Markers of criticality in phase synchronization.
The concept of the brain as a critical dynamical system is very attractive because systems close to criticality are thought to maximize their dynamic range of information processing and communication. To date, there have been two key experimental observations in support of this hypothesis: (i) neuronal avalanches with power law distribution of size and (ii) long-range temporal correlations (LRTCs) in the amplitude of neural oscillations. The case for how these maximize dynamic range of information processing and communication is still being made and because a significant substrate for information coding and transmission is neural synchrony it is of interest to link synchronization measures with those of criticality. We propose a framework for characterizing criticality in synchronization based on an analysis of the moment-to-moment fluctuations of phase synchrony in terms of the presence of LRTCs. This framework relies on an estimation of the rate of change of phase difference and a set of methods we have developed to detect LRTCs. We test this framework against two classical models of criticality (Ising and Kuramoto) and recently described variants of these models aimed to more closely represent human brain dynamics. From these simulations we determine the parameters at which these systems show evidence of LRTCs in phase synchronization. We demonstrate proof of principle by analysing pairs of human simultaneous EEG and EMG time series, suggesting that LRTCs of corticomuscular phase synchronization can be detected in the resting state and experimentally manipulated. The existence of LRTCs in fluctuations of phase synchronization suggests that these fluctuations are governed by non-local behavior, with all scales contributing to system behavior. This has important implications regarding the conditions under which one should expect to see LRTCs in phase synchronization. Specifically, brain resting states may exhibit LRTCs reflecting a state of readiness facilitating rapid task-dependent shifts toward and away from synchronous states that abolish LRTCs.


Normal brain response after interstitial microwave hyperthermia.
The effects of interstitial hyperthermia were assessed in the normal brain after a single 30 min treatment using 2450 MHz microwaves. A single helical coil microwave antenna was inserted into the frontal white matter and reference temperatures of 40, 41, 42, 43 and 44 degrees C maintained for 30 min along a temperature sensing probe 5 mm away and parallel to the antenna. The extent of hyperthermia damage was quantified weekly for 6 weeks using computed tomography (CT), and changes in regional cerebral blood flow (rCBF), tissue vascularity and mean transit time were determined using ultrafast CT. Qualitative histopathological analysis was carried out on tissues at various times after heating. Heat lesions were radiographically characterized by rapid development and resolution and consisted of an area of focal low density surrounded by a ring of contrast enhancement. Histologically, the focus of low density corresponded to regions of tissue necrosis, whereas the ring enhancement showed local reactive changes, including endothelial cell proliferation and infiltration with macrophages. Tissue necrosis occurred at temperatures greater than 43.9 +/- 1.5 degrees C (mean +/- standard deviation), and volumes of necrosis and ring enhancement were at a maximum 1 week following treatment. Relative to the contralateral, unheated hemisphere, rCBF in the heated brain appeared to be reduced for the first 3 weeks after treatment but approached normal by week 4. The mean transit time of blood was increased for weeks 1-3 compared to the untreated hemisphere, and tissue vascularity reached a maximum, 3 weeks after treatment. The rapid CT changes together with ultrafast CT and histopathological findings suggest that focal heat lesions in the brain stimulate a significant and rapid vascular response.


Multicentre randomised controlled trial examining the cost-effectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE).
To determine whether the addition of magnetic resonance imaging (MRI) to current patient evaluation by triple assessment would aid tumour localisation within the breast and thus reduce the reoperation rate in women with primary breast tumours who are scheduled for wide local excision (WLE), and to assess whether the addition of MRI would be cost-effective for the UK NHS. A multicentre, randomised controlled, open, parallel group trial with equal randomisation. The main design was supplemented with a qualitative study to assess patients' experiences of the treatment process and care pathway, and involved the development of a non-scheduled standardised interview (NSSI). The study took place at 45 hospitals throughout the UK. Women aged 18 years or over with biopsy-proven primary breast cancer who had undergone triple assessment, were scheduled for WLE, and were capable of providing written informed consent. Patients were randomised to receive MRI or no MR1. Randomisation was performed using minimisation, incorporating a random element. All MRI was performed at 1.5 T or 1.0 T with a dedicated bilateral breast coil. The primary end point of the trial was the reoperation rate. Secondary outcome measures included discrepancies between imaging and histopathology, and the effectiveness of using both procedures; change in clinical management after using MRI; the clinical significance of MRI-only-detected lesions; the rate of interventions; the ipsilateral tumour recurrence rate; patient quality of life (QoL); and cost-effectiveness. From a total of 1623 patients, 816 were randomised to MRI and 807 to no MRI. No differences in reoperation rates were found between the two groups of patients [MRI patients 18.75%, no MRI 19.33%, difference 0.58%, 95% confidence interval (CI) -3.24 to 4.40]. Therefore, the addition of MRI to conventional triple assessment was not found to be statistically significantly associated with a reduced reoperation rate (odds ratio = 0.96, 95% CI 0.75-1.24, p = 0.7691). The best agreement between all imaging modalities and histopathology with regard to tumour size and extent of disease was found in patients over 50 years old with ductal tumours NST and who were node negative. In the imaging arm, mastectomy was found to be pathologically avoidable for 16 (27.6%) out of 58 patients who underwent the procedure. There were no significant differences between the groups regarding the proportion of patients receiving chemotherapy, radiotherapy or additional adjuvant therapies, as well as for local recurrence-free interval rates and QoL. An acceptable NSSI was developed for use in this population of patients. Economic analysis found no difference in outcomes between the two trial arms. The addition of MRI to triple assessment did not result in a reduction in operation rates, and the use of MRI would thus consume extra resource with few or no benefits in terms of cost-effectiveness or HRQoL. However, MRI showed potential to improve tumour localisation, and preoperative biopsy of MRI-only-detected lesions is likely to minimise the incidence of inappropriate mastectomy. Current Controlled Trials ISRCTN57474502.


Epinephrine-induced mobilization of natural killer (NK) cells and NK-like T cells in HIV-infected patients.
HIV infection is known to cause changes in phenotype and function of natural killer (NK) cells. The aim of this study was to characterize the NK cells mobilized from peripheral reservoirs in human immunodeficiency virus (HIV)-infected patients and controls. Seventeen HIV-infected patients and eight age- and sex-matched controls received a 1-h epinephrine infusion. Epinephrine induced mobilization of high numbers of NK-like T cells with no difference between HIV-infected patients and controls. Interestingly, all subjects mobilized NK cells containing increased proportions of perforin, in particular the CD3(-)CD16(+)CD56(+) NK cell subset. The HIV-infected patients mobilized CD3(-)CD16(-)CD56(+) and CD3(-)CD16(+)CD56(+) NK cells to a lesser extent than did controls. In contrast, the HIV-infected patients mobilized relatively more CD3(-)CD16(+)CD56(-) NK cells independent of antiretroviral treatment. It is suggested that these cells represent an immature NK cell subpopulation possibly resulting from an impaired cytokine tissue environment in HIV-infected patients.


Respiratory distress, pneumonic changes on chest X-ray, hypoxaemia, oral candidiasis in a homosexual male: not always Pneumocystis carinii pneumonia.
A young homosexual male presented to the emergency department with respiratory distress, oropharyngeal candidiasis, hypoxaemia, and renal failure. Pneumocystis carinii pneumonia was considered to be the likely diagnosis - until 24 h later when the patient divulged the true history of paraquat ingestion some 5 days previously. Ingestion of corrosives should be considered in patients with oropharyngeal candidiasis and pneumonic symptoms, especially in the presence of renal failure as an alternative to HIV infection.


Evaluation of antioxidant, antinociceptive, and anti-inflammatory activities of ethanol extracts from Aloe saponaria Haw.
Aloe species are traditionally prescribed for hypertension, burning, and rheumatoid arthritis. To elucidate the mechanism of the antihypertensive and anti-inflammatory activities of this herb, the ethanol fraction from A. saponaria Haw. was evaluated for antioxidative activity using xanthine-xanthine oxidase (XO) assay, 2,2-Diphenyl-lpicrylhydrazyl radical (DPPH) assay, lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cell, and antinociceptive activity using a tail-flick assay and hind paw pressure assay in cisplatin-treated hyperalgesic rats. The ethanol fraction displayed potent antioxidative activities in XO assay. In addition, ethanol fractions showed potent scavenging effects in DPPH assay. We next examined whether ethanol fractions showed anti-inflammatory activities. Ethanol fractions significantly suppressed NO production from LPS-activated RAW264.7 cells. As expected, ethanol fractions dose-dependently inhibited the messenger RNA expression of inducible NO synthase (iNOS). Moreover, ethanol fractions potently suppressed the expression of cycloxygenase (COX)-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are stimulated by LPS in RAW264.7 cells. In addition, ethanol fractions significantly blocked cisplatin-induced hyperalgesia using tail-flick assay and hind paw pressure test in rats. Taken altogether, ethanol extracts of aloe may be useful as a functional food or as a drug against reactive oxygen species (ROS) mediated diseases.


