The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray.
Diverse arrays of glutamate-gated channels in the spinal cord and associated pathways are partly responsible for sensory input, for altered sensitivity to peripheral stimuli during inflammation, and for generation of motor patterns. The expression of 16 genes, encoding all known subunits for the NMDA receptor (NR1, NR2A to NR2D), AMPA/low-affinity kainate (GluR-A to -D), high-affinity kainate ionotropic receptors (KA-1, -2, GluR-5 to -7) and two orphan receptor subunits (delta-1 and -2) was examined by in situ hybridization in rat lumbar spinal cord, and in the periaqueductal gray. Subunit mRNAs for GluR-A, -B Flip, KA-2, and NR1 were abundant in the dorsal horn, with NR2D lightly expressed. Occasional cells in lamina II contained NR2C mRNA. While the GluR-A gene was preferentially expressed in laminae I and II-outer, GluR-B mRNA was evenly expressed throughout all superficial laminae (I, II-outer, II-inner, and III). Large neurons in laminae IV and V expressed mainly NR1, GluR-C, and to lesser extents the GluR-B, GluR-D, and NR2D genes. Lamina I contained occasional cells expressing the GluR-5 gene, whereas GluR-7 mRNA was present in scattered cells in all superficial laminae. In motor neurons, GluR-B Flip, -C Flip, -D Flip, and NR1 mRNAs were expressed heavily, and those of NR2D and KA-1 weakly. Possibly connected to the RNA editing mechanism, GluR-B was the only subunit whose RNA was concentrated in motor neuron cell nuclei in addition to the cytoplasm. delta-1 and -2 mRNAs were found at low levels throughout the gray matter. NR2A, NR2B, and GluR-6 mRNAs were undetectable. For the periaqueductal gray, prominent mRNAs were GluR-A, -B, and NR1. An en passant observation concerned high levels of NR2C mRNA in the pineal gland.


Arylsulfonyl histamine derivatives as powerful and selective α-glucosidase inhibitors.
A series of simple N-arylbenzenesulfonyl histamine derivatives were prepared and screened against α-glucosidase. Inhibition was in the micromolar range for several N α,N τ-di-arylsulfonyl compounds, with N α,N τ-di-4-trifluorobenzenesulfonyl histamine (IId) being the best inhibitor. Compound IId is a reversible and competitive α-glucosidase inhibitor, and presented good selectivity with respect to other target enzymes, including β-glucosidase and α-amylase, and interesting predicted physicochemical properties. Docking studies have been run to postulate ligand-enzyme interactions to account for the experimental results. In vivo, compound IId produced a similar hypoglycemic effect to acarbose with half of its dose.


A small fraction of patients with repetitive injuries account for a large portion of medical costs.
The phenomenon of repetitive injuries has been judged to be of limited importance in the public health context. A study was therefore initiated in order to analyse all types of single and repetitive injuries using a longitudinal approach. Hospital care, medical costs and risk factors were examined for single and repetitive severe injuries. A cross-sectional survey with a 12-year follow-up was performed. Questionnaire information from a survey of a random sample of the adult population 20-89 years old in 1984 in Stockholm County were linked to the Swedish national inpatient and cause-of-death register up to 1996, inclusive. During the study period 13% of males and 15% of females were hospitalized or deceased as a result of injuries. Persons with three or more injuries comprise 19% of the injuries, but account for 63% of the total number of days of hospital care and medical costs. Injuries related to falls were most common among patients requiring hospital care. Factors such as high age, living alone, stroke earlier, and use of hypnotics and sedatives were especially associated with repetitive injuries. The risk factors for single and repetitive injuries covariate, but the size of the risk is overrepresented for stroke, drugs, self-reported injuries and living alone for two or more injuries. These results indicate that subjects with repetitive injuries, and with the observed risk factors for such injuries, should be given extra attention, both in policy and prevention, but also in integrated treatment programmes.


Association of lncRNA THRIL, HOTAIR genes variations and expression levels with pulmonary tuberculosis.
Long non-coding RNA (lncRNA) has been implicated in the pathogenesis of pulmonary tuberculosis (PTB). This study aims to investigate the involvement of lncRNA THRIL and HOTAIR gene single nucleotide polymorphisms (SNPs) and their expression levels in PTB susceptibility. A total of 456 PTB patients and 464 healthy controls participated in our study. we genotyped six SNPs of THRIL and HOTAIR genes using an improved multiple ligase detection reaction (iMLDR). Additionally, real-time reverse-transcriptase polymerase chain reaction was employed to detect the expression levels of THRIL and HOTAIR in peripheral blood mononuclear cells (PBMC) from 78 PTB patients and 84 healthy controls. No significant differences in allele and genotype frequencies were observed for THRIL rs1055472, rs11058000, and HOTAIR rs12427129, rs1899663, rs4759314, and rs7958904 polymorphisms between PTB patients and healthy controls (all P > 0.05). Moreover, genotype frequencies of all SNPs did not show any association with PTB susceptibility in the dominant-recessive model. However, the frequencies of rs7958904 CC genotype and C allele in the HOTAIR gene were significantly correlated with leukopenia in PTB patients. Furthermore, the expression levels of the HOTAIR gene were significantly elevated in PTB patients compared to controls. Our study indicates that THRIL and HOTAIR gene SNPs might not contribute to PTB susceptibility, while the level of HOTAIR was increased in PTB patients.


