Effects of peritoneal dialysis solutions on the secretion of growth factors and extracellular matrix proteins by human peritoneal mesothelial cells.
To compare the effects of different peritoneal dialysis solutions (PDS) on secretion of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGFbeta1), procollagen I C-terminal peptide (PICP), procollagen III N-terminal peptide (PIIINP), and fibronectin by cultured human peritoneal mesothelial cells (HPMC). Using M199 culture medium as control, commercial PDS containing 1.5% or 4.25% glucose and 40 mmol/L lactate [Dianeal 1.5 (D 1.5) and Dianeal 4.25 (D 4.25), respectively; Baxter Healthcare, Deerfield, Illinois, USA]; PDS containing 1.5% or 4.25% glucose with 25 mmol/L bicarbonate and 15 mmol/L lactate [Physioneal 1.5 (P 1.5) and Physioneal 4.25 (P 4.25), respectively; Baxter]; and PDS containing 7.5% icodextrin [Extraneal (E); Baxter] were tested. Growth-arrested and synchronized HPMC were continuously stimulated for 48 hours by test PDS diluted twofold with M199, TGFbeta1 1 ng/mL, or different concentrations of icodextrin. VEGF, TGFbeta1, and fibronectin secreted into the media were analyzed by ELISA, and PICP and PIIINP by radioimmunoassay. Dianeal 1.5, D 4.25, and P 4.25, but not P 1.5 and E, significantly increased VEGF secretion compared with control M199. D 4.25- and P 4.25-induced VEGF secretion was significantly higher than induction by D 1.5 and P 1.5, respectively, suggesting that high glucose may be involved in the induction of VEGF. Physioneal 1.5- and P 4.25-induced VEGF secretion was significantly lower than induction by D 1.5 and D 4.25, respectively, suggesting a role for glucose degradation products (GDP) in VEGF production. TGFbeta1 secretion was significantly increased by D 4.25 and E. Icodextrin increased TGFbeta1 secretion in a dose-dependent manner. All PDS tested significantly increased secretion of PIIINP compared with control. D 1.5- and D 4.25-induced PIIINP secretion was significantly higher than P 1.5, P 4.25, and E. Physioneal 4.25-induced PIIINP secretion was significantly higher than P 1.5, again implicating high glucose and GDP in PIIINP secretion by HPMC. There was no significant increase in PICP or fibronectin secretion using any of the PDS tested. Addition of TGFbeta1 1 ng/mL into M199 control significantly increased VEGF, PICP, PIIINP, and fibronectin secretion by HPMC. The present study provides direct evidence that HPMC can secrete VEGF, TGFbeta1, and PIIINP in response to PDS, and that HPMC may be actively involved in the development and progression of the peritoneal membrane hyperpermeability and fibrosis observed in long-term PD patients. This study also suggests that both high glucose and GDP in PDS may play important roles in inducing VEGF and PIIINP production/secretion by HPMC.


Clinical Application of a High Definition Three-Dimensional Exoscope in Anterior Lumbar Interbody Fusion: Technical Note.
Video-assisted telescope operating monitor (VITOM) or exoscope is currently applied in different surgical specialties with clear visualization advantages in terms of magnification, illumination, and wide field of view. The small and deep surgical field of anterior lumbar interbody fusion (ALIF) seemed to be an ideal setting to assess efficacy of exoscope, also considering limits related to microscopic and endoscopic visualization currently employed. We reported our preliminary experience with exoscope in 9 cases of ALIF at L5-S1 level. These data were retrospectively compared with those obtained from an equal sample of ALIF procedures performed with endoscope as visualization instrument. The technical aspects taken into account were time for procedure and blood loss. Reports from the surgeon about ergonomics and confidence with both techniques were also evaluated. Exoscope proved, in our experience, good visualization and ergonomics and unobstructed access to a small and deep surgical field, allowing abundant space to insert and manipulate the instruments. The instrument contained dimension and its long working distance, superior to endoscope and comparable with operating microscope, showed clear advantages of maneuverability. Moreover, the stereoscopic vision provided by 3-dimensional images proved to be crucial in hand-eye coordination.


[Specific pathological findings in trabeculectomy].
A quick embedding method for trabeculectomy specimens is desirable. It allows a comparison between the observations made during surgery and the histological material as long as the facts are remembered by the surgeon. Embedding by butoxy-ethanol-glycol-methacrylate proved to be adequate. It allows 1- to 2-mu thick sections. 39 trabeculectomy specimens were investigated in regard of topographical origin. In 26 of them, an exact localization was possible. Only 8 pieces contained Schlemm's canal or major parts of it. The others where cut more anteriorly and contained cornea and parts of the trabecular meshwork. The different topographical localization of the ectomized pieces did not influence the regulation of the intraocular tension in the early follow-up period. It is suggested that trabeculectomy does not give direct access to the aqueous to the cut ends of Schlemm's canal and to collector channels but rather by letting filter the aqueous externally along the scleral openings.


Multiple sclerosis spasticity: 'state-of-the-art' questionnaire survey of specialized healthcare professionals.
Spasticity (muscle rigidity and spasms) is a frequent and disabling feature of multiple sclerosis (MS), and it can have a marked negative impact on the patient's overall wellbeing and quality of life through a range of symptoms including impaired mobility, bladder dysfunction, stiffness, spasms and sleep disorders. Numerous antispastic agents such as baclofen and tizanidine, as well as others, are available for the management of MS spasticity but, overall, they offer limited clinical benefit. The current questionnaire survey assessed the epidemiology and management of MS spasticity globally and across the EU, among 157 healthcare professionals (>95% of all respondents were neurologists) attending a large, international MS congress (European Committee for Treatment and Research in Multiple Sclerosis, Lyon, France, 10-13 October 2012). Survey results showed similarity between the EU and rest-of-world respondents in the epidemiology of MS spasticity, the use of assessment tools to monitor patients, the incidence and severity of symptoms, and management options. Respondents indicated that approximately 40% of their MS patients had spasticity and it was rated as mild in approximately 40%, moderate in 35% and severe in 25% of patients. At least 40% of practitioners were dissatisfied with treatment options in their patients with moderate-to-severe MS; this highlights the unmet needs and challenges facing specialists in the management of MS patients with moderate-to-severe spasticity.


Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.
Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also associated with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degradation in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insoluble Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy.


Genetic contributions to influenza virus attenuation in the rat brain.
Influenza is generally regarded as an infection of the respiratory tract; however, neurological involvement is a well-recognized, although uncommon, complication of influenza A virus infection. The authors previously described the development of a rat model for studying influenza virus infection of the central nervous system (CNS). This model was used here to study the role of virus genes in virus replication and spread in brain. In the present work, an infectious cDNA clone of the neurotoxic WSN strain of influenza virus (rWSN) was altered by site-directed mutagenesis at five loci that corresponded to changes previously shown to confer temperature sensitivity and attenuation of the A/Ann Arbor/6/60 strain (PB1Delta 391, PB1Delta 581, and PB1Delta 661; PB2Delta 265, and NPDelta 34). Whereas rWSN and its mutated derivative (mu-rWSN) replicated equally well in MDCK cells at 37 degrees C (the body temperature of rats), rWSN grew to higher titers and infection was more widespread compared to mu-rWSN in rat brain. These results demonstrate that the five mutations that confer attenuation of the A/Ann Arbor/6/60 influenza virus strain for the respiratory system also confer attenuation for the central nervous system. Further in vivo and in vitro examination of these five mutations, both individually and in combination, will likely provide important information on the role of specific virus genes in virulence and pathogenesis.


Fluorescence Cross-Correlation Spectroscopy Yields True Affinity and Binding Kinetics of Plasmodium Lactate Transport Inhibitors.
Blocking lactate export in the parasitic protozoan Plasmodium falciparum is a novel strategy to combat malaria. We discovered small drug-like molecules that inhibit the sole plasmodial lactate transporter, PfFNT, and kill parasites in culture. The pentafluoro-3-hydroxy-pent-2-en-1-one BH296 blocks PfFNT with nanomolar efficiency but an in vitro selected PfFNT G107S mutation confers resistance against the drug. We circumvented the mutation by introducing a nitrogen atom as a hydrogen bond acceptor site into the aromatic ring of the inhibitor yielding BH267.meta. The current PfFNT inhibitor efficiency values were derived from yeast-based lactate transport assays, yet direct affinity and binding kinetics data are missing. Here, we expressed PfFNT fused with a green fluorescent protein in human embryonic kidney cells and generated fluorescent derivatives of the inhibitors, BH296 and BH267.meta. Using confocal imaging, we confirmed the location of the proposed binding site at the cytosolic transporter entry site. We then carried out fluorescence cross-correlation spectroscopy measurements to assign true Ki-values, as well as kon and koff rate constants for inhibitor binding to PfFNT wildtype and the G107S mutant. BH296 and BH267.meta gave similar rate constants for binding to PfFNT wildtype. BH296 was inactive on PfFNT G107S, whereas BH267.meta bound the mutant protein albeit with weaker affinity than to PfFNT wildtype. Eventually, using a set of PfFNT inhibitor compounds, we found a robust correlation of the results from the biophysical FCCS binding assay to inhibition data of the functional transport assay.