Effectiveness and Safety of Anlotinib Monotherapy for Patients with Extensive-stage Small-Cell Lung Cancer Who Progressed to Chemotherapy: A Real-world Exploratory Study.
Anlotinib demonstrated promising efficacy for patients with extensive-stage small-cell lung cancer (ES-SCLC) in clinical trials. However, the real-world evidence of anlotinib monotherapy in ES-SCLC was still limited currently. Therefore, present study was to investigate the effectiveness and safety of anlotinib for patients with ES-SCLC who progressed to chemotherapy in real-world and the potential biomarker during anlotinib monotherapy. A total of 89 patients with ES-SCLC who failed the previous chemotherapy treatment were recruited. All the patients were administered with anlotinib monotherapy. Demographic data of the patients were collected; effectiveness and safety profile during anlotinib monotherapy were documented through electronic medical record system in the hospital. Progression-free survival (PFS) and overall survival (OS) were presented using Kaplan-Meier survival curves and multivariate analysis was adjusted by Cox regression analysis. All the 89 patients with ES-SCLC who progressed to chemotherapy were available for the assessment of effectiveness and safety profile. Best overall response indicated that partial response was observed in 6 patients (6.7%), stable disease was noted in 61 patients (68.5%), and progressive disease was found in 22 patients (24.7%). Therefore, the objective response rate (ORR) and disease control rate (DCR) of the 89 patients with ES-SCLC was 6.7% (95% confidence interval [CI]: 2.5%-14.1%) and 75.3% (95% CI: 65.0%-83.8%), respectively. The prognostic data suggested that the median PFS of the 89 patients was 3.1 months (95% CI: 2.10-4.10), and the median OS was 8.6 months (95% CI: 7.42-9.78). In addition, the most common adverse reactions of the patients who received anlotinib monotherapy were hypertension (34.8%), hand-foot syndrome (30.3%), fatigue (29.2%), loss of appetite (27.0%), and hematological toxicity (21.3%). Association analysis between biomarker (hypertension status) and prognosis indicated that the median PFS of patients with hypertension and patients with non-hypertension was 5.5 and 3.0 months, respectively (χ2 = 4.64, P = .031). Furthermore, multivariate Cox analysis for PFS suggested that hypertension status was an independent factor for PFS (hazard ratio [HR] = 0.71, P = .035]. Anlotinib monotherapy showed encouraging effectiveness and acceptable safety profile for patients with ES-SCLC in real world. Hypertension induced by anlotinib administration might be used as a potential biomarker to predict superior PFS for patients with ES-SCLC.


Molecular characterization of a new potyvirus infecting passion fruit.
A potyvirus (isolate PFV-FJ) infecting passion fruit in China was identified by small-RNA sequencing. The complete genome sequence of PFV-FJ was determined to be 9974 nucleotides, excluding the poly(A) tail. PFV-FJ shares 70-72% nucleotide and 69-74% amino acid sequence identity at the polyprotein level with seven reported potyviruses, but 89% nucleotide and 91% amino acid sequence identity with an unreported potyvirus, tentatively named "passionfruit Vietnam potyvirus" (PVNV-DakNong). This suggests that PFV-FJ and PVNV-DakNong should belong to the same potyvirus species and that PFV-FJ is a new member of the genus Potyvirus. This new potyvirus was tentatively named "passion fruit severe mottle-associated virus".


[Effect of Boron-antimony Interaction on the Uptake and Accumulation of Antimony and Boron by Rice Seedling].
Effect of interactions between boron (B) and antimony on the uptake and accumulation by rice (Oryza sativa L.) seedling was investigated in solution culture. The results showed that Sb(III) and Sb(V) could inhibit rice growth and Sb(III) was more toxic than Sb(V). Concentrations of B in rice roots and shoots were significantly affected by the addition of Sb(III) and Sb(V). The addition of 30 μmol x L(-1) Sb(III) could significantly decrease B of rice shoots and roots by 57.6% and 75.6%, and 30 μmol x L(-1) Sb(V) could decrease B of rice roots by 16.0%, compared with the control treatment, when the B concentration was 0.5 mg x L(-1). Equally, adding B also significantly affected the concentrations of Sb in rice roots and shoots. The addition of 2.0 mg x L(-1) B could decrease the concentrations of Sb in rice roots and shoots,by 39.1% and 9.2%, respectively, compared with 0.5 mg x L(-1) B, when the Sb(III) concentration was 10 μmol x L(-1). Adding 2.0 mg x L(-1) B could decreasd Sb concentrations in rice roots by 13.9%, compared with 0.5 mg x L(-1) B, when the Sb(V) concentration was 10 μmol x L(-1). Furthermore, adding B had significant effect on bioaccumulation factor and distribution ratio of Sb in rice roots and shoots. The results of the study demonstrated that Sb pollution in farmland could be alleviated by adding B fertilizer, thus protecting human health from Sb pollution.


Tioconazole 2% cream in the treatment of Trichomonas vaginalis or mixed vaginal infections.
Twenty patients with documented T. vaginalis infections, six of whom were simultaneously infected with C. albicans and one with G. vaginalis, were treated topically (intravaginally) once daily with 5 g of 2% tioconazole vaginal cream (Trosyd, Pfizer) for 3 consecutive days in an open, non-comparative study. At the first follow-up visit (about 7 days post-treatment), 95% (19/20) of the patients were cured; 95% (18/19) of patients remained cured with respect to the baseline infection at the long-term follow-up (2 months post-treatment) visit, and one patient had a reinfection or relapse with T. vaginalis. Only one patient reported a side-effect, a mild vaginal burning which disappeared with continued treatment. It was concluded that tioconazole 2% vaginal cream is safe and effective for the treatment of T. vaginalis and mixed vaginal infections.


Effects of albaconol from the basidiomycete Albatrellus confluens on DNA topoisomerase II-mediated DNA cleavage and relaxation.
The effect of albaconol on the growth of human tumor cell, DNA topoisomerase (topo)-mediated DNA cleavage and direct DNA breakage was investigated. Albaconol inhibited significantly the growth of the human tumor cell lines K562, A549, BGC-823 and Bcap-37, the IC5s values were 7.99 +/- 0.4, 3.17 +/- 0.89, 4.18 +/- 0.14 and 7.45 +/- 2.5 microM, respectively. Albaconol stabilized and increased the topo 11-mediated DNA cleavable complex and inhibited the religation activity of topo II in a dose-dependent manner, but it failed to affect the activity of topo I. Albaconol directly broke pBR322 DNA at high concentrations, but there was no effect on the macromolecule of K562 cells. These results strongly suggest that albaconol targeted specifically to DNA topo II and that this is one of the mechanisms of its antitumor action; the direct action of albaconol on DNA may partly contribute to its anti-tumor activity at high concentrations.


B(2)A(')-X(2)A(') detection of vibrationally excited HCO produced by the O((3)P)+C(2)H(4) reaction.
The distribution of rotational and vibrational energy in HCO produced by the O((3)P)+C(2)H(4) reaction has been measured using laser-induced fluorescence detection via the B(2)A(')-X(2)A(') transition. Over a detection wavelength range of 248-290 nm, our experiments have shown that HCO is formed in both the ground state and in at least six vibrationally excited states with up to two quanta of energy in the C-O stretch and the bending mode. Dispersed fluorescence experiments were conducted to positively assign all of the HCO vibrational bands. The experiments confirmed that many bands, including the B(000)-X(000) band, are affected by overlap with other HCO bands. Spectral modeling was used to separate the contributions of overlapping HCO B-X bands and to determine a nascent HCO rotational temperature of approximately 600 K, corresponding to approximately 6% of the total energy from the O((3)P)+C(2)H(4) reaction. HCO vibrational distributions were determined for two different average collision energies and were fit with vibrational temperatures of 1850+/-80 K and 2000+/-100 K, corresponding to approximately 15% of the total energy. The observed Boltzmann distribution of vibrational energy in HCO indicates that HCO and CH(3) are formed by the dissociation of an energized intermediate complex.


caGrid 1.0: a Grid enterprise architecture for cancer research.
caGrid is the core Grid architecture of the NCI-sponsored cancer Biomedical Informatics Grid (caBIG) program. The current release, caGrid version 1.0, is developed as the production Grid software infrastructure of caBIG. Based on feedback from adopters of the previous version (caGrid 0.5), it has been significantly enhanced with new features and improvements to existing components. This paper presents an overview of caGrid 1.0, its main components, and enhancements over caGrid 0.5.


Ultra-wideline 14N NMR spectroscopy as a probe of molecular dynamics.
We show that ultra-wideline solid-state (14)N NMR can be used as a quantitative probe of molecular dynamics. Jump rates for the molecular flipping mechanism in crystalline urea are determined at various temperatures and are shown to be in good agreement with other NMR techniques.


Detailed physicochemical characterization of the 2S storage protein from rape (Brassica napus L.).
Chromatographic, chemical, and spectroscopic techniques were used to characterize the physicochemical properties of napin purified by preparative chromatography. The molar extinction coefficient was determined (epsilon = 0.56), and static and dynamic light scattering measurements enabled the average molecular weight (M(w) = 13919), the second virial coefficient (A(2) = 23.95 x 10(-)(5) mol cm(3) g(-)(2)), and the hydrodynamic radius (R(H) = 1.98 nm) to be determined. No conformational changes were observed by fluorescence and circular dichroism measurements in different buffers at pH 3, 4.6, 7, and 12, confirming the high pH stability of this protein. From MALDI-TOF analysis and after enzymatic digestion, it was found that this purified sample, extracted from the rapeseed variety Express, contained mainly isoform 2SS3_BRANA.


Eye position encoding in three-dimensional space: integration of version and vergence signals in the medial posterior parietal cortex.
Eye position signals are pivotal in the visuomotor transformations performed by the posterior parietal cortex (PPC), but to date there are few studies addressing the influence of vergence angle upon single PPC neurons. In the present study, we investigated the influence on single neurons of the medial PPC area V6A of vergence and version signals. Single-unit activity was recorded from V6A in two Macaca fascicularis fixating real targets in darkness. The fixation targets were placed at eye level and at different vergence and version angles within the peripersonal space. Few neurons were modulated by version or vergence only, while the majority of cells were affected by both signals. We advance here the hypothesis that gaze-modulated V6A cells are able to encode gazed positions in the three-dimensional space. In single cells, version and vergence influenced the discharge with variable time course. In several cases, the two gaze variables influence neural discharges during only a part of the fixation time, but, more often, their influence persisted through large parts of it. Cells discharging for the first 400-500 ms of fixation could signal the arrival of gaze (and/or of spotlight of attention) in a new position in the peripersonal space. Cells showing a more sustained activity during the fixation period could better signal the location in space of the gazed objects. Both signals are critical for the control of upcoming or ongoing arm movements, such as those needed to reach and grasp objects located in the peripersonal space.


How to deliver specialized nutritional support.
Integrating specialized nutritional support into long term care facilities will continue to be a multidisciplinary process, involving the education and training of a number of members of the health care team. And as the dynamics of the current health care environment shape the way in which specialized nutritional therapy is provided, standards and protocols for nutritional assessment, enteral and parenteral therapy and staff education will be essential for cost-effective, quality patient care. Specific issues relating to these standards have been discussed--each facility should then develop its own framework for nutritional support, based on individual needs.


