Lakeshore zoning has heterogeneous ecological effects: an application of a coupled economic-ecological model.
Housing growth has been widely shown to be negatively correlated with wildlife populations, avian richness, anadromous fish, and exotic invasion. Zoning is the most frequently used public policy to manage housing development and is often motivated by a desire to protect the environment. Zoning is also pervasive, taking place in all 50 states. One relevant question that has received little research concerns the effectiveness of zoning to meet ecological goals. In this paper, we examined whether minimum frontage zoning policies have made a positive impact on the lakes they were aimed to protect in Vilas County, Wisconsin, U.S.A. We used an economic model that estimated when a given lot will be subdivided and how many new lots will be created as a function of zoning. Using the economic model, we simulated the effects of multiple zoning scenarios on lakeshore development. The simulated development patterns were then input to ecological models that predicted the amount of coarse woody debris (CWD) and the growth rate of bluegills as a function of residential density. Comparison of the ecological outcomes under different simulated zoning scenarios quantified the effect of zoning policies on residential density, CWD, and bluegill growth rates. Our results showed that zoning significantly affected residential density, CWD counts, and bluegill growth rates across our study area, although the effect was less clear at the scale of individual lake. Our results suggest that homogeneous zoning (i.e., for a county) is likely to have mixed results when applied to a heterogeneous landscape. Further, our results suggest that zoning regimes with a higher minimum shoreline frontage are likely to have larger ecological effects when applied to lakes that are less developed.


Successful knowledge translation intervention in long-term care: final results from the vitamin D and osteoporosis study (ViDOS) pilot cluster randomized controlled trial.
Few studies have systematically examined whether knowledge translation (KT) strategies can be successfully implemented within the long-term care (LTC) setting. In this study, we examined the effectiveness of a multifaceted, interdisciplinary KT intervention for improving the prescribing of vitamin D, calcium and osteoporosis medications over 12-months. We conducted a pilot, cluster randomized controlled trial in 40 LTC homes (21 control; 19 intervention) in Ontario, Canada. LTC homes were eligible if they had more than one prescribing physician and received services from a large pharmacy provider. Participants were interdisciplinary care teams (physicians, nurses, consultant pharmacists, and other staff) who met quarterly. Intervention homes participated in three educational meetings over 12 months, including a standardized presentation led by expert opinion leaders, action planning for quality improvement, and audit and feedback review. Control homes did not receive any additional intervention. Resident-level prescribing and clinical outcomes were collected from the pharmacy database; data collectors and analysts were blinded. In addition to feasibility measures, study outcomes were the proportion of residents taking vitamin D (≥800 IU/daily; primary), calcium ≥500 mg/day and osteoporosis medications (high-risk residents) over 12 months. Data were analyzed using the generalized estimating equations technique accounting for clustering within the LTC homes. At baseline, 5,478 residents, mean age 84.4 (standard deviation (SD) 10.9), 71% female, resided in 40 LTC homes, mean size = 137 beds (SD 76.7). In the intention-to-treat analysis (21 control; 19 intervention clusters), the intervention resulted in a significantly greater increase in prescribing from baseline to 12 months between intervention versus control arms for vitamin D (odds ratio (OR) 1.82, 95% confidence interval (CI): 1.12, 2.96) and calcium (OR 1.33, 95% CI: 1.01, 1.74), but not for osteoporosis medications (OR 1.17, 95% CI: 0.91, 1.51). In secondary analyses, excluding seven nonparticipating intervention homes, ORs were 3.06 (95% CI: 2.18, 4.29), 1.57 (95% CI: 1.12, 2.21), 1.20 (95% CI: 0.90, 1.60) for vitamin D, calcium and osteoporosis medications, respectively. Our KT intervention significantly improved the prescribing of vitamin D and calcium and is a model that could potentially be applied to other areas requiring quality improvement. ClinicalTrials.gov: NCT01398527 . Registered: 19 July 2011.


Chronic ventilation and social participation: experiences of men with neuromuscular disorders.
The purpose of this study was to investigate how mechanical ventilation-dependent adults with neuromuscular disorders experience their occupational and social participation. Data were collected through two successive focus-group discussions with six men (aged 23-40 years) living in the same specialized nursing home in the Netherlands. The results showed that the participants wanted to be involved in activities that provide interaction with others in society or community; they desired social participation. Thematic analysis brought out that the participants wanted to be taken seriously in all aspects of life. Four themes emerged: "Responsibility for risk-taking", "The influence of dependency", "Being treated as an employee", and "Maintaining optimism". These men appreciated good information from health care providers, wanted to have more autonomy in decision-making and risk-taking - and did not wish to be patronized. They wanted to have a social network to help them suction their tracheal cannula. Also, they would like activities at the activity centre to be more contributing to society and wished to be treated as employees rather than as clients. In view of their short life expectancy, they would also welcome discussions of end-of-life issues in group sessions led by a professional. Facilitating aspects of social participation, i.e. the experience of meaningful occupations in connection with autonomy and self-determination, would provide a more client-centred approach.


Expert assessments of future photovoltaic technologies.
Subjective probabilistic judgments about future module prices of 26 current and emerging photovoltaic (PV) technologies were obtained from 18 PV technology experts. Fourteen experts provided detailed assessments, including likely future efficiencies and prices under four policy scenarios. While there is considerable dispersion among the judgments, the results suggest a high likelihood that some PV technology will achieve a price of $1.20/Wp by 2030. Only 7 of 18 experts assess a better-than-even chance that any PV technology will achieve $0.30/Wp by 2030; 10 of 18 experts give this assessment by 2050. Given these odds, and the wide dispersion in results, we conclude that PV may have difficulty becoming economically competitive with other options for large-scale, low-carbon bulk electricity in the next 40 years. If $0.30/Wp is not reached, then PV will likely continue to expand in markets other than bulk power. In assessing different policy mechanisms, a majority of experts judged that R&D would most increase efficiency, while deployment incentives would most decrease price. This implies a possible disconnect between research and policy goals. Governments should be cautious about large subsidies for deployment of present PV technology while continuing to invest in R&D to lower cost and reduce uncertainty.


Liquid matrix deposition on conductive hydrophobic surfaces for tuning and quantitation in UV-MALDI mass spectrometry.
With its highly fluctuating ion production matrix-assisted laser desorption/ionization (MALDI) poses many practical challenges for its application in mass spectrometry. Instrument tuning and quantitative ion abundance measurements using ion signal alone depend on a stable ion beam. Liquid MALDI matrices have been shown to be a promising alternative to the commonly used solid matrices. Their application in areas where a stable ion current is essential has been discussed but only limited data have been provided to demonstrate their practical use and advantages in the formation of stable MALDI ion beams. In this article we present experimental data showing high MALDI ion beam stability over more than two orders of magnitude at high analytical sensitivity (low femtomole amount prepared) for quantitative peptide abundance measurements and instrument tuning in a MALDI Q-TOF mass spectrometer. Samples were deposited on an inexpensive conductive hydrophobic surface and shrunk to droplets <10 nL in size. By using a sample droplet <10 nL it was possible to acquire data from a single irradiated spot for roughly 10,000 shots with little variation in ion signal intensity at a laser repetition rate of 5-20 Hz.


Mapping chromosome rearrangement breakpoints to the physical map of Caenorhabditis elegans by fluorescent in situ hybridization.
A scheme for rapidly mapping chromosome rearrangements relative to the physical map of Caenorhabditis elegans is described that is based on hybridization patterns of cloned DNA on meiotic nuclei, as visualized by fluorescent in situ hybridization. From the nearly complete physical map, DNA clones, in yeast artificial chromosomes (YACs), spanning the rearrangement breakpoint were selected. The purified YAC DNAs were first amplified by degenerate oligonucleotide-primed polymerase chain reaction, then reamplified to incorporate fluorescein dUTP or rhodamine dUTP. The site of hybridization was visualized directly (without the use of antibodies) on meiotic bivalents. This allows chromosome rearrangements to be mapped readily if the duplicated, deficient or translocated regions do not pair with a normal homologous region, because the site or sites of hybridization of the probe on meiotic prophase nuclei will be spatially distinct. The pattern, or number, of hybridization signals from probes from within, or adjacent to, the rearranged region of the genome can be predicted from the genetic constitution of the strain. Characterization of the physical extent of the genetically mapped rearrangements places genetic landmarks on the physical map, and so provides linkage between the two types of map.