The transcription factor Rbf1 is the master regulator for b-mating type controlled pathogenic development in Ustilago maydis.
In the phytopathogenic basidiomycete Ustilago maydis, sexual and pathogenic development are tightly connected and controlled by the heterodimeric bE/bW transcription factor complex encoded by the b-mating type locus. The formation of the active bE/bW heterodimer leads to the formation of filaments, induces a G2 cell cycle arrest, and triggers pathogenicity. Here, we identify a set of 345 bE/bW responsive genes which show altered expression during these developmental changes; several of these genes are associated with cell cycle coordination, morphogenesis and pathogenicity. 90% of the genes that show altered expression upon bE/bW-activation require the zinc finger transcription factor Rbf1, one of the few factors directly regulated by the bE/bW heterodimer. Rbf1 is a novel master regulator in a multilayered network of transcription factors that facilitates the complex regulatory traits of sexual and pathogenic development.


Synthesis and characterization of a cyclooctapeptide analogue of ω-agatoxin IVB enhancing the activity of Cav2.1 calcium channels activity in cultured hippocampal neurons.
The structure of the toxin ω-agatoxin IVB, extracted from the venom of funnel-web spider Agelenopsis aperta, is an important lead structure when considering the design of modulators of synaptic transmission which largely involves P/Q-type (CaV2.1) voltage gated calcium channels (VGCC) at central synapses. Focusing on the loop 2 of the ω-agatoxin IVB that seems to be the most preeminent interacting domain of the toxin with the CaV2.1 VGCC, cyclooctapeptides mimicking this loop were synthesized. While (14)Trp is essential for the binding of the neurotoxin to the CaV2.1 VGCC, the substitution of the (12)Cys for a glycidyl residue led to a cyclooctapeptide named EP14 able to enhance CaV2.1 VGCC-associated currents measured with patch-clamp recordings and to evoke ω-agatoxin IVA-sensitive intracellular Ca(2+) increase as measured by fura-2 spectrofluoroimaging. Furthermore, this cyclooctapeptide was able to potentiate spontaneous excitatory synaptic transmission in a network of cultured hippocampal neurons, consistent with the activation of presynaptic VGCC by EP14. In addition, this peptide did not affect cell survival measured with the MTT assay. Therefore, such new cyclopeptidic structures are potential good candidates for synthesis of new agents aimed at the restoration deficient excitatory synaptic transmission.


Interaction of MnO and ZnO nanomaterials with biomedically important proteins and cells.
Zinc and manganese nanomaterials may have potential for biomedical nanotechnology. Here first generation Zn and Mn oxide nanomaterials were prepared as determined by XRD. Transmission electron microscopy confirmed their nanoscale in two dimensions and revealed a rod or belt-like morphology for MnO or ZnO respectively. Association of MnO and ZnO to three model biomedically important proteins (albumin, protamine and thrombin) has been characterized by ultra-violet and dynamic laser light spectroscopy, UVS and DLLS respectively. UVS demonstrated a concentration-dependent loss of protein from the supernatant upon sedimentation of MnO or ZnO. Shifts in the surface charge of the MnO or ZnO by DLLS confirmed the protein's adsorption to the surface. MnO and ZnO were incubated with live human cells in culture (HeLa, A375 or 1321N1). A marked difference was observed for the two nanomaterials behavior in cell culture where the MnO could be discerned associating at the cell surface whereas the ZnO caused the cells to exhibit a rounded up morphology. Trypan blue dye exclusion studies demonstrated cytotoxicity of the ZnO at high concentrations 62.5-31.5 microg/mL whereas surprisingly the MnO demonstrated no cytotoxicity at any of the concentrations tested.


Holocene vegetation in chaco canyon, new Mexico.
Well-preserved plant remains in packrat middens chronicle vegetation change in Chaco Canyon over the past 11,000 years. Early Holocene evidence of communities dominated by Douglas fir, Rocky Mountain juniper, and limber pine in the San Juan Basin calls for revision of traditional constructs based on fossil pollen. Middle and late Holocene vegetation in the canyon was pinyon-juniper woodland up until Anasazi occupation between 1000 and 800 years ago. Instead of climate, Anasazi fuel needs may explain the drastic reduction of pinyon and juniper after 1230 years ago. The lack of pinyon-juniper recovery over the past millennium has implications for contemporary forest and range ecology.


