FAS-mediated apoptosis and its relation to intrinsic pathway activation in an experimental model of retinal detachment.
To determine whether the FAS-mediated apoptosis pathway becomes activated in the retina after retinal detachment and to investigate the temporal relationship between the activation of the FAS-pathway and the intrinsic apoptosis pathway involving caspase-9 and cytochrome c. Experimental retinal detachments were created in Brown-Norway rats by injecting 10% hyaluronic acid into the subretinal space. Retinal tissue was harvested at 2, 4, 8, 24, 72, and 168 hours after creation of the detachment. Immunoprecipitation was performed to assess for FAS-receptor/FAS-ligand complex formation, and activation of caspase-8 and BID (a member of the Bcl-2 family of proteins) was assessed by Western blot analysis. A caspase-9 activity assay and immunoprecipitation of the caspase-9/cytochrome c complex were performed at these same time points. Specific pathway inhibition was performed with the caspase-9 inhibitor zLEHD.fmk or neutralizing antibodies against either the FAS-receptor or FAS-ligand. Transcription levels of FAS and intrinsic pathway intermediates were assessed as a function of time after retinal detachment by using quantitative real-time polymerase chain reaction. Retinal detachment resulted in the time-dependent formation of the FAS-receptor/FAS-ligand complex that preceded the peak of caspase-9 activity and caspase-9/cytochrome c complex formation. Cleavage of caspase-8 and truncation of BID were also observed. Injection of zLEHD.fmk into the subretinal space of a detached retina resulted in decreased caspase-9 activity, as did injection of anti-FAS-receptor antibody into either the subretinal space or the vitreous. Retinal detachment resulted in the transcriptional upregulation of the FAS-receptor, FAS-ligand, caspase-8 and BID, but not caspase-9 and cytochrome c. The FAS-mediated apoptosis pathway becomes activated and transcriptionally upregulated after retinal detachment. The peak of FAS activation precedes that of the intrinsic pathway, and inhibition of FAS activation can decrease caspase-9 activity.


Effects of Knowledge of Results on Reciprocal, lsokinefk Strength and Fatigue.
The purpose of this study was to determine the effects of knowledge of results, i.e., visual feedback from watching the torque curve on the Cybex II recorder, on knee extensor and flexor strength (peak torque in ft-lb), and fatigue (strength decrement) during reciprocal, isokinetic testing at speeds of 15O/sec (slow) and 300 degrees /sec (fast). Knowledge of results induced higher strength and fatigue values in both muscle groups during slow, but not fast, speed tests. The greater amounts of fatigue resulted from elevated initial strength levels at the beginning of the slow speed fatigue tests. The superior quality of the slow speed knowledge of results and longer times to utilize the visual feedback may explain the enhanced strength values. The effect of knowledge of results on strength levels decreased during the course of the slow speed fatigue tests. Results are discussed in terms of information processing and motivation theory. J Orthop Sports Phys Ther 1984;6(3):190-197.


An automated pipette puller for fabrication of glass micropipettes.
Glass micropipettes are versatile probing tools for performing micro- and nano-manipulation tasks. This paper presents the design and development of an automated pipette puller system for fabrication of glass micropipettes. The pipette puller employs a new strategy for fabrication of micropipettes that enables achieving independent control of their taper, tip diameter, and bend-angle, and also facilitates theoretical derivation of simple, approximate relationships between the pipette shape and the pulling parameters. Subsequently, the design and fabrication of the pipette puller is described, which include that of the pipette heating system, the mechanical motion stages, and the control electronics of the pipette puller. The fabricated pipette puller is experimentally evaluated to demonstrate control of the taper, tip diameter, and the bend-angle of the micropipette. Further, the dependence of the taper and tip diameter on the pulling parameters is evaluated and is shown to be in alignment with the proposed theoretical relationships.


Sites and mechanisms of antibiotic-induced neuromuscular block: a pharmacological analysis using quantal content, voltage clamped end-plate currents and single channel analysis.
Since the original observation of Vital Brazil and Corrado (1957) concerning the antibiotic induced neuromuscular block produced by streptomycin, there has been considerable interest in the mechanisms responsible for not only neuromuscular block but also the effects of antibiotics on different systems. We used the voltage clamped end-plate of transacted skeletal muscle to examine the concentration-dependent actions of several groups of antibiotics. The aminoglycoside antibiotics, neomycin and streptomycin, were both more effective at reducing quantal release of acetylcholine (ACh) than interacting with the postjunctional ACh receptor-channel complex. Neomycin was approximately 10 X more potent prejunctionally than streptomycin and the prejunctional effects of each antibiotic were reversed competitively by raising extracellular calcium. Both neomycin and streptomycin also had postjunctional actions at higher concentrations. Neomycin interacted with the open state of the ACh receptor ion channel complex while streptomycin blocks the ACh receptor. The lincosamide antibiotics, lincomycin and clindamycin produced their neuromuscular block postjunctionally by interacting with the open state of the ACh-receptor channel complex. Clindamycin is approximately 20 X more effective at blocking the open channel than was lincomycin. Using cell attached patch clamp recordings in cultured rat myotubes, we demonstrated a lincosamide-induced block of open ion channels with clindamycin having a much slower unblocking rate than lincomycin. Using epimers of the lincosamides, we demonstrated that lipophilicity of the molecule, rather than stereochemical considerations, is important for open channel blockade affecting primarily the "off" rate of channel blocking. This mechanism appears important for not only the lincosamide antibiotics but also for the postjunctional actions of the aminoglycoside antibiotics, particularly neomycin.


Partitioning and Classification of RNA Secondary Structures into Pseudonotted and Pseudoknot-free Regions Using a Graph-Theoretical Approach.
Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined base pairs. In this paper we present a linear-time algorithm to partition dual graphs into maximal topological components called blocks and determine whether each block contains a pseudoknot or not. We show that a block contains a pseudoknot if and only if the block has a vertex of degree 3 or more; this characterization allows us to efficiently isolate smaller RNA fragments and classify them as pseudoknotted or pseudoknot-free regions, while keeping these sub-structures intact. Applications to RNA design can be envisioned since modular building blocks with intact pseudoknots can be combined to form new constructs.


Microfluidic parallel patterning and cellular delivery of molecules with a nanofountain probe.
This brief report describes a novel tool for microfluidic patterning of biomolecules and delivery of molecules into cells. The microdevice is based on integration of nanofountain probe (NFP) chips with packaging that creates a closed system and enables operation in liquid. The packaged NFP can be easily coupled to a micro/nano manipulator or atomic force microscope for precise position and force control. We demonstrate here the functionality of the device for continuous direct-write parallel patterning on a surface in air and in liquid. Because of the small volume of the probes (~3 pL), we can achieve flow rates as low as 1 fL/s and have dispensed liquid drops with submicron to 10 µm diameters in a liquid environment. Furthermore, we demonstrate that this microdevice can be used for delivery of molecules into single cells by transient permeabilization of the cell membrane (i.e., electroporation). The significant advantage of NFP-based electroporation compared with bulk electroporation and other transfection techniques is that it allows for precise and targeted delivery while minimizing stress to the cell. We discuss the ongoing development of the tool toward automated operation and its potential as a multifunctional device for microarray applications and time-dependent single-cell studies.


Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper.
Nonallergic rhinitis (NAR) can be defined as a chronic nasal inflammation which is not caused by systemic IgE-dependent mechanisms. It is common and probably affects far more than 200 million people worldwide. Both children and adults are affected. However, its exact prevalence is unknown and its phenotypes need to be evaluated using appropriate methods to better understand its pathophysiology, diagnosis and management. It is important to differentiate between infectious rhinitis, allergic/NAR and chronic rhinosinusitis, as management differs for each of these cases. Characterization of the phenotype, mechanisms and management of NAR represents one of the major unmet needs in allergic and nonallergic diseases. Studies on children and adults are required in order to appreciate the prevalence, phenotype, severity and co-morbidities of NAR. These studies should compare allergic and NAR and consider different age group populations including elderly subjects. Mechanistic studies should be carried out to better understand the disease(s) and risk factors and to guide towards an improved diagnosis and therapy. These studies need to take the heterogeneity of NAR into account. It is likely that neuronal mechanisms, T cells, innate immunity and possibly auto-immune responses all play a role in NAR and may also contribute to the symptoms of allergic rhinitis.


Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure.
Although expression of numerous ion channels is altered in heart failure (HF), mechanisms by which dysfunction at the ionic and molecular levels lead to ventricular tachyarrhythmias in HF are unknown. Previously, we found that transmural heterogeneities of repolarization play a critical role in the genesis of polymorphic ventricular tachycardia (PVT) when QT interval was prolonged in LQT2. Because QT interval is also prolonged in HF, we hypothesized that transmural heterogeneities are a mechanism of PVT in HF. Optical action potentials were measured simultaneously from cells spanning the entire transmural wall of arterially perfused canine wedge preparations. Wedges were isolated from dogs without (control, n=5) and with HF (n=8) produced by rapid ventricular pacing. In HF, action potential duration (APD) prolongation was markedly heterogeneous across the transmural wall, and was characterized by disproportionate APD prolongation of midmyocardial (M) cells. APD prolongation of M cells accounted for QT-interval prolongation, and caused significant increases (P<0.01) in spatial gradients of repolarization across the ventricular wall from 4.3+/-2.1 (control) to 12.4+/-3.5 ms/mm (HF). Enhanced gradients were directly responsible for development of functional conduction block, leading to PVT in 63% of HF wedges but in no controls (P<0.03). Moreover, intramural decremental conduction and block of the premature impulse, preceded each episode of PVT, and always occurred at the border between M-cell and subepicardial zones, where repolarization gradients were highest. Selective prolongation of APD within M cells underlies several key features of the HF phenotype, including QT-interval prolongation, transmural heterogeneity of repolarization, and susceptibility to conduction block and reentrant PVT.


