Committee.
The annual report of the Regional Infant and Child Mortality Review Committee (RICMRC) is attached. This Committee has as its mission the review of infant and child deaths so that information can be transformed into action to protect young lives. The 2005 review area includes South Dakota's Minnehaha, Turner, Lincoln, Moody, Lake, McCook, Union, Hansen, Miner, and Brookings counties. Although there was only one death meeting the criteria of the Sudden Infant Death Syndrome (SIDS) in our region, there were four infant deaths associated with soft, unsafe, sleeping surfaces where asphyxia could not be excluded. We need to continue to promote the "Back to Sleep" campaign message of not only placing infants to sleep on their backs, but also making sure infants are put down to sleep on safe, firm, sleeping surfaces. Nine of ten accidental deaths were related to motor vehicle crashes (versus three in 2004). Unlike previous years, there were no fire-related deaths. In 2005 there were two child abuse related homicides and one teenage suicide. The RICMRC invites other communities to join in its efforts to review deaths to prevent potential life threatening hazards to children in their local environs.


Extension of the Clinical Significance of the "Cog".
To study the clinical anatomy of the epitympanum, the attic, and its medial wall, to try to discover a new clinical operation-related anatomical landmark, and to investigate the adjacent anatomical relationship with this landmark. Eight donor temporal bone specimens were dissected endoscopically. For 29 healthy persons (17 males and 12 females), CT images of the temporal bone (57 ears) were taken, 3-dimensional (3-D) reconstruction and multidimensional plane reconstruction were performed, and identification and assessment of 3-D spatial relationships between any 2 of these complex structures were done. 3-D images of the temporal bone structures including the facial nerve, the cochlea, the semicircular canal, and the brain plate were reconstructed and shown in detail. We discovered a new clinical surgery-related anatomical landmark (the "cog" tangent and the trailing edge of the cog). Based on the tangent and the trailing edge of the cog, we quantified the anatomical relationship between it and its neighboring important structures. Based on endoscopic anatomy and the temporal bone spiral CT 3-D structure reconstruction of the epitympanum, the attic, and the adjacent structures, we found an extension of the clinical significance the cog. Quantification of the adjacent anatomical relationship of this landmark is very important for otology microsurgical operation.


The pH dependence of the contractile response of fatigued skeletal muscle.
Following a period of intense repetitive stimulation (e.g., brief tetanic stimuli every second for 3 min), muscle isometric tension development is reduced by about 80%. This suppression is reversible at a high external pH (8.0) with a half time of 15-20 min, but if the external pH is low (6.4) or the buffer concentration is low, recovery is prevented. Inhibition of recovery is associated with a slowed rate of lactate loss, which may suggest that intracellular lactacidosis is the cause of the inhibition. Alternatively, a low external pH may affect recovery from fatigue quite independently of its effect on lactate efflux. The possibility that surface membrane properties are changed by fatigue in a pH-dependent fashion was examined by measuring the cable properties and action potentials of fatigued fibres at different external pH values. A low external pH during recovery from fatigue was shown to result in a prolonged membrane depolarization of 10-12 mV, an increased transmembrane resistance, and a prolonged action potential. At a high external pH transmembrane resistance is lowered by fatigue, the depolarization lasts only about 10-15 min, and there is a smaller effect on the action potential. While the fatigued fibre membrane does show a changed response that is dependent on external pH, it is not clear that this could be related to the suppression of contraction. Direct measurements of intracellular pH show a fall of about 0.4 to 0.5 pH units in the surface fibres following fatigue. This results from the lactic acid generated during activity. It is now clear that lactate crosses the membrane in association with protons and at least part of this flux is mediated by a specific carrier mechanism. Efflux is limited by the transmembrane pH gradient, which in turn depends on the extracellular buffer concentration in the diffusion limited space around the fibres. Intracellular lactacidosis in resting muscles can be generated by a reversal of the normal flux. Fibres can be loaded with lactate (L) by increasing the extracellular [H+][L-] product with a resultant fall in intracellular pH. Lactate loads similar to those seen in fatigued muscle simulate some but not all of the responses seen in the postfatigue state. The twitch is prolonged with a slow relaxation phase, an increased time to peak tension but with an increase in peak tension. The effects are reversible but usually result in a reduced contractile response following the washout.(ABSTRACT TRUNCATED AT 400 WORDS)


Hepatogastric fistula as a rare complication of pyogenic liver abscess.
Hepatogastric fistula following a pyogenic liver abscess is extremely rare, and only a handful of cases have been reported. An 88-year-old female presented with generalized weakness, fever and chills. An abdominal computed tomography scan revealed a 5cm-sized hypodense lesion with internal septa in the left lateral section of the liver. Due to initial suspicion of early liver abscess, she was treated with empirical intravenous antibiotics. Initially, aspiration or drainage of the liver abscess was not performed due to immature lesion characteristics. An ultrasonography-guided percutaneous drainage of the liver abscess was performed 17 days after hospitalization due to a more mature lesion appearance on follow-up imaging. On tubography, contrast media leakage through the fistulous tract was visualized. Surgical management was performed, and she was discharged 2 weeks after surgery.


Imaging of the vertebrobasilar system by transcranial color-coded real-time sonography.
The vertebrobasilar system was investigated in 75 persons by TCCS to evaluate the applicability and diagnostic capacity of this transcranial Duplex technique. Transforaminal and transtemporal acoustic windows were employed to identify the vertebral arteries, basilar artery (PCA) and major branches of the vertebrobasilar system. The frequency of identifying the basilar artery and the PCA ranged from 84 to 94% but was poor for the distal segment of the basilar artery (45.3%). The origin of the basilar artery was disclosed by transcranial Duplex sonography at an average depth of 7.0 cm (range 6.0 to 8.0 cm). The assignment of the obtained flow signals to specific vascular segments was improved by this new technique. In addition, four persons received a maximum of six intravenous injections of a transpulmonary stable sonographic contrast agent (SHU 508 A) to enhance Doppler signal intensity derived from the vertebrobasilar system. The vascular trunk and all major branches of the vertebrobasilar system were identified in these four persons. We conclude that TCCS of the vertebrobasilar system will improve reliability of transcranial sonographic examination.


CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis.
Breast cancer is one of the most commonly diagnosed cancers worldwide and the second leading cause of cancer-related deaths among females. CCL28 (mucosa-associated epithelial chemokine, MEC), a CC subfamily chemokine, has been well studied in the process of inflammation, and recently increasing evidence indicates that CCL28 is related to tumor progression. However, little is known concerning its function in breast cancer. In the present study, we generated a CCL28-overexpressing breast cancer cell line MDA-MB-231HM/CCL28 from parental MDA-MB‑231HM cells. We found that overexpression of CCL28 promoted cell proliferation and tumor formation, and also enhanced migration, invasion and metastasis both in vitro and in vivo. Mechanistic studies revealed that CCL28 mediated intracellular activation of the mitogen-activated protein kinase (MAPK) signaling pathway to promote breast cancer cell proliferation and metastasis by upregulating anti-apoptotic protein Bcl-2 and suppressing cell adhesion protein β-catenin. However, overexpression of CCL28 did not influence the expression of metastasis‑related protein matrix metalloproteinase MMP2 and MMP9 and VEGF. Tissue sample analysis from animal models also indicated that overexpression of CCL28 was associated with enhanced pERK expression and reduced β-catenin expression in breast carcinomas. Thus, our results show for the first time that CCL28 contributes to breast cancer progression through the ERK/MAPK‑mediated anti-apoptotic and metastatic signaling pathway. Antagonists of CCL28 and the MAPK signaling pathway may be used synergistically to treat breast cancer patients.


Twin language or phonological disorder?
The acquisition of language in the preschool years by multiple-birth children is often reported to be atypical. Some researchers have claimed that they use 'twin language', i.e. an autonomous language specific to a multiple-birth set. This claim was investigated by describing and comparing the phonological characteristics of the speech of 19 sets of two- to four-year-old multiple-birth children, and by measuring multiple-birth children's understanding of their twins' or triplets' context-free speech. The results indicated that multiple-birth children are prone to phonological disorder and consequently their speech is often unintelligible. Siblings' phonologies evidenced some similarities, although they were not identical. Multiple-birth children were better able to understand their siblings' mispronunciations than were other children of the same age, although that understanding was dependent on how closely the error form resembled the adult form. While these three factors conspire to give the impression that 'twin language' is common, none of these findings provided support for the claim that multiple-birth children use an autonomous language.


Orbital metastatic angiosarcoma.
We report a case of a 48-year-old man who developed metastatic angiosarcoma in her left orbit. A 48-year-old man was first sent to us for a check up of proptosis of the left eye. A left orbital tumor was recognized on orbital computed tomography scans. The open biopsy showed angiosarcoma. Chest X-ray films and thoracic computed tomography showed an abnormal mass in the left inferior lung field. Angiosarcoma was confirmed by transbronchial lung biopsy. In summary, we believed that the orbital tumour was an initial symptom of the metastasis ensuing from the lung angiosarcoma.


Simulation of network activity in stomatogastric ganglion of the spiny lobster, Panulirus.
We have compared experimental and model studies on the rhythmic activity of the lobster stomatogastric ganglion. Both the pyloric and gastric mill systems were simulated using a physiologically based network model. In the pyloric simulation the known synaptic connectivity of the 3 principal cell types in the pyloric rhythm was found to be sufficient to produce the correct sequence of cyclic bursting activity over a substantial range of parameter values, even though we did not simulate the known endogenous oscillatory driver potential of one of the cell types. It is not yet known whether the synaptic inhibition in the real system is in the right range to cause cyclic bursting in the absence of the driver potential, but the synaptic connectivity does appear to reinforce the cyclic pattern. Simulations were also done with alternative connectivity schemes to determine which synapses appear essential to generate the correct bursting sequence (in the absence of endogenous bursting activity). Other, more complex, systems simulated were: (1) all 5 cell groups of the pyloric system, and (2) the cells responsible for movement of the lateral teeth in the gastric mill. In both cases good qualitative agreement was achieved between model and real systems.


Faculty members' perceptions of advising versus mentoring: does the name matter?
The recommendations, during the past 20 years, to improve PhD scientific training and graduate school success, have focused on the significance of mentoring. It is well established that PhD students with mentors have significantly more success in graduate school as demonstrated by publishing papers before they graduate and by making presentations. Have faculty and academic institutions embraced the mentoring role? This study explores the views of 3,500 scientists who have primary responsibilities to educate PhD and MD/PhD students. Faculty members report they are more likely to prefer being viewed as advisors (54 %) than mentors (38 %). Through an examination of perceptions about specific responsibilities of advisors and mentors, faculty members provide a description of their culture and the expectations they have about themselves and others. One would expect that because mentoring requires additional time and involvement that faculty would report differences between advising and mentoring. However, faculty members perceive few differences between advisors and mentors. We examine the implications of these findings. Future scientists need to be confident their education includes the opportunity to acquire the best possible research skills. To develop advisors who have the ability to provide this training, the process begins by defining role expectations and responsibilities and preparing advisors to interact with doctoral students in ways comparable to mentors. We expect faculty members to know how to teach and how to mentor; yet, we rarely discuss how to develop and shape the necessary skills of advisors so, that they more closely resemble those of mentors.