Long-term efficacy of biofeedback therapy for dyssynergic defecation: randomized controlled trial.
Although biofeedback therapy is effective in the short-term management of dyssynergic defecation, its long-term efficacy is unknown. Our aim was to compare the 1-year outcome of biofeedback (manometric-assisted pelvic relaxation and simulated defecation training) with standard therapy (diet, exercise, laxatives) in patients who completed 3 months of either therapy. Stool diaries, visual analog scales (VASs), colonic transit, anorectal manometry, and balloon expulsion time were assessed at baseline, and at 1 year after each treatment. All subjects were seen at 3-month intervals and received reinforcement. Primary outcome measure (intention-to-treat analysis) was a change in the number of complete spontaneous bowel movements (CSBMs) per week. Secondary outcome measures included bowel symptoms, changes in dyssynergia, and anorectal function. Of 44 eligible patients with dyssynergic defecation, 26 agreed to participate in the long-term study. All 13 subjects who received biofeedback, and 7 of 13 who received standard therapy, completed 1 year; 6 failed standard therapy. The number of CSBMs per week increased significantly (P<0.001) in the biofeedback group but not in the standard group. Dyssynergia pattern normalized (P<0.001), balloon expulsion time improved (P=0.0009), defecation index increased (P<0.001), and colonic transit time normalized (P=0.01) only in the biofeedback group. Biofeedback therapy provided sustained improvement of bowel symptoms and anorectal function in constipated subjects with dyssynergic defecation, whereas standard therapy was largely ineffective.


A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct αβ T cell receptors.
αβ T cell receptors (TCRs) interact with peptides bound to the polymorphic major histocompatibility complex class Ia (MHC-Ia) and class II (MHC-II) molecules as well as the essentially monomorphic MHC class Ib (MHC-Ib) molecules. Although there is a large amount of information on how TCRs engage with MHC-Ia and MHC-II, our understanding of TCR/MHC-Ib interactions is very limited. Infection with cytomegalovirus (CMV) can elicit a CD8+ T cell response restricted by the human MHC-Ib molecule human leukocyte antigen (HLA)-E and specific for an epitope from UL40 (VMAPRTLIL), which is characterized by biased TRBV14 gene usage. Here we describe an HLA-E-restricted CD8+ T cell able to recognize an allotypic variant of the UL40 peptide with a modification at position 8 (P8) of the peptide (VMAPRTLVL) that uses the TRBV9 gene segment. We report the structures of a TRBV9+ TCR in complex with the HLA-E molecule presenting the two peptides. Our data revealed that the TRBV9+ TCR adopts a different docking mode and molecular footprint atop HLA-E when compared with the TRBV14+ TCR-HLA-E ternary complex. Additionally, despite their differing V gene segment usage and different docking mechanisms, mutational analyses showed that the TCRs shared a conserved energetic footprint on the HLA-E molecule, focused around the peptide-binding groove. Hence, we provide new insights into how monomorphic MHC molecules interact with T cells.


The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell-Mediated Th1 Differentiation and Autoimmune Encephalomyelitis.
Dendritic cell (DC)-mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/β secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α-mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.


Gene expression profiling in wounded and systemic leaves of Fagus sylvatica reveals up-regulation of ethylene and jasmonic acid signalling.
Wounding is a crucial threat to plants because of the physical damage caused and the possible entry of pathogens. Little is known about the wound reaction in forest trees. Therefore, leaves of young beech trees were wounded and the transcriptional response of wounded leaves and leaves directly above and below was analysed. A total of 123 genes exhibited significant regulation. The magnitude of regulation was slightly weaker in the downward leaves but the regulation pattern resembles that of the local and upward reactions. Thus, the signal was transduced in both vertical directions. Genes exhibiting major regulation lacked functional assignment or belonged to signalling, transcription and defence categories. Signalling included activation of transcripts in the calcium and ethylene pathways. There was also evidence for activation of jasmonic acid signalling, but no activation of jasmonic acid-responsive PR (pathogenesis-related) genes was observed. Moreover, repression of salicylic acid responsive defence was measured. Metabolic changes included induction of a core gene of the phenylpropanoid pathway, while energy metabolism exhibited down-regulation. These results support the conclusion that young beech trees might give up leaves and/or reduce leaf energy content after an attack so as to deprive a putative herbivore of a nutrient supply, instead of investing much energy in leaf defence.