Endangered species: volunteers.
Volunteerism in America is changing. To continue to be an effective force in EMS, volunteers need to embrace rather than resist enhanced levels of care and other advances in providing service. Special care must be taken by medical directors to recognize the strengths and limitations of volunteer squads. In many suburban and rural areas, volunteers are strategically located to work with the EMS system and the medical director to bridge geographic or organizational service gaps.


Localized Amyloidosis of the Upper Aerodigestive Tract: Complex Analysis of the Cellular Infiltrate and the Amyloid Mass.
The aim of this study was to analyse the composition of amyloid mass and the plasmacytic infiltrate of localized amyloidosis of the upper aerodigestive tract. Biopsy materials were studied by light microscopy, immunohistochemistry (IHC), and mRNA in situ hybridization (mRNA-ISH). The amyloid mass was also analysed with high-performance liquid chromatography mass spectrometry- (HPLC-MS-) based proteomics. Nodular and diffuse forms of amyloid deposition were detected. IHC analysis revealed λ-light chain (LC) in two cases, κ-LC in one case. The remaining two were positive with both. Proteins, well known from other amyloidoses like amyloid A (AA), prealbumin/transthyretin (PA), apolipoprotein A-I (ApoAI), and amyloid P component (APC), and also keratin were found with variable intensities in the cases. HPLC-MS revealed dozens of proteins with both LCs in all the lesions but sometimes with surprisingly small intensities. mRNA-ISH analysis revealed identical λ and κ dominance and only one normal κ/λ cell ratio. Cellular infiltrate and protein components in the amyloid showed congruent results in all but one case. The only exception with normal cell ratio and λ-dominant amyloid could be originated from the different protein-secreting activity of plasma cell clones. HPLC-MS analysis explored both LCs in all the amyloid in variable amount, but other proteins with much higher intensities like keratins, apolipoprotein A-IV (ApoAIV), were also detected. Proteins like AA, PA, ApoAI, and APC, previously known about amyloid-forming capability, also appeared. This indicates that localized amyloid in the upper aerodigestive tract is not a homogenous immunoglobulin mass but a mixture of proteins. The sometimes very low light chain intensities might also suggest that not all the localized amyloidosis cases of the upper aerodigestive tract are of convincingly AL type, and the analysis of the cellular infiltrate might indicate that not all are monoclonal.


Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank.
To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent. Cohort study. 22 centres across England, Scotland, and Wales in UK Biobank (2006-10). 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification. Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women. Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest. In a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.


Roles of dietary corn oil in the regulation of cytochromes P450 and glutathione S-transferases in rat liver.
To study the molecular mechanisms by which dietary lipids affect the levels of cytochrome P450 (P450) isozymes, male Sprague-Dawley rats were fed either fat-free (FF) or 20% corn oil (CO) diet in combination with one of the following three treatments: no inducer, phenobarbital (PB) and acetone. Dietary CO did not affect the constitutive level of P450IIB (PB-inducible), but it affected the induction of P450IIB by PB treatment. The induction of P450IIB by PB in the CO group as determined by 7-pentoxy-resorufin O-dealkylase activity and immunochemically detected protein level was twofold higher than that in the FF group, and this difference was also reflected in the level of mRNA for this enzyme. In contrast, dietary CO increased the constitutive level of P450IIE (ethanol-inducible) twofold as indicated by N-nitrosodimethylamine demethylase activity and immunochemically detectable protein, but it had no effect on the induction of P450IIE by acetone. The induced level of P450IIE by acetone in the CO group did not differ from that in the FF group as measured by the enzyme activity and protein level. It was demonstrated that dietary CO affects P450IIB and IIE activities by altering the concentration of the isozymes rather than by modulating their catalytic activities. In addition, dietary CO increased the microsomal testosterone 6 beta-hydroxylase activity but not 7 alpha- and 2 alpha-hydroxylase activities, suggesting an increase in P450IIIA and/or IIC13 but not in IIA1 and IIC11, respectively. Dietary CO also affected the constitutive and induced levels of glutathione S-transferase (GST) isozymes in a different manner: it increased the constitutive level of GST-B but not that of GST-A. Nevertheless, it was important for the induction of both GST-A and GST-B by PB treatment. The results suggest that lipid nutrition affects xenobiotic metabolism activities by altering constitutive and inducible levels of certain P450 and GST isozymes.


Mirabegron, dependent on β3-adrenergic receptor, alleviates mercuric chloride-induced kidney injury by reversing the impact on the inflammatory network, M1/M2 macrophages, and claudin-2.
The β3-adrenergic receptor (β3-AR) agonism mirabegron is used to treat overactive urinary bladder syndrome; however, its role against acute kidney injury (AKI) is not unveiled, hence, we aim to repurpose mirabegron in the treatment of mercuric chloride (HgCl2)-induced AKI. Rats were allocated into normal, normal + mirabegron, HgCl2 untreated, HgCl2 + mirabegron, and HgCl2 + the β3-AR blocker SR59230A + mirabegron. The latter increased the mRNA of β3-AR and miR-127 besides downregulating NF-κB p65 protein expression and the contents of its downstream targets iNOS, IL-4, -13, and -17 but increased that of IL-10 to attest its anti-inflammatory capacity. Besides, mirabegron downregulated the protein expression of STAT-6, PI3K, and ERK1/2, the downstream targets of the above cytokines. Additionally, it enhanced the transcription factor PPAR-α but turned off the harmful hub HNF-4α/HNF-1α and the lipid peroxide marker MDA. Mirabegron also downregulated the CD-163 protein expression, which besides the inhibited correlated cytokines of M1 (NF-κB p65, iNOS, IL-17) and M2 (IL-4, IL-13, CD163, STAT6, ERK1/2), inactivated the macrophage phenotypes. The crosstalk between these parameters was echoed in the maintenance of claudin-2, kidney function-related early (cystatin-C, KIM-1, NGAL), and late (creatinine, BUN) injury markers, besides recovering the microscopic structures. Nonetheless, the pre-administration of SR59230A has nullified the beneficial effects of mirabegron on the aforementioned parameters. Here we verified that mirabegron can berepurposedto treat HgCl2-induced AKI by activating the β3-AR. Mirabegron signified its effect by inhibiting inflammation, oxidative stress, and the activated M1/M2 macrophages, events that preserved the proximal tubular tight junction claudin-2 via the intersection of several trajectories.


Rule-based design of synthetic transcription factors in eukaryotes.
To design and build living systems, synthetic biologists have at their disposal an increasingly large library of naturally derived and synthetic parts. These parts must be combined together in particular orders, orientations, and spacings to achieve desired functionalities. These structural constraints can be viewed as grammatical rules describing how to assemble parts together into larger functional units. Here, we develop a grammar for the design of synthetic transcription factors (sTFs) in eukaryotic cells and implement it within GenoCAD, a Computer-Aided Design (CAD) software for synthetic biology. Knowledge derived from experimental evidence was captured in this grammar to guide the user to create designer transcription factors that should operate as intended. The grammar can be easily updated and refined as our experience with using sTFs in different contexts increases. In combination with grammars that define other synthetic systems, we anticipate that this work will enable the more reliable, efficient, and automated design of synthetic cells with rich functionalities.


Plasma membrane coating with cationic silica particles and osmotic shock alters the morphology of bovine aortic endothelial cells.
We have used a published method of membrane preparation based on the precoating of the apical membrane of aortic endothelial cells with cationic silica microbeads (with or without polyacrylic acid) in combination with an osmotic shock and mechanical shearing to isolate the apical from the basal plasma membranes of these cells, in vitro. After labeling of the plasma membrane of adherent endothelial cells with a fluorescent derivative of phosphatidylcholine and by using laser confocal fluorescence scanning microscopy, we found that this method of membrane isolation rapidly induced invaginations of the basal plasma membrane to an extent which makes this method unsuitable for further membrane lipid analysis. Morphological analysis of the cells and fluorescence recovery after photobleaching experiments on the plasma membranes were performed at each step of the purification procedure and showed that only hypotonic shock and mechanical shearing of the cells enabled the basal plasma membranes to be purified without significant morphological changes.