Prioritising research funding for cardiovascular disease and diabetes in Australia.
The Targeted Translation Research Accelerator program was created to address cardiovascular disease and diabetes in Australia. To maximise the impact of the considerable investment in this program, a structured prioritisation project was undertaken to determine the highest priority health and medical unmet needs in cardiovascular disease and diabetes. The project was led by Monash University's Behaviour Works Australia in collaboration with Australian National University, Research Australia, and MTPConnect. We conducted an online survey with 318 experts and community representatives to generate a 'long list' of unmet needs for (1) cardiovascular disease; (2) diabetes; and (3) interactions in the pathogenesis of Type 1 diabetes, Type 2 diabetes, and cardiovascular disease. We then convened roundtables of clinical, research, and community leaders to discuss survey results. They prioritised unmet needs against six predefined criteria then discussed results. We present the final priority areas for funding. We demonstrate how a feasible, reproducible, and collaborative prioritisation methodology can be used when designing research funding programs. Such approaches can ensure that funding is directed towards projects that are valuable to the community and reflective of expert opinion.


Updated Strategies and Therapies for Reducing Ischemic and Vascular Events (STRIVE) unstable angina/non-ST elevation myocardial infarction critical pathway toolkit.
The Strategies and Therapies for Reducing Ischemic and Vascular Events (STRIVE) acute coronary syndromes (ACS) critical pathway toolkit, developed in 2002, has been revised and updated. The updated toolkit is based on the American College of Cardiology/American Heart Association 2007 guidelines for the management of patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI). This review highlights the major revisions to the UA/NSTEMI guidelines and illustrates and describes the revised STRIVE critical pathway tools, which include pathway flowcharts, standing orders, pocket cards, posters, and form letters. These materials are being made available online to help physicians, nurses, and hospitals implement the new guidelines and thus improve the quality of care and outcomes for patients with ACS.


Solar simulator for concentrator photovoltaic systems.
A solar simulator for measuring performance of large area concentrator photovoltaic (CPV) modules is presented. Its illumination system is based on a Xenon flash light and a large area collimator mirror, which simulates natural sun light. Quality requirements imposed by the CPV systems have been characterized: irradiance level and uniformity at the receiver, light collimation and spectral distribution. The simulator allows indoor fast and cost-effective performance characterization and classification of CPV systems at the production line as well as module rating carried out by laboratories.


Cellular responses of periodontal ligament stem cells to a novel synthesized form of calcium hydrogen phosphate with a hydroxyapatite-like surface for periodontal tissue engineering.
Calcium hydrogen phosphate with a hydroxyapatite-like surface (CHP-HA) is a novel synthesized compound designed to overcome the limitations of bioactive ceramics. It was originally applied as nano-sized HA strips covering core plates to enhance the degree of interfacial attachment. The objective of the present study was to examine the cellular attachment, proliferation, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs) on a CHP-HA substrate in comparison with conventional nanohydroxyapatite (NanoHA). The PDLSCs were cultivated with either CHP-HA or NanoHA for cellular attachment, proliferation, and osteogenic differentiation assay. Osteogenic differentiation was examined using quantitative polymerase chain reaction and immunofluorescence after confirmation by Alizarin red staining. We found that between 14 and 21 days, CHP-HA exhibited a well-organized matrix distribution, a high degree of cell proliferation, and a high level of Alizarin red staining in comparison to NanoHA. Expression of all the osteogenic markers examined was increased significantly relative to NanoHA at 14 days, but no significant differences in some osteogenic genes were found at 21 days. Immunofluorescence revealed stronger staining in the CHP-HA group. In conclusion, PDLSCs cultivated with this novel CHP-HA show enhanced cellular responses. We propose that CHP-HA may be a promising alternative biomaterial for periodontal tissue engineering.


Incidence of heterotopic ossification following hip arthroscopy is low: considerations for routine prophylaxis.
This scoping review aims to map and summarise the available literature on heterotopic ossification (HO) following hip arthroscopy, with particular focus on incidence, distribution as per Brooker classification, efficacy of prophylactic measures and factors that may influence the likelihood of production of HO. A computer-based search was performed on PubMed, Embase, Emcare, Cinahl, ISI web of science and Scopus using the terms 'heterotopic ossification' and 'hip arthroscopy'. Articles reporting heterotopic ossification following hip arthroscopy for any condition were included after two-stage title/abstract and full-text screening. Of the 663 articles retrieved, 45 studies were included. The proportion of patients with HO ranged from 0 to 44%. The majority of the cases were either Brooker grade I or II. Of the six studies investigating the effect of NSAID prophylaxis, five reported a significantly lower incidence of heterotopic ossification associated with its use. Weak evidence suggests that an outside-in arthroscopic approach, no capsular closure, male sex and mixed cam and pincer resection may be associated with an increased risk of HO. Although there is a large variation in rates of HO following hip arthroscopy in the current literature, the majority of studies report a low incidence. Evidence exists advocating the administration of post-operative NSAIDs to reduce the incidence of HO following hip arthroscopy. This, combined with the low risk of complications, means there is a favourable risk-benefit ratio for prophylactic NSAID used in HA. Future research should work to identify patient clinical and demographic factors which may increase the risk of development of HO, allowing clinicians to risk stratify and select only specific patients who would benefit from receiving NSAID prophylaxis.


Kynurenine produced by indoleamine 2,3-dioxygenase 2 exacerbates acute liver injury by carbon tetrachloride in mice.
Kynurenine (Kyn) plays an important role as an immune check-point molecule and regulates various immune responses through its aryl hydrocarbon receptor (Ahr). Kyn is synthesized by indoleamine 2,3-dioxygenase (Ido) and tryptophan 2,3-dioxygenase (Tdo). Ido contributes approximately 90% of tryptophan catabolism. Although Kyn is increased in various liver disorders, the roles of Kyn in liver injury are complicated because Ido1, Ido2, and Tdo are activated in different cell types. In this study, the roles of Ido2 in carbon tetrachloride (CCl4; 1 ml/kg, i.p.)-induced acute liver injury were examined using Ido2 knockout mice and Ido2 inhibitor. After CCl4 treatment, the ratio of Kyn to tryptophan and levels of Kyn in the liver were increased, accompanied by activation of Ahr-mediated signaling, as revealed by increased nuclear Ahr and Cyp1a1 mRNA. Knockout of Ido2 (Ido2-/-) and treatment with Ido2 inhibitor 1-methyl-D-tryptophan (D-1MT; 100 mg/kg, i.p.) attenuated CCl4-induced liver injury, with decreased induction of Ahr-mediated signaling. Administration of D-Kyn (100 mg/kg, i.p.) to Ido2-/- mice canceled the effect of Ido2 deficiency and exacerbated acute liver damage by CCl4 treatment. In addition, liver fibrosis induced by repeated CCl4 administration was suppressed in Ido2-/- mice. In conclusion, the action of Ido2 and Kyn in the liver may prevent severe hepatocellular damage and liver fibrosis.


Real-time monitoring of in vivo acute necrotic cancer cell death induced by near infrared photoimmunotherapy using fluorescence lifetime imaging.
A new type of monoclonal antibody (mAb)-based, highly specific phototherapy (photoimmunotherapy; PIT) that uses a near infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with a mAb, has recently been described. NIR light exposure leads to immediate, target-selective necrotic cell death in vitro. Detecting immediate in vivo cell death is more difficult because it takes at least 3 days for the tumor to begin to shrink in size. In this study, fluorescence lifetime (FLT) was evaluated before and after PIT for monitoring the immediate cytotoxic effects of NIR mediated mAb-IR700 PIT. Anti-epidermal growth factor receptor (EGFR) panitumumab-IR700 was used for targeting EGFR-expressing A431 tumor cells. PIT with various doses of NIR light was conducted in cell pellets in vitro and in subcutaneously xenografted tumors in mice in vivo. FLT measurements were obtained before and 0, 6, 24, and 48 hours after PIT. In vitro, PIT at higher doses of NIR light immediately led to FLT shortening in A431 cells. In vivo PIT induced immediate shortening of FLT in treated tumors after a threshold NIR dose of 30 J/cm(2) or greater. In contrast, lower levels of NIR light (10 J/cm(2) or smaller) did not induce shortening of FLT. Prolongation of FLT in tissue surrounding the tumor site was noted 6 hours after PIT, likely reflecting phagocytosis by macrophages. In conclusion, FLT imaging can be used to monitor the acute cytotoxic effects of mAb-IR700-induced PIT even before morphological changes can be seen in the targeted tumors.


DNA and estrogen receptor interaction revealed by fragment molecular orbital calculations.
Molecular orbital calculations of the complex between DNA-ERE (estrogen response element) and ER (estrogen receptor)-DBD (DNA-binding domain) were performed using the fragment molecular orbital (FMO) method, which enables large-scale MO (molecular orbital) calculations by reducing the computational cost and by significantly increasing efficiency for parallel computation. Such a large system, which contains 3354 atoms, is impractical via conventional MO methods due to the immense computational cost. Details of the interaction between DNA-ERE and ER-DBD were revealed in this study as follows by using the FMO calculations to analyze the interfragment interaction energies (IFIEs) and the electrostatic potentials (ESPs). An area with a high positive ESP is identified on the DNA-binding side of ER-DBD and is the main driving force behind access to the DNA. The position of the ER-DBD monomer can be fixed on a phosphate group of DNA-ERE by the strong electrostatic interactions, whereas the rotation cannot be fixed. In contrast, both the position and rotation of the ER-DBD dimer can be fixed and can therefore form the stable (ER-DBD)2...DNA-ERE complex. Dimerization of the ER-DBD monomers, each of which have a charge of +5 , is mainly due to large attractive interaction energies of the second Zn fragments. The base pairs in the consensus sequence of DNA-ERE interact only with the recognition helix located in the major groove due to the large shielding effect of the phosphate groups of DNA. The recognition helix has weaker interactions with the base pairs than the electrostatic interactions with the phosphate groups. Thus, the DNA-binding machinery of the ER-DBD dimer, which can secure the recognition helix in the major groove of DNA, is crucial for interactions between the recognition helix and base pairs.