Factors Associated With Participation in Clinical Trials Among Patients With Lupus.
Participation rates for clinical trials, including lupus trials, in the United States are low, but are even lower for underrepresented minorities. The impact of underrepresentation in trials can be far-reaching and is problematic because female subjects of color with lupus experience greater morbidity and mortality. As such, the overarching goal of this study was to characterize the factors that influence participation in lupus clinical trials. The Lupus and Allied Diseases Association, the Lupus Foundation of America, and the Lupus Research Alliance collected data for their externally led Patient-Focused Drug Development Initiative-for the purpose of understanding and improving the rates of participation in lupus-related clinical trials. Participants completed a 46-question survey (in English or Spanish) electronically or on paper, which was distributed online or at lupus events. Logistic regression was used to test whether demographic and disease characteristics were associated with participation in past lupus trials. Data were available for 2220 respondents. Black respondents with lupus were more likely, than their White and Hispanic counterparts, to have participated in past clinical trials (p < 0.05). Although not statistically significant, Hispanic respondents were also more likely to have participated than their White counterparts (odds ratio, 1.40; 95% confidence interval, 0.96-2.11). Both demographic (ie, race/ethnicity) and medical (ie, disease severity defined as more organ involvement) factors seem to be important determinants of participation in clinical trials (p < 0.05). Combining the results from this study and prior research provides insight into recruitment strategies to increase participation rates of historically underrepresented minorities.


Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis?
The pathogenesis of acute pancreatitis is poorly understood, despite well-recognised precipitating factors. Current evidence suggests that the earliest abnormalities of acute pancreatitis arise within acinar cells, but the key intracellular trigger has yet to be identified. Within the pancreas, physiological concentrations of secretagogues bind to G-protein-linked cell-surface receptors on acinar cells, evoking short, oscillatory spikes of acinar cytosolic-free ionised calcium ([Ca2+]i), an ubiquitous intracellular messenger. Specific effects within acinar cells include initiation of enzyme release through the phosphorylation cascades of stimulus-secretion coupling. Low resting levels of [Ca2+]i are restored by Ca(2+)-ATPase, which pumps calcium into the endoplasmic reticulum and out of the cell. If high concentrations of [Ca2+]i persist, toxicity results, intracellular signalling is disrupted, and cell damage occurs. Sustained elevations in acinar [Ca2+]i result from exposure to high concentrations of secretagogues, high doses of which also induce acute pancreatitis. Similarly, sustained elevations of [Ca2+]i may result from ductal hypertension, alcohol, hypoxia, hypercalcaemia, hyperlipidaemia, viral infection, and various drugs--all factors known to precipitate acute pancreatitis. We suggest that these factors precipitate acute pancreatitis by causing either excessive release of acinar [Ca2+]i, or damage to the integrity of mechanisms that restore low resting levels of [Ca2+]i, and that the consequent calcium toxicity is the key trigger in the pathogenesis of acute pancreatitis.


Lycopersicon esculentum seeds: an industrial byproduct as an antimicrobial agent.
Lycopersicon esculentum (tomato) fruit is a widely studied matrix. However, only few works focus their attention on its seeds, which constitute a major byproduct of the tomato processing industry. In this study the antimicrobial potential of ten different tomato seed extracts from "Bull's heart" and "Cherry" varieties were analyzed against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Enterococcus faecalis and Bacillus cereus) and Gram-negative (Proteus mirabilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhimurium) bacteria and fungi (Candida albicans, Aspergillus fumigatus and Trichophyton rubrum). Regarding antibacterial capacity, the different extracts were revealed to be active only against Gram-positive bacteria, E. faecalis being the most susceptible one (MIC: 2.5-10 mg/mL). Concerning antifungal activity, "Bull's heart" extracts were the most active. In a general way C. albicans was the most susceptible species (MIC: 5-10 mg/mL). The chemical composition of the extracts was also pursued, concerning organic acids, phenolics and fatty acids, in order to establish a possible relationship with the observed antimicrobial effect.


Biopsy Marker Standardization: What's in a Name?
OBJECTIVE. The purposes of this study were to compile mammographic images in various projections showing commercially available breast biopsy site markers and to provide a standardized nomenclature and marker guide to improve physician communication and patient care. MATERIALS AND METHODS. A retrospective review of all breast biopsy markers encountered at one institution was conducted from January 2012 to January 2018. Markers placed at the facility and those placed at outside institutions with the patient subsequently referred to the study institution were included. Additional drawings and photographs and biopsy marker information were compiled from manufacturers and the literature. Intrinsic properties, features, pitfalls, and biopsy marker mimics were recorded from the institution's experience and the literature. RESULTS. Thirty-eight different biopsy marker shapes available from six manufacturers were identified, and mammograms of 37 were compiled and organized by manufacturer. Nomenclature was compiled on the basis of the manufacturer names of each marker. Potential pitfalls and mimics were identified. Manufacturer-reported marker material composition and carrier properties were summarized, including decreased marker migration, enhanced ultrasound visibility, and varying MRI susceptibility. CONCLUSION. Variability in the appearance and nomenclature of breast biopsy site markers may contribute to misinterpretation, miscommunication, and possibly removal of the incorrect lesion. A comprehensive guide to breast biopsy marker nomenclature is clinically useful, and standardization is necessary.


T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression.
Interleukin (IL)-17A, a recently described novel T cell cytokine, orchestrates inflammation in a variety of immune-mediated diseases. In the present investigation, we analyzed the temporal gene expression pattern of IL-17A and its main regulators IL-23 and IL-15 after chronic constriction injury (CCI) of the sciatic nerve, a lesion paradigm inducing neuropathic pain, by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in mice. IL-17A displayed a monophasic expression in degenerating nerves at day 7 after CCI while transcripts for the IL-17A regulatory cytokines IL-23 and IL-15 peaked earlier. Accordingly, IL-17A positive T cells were detectable within the endoneurium of the injured nerves by immunocytochemistry. In support of a crucial role of T cell inflammation, RAG-1 knockout mice lacking functional T lymphocytes did not express IL-17A mRNA in distal nerve segments following CCI. Interestingly, T cell deficiency was associated with less thermal hyperalgesia and reduced mRNA levels for the macrophage marker molecule F4/80 and the chemokine macrophage chemoattractant protein-1 (MCP-1) after CCI. Our study supports the notion that T cells and T-cell-derived cytokines contribute to the inflammatory response after peripheral nerve injury.


Stress-responsive gene TauT and acute kidney injury.
Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have demonstrated that cisplatin down-regulates the expression of the taurine transporter gene (TauT) in renal cells and that forced overexpression of TauT protects against cisplatin-induced apoptosis in renal cells in vitro and in vivo. In the present study, we have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI). Regulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry. TauT was down-regulated by p53 and up-regulated by c-Jun. Two potential binding sites for c-Jun were identified in the promoter region of TauT. Inhibition of c-Jun N-terminal kinase (JNK) enhanced TauT promoter activity. Overexpression of TauT protects against cisplatin-induced kidney injury in a TauT transgenic mouse model. Our findings suggest that TauT plays a critical role in renal function. Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway. The outcome level of TauT may determine the fate of renal cells during stress-induced AKI.


From therapeutic antibodies to chimeric antigen receptors (CARs): making better CARs based on antigen-binding domain.
A variety of approaches are being pursued to improve the safety and antitumor potency of chimeric antigen receptor (CAR) T-cell therapy. However, most engineering efforts have thus far been focused on its intracellular signaling domain, while its extracellular antigen-binding domain has received less attention. Areas covered: Herein, the authors summarize the current knowledge of CAR T-cell therapy. Accordingly, they focus on its antigen-binding domain, discuss key considerations for selecting an optimal single-chain variable fragment (scFv) when designing a CAR, and suggest potential directions aimed at developing the next-generation CARs. Expert opinion: The extracellular region of CARs can play a decisive role in their safety and efficacy. Instead of directly translating an available therapeutic mAb to a scFv-based CAR construct, the authors suggest that various CAR-displayed scFvs with different affinity, specificity and binding epitopes against an individual target molecule should be generated and evaluated side-by-side. Incorporating new antibody formats that possess characteristics superior to those of scFvs may be one way to engineer safer and more effective CARs. The authors expect that further CAR engineering will enable us to target more antigens involved in hematological and solid malignancies with minimal side effects to serve unmet clinical needs.


Mean-field nucleation theory with nonlocal interactions.
Mean-field nucleation theory has for a long time been successfully used to extract microscopic parameters from island density data in growth experiments. However, it produces grossly incorrect results when used to analyze weakly corrugated systems, where adsorbate interactions cannot be neglected. Here, a mean-field theory that includes nonlocal adsorbate interactions is developed and successfully tested against kinetic Monte Carlo growth simulations for a realistic adsorbate system.


The guilds in green algal lichens-an insight into the life of terrestrial symbiotic communities.
Lichenized algae and cyanobacteria are known to be shared and selected by unrelated lichen-forming fungi coexisting in so-called photobiont-mediated guilds. Life in such a guild could be crucial for the survival of a large group of lichen fungi dependent on horizontal transmission of photobionts. Here, we investigate frequent lichen phycobionts of the genus Trebouxia in rock-dwelling lichen communities. We found intensive and repeated sharing of specific Trebouxia assemblages by co-occurring lichens across distant localities. Rock chemistry, expressed as pH, determined the composition of photobiont pools and separated three saxicolous lichen guilds, sharing environmentally specific photobiont groups. Moreover, unlike the majority of lichen fungi, many Trebouxia photobionts represented opportunists in the choice of general substrate form (soil-rock-tree bark/wood), maintaining their pH preferences. Thus, saxicolous communities form just a part of a complex guild system that is in principle mediated by environmentally conditioned groups of naturally co-occurring photobionts. The complexity of the system is influenced by diverse photobiont life strategies, including also dispersal style. The findings of photobionts strictly or predominantly associated with sexually reproducing fungi stimulated us to emphasize the role of free-dispersing photobionts in the establishment and maintenance of lichen guilds.