One to one interventions to reduce sexually transmitted infections and under the age of 18 conceptions: a systematic review of the economic evaluations.
To systematically review and critically appraise the economic evaluations of one to one interventions to reduce sexually transmitted infections (STIs) and teenage conceptions. Systematic review. Search of four electronic bibliographic databases from 1990 to January 2006. Search keywords included teenage, pregnancy, adolescent, unplanned, unwanted, cost benefit, cost utility, economic evaluation, cost effectiveness and all terms for STIs, including specific diseases. We included studies that evaluated a broad range of one to one interventions to reduce STIs. Outcomes included major outcomes averted, life years and quality adjusted life years (QALY). All studies were assessed against quality criteria. Of 3,190 identified papers, 55 were included. The majority of studies found one to one interventions to be either cost saving or cost effective, although one highlighted the need to target the population to receive post-exposure prophylaxis to reduce transmission of HIV. Most studies used a static approach that ignores the potential re-infection of treated patients. One to one interventions have been shown to be cost saving or cost effective but there are some limitations in applying this evidence to the UK policy context. More UK research using dynamic modelling approaches and QALYs would provide improved evidence, enabling more robust policy recommendations to be made about which one to one interventions are cost effective in reducing STIs in the UK setting. The results of this review can be used by policy makers, health economists and researchers considering further research in this area.


Evaluation of atazanavir Ctrough, atazanavir genotypic inhibitory quotient, and baseline HIV genotype as predictors of a 24-week virological response in highly drug-experienced, HIV-infected patients treated with unboosted atazanavir.
The objective of this study was to evaluate virological and pharmacological determinants of a 24-week virological response to unboosted atazanavir (ATV) in highly drug-experienced HIV-infected patients. Among patients enrolled in the ATV Expanded Access Program, those with HIV-RNA >1000 copies/mL, a genotype performed within three months from the baseline (BL), and who completed 24 weeks of treatment, were included. They received at least three antiretrovirals, including ATV 400 mg once daily without boosting. ATV plasma levels were evaluated after four weeks of treatment by high performance liquid chromatography (HPLC). ATV genotypic inhibitory quotient (GIQ) was calculated as the ratio between ATV Ctrough and the number of the BL ATV-related protease resistance mutations (among the following: 10I/V/F, 20R/M/I, 24I, 331/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M). Thirty-five subjects were included. At baseline, median (interquartile range) CD4+ T-lymphocytes, HIV-RNA, and ATV resistance mutations were 232.5 (106-303)/microL, 4.7 (4.2-5.1) log10 copies/mL, 2 (1-6), respectively. Thirteen (37.1%) subjects were off-therapy and 11 (31.4%) showed no PI mutation at baseline. Median steady-state ATV Ctrough was 230 ng/mL (87-520), for an ATV GIQ of 86.5 (25.5-165.5). Median HIV-RNA changes from baseline at weeks 4, 12 and 24 were -1.76 (from -0.44 to -2.12), -1.41 (from -0.41 to -2.81) and -1.44 (from -0.42 to -2.71) log10, respectively. The HIV-RNA changes were correlated to the number of ATV resistance mutations at each time point (P < 0.05), whereas no correlation was found between ATV Ctrough or ATV GIQ and HIV-RNA changes. In conclusion, the number of ATV resistance mutations is the only correlate to virological response through 24 weeks of treatment with unboosted atazanavir 400 mg once daily.


Effect of Retinitis Pigmentosa Blindness on Functional Brain Network Measures.
Our brain undergoes significant alteration in response to blindness. Understanding these neuroplastic changes and finding reliable methods for quantification of such reorganization is consequential for devising optimum sight restoration therapies and clinical rehabilitation. In recent years, graph theory measures have been applied to brain connectivity, but few studies have examined blindness-induced cortical alterations using these methods. In this study, we investigated alterations in key global and local measures of functional plasticity in the brain network after visual deprivation. Four resting-state functional MRI runs from 10 sighted and 10 blind subjects, with severe retinitis pigmentosa, provided data for our analysis. The whole-brain ROI-ROI resting-state functional connectivity (rsFC) matrices were created for all subjects. Using the resulting rsFC matrices, the global density and efficiency were extracted for the whole brain and the visual system. Additionally, weighted degree, as a local metric, was investigated for all the nodes in the functional brain network. Our results revealed a statistically significant decrease in global density and efficiency of the visual system and weighted degree for lower visual areas, following visual deprivation in the blind group. The explored network measures can serve as tools to gauge functional neuroplasticity following blindness, as a complement to the behavioral indices. Future investigation with a larger number of test subjects for this rare condition can enable correlation analysis with patients' characteristics and further verify the application of these metrics as biomarkers of brain reorganization following vision loss.


Rapid Corneal Nerve Fiber Loss: A Marker of Diabetic Neuropathy Onset and Progression.
Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables. We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes. Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA1c or its change over follow-up. An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP.


First observations of a potential association between accumulation of per- and polyfluoroalkyl substances in the central nervous system and markers of Alzheimer's disease.
The entire human population is exposed to persistent organic pollutants throughout their lives. Among them, Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in industrial and consumer products that are known to exert adverse effects on human health. As they bioaccumulate in human brain and are known to be neurotoxic in experimental models, they are assumed to be involved in neurodegenerative processes. In this proof-of-concept study, we measured the level of 18 PFAS in cerebrospinal fluid (CSF) from eight patients hospitalized with suspected normal pressure hydrocephalus. We then analyzed whether PFAS levels could be related to both biological and clinical markers of Alzheimer's disease. We showed that PFAS and perfluorooctanesulfonate (PFOS) were found in all CSF samples from a French region without fluorochemical industries. Moreover, we observed a significant difference between the levels of PFAS and PFOS in the CSF of patients with both Alzheimer's disease markers and cognitive impairment compared to those with only one or neither. Two previous studies have shown that PFAS levels in Human CSF increase with age and are linked to impaired blood-brain barrier integrity. Our results provide a first evidence of a link between PFAS accumulation in the central nervous system and clinical and biological markers of Alzheimer's disease.


A very rare cause of protein losing enteropathy: Gaucher disease.
Mesenteric lymphadenopathy is a rare manifestation of Gaucher disease (GD) in children and can be accompanied by protein losing enteropathy (PLE). PLE is a difficult-to-treat complication of GD. To date, only a few pediatric GD cases with PLE and massive mesenteric lymphadenopathies have been reported. Here, we report a girl with chronic neuronopathic GD, whose disease course was complicated by massive mesenteric lymphadenopathies with resultant protein losing enteropathy despite a regular and appropriate enzyme replacement therapy of 60 IU/kg/biweekly until the development of mesenteric lymphadenopathies and 120 IU/kg/biweekly thereafter. PLE is a devastating and life threatening complication of GD developing despite long term use of high dose ERT. Clinicians should be alert for this complication particularly in GD patients presenting with progressive abdominal distension, edema, ascites and diarrhea or in patients who have already developed mesenteric lymphadenopathies. Timely diagnosis may allow early intervention with previously suggested surgical or medical treatment options. Although there is no specific and effective treatment, surgical and aggressive medical interventions in addition to ERT were reported to relieve diarrhea and halt progression of mesenteric lymphadenopathies.


[Clinical evaluation of Chymodiactin and post-marketing surveillance].
After a short summary of the development of chemonucleolysis technique and of Chymodiactin, the result of a randomized double-blind placebo controlled trial, conducted in the USA with Chymodiactin in 108 patients with monosegmental lumbar disc hernia and an open multicentre-study in 1498 patients, are shown. Furthermore an interim evaluation is presented of an open controlled multicentre-study with Chymodiactin, started in Germany in 1983. The results of these three clinical studies as well as the post-marketing surveillance pending in the USA demonstrate that chemonucleolysis with Chymodiactin is a secure technique with good results, representing a valuable enrichment in the treatment of lumbar herniated nucleus pulposus.


Fungal microbiota from rain water and pathogenicity of Fusarium species isolated from atmospheric dust and rainfall dust.
In order to determine the presence of Fusarium spp. in atmospheric dust and rainfall dust, samples were collected during September 2007, and July, August, and October 2008. The results reveal the prevalence of airborne Fusarium species coming from the atmosphere of the South East coast of Spain. Five different Fusarium species were isolated from the settling dust: Fusarium oxysporum, F. solani, F. equiseti, F. dimerum, and F. proliferatum. Moreover, rainwater samples were obtained during significant rainfall events in January and February 2009. Using the dilution-plate method, 12 fungal genera were identified from these rainwater samples. Specific analyses of the rainwater revealed the presence of three species of Fusarium: F. oxysporum, F. proliferatum and F. equiseti. A total of 57 isolates of Fusarium spp. obtained from both rainwater and atmospheric rainfall dust sampling were inoculated onto melon (Cucumis melo L.) cv. Piñonet and tomato (Lycopersicon esculentum Mill.) cv. San Pedro. These species were chosen because they are the main herbaceous crops in Almeria province. The results presented in this work indicate strongly that spores or propagules of Fusarium are able to cross the continental barrier carried by winds from the Sahara (Africa) to crop or coastal lands in Europe. Results show differences in the pathogenicity of the isolates tested. Both hosts showed root rot when inoculated with different species of Fusarium, although fresh weight measurements did not bring any information about the pathogenicity. The findings presented above are strong indications that long-distance transmission of Fusarium propagules may occur. Diseases caused by species of Fusarium are common in these areas. They were in the past, and are still today, a problem for greenhouses crops in Almería, and many species have been listed as pathogens on agricultural crops in this region. Saharan air masses dominate the Mediterranean regions. The evidence of long distance dispersal of Fusarium spp. by atmospheric dust and rainwater together with their proved pathogenicity must be taken into account in epidemiological studies.