Circumcostal gastropexy for preventing recurrence of gastric dilatation-volvulus in the dog: an evaluation of 30 cases.
Follow-up evaluation (mean, 13.7 months) was obtained in 30 dogs with gastric dilatation-volvulus that were surgically treated with circumcostal gastropexy. Evaluation was performed by questionnaire (29 dogs), radiographic contrast studies (23 dogs), and necropsy (6 dogs). The gastropexy was thought to be intact in all 23 dogs examined radiographically. Necropsy of 6 dogs dying from causes unrelated to gastric dilatation-volvulus (mean of 12.7 months after surgery) revealed an intact gastropexy site in each dog. Only 1 (3.3%) dog had clinical recurrence of gastric dilatation after surgery. Five additional dogs dying postoperatively were necropsied and had intact gastropexy sites.


Cancer Patients' Mental Health Distress and Suicidality.
Background: A substantial number of people with cancer endorse suicidality when compared with the general population. Thus, oncology healthcare workers may experience the death of a patient to suicide over their careers. Aims: To explore the impact of patients' mental health distress and suicidality on oncology personnel with a secondary aim of exploring how personnel cope with these types of events. Method: We interviewed 61 healthcare professionals (HCPs) at two cancer centers. The grounded theory method (GT) was used. Results: The impact of patients' mental health distress and suicidal ideation on oncology HCPs included sadness, depression, worry and concern, and feeling emotionally overwhelmed. The impact of patient suicide on HCPs included trauma, guilt, and surprise. Oncology personnel reported a change in practice, including communication style, being attuned to patient cues, and changing the physical environment. Coping strategies included colleague support, seeking professional help, and setting boundaries between their work and home life. Limitations: It is likely that HCPs who participated in the study represent those who are more willing to discuss issues related to suicide. Thus, the impact of patient suicide on healthcare providers may be even more pronounced among the general oncology HCP community. Conclusion: Given the higher risk of suicide among cancer patients, it is necessary to increase awareness about the impact these events may have on HCPs. Professional guidelines can highlight the need for a balance between ensuring the availability of informal support and more formal methods of help.


Long-term blood pressure variability and frailty risk in older adults.
In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain. Secondary analysis of blood pressure variability (BPV) and incident frailty in >13 000 participants ≥65-70 years enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its observational follow-up (ASPREE-XT). Participants were without dementia, physical disability, or cardiovascular disease at baseline. BPV was estimated using standard deviation of mean BP from three annual visits (baseline through the second annual follow-up). Frailty was defined using Fried phenotype and a frailty deficit accumulation index (FDAI). Participants with frailty during the BPV estimation period were excluded from the main analysis. Adjusted Cox proportional hazards regression evaluated the association between BPV and incident frailty, and linear mixed models for change in frailty scores, through a maximum of 9 years of follow-up. Participants in the highest systolic BPV tertile were at higher risk of frailty compared to those in the lowest (referent) tertile of systolic BPV [Fried hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.31; FDAI HR 1.18, 95% CI 1.07-1.30]. Findings were consistent when adjusted for multiple covariates and when stratified by antihypertensive use. Linear mixed models showed that higher systolic BPV was associated with increasing frailty score over time. Diastolic BPV was not consistently associated. High systolic BPV, independent of mean BP, is associated with increased risk of frailty in healthy older adults. Variability of BP across visits, even in healthy older adults, can convey important risk information beyond mean BP. ClinicalTrials.gov NCT01038583 and ISRCTN83772183.


Is the atherosclerotic process accentuated under conditions of HIV infection, antiretroviral therapy, and protease inhibitor exposure? Meta-analysis of the markers of arterial structure and function.
To evaluate the apparent association of human immunodeficiency virus (HIV) infection, antiretroviral therapy (ART), and protease inhibitor (PI) exposure with the functional and structural markers of vasculature. A meta-analysis of the relationship between HIV infection, ART, and PI exposure and the functional and structural markers of vasculature. A systematic literature search was performed electronically using specific eligibility criteria. Weighted mean difference (WMD) and corresponding 95% confidence interval (CI) were calculated and combined appropriately. Fifty-seven articles were included with nine different outcomes. Compared with HIV-negative patients, HIV-positive patients demonstrated significant elevated intima-media thickness (IMT) (WMD (95% CI) = 0.042 (0.028-0.057)), increased pulse wave velocity (PWV) (0.538 (0.283-0.792)), and reduced flow-mediated vasodilation (FMD) (-2.049 (-2.806 to -1.293)). Elevated IMT was observed in HIV patients receiving ART when compared with those naïve to ART in the 20- to 40-year-old age group (0.078 (0.033-0.123)), the >40-year-old age group (0.038 (0.018-0.057)), and the group comprising >50% males (0.070 (0.041-0.099)). In addition, ART resulted in an increased PWV in HIV patients receiving ART in the group with >50% male proportion (0.628 (0.405-0.851)). HIV patients exposed to PI showed a significant trend toward elevated IMT (0.033 (0.007-0.058)) and increased PWV (0.264 (0.118-0.410)) compared with those without PI exposure. The atherosclerotic process was accentuated by elevated IMT, increased PWV, and reduced FMD under condition of HIV infection. Comparison of ART-receiving with ART-naïve patients showed a significant trend toward elevated IMT and increased PWV, especially under treatment with PI-containing drugs.


Reassessment of phenotypic traits for Saccharomyces bayanus var. uvarum wine yeast strains.
Among Saccharomyces yeast, S. cerevisiae and S. bayanus var. uvarum are related species, sharing the same ecosystem in sympatry. The physiological and technological properties of a large collection of genetically-identified S. bayanus var. uvarum wine strains were investigated in a biometric study and their fermentation behavior was compared at 24 degrees C and 13 degrees C. The variability of the phenotypic traits was considered at both intraspecific and interspecific levels. Low ethanol tolerance at 24 degrees C and production of high levels of 2-phenylethanol and its acetate were clearly revealed as discriminative technological traits, distinguishing the S. bayanus var. uvarum strains from S. cerevisiae. Although some S. bayanus var. uvarum strains produced very small amounts of acetic acid, this was not a species-specific trait, as the distribution of values was similar in both species. Fermentation kinetics at 24 degrees C showed that S. bayanus var. uvarum maintained a high fermentation rate after Vmax, with low nitrogen requirements, but stuck fermentations were observed at later stages. In contrast, a shorter lag phase compared with S.cerevisiae, higher cell viability, and the ability to complete alcoholic fermentation at 13 degrees C confirmed the low-temperature adaptation trait of S.bayanus var. uvarum. This study produced a phenotypic characterization data set for a collection of S. bayanus var. uvarum strains, thus paving the way for industrial developments using this species as a new genetic resource.


[COX-2 as an early diagnostic marker of virus-associated human malignant neoplasms].
The review analyzes recent data and current ideas on the enzyme cyclooxygenase 2 (COX-2) as a possible biomarker of virus-associated human malignant neoplasm. Possible mechanisms of COX-2 activation in the cells infected with oncogenic human viruses, such as hepatitis B virus, Epstein-Barr virus, and human papillomavirus are considered in detail.


Activity-Based Sensing with a Metal-Directed Acyl Imidazole Strategy Reveals Cell Type-Dependent Pools of Labile Brain Copper.
Copper is a required nutrient for life and particularly important to the brain and central nervous system. Indeed, copper redox activity is essential to maintaining normal physiological responses spanning neural signaling to metabolism, but at the same time copper misregulation is associated with inflammation and neurodegeneration. As such, chemical probes that can track dynamic changes in copper with spatial resolution, especially in loosely bound, labile forms, are valuable tools to identify and characterize its contributions to healthy and disease states. In this report, we present an activity-based sensing (ABS) strategy for copper detection in live cells that preserves spatial information by a copper-dependent bioconjugation reaction. Specifically, we designed copper-directed acyl imidazole dyes that operate through copper-mediated activation of acyl imidazole electrophiles for subsequent labeling of proximal proteins at sites of elevated labile copper to provide a permanent stain that resists washing and fixation. To showcase the utility of this new ABS platform, we sought to characterize labile copper pools in the three main cell types in the brain: neurons, astrocytes, and microglia. Exposure of each of these cell types to physiologically relevant stimuli shows distinct changes in labile copper pools. Neurons display translocation of labile copper from somatic cell bodies to peripheral processes upon activation, whereas astrocytes and microglia exhibit global decreases and increases in intracellular labile copper pools, respectively, after exposure to inflammatory stimuli. This work provides foundational information on cell type-dependent homeostasis of copper, an essential metal in the brain, as well as a starting point for the design of new activity-based probes for metals and other dynamic signaling and stress analytes in biology.


Performance evaluation of the Personal Mobility and Manipulation Appliance (PerMMA).
The Personal Mobility and Manipulation Appliance (PerMMA) is a recently developed personal assistance robot created to provide people with severe physical disabilities enhanced assistance in both mobility and manipulation. PerMMA aims to improve functional independence when a personal care attendant is not available on site. PerMMA integrates both a smart powered wheelchair and two dexterous robotic arms to assist its users in completing essential mobility and manipulation tasks during basic and instrumental activities of daily living (ADL). Two user interfaces were developed: a local control interface and a remote operator controller. This paper reports on the evaluation of PerMMA with end users completing basic ADL tasks. Participants with both lower and upper extremity impairments (N=15) were recruited to operate PerMMA and complete up to five ADL tasks in a single session of no more than two hours (to avoid fatigue or frustration of the participants). The performance of PerMMA was evaluated by participants completing ADL tasks with two different control modes: local mode and cooperative control. The users' task completion performance and answers on pre/post-evaluation questionnaires demonstrated not only the ease in learning and usefulness of PerMMA, but also their attitudes toward assistance from advanced technology like PerMMA. As a part of the iterative development process, results of this work will serve as supporting evidence to identify design criteria and other areas for improvement of PerMMA.