Breast cancer resistance protein BCRP (ABCG2)-mediated transepithelial nitrofurantoin secretion and its regulation in human intestinal epithelial (Caco-2) layers.
In order to determine the capacity and regulation of the breast cancer resistance protein (BCRP)-mediated transport in intact human intestinal epithelial monolayers (Caco-2) in which multiple ABC transporters are expressed, nitrofurantoin has been used as a selective transported substrate. Nitrofurantoin transepithelial secretion was confirmed in both human BCRP and mouse bcrp-transfected MDCKII epithelia, whereas no net transepithelial secretion was observed in native or human MDR1-MDCKII epithelia. Furthermore, nitrofurantoin transepithelial secretion by BCRP-MDCKII monolayers was inhibited by Ko143 (10 μM), but not verapamil (100 μM). In Caco-2 cells grown upon permeable supports, nitrofurantoin displayed a dose-dependent transepithelial secretion with an apparent Km=69.41 ± 22.3 μM and Vmax=14.03 ± 2.27 nmol/(cm(2).h). Net nitrofurantoin transepithelial secretion by Caco-2 epithelia was inhibited 92% by 10 μM Ko143. Regulation of expression and function of BCRP in Caco-2 epithelial monolayers was determined after 72-h pre-exposure of the monolayers to a number of potential inducing agents. Quantitative real-time PCR and Western blotting were used to correlate induction of BCRP transcript and protein levels with transport activity. 72-h pre-treatment with β-napthoflavone and rosiglitazone up-regulates BCRP mRNA and protein expression and transport of nitrofurantoin. Ko143-sensitive transepithelial secretion of the bi-substrate (MDR1/BCRP) prazosin was also increased in the presence of rosiglitazone. We conclude that nitrofurantoin may be used to unambiguously measure BCRP-mediated fluxes in Caco-2 epithelial layers. Since dynamic regulation of BCRP expression and function is retained, the Caco-2 cell-line is useful as a screen for drug-drug and drug-diet interactions mediated by BCRP.


Molecular aspects of the cellular activities of ADP-ribosylation factors.
Adenosine diphosphate-ribosylation factor (Arf) proteins are members of the Arf arm of the Ras superfamily of guanosine triphosphate (GTP)-binding proteins. Arfs are named for their activity as cofactors for cholera toxin-catalyzed adenosine diphosphate-ribosylation of the heterotrimeric G protein Gs. Physiologically, Arfs regulate membrane traffic and the actin cytoskeleton. Arfs function both constitutively within the secretory pathway and as targets of signal transduction in the cell periphery. In each case, the controlled binding and hydrolysis of GTP is critical to Arf function. The activities of some guanine nucleotide exchange factors (GEFs) and guanosine triphosphatase (GTPase)-activating proteins (GAPs) are stimulated by phosphoinositides, including phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA), likely providing both a means to respond to regulatory signals and a mechanism to coordinate GTP binding and hydrolysis. Arfs affect membrane traffic in part by recruiting coat proteins, including COPI and clathrin adaptor complexes, to membranes. However, Arf function likely involves many additional biochemical activities. Arf activates phospholipase D and phosphatidylinositol 4-phosphate 5-kinase with the consequent production of PA and PIP2, respectively. In addition to mediating Arf's effects on membrane traffic and the actin cytoskeleton, PA and PIP2 are involved in the regulation of Arf. Arf also works with Rho family proteins to affect the actin cytoskeleton. Several Arf-binding proteins suspected to be effectors have been identified in two-hybrid screens. Arf-dependent biochemical activities, actin cytoskeleton changes, and membrane trafficking may be integrally related. Understanding Arf's role in complex cellular functions such as protein secretion or cell movement will involve a description of the temporal and spatial coordination of these multiple Arf-dependent events.


A quantitative morphometric study of the human anterior cingulate cortex.
Morphometric alterations in the anterior cingulate cortex (ACC) have been reported in schizophrenia and mood disorders. Parameters affected include glial and neuronal density, neuronal size and cortical thickness. Some data, especially in mood disorders, suggest that the left subgenual ACC is preferentially involved. Qualitative studies show that the ACC cytoarchitecture is heterogeneous, but there are few quantitative data. We performed a quantitative morphometric study of five anatomical levels within the ACC (caudal and rostral subgenual [area 24b sg], rostral and intermediate supragenual [area 24b] and caudal supragenual [area 24b']) in both hemispheres of five normal brains. We measured cortical depth, layer depths, neuronal density, neuronal size, and glial density, using the optical disector and nucleator. Relative to the subgenual ACC, the supragenual ACC was thicker, with a deeper layer V. Supragenual neurons were substantially larger in all layers, and were less densely packed in layers V and VI, than subgenual neurons. Glial density, and the glia to neuron ratio, was higher in supragenual than subgenual ACC. Only minor differences were seen between left and right ACC, between caudal and rostral subgenual ACC, and between the three supragenual levels. These data complement the qualitative descriptions of the heterogeneity of human ACC cytoarchitecture, connections, and functions, especially between supragenual and subgenual regions. Our findings also indicate that care must be taken when selecting ACC tissue to be used for morphometric studies of psychiatric disorders, since the normal anatomical variation is of a similar magnitude as the reported disease-related alterations.


Airway PI3K pathway activation is an early and reversible event in lung cancer development.
Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.


Amla prevents fructose-induced hepatic steatosis in ovariectomized rats: role of liver FXR and LXRα.
Increased fructose consumption causes dyslipidemia and fatty liver in postmenopausal women, both independent risk factors for cardiovascular disease. This study explored the potential mechanisms by which amla (Emblica officinalis) reduced hypercholesterolemia and hypertriglyceridemia and prevented fatty liver in a fructose-fed, ovariectomized rat model of menopause. Sham-operated and ovariectomized rats were put on a chow or high fructose diet. They were further divided into groups with or without amla. After 18 weeks of treatment, livers were harvested and subjected to Western blot and histological analyses. In all groups, amla increased the protein expression of liver farnesoid X receptor (FXR) and liver X receptor (LXR), key proteins involved in lipid metabolism. Fructose-fed rats developed fatty liver and amla prevented this. Here amla produced an exceptional rise in LXR and insulin-induced gene-2 (Insig-2) which prevented the maturation of sterol regulatory element-binding protein-1 and steroyl CoA desaturase-1, responsible for triglyceride synthesis. Amla also increased the protein expression of ATP binding cassette transporter A1 (ABCA1), involved in high density lipoprotein (HDL) synthesis as well as low density lipoprotein receptor (LDLR) responsible for uptake of LDL cholesterol. Besides this, amla increased the protein expression of peroxisome proliferator activated receptor α (PPARα) involved in β oxidation of fatty acids. Amla increased the protein expression of liver FXR, LXRα, PPARα and their downstream proteins Insig-2, ABCA1 and LDLR. This property of amla to modulate some of the key proteins involved in lipid metabolism promises its usefulness as a preventive agent for dyslipidemia and hepatic steatosis.


Probing secondary interactions in biomolecular recognition by dynamic combinatorial chemistry.
Artificial multivalent recognition systems offer promising perspectives for developing synthetic compounds capable of interacting effectively and selectively with biomolecules in aqueous medium. The identification of multi-point binding ligands requires screening of a large number of complex structures, with different spacers, different ligands, and varying valency. This represents a challenge for rational design approaches. On the other hand, the use of dynamic covalent chemistry enables a target-driven one-pot screening approach for probing secondary interactions, thereby facilitating the identification of multivalent recognition systems that optimally combine multiple fragments. Herein we review the recent developments in the implementation of dynamic combinatorial chemistry for probing secondary interactions and thereby identify multi-point binding ligands of biomolecules.


Virtual Reality exposure therapy for public speaking anxiety in routine care: a single-subject effectiveness trial.
Virtual Reality (VR) can be used as a therapeutic tool to conduct efficacious in-session exposure therapy by presenting virtual equivalents of phobic stimuli, yet past hardware restrictions hindered implementation in routine care and effectiveness studies. The current study examines the effectiveness of a VR-assisted treatment protocol for public speaking anxiety with demonstrated efficacy, this time in routine care, using affordable VR hardware. Participants (n = 23) were recruited via a private clinic and treated by one of four psychologists with only minimal VR-training. Using a single-subject design and dual-slope modeling (adjusting the treatment-onset slope for treatment effects), we found a significant, large decrease in self-rated public speaking anxiety following the primary three-hour session, similar in magnitude to the previous efficacy trial. Multilevel modeling of in-session process measures suggests that the protocol works as intended, by decreasing catastrophic belief expectancy and distress, and increasing perceived performance quality. Adherence to the online transition program that followed-encouraging in-vivo exposure-was relatively poor, yet symptoms decrease continued. No change was observed over the three-month follow-up period. We conclude that VR exposure therapy can be effective under routine care conditions and is an attractive approach for future, large-scale implementation and effectiveness trials.


Supporting and resourcing treatment decision-making: some policy considerations.
This paper considers some of the policy implications of issues raised during a conference about treatment decision-making in the clinical encounter held in Hamilton, Ontario in May 1999. Policies promoting patient participation in treatment decision-making need to be flexible enough to ensure that they are appropriate across the range of contexts in which health care decisions are made and acceptable to people with diverse preferences and abilities. They should also be formulated in consideration of other health policies and of available resources. Policies of informing people and involving them in decisions about their care are unlikely to be simple to implement. Various strategies might be needed to support them. These include the development of appropriate skills among health professionals and in the general population, the use of interventions to encourage people to play more active roles in decisions about their health care, the provision of decision aids for people facing specific decisions and the provision and accreditation of more general information resources and services. If information and other facilitators of patient participation in decision-making are seen as integral to good quality health care, then funding should be made available for them. This will, however, have opportunity costs. Policy makers' decisions about how much health care funding should be invested in which strategies should be underpinned by good research evidence about the effects that different types of intervention have on a range of outcomes for individuals, health care systems and populations. The knowledge on which current policies are based is limited. The development of future policies will be enhanced if policy makers invest in critical conceptual thinking, reflective practice, imaginative development work and good quality evaluative research.