Correlation between the Oswestry Disability Index and the 4-item short forms for physical function and pain interference from PROMIS.
The Oswestry Disability Index (ODI) is one of the most commonly used patient-reported outcome instruments, but completion of this 10-question survey can be cumbersome. Tools from the Patient-Reported Outcomes Measurement Information System (PROMIS) are an alternative, and potentially more efficient, means of assessing physical, mental, and social outcomes in spine surgery. Authors of this retrospective study assessed whether scores on the 4-item surveys of function and pain from the PROMIS initiative correlate with those on the ODI in lumbar spine surgery. Patients evaluated in the adult neurosurgery spine clinic at a single institution completed the ODI, PROMIS Short Form v2.0 Physical Function 4a (PROMIS PF), and PROMIS Short Form v1.0 Pain Interference 4a (PROMIS PI) at various time points in their care. Score data were retrospectively analyzed using linear regressions with calculation of the Pearson correlation coefficient. Three hundred forty-three sets of surveys (ODI, PROMIS PF, and PROMIS PI) were obtained from patients across initial visits (n = 147), 3-month follow-ups (n = 107), 12-month follow-ups (n = 52), and 24-month follow-ups (n = 37). ODI scores strongly correlated with PROMIS PF t-scores at baseline (r = -0.72, p < 0.0001), 3 months (r = -0.79, p < 0.0001), 12 months (r = -0.85, p < 0.0001), and 24 months (r = -0.89, p < 0.0001). ODI scores also correlated strongly with PROMIS PI t-scores at baseline (r = 0.71, p < 0.0001), at 3 months (r = 0.82, p < 0.0001), at 12 months (r = 0.86, p < 0.0001), and at 24 months (r = 0.88, p < 0.0001). Changes in ODI scores moderately correlated with changes in PROMIS PF t-scores (r = -0.68, p = 0.0003) and changes in PROMIS PI t-scores (r = 0.57, p = 0.0047) at 3 months postoperatively. A strong correlation was found between the ODI and the 4-item PROMIS PF/PI at isolated time points for patients undergoing lumbar spine surgery. Large cohort studies are needed to determine longitudinal accuracy and precision and to assess possible benefits of time savings and improved rates of survey completion.


Electrocution as an alternative euthanasia method to blunt force trauma to the head followed by exsanguination for non-viable piglets.
On farms, the currently approved and most widely practised method of euthanising non-viable piglets is blunt force trauma to the head followed by exsanguination. However, the use of this method is criticised due to public perceptions and aversion to the methodology by caretakers. Therefore, electrocution after electrical stunning was examined as an alternative approach in 80 hybrid piglets. Initially, electrocution was simulated with finite element analysis using a computer piglet-model, where current density in the heart was visualised and size and position of the electrodes were defined. The following step investigated electrical parameters for electrocution in anaesthetised piglets; first, with a constant voltage power source and then with a constant current power source. The electrical stunning was examined using the constant current supply. Finally, the results of electrical stunning and electrocution were verified in 25 healthy piglets with a body weight between 1 and 2 kg. Unconsciousness was proven by testing palpebral, corneal and nociceptive reflexes. Time of death was confirmed by electroencephalography (EEG) and electrocardiography (ECG) records. Stunning succeeded with the preset of 1.3 A and 50 Hz, placing the electrodes on both sides of the head between the eyes and ears using different timespans between 8 and 20 s. Prolonged electrical flow resulted in reduced paddling movements after the epileptic seizure, and allowed undisturbed reflex tests and installation of electrodes for EEG and ECG recording during electrocution. Using 0.75 A and 400 Hz, pin-shaped electrodes were first positioned on both sides of the chest for 5 s, followed by a break of 20-30 s and a second current flow, whereby the electrodes were placed above the withers and the sternum for 5 s. Cardiac arrest and an isoelectric EEG were induced within 3 min after the onset of the electrical flow through the chest. The most obvious indicator of effective stunning and electrocution was termination of rhythmic breathing. Piglets with cardiac arrest showed only single gasps lasting up to 3 min after electrocution. The evaluated stunning and electrocution protocol might ease concerns about timely piglet euthanasia. However, this should be verified in non-viable piglets to exclude influencing factors like dehydration and diseases.


Effect of monoclonal antibodies to enteroglucagon on ileal adaptation after proximal small bowel resection.
On the basis of circumstantial clinical and experimental evidence, it has been suggested that enteroglucagon (EG) may act as an enterotrophic factor. This study was undertaken to evaluate the effects of long term in vivo immunoneutralisation of EG, using monoclonal antibodies to EG, on the hyperplastic ileal response after small bowel resection. Nineteen rats had a 70% proximal resection. A group of 10 rats was given iv 0.5 ml of undiluted hybridoma ascites immediately after the operation and on the 7th day postoperatively. Furthermore 0.025 ml/day of the same hybridoma ascitic fluid was continuously delivered ip for 14 days via mini-osmotic pumps. The hybridoma ascites was prepared from the clone 23.6B4 synthesising a monoclonal antibody directed toward the N-terminal to central region of the glucagon molecule which showed a marked crossreaction with EG. A control group of 9 rats was given a corresponding amount of antibody-free plasmacytoma ascites (Ag 8.653) by the same technique. Seven and 14 days postoperatively there was a plasma anti-EG-antibody excess with an excess binding capacity of 84.9 glucagon eq nM and 88.5 glucagon eq nM respectively. The three dimensional architecture and the proliferative activity of the ileal remnant were evaluated two weeks postoperatively. Despite a continuous immunoneutralisation of circulating endogenous EG by monoclonal antibodies, the adaptive response of the ileal remnants was of the same magnitude as that seen in the control group. These data do not support the hypothesis that EG is a circulating enterotrophic regulatory peptide.


Melting of a nonequilibrium vortex crystal in a fluid film with polymers: Elastic versus fluid turbulence.
We perform a direct numerical simulation of the forced, incompressible two-dimensional Navier-Stokes equation coupled with the FENE-P equations for the polymer-conformation tensor. The forcing is such that, without polymers and at low Reynolds numbers Re, the film attains a steady state that is a square lattice of vortices and antivortices. We find that, as we increase the Weissenberg number Wi, a sequence of nonequilibrium phase transitions transforms this lattice, first to spatially distorted, but temporally steady, crystals and then to a sequence of crystals that oscillate in time, periodically, at low Wi, and quasiperiodically, for slightly larger Wi. Finally, the system becomes disordered and displays spatiotemporal chaos and elastic turbulence. We then obtain the nonequilibrium phase diagram for this system, in the Wi-Ω plane, where Ω∝Re, and show that (a) the boundary between the crystalline and turbulent phases has a complicated, fractal-type character and (b) the Okubo-Weiss parameter Λ provides us with a natural measure for characterizing the phases and transitions in this diagram.


User Experiences of the McMaster Optimal Aging Portal's Evidence Summaries and Blog Posts: Usability Study.
Evidence summaries and blogs can support evidence-informed healthy aging, by presenting high-quality health research evidence in plain language for a nonprofessional (citizen) audience. Our objective was to explore citizens' perceptions about the usability of evidence summaries and blog posts on the Web-based McMaster Optimal Aging Portal. Twenty-two citizens (aged 50 years and older) and informal caregivers participated in a qualitative study using a think-aloud method and semistructured interviews. Eleven interviews were conducted in person, 7 over the telephone, and 4 by Skype. We identified themes that fell under 4 user-experience categories: (1) desirability: personal relevance, (2) understandability: language comprehension, grasping the message, dealing with uncertainty, (3) usability: volume of information, use of numbers, and (4) usefulness: intention to use, facility for sharing. Participants recognized that high-quality evidence on aging was valuable. Their intended use of the information was influenced by how much it applied to their own health circumstances or those of a loved one. Some specific formatting features that were preferred included consistent layout, content organized by subheadings, catchy titles, numerical information summarized in a table, and inclusion of a glossary.


An overview on extremity dosimetry in medical applications.
Some activities of EURADOS Working Group 9 (WG9) are presently funded by the European Commission (CONRAD project). The objective of WG9 is to promote and co-ordinate research activities for the assessment of occupational exposures to staff at workplaces in interventional radiology (IR) and nuclear medicine. For some of these applications, the skin of the fingers is the limiting organ for individual monitoring of external radiation. Therefore, sub-group 1 of WG9 deals with the use of extremity dosemeters in medical radiation fields. The wide variety of radiation field characteristics present in a medical environment together with the difficulties in measuring a local dose that is representative for the maximum skin dose, usually with one single detector, makes it difficult to perform accurate extremity dosimetry. Sub-group 1 worked out a thorough literature review on extremity dosimetry issues in diagnostic and therapeutic nuclear medicine and positron emission tomography, interventional radiology and interventional cardiology and brachytherapy. Some studies showed that the annual dose limits could be exceeded if the required protection measures are not taken, especially in nuclear medicine. The continuous progress in new applications and techniques requires an important effort in radiation protection and training.


Discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys.
The present study characterized the discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys. Six monkeys discriminated 0.1 mg/kg of triazolam from vehicle under a fixed-ratio 5 (FR 5) schedule of stimulus-shock termination (SST). Four monkeys subsequently discriminated 0.56 mg/kg of midazolam from vehicle under the same schedule of reinforcement. Benzodiazepine (BDZ) agonists midazolam and diazepam, and the barbiturate pentobarbital, substituted for triazolam, and the non-competitive N-methyl-D-aspartate (NMDA) antagonist ketamine did not. Triazolam, diazepam, lorazepam, flunitrazepam, as well as the barbiturates amobarbital and pentobarbital, substituted for midazolam, and ketamine did not. The BDZ antagonist flumazenil antagonized both the triazolam and midazolam discriminative stimuli. Bretazenil, a low-efficacy BDZ agonist, did not substitute for the midazolam discriminative stimulus in three of the monkeys and shifted the midazolam dose-effect curve to the right; in a fourth monkey, bretazenil substituted for midazolam and shifted the midazolam dose-effect curve to the left. Schild analyses with flumazenil or bretazenil, in combination with midazolam, yielded slopes that deviated significantly from unity. While clearly supporting the notion that BDZ agonists produce stimulus effects by acting at the gamma-aminobutyric acidA (GABA(A)) receptor complex, these data also suggest that the discriminative-stimulus effects of midazolam might be mediated by more than one BDZ receptor subtype.


Analysis of light emission and Schlieren from short gap high voltage streamers representing lightning impulses.
Light emissions and Schlieren structures were simultaneously observed from streamers produced by tens of kilovolts 1.2/50 μs impulses, representing the high voltage component of lightning, applied across a 4 cm air gap between a variety of electrode geometries and a ground plane in an unconfined environment. The results demonstrated that the light emissions and Schlieren structures coincide along the same streamer filaments but on different timescales; the light existing only during the microsecond timeframe impulse whereas the Schlieren continued to develop into the millisecond timeframe, moving towards the centre of the air gap whilst diffusing into the surrounding air within 100 ms. If an electrical breakdown did occur, the Schlieren structures outside the arc remained visible. Streamer formation theory for high voltage impulses is subsequently refined to include the observed Schlieren mechanism.


Basic properties mapping of anodic oxides in the hafnium-niobium-tantalum ternary system.
A thin film combinatorial library deposited by co-sputtering of Hf, Nb and Ta was employed to characterise fundamental properties of the Hf-Nb-Ta system. Compositional mappings of microstructure and crystallography revealed similarities in alloy evolution. Distinct lattice distortion was observed upon addition of hexagonal Hf, leading to amorphisation of alloys containing more than 32 at.% Hf and less than 27 and 41 at.% Nb and Ta, respectively. Volta potential and open circuit potential mappings indicated minimal values for the highest Hf concentration. Localised anodisation of the library by scanning droplet cell microscopy revealed valve metal behaviour. Oxide formation factors above 2 nm V-1 were identified in compositional zones with high amounts of Nb and Ta. Fitting of electrochemical impedance spectroscopy data allowed electrical permittivity and resistivity of mixed oxides to be mapped. Their compositional behaviours were attributed to characteristics of the parent metal alloys and particularities of the pure oxides. Mott-Schottky analysis suggested n-type semiconductor properties for all Hf-Nb-Ta oxides studied. Donor density and flat-band potential were mapped compositionally, and their variations were found to be related mainly to the Nb amount. Synergetic effects were identified in mappings of Hf-Nb-Ta parent metals and their anodic oxides.


Clostridium akagii sp. nov. and Clostridium acidisoli sp. nov.: acid-tolerant, N2-fixing clostridia isolated from acidic forest soil and litter.
Two anaerobic acid-tolerant bacteria, CK58T and CK74T, were isolated from acidic beech litter and acidic peat-bog soil, respectively. Both bacteria were spore-forming, motile rods with peritrichous flagella. The capacity to sporulate decreased with prolonged cultivation. Cells of CK58T formed chains or aggregates and were linked by a connecting filament that consisted of a core and a surrounding sheath. Cellobiose, glucose, xylose, arabinose, maltose, mannose and salicin supported growth of CK58T. These substrates, as well as mannitol, lactose, sucrose, glycerol, melezitose, raffinose and rhamnose, supported growth of CK74T. Sorbitol, trehalose, H2/CO2, CO/CO2, vanillate, Casamino acids, peptone, and various purines and pyrimidines did not support the growth of either organism. Growth of CK58T and CK74T on glucose yielded butyrate, lactate, acetate, formate, H2 and CO2 as end products. Growth of CK58T and CK74T was observed at pH 3.7-7.1 and 3.6-6.9, respectively. CK58T and CK74T grew in nitrogen-free medium at pH 3.7 under an N2 atmosphere and reduced acetylene at rates approximating 1 nmol min-1 (mg protein)-1. CK58T and CK74T did not contain carbon monoxide dehydrogenase or cytochromes, produce methane, or dissimilate nitrate or sulfate. Thus, CK58T and CK74T were characterized as nonacetogenic, N2-fixing, fermentative chemo-organotrophs. The G + C contents of CK58T and CK74T were 31.4 and 30.7 mol%, respectively. CK58T and CK74T were phylogenetically most closely related to Clostridium pasteurianum. The 16S rRNA gene sequence similarity values of CK58T and CK74T to C. pasteurianum and each other did not exceed 96.5%, and it is proposed that strains CK58T and CK74T be named Clostridium akagii CK58T (DSM 12554T) and Clostridium acidisoli CK74T (DSM 12555T), respectively. These results suggest that previously uncharacterized clostridial species reside and might fix N2 in the annoxic microzones of acidic forest soil and litter.


Spinal cord stimulation for spinal cord injury patients with paralysis: To regain walking and dignity.
Spinal cord injury (SCI) usually leads to disconnection between traversing neuronal pathway. The impairment of neural circuitry and its ascending and descending pathway usually leave severe SCI patients with both motor disability and loss of sensory function. In addition to poor quality of life, SCI patients not only have disabling respiratory function, urinary retention, impaired sexual function, autonomic dysregulation but also medical refractory neuropathic pain in the long term. Some translational studies demonstrated that spinal networks possess a dynamic state of synaptic connection and excitability that can be facilitated by epidural spinal cord stimulation. In addition, preliminary human studies also confirmed that spinal cord stimulation enables stepping or standing in individuals with paraplegia as well. In this review, we examined the plausible interventional mechanisms underlying the effects of epidural spinal cord stimulation in animal studies. Following the success of translational research, chronic paralyzed subjects due to SCI, defined as motor complete status, regained their voluntary control and function of overground walking and even stepping for some. These progresses lead us into a new hope to help SCI patients to walk and regain their independent life again.


Dietary soy and isoflavone intake and risk of colorectal cancer in the Japan public health center-based prospective study.
Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women.


Losartan renography for the detection of renal artery stenosis: comparison with captopril renography and evaluation of dose and timing.
Radionuclide renography with angiotensin converting enzyme (ACE) inhibition plays an important role in the diagnosis of haemodynamically significant renal artery stenosis. Angiotensin receptor antagonists inhibit the renin angiotensin system at different levels from ACE inhibitors by selectively blocking the binding of angiotensin II to AT1 receptors. The AT1 angiotensin receptor antagonist losartan has recently been used clinically in the treatment of hypertension. However, the available data on the use of losartan with renography for the detection of renovascular hypertension are limited and contradictory. The purpose of this prospective study was to compare the effectiveness of losartan renography and captopril scintigraphy in revealing renal artery stenosis. A total of 61 renal units in 32 patients with hypertension were studied in two groups based on the losartan dosage (50 mg in group A and 100 mg in group B). Group A consisted of 17 patients, in whom 19 renal units had angiographically proven renal artery stenosis (>or=50%). In group B, there were 15 patients, in whom 20 renal arteries were stenotic. All of the patients underwent three renographies (baseline, captopril renography and early losartan renography). Early losartan renography was performed at 1 h after oral losartan administration in both groups. In group B, seven patients underwent additional losartan renography (late losartan) performed 3 h after oral losartan administration; these patients composed group B1. The sensitivities of captopril and losartan studies were 63.2% and 42% in group A, 65% and 65% in group B and 55.6% and 66.6% in group B1, respectively. From our preliminary results, we conclude that losartan is not superior to captopril renography for the detection of haemodynamically significant renal artery stenosis. However, a high dose (100 mg) of losartan provided higher sensitivity than the lower dose (50 mg). Late losartan scintigraphy provided similar diagnostic efficacy to early losartan renography.


"It's Also Pushed People to a New Level of Desperation:" COVID-19 Impacts on Experiences of Persons Who Use Illicit Opioids.
The purpose of this qualitative study is to characterize the impacts of the COVID-19 pandemic on drug use experiences among persons who use illicit opioids (PWUO) in Arizona. Between 12/2020 and 05/2021, interviews were conducted via Zoom with 22 PWUO from across Arizona. Participants were recruited through Craigslist and social media ads, referrals by a local harm reduction organization, and other participants. The interviews were transcribed and analyzed using NVivo. Participants were 25-51 years of age, 36% were female, and 55% non-Hispanic White. Most reported past month use of heroin, and/or counterfeit (pressed) non-pharmaceutical fentanyl (NPF) pills. Nearly all reported changes in their drug use during the pandemic. Participants discussed profound negative impacts of social isolation with escalating mental health problems, boredom, and ease of hiding drug use from others, leading to increases in drug use. Loss of daily routines, employment difficulties, and challenges of accessing treatment due to COVID-19 restrictions were also driving factors for increased drug use. The growing availability of NPF pills during the pandemic led many individuals to transition from heroin to more frequent NPF pill use. The results emphasize the need for quality behavioral care services with an increased focus on economic and social support systems.