Prevention of smoking in adolescents with lower education: a school based intervention study.
To assess the effect of an antismoking intervention focusing on adolescents in lower education. Students with lower education smoke more often and perceive more positive norms, and social pressure to smoke, than higher educated students. An intervention based on peer group pressure and social influence may therefore be useful to prevent smoking among these students. Group randomised controlled trial. 26 Dutch schools that provided junior secondary education. 1444 students in the intervention and 1118 students in the control group, all in the first grade, average age 13 years. Three lessons on knowledge, attitudes, and social influence, followed by a class agreement not to start or to stop smoking for five months and a class based competition. Comparison of smoking status before and immediately after and one year after the intervention, using multilevel analysis. In the intervention group, 9.6% of non-smokers started to smoke, in the control group 14.2%. This leads to an odds ratio of 0.61 (95% CI= 0.41 to 0.90) to uptake smoking in the intervention group compared with the control group. One year after the intervention, the effect was no longer significant. In the short-term, an intervention based on peer pressure decreases the proportion of adolescents with lower education who start smoking. Influencing social norms and peer pressure would therefore be a promising strategy in terms of preventing smoking among adolescents. The results also suggest that additional interventions in later years are needed to maintain the effect.


The neurology-psychiatry interface in epilepsy.
Epilepsy and mental illness have a bidirectional association. Psychiatrists are likely to encounter epilepsy as comorbidity. Seizures may present as mental illness. Equally, the management of psychiatric conditions has the potential to destabilise epilepsy. There is a need for structured epilepsy awareness and training amongst psychiatrists. This paper outlines key considerations around diagnosis, treatment and risk while suggesting practical recommendations.


[Characteristics of temperature dependence of Na,K-ATPase].
The character of temperature dependence of hydrolytic and transport functions of Na, K-ATPase is analyzed. It is shown that the nonlinear Arrhenius plot is typical only of "allosteric" substrates ATP and CTP, the inflection of curves reflecting sensitivity of the enzyme to the phase reconstructions of membrane lipids. The linear Arrhenius plots are typical of GTP, UTP- p-NPP and acetyl phosphate, the substrates demonstrating "normal" kinetics of Michaelis and not providing the active transport of ions. A conclusion is drawn that anomalies on the Na, K-ATPase temperature dependence evidence for the lipid control of intersubunit interactions in the supermolecular complex of Na, K-ATPase which are realized during the active transport of ions.


Heritability of parental effort in a passerine bird.
The study of the evolution of parental care is central to our understanding of social systems, sexual selection, and interindividual conflict, yet we know virtually nothing about the genetic architecture of parental care traits in natural populations. In this paper, we use data from a long term field study of a passerine bird, the long-tailed tit (Aegithalos caudatus), to examine the heritability of the rate at which parents feed offspring. This measure of effort is positively related to offspring survival, is repeatable within individuals, and does not appear to be confounded by environmental effects. Using both parent-offspring regression, and an animal model approach, with a pedigree derived from ringing data, we show that our measure of effort has a significant heritable component.


Predictively consistent prior effective sample sizes.
Determining the sample size of an experiment can be challenging, even more so when incorporating external information via a prior distribution. Such information is increasingly used to reduce the size of the control group in randomized clinical trials. Knowing the amount of prior information, expressed as an equivalent prior effective sample size (ESS), clearly facilitates trial designs. Various methods to obtain a prior's ESS have been proposed recently. They have been justified by the fact that they give the standard ESS for one-parameter exponential families. However, despite being based on similar information-based metrics, they may lead to surprisingly different ESS for nonconjugate settings, which complicates many designs with prior information. We show that current methods fail a basic predictive consistency criterion, which requires the expected posterior-predictive ESS for a sample of size N to be the sum of the prior ESS and N. The expected local-information-ratio ESS is introduced and shown to be predictively consistent. It corrects the ESS of current methods, as shown for normally distributed data with a heavy-tailed Student-t prior and exponential data with a generalized Gamma prior. Finally, two applications are discussed: the prior ESS for the control group derived from historical data and the posterior ESS for hierarchical subgroup analyses.


Full-field Electroretinography in Age-related Macular Degeneration: can retinal electrophysiology predict the subjective visual outcome of cataract surgery?
Predicting the visual gain from cataract surgery when the main cause of vision loss is age-related macular degeneration may be difficult and warrants the need for an objective predictor of subjective outcome. Full-field electroretinography is an objective measure of overall retinal function. We therefore wanted to study if full-field electroretinography can predict subjective visual outcome using visual function questionnaire. Thirty-one patients with age-related macular degeneration operated for bilateral cataract underwent full-field electroretinography preoperatively. Full-field electroretinography was performed according to International Society for the Clinical Electrophysiology of Vision standards using a Ganzfeld bowl (RETI-port/scan 21, Roland, Berlin) and Dawson-Trick-Litzkow fibre electrodes. Vision-related quality of life was measured using the National Eye Institute Visual Function Questionnaire-39 before first-eye surgery and 4.12 ± 2.11 months after second-eye surgery. Mean change in composite visual function questionnaire score after cataract surgery was 9.2 ± 11.9. The patients were divided into three groups: visual function questionnaire composite score increase >10 (n = 17); no change (n = 8); and decrease (n = 6). In the dark-adapted full-field electroretinography responses, we found a significant difference between the three groups in the 0.01 b-wave amplitude (p = 0.05), the 10.0 b-wave amplitude (p = 0.04) and a near-significant difference in 3.0 a-wave amplitude (p = 0.09). Other dark-adapted responses (the 3.0 b-wave and 10.0 a-wave) did not show any significant differences between the three groups, and neither did the light-adapted responses. Patients with low dark-adapted responses on full-field electroretinography preoperatively experience a decrease in subjective vision-related quality of life, suggesting that maintained rod function before cataract surgery may be important.


Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients.
A specific missense mutation in the p53 tumor gene at codon 249 has been reported in over 50% of hepatocellular carcinoma (HCC) tumors and in paired blood samples from areas of high dietary exposure to aflatoxin B1, including Qidong, People's Republic of China. Using a combination of pre-digestion with HaeIII, PCR and mass spectrometry, the temporality of this mutation in plasma before and after the clinical diagnosis of HCC was examined. Sixteen liver cancer cases, diagnosed between 1997 and 2001, were selected from a prospective cohort of 1638 high-risk individuals in Qidong on the basis of available annual plasma samples spanning the years before and after diagnosis. The codon 249 mutation was detected in plasma samples obtained after diagnosis in seven of the 15 cases (46.7%) with PCR amplifiable DNA, which is in accord with the reported prevalence of this mutation in HCC. The persistent detection of this mutation in plasma collected annually following diagnosis was statistically significant (P = 0.024, two-tailed) in repetitive samples following diagnosis. Moreover, the mutation was detected in the plasma of four of eight cases positive at the time of diagnosis at least 1 year and in one case 5 years prior to diagnosis. Tracking of the marker in pre-diagnostic samples was borderline statistically significant (P = 0.066). None of the 18 healthy US control plasma samples had any detectable mutations. We have therefore found that pre-diagnosis biomarkers of specific p53 mutations can be measured in plasma and this suggests a paradigm for developing these markers for use in prevention and intervention trials.


Multiple sclerosis: immune mechanism and update on current therapies.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) afflicting approximately 250,000 individuals in the United States. This inflammatory disease has variable clinical manifestations, ranging from a relapsing-remitting course to a chronic progressive disease. Approximately one third of MS patients have chronic progressive disease often leading to severe impairment of mobility, paralysis, poor vision, and disturbances of bladder and bowel function. Although the etiology and pathogenesis remain unknown, accumulating evidence supports the hypothesis that exposure to an as-yet-unidentified infectious agent(s) triggers an aberrant immune response against self nervous tissue in genetically susceptible individuals. The tenfold higher concordance rate for MS in monozygotic twins compared to dizygotic twins, the increased incidence of MS in women compared to men (2:1), and the familial and racial occurrence of MS provide strong evidence that genetic factors influence susceptibility to MS. The major predisposing genes in MS are the human leukocyte antigen (HLA) class II molecules, DR15 and DQw6, molecularly defined as HLA-DRB1, 1501-DQA1 0102-DQB1 0602. In certain ethnic groups, MS susceptibility is more strongly associated with other DR molecules. Environmental factors are also believed to play a role, as suggested by the unique worldwide prevalence, migration effects, and epidemiological studies. Increased serum and cerebrospinal fluid antibody titers to numerous viruses have been reported; however, there have been no confirmed studies detecting viral RNA or antigen in MS brain tissue. At the present time, no known treatment can significantly alter the progression of MS. Based on the postulate that MS is an autoimmune disease associated with abnormalities in immunoregulation, a number of different immunosuppressive and immunomodulating agents have been tested as therapeutic modalities. In this article, we review the circumstantial evidence suggesting that immune system abnormalities are associated with the disease process, and provide an update on current therapies used in MS.