The M34A mutant of Connexin26 reveals active conductance states in pore-suspending membranes.
Connexin26 (Cx26) is a member of the connexin family, the building blocks for gap junction intercellular channels. These dodecameric assemblies are involved in gap junction-mediated cell-cell communication allowing the passage of ions and small molecules between two neighboring cells. Mutations in Cx26 lead to the disruption of gap junction-mediated intercellular communication with consequences such as hearing loss and skin disorders. We show here that a mutant of Cx26, M34A, forms an active hemichannel in lipid bilayer experiments. A comparison with the Cx26 wild-type is presented. Two different techniques using micro/nano-structured substrates for the formation of pore-suspending lipid membranes are used. We reconstituted the Cx26 wild-type and Cx26M34A into artificial lipid bilayers and observed single channel activity for each technique, with conductance levels of around 35, 70 and 165 pS for the wild-type. The conductance levels of Cx26M34A were found at around 45 and 70 pS.


Prosome cytodistribution relative to desmin and actin filaments in dividing C2.7 myoblasts and during myotube formation in vitro.
Prosomes constitute the multicatalytic proteinase (MCP) core of the 26S proteasomes, but were first observed as subcomplexes of untranslated mRNP; this suggests that they play a putative role in the control of protein biosynthesis in addition to their catabolic enzymatic function. In previous investigations it was shown that some prosomes colocalize with the intermediate filaments (IF) of the cytoskeleton, of the cytokeratin type in epithelial cells, and of the vimentin type in fibroblasts. Studies on adult rat muscle carried out with prosome-specific monoclonal antibodies (p-mAbs) have shown, surprisingly, that specific types of prosomes predominantly occupy a particular zone in between the M and the Z lines of the sarcomeric structure. The data presented here show that the subunit composition of prosomes changes when the dividing C2.7 myoblasts fuse into myotubes. We show furthermore that, in dividing C2.7 myoblasts, prosomes colocalize with the desmin network as well as with that of actin, in a distribution that changes with the subunit pattern of the prosomes investigated by individual p-mAbs. Surprisingly, when myogenic fusion is induced, specific types of prosomes move first to the nuclei; later on, they reappear in the cytoplasm. There, superimposing initially onto the reorganizing desmin filaments that run from one pole of the prefusion myoblast to the other, prosomes gradually colocalize with the actin fibers in the fusing myotubes, finally forming a "pearl on a string" pattern. These results are discussed in relation to parallel observations of prosome distribution between the actin and IF networks not only in epithelial cells but also in fusing muscle satellite cells, which made it possible to monitor the complete buildup of the sarcomeric structure.


Power scaling of a pico-second Nd:YVO(4) master-oscillator power amplifier with a phase-conjugate mirror.
We investigated design issues for the power scaling of a pico-second Nd:YVO(4) master-oscillator power amplifier system with a photorefractive phase-conjugate mirror by using standard beam propagation analysis. We also demonstrated a 25 W diffraction-limited pico-second output. A corresponding extraction efficiency of 31 % was achieved.


Coagglutination and enzyme capture tests for detection of Escherichia coli beta-galactosidase, beta-glucuronidase, and glutamate decarboxylase.
Polyclonal antibodies to Escherichia coli beta-galactosidase, beta-glucuronidase, and glutamate decarboxylase were used in coagglutination tests for identification of these three enzymes in cell lysates. Enzyme capture assays were also developed for the detection of E. coli beta-galactosidase and beta-glucuronidase. The enzymes were released by using a gentle lysis procedure that did not interfere with antibody-enzyme interactions. All three enzymes were detected in 93% (51 of 55) of the E. coli strains tested by coagglutination; two of the three enzymes were identified in the remaining 7%. Of 42 non-E. coli tested by coagglutination, only four nonspecifically agglutinated either two or three of the anti-enzyme conjugates. Thirty-two (76%) non-E. coli isolates were negative by coagglutination for all three enzymes. The enzyme capture assay detected the presence of beta-galactosidase in seven of eight and beta-glucuronidase in all eight strains of E. coli tested. Some strains of beta-galactosidase-positive Citrobacter freundii and Enterobacter cloacae were also positive by the enzyme capture assay, indicating that the antibodies were not entirely specific for E. coli beta-galactosidase; however, five other gas-positive non-E. coli isolates were negative by the enzyme capture assay. The coagglutination tests and enzyme capture assays were rapid and sensitive methods for the detection of E. coli beta-galactosidase, beta-glucuronidase, and glutamate decarboxylase.


Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort.
Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD. The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point. Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (rs=-0.77, p<0.001) and within each genetic group (rs=-0.67 to -0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls -0.1 (6.0) for FRS, -0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers -0.5 (8.2), 0.2 (0.9), prodromal disease -2.3 (9.9), 0.6 (2.7), mild disease -10.2 (18.6), 3.0 (4.1), moderate disease -9.6 (16.6), 4.4 (4.0), severe disease -2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS. Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.


[Neonatal refractory seizures].
Convulsions appearing in the neonatal or first year of life can have a very different origin, treatment or prognosis and it shall be up to the neonatologist or neuropediatrician to resolve the problem since they are the ones who know their patients best. There are severe forms of epileptic encephalopathy in the neonatal period such as Ohtahara syndrome or Aicardi myoclonic encephalopathy with poor prognosis and high morbimortality. Furthermore, there are forms of convulsions and epilepsies during the neonatal and infant period which do not respond to AED. In such cases, it is important to initiate as soon as possible another type of treatment to prevent a neurological deterioration due to repeated convulsion crises and thus allow the patients to lead a normal life with the only obligation to take a different medication from AED during their whole life. We discuss the metabolic defects which lead to convulsions and epilepsies and their various treatments. We also include a revision of some forms of convulsions and epilepsies in the infant insisting on treatments with substances completely different from AEDs.


Procalcitonin as a biomarker of bacterial infection in critically ill patients admitted with suspected Sepsis in Intensive Care Unit of a tertiary care hospital.
To compare the diagnostic accuracy of procalcitonin (PCT), C- reactive protein (CRP), total leukocyte count (TLC) and lactate in critically ill patients admitted with suspicion of sepsis. It was a cross sectional study conducted at the department of Chemical Pathology and Endocrinology AFIP, Rawalpindi, in collaboration with Medical and surgical intensive care units (ICU) of CMH Rawalpindi from January 2019 to December 2019. A total of 126 patients of both genders with age above 18 years and fulfilling the inclusion criteria of systemic inflammatory response syndrome (SIRS) were inducted in the study. Out of 126 patients 82 (65%) patients have positive blood culture results. Male predominance was noted in patients with positive blood culture. Out of 82 patients with positive blood culture results 69(84%) patients have positive PCT results as well whereas 13(15%) patients with positive blood culture results have negative PCT values. 57(69%) patients had Gram negative bacterial infection and 25(30%) patients had Gram positive bacterial infection. Significant difference was noted between the medians of PCT in blood culture positive and blood culture negative group (p value< 0.05) whereas no significant difference was found between medians of CRP, TLC and lactate between blood culture positive and blood culture negative patients (p value > 0.05). ROC curve analysis of PCT, CRP and TLC were done, keeping blood culture as reference standard, PCT showed largest area under the curve (AUC) and clearly outperformed TLC and CRP. PCT showed AUC of 0.781 as compared to CRP and TLC, which was 0.568 and 0.617 respectively. PCT showed sensitivity of 93.9%, specificity of 47.7%, positive predictive value (PPV) of 77% and negative predictive value (NPV) of 80.8%. Higher NPV makes it a reliable marker for screening out sepsis in suspected cases.


Laminar differences in gamma and alpha coherence in the ventral stream.
Attention to a stimulus enhances both neuronal responses and gamma frequency synchrony in visual area V4, both of which should increase the impact of attended information on downstream neurons. To determine whether gamma synchrony is common throughout the ventral stream, we recorded from neurons in the superficial and deep layers of V1, V2, and V4 in two rhesus monkeys. We found an unexpected striking difference in gamma synchrony in the superficial vs. deep layers. In all three areas, spike-field coherence in the gamma (40-60 Hz) frequency range was largely confined to the superficial layers, whereas the deep layers showed maximal coherence at low frequencies (6-16 Hz), which included the alpha range. In the superficial layers of V2 and V4, gamma synchrony was enhanced by attention, whereas in the deep layers, alpha synchrony was reduced by attention. Unlike these major differences in synchrony, attentional effects on firing rates and noise correlation did not differ substantially between the superficial and deep layers. The results suggest that synchrony plays very different roles in feedback and feedforward projections.