Effects of macrophage-colony-stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor.
Macrophage-colony-stimulating factor (M-CSF) regulates the survival, proliferation and differentiation of the mononuclear phagocyte lineage. Osteopetrotic (op/op) mice defective in producing functional M-CSF were used in order to investigate the role of M-CSF on the development of microglia and brain macrophages and the expression of scavenger receptor (SR). Adult op/op and littermate mice at 10-47 weeks of age were investigated by immunohistochemistry with a panel of monoclonal antibodies (F4/80, Mac-1, anti-major histocompatibility complex (MHC) class II and anti-SR), electron microscopy and reverse transcriptase-polymerase chain reaction (RT-PCR). Microglia were weakly immunolabeled with F4/80 and Mac-1 in op/op and littermate mice, but the number of microglia in op/op mice was reduced in the cerebrum, cerebellum and brainstem compared with that of normal littermates. The numbers of Mac-1-positive microglia in op/op mice was 39% (pons) and 30% (cerebellar cortex) lower than that in normal littermates (P<0.05). In addition, the microglia cell processes in op/op mice were often shorter than those in control mice. In op/op and littermate mice, both MHC class II and SR were present in perivascular cells and macrophages of the leptomeninx and choroid plexus. Ultrastructurally, perivascular cells appeared to be immature, since their cytoplasm was narrow and contained few inclusion bodies compared with those of control mice. Reverse transcriptase-polymerase chain reaction showed a weak expression for SR mRNA in the brains of op/op mice as well as littermate mice. These results indicate that microglia are partly dependent on M-CSF for their proliferation and differentiation and that M-CSF has no significant effect on the expression of SR in the physiological brain. The study also suggests that M-CSF affects the maturation of perivascular cells at the ultrastructural level.


Molecularly imprinted adsorbents for positional isomer separation.
2,4-Dihydroxybenzophenone (2,4-DHB) imprinted polymers were synthesized by surface imprinting technique, using allyl alcohol as the functional monomer. The polymers showed a very high selectivity for 2,4-DHB when compared with various positional isomers such as 2-HB, 2,2'-DHB, 4,4'-DHIB and 4,4'-DMB. Solvents were found to affect the selectivity as well as sorption capacity in the case of surface imprinted polymers. The selectivities decreased drastically when the imprint cavity was blocked. This validated the importance of the cavity and the rebinding interactions in governing the selectivity in the case of MIPs. The surface imprinted polymers also showed a high selectivity under non-equilibrium conditions thereby making them suitable adsorbents for industrial separations.


Pain in young adults--III: Relationships of three pain-coping measures to pain and activity interference.
The study had two purposes: (a) to examine the relationships among coping strategies measured by the Coping Strategies Questionnaire (CSQ) (1), the Vanderbilt Pain Management Inventory (VPMI) (2), and the Ways of Coping Inventory (WOC) (3) and identify the higher-order composite factors representing these relationships; and (b) to determine the degree to which individual coping scale scores and composite coping factor scores could explain variability in the pain intensity and pain-related activity interference reported by young adults. Measures of pain coping were collected from 206 young adults using the CSQ, VPMI, and WOC, along with measures of pain intensity, pain location, and the extent to which pain interfered with daily activities. Results indicated considerable variability in the reported frequency of use of pain-coping strategies and in pain intensity, location, and activity interference. Principal components factor analysis identified three higher-order coping factors (Emotional and Other-Directed Coping, Active Cognitive Coping, and Self-Efficacy for Pain Control) that explained 87% of the variance in individual coping scale scores. The degree to which individual scale scores and composite factor scores explained variability in pain intensity and activity interference variables was determined through a series of multiple regression analyses. The results revealed that individual scale scores, particularly the CSQ scales of catastrophizing and praying or hoping, were best able to explain the variance in measures of pain and activity interference. Taken together, these findings provide further support for the importance of coping variables in explaining the experience of pain and adjustment in young adults.


Acorn: a grid computing system for constraint based modeling and visualization of the genome scale metabolic reaction networks via a web interface.
Constraint-based approaches facilitate the prediction of cellular metabolic capabilities, based, in turn on predictions of the repertoire of enzymes encoded in the genome. Recently, genome annotations have been used to reconstruct genome scale metabolic reaction networks for numerous species, including Homo sapiens, which allow simulations that provide valuable insights into topics, including predictions of gene essentiality of pathogens, interpretation of genetic polymorphism in metabolic disease syndromes and suggestions for novel approaches to microbial metabolic engineering. These constraint-based simulations are being integrated with the functional genomics portals, an activity that requires efficient implementation of the constraint-based simulations in the web-based environment. Here, we present Acorn, an open source (GNU GPL) grid computing system for constraint-based simulations of genome scale metabolic reaction networks within an interactive web environment. The grid-based architecture allows efficient execution of computationally intensive, iterative protocols such as Flux Variability Analysis, which can be readily scaled up as the numbers of models (and users) increase. The web interface uses AJAX, which facilitates efficient model browsing and other search functions, and intuitive implementation of appropriate simulation conditions. Research groups can install Acorn locally and create user accounts. Users can also import models in the familiar SBML format and link reaction formulas to major functional genomics portals of choice. Selected models and simulation results can be shared between different users and made publically available. Users can construct pathway map layouts and import them into the server using a desktop editor integrated within the system. Pathway maps are then used to visualise numerical results within the web environment. To illustrate these features we have deployed Acorn and created a web server allowing constraint based simulations of the genome scale metabolic reaction networks of E. coli, S. cerevisiae and M. tuberculosis. Acorn is a free software package, which can be installed by research groups to create a web based environment for computer simulations of genome scale metabolic reaction networks. It facilitates shared access to models and creation of publicly available constraint based modelling resources.


Long-term nicotine replacement therapy: a randomized clinical trial.
The US Food and Drug Administration adopted labeling for nicotine patches to allow use beyond the standard 8 weeks. This decision was based in part on data showing increased efficacy for 24 weeks of treatment. Few studies have examined whether the use of nicotine patches beyond 24 weeks provides additional therapeutic benefit. To compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence. We recruited 525 treatment-seeking smokers for a randomized clinical trial conducted from June 22, 2009, through April 15, 2014, through 2 universities. Smokers received 12 smoking cessation behavioral counseling sessions and were randomized to 8, 24, or 52 weeks of nicotine patch treatment. The primary outcome was 7-day point prevalence abstinence, confirmed with breath levels of carbon monoxide at 6 and 12 months (intention to treat). At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (χ(2)(1) = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03-2.81]; P = .04), had a longer duration of abstinence until relapse (β = 21.30 [95% CI, 10.30-32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; β = 0.43 [95% CI, 0.06-0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06-2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard and extended treatment arms (20.3% vs 23.8%; OR, 1.17 [95% CI, 0.69-1.98]; P = .57). Similarly, we found no difference in week 52 abstinence rates between participants in the extended and standard treatment arms (26.0% vs 21.7%; OR, 1.33 [95% CI, 0.72-2.45]; P = .36). Treatment duration was not associated with any adverse effects or adherence to the counseling regimen, but participants in the maintenance treatment arm reported lower adherence to the nicotine patch regimen compared with those in the standard and extended treatment arms (mean [SD], 3.94 [2.5], 4.61 [2.0], and 4.7 [2.4] patches/wk, respectively; F2,522 = 6.03; P = .003). The findings support the safety of long-term use of nicotine patch treatment, although they do not support efficacy beyond 24 weeks of treatment in a broad group of smokers. clinicaltrials.gov Identifier: NCT01047527.


Metastatic spinal lesions: state-of-the-art treatment options and future trends.
The purpose of this article is to review the current state of the art for treating symptomatic spinal fractures associated with malignant lesions and to present potential future trends in treatments for this patient population. Epidemiology, clinical presentation, and biomechanical ramifications of these lesions are summarized and treatment regimes, clinical outcomes, and complications and technical issues associated with treatments are presented. Potential future trends and new technologies for performing vertebral body augmentation in patients with metastatic spinal lesions are also discussed.


Health-related quality of life in patients undergoing peritoneal dialysis: effects of a nurse-led case management programme.
This paper is a report of an examination of the effectiveness of a nurse-led case management programme in improving the quality of life of peritoneal dialysis patients in Hong Kong. Patients with end-stage renal failure need integrated health care to maintain a desirable quality of life. Studies suggest that transitional care using a nurse case management model has a positive effect for patients suffering from chronic diseases, but the results have not been conclusive. Eighty-five patients participated in the study in 2005, 43 in the study group and 42 in the control group. Patients in the control group received routine hospital discharge services. Study group patients received a comprehensive education programme prior to discharge and standardized, 6-week nurse-initiated telephone follow-up. Kidney disease quality of life was measured for each patient at three time intervals: before the intervention, at completion of the 6-week intervention and 6 weeks after completion of the programme. Repeated measures analysis of variance, general linear model was carried out. Statistically significant within-group effects were found for symptoms/problems, effects of kidney disease, sleep, role-physical, pain, emotional wellbeing and social function. Statistically significant interaction effects were demonstrated for staff encouragement, patient satisfaction, sleep and social function. The nurse-led case management programme can be applied effectively to patients receiving peritoneal dialysis. The new model of care is particularly useful for enhancing patients' wellbeing in the transition from hospital to home.