Implicit trauma identity associations in treatment-seeking U.S. military personnel do not predict or change in response to cognitive processing therapy for PTSD.
This study evaluated implicit associations (i.e., associations in memory that are automatically activated and difficult to control consciously) related to trauma and one's self in the context of a clinical trial for active duty service members seeking treatment for posttraumatic stress disorder (PTSD). Previous studies with nontreatment-seeking community samples found that implicit trauma identity associations were associated with PTSD symptoms even after controlling for amount of trauma exposure and self-reported negative cognitions about the self. This study extended prior work by evaluating whether trauma-related implicit associations were associated with PTSD and depressive symptoms in a clinical sample seeking treatment for PTSD, predicted PTSD treatment response, or changed over the course of treatment. This secondary analysis examined implicit trauma identity associations using data from a clinical trial evaluating a variable-length adaptation of cognitive processing therapy for military personnel. Participants were 127 active duty U.S. military personnel (13.4% women) seeking PTSD treatment. Implicit trauma identity associations were evaluated at baseline and posttreatment. Study hypotheses and data analysis plan were preregistered. Contrary to predictions, baseline implicit trauma identity associations were not significantly associated with baseline PTSD or depressive symptoms and did not predict treatment response. Implicit trauma identity associations did not change significantly in response to treatment. More tailoring of implicit trauma measures for military personnel and/or treatment-seeking patients may be needed. The measure may lack sensitivity to change in response to treatment and have reduced utility in treatment-seeking samples with high symptom burden and less variability in symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Ion-pair reorganization regulates reactivity in photoredox catalysts.
Cyclometalated and polypyridyl complexes of d6 metals are promising photoredox catalysts, using light to drive reactions with high kinetic or thermodynamic barriers via the generation of reactive radical intermediates. However, while tuning of their redox potentials, absorption energy, excited-state lifetime and quantum yield are well-known criteria for modifying activity, other factors could be important. Here we show that dynamic ion-pair reorganization controls the reactivity of a photoredox catalyst, [Ir[dF(CF3)ppy]2(dtbpy)]X. Time-resolved dielectric-loss experiments show how counter-ion identity influences excited-state charge distribution, evincing large differences in both the ground- and excited-state dipole moment depending on whether X is a small associating anion (PF6-) that forms a contact-ion pair versus a large one that either dissociates or forms a solvent-separated pair (BArF4-). These differences correlate with the reactivity of the photocatalyst toward both reductive and oxidative electron transfer, amounting to a 4-fold change in selectivity toward oxidation versus reduction. These results suggest that ion pairing could be an underappreciated factor that modulates reactivity in ionic photoredox catalysts.


Looking back at the lawsuit that transformed the chiropractic profession part 2: Rise of the American Medical Association.
This paper is the second in a series that explores the historical events surrounding the Wilk v American Medical Association (AMA) lawsuit in which the plaintiffs argued that the AMA, the American Hospital Association, and other medical specialty societies violated anti-trust law by restraining chiropractors' business practices. The purpose of this paper is to provide a brief review of the history of how the AMA rose to dominate health care in the United States, and within this social context, how the chiropractic profession fought to survive in the first half of the 20th century. This historical research study used a phenomenological approach to qualitative inquiry into the conflict between regular medicine and chiropractic and the events before, during, and after a legal dispute at the time of modernization of the chiropractic profession. Our methods included obtaining primary and secondary data sources. The final narrative recount was developed into 8 papers following a successive timeline. This paper is the second of the series that explores the growth of medicine and the chiropractic profession. The AMA's code of ethics established in 1847 continued to direct organized medicine's actions to exclude other health professions. During the early 1900s, the AMA established itself as "regular medicine." They labeled other types of medicine and health care professions, such as chiropractic, as "irregulars" claiming that they were cultists and quacks. In addition to the rise in power of the AMA, a report written by Abraham Flexner helped to solidify the AMA's control over health care. Chiropractic as a profession was emerging and developing in practice, education, and science. The few resources available to chiropractors were used to defend their profession against attacks from organized medicine and to secure legislation to legalize the practice of chiropractic. After years of struggle, the last state in the US legalized chiropractic 79 years after the birth of the profession. In the first part of the 20th century, the AMA was amassing power as chiropractic was just emerging as a profession. Events such as publication of Flexner's report and development of the medical basic science laws helped to entrench the AMA's monopoly on health care. The health care environment shaped how chiropractic grew as a profession. Chiropractic practice, education, and science were challenged by trying to develop outside of the medical establishment. These events added to the tensions between the professions that ultimately resulted in the Wilk v AMA lawsuit.


Quantitative Comparison of Vertebral Structural Changes After Percutaneous Vertebroplasty Between Unilateral Extrapedicular Approach and Bilateral Transpedicular Approach Using Voxel-Based Morphometry.
: To compare unilateral extrapedicular vertebroplasty (UEV) and bilateral transpedicular vertebroplasty (BTV) by quantitatively calculating the structural changes of fractured vertebral body after percutaneous vertebroplasty (PVP) using 3-dimensional voxel-based morphometry (VBM). : We calculated bone cement volume (BCV); vertebral body volume (VBV); leaked intradiscal BCV; and spatial, symmetric, and even bone cement distribution (BCD) in and out of 222 vertebral bodies treated with 2 different PVPs using VBM and evaluated the incidence of subsequent vertebral compression fracture (SVCF). Statistical analyses were conducted to compare values between the 2 different PVPs. : Relative BCV, which is a potential risk factor for SVCF, was higher in the BTV group based on the data using VBM (0.22±0.03 vs. 0.29±0.03; p<0.001, t-test); however, the SVCF incidence between the 2 surgeries was not significantly different (UEV, 24.7%; BTV, 31%; p=0.046, chi-square test). Spatial, even, and symmetric BCD along the 3 axes was not significantly different between UEV and BTV using VBM (x, y, z-axis, p=0.893, p= 0.590, p=0.908 respectively, chi-square test). : Contrary to intuitive concerns, UEV can inject a sufficient and more optimal BCV than BTV. Additionally, it can inject bone cement spatially, symmetrically, and evenly well-distributed without an increased rate of intradiscal leakage and SVCF compared with BTV based on VBM. Therefore, UEV could be a superior alternative surgical method with similar clinical effectiveness and safety, considering the above results and the consensus that UEV is less invasive.