Rotavirus vaccines: targeting the developing world.
For the past 2 decades, rotavirus infection, the most common cause of severe diarrhea in children, has been a priority target for vaccine development. This decision to develop rotavirus vaccines is predicated on the great burden associated with fatal rotavirus disease (i.e., 440,000 deaths/year), the firm scientific basis for developing live oral vaccines, the belief that increased investment in development at this time could speed the introduction of vaccines in developing countries, and the appreciation that implementation of a vaccine program should result in a measurable decrease in the number of hospitalizations and deaths associated with rotavirus disease within 2-3 years. RotaShield (Wyeth-Ayerst), the first rotavirus vaccine licensed in the United States, was withdrawn after 9 months because of a rare association of the vaccine with the development of intussusception. In the developing world, this vaccine could still have had a measurable effect, because the benefits of preventing deaths due to rotavirus disease would have been substantially greater than the rare risk of intussusception. Two live oral vaccines being prepared by GlaxoSmithKline and Merck have completed large-scale clinical trials. The GlaxoSmithKline vaccine has been licensed in Mexico and the Dominican Republic, and the Merck vaccine could be licensed in the United States within 1 year; several other candidate vaccines are in earlier stages of testing. However, many challenges remain before any of these vaccines can be incorporated into childhood immunization programs in the developing world. First, vaccine efficacy, which has already been demonstrated in children in industrialized and middle-income countries, needs to be proven in poor developing countries in Africa and Asia. The safety of vaccines with regard to the associated risk of intussusception must be demonstrated as well. Novel financing strategies will be needed to ensure that new vaccines are affordable and available in the developing world. Decision makers and parents in developing countries need to know about this disease that has little name recognition and is rarely diagnosed. Finally, for the global effort toward the prevention of rotavirus disease to be successful, special efforts will be required in India, China, and Indonesia, because one-third of all deaths due to rotavirus disease occur in these countries, and because these countries depend almost entirely on vaccines manufactured domestically.


Electrophysiological evidence for reversed lexical repetition effects in language processing.
Effects of word repetition are extremely robust, but can these effects be modulated by discourse context? We examined this in an ERP experiment that tested coreferential processing (when two expressions refer to the same person) with repeated names. ERPs were measured to repeated names and pronoun controls in two conditions: (1) In the prominent condition the repeated name or pronoun coreferred with the subject of the preceding sentence and was therefore prominent in the preceding discourse (e.g., "John went to the store after John/he."); (2) in the nonprominent condition the repeated name or pronoun coreferred with a name that was embedded in a conjoined noun phrase, and was therefore nonprominent (e.g., "John and Mary went to the store after John/he."). Relative to the prominent condition, the nonprominent condition always contained two extra words (e.g., "and Mary"), and the repetition lag was therefore smaller in the prominent condition. Typically, effects of repetition are larger with smaller lags. Nevertheless, the amplitude of the N400 was reduced to a coreferentially repeated name when the antecedent was nonprominent as compared to when it was prominent. No such difference was observed for the pronoun controls. Because the N400 effect reflects difficulties in lexical integration, this shows that the difficulty of achieving coreference with a name increased with the prominence of the referent. This finding is the reverse of repetition lag effects on N400 previously found with word lists, and shows that language context can override general memory mechanisms.


[Antibody-related neuroimmunological disorders: update on the diagnosis and treatment].
Varieties of autoantibodies are known to relate to autoimmune neurological disorders as the diagnostic and therapeutic markers. Some of them affected directly to the pathomechanisms of neurological diseases. Recently several autoantibodies with such roles have been reported showing the common characters as recognizing cell surface antigens. Among them, anti-aquaporin 4 antibody (AQP4-Ab) in neuromyelitis optica (NMO) and anti-NMDA receptor antibody (NMDAR-Ab) in non-herpetic limbic encephalitis are drawn considerable attention. The features of NMO with AQP4-Ab are as higher age at onset, extreme women preponderance, severe optic neuritis and myelitis with longitudinary extended spinal cord lesions. AQP4-Ab binds to the astrocytic endfeet extended toward cerebrospinal fluid space or vessel wall, related to the common lesions of NMO, and passive transfer of the antibody with complements to rodents showed NMO pathology. The NMDAR-Ab related encephalitis is seen in young women having ovary teratoma showing memory and consciousness disturbances, agitation, epilepsy, respiratory failure, autonomic disorders and involuntary movements. We showed this antibody really affects to NMDAR specific signal transduction using rodent hippocampal slices with suppression of long-term potentiation induction. The discovery of newly characterized autoantibodies with relation to certain neurological diseases will be expected to expand in the future.


Transformation of the sex pheromone signal in the noctuid moth Agrotis ipsilon: from peripheral input to antennal lobe output.
How information is transformed along synaptic processing stages is critically important to understand the neural basis of behavior in any sensory system. In moths, males rely on sex pheromone to find their mating partner. It is essential for a male to recognize the components present in a pheromone blend, their ratio, and the temporal pattern of the signal. To examine pheromone processing mechanisms at different levels of the olfactory pathway, we performed single-cell recordings of olfactory receptor neurons (ORNs) in the antenna and intracellular recordings of central neurons in the macroglomerular complex (MGC) of the antennal lobe of sexually mature Agrotis ipsilon male moths, using the same pheromone stimuli, stimulation protocol, and response analyses. Detailed characteristics of the ORN and MGC-neuron responses were compared to describe the transformation of the neuronal responses that takes place in the MGC. Although the excitatory period of the response is similar in both neuron populations, the addition of an inhibitory phase following the MGC neuron excitatory phase indicates participation of local interneurons (LN), which remodel the ORN input. Moreover, MGC neurons showed a wider tuning and a higher sensitivity to single pheromone components than ORNs.


Rethinking ADHD intervention trials: feasibility testing of two treatments and a methodology.
Attention deficit hyperactivity disorder (ADHD) is a lifelong condition associated with considerable costs. The long-term effectiveness and acceptability of treatments to improve outcomes remains in doubt. Long-term trials are needed comparing interventions with standard care and each other. The Sheffield Treatments for ADHD Research (STAR) project used the Trials within Cohorts (TwiCs) approach. A cohort of children with ADHD was recruited and outcomes collected from carers and teachers. A random selection was offered treatment by homoeopaths (hom) or nutritional therapists (NT). Their outcomes (Conners Global ADHD Index) were compared with those not offered interventions. The feasibility of the methods and interventions was assessed. The TwiCs approach was feasible with modifications. 144 participants were recruited to the cohort, 83 offered treatment, 72 accepted, and 50 attended 1+ appointments. Results according to carers assessments at 6 months were as follows: t = 1.08, p = .28 (- 1.48, 4.81) SMD .425 (hom); t = 1.71, p = .09 (- .347, 5.89), SMD = .388 (NT). Teachers' responses were too few and unstable. No serious treatment adverse events occurred.Conclusion: the STAR project demonstrated the feasibility of the TwiCs approach for testing interventions for children with ADHD. What is Known: • Attention deficit hyperactivity disorder (ADHD) is a lifelong condition associated with considerable costs to ADHD stakeholders. Children are at risk of negative outcomes and in need of pre-emptive strategies • The long-term effectiveness and acceptability of recommended treatments to improve outcomes remains in doubt What is New: • A small-scale test of the design demonstrated that the Trials within Cohorts (TwiCs) approach is feasible and can make a useful contribution regarding testing the effectiveness of interventions for children with ADHD to improve long-term negative outcomes • Treatment by homoeopaths and nutritional therapists may offer novel opportunities to improve outcomes.


Mixed dementia: A review of the evidence.
Mixed dementia is the coexistence of Alzheimer's disease and cerebrovascular disease (CVD) in the same demented patient. Currently, its diagnosis and treatment remains a challenge for practitioners. To provide an overview of the epidemiology, pathogenesis, natural history, diagnosis, and therapy of Mixed Vascular-Alzheimer Dementia (MVAD). The literature was reviewed for articles published between 1990-2016 by using the keywords linked to MVAD. Neuropathological studies indicate that MVAD is a very common pathological finding in the elderly with a prevalence about of 22%. The distinction between Alzheimer's dementia and vascular dementia (VD) is complex because their clinical presentation can overlap. There are international criteria for the MVAD diagnosis. The pharmacologic therapy shows modest clinical benefits that are similar among all drugs used in patients with Alzheimer's dementia and VD. The non-pharmacologic therapy includes the rigorous management of cardiovascular risk factors (especially hypertension) and the promotion of a healthy diet. The diagnosis and treatment of MVAD cannot be improved without further studies. Currently available medications provide only modest clinical benefits once a patient has developed MVAD. In subjects at risk, the antihypertensive therapy and healthy diet should be recommend for preventing or slowing the progression of MVAD.


Kinetics of Vibrio cholerae sialidase action on gangliosidic substrates at different supramolecular-organizational levels.
G(d1a), G(d1b) and G(t1b) gangliosides were dispersed in the following membrane-mimicking systems: (a) homogeneous micelles; (b) mixed micelles with G(m1) ganglioside (which is resistant to the enzyme action), Triton X-100 or bovine serum albumin; (c) small unilamellar vesicles of egg phosphatidylcholine. The effect of dispersion on sialic acid release by Vibrio cholerae sialidase was studied. As reference substrates freely interacting with the enzyme the lipid-free carbohydrates of G(d1a) and 3'-sialosyl-lactose were employed. The apparent V(max.) of the enzyme was, with all the gangliosides, dependent on the type of ganglioside dispersion. It was lowest for homogeneous micelles and mixed micelles with ganglioside G(m1), and increased about 6-fold for ganglioside/bovine serum albumin lipoprotein micelles, 15-fold for mixed-ganglioside/Triton X-100 micelles (optimal molar ratio 1:7.5) and 30-fold for phosphatidylcholine vesicles containing 2.5 mol% ganglioside (this proportion was optimal for enzyme activity on the vesicles). For ganglioside G(d1a), the activity on Triton X-100 mixed micelles and on mixed vesicles was even greater (3- and 6-fold respectively) than that displayed on G(d1a) lipid-free carbohydrate. With each of the used gangliosides the apparent K(m) values were very similar values for homogeneous micelles and vesicular dispersions, but showed marked increases for Triton X-100 mixed micelles, approaching the values exhibited by reference oligosaccharides. Triton X-100 micelles and phosphatidylcholine vesicles did not appreciably alter the kinetics of sialidase action on 3'-sialosyl-lactose and on G(d1a) lipid-free carbohydrate, indicating that the above effects are dependent on the intrinsic characteristics of the membrane-like systems containing gangliosides.