Ex vivo Sensitivity Profile of Plasmodium falciparum Clinical Isolates to a Panel of Antimalarial Drugs in Ghana 13 Years After National Policy Change.
Malaria continues to be a major health issue globally with almost 85% of the global burden and deaths borne by sub-Saharan Africa and India. Although the current artemisinin derived combination therapies in Ghana are still efficacious against the Plasmodium falciparum (Pf) parasite, compounding evidence of artemisinin and amodiaquine resistance establish the need for a full, up-to-date understanding and monitoring of antimalarial resistance to provide evidence for planning control strategies. The study was cross-sectional and was conducted during the peak malaria transmission seasons of 2015, 2016, and 2017 in two ecological zones of Ghana. Study participants included children aged 6 months to 14 years. Using ex vivo 4,6-diamidino-2-phenylindole (DAPI) drug sensitivity assay, 330 Pf isolates were used to investigate susceptibility to five antimalarial drugs: chloroquine (CQ), amodiaquine (AMD) dihydroartemisinin (DHA), artesunate (ART) and mefloquine (MFQ). The pooled geometric mean IC50S (GMIC50) of the five drugs against the parasites from Cape Coast and Begoro were 15.5, 42.4, 18.9, 4.6 and 27.3nM for CQ, AMD, DHA, ART, and MFQ, respectively. The GMIC50 values for CQ (p<0.001), ART (p<0.011) and DHA (p<0.018) were significantly higher for Cape Coast isolates as compared to Begoro isolates. However, GMIC50 estimates for MFQ (p<0.022) were significantly higher for Begoro isolates. Positive correlations were found between each pair of drugs with the weakest found between MFQ and DHA (r = 0.34;p<0.001), and the strongest between ART and DHA (r =0.66; p<0.001). The parasites showed reduced sensitivities to three (AMD, DHA and MFQ) out of the five drugs assessed. The study also demonstrated the continual return of chloroquine-sensitive parasites after 13 years of its withdrawal as the first-line drug for the treatment of uncomplicated malaria in Ghana. The ex vivo DAPI assay is a reliable method for assessing antimalarial drug sensitivities of Pf field isolates under field settings.


α-Lactalbumin peptide Asp-Gln-Trp alleviates hepatic insulin resistance and modulates gut microbiota dysbiosis in high-fat diet-induced NAFLD mice.
The progression of nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and gut microbiota. Dietary interventions have emerged as effective palliative strategies for NAFLD. The present study investigated the potential mechanisms by which α-lactalbumin peptide Asp-Gln-Trp (DQW) ameliorated insulin resistance and gut microbiota dysbiosis in high-fat diet (HFD)-induced NAFLD mice. The results demonstrated that DQW treatment alleviated HFD-induced body weight gain, hepatic steatosis, insulin resistance, and dyslipidemia. DQW treatment also increased the ratio of Bacteroides to Firmicutes in the gut, reduced the relative abundance of pathogenic bacteria (such as Bacteroides, Blautia, and Alistipes) and enhanced the relative abundance of short-chain fatty acid (SCFA)-producing bacteria (such as Muribaculaceae, Lachnospiraceae_NK4A136_group, and Rikenellaceae_RC9_gut_group). DQW treatment promoted the production of SCFAs and subsequently improved intestinal barrier integrity and inflammation. Furthermore, the results of real-time quantitative PCR (qRT-PCR) and western blotting further proved that the effects of DQW on the attenuation of hepatic insulin resistance were mediated by the PPARα and IRS1/PI3K/AKT pathways. Taken together, these results indicated that DQW treatment could attenuate HFD-induced NAFLD and insulin resistance by modulating gut microbiota composition, enhancing the SCFA levels, and activating the PPARα and IRS1/PI3K/Akt pathways.


Triple-layer sealing with absorptive mesh and fibrin glue is effective in preventing air leakage after segmentectomy: results from experiments and clinical study.
Fibrin glue in combination with polyglycolic acid (PGA) mesh is effective in preventing air leakage after segmentectomy, but we frequently experienced air leakage with single-layer application. To investigate improved usage, we compared the sealing effect among single-, double- and triple-layer PGA mesh and fibrin glue in both experimental and clinical segmentectomy. Ex vivo pig lungs were used for experiments. As a model of segmentectomy, the lateral segment of the left lung was removed using electrocautery. As a model of peripheral lung defect, peripheral lung tissue was resected with scissors. The inter-segmental plane and the peripheral lung defect were sealed using one of the following four methods: (i) fibrin glue alone (Group 1, n = 8), (ii) single-layer with PGA mesh and fibrin glue (Group 2, n = 8), (iii) double-layer (Group 3, n = 8) and (iv) triple-layer (Group 4, n = 8). The seal-breaking pressures among them were compared. In clinical segmentectomy, the periods of chest-tube drainage were compared retrospectively between 17 patients treated by the single-layer and 17 treated by the triple-layer method. In experimental segmentectomy, the seal-breaking pressure in the triple-layer (100 ± 25 cmH2O) was significantly higher than those in the other methods (26 ± 17, 48 ± 12 and 69 ± 19 cmH2O in the Groups 1, 2 and 3, respectively, P < 0.001-0.05), while there were no significant differences among other methods. For peripheral lung defect, the seal-breaking pressures did not differ among the methods. In clinical segmentectomy, the mean chest-drainage period with the triple-layer was 2 ± 0.9 days, which was significantly shorter than 3.6 ± 2.8 days with the single-layer (P = 0.009). Stronger sealants are required to prevent air leakage from inter-segmental planes than from peripheral lung. To prevent air leakage after segmentectomy, triple-layer PGA mesh and fibrin glue is recommended.


Th1/Th17-mediated Immunity and Protection from Peripheral Neuropathy in Wildtype and IL10-/- BALB/c Mice Infected with a Guillain-Barré Syndrome-associated Campylobacter jejuni Strain.
Campylobacter jejuni is an important cause of bacterial gastroenteritis worldwide and is linked to Guillain-Barré syndrome (GBS), a debilitating postinfectious polyneuropathy. The immunopathogenesis of GBS involves the generation of antibodies that are cross reactive to C. jejuni lipooligosaccharide and structurally similar peripheral nerve gangliosides. Both the C. jejuni infecting strain and host factors contribute to GBS development. GBS pathogenesis is associated with Th2-mediated responses in patients. Moreover, induction of IgG1 antiganglioside antibodies in association with colonic Th2-mediated immune responses has been reported in C. jejuni-infected C57BL/6 IL10-/- mice at 4 to 6 wk after infection. We hypothesized that, due to their Th2 immunologic bias, BALB/c mice would develop autoantibodies and signs of peripheral neuropathy after infection with a GBS patient-derived strain of C. jejuni (strain 260.94). WT and IL10-/- BALB/c mice were orally inoculated with C. jejuni 260.94, phenotyped weekly for neurologic deficits, and euthanized after 5 wk. Immune responses were assessed as C. jejuni-specific and antiganglioside antibodies in plasma and cytokine production and histologic lesions in the proximal colon. Peripheral nerve lesions were assessed in dorsal root ganglia and their afferent nerve fibers by scoring immunohistochemically labeled macrophages through morphometry. C. jejuni 260.94 stably colonized both WT and IL10-/- mice and induced systemic Th1/Th17-mediated immune responses with significant increases in C. jejuni-specific IgG2a, IgG2b, and IgG3 plasma antibodies. However, C. jejuni 260.94 did not induce IgG1 antiganglioside antibodies, colitis, or neurologic deficits or peripheral nerve lesions in WT or IL10-/- mice. Both WT and IL10-/- BALB/c mice showed relative protection from development of Th2-mediated immunity and antiganglioside antibodies as compared with C57BL/6 IL10-/- mice. Therefore, BALB/c mice infected with C. jejuni 260.94 are not an effective disease model but provide the opportunity to study the role of immune mechanisms and host genetic background in the susceptibility to post infectious GBS.


Individually distinct Ig homology domains in PECAM-1 regulate homophilic binding and modulate receptor affinity.
PECAM-1 (CD31) is a 130-kDa member of the immunoglobulin (Ig) gene superfamily that is constitutively expressed at high concentration at endothelial cell intercellular junctions and at moderate density on the surface of circulating leukocytes and platelets. Recent in vitro and in vivo studies have shown the PECAM-1 plays a central role in mediating the extravasation of leukocytes from the vessel wall in response to inflammatory mediators. To study the binding characteristics of PECAM-1, phospholipid vesicles were prepared and examined by flow cytometry and immunofluorescence microscopy for their ability to associate with each other and with cells. Proteoliposomes containing high concentrations of PECAM-1 interacted homophilically with each other, forming large self-aggregates. PECAM-1 proteoliposomes, as well as soluble bivalent PECAM-1 in the form of a PECAM-1/IgG immunoadhesin, associated homophilically with cells expressing human, but not murine, PECAM-1. This binding could be completely inhibited by monoclonal antibody Fab fragments specific for Ig homology Domain 1 or Domains 1 + 2. Binding studies using cells expressing human PECAM-1 deletion mutants and murine/human chimeras confirmed that both Ig Domains 1 and 2 were both necessary and sufficient for homophilic binding. In contrast, engagement of membrane-proximal Domain 6 with monoclonal antibody Fab fragments had the opposite effect and augmented the binding of PECAM-1 proteoliposomes to cells. Thus, PECAM-1, like certain integrins, appears to be capable of antibody-induced conformational changes that alter affinity for its ligand. Similar changes induced by physiologic stimuli could be important in regulating the function of PECAM-1 in vascular cells.