Glycerol metabolism is important for cytotoxicity of Mycoplasma pneumoniae.
Glycerol is one of the few carbon sources that can be utilized by Mycoplasma pneumoniae. Glycerol metabolism involves uptake by facilitated diffusion, phosphorylation, and the oxidation of glycerol 3-phosphate to dihydroxyacetone phosphate, a glycolytic intermediate. We have analyzed the expression of the genes involved in glycerol metabolism and observed constitutive expression irrespective of the presence of glycerol or preferred carbon sources. Similarly, the enzymatic activity of glycerol kinase is not modulated by HPr-dependent phosphorylation. This lack of regulation is unique among the bacteria for which glycerol metabolism has been studied so far. Two types of enzymes catalyze the oxidation of glycerol 3-phosphate: oxidases and dehydrogenases. Here, we demonstrate that the enzyme encoded by the M. pneumoniae glpD gene is a glycerol 3-phosphate oxidase that forms hydrogen peroxide rather than NADH(2). The formation of hydrogen peroxide by GlpD is crucial for cytotoxic effects of M. pneumoniae. A glpD mutant exhibited a significantly reduced formation of hydrogen peroxide and a severely reduced cytotoxicity. Attempts to isolate mutants affected in the genes of glycerol metabolism revealed that only the glpD gene, encoding the glycerol 3-phosphate oxidase, is dispensable. In contrast, the glpF and glpK genes, encoding the glycerol facilitator and the glycerol kinase, respectively, are essential in M. pneumoniae. Thus, the enzymes of glycerol metabolism are crucial for the pathogenicity of M. pneumoniae but also for other essential, yet-to-be-identified functions in the M. pneumoniae cell.


Large-Area Supercapacitor Textiles with Novel Hierarchical Conducting Structures.
Supercapacitor textiles with large sizes are developed to satisfy practical applications by designing a novel hierarchical conducting structure. They display remarkable capacitance, power, and energy of 69.3 F, 80.7 mW, and 5.4 mW h, respectively, representing an important step toward real-world applications.


Insulin enhances neurite extension and myelination of diabetic neuropathy neurons.
The authors established an in vitro model of diabetic neuropathy based on the culture system of primary neurons and Schwann cells (SCs) to mimic similar symptoms observed in in vivo models of this complication, such as impaired neurite extension and impaired myelination. The model was then utilized to investigate the effects of insulin on enhancing neurite extension and myelination of diabetic neurons. SCs and primary neurons were cultured under conditions mimicking hyperglycemia prepared by adding glucose to the basal culture medium. In a single culture, the proliferation and maturation of SCs and the neurite extension of neurons were evaluated. In a co-culture, the percentage of myelination of diabetic neurons was investigated. Insulin at different concentrations was supplemented to culture media to examine its effects on neurite extension and myelination. The cells showed similar symptoms observed in in vivo models of this complication. In a single culture, hyperglycemia attenuated the proliferation and maturation of SCs, induced apoptosis, and impaired neurite extension of both sensory and motor neurons. In a co-culture of SCs and neurons, the percentage of myelinated neurites in the hyperglycemia-treated group was significantly lower than that in the control group. This impaired neurite extension and myelination was reversed by the introduction of insulin to the hyperglycemic culture media. Insulin may be a potential candidate for improving diabetic neuropathy. Insulin can function as a neurotrophic factor to support both neurons and SCs. Further research is needed to discover the potential of insulin in improving diabetic neuropathy.


The radical stabilization energy of a substituted carbon-centered free radical depends on both the functionality of the substituent and the ordinality of the radical.
Chemical intuition suggests that the stabilization of a carbon-centered free radical by a substituent X would be the greatest for a prim and least for a more stable tert radical because of "saturation". However, analysis of a comprehensive recent set of bond dissociation energies computed by Coote and co-workers (Phys. Chem. Chem. Phys. 2010, 12, 9597) and transformed into radical stabilization energies (RSE) suggests that this supposition is often violated. The RSE for a given X depends not only on the nature of X but also on the ordinality (i.e., prim, sec, or tert) of the radical onto which it is substituted. For substituents that stabilize by electron delocalization but also contain electron-withdrawing centers, such as the carbonyl function, the stabilization of XCMe(2)(•) compared with HCMe(2)• is greater than that for XCH(2)• compared with HCH(2)•. However, for substituents that stabilize by lone-pair electron donation, such as N or O centers, the order is strongly reversed. This contrast can be qualitatively rationalized by considering charge-separated VB contributors to the radical structure (R(2)C(+)-X(-•) and R(2)C(-)-X(+•)) and the contrasting effects of methyl substituents on them. This conclusion is not dependent on the particular definition used for RSE.


A combined treatment with erythrocyte lysis solution and Sudan Black B reduces tissue autofluorescence in double-labeling immunofluorescence.
The autofluorescence of animal tissues complicates the results obtained using fluorescence microscopy. Many techniques have been used to reduce autofluorescence; however, all these techniques have the disadvantage of reducing the intensity of immunofluorescence staining. We observed the features of autofluorescence in formalin-fixed paraffin-embedded (FFPE) vascularized liver and kidney sections and assessed the effects of an intravascular treatment with erythrocyte lysis solution (ELS) before a routine perfusion with normal saline (NS) and Sudan Black B (SBB) treatment after antigen retrieval on reducing autofluorescence reduction and the visualization of antigens to establish an optimal method for reducing autofluorescence. Erythrocytes exhibited bright autofluorescence in FFPE liver and kidney sections, which altered the results of actin and destrin immunofluorescence staining. The SBB treatment significantly reduced background autofluorescence and exerted a moderate effect on reducing the autofluorescence of erythrocytes, and the intravascular ELS treatment eliminated erythrocyte autofluorescence in FFPE liver and kidney sections. A combined treatment with ELS and SBB further reduced autofluorescence but did not decrease actin and destrin immunofluorescence staining in double-labeled FFPE liver and kidney sections. In conclusion, the application of an intravascular ELS treatment before the NS perfusion combined with an SBB treatment after antigen retrieval is a simple and efficient strategy for reducing autofluorescence in FFPE vascularized tissues and can be broadly used in fluorescence microscopy analyses.


[Possible advantages of visual evoked potentials and computerized static perimetry in early diagnosis of glaucoma].
Aim of the studies was to evaluate usefulness of the visual evoked potentials and static perimetry in diagnosis of an early glaucoma. There were 12 examined cases, divided into 3 equal groups: 1) patients suspected for glaucoma basing on the characteristic picture of the optic disc, 2) patients after acute glaucoma in one eye with no history of the disease in the fellow eye, 3) patients with open angle glaucoma diagnosed in one eye. Abnormal results of the examinations were found only in the second group. The authors concluded that visual evoked potentials and static perimetry could be helpful in proper diagnosis of many difficult cases suspected for glaucoma.