Improvement of the fringe analysis algorithm for wavelength scanning interferometry based on filter parameter optimization.
The phase slope method which estimates height through fringe pattern frequency and the algorithm which estimates height through the fringe phase are the fringe analysis algorithms widely used in interferometry. Generally they both extract the phase information by filtering the signal in frequency domain after Fourier transform. Among the numerous papers in the literature about these algorithms, it is found that the design of the filter, which plays an important role, has never been discussed in detail. This paper focuses on the filter design in these algorithms for wavelength scanning interferometry (WSI), trying to optimize the parameters to acquire the optimal results. The spectral characteristics of the interference signal are analyzed first. The effective signal is found to be narrow-band (near single frequency), and the central frequency is calculated theoretically. Therefore, the position of the filter pass-band is determined. The width of the filter window is optimized with the simulation to balance the elimination of the noise and the ringing of the filter. Experimental validation of the approach is provided, and the results agree very well with the simulation. The experiment shows that accuracy can be improved by optimizing the filter design, especially when the signal quality, i.e., the signal noise ratio (SNR), is low. The proposed method also shows the potential of improving the immunity to the environmental noise by adapting the signal to acquire the optimal results through designing an adaptive filter once the signal SNR can be estimated accurately.


Prenatal exposure to organochlorine compounds and birth size.
To investigate the possible association between birth size and cord concentrations of some organochlorine compounds (OCs), including 4,4'-dichlorodiphenyltrichloroethane (DDT), 4,4'-1,1-dichloro-2,2-bis(p-dichlorodiphenyl)ethylene (DDE), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), 4 polychlorinated biphenyl (PCB) congeners (118, 138, 153, and 180), and their sum (ΣPCBs) in a birth cohort in Valencia, Spain. A total of 494 mothers and their newborns (born 2003-2006) participated in the study. Multivariate linear regression analyses were performed between birth weight, length, or head circumference and OC concentrations. Median concentrations of 4,4'-DDT, 4,4'-DDE, HCB, β-HCH, and ΣPCBs were 0.02, 0.46, 0.22, 0.09, and 0.35 ng/mL, respectively. For birth weight there was a significant decrease of 63 and 107 g for each 10-fold increase in cord serum 4,4'-DDT and 4,4'-DDE concentrations, and a marginally significant decrease of 79 and 53 g for each 10-fold increase in HCB and β-HCH concentrations. A significant decrease of 0.39 cm in birth length was found for each 10-fold increase in HCB concentrations. For newborns with cord 4,4'-DDT concentrations above the median there was a significant decrease of 0.26 cm in birth head circumference. These results reveal that prenatal exposure to some OCs could impair the anthropometric development of the fetus, reducing the birth weight, length, and head circumference.


Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis.
The pyramidal pathway is frequently affected early on in multiple sclerosis (MS) and impaired motor performance is a major cause of disability. Pyramidal tract function can be assessed using transcranial magnetic stimulation (TMS). TMS supports the diagnosis of MS, detecting corticospinal tract involvement and monitoring its course with or without treatment. It has been never investigated whether any relationship exists between the TMS outcome measure and minimally invasive treatment of multiple severe extracranial stenosis, affecting the principal ce rebrospinal venous segments in MS patients. We report the clinical and transcranial magnetic stimulation follow-up of a patient during a relapse in relapsing-remitting MS. She underwent percutaneous balloon angioplasty of the associated chronic cerebrospinal venous insufficiency (CCSVI), due to membranous obstruction of the proximal azygous vein, with severe stenosis of the left internal jugular vein. Treatment of the associated CCSVI made a parallel improvement in both clinical and neurophysiological parameters, allowing us to avoid high dose steroid therapy. The relationship between the clinical and neurophysiological course on the one hand, and haemodynamic correction of the associated CCSVI on the other, calls for further exploration on a wider number of patients. The impact of CCSVI on the different neuro-physiological parameters has not been fully estimated, but the intriguing case here reported suggests that it may be greater than previously assumed. The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.


Hybrid approach for hypoplastic left heart syndrome and its variants: the fate of the pulmonary arteries.
To analyse the results of hybrid palliation of hypoplastic left heart syndrome (HLHS) patients and its variants with an emphasis on the long-term fate of the pulmonary arteries. We analysed 28 neonates (2006-11) with HLHS and its variants, who underwent bilateral pulmonary artery banding, patent ductus arteriosus (PDA) stenting and balloon atrial septostomy using a true hybrid approach. Median age and weight were 4 (0-36) days and 3 (1.9-3.7) kg respectively. Diagnoses included 23 HLHS and 5 variants. The fate of all surviving branch pulmonary arteries (PA) after a hybrid approach were compared with their counterparts in 29 Norwood I survivors (2002-11). Four of 28 hybrid procedures needed to be converted to a Norwood procedure. Mortality after stage I hybrid palliation was 3/24 (12.5%). All 21 acute survivors underwent a comprehensive stage II at a median age of 4 (2.3-5.7) months, without any mortality (0%). Eleven of 21 comprehensive stage II survivors have undergone extracardiac Fontan; including 1 who underwent a rescue Fontan at 7 months of age and died (1/11: 9%). While 18/21 (86%) needed branch PA intervention in the hybrid group during the median follow-up duration of 39 (10-81) months, 9/29 (31%) needed the same in the Norwood group during a median follow-up duration of 58 (16-128) months (P < 0.001). Eight of 21 (38%) needed stenting [all on the left pulmonary artery (LPA)] in the hybrid group vs 5/29 (17%) in the Norwood group (P = 0.097). Ten of 21 (48%) patients had surgical/catheter intervention on both branch PA in the hybrid group vs 2/29 (7%) in the Norwood group (P = 0.001). Pre-Fontan Nakata index was significantly better in the Norwood group 206 (118-406) compared with the hybrid group 153 (56-230) mm(2)/m(2) (P = 0.01). The comparable lower lobe indices were 149 (103-333) and 137 (45-178) mm(2)/m(2) (P = 0.04), respectively. Hybrid approach can be pursued with a low mortality. However, the high frequency of catheter and/or surgical interventions, and the sluggish growth of the branch PA pre-Fontan need innovative solutions. A comparison of the neurodevelopmental outcome for the hybrid vs the Norwood cohort would define the role of the hybrid strategy in the treatment of HLHS and its variants.


Predictors of complicated grief among dementia caregivers: a prospective study of bereavement.
Most family caregivers adapt well to the death of their care recipient relative; however, a sizable minority continues to experience postdeath psychiatric morbidity. The purpose of this study was to better understand why some caregivers manifest clinical levels of complicated grief postdeath. This is the first study to prospectively assess predictors of complicated grief among family caregivers of patients with dementia who experience the death of their care recipient. The sample of bereaved caregivers is drawn from a larger study of 1,222 family caregivers providing in-home care to their relative with dementia. In-home assessments of caregivers and patients were carried out at baseline and six-month intervals for a total of 18 months. This article is based on the 217 caregivers who experienced the death of their care recipient in the course of the study. Three logistic regression models are tested to identify pre- and postbereavement predictors of complicated grief, including sociodemographic factors, characteristics of the caregiving experience, including participation in a caregiver intervention, other psychiatric morbidities, and medication use. Twenty percent of dementia caregivers evidenced complicated grief along with high levels of depressive symptomatology postdeath. Controlling for sociodemographic factors, caregivers who had high levels of preloss depressive symptoms and burden, reported positive features of the caregiving experience, and were caring for a more cognitively impaired patient were more likely to report clinical levels of complicated grief postloss. In addition, caregivers who were enrolled in a psychosocial caregiver intervention designed to reduce depression and burden reported lower levels of complicated grief. This study identifies predictors of complicated grief for which interventions could be developed to not only ease caregiver distress, but also serve as preventive interventions for bereavement. Reducing the burden of active caregiving, treating depression before the death of the loved one and providing supportive psychosocial and skills training caregiver interventions can prevent the emergence of postdeath psychiatric morbidity.