Methylene blue adjuvant therapy of schizophrenia.
There is growing interest in the role of the nitric oxide (NO) pathway in idiopathic psychotic disorders such as schizophrenia. In this preliminary study, we examined the therapeutic efficacy of methylene blue (MB), a "downstream" inhibitor of one of NO's actions, administered orally as an adjuvant to conventional neuroleptic medications. Specifically, MB blocks NO's activation of soluble guanylyl cyclase. MB has previously been reported to have therapeutic effects in the treatment of psychosis and mania. Preclinical data also suggest that MB might possess antipsychotic potential. Participants in the current study were eight patients with schizophrenia who had incomplete responses to conventional antipsychotics (as evidenced by a Brief Psychiatric Rating Scale [BPRS] total score of 35 or more). These patients completed a 4-week open-label study with a 1 week "off", 2 week "on", and one final week "off" design. Measures of treatment efficacy were the BPRS, Schedule for the Assessment of Negative Symptoms, and Clinical Global Improvement Scale administered weekly. Final scores for each outcome measure item were based on the consensus of at least two trained raters present during each rating interview. A statistically significant, albeit modest, decrease in the severity of psychopathology was observed while the subjects were taking MB, and psychopathology significantly worsened when MB was discontinued. The results suggest a need for further study with MB or perhaps other NO-dependent guanylyl cyclase-inhibiting medications.


Athlete Information Sources About Dietary Supplements: A Review of Extant Research.
In the United States, the Dietary Supplement Health and Education Act of 1994 (DSHEA) classified dietary supplements as a subcategory of food, exempting manufacturers from providing premarket evidence of product safety and efficacy. Under DSHEA, agencies such as the U.S. Food and Drug Administration (FDA) cannot inspect supplements until after the products have entered the marketplace. Recognizing that both limited resources and DSHEA prevent the FDA from conducting broad-based inspections on a regular basis, disreputable manufacturers have spiked products with drugs such as anabolic steroids and amphetamines. With contaminated supplements now causing athletes to fail drug tests and, in some instances, threatening public health, it becomes important to examine sources of supplement information. This article reviews 53 studies that have addressed athlete information sources about dietary supplements. It finds that athletes, in general, rely heavily on coaches and trainers as well as friends and family for information. Relative to U.S. athletes, those competing internationally appear more likely to seek information from a physician or nutritionist. The article offers recommendations for individuals and organizations based on the most frequent information sources identified by athletes.


Heterogeneous Graph Attention Network for Unsupervised Multiple-Target Domain Adaptation.
Domain adaptation, which transfers the knowledge from label-rich source domain to unlabeled target domains, is a challenging task in machine learning. The prior domain adaptation methods focus on pairwise adaptation assumption with a single source and a single target domain, while little work concerns the scenario of one source domain and multiple target domains. Applying pairwise adaptation methods to this setting may be suboptimal, as they fail to consider the semantic association among multiple target domains. In this work we propose a deep semantic information propagation approach in the novel context of multiple unlabeled target domains and one labeled source domain. Our model aims to learn a unified subspace common for all domains with a heterogeneous graph attention network, where the transductive ability of the graph attention network can conduct semantic propagation of the related samples among multiple domains. In particular, the attention mechanism is applied to optimize the relationships of multiple domain samples for better semantic transfer. Then, the pseudo labels of the target domains predicted by the graph attention network are utilized to learn domain-invariant representations by aligning labeled source centroid and pseudo-labeled target centroid. We test our approach on four challenging public datasets, and it outperforms several popular domain adaptation methods.


Inhibitory effect of caffeine on pacemaker activity in the oviduct is mediated by cAMP-regulated conductances.
Spontaneous electrical activity, termed slow waves, drives rhythmic, propulsive contractions in the smooth muscle of the oviduct (myosalpinx). Myosalpinx contractions cause egg transport through the oviduct. Agents that disrupt slow wave pacemaker activity will therefore disrupt myosalpinx contractions and egg transport. Caffeine is commonly used as a ryanodine receptor agonist and has been previously associated with delayed conception. Here we assessed the effects of caffeine on pacemaker activity in the murine myosalpinx. The effects of caffeine on electrical pacemaker activity were studied using intracellular microelectrode and isometric force measurements on intact oviduct muscle preparations. Responses to caffeine were compared with responses caused by 3-isobutyl-1-methylxanthine (IBMX) and forskolin. Caffeine caused hyperpolarization of membrane potential and inhibited slow wave generation and myosalpinx contractions. The effects of caffeine could be mimicked by the K(ATP) channel agonist pinacidil and antagonized by the K(ATP) channel antagonist glibenclamide. Caffeine is known to inhibit cyclic nucleotide phosphodiesterases (PDEs), leading to an increase in cytosolic cAMP and stimulation of downstream cAMP-dependent mechanisms. The effects of caffeine were mimicked by the PDE inhibitor, IBMX, and the adenylyl cyclase activator forskolin. These effects were also reversed by glibenclamide. These results suggest that caffeine activates K(ATP) channels in oviduct myosalpinx. Since caffeine abolishes slow waves and associated contractions of the myosalpinx, it would have a negative effect on egg transport through the oviduct and may contribute to the documented delayed conception in women consuming caffeinated beverages.


Vasopressor Therapy in the Intensive Care Unit.
After fluid administration for vasodilatory shock, vasopressors are commonly infused. Causes of vasodilatory shock include septic shock, post-cardiovascular surgery, post-acute myocardial infarction, postsurgery, other causes of an intense systemic inflammatory response, and drug -associated anaphylaxis. Therapeutic vasopressors are hormones that activate receptors-adrenergic: α1, α2, β1, β2; angiotensin II: AG1, AG2; vasopressin: AVPR1a, AVPR1B, AVPR2; dopamine: DA1, DA2. Vasopressor choice and dose vary widely because of patient and physician practice heterogeneity. Vasopressor adverse effects are excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. To date, no randomized controlled trial (RCT) of vasopressors has shown a decreased 28-day mortality rate. There is a need for evidence regarding alternative vasopressors as first-line vasopressors. We emphasize that vasopressors should be administered simultaneously with fluid replacement to prevent and decrease duration of hypotension in shock with vasodilation. Norepinephrine is the first-choice vasopressor in septic and vasodilatory shock. Interventions that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality significantly. In patients not responsive to norepinephrine, vasopressin or epinephrine may be added. Angiotensin II may be useful for rapid resuscitation of profoundly hypotensive patients. Inotropic agent(s) (e.g., dobutamine) may be needed if vasopressors decrease ventricular contractility. Dopamine has fallen to almost no-use recommendation because of adverse effects; angiotensin II is available clinically; there are potent vasopressors with scant literature (e.g., methylene blue); and the novel V1a agonist selepressin missed on its pivotal RCT primary outcome. In pediatric septic shock, vasopressors, epinephrine, and norepinephrine are recommended equally because there is no clear evidence that supports the use of one vasoactive agent. Dopamine is recommended when epinephrine or norepinephrine is not available. New strategies include perhaps patients will be started on several vasopressors with complementary mechanisms of action, patients may be selected for particular vasopressors according to predictive biomarkers, and novel vasopressors may emerge with fewer adverse effects.


The polycomb group protein Bmi1 binds to the herpes simplex virus 1 latent genome and maintains repressive histone marks during latency.
The mechanism by which herpes simplex virus 1 (HSV-1) establishes latency in sensory neurons is largely unknown. Recent studies indicate that epigenetic modifications of the chromatin associated with the latent genome may play a key role in the transcriptional control of lytic genes during latency. In this study, we found both constitutive and facultative types of heterochromatin to be present on the latent HSV-1 genome. Deposition of the facultative marks trimethyl H3K27 and histone variant macroH2A varied at different sites on the genome, whereas the constitutive marker trimethyl H3K9 did not. In addition, we show that in the absence of the latency-associated transcript (LAT), the latent genome shows a dramatic increase in trimethyl H3K27, suggesting that expression of the LAT during latency may act to promote an appropriate heterochromatic state that represses lytic genes but is still poised for reactivation. Due to the presence of the mark trimethyl H3K27, we examined whether Polycomb group proteins, which methylate H3K27, were present on the HSV-1 genome during latency. Our data indicate that Bmi1, a member of the Polycomb repressive complex 1 (PRC1) maintenance complex, associates with specific sites in the genome, with the highest level of enrichment at the LAT enhancer. To our knowledge, these are the first data demonstrating that a virus can repress its gene transcription to enter latency by exploiting the mechanism of Polycomb-mediated repression.


Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy.
Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation-inhibition balance in the brain, and it can serve as a mouse model of epilepsy.


Astragaloside II promotes intestinal epithelial repair by enhancing L-arginine uptake and activating the mTOR pathway.
Astragaloside II (AS II) extracted from Astragalus membranaceus has been reported to promote tissue wound repair. However, the effect of AS II on inflammatory bowel disease is unknown. We investigated the effects and mechanism of AS II on intestinal wound healing in both in vitro and in vivo models. Human intestinal Caco-2 cells were treated with multiple concentrations of AS II to assess cell proliferation, scratch wound closure, L-arginine uptake, cationic amino acid transporter activity, and activation of the mTOR signaling pathway. These effects were also measured in a mouse model of colitis. AS II promoted wound closure and increased cell proliferation, L-arginine uptake, CAT1 and CAT2 protein levels, total protein synthesis, and phosphorylation of mTOR, S6K, and 4E-BP1 in Caco-2 cells. These effects were suppressed by lysine or rapamycin treatment, suggesting that the enhanced arginine uptake mediates AS II-induced wound healing. Similar results were also observed in vivo. Our findings indicate that AS II can contribute to epithelial barrier repair following intestinal injury, and may offer a therapeutic avenue in treating irritable bowel disease.