Controlling the energy of defects and interfaces in the amplitude expansion of the phase-field crystal model.
One of the major difficulties in employing phase-field crystal (PFC) modeling and the associated amplitude (APFC) formulation is the ability to tune model parameters to match experimental quantities. In this work, we address the problem of tuning the defect core and interface energies in the APFC formulation. We show that the addition of a single term to the free-energy functional can be used to increase the solid-liquid interface and defect energies in a well-controlled fashion, without any major change to other features. The influence of the newly added term is explored in two-dimensional triangular and honeycomb structures as well as bcc and fcc lattices in three dimensions. In addition, a finite-element method (FEM) is developed for the model that incorporates a mesh refinement scheme. The combination of the FEM and mesh refinement to simulate amplitude expansion with a new energy term provides a method of controlling microscopic features such as defect and interface energies while simultaneously delivering a coarse-grained examination of the system.


Extraocular muscle forces in normal human subjects.
Actively developed horizontal muscle forces and tissue stiffnesses were measured in 29 normal orthophoric volunteer subjects (18 to 33 years old) by means of noninvasive length-tension forceps. Mean active fixation force developed at 50 deg extreme gaze was 26% greater for the medial rectus (74.8 gm) than for the lateral rectus (59.1 gm). The variation of maximum active force among individuals was 2:1 (48 to 103 gm). These muscles developed up to 25% of their maximum active force out of their field of action. Active (counter) hysteresis force differences of over 10 gm were measured between nasal and temporal gaze directions. This study suggests that a muscle which develops a maximum active force of less than 45 gm would be suspect as paretic. Variations from the normal pattern of reciprocal innervation, reflected in the graded active force of individual muscle contraction, may help in understanding some types of oculomotor pathology. The mean tissue stiffness-restraining movement of the globe in the nasal direction (1.05 gm/deg) is 11% greater than in the temporal direction (0.94 gm/deg). This is consistent with a stronger medial rectus balanced by a greater load. Variation of stiffness of 2:1 was observed among individuals; 0.8 to 1.7 gm/deg pulling nasally and 0.77 to 1.2 gm/deg temporally. Passive hysteresis and viscous force differences of over 10 gm were observed between the passive forced pull and normal spring-return of the eye. Large stiffnesses may be normal if balanced by large active forces. Abrupt changes of the length-tension curve indicate the magnitude and location of restrictions.


Digit-color synaesthesia only enhances memory for colors in a specific context: A new method of duration thresholds to measure serial recall.
For digit-color synaesthetes, digits elicit vivid experiences of color that are highly consistent for each individual. The conscious experience of synaesthesia is typically unidirectional: Digits evoke colors but not vice versa. There is an ongoing debate about whether synaesthetes have a memory advantage over non-synaesthetes. One key question in this debate is whether synaesthetes have a general superiority or whether any benefit is specific to a certain type of material. Here, we focus on immediate serial recall and ask digit-color synaesthetes and controls to memorize digit and color sequences. We developed a sensitive staircase method manipulating presentation duration to measure participants' serial recall of both overlearned and novel sequences. Our results show that synaesthetes can activate digit information to enhance serial memory for color sequences. When color sequences corresponded to ascending or descending digit sequences, synaesthetes encoded these sequences at a faster rate than their non-synaesthetes counterparts and faster than non-structured color sequences. However, encoding color sequences is approximately 200 ms slower than encoding digit sequences directly, independent of group and condition, which shows that the translation process is time consuming. These results suggest memory advantages in synaesthesia require a modified dual-coding account, in which secondary (synaesthetically linked) information is useful only if it is more memorable than the primary information to be recalled. Our study further shows that duration thresholds are a sensitive method to measure subtle differences in serial recall performance. (PsycINFO Database Record


Effect of primary care referral on emergency department use: evaluation of a statewide Medicaid program.
Medicaid recipients without a regular source of care frequently use hospital emergency departments (EDs) for minor problems. This study examined whether referring Medicaid patients to primary care physicians and obstetricians results in a decrease in ED use and an increase in physician office visits. The statewide Voluntary Initiative Program (VIP), which referred Medicaid patients to primary care physicians and obstetricians without any managed care component, was examined. Claims data were reviewed for Medicaid clients 0-64 years old who obtained VIP referrals during the first five months of the program. The change in rate of visits to hospital EDs and physician offices was compared for the study group (n = 444) and for the state's overall Medicaid population (n = 40,860). After referral, ED use decreased 24 percent for the VIP group and 4 percent for the Medicaid population. During the same period, physician office visits increased 50 percent for the VIP group but decreased 13 percent for the Medicaid population. Even in the absence of managed care, referral to primary care physicians and obstetricians resulted in fewer ED visits and more physician office visits. These findings confirm the importance of primary care in improving the efficiency of health care delivery for the Medicaid population.