Quality of life of leprosy patients in Sabah.
To determine the Dermatology Life Quality Index (DLQI) among the subtypes of leprosy and to examine correlation with deformity and lepra reactions. This was a cross-sectional study done at Dermatology Outpatient Clinic, Queen Elizabeth Hospital and two health clinics in Kota Kinabalu between 1st April 2019 and 30th November 2019. A standardised case report form was formulated to collect the demographic data and disease profile of the leprosy patients. The quality of life (QoL) was assessed using Dermatology Life Quality Index (DLQI) questionnaire. A total of 54 patients were included with a male to female ratio of 2.4:1 (38 males and 16 females). The mean DLQI score was 8.31±6.15. The difference between the mean DLQI scores among the leprosy subtypes was not significant. The most affected domain was symptoms and feeling followed by daily activities and leisure. Twenty-one patients (38.9%) had facial deformity and they were found to have significantly higher DLQI score. WHO grade 1 and 2 disability were observed in 37 patients (68.5%) with higher DLQI score compared to those without any disability. More than half of patients with MB leprosy (52.2%) developed lepra reactions but the difference of mean DLQI scores were not significant. Leprosy-related disabilities may predispose patients to develop psychosocial problems which may have negative impact on QoL. Thus, periodic assessment of QoL should be incorporated into the management of leprosy patients.


Calmodulin activation of an endoplasmic reticulum-located calcium pump involves an interaction with the N-terminal autoinhibitory domain.
To investigate how calmodulin regulates a unique subfamily of Ca(2+) pumps found in plants, we examined the kinetic properties of isoform ACA2 identified in Arabidopsis. A recombinant ACA2 was expressed in a yeast K616 mutant deficient in two endogenous Ca(2+) pumps. Orthovanadate-sensitive (45)Ca(2+) transport into vesicles isolated from transformants demonstrated that ACA2 is a Ca(2+) pump. Ca(2+) pumping by the full-length protein (ACA2-1) was 4- to 10-fold lower than that of the N-terminal truncated ACA2-2 (Delta2-80), indicating that the N-terminal domain normally acts to inhibit the pump. An inhibitory sequence (IC(50) = 4 microM) was localized to a region within valine-20 to leucine-44, because a peptide corresponding to this sequence lowered the V(max) and increased the K(m) for Ca(2+) of the constitutively active ACA2-2 to values comparable to the full-length pump. The peptide also blocked the activity (IC(50) = 7 microM) of a Ca(2+) pump (AtECA1) belonging to a second family of Ca(2+) pumps. This inhibitory sequence appears to overlap with a calmodulin-binding site in ACA2, previously mapped between aspartate-19 and arginine-36 (J.F. Harper, B. Hong, I. Hwang, H.Q. Guo, R. Stoddard, J.F. Huang, M.G. Palmgren, H. Sze ¿1998 J Biol Chem 273: 1099-1106). These results support a model in which the pump is kept "unactivated" by an intramolecular interaction between an autoinhibitory sequence located between residues 20 and 44 and a site in the Ca(2+) pump core that is highly conserved between different Ca(2+) pump families. Results further support a model in which activation occurs as a result of Ca(2+)-induced binding of calmodulin to a site overlapping or immediately adjacent to the autoinhibitory sequence.


The reconstruction on the game networks with binary-state and multi-state dynamics.
Reconstruction of network is to infer the relationship among nodes using observation data, which is helpful to reveal properties and functions of complex systems. In view of the low reconstruction accuracy based on small data and the subjectivity of threshold to infer adjacency matrix, the paper proposes two models: the quadratic compressive sensing (QCS) and integer compressive sensing (ICS). Then a combined method (CCS) is given based on QCS and ICS, which can be used on binary-state and multi-state dynamics. It is found that CCS is usually a superior method comparing with compressive sensing, LASSO on several networks with different structures and scales. And it can infer larger node correctly than the other two methods. The paper is conducive to reveal the hidden relationship with small data so that to understand, predicate and control a vast intricate system.


Convective heat transport in compressible fluids.
We present hydrodynamic equations of compressible fluids in gravity as a generalization of those in the Boussinesq approximation used for nearly incompressible fluids. They account for adiabatic processes taking place throughout the cell (the piston effect) and those taking place within plumes (the adiabatic temperature gradient effect). Performing two-dimensional numerical analysis, we reveal some unique features of plume generation and convection in transient and steady states of compressible fluids. As the critical point is approached, the overall temperature changes induced by plume arrivals at the boundary walls are amplified, giving rise to overshoot behavior in transient states and significant noise in the temperature in steady states. The velocity field is suggested to assume a logarithmic profile within boundary layers. Random reversal of macroscopic shear flow is examined in a cell with unit aspect ratio. We also present a simple scaling theory for moderate Rayleigh numbers.


An open-label evaluation of the tolerability and safety of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease patients experiencing wearing-off.
To evaluate the tolerability, safety and efficacy of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease (PD). Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound. An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments. 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments. Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.


Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel.
Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of -7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.


Treatment of an infundibular aneurysm by posterior communicating origin disconnection, induced flow reversal and flow diversion after attempted surgical clipping: Case report.
Infundibular aneurysms are rare lesions that present unique challenges for both surgical and endovascular approaches. We present a case of a 58-year old man with an incidental 7.5 × 3 mm infundibular aneurysm that incorporated the origin of the posterior communicating artery (PCoA). The fusiform aneurysm incorporated the supraclinoid ICA to the terminus. An attempt at surgical clip reconstruction of the aneurysm to preserve the PCoA was not technically possible due to atherosclerosis at the aneurysm neck. The aneurysm was treated with disconnection of the PCoA origin, induced flow reversal and placement of a flow diverter, after confirmation of adequate collateral flow to the PCoA perforators from the posterior circulation. The case illustrates important concepts in the evaluation and management of infundibular aneurysms, including both reconstructive and deconstructive strategies.


Morphometry of human lumbar apophyseal joints. A novel technique.
The anatomy of cadaveric lumbar apophyseal joints was examined as part of a study of possible correlations between lumbar apophyseal morphology, arthrosis, and cartilage thickness and stiffness. To establish the morphometry of human upper lumbar apophyseal joints using an objective technique. The apophyseal joints of 30 unfixed lumbar motion segments, all from different cadavers (24 male, five female, and one unknown, mean age 35 years, range 16-78 years) were exposed by dissection and disarticulation. Twenty-five motion segments were L1-L2, three were L2-L3, and two were L3-L4. The extent of fibrillation and linear dimensions of 29 of these specimens were examined, whereas the vertebrae and joints of 22 of them (18 being L1-L2) were cast in araldite resin. The casts of the vertebrae were sectioned cephalocaudally at 1-mm intervals. Image processing of photographic slides of the sections established the orientations and dimensions of the lumbar apophyseal joints and their shapes using Fourier analysis. Apophyseal joint surface area was 158 +/- 43 mm2, cephalocaudal length 15.2 +/- 2.7 mm, and straight line length between anterior and posterior borders was 13.2 +/- 1.9 mm. The joints were orientated at 62.5 +/- 11.8 degrees to the coronal plane. Average maximum depth of concavity was 1.8 +/- 0.7 mm. The posterior edges of two joint pairs twisted inward toward the midsagittal plane in a cephalocaudal direction; thus, some apophyseal joints bear part of the axial spinal load. The right inferior surfaces were more elongated cephalocaudally (but not longer) than their contralateral partners. Inferior apophyses were significantly more elongated cephalocaudally (but not longer) than their ipsilateral articulating superior surfaces. In theory, Fourier analysis of joint surfaces was objective, but it dictated the criterion by which joints were grouped; care must be exercised so that measurement methods do not categorize joints artificially. "Symmetry" is too subjective to be applied to contralateral apophyseal joints; correlation coefficients should be quoted for areas and orientations. The morphology of contralateral lumbar apophyseal joint pairs was significantly correlated in all respects, as was the morphology of articulating lumbar apophyseal surfaces.


Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes.
Holoprosencephaly (HPE), the most common structural malformation of the forebrain in humans, can be detected early during pregnancy using prenatal ultrasonography . Among foetuses with a normal karyotype, 14% have mutations in the four main HPE genes (SHH, ZIC2, SIX3 and TGIF). Genomic rearrangements have now been implicated in many genetic diseases, so we hypothesized that microdeletions in the major HPE genes may also be common in HPE foetuses with severe phenotype or other associated malformations. We screened the DNA obtained from 94 HPE foetuses with a normal karyotype for the presence of microdeletions involving the four major HPE genes (SHH, ZIC2, SIX3 and TGIF). Thirteen of the foetuses had a point mutation in one of the 4 genes and 81 had no known mutations. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis was used for rapid determination of HPE genes copy numbers and the identified microdeletions were confirmed by real time quantitative PCR, or fluorescent in situ hybridization (FISH) (if a cell line was available). Microdeletions were detected in 8 of 94 foetuses (8.5%) (2 in SHH, 2 in SIX3, 3 in ZIC2 and 1 in TGIF genes), and only among the 81 foetuses with a normal karyotype and no point mutations. These data suggest that microdeletions in the four main HPE genes are a common cause of prenatal HPE, as well as point mutations, and increase the total diagnosis rate close to approximately 22.3% of foetuses with normal karyotype. Detection can be achieved by the QMPSF testing method that proved to be efficient for testing several genes in a single assay.


Stochastic kinetic models of chiral autocatalysis: a general tool for the quantitative interpretation of total asymmetric synthesis.
A continuous time discrete state stochastic kinetic approach is used to study various chiral autocatalytic models in which the possibility of total asymmetric synthesis arises. It is shown that this approach is superior to the deterministic approaches used earlier and is able to interpret many aspects of chiral autocatalysis. First-order autocatalysis, independently of further kinetic details of the system, leads to a unique final statistical distribution of enantiomers. Higher order autocatalysis, on the other hand, leads to a final state where one of the enantiomers is in overwhelming excess over the other. Criteria are postulated to differentiate between inherently stochastic phenomena in chiral autocatalytic reactions and irreproducibility because of insufficient control of external factors.


Pharmacophore and three-dimensional quantitative structure activity relationship methods for modeling cytochrome p450 active sites.
Structure activity relationships (SAR), three-dimensional structure activity relationships (3D-QSAR), and pharmacophores represent useful tools in understanding cytochrome P450 (CYP) active sites in the absence of crystal structures for these human enzymes. These approaches have developed over the last 30 years such that they are now being applied in numerous industrial and academic laboratories solely for this purpose. Such computational approaches have helped in understanding substrate and inhibitor binding to the major human CYPs 1A2, 2B6, 2C9, 2D6, 3A4 as well as other CYPs and additionally complement homology models for these enzymes. Similarly, these approaches may assist in our understanding of CYP induction. This review describes in detail the development of pharmacophores and 3D-QSAR techniques, which are now being more widely used for modeling CYPs; the review will also describe how such approaches are likely to further impact our active site knowledge of these omnipresent and important enzymes.