Beta-band frequency peaks inside the subthalamic nucleus as a biomarker for motor improvement after deep brain stimulation in Parkinson's disease.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) remains an empirical, yet highly effective, surgical treatment for advanced Parkinson's disease (PD). DBS outcome depends on accurate stimulation of the STN sensorimotor area which is a trial-and-error procedure taking place during and after surgery. Pathologically enhanced beta-band (13-35 Hz) oscillatory activity across the cortico-basal ganglia pathways is a prominent neurophysiological phenomenon associated with PD. We hypothesized that weighing together beta-band frequency peaks from simultaneous microelectrode recordings in "off-state" PD patients could map the individual neuroanatomical variability and serve as a biomarker for the location of the STN sensorimotor neurons. We validated our hypothesis with 9 and 11 patients that, respectively, responded well and poorly to bilateral DBS, after at least two years of follow up. We categorized "good" and "poor" DBS responders based on their clinical assessment alongside a > 40% and <30% change, respectively, in "off" unified PD rating scale motor scores. Good (poor) DBS responders had, in average, 1 mm (3.5 mm) vertical distance between the maximum beta-peak weighted across the parallel microelectrodes and the center of the stimulation area. The distances were statistically different in the two groups ( p = 0.0025 ). Our biomarker could provide personalized intra- and postoperative support in stimulating the STN sensorimotor area associated with optimal long-term clinical benefits.


African Swine Fever Epidemiology and Control.
African swine fever is a devastating disease that can result in death in almost all infected pigs. The continuing spread of African swine fever from Africa to Europe and recently to the high-pig production countries of China and others in Southeast Asia threatens global pork production and food security. The African swine fever virus is an unusual complex DNA virus and is not related to other viruses. This has presented challenges for vaccine development, and currently none is available. The virus is extremely well adapted to replicate in its hosts in the sylvatic cycle in East and South Africa. Its spread to other regions, with different wildlife hosts, climatic conditions, and pig production systems, has revealed unexpected epidemiological scenarios and different challenges for control. Here we review the epidemiology of African swine fever in these different scenarios and methods used for control. We also discuss progress toward vaccine development and research priorities to better understand this complex disease and improve control.


Living with a chronic deteriorating disease: the trajectory with muscular dystrophy over ten years.
The aim of the study was to elucidate experiences of living with muscular dystrophy in terms of consequences for activity over 10 years. The study population was identified in a prevalence study in a county of Sweden. Forty-six persons of this cohort with MD were interviewed. A qualitative research approach was chosen. The World Health Organization's International Classification of Functioning, Disability and Health (ICF) was used for categorization. Nearly all the subjects experienced a deterioration of physical capacity. Most obvious were the restrictions on mobility and increased fatigue and feebleness. The persons described psychosocial consequences of the muscular dystrophy as well as stigma when the disability had become more obvious. In spite of reported distress several persons experienced better psychological adaptation over time. The image of the future was often dark but several focus on today and avoid thoughts about the future. ICF showed some limitation with regard to temporal aspects, emotions and the subjective perspective. The knowledge of the trajectory with MD is important in order to offer the best possible treatment and support. Repeated assessment by ICF can serve as a valuable source of such knowledge, and a development of the classification would increase its usefulness in future analysis of functioning and disability.


Thickness of the human round window membrane in different forms of otitis media.
The thickness and morphologic characteristics of the round window membrane were evaluated in temporal bones from normal subjects as well as those with serous otitis media, purulent otitis media, and chronic otitis media. Temporal bones were studied in chronological order in six age ranges to determine the possibility of age-related differences. No significant difference in the mean thickness of the round window membrane was observed in terms of age groups in normal temporal bones or temporal bones from patients with otitis media; however, a significant difference in the mean thickness was observed in the various forms of otitis media compared with the normal round window membrane in all age groups. The membrane was thickest in patients with chronic otitis media when compared with that in normal subjects or those with serous or purulent otitis media. The epithelial layer (including the subepithelial space) and the fibrous layer were measured individually to determine in which layer the change in mean thickness occurred. These measurements showed an involvement of all layers of the round window membrane in those groups with otitis media, with maximal involvement of the combined epithelial layer and subepithelial space.


Microfluidic electroporation for selective release of intracellular molecules at the single-cell level.
Analysis of intracellular materials at the single-cell level presents opportunities for probing the heterogeneity of a cell population. Lysis by electroporation has been gaining popularity as a rapid method for disruption of the cell membrane and release of intracellular contents. In this report, we selectively released specific intracellular molecules for interrogation at the single-cell level by tuning the parameters of electroporation. We examined the release of a small molecule, calcein (MW approximately 600), and a 72-kDa protein kinase, Syk, tagged by enhanced green fluorescent protein (EGFP) from chicken B cells during electroporation at the single-cell level. We studied the effects of the field intensity and the field duration on the release of the two molecules. We found that calcein in general was released at lower field intensities and shorter durations than did SykEGFP. By tuning the electrical parameters, we were able to deplete calcein from the cells before SykEGFP started to release. This approach potentially provides a high-throughput alternative for probing different intracellular molecules at the single-cell level compared to chemical cytometry by eliminating complete disruption of the cell membrane.


ZNF281/Zfp281 is a target of miR-1 and counteracts muscle differentiation.
Defects in achieving a fully differentiated state and aberrant expression of genes and microRNAs (miRs) involved in differentiation are common to virtually all tumor types. Here, we demonstrate that the zinc finger transcription factor ZNF281/Zfp281 is down-regulated during epithelial, muscle, and granulocytic differentiation in vitro. The expression of this gene is absent in terminally differentiated human tissues, in contrast to the elevated expression in proliferating/differentiating ones. Analysis of the 3'UTR of ZNF281/Zfp281 revealed the presence of numerous previously undescribed miR binding sites that were proved to be functional for miR-mediated post-transcriptional regulation. Many of these miRs are involved in differentiation pathways of distinct cell lineages. Of interest, ZNF281/Zfp281 is able to inhibit muscle differentiation promoted by miR-1, of which ZNF281/Zfp281 is a direct target. These data suggest that down-regulation of ZNF281/Zfp281 during differentiation in various cell types may occur through specific miRs whose expression is tissue-restricted. In addition, we found that in rhabdomyosarcoma and leiomyosarcoma tumors, the expression of ZNF281/Zfp281 is significantly higher compared with normal counterparts. We extended our analysis to other human soft tissue sarcomas, in which the expression of ZNF281 is associated with a worse prognosis. In summary, we highlight here a new role of ZNF281/Zfp281 in counteracting muscle differentiation; its down-regulation is at least in part mediated by miR-1. The elevated expression of ZNF281/Zfp281 in soft tissue sarcomas warrants further analysis for its possible exploitation as a prognostic marker in this class of tumors.


Where do livestock guardian dogs go? Movement patterns of free-ranging Maremma sheepdogs.
In many parts of the world, livestock guardian dogs (LGDs) are a relatively new and increasingly popular method for controlling the impact of wild predators on livestock. On large grazing properties in Australia, LGDs are often allowed to range freely over large areas, with minimal supervision by their owners. How they behave in this situation is mostly unknown. We fitted free-ranging Maremma sheepdogs with GPS tracking collars on three properties in Victoria, Australia; on two properties, four sheep were also fitted with GPS collars. We investigated how much time the Maremmas spent with their livestock, how far they moved outside the ranges of their stock, and tested whether they use their ranges sequentially, which is an effective way of maintaining a presence over a large area. The 95% kernel isopleth of the Maremmas ranged between 31 and 1161 ha, the 50% kernel isopleth ranged between 4 and 252 ha. Maremmas spent on average 90% of their time in sheep paddocks. Movements away from sheep occurred mostly at night, and were characterised by high-speed travel on relatively straight paths, similar to the change in activity at the edge of their range. Maremmas used different parts of their range sequentially, similar to sheep, and had a distinct early morning and late afternoon peak in activity. Our results show that while free-ranging LGDs spend the majority of their time with livestock, movements away from stock do occur. These movements could be important in allowing the dogs to maintain large territories, and could increase the effectiveness of livestock protection. Allowing LGDs to range freely can therefore be a useful management decision, but property size has to be large enough to accommodate the large areas that the dogs use.


[Cholesterol metabolism modulators and the future of atherosclerosis therapy].
Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).


Home care nursing after elective vascular surgery: an opportunity to reduce emergency department visits and hospital readmission.
Events occurring outside the hospital setting are underevaluated in surgical quality improvement initiatives and research. To quantify regional variation in home care nursing following vascular surgery and explore its impact on emergency department (ED) visits and hospital readmission. Patients who underwent elective vascular surgery and were discharged directly home were identified from population-based administrative databases for the province of Ontario, Canada, 2006-2015. The index surgeries included carotid endarterectomy, open and endovascular aortic aneurysm repair and bypass for lower extremity peripheral arterial disease. Home care nursing within 30 days of discharge was captured and compared across regions. Using multilevel logistic regression, we characterised the association between home care nursing and the risk of an ED visit or hospital readmission within 30 days of discharge. The cohort included 23 617 patients, of whom 9002 (38%) received home care nursing within 30 days of discharge home. Receipt of nursing care after discharge home varied widely across Ontario's 14 administrative health regions (range 16%-84%), even after accounting for differences in patient case mix. A lower likelihood of an ED visit or hospital readmission within 30 days of discharge was observed among patients who received home care nursing following three of four index surgeries: carotid endarterectomy OR 0.74, 95% CI 0.61 to 0.91; endovascular aortic aneurysm repair OR 0.85, 95% CI 0.72 to 0.99; open aortic aneurysm repair OR 1.06, 95% CI 0.91 to 1.23; bypass for lower extremity peripheral arterial disease OR 0.81, 95% CI 0.72 to 0.92. Home care nursing may contribute to reducing ED visits and hospital readmission and is variably prescribed after vascular surgery.