Role of somatosensory evoked potentials in the diagnosis of peripheral nerve lesions: recent advances.
Short-latency somatosensory evoked potentials (SEPs) have become an important tool in the investigation of peripheral nerve lesions. Electrically evoked SEPs are most suitable because they provide results with small variations and are readily repeatable. Techniques for testing 10 different upper and lower limb nerves, dermatomes, cutaneous fibers of trigeminal nerve, and nerves supplying urogenital areas are now available. The established, principal areas of application are in the investigation of brachial plexus lesions, proximal injuries of individual nerves in upper and lower limbs, and painful dysesthesias and in the differential diagnosis of pain caused by psychogenic causes or organic lesions. The techniques have proven to be of value in demonstrating early proximal abnormalities in polyneuropathies. Abnormalities have occurred in trigeminal nerve lesions, urogenital dysfunctions, hereditary ataxias, and rare neuropathies. Unexpected abnormalities have also been reported in motor neuron disease, myotonic muscular dystrophies, and other conditions. Applications in the diagnosis of spondylopathic root lesions are not satisfactory; the techniques' usefulness in the investigation of these lesions does not extend beyond aiding the selection of patients for other diagnostic modalities, such as myelography, computed tomography (CT), and nuclear magnetic resonance (NMR) imaging. The usefulness of SEP techniques in the diagnosis of peripheral nerve lesions will remain, even if advances in organ imaging techniques can provide more specific information about the level and magnitude of lesions in the central nervous system. SEP techniques are an important complement to the other well-established methods, such as clinical testing, electromyography, and nerve conduction studies.


Individual Objective and Subjective Fixation Disparity in Near Vision.
Binocular vision refers to the integration of images in the two eyes for improved visual performance and depth perception. One aspect of binocular vision is the fixation disparity, which is a suboptimal condition in individuals with respect to binocular eye movement control and subsequent neural processing. The objective fixation disparity refers to the vergence angle between the visual axes, which is measured with eye trackers. Subjective fixation disparity is tested with two monocular nonius lines which indicate the physical nonius separation required for perceived alignment. Subjective and objective fixation disparity represent the different physiological mechanisms of motor and sensory fusion, but the precise relation between these two is still unclear. This study measures both types of fixation disparity at viewing distances of 40, 30, and 24 cm while observers fixated a central stationary fusion target. 20 young adult subjects with normal binocular vision were tested repeatedly to investigate individual differences. For heterophoria and subjective fixation disparity, this study replicated that the binocular system does not properly adjust to near targets: outward (exo) deviations typically increase as the viewing distance is shortened. This exo proximity effect-however-was not found for objective fixation disparity, which-on the average-was zero. But individuals can have reliable outward (exo) or inward (eso) vergence errors. Cases with eso objective fixation disparity tend to have less exo states of subjective fixation disparity and heterophoria. In summary, the two types of fixation disparity seem to respond in a different way when the viewing distance is shortened. Motor and sensory fusion-as reflected by objective and subjective fixation disparity-exhibit complex interactions that may differ between individuals (eso versus exo) and vary with viewing distance (far versus near vision).


Addressing feasibility challenges to delivering intradialytic exercise interventions: a theory-informed qualitative study.
Intradialytic exercise (IDE) may improve physical function and health-related quality of life. However, incorporating IDE into standard hemodialysis care has been slow due to feasibility challenges. We conducted a multicenter qualitative feasibility study to identify potential barriers and enablers to IDE and generate potential solutions to these factors. We conducted 43 semistructured interviews with healthcare providers and patients across 12 hospitals in Ontario, Canada. We used the Theoretical Domains Framework and directed content analysis to analyze the data. We identified eight relevant domains (knowledge, skills, beliefs about consequences, beliefs about capabilities, environmental context and resources, goals, social/professional role and identity, and social influences) represented by three overarching categories: knowledge, skills and expectations: lack of staff expertise to oversee exercise, uncertainty regarding exercise risks, benefits and patient interest, lack of knowledge regarding exercise eligibility; human, material and logistical resources: staff concerns regarding workload, perception that exercise professionals should supervise IDE, space, equipment and scheduling conflict concerns; and social dynamics of the unit: local champions and patient stories contribute to IDE sustainability. We developed a list of actionable solutions by mapping barriers and enablers to behavior change techniques. We also developed a feasibility checklist of 47 questions identifying key factors to address prior to IDE launch. Evidence-based solutions to identified barriers to and enablers of IDE and a feasibility checklist may help recruit and support units, staff and patients and address key challenges to the delivery of IDE in diverse clinical and research settings.


Field-based evidence for devolatilization in subduction zones: implications for arc magmatism.
Metamorphic rocks on Santa Catalina Island, California, afford examination of fluid-related processes at depths of 15 to 45 kilometers in an Early Cretaceous subduction zone. A combination of field, stable isotope, and volatile content data for the Catalina Schist indicates kilometer-scale transport of large amounts of water-rich fluid with uniform oxygen and hydrogen isotope compositions. The fluids were liberated in devolatilizing, relatively low-temperature (400 degrees to 600 degrees C) parts of the subduction zone, primarily by chlorite-breakdown reactions. An evaluation of pertinent phase equilibria indicates that chlorite in mafic and sedimentary rocks and melange may stabilize a large volatile component to great depths (perhaps >100 kilometers), depending on the thermal structure of the subduction zone. This evidence for deep volatile subduction and large-scale flow of slab-derived, water-rich fluids lends credence to models that invoke fluid addition to sites of arc magma genesis.


Global, regional, and national burden of Guillain-Barré syndrome and its underlying causes from 1990 to 2019.
This article presents the first detailed analysis of the prevalence and disability burden of Guillain-Barré syndrome (GBS) from 1990 to 2019 by cause, age, sex, and Socio-demographic Index (SDI) in 204 countries and territories. Data from the Global Burden of Diseases Study (GBD) 2019 were used. GBD 2019 modelled the prevalence of GBS using hospital and claims data. Years lived with disability (YLDs) were estimated as the product of the GBS prevalence and the disability weight. This article also reported proportions in the age-standardised prevalence rate that were due to six underlying causes of GBS. In 2019, there were 150,095 [95% uncertainty intervals (UI) 119,924 to 188,309] total cases of GBS worldwide, which resulted in 44,407 (95% UI 28,016 to 64,777) YLDs. Globally, there was a 6.4% (95% UI 3.6 to 9.5) increase in the age-standardised prevalence of GBS per 100,000 population between 1990 and 2019. High-income Asia Pacific [1.9 (95% UI: 1.5 to 2.4)] and East Asia [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000), respectively, in 2019. Nationally, Japan [6.4 (95% UI: 5.3 to 7.7)] and China [0.8 (95% UI: 0.6 to 1.0)] had the highest and lowest age-standardised prevalence rates (per 100,000). The age-standardised burden of GBS increased with increasing age and was higher in males in all age groups. Furthermore, the age-standardised prevalence of GBS (per 100,000) had a positive association with the level of development, as measured by SDI, although this association was not strong. Upper respiratory infections and unknown causes accounted for the highest proportions of underlying causes. Globally, the prevalence of GBS continues to increase. Geographical differences and strategies aimed at preventing infectious diseases should be considered in future health policy planning and decision-making processes. This study had several limitations, such as using the same disability weight for all causes and a reliance on hospital- and self-reported data, which should be addressed in future research.


[Flavonoid constituents of Melicope triphylla MERR.II].
From the leaves of Melicope triphylla MERR., three new flavonoids (1-3) were isolated, together with nine known flavonoids, 4',5-dihydroxy-3,3',7- trimethoxyflavone (4), 5-hydroxy-3,3',4',7-tetramethoxyflavone (5), 3,3',4',5,7-pentamethoxyflavone (6), 7-hydroxy-3,3',4',5,8-pentamethoxyflavone (7), 3,3',4',5,7,8-hexamethoxyflavone (8), 5-hydroxy-3,7,8-trimethoxy-3',4'-methylenedioxyflavone (9), 7-hydroxy-3,5,8- trimethoxy-3',4'-methylenedioxyflavone (10), 3,5,7,8-tetramethoxy-3',4'-methylenedioxyflavone (11), and 5-hydroxy- 3,6,7,8-tetramethoxy-3',4'-methylenedioxyflavone (12). The structures of 1, 2, and 3 were established as 5-hydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone, 5-hydroxy-7-isopentenyloxy-3,8-dimethoxy-3',4'-methylenedioxyfl avone, and 4'-hydroxy-7-isopentenyloxy-3,3',5,8-tetramethoxyflavone by their respective chemical and spectral data. The 20 flavonoids isolated from this plant were examined for the piscicidal activities.