Chronic prostatitis/chronic pelvic pain syndrome: national survey of genitourinary medicine clinics.
We sought to determine current practice in the diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in genitourinary medicine departments in the UK, using a detailed questionnaire survey. Evaluable responses were received from 147 (69%) clinics. Seventy-nine (54%) clinics reported seeing >10 new CPPS patients per year. A broad range of investigations was reported to be used in the diagnosis of CPPS. Whilst 89 (61%) clinics reported using the four-glass test in diagnosis, 46 (32%) reported using the test in >90% of patients with CPPS, and 42 (29%) reported never using the test. In the treatment, doxycycline or ciprofloxacin were reported to be first line treatment by 98% clinics, mostly in 4-6 week courses; however, great variation was recorded in second-line choices and use of non-antibiotic approaches. This survey demonstrates that patients with CPPS are regularly diagnosed and managed in genitourinary clinics in the UK, with wide variations in diagnostic and treatment practices.


Automatic sleep staging using multi-dimensional feature extraction and multi-kernel fuzzy support vector machine.
This paper employed the clinical Polysomnographic (PSG) data, mainly including all-night Electroencephalogram (EEG), Electrooculogram (EOG) and Electromyogram (EMG) signals of subjects, and adopted the American Academy of Sleep Medicine (AASM) clinical staging manual as standards to realize automatic sleep staging. Authors extracted eighteen different features of EEG, EOG and EMG in time domains and frequency domains to construct the vectors according to the existing literatures as well as clinical experience. By adopting sleep samples self-learning, the linear combination of weights and parameters of multiple kernels of the fuzzy support vector machine (FSVM) were learned and the multi-kernel FSVM (MK-FSVM) was constructed. The overall agreement between the experts' scores and the results presented was 82.53%. Compared with previous results, the accuracy of N1 was improved to some extent while the accuracies of other stages were approximate, which well reflected the sleep structure. The staging algorithm proposed in this paper is transparent, and worth further investigation.


Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans.
We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per cell basis. Consistent with preclinical findings, HDAC inhibition also increased signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT.


Two Cases of Hepatocellular Carcinoma Arising Over 20 Years after a Sustained Virologic Response Following Interferon Therapy for Chronic Hepatitis C.
The development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) due to interferon (IFN) therapy for hepatitis C virus infection remains a serious problem. We herein report 2 cases of HCC that developed more than 20 years after SVR with IFN therapy for chronic hepatitis C. The patients were 89- and 72-year-old men with HCC that developed 24-25 years after an SVR with IFN therapy. These patients regularly underwent imaging examinations; therefore, the HCC was detected in the early stage, when it was still curable. Both cases suggest that long-term surveillance after an SVR is effective for the detection of HCC, and radical treatment is possible.


Kanamycin Sulphate Loaded PLGA-Vitamin-E-TPGS Long Circulating Nanoparticles Using Combined Coating of PEG and Water-Soluble Chitosan.
Kanamycin sulphate (KS) is a Mycobacterium tuberculosis protein synthesis inhibitor. Due to its intense hydrophilicity, KS is cleared from the body within 8 h. KS has a very short plasma half-life (2.5 h). KS is used in high concentrations to reach the therapeutic levels in plasma, which results in serious nephrotoxicity/ototoxicity. To overcome aforementioned limitations, the current study aimed to develop KS loaded PLGA-Vitamin-E-TPGS nanoparticles (KS-PLGA-TPGS NPs), to act as an efficient carrier for controlled delivery of KS. To achieve a substantial extension in blood circulation, a combined design, affixation of polyethylene glycol (PEG) to KS-PLGA-TPGS NPs and adsorption of water-soluble chitosan (WSC) (cationic deacetylated chitin) to particle surface, was raised for surface modification of NPs. Surface modified NPs (KS-PEG-WSC NPs) were prepared to provide controlled delivery and circulate in the bloodstream for an extended period of time, thus minimizing dosing frequency. In vivo pharmacokinetics and in vivo biodistribution following intramuscular administration were investigated. NPs surface charge was close to neutral +3.61 mV and significantly affected by the WSC coating. KS-PEG-WSC NPs presented striking prolongation in blood circulation, reduced protein binding, and long drew-out the blood circulation half-life with resultant reduced kidney sequestration vis-à-vis KS-PLGA-TPGS NPs. The studies, therefore, indicate the successful formulation development of KS-PEG-WSC NPs with reduced frequency of dosing of KS indicating low incidence of nephrotoxicity/ototoxicity.


Organic Semiconductor Based on N, S-Containing Crown Ether Enabling Efficient and Stable Perovskite Solar Cells.
The uncoordinated lead cations are ubiquitous in perovskite films and severely affect the efficiency and stability of perovskite solar cells (PSCs). In this work, 15-crown-5 with various heteroatoms are connected to the organic semiconductor carbazole diphenylamine, and two new compounds, CDT-S and CDT-N, are developed to modify the Pb2+ defects in perovskite films through the anti-solvent method. Apart from the oxygen atoms, there are also N atoms on crown ether ring in CDT-N, and both S and N heteroatoms in CDT-S. The heteroatoms enhance the interaction between the crown ether-based semiconductors and the undercoordinated Pb2+ defect in perovskite. Particularly, the stronger interaction between S atoms and Pb2+ further enhances the defect passivation effect of CDT-S than CDT-N, thereby more effectively suppressing the non-radiative recombination of charge carriers. Finally, the efficiency of the device treated with CDT-S is up to 23.05 %. Moreover, the unencapsulated device based on CDT-S maintained 90.5 % of the initial efficiency after being stored under dark conditions for 1000 hours, demonstrating good long-term stability. Our work demonstrates that crown ethers are promising in perovskite solar cells, and the crown ether containing multiple heteroatoms could effectively improve both efficiency and stability of devices.