Analysis of Cx43alpha1 promoter function in the developing zebrafish embryo.
The Cx43alpha1 gap junctions play an important role in cardiovascular development. Studies using transgenic mouse models have indicated that this involves an essential role for Cx43alpha1 in modulating neural crest cell motility. We previously showed that a 6.8 kb mouse genomic sequence containing the promoter and upstream regulatory sequences of the Cx43alpha1 gene can drive lacZ reporter gene expression in all neural crest cell lineages in the mouse embryo. To obtain further insights into the sequence motifs and regulatory pathways involved in targeting Cx43alpha1 gene expression in neural crest cells, we assayed the activity of the mouse Cx43alpha1 promoter in evolutionarily distantly related zebrafish embryos. For these studies, the 6.8kb Cx43alpha1 genomic sequence and various deletion derivatives were used to generate GFP or lacZ expression vectors. The transcriptional activities of these constructs were analyzed in vivo after microinjection into one- or two- cell stage zebrafish embryos. These studies indicated that the mouse Cx43alpha1 promoter can drive lacZ expression in neural crest cells in the zebrafish embryos. Analysis by whole mount in situ hybridization showed that the endogenous zebrafish Cx43alpha1 gene is expressed maternally and zygotically, and expression is observed in regions where neural crest cells are found. To further elucidate the developmental regulation of Cx43alpha1 gene expression, we screened a zebrafish BAC library and identified a clone containing the entire zebrafish Cx43alpha1 gene and flanking upstream and downstream sequences. The upstrean Cx43alpha1 promoter sequences from zebrafish, mouse, and human were analyzed for evolutionarily conserved DNA motifs. Overall these studies suggest that the sequence motifs and transcriptional regulation involved in the targeting Cx43alpha1 expression to neural crest cells are evolutionarily conserved in zebrafish and mouse embryos.


[Predictive factors for noncompliance with tuberculosis treatment in an endemic region of Peru].
To identify factors that predict noncompliance with tuberculosis treatment in the province of Ica, Peru. Between 1998 and 2000 a case-control study (1:1 ratio) was conducted in the province of Ica, with 55 cases (persons who dropped out of treatment) being identified. The factors evaluated were chosen from Lalonde's model of the field of health. The respective odds ratios were calculated by means of univariate analysis and multivariate analysis. The following factors were identified as being predictive of noncompliance with tuberculosis treatment: thinking that the information that health workers provided on treatment was insufficient (odds ratio (OR) = 4.20; 95% confidence interval (95% CI), 1.77-10.02), thinking that the office hours for receiving treatment were inadequate (OR = 9.95; 95% CI, 1.97-50.21), and consuming illegal drugs (OR = 7.15; 95% CI, 1.69-30.23). To improve compliance with tuberculosis treatment, it is necessary to provide patients with personalized information on the disease and its treatment, and to offer them flexible, appropriate times to receive treatment. Drug consumption is the most serious risk factor for noncompliance, and identifying and following up with drug users is crucial.


When students become patients: TB disease among medical undergraduates in Cape Town, South Africa.
Medical students acquire latent tuberculosis (TB) infection at a rate of 23 cases/100 person-years. The frequency and impact of occupational TB disease in this population are unknown. A self-administered questionnaire was distributed via email and social media to current medical students and recently graduated doctors (2010 - 2015) at two medical schools in Cape Town. Individuals who had developed TB disease as undergraduate students were eligible to participate. Quantitative and qualitative data collected from the questionnaire and semi-structured interviews were analysed with descriptive statistics and a framework approach to identify emerging themes. Twelve individuals (10 female) reported a diagnosis of TB: pulmonary TB (n=6), pleural TB (n=3), TB lymphadenitis (n=2) and TB spine (n=1); 2/12 (17%) had drug-resistant disease (DR-TB). Mean diagnostic delay post consultation was 8.1 weeks, with only 42% of initial diagnoses being correct. Most consulted private healthcare providers (general practitioners (n=7); pulmonologists (n=4)), and nine underwent invasive procedures (bronchoscopy, pleural fluid aspiration and tissue biopsy). Substantial healthcare costs were incurred (mean ZAR25 000 for drug-sensitive TB, up to ZAR104 000 for DR-TB). Students struggled to obtain treatment, incurred high transport costs and missed academic time. Students with DR-TB interrupted their studies and experienced severe side-effects (hepatotoxicity, depression and permanent ototoxicity). Most participants cited poor TB infection-control practices at their training hospitals as a major risk factor for occupational TB. Undergraduate medical students in Cape Town are at high risk of occupationally acquired TB, with an unmet need for comprehensive occupational health services and support.


A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis.
Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.


Effect of pregnancy on anti-HEV antibody titres, plasma cytokines and the corresponding gene expression levels in the PBMCs of patients presenting with self-recovering clinical and subclinical hepatitis E.
High mortality in pregnant women (PR) is a characteristic of hepatitis E in developing countries. To understand the pathogenesis of HEV infection in self-limiting disease during pregnancy, we compared clinical (PR-patients) and subclinical-HEV-infections in pregnant women in the first (SC-PR-1) and later (2nd and 3rd, SC-PR-2+3) trimesters with the respective healthy controls and acute non-PR patients. The SC-PR-2+3 exhibited lower ALT, bilirubin levels, anti-HEV-IgM/IgG titres than the acute-PR/non-PR-patients (p<0.05-0.0001). IFNγ/IL4ratios indicated Th2/Th1 bias in non-PR and PR-patients respectively. Raised levels of 10/20 plasma cytokines in the non-PR-patients reflect predominant inflammatory response, unaltered- IFNγ/reduced-IFNα responses and a robust chemokine secretion. On contrary, the acute-PR-patients exhibited drastic reduction in majority of the cytokines relative to in the non-PR-patients. Importantly, diminished or unaltered response was noted in the acute-PR-group when compared to the corresponding controls. The only exception was sIL2RA, increasing in both patient categories. Of the 14 genes evaluated, the expression of IFNγ/IL10/IL1A/IL7/CCL2/CCL3/CXCL8/CXCL10 was higher in the non-PR patients. Of these, the expression of IFNγ/IL10/IL1A/CCL2/CCL3/CXCL8 and, additionally, IL2/IL6/TNF genes was higher in the clinical-PRs. Almost identical pattern was noted in the control-PR-2+3 category indicating no influence of HEV infection. Comparison of patient-categories identified significant elevation of IFNγ(P<0.001), CCL2(p<0.01), CXCL8(P<0.05), IL1B(p<0.05) and IL10(P<0.0001) and decrease in CXCL10(<0.05) in the PR-patients. The results suggest antibody-dependent disease severity and impaired immune response in the PR patients. Higher expression of cytokine-genes in the PBMCs did not correlate with the plasma-cytokine levels in the PR-patients.


HLA and genetic susceptibility to sleepwalking.
HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P = 0.0056; odds ratio = 3.5, 95% CI = 1.4-8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission-disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P = 0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.


Neutrophil association and degradation of normal and acute-phase high-density lipoprotein 3.
The interaction of normal and acute-phase high-density lipoproteins of the subclass 3 (N-HDL3 and AP-HDL3) with human neutrophils and the accompanying degradation of HDL3 apolipoproteins have been studied in vitro. The chemical composition of normal and acute-phase HDL3 was similar except that serum amyloid A protein (apo-SAA) was a major apolipoprotein in AP-HDL3 (approx. 30% of total apolipoproteins). 125I-labelled AP-HDL3 was degraded 5-10 times faster than 125I-labelled N-HDL3 during incubation with neutrophils or neutrophil-conditioned medium. Apo-SAA, like apolipoprotein A-II (apo-A-II), was more susceptible than apolipoprotein A-I (apo-A-I) to the action of proteases released from the cells. The amounts of cell-associated AP-HDL3 apolipoproteins at saturation were up to 2.8 times greater than N-HDL3 apolipoproteins; while apo-A-I was the major cell-associated apolipoprotein when N-HDL3 was bound, apo-SAA constituted 80% of the apolipoproteins bound in the case of AP-HDL3. The associated intact apo-SAA was mostly surface-bound as it was accessible to the action of exogenous trypsin. alpha 1-Antitrypsin-resistant (alpha 1-AT-resistant) cellular degradation of AP-HDL3 apolipoproteins also occurred; experiments in which pulse-chase labelling was performed or lysosomotropic agents were used indicated that insignificant intracellular degradation occurred which points to the involvement of cell-surface proteases in this degradation.


Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer.
Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy. SIGNIFICANCE: Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/5008/F1.large.jpg.