Secular evolution of femoral morphology from a clinical perspective.
Intramedullary nailing is the surgical method of choice for the treatment of proximal femur or femoral shaft fractures. Implant manufacturers aim to design implants fitting for the broadest possible population segment. As complete morphological data sets of long bones are not widely available, anatomical collections of historical dry bone specimens may represent abundant additional sources of morphological three-dimensional (3D) data for implant design, provided they are consistent with present populations. This study aims to investigate secular trends and age-related changes of femoral morphology of the Caucasian population over the past 800 years. Computer graphical measurements of 3D-datasets of right and left femora derived from computed tomography (CT) scans, representative of the present Caucasian population, were compared to computer graphical measurements of 3D-datasets of right and left femora derived from CT scans of specimens from a historical medieval European bone collection. Clinically relevant parameters of historical medieval European femora were found mostly consistent with correlative data of the present Caucasian population. Additionally, for some of the evaluated parameters, particularly anteversion, morphological differences significantly correlated to individual age and sex could be identified, whereas other parameters such as caput-collum-diaphyseal angle or radius of anterior femoral bowing were not correlated to individual age or sex. The findings suggest that more recent historical specimen collections may be a convenient and easily accessible source of new 3D morphological data, as well as to complement existing data, to be used by researchers and manufacturers for the development of intramedullary femoral nails.


Isolation of fucoxanthin from edible brown algae by microwave-assisted extraction coupled with high-speed countercurrent chromatography.
A rapid and efficient method for the separation and purification of fucoxanthin from edible brown algae by microwave-assisted extraction coupled with high-speed countercurrent chromatography was developed. The algae were first extracted using microwave-assisted extraction, then the dried extract was dissolved and directly introduced into the high-speed countercurrent chromatography system with a two-phase solvent system consisting of hexane-ethyl acetate-ethanol-water (5:5:6:4, v/v/v/v). The isolation was done in less than 75 min, and a total of 0.83 mg, 1.09 mg, and 0.20 mg fucoxanthin were obtained from 25.0 g fresh Laminaria japonica Aresch, 1.5 g dry Undaria pinnatifida (Harv) Sur, and 15.0 g dry Sargassum fusiforme (Harv) Setch, respectively. The purity of fucoxanthin determined by HPLC was over 90% and its structure was further identified by LC-ESI-MS and (1) H-NMR.


Transient vortex states in Bi2Sr2CaCu2O(8+delta) crystals
A high temporal resolution magneto-optical system is employed to observe the time evolution of the vortex structure in Bi(2)Sr(2)CaCu(2)O(8+delta) crystals after a sudden application of a magnetic field. The magneto-optical images reveal dynamic coexistence of two vortex phases: a quasiordered phase in the sample interior and a transient disordered phase near the sample edges. The border between these two phases, marked by an abrupt change in the gradient of the local induction, moves with time. This motion enables tracing the decay of the transient state and the concurrent growth of the thermodynamic vortex phases. The growth rate is sensitive to the location in the field-temperature phase diagram.


The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer.
To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (greater than 2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (less than or equal to 2 mm), and (d) 346 patients with an unknown margin. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p less than .0001). There was no significant difference among the four groups for 5-year actuarial overall survival (p = .19), no evidence of disease (NED) survival (p = .95), or relapse-free survival (p = .80). There was no significant difference among the four groups for five year actuarial local or regional control (all p greater than or equal to .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients.


Diagnosis of human strongyloidiasis by immunofluorescence, using Strongyloides ratti and S. stercoralis larvae.
The sensitivity and specificity of an indirect immunofluorescent antibody assay for the diagnosis of human strongyloidiasis has been investigated. Sera were obtained from 160 Australian ex-servicemen who had been prisoners-of-war in Southeast Asia during World War II, 44 of whom proven parasitologically to have strongyloidiasis; these men did not have concurrent infections with other helminths. In addition, sera were collected from 44 age- and sex-matched Australians who were not thought to have been exposed to S. stercoralis, and from 44 Filipino subjects. Antibodies were measured by using living filariform S. ratti larvae as the source of antigen. The assay was highly sensitive; antibodies were found at a titer of 1:4 or greater in 98% of men with strongyloidiasis and in 2% of Australian control subjects. Fifteen percent of exposed ex-servicemen in whom parasites had not been found had antibody titers of 1:4 or more, and it is thought that they had cryptic infections. Incubation of pooled positive sera with soluble S. ratti antigen produced a marked fall in antibody titer, but no changes were seen after incubation with soluble Ascaris suum or Dirofilaria immitis antigens. It is thought that this indicates that the test is specific and that the 84% of Filipinos with antibody titers of 1:4 or greater had unsuspected strongyloidiasis. When antibody titers against S. ratti were compared with those obtained using living filariform S. stercoralis larvae, a high correlation was found (r = 0.89, P less than 0.001). It is concluded that this assay provides a simple, safe, and specific method for the diagnosis of strongyloidiasis.


Stopping power and ranges of low-energy protons in tissue-equivalent gas.
Stopping power data for protons in tissue-equivalent gas (64.4% CH4 + 32.4% CO2 + 3.2% N2, partial pressures) were derived from experimentally determined ranges and from differential ionisation distributions using the differential energy required per ion pair formed to convert ionisation to energy loss. The proton energy covered the region from 1 to 100 keV. The results are compared with other data available. In general the present experimental stopping power data tend to higher values than calculated data for energies lower than 20 keV; between 20 and 100 keV they agree well within the stated uncertainties.


Comparative Performance of Comorbidity Measures in Predicting Health Outcomes in Patients with Chronic Obstructive Pulmonary Disease.
Multiple studies have suggested that comorbidities pose negative impacts on the survival of patients with chronic obstructive pulmonary disease (COPD); few have applied comorbidity measures driven from health insurance claims databases to predict various health outcomes. We aimed to examine the performance of commonly used comorbidity measures based on diagnosis and pharmacy dispensing claims information in predicting future death and hospitalization in COPD patients. We identified COPD patients in a population-based Taiwanese database. We built logistic regression models with age, sex, and baseline comorbidities measured by either diagnosis or pharmacy claims information as predictors of subsequent-year death or hospitalization in a random 50% sample and validated the discrimination in the other 50%. The diagnosis-based comorbidity measures included the Charlson Index and the Elixhauser comorbidity measure; the pharmacy-based comorbidity measures included the updated Chronic Disease Score (CDS) and the Pharmacy-Based Comorbidity Index (PBDI). We identified 428,251 eligible patients. For overall death, the Elixhauser comorbidity measure showed the best predictive performance (c-statistic=0.832), followed by the PBDI (c-statistic=0.822), the Charlson Index (c-statistic=0.815), and the updated CDS (c-statistic=0.808). For overall hospitalization, the PBDI (c-statistics=0.730) and the Elixhauser comorbidity measure (c-statistics=0.724) outperformed the updated CDS (c-statistics=0.714) and the Charlson Index (c-statistics=0.710). For hospitalization due to cardiovascular, cerebrovascular, or respiratory diseases, the comorbidity models showed similar predictive ranks and demonstrated c-statistics higher than 0.75. However, none of the models could adequately predict hospitalization due to other reasons (c-statistics < 0.60). Our study comprehensively compared the predictive performance of comorbidity measures. The Elixhauser comorbidity measure and the PBDI are useful tools for describing comorbid conditions and predicting health outcomes in COPD patients.


Incremental sparse Bayesian ordinal regression.
Ordinal Regression (OR) aims to model the ordering information between different data categories, which is a crucial topic in multi-label learning. An important class of approaches to OR models the problem as a linear combination of basis functions that map features to a high-dimensional non-linear space. However, most of the basis function-based algorithms are time consuming. We propose an incremental sparse Bayesian approach to OR tasks and introduce an algorithm to sequentially learn the relevant basis functions in the ordinal scenario. Our method, called Incremental Sparse Bayesian Ordinal Regression (ISBOR), automatically optimizes the hyper-parameters via the type-II maximum likelihood method. By exploiting fast marginal likelihood optimization, ISBOR can avoid big matrix inverses, which is the main bottleneck in applying basis function-based algorithms to OR tasks on large-scale datasets. We show that ISBOR can make accurate predictions with parsimonious basis functions while offering automatic estimates of the prediction uncertainty. Extensive experiments on synthetic and real word datasets demonstrate the efficiency and effectiveness of ISBOR compared to other basis function-based OR approaches.


Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst Fenestration for Massive Polycystic Liver Disease.
Partial hepatectomy and cyst fenestration (PHCF) selectively provides clinical benefit in highly symptomatic patients with polycystic liver disease (PLD). This study aims to ascertain whether the reduction in liver volume (LV) achieved by PHCF is sustained long term. Clinical data were retrieved from the electronic records of all patients with PLD who underwent PHCF between 1985 and 2014. Preoperative LVs (LV1), postoperative LVs (LV2), and late follow-up LVs (LV3) were measured from magnetic resonance or CT images. Among 186 patients who underwent PHCF, 91% were Caucasian women with autosomal dominant polycystic kidney disease with a mean age of 49 years. Major perioperative complications (Clavien III/IV) occurred in 21% of the patients. Operative mortality (<90 days) was 2.7%. Eleven patients had liver failure develop, received liver transplants, or had liver-related deaths. Overall survival was 95.7%, 93.3%, 85.6%, and 77.7% at 1, 5, 10, and 15 years respectively. Imaging records for volumetry were unavailable in 32 patients. Of the remaining 154 patients, 34 had imaging for 1 LV, 64 for 2 LVs, and 55 for all 3 LVs. Median LV was 6,781 mL (interquartile range 4,903 to 8,341 mL) preoperatively and 2,502 mL (interquartile range 2,089 to 3,136 mL) after PHCF, leading to a median postoperative LV reduction of 61%. At follow-up (mean 8 years), median LV was 2,519 mL (interquartile range 2,083 to 3,752 mL). Interestingly, 33 of 62 patients with available LV2 and LV3 showed additional regression in LV at follow-up (median -14.1%), and the rest showed mild growth of 9.9%. Overall volumetric comparison of preoperative with follow-up liver imaging showed sustained LV reduction (median 61%). Sustained long-term reductions in LV after PHCF can be achieved in selected patients with severe, highly symptomatic PLD. In our experience, liver-related death and subsequent liver transplantation are infrequent after PHCF.