Frequency and Detection of Stanford Type A Aortic Dissection in Hyperacute Stroke Management.
Acute Stanford type A aortic dissection (AAD) is a devastating aortic disease, and prompt diagnosis is sometimes difficult to make. Identification of AAD in suspected acute stroke patients is especially challenging. Nevertheless, the frequencies and predictive factors of AAD in suspected acute stroke patients have not been well investigated. The aim of this study was to elucidate the prevalence of and predictors for AAD in patients with suspected acute stroke. From January 2012 through January 2013, consecutive patients who visited our emergency department (ED) due to suspected acute (<24 h from onset) stroke were retrospectively enrolled. Clinical parameters including systolic blood pressure (SBP) and laboratory data were collected. Frequency of AAD in suspected acute stroke patients and acute ischemic stroke (AIS) subjects were assessed, and factors associated with AAD among AIS patients were investigated. A total of 1,637 patients were included in this study. Five patients (0.31%, 95% CI 0.04-0.57) were diagnosed as having AAD. The prevalence of AAD in all AIS individuals during the study period was 1.09% (95% CI 0.14-2.05), and AAD accounted for 1.70% (95% CI 0.05-3.36) of AIS patients who appeared at the hospital within 4 h from onset. Most AAD patients presented with disturbed consciousness, and none of the AAD patients complained of chest pain. Neck ultrasonography detected an intimal flap in AAD patients. Two AAD cases died soon after ED arrival. The remaining 3 were promptly diagnosed as having AAD in the ED and underwent emergency surgery; all were discharged with only mild neurological symptoms. Low SBP in the right arm (cut-off value ≤110 mm Hg, sensitivity 100%, specificity 94.4%) and high D-dimer level (cut-off value ≥5.0 μg/ml, sensitivity 100%, specificity 91.7%) had high predictive values for detecting AAD in patients with AIS presenting within 4 h from onset. AAD was seen in 0.31% of suspected acute stroke patients and 1.70% of AIS patients presenting within 4 h from onset. AAD patients who were initially suspected as having acute stroke had severe neurological symptoms, including disturbance of consciousness, did not complain of typical chest pain, and when emergency surgery was performed, favorable neurological and survival outcomes were achieved. Low SBP in the right arm and high D-dimer level could predict AAD.


The conception of the ABCD study: From substance use to a broad NIH collaboration.
Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.


Identification and verification of microRNAs by high-throughput sequencing.
High-throughput sequencing methods have become invaluable for detection and analysis of small RNAs. The results are millions of sequences that need to be carefully analyzed by computational methods and preferentially verified by different experimental techniques. Here we describe how to use high-throughput sequencing followed by bioinformatics and northern blot to identify one particular class of small RNA, microRNAs.


Biologically enhanced hydrogen sulfide absorption from sour gas under haloalkaline conditions.
We studied a biotechnological desulfurization process for removal of toxic hydrogen sulfide (H2S) from sour gas. The process consists of two steps: i) Selective absorption of H2S into a (bi)carbonate solution in the absorber column and ii) conversion of sulfide to sulfur by sulfide oxidizing bacteria (SOB) in the aerated bioreactor. In previous studies, several physico-chemical factors were assessed to explain the observed enhancement of H2S absorption in the absorber, but a full explanation was not provided. We investigated the relation between the metabolic activity of SOB and the enhancement factor. Two continuous experiments on pilot-scale were performed to determine H2S absorption efficiencies at different temperatures and biomass concentrations. The absorption efficiency improved at increasing temperatures, i.e. H2S concentration in the treated gas decreased from 715 ± 265 ppmv at 25.4 °C to 69 ± 25 ppmv at 39.4 °C. The opposite trend is expected when H2S absorption is solely determined by physico-chemical factors. Furthermore, increasing biomass concentrations to the absorber also resulted in decreased H2S concentrations in the treated gas, from approximately 6000 ppmv without biomass to 1664 ± 126 ppmv at 44 mg N/L. From our studies it can be concluded that SOB activity enhances H2S absorption and leads to increased H2S removal efficiencies in biotechnological gas desulfurization.


Complications of fluoroscopically directed facet joint nerve blocks: a prospective evaluation of 7,500 episodes with 43,000 nerve blocks.
Chronic spinal pain is common along with numerous modalities of diagnostic and therapeutic interventions utilized, creating a health care crisis. Facet joint injections and epidural injections are the 2 most commonly utilized interventions in managing chronic spinal pain. While the literature addressing the effectiveness of facet joint nerve blocks is variable and emerging, there is paucity of literature on adverse effects of facet joint nerve blocks. A prospective, non-randomized study of patients undergoing interventional techniques from May 2008 to December 2009. A private interventional pain management practice, a specialty referral center in the United States. Investigation of the incidence in characteristics of adverse effects and complications of facet joint nerve blocks. The study was carried out over a period of 20 months including almost 7,500 episodes of 43,000 facet joint nerve blocks with 3,370 episodes in the cervical region, 3,162 in the lumbar region, and 950 in the thoracic region. All facet joint nerve blocks were performed under fluoroscopic guidance in an ambulatory surgery center by 3 physicians. The complications encountered during the procedure and postoperatively were evaluated prospectively. This study was carried out over a period of 20 months and included over 7,500 episodes or 43,000 facet joint nerve blocks. All of the interventions were performed under fluoroscopic guidance in an ambulatory surgery center by one of 3 physicians. The complications encountered during the procedure and postoperatively were prospectively evaluated. Measurable outcomes employed were intravascular entry of the needle, profuse bleeding, local hematoma, dural puncture and headache, nerve root or spinal cord irritation with resultant injury, and infectious complications. There were no major complications. Multiple side effects and complications observed included overall intravascular penetration in 11.4% of episodes with 20% in cervical region, 4% in lumbar region, and 6% in thoracic region; local bleeding in 76.3% of episodes with highest in thoracic region and lowest in cervical region; oozing with 19.6% encounters with highest in cervical region and lowest in lumbar region; with local hematoma seen only in 1.2% of the patients with profuse bleeding, bruising, soreness, nerve root irritation, and all other effects such as vasovagal reactions observed in 1% or less of the episodes. Limitations of this study include lack of contrast injection, use of intermittent fluoroscopy and also an observational nature of the study. This study illustrate that major complications are extremely rare and minor side effects are common.


Characterisation of Microparticle Waste from Dental Resin-Based Composites.
Clinical applications of resin-based composite (RBC) generate environmental pollution in the form of microparticulate waste. SEM, particle size and specific surface area analysis, FT-IR and potentiometric titrations were used to characterise microparticles arising from grinding commercial and control RBCs as a function of time, at time of generation and after 12 months ageing in water. The RBCs were tested in two states: (i) direct-placement materials polymerised to simulate routine clinical use and (ii) pre-polymerised CAD/CAM ingots milled using CAD/CAM technology. The maximum specific surface area of the direct-placement commercial RBC was seen after 360 s of agitation and was 1290 m2/kg compared with 1017 m2/kg for the control material. The median diameter of the direct-placement commercial RBC was 6.39 μm at 360 s agitation and 9.55 μm for the control material. FTIR analysis confirmed that microparticles were sufficiently unique to be identified after 12 months ageing and consistent alteration of the outermost surfaces of particles was observed. Protonation-deprotonation behaviour and the pH of zero proton charge (pHzpc) ≈ 5-6 indicated that the particles are negatively charged at neutral pH7. The large surface area of RBC microparticles allows elution of constituent monomers with potential environmental impacts. Characterisation of this waste is key to understanding potential mitigation strategies.


Prevalence of baseline hypocalcemia and symptomatic hypocalcemia during leukapheresis.
Symptoms of hypocalcemia are reported in up to 50% of patients undergoing leukapheresis procedures. There is no set standard of practice for administering calcium supplementation in the prevention or treatment of hypocalcemia symptoms. The goal of this descriptive, retrospective study was to determine the prevalence of baseline hypocalcemia and symptomatic hypocalcemia during leukapheresis with acid citrate dextrose solution A and to identify patient characteristics associated with symptomatic hypocalcemia. Three percent of patients were found to have hypocalcemia before leukapheresis with 35% experiencing hypocalcemia symptoms during leukapheresis. Older age, higher albumin levels, and longer procedure time were associated with increased risk of hypocalcemia symptoms.


Cyanide production by Pseudomonas fluorescens and Pseudomonas aeruginosa.
Of 200 water isolates screened, five strains of Pseudomonas fluorescens and one strain of Pseudomonas aeruginosa were cyanogenic. Maximum cyanogenesis by two strains of P. fluorescens in a defined growth medium occurred at 25 to 30 degrees C over a pH range of 6.6 to 8.9. Cyanide production per cell was optimum at 300 mM phosphate. A linear relationship was observed between cyanogenesis and the log of iron concentration over a range of 3 to 300 microM. The maximum rate of cyanide production occurred during the transition from exponential to stationary growth phase. Radioactive tracer experiments with [1-14C]glycine and [2-14C]glycine demonstrated that the cyanide carbon originates from the number 2 carbon of glycine for both P. fluorescens and P. aeruginosa. Cyanide production was not observed in raw industrial wastewater or in sterile wastewater inoculated with pure cultures of cyanogenic Pseudomonas strains. Cyanide was produced when wastewater was amended by the addition of components of the defined growth medium.