Encouraging survival rates in patients with acute myocardial infarction treated with an intra-aortic balloon pump.
OBJECTIVE: To evaluate a 30-day and long-term outcome of patients with acute myocardial infarction (AMI) treated with intra-aortic balloon pump (IABP) counterpulsation and to identify predictors of a 30-day and long-term all-cause mortality. METHODS: Retrospective cohort study of 437 consecutive AMI patients treated with IABP between January 1990 and June 2004. A Cox proportional hazards model was used to identify predictors of a 30-day and long-term all-cause mortality. RESULTS: Mean age of the study population was 61 ± 11 years, 80% of the patients were male, and 68% had cardiogenic shock. Survival until IABP removal after successful haemodynamic stabilisation was 78% (n = 341). Cumulative 30-day survival was 68%. Median follow-up was 2.9 years (range, 6 months to 15 years). In patients who survived until IABP removal, cumulative 1-, 5-, and 10-year survival was 75%, 61%, and 39%, respectively. Independent predictors of higher long-term mortality were prior cerebrovascular accident (hazard ratio (HR), 1.8; 95% confidence interval (CI), 1.0-3.4), need for antiarrhythmic drugs (HR, 2.3; 95% CI, 1.5-3.3), and need for renal replacement therapy (HR, 2.3; 95% CI, 1.2-4.3). Independent predictors of lower long-term mortality were primary percutaneous coronary intervention (PCI; HR, 0.6; 95% CI, 0.4-1.0), failed thrombolysis with rescue PCI (HR, 0.5; 95% CI, 0.3-0.9), and coronary artery bypass grafting (HR, 0.3; 95% CI, 0.1-0.5). CONCLUSIONS: Despite high in-hospital mortality in patients with AMI treated with IABP, a favourable number of patients survived in the long-term. These results underscore the value of aggressive haemodynamic support of patients throughout the acute phase of AMI.


Bone metabolic marker concentrations across the menstrual cycle and phases of combined oral contraceptive use.
There is a need to further understand the impact of the menstrual cycle and phase of combined oral contraceptive (COC) use on the pre-analytical variability of markers of bone metabolism in order to improve standardisation procedures for clinical practice and research. The aim of this study was to assess bone metabolism marker concentrations across the menstrual cycle and phases of COC use. Carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX), procollagen type 1 N propeptide (P1NP) and Bone alkaline phosphatase (Bone ALP) concentrations were assessed in eumenorrheic women (n = 14) during the early follicular, ovulatory and mid-luteal phases of the menstrual cycle and in COC (Microgynon®) (n = 14) users on day 2-3 of pill consumption (PC1), day 15-16 pill consumption (PC2) and day 3-4 of the pill free interval (PFI). β-CTX was significantly (-16%) lower at PC2 compared to PC1 (P = 0.015) in COC users and was not affected by menstrual cycle phase (P > 0.05). P1NP and Bone ALP were not significantly different across either menstrual cycle phase or phase of COC use (all P > 0.05). There was no difference in pooled bone marker concentrations between eumenorrheic women and COC users (P > 0.05). In contrast to some previous studies, this study showed that bone marker concentrations do not significantly fluctuate across the menstrual cycle. Furthermore, bone resorption markers are significantly affected by phase of COC use, although bone formation markers do not significantly vary by COC phase. Therefore, the phase of COC use should be considered in clinical practice and research when assessing markers of bone metabolism as this can impact circulating concentrations of bone metabolic markers yet is not currently considered in existing guidelines for best practice.


Integration of a K+ channel-associated peptide in a lipid bilayer: conformation, lipid-protein interactions, and rotational diffusion.
The 26-residue peptide of sequence KEALYILMVLGFFGFFTLGIMLSYIR, which contains the single putative transmembrane domain of a small protein that is associated with slow voltage-gated K+ channels, has been incorporated in bilayers of dimyristoylphosphatidylcholine by dialysis from 2-chloroethanol to form complexes of homogeneous lipid/peptide ratio. Fourier transform infrared spectroscopy indicates that the peptide is integrated in the lipid bilayer wholly in a beta-sheet conformation. The electron spin resonance spectra of spin-labeled lipids in the lipid/peptide complexes contain a component corresponding to lipids whose chains are motionally restricted in a manner similar to those of lipids at the hydrophobic surface of integral transmembrane proteins. From the dependence of the lipid spin label spectra on the lipid/peptide ratio of the complexes, it is found that ca. 2.5 lipids per peptide monomer, independent of the species of spin-labeled lipid, are motionally restricted by direct interaction with the peptide in the bilayer. This value would be consistent with, e.g., a beta-barrel structure for the peptide in which the beta-strands either are strongly tilted or have a reverse turn at their center. A preferential selectivity of interaction with the peptide is observed for the negatively charged spin-labeled lipids phosphatidic acid, stearic acid, and phosphatidylserine, which indicates close proximity of the positively charged residues at the peptide termini to the lipid headgroups. The saturation-transfer electron spin resonance spectra of the peptide spin-labeled at a cysteine residue replacing Leu18 evidence rather slow rotational diffusion in the lipid complexes.(ABSTRACT TRUNCATED AT 250 WORDS)


Information technology for the treatment of diabetes: improving outcomes and controlling costs.
Diabetes in particular presents an ideal opportunity for the incorporation of information technology (IT) in the provision of care. The disease is highly prevalent in managed care populations, is frequently associated with comorbid conditions, and requires multiple medications in its management. Furthermore, effective diabetes care involves the monitoring of several measures of disease control, such as hemoglobin A1c (A1c) and lipid levels, by several different levels of providers, such as physicians, nurse practitioners, physician assistants, pharmacists, and dieticians. All of these factors combined make diabetes an opportune disease state for a case study of the implementation of health information technology (HIT) in managed care. To review practical applications of HIT for improving the delivery of care in diabetes management. Between 1990 and 2002, the incidence of type 2 diabetes increased by 61% in the United States. The total costs associated with diabetes have been increasing since the late 1970s as well, with a more dramatic rise over the last 10 years. In fact, the total cost of diabetes in the United States will approach $200 billion per year by the year 2020. In order to improve diabetes management efforts nation wide, the goal of glucose lowering therapy has been recommended to lower the hemoglobin A1c (A1c) to < 7% and keep it below that level long term. Other measures beyond A1c levels have also been identified as being important components to effective diabetes management and incorporated into national treatment recommendations, providing an ideal opportunity for the incorporation of HIT interventions. These interventions have been aimed at 3 different groups of stakeholders in managed care: payers, providers, and patients. While uncontrolled diabetes remains a major concern in managed care from both a health and a cost perspective, implementation of information technology enabled diabetes management (ITDM) has demonstrated significant potential for improving processes of care, preventing the development of diabetic complications, and generating cost savings. ITDM improves the synthesis of information, the delivery of knowledge, and the efficiency of communication, allowing for coordination of care across delivery teams. Of the existing technologies targeting providers, patients, and payers, provider centered interventions, such as diabetes registries currently show the most potential for benefit in improving outcomes and reducing costs.


The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance.
Opioids remain among the most effective pain-relieving therapeutics. However, their long-term use is limited due to the development of tolerance and potential for addiction. For many years, researchers have explored the underlying mechanisms that lead to this decreased effectiveness of opioids after repeated use, and numerous theories have been proposed to explain these changes. The most widely studied theories involve alterations in receptor trafficking and intracellular signaling. Other possible mechanisms include the recruitment of new structural neuronal and microglia networks. While many of these theories have been developed using molecular and cellular techniques, more recent behavioral data also supports these findings. In this review, we focus on the mechanisms that underlie tolerance within the descending pain modulatory pathway, including alterations in intracellular signaling, neural-glial interactions, and neurotransmission following opioid exposure. Developing a better understanding of the relationship between these various mechanisms, within different parts of this pathway, is vital for the identification of more efficacious, novel therapeutics to treat chronic pain.


Household cost of out-patient treatment of Buruli ulcer in Ghana: a case study of Obom in Ga South Municipality.
The economic burden of diseases has become increasingly relevant to policy makers as healthcare expenditure keep rising in the face of limited and competing resources. Buruli ulcer (BU), a neglected but treatable tropical disease caused by Mycobacterium ulcerans, the only known environmental mycobacterium is capable of causing long term disability when left untreated. However, most BU studies have tended to focused on its bacteriology, epidemiology, entomology and other social determinants to the neglect of its economic evaluation. This paper reports estimated the household economic costs of BU and describe the intangible cost suffered by BU patients in an endemic area. Retrospective one year cost data was used. A total of 63 confirmed BU cases were randomly sampled for the study. Economic cost and cost burden of BU were estimated. Sensitivity analysis was conducted to test the robustness of the cost estimates. Intangible cost measured stigmatization, pain, functional limitation and social isolation of children. The annual total household economic cost was US$35,915.98, of which about 65% was cost incurred by children with a mean cost of US$521.04. The mean annual household cost was US$570.09. The direct cost was 96% of the total cost. Non-medical cost accounts for about 97% of the direct cost with a mean cost of US$529.27. The mean medical cost was US$18.94. The main cost drivers of the household costs were transportation (78%) and food (12%). Caregivers and adult patients lost a total of 535 productive days seeking care, which gives an indirect cost valued at US$1,378.67 with a mean of US$21.88. A total of 365 school days (about 1 year) were lost by 19 BU patients (mean, 19.2 days). Functional loss and pain were low, and stigma rated moderate. Most children suffering from BU (84%) were socially isolated. Household cost burden of out-patient BU ulcer treatment was high. Household cost of BU is therefore essential in the design of its intervention. BU afflicted children experience social isolation.