Regional ketone body utilization by rat brain in starvation and diabetes.
The rate of ketone body (beta-hydroxybutyrate and acetoacetate) metabolism was measured in individual cerebral structures of fed, starved, and diabetic rats. This was done by infusing beta-[3-14C]hydroxybutyrate intravenously and measuring the incorporation of 14C into brain by quantitative autoradiography. The capacity of the brain to use ketone bodies, expressed as plasma clearance, increased in starvation and diabetes by approximately 50-60%. Plasma clearance was near maximal after 2 days starvation and was not significantly increased after 4 days starvation, 6 days of diabetes or 28 days of diabetes. In all situations the ketone bodies provided only a modest amount of fuel for brain energy metabolism; 3.2% after 2 days starvation and 6.5 and 9.9% after 6 and 28 days of diabetes. The fraction of their energy requirement which the various structures could derive from the ketone bodies differed widely. In general the telencephalon made greatest use of ketone bodies, whereas the hindbrain used least. There was no correlation between the energy requirement of structures (estimated from glucose use in fed rats) and the fraction of energy they could derive from ketone bodies.


Intermediate to Long-Term Follow-up of Cementing Liners into Well-Fixed Acetabular Components.
The cementation of a new liner into a well-fixed acetabular component is common during revision total hip arthroplasty (THA) for many indications, but most commonly for lack of a modern, compatible, highly cross-linked polyethylene (HXLPE) liner. However, little is known about the intermediate-term to long-term durability of this strategy. The purpose of this study was to evaluate the implant survivorship, risk of complications, clinical outcomes, and radiographic results of cementing a new HXLPE liner into a well-fixed acetabular component. We retrospectively identified 323 revision THAs in which a nonconstrained HXLPE liner was cemented into a well-fixed acetabular component. The mean age at the time of the revision THA was 63 years, and 50% of patients were female. The most common indications for revision THA were polyethylene wear and osteolysis (48%), aseptic femoral loosening (35%), and hip instability (8%). The mean follow-up was 9 years. Polyethylene liner failure occurred in 11 cases (3%). In all cases, the cemented liner dissociated from the acetabular component. At 10 years, the survivorship free from any revision was 80% (95% confidence interval [CI], 75% to 84%) and the survivorship free from any reoperation was 77% (95% CI, 72% to 82%). The most common reason for re-revision was dislocation (45% of reoperations). A dislocation occurred in 17% of cases. Hips that underwent revision for instability were significantly more likely to dislocate compared with hips that underwent revision for liner wear (hazard ratio [HR], 2.3 [95% CI, 1.2 to 4.5]; p = 0.02). Elevated rim or face-changing liners were significantly more likely to dissociate than flat liners (HR, 9.0 [95% CI, 1.2 to 70.6]; p = 0.04). Cementation of a nonconstrained HXLPE liner into a well-fixed acetabular component during revision THA provided durable fixation with only a small number of failures at the cement interface (3%). Instability after this procedure remains a concern, but this is multifactorial in nature. These data support the continued use of this technique, when necessary, during revision THA. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Fabrication of ultrathin multilayered superomniphobic nanocoatings by liquid flame spray, atomic layer deposition, and silanization.
Superomniphobic, i.e. liquid-repellent, surfaces have been an interesting area of research during recent years due to their various potential applications. However, producing such surfaces, especially on hard and resilient substrates like stainless steel, still remains challenging. We present a stepwise fabrication process of a multilayered nanocoating on a stainless steel substrate, consisting of a nanoparticle layer, a nanofilm, and a layer of silane molecules. Liquid flame spray was used to deposit a TiO2 nanoparticle layer as the bottom layer for producing a suitable surface structure. The interstitial Al2O3 nanofilm, fabricated by atomic layer deposition (ALD), stabilized the nanoparticle layer, and the topmost fluorosilane layer lowered the surface energy of the coating for enhanced omniphobicity. The coating was characterized with field emission scanning electron microscopy, focused ion beam scanning electron microscopy, x-ray photoelectron spectroscopy, contact angle (CA) and sliding angle (SA) measurements, and microscratch testing. The widely recognized requirements for superrepellency, i.e. CA > 150° and SA < 10°, were achieved for deioinized water, diiodomethane, and ethylene glycol. The mechanical stability of the coating could be varied by tuning the thickness of the ALD layer at the expense of repellency. To our knowledge, this is the thinnest superomniphobic coating reported so far, with the average thickness of about 70 nm.


Characterization of puff-by-puff resolved cigarette mainstream smoke by single photon ionization-time-of-flight mass spectrometry and principal component analysis.
Soft single photon ionization-time-of-flight mass spectrometry (SPI-TOFMS) and principal component analysis (PCA) were applied for the characterization and discrimination of the chemical patterns of all individual cigarette puffs from the 2R4F University of Kentucky research reference cigarette. The SPI-TOFMS was connected to a smoking machine, and 10 cigarettes were smoked under defined smoking conditions. A total of 41 detected mass signals could be clearly assigned to smoke constituents (e.g., unsaturated hydrocarbons, aromatic species, sulfurous compounds, and nitrogen-containing substances). For further analysis, the on-line recorded mass signals were added up for each cigarette puff resulting in a single summed mass spectrum for each puff. The so-achieved puff-by-puff resolved yields were additionally normalized by the corresponding total ion signal, which eliminated the influences of varying amounts of burnt tobacco. These values were incorporated into a PCA to find differences and similarities in the chemical patterns of the individual cigarette puffs. In addition, absolute (without normalization) and normalized puff resolved yields were used to clarify occurring trends. Thereby, it was shown that the chemical pattern of the first cigarette puff was very unique, whereby extraordinary high yields of unsaturated hydrocarbons are mainly responsible for this. Depending on the smoking procedure, the chemical pattern of the second puff can also be separated from the first and the third puff. In this case, nitrogen-containing substances play an important role. Puffs three to eight show only small but observable differences. These changes are greater influenced by oxygen-containing and sulfurous smoke constituents. The findings reveal that the overall chemical patterns of machine-smoked cigarette puffs vary quite a lot during the smoking process. This lets us assume that the burden of hazardous compounds for the human smoker also differs from puff to puff.


Follow up care of bereaved parents after treatment withdrawal from newborns.
To explore parents' experiences of bereavement care after withdrawal of newborn intensive care. Face to face interviews with 108 parents of 62 babies born over two calendar years in the East of Scotland. Only 22% were seen by six weeks after the death, 10% were not recalled before 6-11 months, and 8% were not seen at all in the first year. All except one couple saw the neonatologist who had cared for their baby. Only 33% remembered a neonatal nurse being present. Most (88%) were seen in the study hospital. Parents highlighted a number of specific needs. Appointments should be: (a) scheduled soon after the death of the baby and certainly within two months of the death irrespective of whether or not autopsy results are available; (b) with the named neonatologist; (c) in a setting away from the hospital if possible. Parents value: (a) efforts to find out how they are coping; (b) full frank information given sensitively to enable them to build up a cohesive picture of what happened and assess their future risks; (c) reassurance where possible, but half truths, false reassurances, and broken promises are unacceptable. Follow up care is a crucial part of the management of families from whose babies treatment has been withdrawn. Resources devoted to it should be re-examined to provide a service more in tune with parental need. In choosing the place, timing, and conduct of the meeting, staff should be sensitive to the expressed wishes of the parents themselves.


Biosensors based on membrane transport proteins.
We propose a novel class of biosensors based on membrane bound receptors or transport proteins as the sensing element. The protein is incorporated in a planar lipid bilayer which covers the transducer. The transducer may detect an electric current, a voltage, or a change in fluorescence. A prototype lactose sensor is presented which consists of a quartz slide covered by a lipid membrane containing the protein lactose permease from Escherichia coli. This protein is a lactose/H+ cotransporter, hence lactose in the external medium initiates lactose/H+ cotransport across the lipid membrane. This leads to a rise in proton concentration in the small volume between the lipid membrane and the quartz surface which can be detected by a pH-sensitive fluorescence dye.


Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease.
Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10-4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.


Comparison of plasma B-type natriuretic peptide levels in single ventricle patients with systemic ventricle heart failure versus isolated cavopulmonary failure.
The measurement of plasma B-type natriuretic peptide (BNP) has emerged as a useful biomarker of heart failure in patients with cardiomyopathy. The pathophysiology of heart failure in single ventricle (SV) circulation may be distinct from that of cardiomyopathies. A distinct pattern of BNP elevation in heart failure in the SV population was hypothesized: it is elevated in heart failure secondary to ventricular dysfunction but not in isolated cavopulmonary failure. BNP was measured prospectively in SV patients at catheterization (n = 22) and when assessing for heart failure (n = 11) (7 normal controls). Of 33 SV subjects (median age 62 months), 13 had aortopulmonary connections and 20 had cavopulmonary connections. Median and mean +/- SD BNP levels by shunt type were 184 and 754 +/- 1,086 pg/ml in the patients with aortopulmonary connections, 38 and 169 +/- 251 pg/ml in the patients with cavopulmonary connections, and 10 and 11 +/- 5 pg/ml in normal controls, respectively (p = 0.004). Median systemic ventricular end-diastolic pressure (8mm Hg, R = 0.45), mean pulmonary artery pressure (14.5 mm Hg, R = 0.62), and mean right atrial pressure (6.5 mm Hg, R = 0.54) were correlated with plasma BNP. SV subjects with symptomatic heart failure from dysfunctional systemic ventricles had median and mean +/- SD BNP levels of 378 and 714 +/- 912 pg/ml (n = 18) compared with patients with isolated failed Glenn or Fontan connections (19 and 23 +/- 16 pg/ml [n = 7, p = 0.001]) and those with no heart failure (22 and 22 +/- 12 pg/ml [n = 8, p = 0.001]). Excluding the group with cavopulmonary failure, the severity of heart failure from systemic ventricular dysfunction was associated with plasma BNP. In conclusion, plasma BNP is elevated in SV patients with systemic ventricular or left-sided cardiac failure. BNP is not elevated in patients missing a pulmonary ventricle with isolated cavopulmonary failure.