Multiple pathways suppress non-allelic homologous recombination during meiosis in Saccharomyces cerevisiae.
Recombination during meiosis in the form of crossover events promotes the segregation of homologous chromosomes by providing the only physical linkage between these chromosomes. Recombination occurs not only between allelic sites but also between non-allelic (ectopic) sites. Ectopic recombination is often suppressed to prevent non-productive linkages. In this study, we examined the effects of various mutations in genes involved in meiotic recombination on ectopic recombination during meiosis. RAD24, a DNA damage checkpoint clamp-loader gene, suppressed ectopic recombination in wild type in the same pathway as RAD51. In the absence of RAD24, a meiosis-specific recA homolog, DMC1, suppressed the recombination. Homology search and strand exchange in ectopic recombination occurred when either the RAD51 or the DMC1 recA homolog was absent, but was promoted by RAD52. Unexpectedly, the zip1 mutant, which is defective in chromosome synapsis, showed a decrease, rather than an increase, in ectopic recombination. Our results provide evidence for two types of ectopic recombination: one that occurs in wild-type cells and a second that occurs predominantly when the checkpoint pathway is inactivated.


Synthesis of Hemiprotonic Phenanthroline-Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity.
Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph-ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph-ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.


Transport and modification of humic substances present in Antarctic snow and ancient ice.
We performed a study of fulvic acids extracted from fresh and aged snow, and from recent and ancient ice in Antarctica. The fresh snow samples were collected in coastal and inland sites to evaluate the influence of the distance from the sea on organic matter transport. Moreover, in a site (Melbourne Mountain) samples were collected at different heights to study the influence of altitude on transport. The obtained results showed that dissolved fulvic acid concentrations are influenced neither by distance nor by height while particulate fulvic acid concentrations are influenced by both parameters. Moreover, the results showed that fulvic acids transported for a long distance can undergo chemical modifications. Chemical modifications are better evidenced by the analysis of samples taken in trenches at different depth, which showed structural changes attributable to the loss of nitrogen-containing compounds and to an increase in aromatic character of the structures due to reduction and/or condensation processes. With ageing, the humification process proceeds with heavy carbon losses as demonstrated by results obtained from fulvic acids isolated from ice aged between twenty-five thousand and seventy thousand years.


Effect of a dried Bacillus subtilis culture on gosling growth performance.
1. The study was conducted to evaluate the effects of a dried Bacillus subtilis culture (DBSC) on growth performance and nutrient retention of goslings. 2. A total of 240 goslings were randomly divided into 4 dietary treatments with 6 replicates of 10 goslings per pen from 0 to 4 weeks of age. The 4 treatments consisted of a basal diet containing neither antibiotics nor DBSC (control), basal diet supplemented 5 mg Flavomycin/kg, and basal diet supplemented with 250 or 500 mg DBSC/kg. 3. Body weight and feed consumption were measured with pen as the experimental unit at 14 and 28 d of age, and excreta collections from each pen were carried out to determine nutrient retention ratio during the 4th week. 4. The results showed that the diet supplemented with 250 mg DBSC/kg increased average daily gain (ADG) by 6.9%, reduced average daily feed intake (ADFI) by 3.9%, and improved feed conversion ratio (FCR) by 10.3% in a 0-28 d feeding period, compared with the control diet. However, the diet containing 500 mg DBSC/kg did not effect these performance of goslings. 5. The goslings given the diet with 250 mg DBSC/kg had similar ADG, lower ADFI and significantly lower FCR to or than the goslings fed on the Flavomycin diet. 6. The results also showed that dietary DBSC supplementation improved dry matter and energy retention of goslings. 7. This study indicated that the diet containing a dried B. subtilis culture at 250 mg/kg offered large benefits to the growth performance of goslings, and these benefits could equal or exceed those from Flavomycin. It is suggested that the growth promoting effect of DBSC may be attributed to the improvement in the availability of dietary nutrients.


Transitions in Care: When Words Can Save Lives.
Among the myriad of skills required of emergency medicine (EM) physicians, communicating concise and effective transitions in care is one of the most critical for patient safety. EM physicians transition care daily, both within their own department and among other specialties. We will discuss the crucial link between care transitions and patient safety, the processes and challenges in the hand-over exchange, and recommend an approach to improve your current system with transitions in care.


Pharmacological in vivo test to evaluate the bioavailability of some St John's Wort innovative oral preparations.
In this study, the optimisation of biopharmaceutical properties of a dried commercial extract of St John's Wort were evaluated employing the in vivo forced swimming test (FST). Three new dosage forms containing beta-cyclodextrin and surfactants (SDS, ASC8) were compared in the FST with the commercial extract. The commercial extract showed antidepressant activity in mice after 60 min at a dosage of 100 mg/kg. The same antidepressant activity appeared in 30 min with a micellar solution of SDS containing the same quantity of extract (100 mg/kg), while with micelles of ASC8 the effect appeared at 15 min and with a dosage of 30 mg/kg. In the case of beta-cyclodextrin the best results were obtained at 30 min, administering 60 mg/kg of the extract. Finally, the influence of the formulations on the water solubility of the constituents of the extract is reported. The tensides dramatically enhanced solubility, in particular that of the more lipophilic compounds, in the case of beta-cyclodextrin this effect was very pronounced for flavonoids and biapigenin, lower for hypericins and practically insignificant for hyperforins.


Note: Submicrometer-precision sample holder for accurate re-positioning of samples in scanning force microscopy.
In this work we describe two simple and compact submicrometer-precision sample holders that are easily integrated into a Scanning Force Microscopy (SFM) system. The designs are based on a traditional kinematic mounting or on self-adjustment of the sample holder and the upper piece of the piezoelectric scanner. With these sample holders the sample position is automatically recovered to within about 100 nm. The setup allows ex situ manipulation of the sample and SFM imaging of the same region without the aid of an optical microscope, positioning marks, and tedious re-allocation.


Infections with nontyphoidal Salmonella species producing TEM-63 or a novel TEM enzyme, TEM-131, in South Africa.
Salmonella spp. producing extended-spectrum beta-lactamases (ESBLs) have been reported in many countries, but there is no information on their prevalence in Africa. ESBL-producing Salmonella enterica serotype Isangi and S. enterica serotype Typhimurium strains have been noted in South Africa since 2001. A total of 160 consecutive isolates of Salmonella spp. were collected from 13 hospitals located in different cities in South Africa over a 5-month period from December 2002 to April 2003. All strains were screened for production of ESBLs by the double disk diffusion test and for AmpC production by assessing resistance to cefoxitin. bla(SHV), bla(TEM), bla(CTX-M), and bla(CMY-2) were sought from all ESBL-positive and cefoxitin-resistant isolates. A total of 15.6% (25 of 160) isolates produced SHV or TEM ESBLs, and 1.9% (3 of 160) produced CMY-2. Nine S. enterica serotype Typhimurium, eight S. enterica serotype Isangi, and three S. enterica serotype Muenchen strains produced either TEM-63 or a derivative of TEM-63 designated TEM-131. Both TEM-63 and TEM-131 have an isoelectric point of 5.6, and their sequences have the following amino acid substitutions compared to the TEM-1 sequence: Leu21Phe, Glu104Lys, Arg164Ser, and Met182Thr. Additionally, TEM-131 has an Ala237Thr substitution. ESBL-producing Salmonella spp. have become a significant public health problem in South Africa with particular implications for the treatment of serious nontyphoidal Salmonella infections in children, for whom extended-spectrum cephalosporins were the preferred treatment.


Epidermal growth factor receptor (EGFR) inhibitor associated skin eruption.
EGFR Inhibitors are used to treat Non-Small-Cell Lung Cancer (NSCLC) and colorectal cancer (CRC). A common side effect of EGFR Inhibitors is a follicular/pustular skin eruption. We report a case of gefitinib (Iressa) associated skin eruption. The treatment regimen consisted of triamcinolone 0.1% cream twice daily, clindamycin 1% lotion twice daily and sodium sulfacetamide lotion twice daily. The clinical presentation, etiology, and management options of EGFR Inhibitor associated skin eruptions are discussed.


Nanoantioxidants: Pioneer Types, Advantages, Limitations, and Future Insights.
Free radicals are generated as byproducts of normal metabolic processes as well as due to exposure to several environmental pollutants. They are highly reactive species, causing cellular damage and are associated with a plethora of oxidative stress-related diseases and disorders. Antioxidants can control autoxidation by interfering with free radical propagation or inhibiting free radical formation, reducing oxidative stress, improving immune function, and increasing health longevity. Antioxidant functionalized metal nanoparticles, transition metal oxides, and nanocomposites have been identified as potent nanoantioxidants. They can be formulated in monometallic, bimetallic, and multi-metallic combinations via chemical and green synthesis techniques. The intrinsic antioxidant properties of nanomaterials are dependent on their tunable configuration, physico-chemical properties, crystallinity, surface charge, particle size, surface-to-volume ratio, and surface coating. Nanoantioxidants have several advantages over conventional antioxidants, involving increased bioavailability, controlled release, and targeted delivery to the site of action. This review emphasizes the most pioneering types of nanoantioxidants such as nanoceria, silica nanoparticles, polydopamine nanoparticles, and nanocomposite-, polysaccharide-, and protein-based nanoantioxidants. This review overviews the antioxidant potential of biologically synthesized nanomaterials, which have emerged as significant alternatives due to their biocompatibility and high stability. The promising nanoencapsulation nanosystems such as solid lipid nanoparticles, nanostructured lipid carriers, and liposome nanoparticles are highlighted. The advantages, limitations, and future insights of nanoantioxidant applications are discussed.