Postpartum HELLP syndrome after a normotensive pregnancy.
Severe pre-eclampsia, associated with HELLP syndrome, can occur after a normal delivery and birth in a woman whose blood pressure has remained normal throughout the antenatal period. Although rare, the syndrome can lead to pulmonary oedema or renal failure, and should be borne in mind when a woman develops epigastric or right upper-quadrant pain after a normal pregnancy and delivery. A significant fall in the platelet count in the antenatal period may be a useful indicator of risk.


Antigenic and molecular characterization of unusual rotavirus strains in Burkina Faso in 1999.
Thirty-six of 37 rotavirus strains recovered from the diarrheal stools of 166 children <3 years of age in Burkina Faso were characterized at both the antigenic and molecular levels. The rotavirus strains were confirmed by polyacrylamide gel electrophoresis; 30 displayed predominantly short electropherotype patterns, and 6 had a long RNA pattern. The strains were subgrouped by monoclonal antibody enzyme immunoassay for VP6 and were typed as subgroup I (29 of 30 short rotavirus strains) and subgroup II (5 of 6 long strains). The VP7 serotyping and genotyping showed that all 6 viruses with long electropherotype patterns were G1. The short strains were determined to be VP7 serotype G2 by reverse-transcription polymerase chain reaction (PCR) in 27 strains and nucleic acid sequencing of selected strains, although only 1 reacted with the G2-specific monoclonal antibodies. Finally, the short patterns were shown by the PCR genotyping method to be VP4 genotype P[6], and the long patterns were shown to be P[8]. The predominant strain found in Burkina Faso in this small study was an unusual G2P[6] strain that showed a short RNA electropherotype and VP6 subgroup I specificity and failed to react with a panel of G2-specific monoclonal antibodies.


Using delaunay triangularization to characterize non-affine displacement fields during athermal, quasistatic deformation of amorphous solids.
We investigate the non-affine displacement fields that occur in two-dimensional Lennard-Jones models of metallic glasses subjected to athermal, quasistatic simple shear (AQS). During AQS, the shear stress versus strain displays continuous quasi-elastic segments punctuated by rapid drops in shear stress, which correspond to atomic rearrangement events. We capture all information concerning the atomic motion during the quasi-elastic segments and shear stress drops by performing Delaunay triangularizations and tracking the deformation gradient tensor Fα associated with each triangle α. To understand the spatio-temporal evolution of the displacement fields during shear stress drops, we calculate Fα along minimal energy paths from the mechanically stable configuration immediately before to that after the stress drop. We find that quadrupolar displacement fields form and dissipate both during the quasi-elastic segments and shear stress drops. We then perform local perturbations (rotation, dilation, simple and pure shear) to single triangles and measure the resulting displacement fields. We find that local pure shear deformations of single triangles give rise to mostly quadrupolar displacement fields, and thus pure shear strain is the primary type of local strain that is activated by bulk, athermal quasistatic simple shear. Other local perturbations, e.g. rotations, dilations, and simple shear of single triangles, give rise to vortex-like and dipolar displacement fields that are not frequently activated by bulk AQS. These results provide fundamental insights into the non-affine atomic motion that occurs in driven, glassy materials.


Broad Developmental Screening Misses Young Children With Social-Emotional Needs.
Many pediatricians use a broad developmental screening test as part of well-child care, but do not specifically screen for behavioral and emotional disorders. Parents at 2 urban community agencies completed both the Ages and Stages Questionnaire (ASQ-3) and the Ages and Stages Questionnaire: Social Emotional (ASQ:SE) for 608 children, ages 2 to 60 months; 51.8% in Spanish. Less than half of the children with a positive screen on the ASQ:SE would have been identified as needing additional assessment or intervention if only the ASQ-3 had been administered. Younger children with positive ASQ:SE screens were significantly less likely to be referred for mental health services compared with older children. Physicians should consider screening all young children for social-emotional and behavioral needs, and referring those identified for infant and early childhood mental health services.


Distribution of the feline calicivirus receptor junctional adhesion molecule a in feline tissues.
Junctional adhesion molecule A (JAM-A) is an immunoglobulin superfamily protein that plays an important role in the assembly and maintenance of tight junctions and the establishment of epithelial cell polarity. The feline JAM-A (fJAM-A) is a functional receptor for feline calicivirus (FCV). Among natural diseases associated with FCV infection, isolates that cause oral vesicular disease are detected in epithelial cells; however, isolates that cause systemic disease are detected in multiple cell types. The distribution of an FCV receptor or receptors in feline tissues is relevant to viral pathogenesis in that it should reflect the wide latitude of clinical sequelae associated with FCV infection. The authors examined the expression of feline JAM-A in the cat by using confocal immunofluorescence localization on normal tissues, with special regard to tissue targets of naturally occurring FCV. As described in the human and the mouse, fJAM-A was widely distributed in feline tissues, where it localized at cell-cell junctions of epithelial and endothelial cells. fJAM-A was highly expressed on feline platelets, with lower levels of expression on feline peripheral blood leukocytes. Additionally, FCV infection of a feline epithelial cell monolayer causes redistribution of fJAM-A to the cytosol of infected cells. It is reasonable to propose that the spectrum of lesions caused by FCV reflects disruption of intercellular junctions that rely on fJAM-A function and tight junctional integrity.


Dielectric concentrator for Cherenkov radiation.
We report on a dielectric target that concentrates Cherenkov radiation into a small spatial area. In contrast to traditional devices, this target can focus almost all of the radiation without using additional lenses or mirrors. We consider the case where radiation is produced by a point charge moving along the axis of a cylindrical channel inside an axially symmetrical target. The specific form of the target is determined using the laws of ray optics. The field is calculated using an aperture integration method that can determine the field near the focus. Typical field plots and the spatial distribution of the field outside the target are presented. We demonstrate that at terahertz frequencies, this concentrator can increase the field magnitude by up to at least 2 orders of magnitude relative to that on the surface of the target.


Colocalization of fluorescence and Raman microscopic images for the identification of subcellular compartments: a validation study.
A major promise of Raman microscopy is the label-free detailed recognition of cellular and subcellular structures. To this end, identifying colocalization patterns between Raman spectral images and fluorescence microscopic images is a key step to annotate subcellular components in Raman spectroscopic images. While existing approaches to resolve subcellular structures are based on fluorescence labeling, we propose a combination of a colocalization scheme with subsequent training of a supervised classifier that allows label-free resolution of cellular compartments. Our colocalization scheme unveils statistically significant overlapping regions by identifying correlation between the fluorescence color channels and clusters from unsupervised machine learning methods like hierarchical cluster analysis. The colocalization scheme is used as a pre-selection to gather appropriate spectra as training data. These spectra are used in the second part as training data to establish a supervised random forest classifier to automatically identify lipid droplets and nucleus. We validate our approach by examining Raman spectral images overlaid with fluorescence labelings of different cellular compartments, indicating that specific components may indeed be identified label-free in the spectral image. A Matlab implementation of our colocalization software is available at .


Effect of lateral ankle ligament anesthesia on single-leg stance stability.
This study was designed to determine, in isolation, the contribution of lateral ankle ligament mechanoreceptors to postural stability during single leg static (eyes open, eyes closed) and landing tasks. Fourteen healthy subjects (nine males, five females) underwent two different treatment conditions (control, anesthesia) in a counterbalanced order (48-h interval). During the anesthetic treatment, lidocaine was injected into the anterior talofibular and calcaneofibular ligament (1.5 cc each) regions. Postural stability was measured using forceplate and kinematic variables. The average of each variable across multiple trials under each treatment for the three tasks was analyzed statistically. Results of all statistical analyses failed to demonstrate significant alterations (P > 0.05) in postural control attributable to the treatment condition. These results suggest that lateral ankle ligament mechanoreceptors either do not make a significant contribution to single leg stance stability, do not have a unique, irreplaceable role, or have a role that is too subtle to be detected given the measurement techniques used. Thus, the idea that single leg stability becomes altered after ankle joint injury because of proprioceptive disruption was not supported. This would suggest that reported postural control alterations in persons after repetitive ankle injury more likely occur as a result of alterations in mechanical stability, motor components, and/or central motor programming.


The latitude gradient for multiple sclerosis prevalence is established in the early life course.
The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females.


Love grows with sex: teenagers negotiating sex and gender in the context of HIV and the implications for sex education.
How do teenagers located in the KwaZulu-Natal province of South Africa, the epicentre of the HIV pandemic, give meaning to sexuality? This paper examines teenage black Africans investments in sex and sexuality and the gendered dynamics through which sexuality is articulated. Whilst unequal gender relations of power continue to feature prominently within relationship dynamics fuelling the gendering of HIV, attention to the micro-processes through which relationships are forged remain significant in illustrating the complex connections between love, sex and gender. Drawing on empirical findings with teenagers between the ages of 16 and 17 years old, the paper shows how relationships are conceptualised based on discourses of love. Love is inextricably bound up with sex and when teenagers talk about love and sex they also talk about condom use, multiple sexual partners and gender inequalities. What teenagers were interested in for their sexual relationships was not raised in sex education programmes at school. Implications for addressing teenage constructions of sexuality are discussed in the conclusion.