Role of Inflammation in Progression of Chronic Kidney Disease in Type 2 Diabetes Mellitus: Clinical Implications.
Progression of chronic kidney disease in type 2 diabetes has been understood conventionally as a consequence of intraglomerular hemodynamic changes and aberrant metabolic pathways. However, an increasing body of experimental evidence has highlighted the role of inflammatory response in the progression of diabetic kidney disease. Macrophage polarization in response to specific microenvironmental stimuli affects the pathology of diabetic kidneys. The diabetic milieu also up-regulates inflammatory cytokines, chemokines, and adhesion molecules, and promotes inflammatory signal transduction pathways, including inflammasomes. Therefore, from a reverse translational perspective, modulation of the inflammatory response may be the driving force of the renoprotective effects of renin-angiotensin system inhibitors, sodium-glucose cotransporter-2 inhibitors, and mineralocorticoid receptor antagonists, all of which have been shown to slow disease progression. Currently, many agents that target the inflammation in the kidneys directly are evaluated in clinical trials. This article discusses recent clinical and experimental milestones in drug development for diabetic kidney disease with a perspective on inflammation in the kidneys. Such insights may enable a targeted approach to discovering novel drugs against chronic kidney disease in type 2 diabetes.


Role of leptin in growth and adiposity in early infancy: impact of nutritional pattern.
This study was planned to investigate leptin levels under different models of nutrition and their relation with anthropometric parameters in early infancy. Sixty four infants (28 exclusively breast-fed, 15 exclusively formula-fed and 21 mixed-fed), aged 4 months were included and their leptin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) levels were measured. Leptin, IGF-I and IGFBP-3 levels of the three groups were not statistically different (P > 0.05). The results of our study questions the role of leptin as a link between nutritional pattern and adiposity-growth in early infancy.


Nitroxide Radical-Containing Redox Nanoparticles Protect Neuroblastoma SH-SY5Y Cells against 6-Hydroxydopamine Toxicity.
Parkinson's disease (PD) patients can benefit from antioxidant supplementation, and new efficient antioxidants are needed. The aim of this study was to evaluate the protective effect of selected nitroxide-containing redox nanoparticles (NRNPs) in a cellular model of PD. Antioxidant properties of NRNPs were studied in cell-free systems by protection of dihydrorhodamine 123 against oxidation by 3-morpholino-sydnonimine and protection of fluorescein against bleaching by 2,2-azobis(2-amidinopropane) hydrochloride and sodium hypochlorite. Model blood-brain barrier penetration was studied using hCMEC/D3 cells. Human neuroblastoma SH-SY5Y cells, exposed to 6-hydroxydopamine (6-OHDA), were used as an in vitro model of PD. Cells were preexposed to NRNPs or free nitroxides (TEMPO or 4-amino-TEMPO) for 2 h and treated with 6-OHDA for 1 h and 24 h. The reactive oxygen species (ROS) level was estimated with dihydroethidine 123 and Fluorimetric Mitochondrial Superoxide Activity Assay Kit. Glutathione level (GSH) was measured with ortho-phtalaldehyde, ATP by luminometry, changes in mitochondrial membrane potential with JC-1, and mitochondrial mass with 10-Nonyl-Acridine Orange. NRNP1, TEMPO, and 4-amino-TEMPO (25-150 μM) protected SH-SY5Y cells from 6-OHDA-induced viability loss; the protection was much higher for NRNP1 than for free nitroxides. NRNP1 were better antioxidants in vitro and permeated better the model BBB than free nitroxides. Exposure to 6-OHDA decreased the GSH level after 1 h and increased it considerably after 24 h (apparently a compensatory overresponse); NRNPs and free nitroxides prevented this increase. NRNP1 and free nitroxides prevented the decrease in ATP level after 1 h and increased it after 24 h. 6-OHDA increased the intracellular ROS level and mitochondrial superoxide level. Studied antioxidants mostly decreased ROS and superoxide levels. 6-OHDA decreased the mitochondrial potential and mitochondrial mass; both effects were prevented by NRNP1 and nitroxides. These results suggest that the mitochondria are the main site of 6-OHDA-induced cellular damage and demonstrate a protective effect of NRNP1 in a cellular model of PD.


Enhanced recovery after surgery pathway in patients with soft tissue sarcoma.
Patients undergoing surgery for soft tissue sarcoma have high morbidity rates, particularly after preoperative radiation therapy (RT). An enhanced recovery after surgery (ERAS) programme may improve perioperative outcomes in abdominal surgery. This study reported outcomes of an ERAS programme tailored to patients with soft tissue sarcoma. A prospective ERAS protocol was implemented in 2015 at a high-volume sarcoma centre. Patients treated within the ERAS programme from 2015 to 2018 were case-matched retrospectively with patients treated between 2012 and 2018 without use of the protocol, matched by surgical site, surgeon, sarcoma histology and preoperative RT treatment. Postoperative outcomes, specifically wound complications and duration of hospital stay, were reported. In total, 234 patients treated within the ERAS programme were matched with 237 who were not. The ERAS group had lower wound dehiscence rates overall (2 of 234 (0·9 per cent) versus 31 of 237 (13·1 per cent); P < 0·001), after preoperative RT (0 of 41 versus 11 of 51; P = 0·004) and after extremity sarcoma surgery (0 of 54 versus 6 of 56; P = 0·040) compared with the non-ERAS group. Rates of postoperative ileus or obstruction were lower in the ERAS group (21 of 234 (9·9 per cent) versus 40 of 237 (16·9 per cent); P = 0·016) and in those with retroperitoneal sarcoma (4 of 36 versus 15 of 36; P = 0·007). Duration of hospital stay was shorter in the ERAS group (median 5 (range 0-36) versus 6 (0-67) days; P = 0·003). Treatment within an ERAS protocol for patients with soft tissue sarcoma was associated with lower morbidity and shorter hospital stay.