Unsuspected pulmonary embolism identified using multidetector computed tomography in hospital outpatients.
To evaluate the incidence of unsuspected pulmonary embolism (PE) in an unselected population of outpatients undergoing contrast-enhanced multidetector computed tomography (MDCT) for indications other than the investigation of PE. Outpatients undergoing CT of the chest over a 6-month period were retrospectively identified and images reviewed. Inpatients and patients undergoing unenhanced CT of the chest were excluded. Data, including referring specialty, patient age and sex, reasons for examination, level of embolism, image quality, and section thickness were recorded. Radiology reports were reviewed with respect to whether or not the embolism was noted at the time of initial reporting. Following exclusions 440 patients were reviewed (195 women and 245 men). PE was identified in 10 of the 440 patients, an incidence of 2.23%. One pulmonary embolus was in the main pulmonary artery, three were in lobar arteries, three in segmental arteries, and three in subsegmental arteries. Patients over the age of 60 years were more likely to have an embolism (9/300, 2.9%) compared with those under 60 years (1/140, 0.7%). Seven of the 10 positive examinations were carried out in patients who were known or later shown to have malignancy. Seven of the 10 emboli were reported at the time of initial reporting. The outpatient population has a significant incidence of unsuspected PE. PE should be actively sought when reporting examinations performed for alternative indications, particularly where cancer is a known or suspected diagnosis.


Cold exposure reveals two populations of microtubules in pulmonary endothelia.
Microtubules are composed of α-tubulin and β-tubulin dimers. Microtubules yield tubulin dimers when exposed to cold, which reassemble spontaneously to form microtubule fibers at 37°C. However, mammalian neurons, glial cells, and fibroblasts have cold-stable microtubules. While studying the microtubule toxicity mechanisms of the exotoxin Y from Pseudomonas aeruginosa in pulmonary microvascular endothelial cells, we observed that some endothelial microtubules were very difficult to disassemble in the cold. As a consequence, we designed studies to test the hypothesis that microvascular endothelium has a population of cold-stable microtubules. Pulmonary microvascular endothelial cells and HeLa cells (control) were grown under regular cell culture conditions, followed by exposure to an ice-cold water bath and a microtubule extraction protocol. Polymerized microtubules were detected by immunofluorescence confocal microscopy and Western blot analyses. After cold exposure, immunofluorescence revealed that the majority of HeLa cell microtubules disassembled, whereas a smaller population of endothelial cell microtubules disassembled. Immunoblot analyses showed that microvascular endothelial cells express the microtubule cold-stabilizing protein N-STOP (neuronal stable tubule-only polypeptides), and that N-STOP binds to endothelial microtubules after cold exposure, but not if microtubules are disassembled with nocodazole before cold exposure. Hence, pulmonary endothelia have a population of cold-stable microtubules.


Prediction of improvement in left ventricular function with iodine-123-IPPA after coronary revascularization.
Iodine-123-phenylpentadecanoic acid (IPPA) is a synthetic fatty acid suitable for myocardial imaging. This study is the result of a Phase I/II trial to evaluate IPPA's ability to predict functional recovery in patients undergoing coronary revascularization. Twenty-three patients with documented coronary disease underwent sequential SPECT imaging with IPPA before and radionuclide ventriculography both before and 8 wk after revascularization. Software was developed to evaluate myocardial IPPA metabolism and to determine the fraction of the left ventricle with intermediate metabolism. There was a significant correlation between initial IPPA uptake and final LVEF. The fractional area of the left ventricle demonstrating IPPA metabolism in the intermediate metabolic range was significantly higher in patients who demonstrated a 5% or greater increase in EF after revascularization (0.90 +/- 0.08 versus 0.78 +/- 0.17, p = 0.04). When only the patients who received complete revascularization were evaluated, there was a more significant difference (improved 0.92 +/- 0.05 versus 0.74 +/- 0.17, p = 0.011). Taking a lower limit of 1 s.d. from the mean, (87%) the six patients who had > or = 5% increase in LVEF after revascularization had more than 87% of the left ventricle in the intermediate metabolic range, whereas seven of ten patients whose change in LVEF was < 5% had less than 87% in the intermediate metabolic range (p = 0.011). In this initial experience, the amount of myocardium in the intermediate metabolic range is associated with improvement in LVEF after revascularization, especially in patients receiving complete revascularization.


Disparity between tonic and phasic ethanol-induced dopamine increases in the nucleus accumbens of rats.
Dopamine concentrations in the nucleus accumbens fluctuate on phasic (subsecond) and tonic (over minutes) timescales in awake rats. Acute ethanol increases tonic concentrations of dopamine, but its effect on subsecond dopamine transients has not been fully explored. We measured tonic and phasic dopamine fluctuations in the nucleus accumbens of rats in response to ethanol (within-subject cumulative dosing, 0.125 to 2 g/kg, i.v.). Microdialysis samples yielded significant tonic increases in dopamine concentrations at 1 to 2 g/kg ethanol in each rat, while repeated saline infusions had no effect. When monitored with fast scan cyclic voltammetry, ethanol increased the frequency of dopamine transients in 6 of 16 recording sites, in contrast to the uniform effect of ethanol as measured with microdialysis. In the remaining 10 recording sites that were unresponsive to ethanol, dopamine transients either decreased in frequency or were unaffected by cumulative ethanol infusions, patterns also observed during repeated saline infusions. The responsiveness of particular recording sites to ethanol was not correlated with either core versus shell placement of the electrodes or the basal rate of dopamine transients. Importantly, the phasic response pattern to a single dose of ethanol at a particular site was qualitatively reproduced when a second dose of ethanol was administered, suggesting that the variable between-site effects reflected specific pharmacology at that recording site. These data demonstrate that the relatively uniform dopamine concentrations obtained with microdialysis can mask a dramatic heterogeneity of phasic dopamine release within the accumbens.


Opioid Pharmacology: Developmental Effects on Opioid Metabolism.
Children represent a patient demographic composed of multiple, unique subpopulations differentiated by rapidly changing age-related physiology, which includes the means of metabolizing opioids. Opioids are an important part of the pharmacological treatment of both acute and chronic pain. In both clinical medicine and clinical research, it is necessary to understand the differences in drug handling by age cohort in order to appropriately dose children to effect, and to avoid exacerbating deleterious adverse events with potentially grave sequelae. Topical review using data from a targeted PubMed literature search. Protein binding, tissue solubility, weight, size (body mass, surface area), blood flow, drug metabolism, and renal function are key determinants of dosing across the different pediatric age cohorts. Each variable functions to elicit a change in drug exposure and therefore varying clinical effect. Understanding how these variables change the pharmacokinetics and pharmacodynamics of each opioid is critical to the successful and safe management of pain in children.


[Comparative characteristics of the Haemophilus influenzae strains isolated from healthy children and from patients with acute and chronic bronchopulmonary diseases].
The comparative biochemical and serological characterization of 424 H. influenzae strains isolated from healthy children and patients with acute and chronic bronchopulmonary diseases is presented. As the result of biotyping H. influenzae strains, 82.3-90.9% of the strains isolated from both healthy children and patients with acute and chronic bronchopulmonary diseases were found to belong to the first three biotypes according to M. Kilian's classification. Among H. influenzae strains isolated from healthy children no capsular variants were detected in the coagglutination test. From patients with acute and chronic diseases of respiratory organs, as a rule, the capsular variants of H. influenzae were isolated (94.4% and 98.1%, respectively). In patients with chronic pneumonia biotypes I, II and III, more seldom biotype V, proved to be mo st invasive. In the determination of the minimum inhibiting concentration of ampicillin, no H. influenzae strains resistant to this antibiotic were detected.


Mini drug pump for ophthalmic use.
To evaluate the feasibility of developing a novel mini drug pump for ophthalmic use. Using principles of microelectromechanical systems engineering, a mini drug pump was fabricated. The pumping mechanism is based on electrolysis, and the pump includes a drug refill port as well as a check valve to control drug delivery. Drug pumps were tested first on the benchtop and then after implantation in rabbits. For the latter, we implanted 4 elliptical (9.9 x 7.7 x 1.8 mm) non-electrically active pumps into 4 rabbits. The procedure is similar to implantation of a glaucoma seton. To determine the ability to refill and also the patency of the cannula, at intervals of 4 to 6 weeks after implantation, we accessed the drug reservoir with a transconjunctival needle and delivered approximately as low as 1 microL of trypan blue solution (0.06%) into the anterior chamber. Animals were followed up by slit-lamp examination, photography, and fluorescein angiography. Benchtop testing showed 2.0 microL/min delivery when using 0.4 mW of power for electrolysis. One-way valves showed reliable opening pressures of 470 mm Hg. All implanted devices refilled at 4- to 6-week intervals for 4 to 6 months. No infection was seen. No devices extruded. No filtering bleb formed over the implant. A prototype ocular mini drug pump was built, implanted, and refilled. Such a platform needs more testing to determine the long-term biocompatibility of an electrically controlled implanted pump. Testing with various pharmacologic agents is needed to determine its ultimate potential for ophthalmic use.


Adipokines influencing metabolic and cardiovascular disease are differentially regulated in maintenance hemodialysis.
Adipokines including leptin, adiponectin, visfatin, resistin, and interleukin (IL)-6 significantly influence energy metabolism, insulin sensitivity, and cardiovascular health. In the current study, we investigated serum levels of these adipokines in diabetic and nondiabetic patients on maintenance hemodialysis (MD) as compared with controls with a glomerular filtration rate greater than 50 mL/min. Serum leptin, adiponectin, high-molecular-weight (HMW) adiponectin, visfatin, resistin, and IL-6 were determined by enzyme-linked immunosorbent assay in control (n = 60) and MD (n = 60) patients and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. Adiponectin, visfatin, resistin, and IL-6 were significantly elevated in MD patients as compared with controls. In multivariate analyses, sex and body mass index were independently correlated with serum leptin levels in both controls and MD patients. Furthermore, insulin resistance was independently and negatively associated with adiponectin and HMW adiponectin in both groups. Moreover, circulating resistin levels were independently correlated with serum visfatin concentrations in control and MD patients. However, various independent associations were only found in either controls or patients on MD. Thus, serum IL-6 levels were strongly and independently associated with C reactive protein and resistin in MD patients but not control subjects. We show that levels of various adipokines are significantly increased in MD patients. Furthermore, regulation of adipokines in vivo strongly depends on renal function. Regulation of HMW adiponectin is similar as compared with total adiponectin in the patients studied.