Hemodynamic regulation of CD34+ cell localization and differentiation in experimental aneurysms.
Bone marrow-derived vascular progenitor cells (CD34+) are present in human and animal models of abdominal aortic aneurysm (AAA) disease. These preterminally differentiated cells may modulate disease resistance. We examined the influence of variable hemodynamic conditions on progenitor cell localization and differentiation in experimental AAAs. Murine AAAs were created via porcine pancreatic elastase (PPE) infusion. AAA blood flow was increased by aortocaval fistula (ACF) formation (HF-AAA), decreased via left iliac ligation (LF-AAA), or left unchanged (NF-AAA). ACF creation increased flow by 1700%, whereas iliac ligation decreased flow 79% compared with baseline (0.6+/-0.1 mL/min). Wall shear stress (WSS) increased or decreased accordingly, and remained elevated (9.2+/-2.0 dynes/cm2) in HF-AAA 14 days after PPE infusion. CD34+ cells were identified throughout the aortic wall in all flow conditions. Seven days after PPE infusion, HF-AAAs had more CD34+ cells than LF-AAA (187+/-10 versus 155+/-7 CD34+ cells/cross sectional, P<0.05), more medial smooth muscle cells, fewer infiltrative macrophages, and a smaller diameter than LF-AAA. LF-AAAs also contained more adventitial capillaries (CD34+ capillaries 181+/-12 versus 89+/-32/cross-sectional area in HF-AAA, P<0.05). The total progenitor cell/capillary index (CD34+ capillary plus CD31+ capillary/cross sectional area) was higher in LF-AAA (282+/-31 versus 129+/-47, P<0.05). Vascular endothelial (VEGF) and platelet-derived growth factor (PDGF) expression varied directly with capillary density between groups. Increased granulocyte-macrophage colony-stimulating factor (GM-CSF) expression was also present in LF-AAAs. Hemodynamic conditions influence CD34+ cell localization and differentiation in experimental AAA. Adventitial capillary angiogenesis may augment inflammation and disease progression. Modulating cell lineage differentiation of mature progenitor cells may represent a novel therapeutic strategy to maintain medial cellularity and extracellular matrix integrity in AAA disease.


Soil erosion in developing countries: a socio-economic appraisal.
Soil erosion is the single most important environmental degradation problem in the developing world. Despite the plethora of literature that exists on the incidence, causes and impacts of soil erosion, a concrete understanding of this complex problem is lacking. This paper examines the soil erosion problem in developing countries in order to understand the complex inter-relationships between population pressure, poverty and environmental-institutional dynamics. Two recent theoretical developments, namely Boserup's theory on population pressure, poverty and soil erosion and Lopez's theory on environmental and institutional dynamics have been reviewed. The analysis reveals that negative impacts of technical change, inappropriate government policies and poor institutions are largely responsible for the continued soil erosion in developing countries. On the other hand, potential for market-based approaches to mitigate the problem is also low due to the negative externalities involved. A deeper appreciation of institutional and environmental dynamics and policy reforms to strengthen weak institutions may help mitigate the problem.


Inhibition of Babesia spp. by plastics.
Five commercially available plastic containers were compared with glass for toxicity toward Babesia rodhaini and Babesia bigemina. Comparisons were made by using infectivity tests in mice (B. rodhaini) and cattle (B. bigemina). Low-density polypropylene and polystyrene containers were not toxic, but two of the three polyvinyl chloride containers tested significantly reduced the viability of both species of Babesia. Plasticizer present in various amounts on the surface of the toxic containers was most likely the inhibitory material.


Azithromycin-liposomes as a novel approach for localized therapy of cervicovaginal bacterial infections.
Efficient localized cervicovaginal antibacterial therapy, enabling the delivery of antibiotic to the site of action at lower doses while escaping systemic drug effects and reducing the risk of developing microbial resistance, is attracting considerable attention. Liposomes have been shown to allow sustained drug release into vaginal mucosa and improve delivery of antibiotics to bacterial cells and biofilms. Azithromycin (AZI), a potent broad-spectrum macrolide antibiotic, has not yet been investigated for localized therapy of cervicovaginal infections, although it is administered orally for the treatment of sexually transmitted diseases. Encapsulation of AZI in liposomes could improve its solubility, antibacterial activity, and allow the prolonged drug release in the cervicovaginal tissue, while avoiding systemic side effects. The objective of this study was to develop AZI-liposomes and explore their potentials for treating cervicovaginal infections. AZI-liposomes that differed in bilayer elasticity/rigidity and surface charge were prepared and evaluated under simulated cervicovaginal conditions to yield optimized liposomes, which were assessed for antibacterial activity against several planktonic and biofilm-forming Escherichia coli strains and intracellular Chlamydia trachomatis, ex vivo AZI vaginal deposition/penetration, and in vitro cytotoxicity toward cervical cells. Negatively charged liposomes with rigid bilayers (CL-3), propylene glycol liposomes (PGL-2) and deformable propylene glycol liposomes (DPGL-2) were efficient against planktonic E. coli ATCC 700928 and K-12. CL-3 was superior for preventing the formation of E. coli ATCC 700928 and K-12 biofilms, with IC50 values (concentrations that inhibit biofilm viability by 50%) up to 8-fold lower than those of the control (free AZI). DPGL-2 was the most promising for eradication of already formed E. coli biofilms and for treating C. trachomatis infections. All AZI-liposomes were biocompatible with cervical cells and improved localization of the drug inside vaginal tissue compared with the control. The performed studies confirm the potentials of AZI-liposomes for localized cervicovaginal therapy.


Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila.
We investigated in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of dj-1β, Lrrk, DCTN2-p50, DCTN1-p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human HSPA9 broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.Abbreviations: AEL: after egg laying; AZ: active zone; brp: bruchpilot; Csp: cysteine string protein; dlg: discs large; eEJPs: evoked excitatory junctional potentials; GluR: glutamate receptor; H2O2: hydrogen peroxide; mEJP: miniature excitatory junctional potentials; MT: microtubule; NMJ: neuromuscular junction; PD: Parkinson disease; Pink1: PTEN-induced putative kinase 1; PSD: postsynaptic density; SSR: subsynaptic reticulum; SV: synaptic vesicle; VGlut: vesicular glutamate transporter.


Coronal ridge augmentation in the absence of bilateral bony plates around a pathologically denuded implant surface.
Guided bone regeneration via an osteopromotive barrier is indicated in different alveolar bone deficiencies and in periimplant bone destruction around pathologically denuded exposed implants. Regeneration of the osseous volume is determined by understanding the biologic behavior response of hard and soft tissues in guided tissue regeneration procedures. Consequently, a meticulous surgical approach is mandatory to preserve wound healing cascades and tissue stability. However, hard tissue augmentation in the nonsupported coronal direction has been unpredictable. A case report is presented in which a severely defected ridge around a pathologically exposed functional implant combined with a destructive extraction site was restored and regenerated. Bovine bone mineral particles (Bio-Oss) served as the graft material and were followed by an expanded polytetrafluoroethylene (e-PTFE) occlusive membrane as a bilateral regenerative tissue guide. Subsequently, 2 additional implants were placed in the augmented hard tissue ridge.


Tardive syndromes.
Dopamine receptor-blocking antipsychotics, first introduced into clinical practice in 1952, were hailed as a panacea in the treatment of a number of psychiatric disorders. However, within 5 years, this notion was to be shattered by the recognition of both acute and chronic drug-induced movement disorders which can accompany their administration. Tardive syndromes, denoting the delayed onset of movement disorders following administration of dopamine receptor-blocking (and also other) drugs, have diverse manifestations ranging from the classic oro-bucco-lingual dyskinesia, through dystonic craniocervical and trunk posturing, to abnormal breathing patterns. Although tardive syndromes have been an important part of movement disorder clinical practice for over 60 years, their pathophysiologic basis remains poorly understood and the optimal treatment approach remains unclear. This review summarises the current knowledge relating to these syndromes and provides clinicians with pragmatic, clinically focused guidance to their management.


Hostility and recidivism in sexual offenders.
In this study, we examined the association of hostility, as measured by the Buss-Durkee Hostility Inventory (BDHI), with offence characteristics and recidivism in 656 adult male sexual offenders. Hostility was significantly associated with having prior violent charges, the use of violence in the index sexual offence, sexual recidivism, and violent recidivism. After controlling for risk level, as measured by a modified version of the Rapid Risk Assessment for Sexual Offence Recidivism (RRASOR-mod), the significant association between hostility and sexual and violent recidivism remained. When examined by type of offender, hostility was significantly associated with recidivism in intrafamilial and extrafamilial child molesters, but not in rapists or mixed offenders. Given the predictive value of hostility independent of the RRASOR-mod, the present findings confirm and encourage treatment efforts directed toward the management of hostility and anger in sexual offenders.