The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model.
Allergic conjunctivitis (AC) is a common allergic eye disease characterized by clinical symptoms such as itchiness, conjunctival congestion, elevated Ag-specific IgE, mast cell activation, and local eosinophil infiltration. In this study we established a murine model for Ag-induced AC to understand the pathogenesis of the disease. Cell transfer experiments indicated that AC can be divided into early and late phase responses (EPR and LPR). EPR was associated with IgE responses, leading to itchiness, whereas LPR was characterized by local eosinophil infiltration. Both EPR and LPR were significantly inhibited in STAT6-deficient mice, and adoptive transfer of Th2 cells reconstituted LPR. Furthermore, SOCS3 was highly expressed at the disease site, and T cell-specific expression of SOCS3 deteriorated clinical and pathological features of AC, indicating that Th2-mediated SOCS3 expression controls the development and persistence of AC. Reduction of the expression level in SOCS3 heterozygous mice or inhibition of function in dominant-negative SOCS3 transgenic mice clearly reduced the severity of AC. In contrast, constitutive expression of SOCS5, a specific inhibitor of IL-4 signaling, resulted in reduced eosinophil infiltration. These results suggest that negative regulation of the Th2-mediated response by dominant-negative SOCS3 and SOCS5 could be a target for therapeutic intervention in allergic disease.


Androgen dynamics in vitro in the normal and hyperplastic human prostate gland.
The dynamics of uptake and metabolism in vitro of androgens by normal and hyperplastic human prostate glands was studied by means of a new experimental design proposed by Gurpide & Welch (1969). Prostate slices were perfused with a medium containing [(3)H]testosterone and [(14)C]androstenedione, or 5alpha-dihydro-[(3)H]testosterone and [(14)C]testosterone. The entry into the slices, the irreversible metabolism, the conversion between the compounds and the tissue retention or ;uptake' of the steroids were measured at the steady state. A similar portion of the three androgens entered the tissue and was irreversibly metabolized. Conversion of testosterone into 5alpha-dihydrotestosterone was much greater than the interconversion of testosterone and androstenedione. The prostate slices retained 5alpha-dihydrotestosterone at a concentration three times that in the medium, whereas testosterone and androstenedione were retained to a smaller extent. At a steroid concentration of 0.11mumol/l in the medium, the various parameters did not differ significantly in experiments performed with slices from normal and hyperplastic glands. When the steroid concentration in the medium was increased tenfold, however, a difference between normal and hyperplastic glands was evident. The normal glands increased the uptake and metabolism proportionally to the elevation of the steroid concentration in the medium. In the hyperplastic glands the entry and metabolism lagged behind the increase in steroid supply, whereas the tissue uptake became disproportionately high. The possible causes of this finding are discussed.


Alpha 1-antitrypsin and alpha 2-macroglobulin do not inhibit the kinin-releasing activity of kallikreins from human urine and saliva.
Alpha 1-Antitrypsin, alpha 2-macroglobulin and low-molecular weight kininogen were isolated from human serum and kallikreins from human urine and saliva. Alpha 1-antitrypsin and alpha 2-macroglobulin inhibited the activity of trypsin in releasing kinin from low-molecular weight kininogen, due to their binding with the enzyme, but did not inhibit or bind with urinary and salivary kallikreins.


Intraflagellar transport protein IFT52 recruits IFT46 to the basal body and flagella.
Cilia are microtubule-based organelles and perform motile, sensing and signaling functions. The assembly and maintenance of cilia depend on intraflagellar transport (IFT). Besides ciliary localization, most IFT proteins accumulate at basal bodies. However, little is known about the molecular mechanism of basal body targeting of IFT proteins. We first identified the possible basal body-targeting sequence in IFT46 by expressing IFT46 truncation constructs in an ift46-1 mutant. The C-terminal sequence between residues 246-321, termed BBTS3, was sufficient to target YFP to basal bodies in the ift46-1 strain. Interestingly, BBTS3 is also responsible for the ciliary targeting of IFT46. BBTS3::YFP moves bidirectionally in flagella and interacts with other IFT complex B (IFT-B) proteins. Using IFT and motor mutants, we show that the basal body localization of IFT46 depends on IFT52, but not on IFT81, IFT88, IFT122, FLA10 or DHC1b. IFT52 interacts with IFT46 through residues L285 and L286 of IFT46 and recruits it to basal bodies. Ectopic expression of the C-terminal domain of IFT52 in the nucleus resulted in accumulation of IFT46 in nuclei. These data suggest that IFT52 and IFT46 can preassemble as a complex in the cytoplasm, which is then targeted to basal bodies.


[Fluoroscopy dose reduction of computed tomography guided chest interventional radiology using real-time iterative reconstruction].
The purpose of this study was to evaluate the radiation dose reduction to patients and radiologists in computed tomography (CT) guided examinations for the thoracic region using CT fluoroscopy. Image quality evaluation of the real-time filtered back-projection (RT-FBP) images and the real-time adaptive iterative dose reduction (RT-AIDR) images was carried out on noise and artifacts that were considered to affect the CT fluoroscopy. The image standard deviation was improved in the fluoroscopy setting with less than 30 mA on 120 kV. With regard to the evaluation of artifact visibility and the amount generated by the needle attached to the chest phantom, there was no significant difference between the RT-FBP images with 120 kV, 20 mA and the RT-AIDR images with low-dose conditions (greater than 80 kV, 30 mA and less than 120 kV, 20 mA). The results suggest that it is possible to reduce the radiation dose by approximately 34% at the maximum using RT-AIDR while maintaining image quality equivalent to the RT-FBP images with 120 V, 20 mA.


Pulmonary Arterial Hypertension as a Fatal Complication of Neurofibromatosis Type 1 in a Neonate: A Diagnostic Dilemma.
Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is a genetically transmitted autosomal dominant disease, with a prevalence of one per 4000 live births. Pulmonary arterial hypertension (PAH) is a rare but potentially life-threatening complication of NF1. There are no confirmatory data about the congenital association between PAH and NF1. However, in most cases, PAH is observed in late childhood or adulthood. Herein, we present a preterm baby with genetically confirmed NF1 who presented with PAH.