Flow. A Socially Responsible 3D Printed One-Handed Recorder.
The recorder is one of the most common instruments used during primary school in the formal education system in the EU. However, there are a percentage of students with only one functional hand. The existing one-handed recorders available for them to be able to play and perform in the same way as their peers are expensive and difficult to use. This study's purpose is to document the development of Flow-a low cost one-handed recorder as well as the user's assessment of the psychosocial benefits of the recorder. The methods used for fabrication were 3D modelling and additive manufacturing (AM) technology or 3D printing using the technique of stereolithography, and for the assessment of the product, the Psychosocial Impact of Assistive Devices Scale (PIADS) questionnaire was distributed to 20 primary school users. The results show that the use of resins and Stereolithography is appropriate for wind instruments providing quality and strength at a fair price. Flow also proved to have a positive impact on the users and their inclusion in school. The main conclusions of this study underscore the adequacy of using AM for adaptations required for people with disabilities and the positive psychosocial benefits generated by the use of Flow in children.


Transport of metformin metabolites by guanidinium exporters of the Small Multidrug Resistance family.
Proteins from the Small Multidrug Resistance (SMR) family are frequently associated with horizontally transferred multidrug resistance gene arrays found in bacteria from wastewater and the human-adjacent biosphere. Recent studies suggest that a subset of SMR transporters might participate in metabolism of the common pharmaceutical metformin by bacterial consortia. Here, we show that both genomic and plasmid-associated transporters of the SMRGdx functional subtype export byproducts of microbial metformin metabolism, with particularly high export efficiency for guanylurea. We use solid supported membrane electrophysiology to evaluate the transport kinetics for guanylurea and native substrate guanidinium by four representative SMRGdx homologues. Using an internal reference to normalize independent electrophysiology experiments, we show that transport rates are comparable for genomic and plasmid-associated SMRGdx homologues, and using a proteoliposome-based transport assay, we show that 2 proton:1 substrate transport stoichiometry is maintained. Additional characterization of guanidinium and guanylurea export properties focuses on the structurally characterized homologue, Gdx-Clo, for which we examined the pH dependence and thermodynamics of substrate binding and solved an x-ray crystal structure with guanylurea bound. Together, these experiments contribute in two main ways. By providing the first detailed kinetic examination of the structurally characterized SMRGdx homologue Gdx-Clo, they provide a functional framework that will inform future mechanistic studies of this model transport protein. Second, this study casts light on a potential role for SMRGdx transporters in microbial handling of metformin and its microbial metabolic byproducts, providing insight into how native transport physiologies are co-opted to contend with new selective pressures.


EEG-based Approach-Withdrawal index for the pleasantness evaluation during taste experience in realistic settings.
The taste is a vital sense in humans, because of its active role in regulating nutrition or avoiding harmful substances. Several studies showed the important role of the brain Pre-Frontal Cortex in decoding information coming from the gustatory system. It is also widely known, in neuroscientific literature, that the asymmetry of Pre-Frontal Cortex Activity is closely linked to the feeling of pleasantness experienced by the subject during sensorial stimulation. In this regard, from the electroencephalographic (EEG) signal it is possible to estimate the Approach/Withdrawal (AW) index, which has been largely investigated and validated in scientific literature, regarding visual, acoustic and olfactory stimuli.


Putting a price tag on physician services. Reform of Medicare's payment system moves ahead.
Medicare's reasonable-charge method of reimbursing physicians may be replaced soon with a fee schedule based on a relative value scale. The new system will attempt to apportion physician payments more equitably than in the past and significantly reduce long-term spending growth. The new system's linchpin will be a relative value scale derived from the resource costs that efficient physicians are expected to incur when rendering service. The higher a service's expected cost in relation to a standard service, the higher its relative value and payment amount. Harvard researchers recently developed a resource-based relative value scale based on a survey of about 410 services in 18 specialties. They divided total resource costs into two components: physician work and practice costs. The former, more difficult to measure, represents the physician's time, skill, physical and mental effort, and stress from iatrogenic risk. The ultimate objectives are to allow relative values across specialties to be comparable and to allow one conversion factor to transform these values into dollar amounts. Other critical factors include transition period, conversion factors, geographic multipliers, mandatory assignment, and volume controls.


Human Neural Stem Cells Overexpressing Choline Acetyltransferase Restore Unconditioned Fear in Rats with Amygdala Injury.
Amygdala is involved in the fear memory that recognizes certain environmental cues predicting threatening events. Manipulation of neurotransmission within the amygdala affects the expression of conditioned and unconditioned emotional memories such as fear freezing behaviour. We previously demonstrated that F3.ChAT human neural stem cells (NSCs) overexpressing choline acetyltransferase (ChAT) improve cognitive function of Alzheimer's disease model rats with hippocampal or cholinergic nerve injuries by increasing acetylcholine (ACh) level. In the present study, we examined the effect of F3.ChAT cells on the deficit of unconditioned fear freezing. Rats given N-methyl-d-aspartate (NMDA) in their amygdala 2 weeks prior to cat odor exposure displayed very short resting (freezing) time compared to normal animals. NMDA induced neuronal degeneration in the amygdala, leading to a decreased ACh concentration in cerebrospinal fluid. However, intracerebroventricular transplantation of F3.ChAT cells attenuated amygdala lesions 4 weeks after transplantation. The transplanted cells were found in the NMDA-injury sites and produced ChAT protein. In addition, F3.ChAT-receiving rats recuperated freezing time staying remote from the cat odor source, according to the recovery of brain ACh concentration. The results indicate that human NSCs overexpressing ChAT may facilitate retrieval of unconditioned fear memory by increasing ACh level.


Metabolic acidemia with hypoxia attenuates the hemodynamic responses to epinephrine during resuscitation in lambs.
To examine the effects of metabolic acidemia and hypoxia on the hemodynamic responses to epinephrine in an intact neonatal animal model. Multi-experiment, randomized, controlled trial. Animal research laboratory of a university hospital. Sixteen lambs, ranging in age from 2 to 14 days. The lambs were chronically catheterized; the ductus arteriosus was ligated; and a pulmonary arterial flow probe was inserted to measure cardiac output, blood pressure (BP), and heart rate. In the first protocol, hemodynamic responses to epinephrine during pure metabolic acidemia or metabolic alkalosis were studied in eight lambs. Each lamb was studied on four different days at a different arterial pH: 6.9, 7.1, 7.4, and 7.6. Ventilation was controlled to maintain PCO2 at 35 to 45 torr (4.66 to 5.99 kPa). Acidemia was induced by the infusion of lactic acid and alkalosis by the infusion of sodium bicarbonate. When the appropriate arterial pH was achieved, 10 micrograms/kg of epinephrine was administered intravenously. In a second protocol, hemodynamic responses to epinephrine during metabolic acidemia or alkalosis plus hypoxia were studied in eight lambs. When the appropriate arterial pH was achieved, hypoxia was induced until cardiac output decreased to 40% of baseline. Epinephrine bolus was given, and after 90 secs, the lambs were resuscitated with oxygen. Epinephrine administered during uncompromised hemodynamics led to hypertension, bradycardia, and decreased cardiac output that were unaffected by arterial pH values between 6.9 and 7.6. Acidemia with hypoxia compromised hemodynamics with decreases in heart rate and cardiac output. Epinephrine administered during this compromised condition did not improve cardiac output, heart rate, or BP before resuscitation with oxygen at any arterial pH studied. Resuscitation with epinephrine and oxygen during hemodynamically compromised states led to increases in heart rate, BP, and cardiac output with significant attenuation of these hemodynamic responses during metabolic acidemia at pH values of 6.9 and 7.1. During the physiologic conditions associated with neonatal resuscitation, that is, hypoxia with a compromised hemodynamic state, metabolic acidemia significantly attenuates the hemodynamic responses to resuscitation with epinephrine and oxygen. Correction of metabolic acidosis may be warranted in newborn resuscitation.


CDER photosafety guidance for industry.
In the Federal Register of January 10, 2000 (65 FR 1399), FDA published a draft guidance entitled "Photosafety Testing." The notice gave interested persons an opportunity to submit comments. As a result of the comments, certain sections of the guidance were reworded to improve clarity. A final guidance was published in May 2003. The final guidance further emphasizes that a flexible approach can be used to address adverse photoeffects and that specific assays are not required. Moreover, it encourages the development of methods that can efficiently be used to evaluate human safety. The guidance describes a consistent, science-based approach for testing of topically and systemically administered drug products.


[Level of CD4(+) CD25(high) CD127(low/-) regulatory T cells in transitional cell carcinoma patients and its clinical significance].
To evaluate the expressions of CD4+ CD25high CD127low/- regulatory T cells (Treg) in peripheral blood from patients with transitional cell carcinoma (TCC) in urinary system. The proportion of Treg population in CD4+ T cells from 93 patients with transitional cell carcinoma was evaluated. And flow cytometry was employed to analyze different clinicopathologic characteristics and detect the pre- and post-operative changes in 38 patients with benign urinary diseases and 37 healthy subjects. The proportion of Treg population in CD4+ T cells in peripheral blood of patients with TCC significantly increased as compared with those with benign urinary diseases and healthy subjects. There was a strong correlation between the proportion of Treg and tumor recurrence, quantity, lymph node metastasis (P < 0. 01) as well as pathological stage; no correlation was found between the proportion of Treg and clinical TNM stage (P > 0. 05). The proportion of Treg was also different at pre- and post-operation (P < 0. 05). CD4+ CD25high CD127low/- regulatory T cells in peripheral blood from patients with TCC significantly increased as compared with that in patients with benign urinary diseases and in healthy subjects. It may be responsible for immune suppression in TCC patients. Tumor resection could decrease the proportion of Treg in peripheral blood, but the long-term change in immune function requires further investigations.