Primacy and recency effects in rhesus monkeys (Macaca mulatta) using a serial probe recognition task. III. A developmental analysis.
In children, the recency effect emerges prior to the primacy effect. To determine whether this dissociation is also seen in nonhuman primates, we evaluated the development of the primacy and recency effect in 3 young adult (35 months) and 4 adolescent (21 months) male rhesus monkeys (Macaca mulatta) using a six-item serial probe recognition (SPR) task. As predicted, the young adult monkeys displayed both effects, while the adolescent monkeys only displayed the recency effect. Not until after 26 months of training on the SPR task did the adolescent monkeys exhibit both the primacy and recency effect. Interference and strategy differences are discussed in terms of the results along with an interpretation of Rudy's (1992) configural association theory of cognitive development. Additional possible explanations for this developmental dissociation include the delayed maturation of the neocortical, hippocampal, and/or cholinergic systems, the latter two having been shown to be important in the expression of the primacy but not the recency effect.


Immune depression in Trypanosoma brucei brucei infected mice. Sequential histological and immunological findings.
Pathological findings in various organs and tissues, T and B lymphocyte inability to proliferate towards several mitogens, and the appearance of serum interferon at progressive stages after intraperitoneal infection of BALB/c mice with Trypanosoma brucei brucei are reported. Heavy parasitaemia is evident throughout infection and complete hyporesponsiveness is already present on day 3. A sharp interferon production peak appears after 48 hours. The anatomopathological picture makes it clear that infection is substantially restricted to the blood. Secondary involvement of liver, lung and kidney takes the form of perivascular cuffs. These appear at relatively early stages. By contrast, spleen and lymph nodes appear to be greatly altered.


[Specialists in endocrine and thyroid surgery].
It was common for specialists in endocrine and thyroid surgery to join both the Japan Association of Endocrine Surgeons (with membership of approximately 1,000 surgeons and urologists) and the Japanese Society of Thyroid Surgery (with membership of approximately 1,000 surgeons and otolaryngologists), which was established in 2008. On January 1, 2009, the category of specialist in endocrine and thyroid surgery was created, and as of January 2012, 358 specialists were listed. The first specialist examination (written and oral) will be conducted in October 2012, allowing specialists to be certified. There are now total of 127 authorized and associated institutions. This report gives an outline of this system and future issues to be addressed.


Off label and unlicensed drugs use in paediatric cardiology.
The use of drugs in an off label or unlicensed manner to treat children is a widespread phenomenon in Europe and the United States. The incidence of unlicensed and off label prescribing in paediatric cardiology practice has not been studied to date. This study was designed to assess the extent and nature of off label and unlicensed drug use in paediatric cardiology inpatients. In a prospective study, drug prescriptions in a paediatric cardiology ward were reviewed during a 2-year period. Data were collected and analyzed by special software created for this purpose. The children (n = 544) studied varied in age from 4 h to 18 years. One or more off label and unlicensed prescriptions were given to 414 (76%) patients. Of the 2,130 prescriptions given during the 2-year period, more than one-half were unlicensed (11%) or off label (47%). While children aged 2-11 years received most of the unlicensed drug prescriptions (17%), neonates, who did not receive unlicensed drugs, led (64%) in the use of off label drugs. CONCLUSIONS. This study showed that the problem of off label and unlicensed drug use also exists in paediatric cardiology. The findings imply that the phenomenon of off label and unlicensed use of drugs in children can be correlated with the deficiency of paediatric drug formulations on the global market and insufficient data from clinical studies which must be performed to confirm the efficacy and safety of drugs in the paediatric population. Therefore, efforts to improve paediatric labelling are important and need the full support of all involved.


Gramicidin A induced fusion of large unilamellar dioleoylphosphatidylcholine vesicles and its relation to the induction of type II nonbilayer structures.
The fusogenic properties of gramicidin were investigated by using large unilamellar dioleoylphosphatidylcholine vesicles. It is shown that gramicidin induces aggregation and fusion of these vesicles at peptide to lipid molar ratios exceeding 1/100. Both intervesicle lipid mixing and mixing of aqueous contents were demonstrated. Furthermore, increased static and dynamic light scattering and a broadening of 31P NMR signals occurred concomitant with lipid mixing. Freeze-fracture electron microscopy revealed a moderate vesicle size increase. Lipid mixing is paralleled by changes in membrane permeability: small solutes like carboxyfluorescein and smaller dextrans, FD-4(Mr approximately 4000), rapidly (1-2 min) leak out of the vesicles. However, larger molecules like FD-10 and FD-17 (Mr approximately 9400 and 17,200) are retained in the vesicles for greater than 10 min after addition of gramicidin, thereby making detection of contents mixing during lipid mixing possible. At low lipid concentrations (5 microM), lipid mixing and leakage are time resolved: leakage of CF shows a lag phase of 1-3 min, whereas lipid mixing is immediate and almost reaches completion during this lag phase. It is therefore concluded that leakage, just as contents mixing, occurs subsequent to aggregation and lipid mixing. Although addition of gramicidin at a peptide/lipid molar ratio exceeding 1/50 eventually leads to hexagonal HII phase formation and a loss of vesicle contents, it is concluded that leakage during fusion (1-2 min) is not the result of HII phase formation but is due to local changes in lipid structure caused by precursors of this phase. By making use of gramicidin derivatives and different solvent conformations, it is shown that there is a close parallel between the ability of the peptide to induce the HII phase and its ability to induce intervesicle lipid mixing and leakage. It is suggested that gramicidin-induced fusion and HII phase formation share common intermediates.


Spaceflight modulates gene expression in the whole blood of astronauts.
Astronauts are exposed to a unique combination of stressors during spaceflight, which leads to alterations in their physiology and potentially increases their susceptibility to disease, including infectious diseases. To evaluate the potential impact of the spaceflight environment on the regulation of molecular pathways mediating cellular stress responses, we performed a first-of-its-kind pilot study to assess spaceflight-related gene-expression changes in the whole blood of astronauts. Using an array comprised of 234 well-characterized stress-response genes, we profiled transcriptomic changes in six astronauts (four men and two women) from blood preserved before and immediately following the spaceflight. Differentially regulated transcripts included those important for DNA repair, oxidative stress, and protein folding/degradation, including HSP90AB1, HSP27, GPX1, XRCC1, BAG-1, HHR23A, FAP48, and C-FOS. No gender-specific differences or relationship to number of missions flown was observed. This study provides a first assessment of transcriptomic changes occurring in the whole blood of astronauts in response to spaceflight.


Responsiveness of a simple RAPID-3-like index compared to disease-specific BASDAI and ASDAS indices in patients with axial spondyloarthritis.
To evaluate the responsiveness of a simple routine assessment of patient index data (RAPID3)-like index that includes only 3 patient self-report measures (physical function, pain and patient global estimate) compared to that of traditional composite indices to assess change in patients with axial spondyloarthritis (Ax-SpA). Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR) is a prospective cohort of patients with inflammatory back pain suggestive of Ax-SpA. The study included 461 patients, who met the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for Ax-SpA. A simple RAPID3-like index was compared with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the AS Disease Activity Score (ASDAS) scores for responsiveness over 6 months. Construct validity was also evaluated through Pearson correlations and discrimination of disease activity through standardised mean differences for the 3 indices. The RAPID3-like index was correlated significantly with BASDAI (r=0.84, p<0.005) and ASDAS-C-reactive protein (CRP) (r=0.74, p<0.005), similar to correlations of BASDAI with ASDAS-CRP (r=0.76, p<0.005). The percentage of patients with inactive disease ranged from 9% to 25% and with high activity from 10% to 45%, according to various measures. The capacity to discriminate between high and low disease activity was similar for the 3 indices. The strength of agreement of RAPID3 with ASDAS-CRP was moderate (0.44) and lower with BASDAI (0.37). Responsiveness over 6 months was slightly higher for ASDAS-CRP and the RAPID3-like index than that for BASDAI. The RAPID3-like index provides similar information to BASDAI and ASDAS-CRP concerning responsiveness over 6 months. RAPID3 appears feasible to assess patients with Ax-SpA quantitatively over time in busy clinical settings.


Serpins, the vasculature, and viral therapeutics.
Serine protease inhibitors, termed serpins, are key regulators of numerous biological pathways that initiate inflammation, coagulation, angiogenesis, apoptosis, extra-cellular matrix composition and complement activation responses. Viruses have encoded serpins to guard themselves from host immune attack. The myxoma virus which infects rabbits secretes a highly potent anti-inflammatory serpin, Serp-1, which targets thrombolytic and thrombotic proteases as a means to fend off coagulation and inflammatory reactions to viral infection. These reactions act as a defense, produced by the host, to counter viral infection and invasion. When infused in animals after vascular injury, Serp-1 elicits exceptional anti-inflammatory activity, whereas the mammalian serpin, plasminogen activator inhibitor-1 (PAI-1), which also targets thrombotic and thrombolytic proteases can induce a pro-thrombotic response. During arterial injury, PAI-1 is highly expressed and increased PAI-1 concentration can result in acute thrombosis after aortic transplant in mouse models. The reactive center loop amino acid sequence is a fingerprint for serpin function and this function is highly sequence specific such that modification in this sequence can markedly alter activity. For instance, the alteration of the serpin reactive site loop P1-P1I amino acid sequence nullified the anti-inflammatory activity of Serp-1 and modification of P2-P7 initiated a pro-inflammatory response with vascular remodeling with aneurysm formation. Furthermore Serp-1 has demonstrated the capacity to utilize a mammalian serine protease receptor, the urokinase-type plasminogen activator receptor (uPAR), to alter cellular signaling in part through the actin binding protein cytoskeletal system (via filamin B). In this review, the molecular mechanisms relating inflammation and coagulation pathways to atherosclerosis and how the viral serpin, Serp-1, modifies these pathways in order to exhibit this profound anti-inflammatory activity without associated adverse thrombosis are discussed. Viral and vascular serpins targeting the thrombolytic cascade represent a potential new and untapped therapeutic resource.


Interaction effects on number fluctuations in a Bose-Einstein condensate of light.
We investigate the effect of interactions on condensate-number fluctuations in Bose-Einstein condensates. For a contact interaction we variationally obtain the equilibrium probability distribution for the number of particles in the condensate. To facilitate comparison with experiment, we also calculate the zero-time delay autocorrelation function g((2))(0) for different strengths of the interaction. Finally, we focus on the case of a condensate of photons and find good agreement with recent experiments.


[Dopamine effects on the pulmonary circulation of innervated and autotransplanted lungs (author's transl)].
The effects of dopamine on the pulmonary vascular resistance were investigated in 7 normal and 9 autotransplanted canine lungs during perfusion in situ. Dopamine (up to 13,5 gamma/kg BW, rapid injection) acts as a vasoconstrictor by alpha-receptor stimulation. Vasodilative effects could not be registered neither by very small amounts of dopamine nor during alpha-blockade with phentolamine. No difference could be detected between the vascular reactions of normal and autotransplanted lungs.


Predicting cognitive change within domains.
Standardized regression based (SRB) formulas, a method for predicting cognitive change across time, traditionally use baseline performance on a neuropsychological measure to predict future performance on that same measure. However, there are instances in which the same tests may not be given at follow-up assessments (e.g., lack of continuity of provider, avoiding practice effects). The current study sought to expand this methodology by developing SRBs to predict performance on different tests within the same cognitive domain. Using a sample of 127 non-demented community-dwelling older adults assessed at baseline and after 1 year, two sets of SRBs were developed: (1) those predicting performance on the same test, and (2) those predicting performance on a different test within the same cognitive domain. The domains examined were learning and memory, processing speed, and language. Across both sets of SRBs, 1-year scores were significantly predicted by baseline scores, especially for the learning and memory and processing speed measures. Although SRBs developed for the same test were comparable to those developed for different tests within the same domain, less variance was accounted for as tests became less similar. The current results lend preliminary support for additional development of SRBs, both for same and different tests, as well as beginning to examine domain-based SRBs.