Extracorporeal membrane oxygenation support in refractory perioperative anaphylactic shock to rocuronium: a report of two cases.
In recent years, extracorporeal membrane oxygenation has become increasingly common in the treatment of in-hospital cardiac arrest in non-cardiac surgery patients. This includes cardiac arrest secondary to perioperative anaphylactic shock refractory to standard advanced life support protocols, which is a rare but catastrophic event associated with significant mortality. Neuromuscular blocking drugs are most commonly implicated in perioperative anaphylaxis, with rocuronium playing a major role. In this article, we report two cases of young and otherwise fit and well patients who experienced a perioperative arrest secondary to rocuronium anaphylaxis before elective surgery; both patients did not respond to conventional advanced life support, but survived neurologically intact after institution of urgent veno-arterial extracorporeal membrane oxygenation.


The institutional development award states pediatric clinical trials network: building research capacity among the rural and medically underserved.
The institutional development award (IDeA) program was created to increase the competitiveness of investigators in states with historically low success rates for National Institutes of Health (NIH) research funding applications. IDeA states have high numbers of rural and medically underserved residents with disproportionately high rates of infant mortality, obesity, and poverty. This program supports the development and expansion of research infrastructure and research activities in these states. The IDeA States Pediatric Clinical Trials Network (ISPCTN) is part of the environmental influences on child health outcomes program. Its purpose is to build research capacity within IDeA states and provide opportunities for children in IDeA states to participate in clinical trials. This review describes the current and future activities of the network. In its initial year, the ISPCTN created an online series on clinical trials, initiated participation in a study conducted by the pediatric trials network, and proposed two novel clinical trials for obese children. Capacity building and clinical trial implementation will continue in future years. The ISPCTN is uniquely poised to establish and support new pediatric clinical research programs in underserved populations, producing both short and long-term gains in the understanding of child health.


Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa.
Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.


Urethral lift for benign prostatic hyperplasia: a comprehensive review of the literature.
Current treatments for benign prostatic hyperplasia (BPH) include watchful waiting, medical therapy, and interventional procedures. The post-surgical complication profile and the early discontinuation of medical therapy are significant drawbacks of the established approach and stimulate the search for less-invasive approaches. Our aim is to provide a comprehensive review all available literature on prostatic urethral lift (PUL), presenting an overview of safety, indications, surgical technique and results of the procedure, and to evaluate the potential role it could play in the treatment of BPH. A comprehensive search was conduct on PubMed and Scopus database to identify original articles in English dealing with PUL without any limit to publication date. Keywords used were prostatic urethral lift, urethral lifting, Urolift, benign prostatic hyperplasia and minimally invasive therapy. The PUL seems to offer a better IPSS improvement when compared to medical therapy, but the result is inferior when compared to surgical therapy. Published studies report an absence of degradation of erectile or ejaculatory function after treatment, which appears a noteworthy benefit of PUL. Additional advantages of the PUL are a better complication profile in comparison to other surgical therapies and the use of a local anesthesia, sometimes without postoperative catheterization. The PUL, a novel, minimally invasive treatment option for men affected by BPH, presents a promising potential although it is clear that PUL is not a substitute for traditional ablative surgical approach, as this procedure requires a scrupulous selection of the patient.


LocalMove: computing on-lattice fits for biopolymers.
Given an input Protein Data Bank file (PDB) for a protein or RNA molecule, LocalMove is a web server that determines an on-lattice representation for the input biomolecule. The web server implements a Markov Chain Monte-Carlo algorithm with simulated annealing to compute an approximate fit for either the coarse-grain model or backbone model on either the cubic or face-centered cubic lattice. LocalMove returns a PDB file as output, as well as dynamic movie of 3D images of intermediate conformations during the computation. The LocalMove server is publicly available at http://bioinformatics.bc.edu/clotelab/localmove/.


Characterisation of regulatory T cells in nasal associated lymphoid tissue in children: relationships with pneumococcal colonization.
Regulatory T cells (Treg) diminish immune responses to microbial infection, which may contribute to preventing inflammation-related local tissue damage and autoimmunity but may also contribute to chronicity of infection. Nasopharyngeal carriage of pneumococcus is common in young children and can persist for long periods but it is unknown whether the presence of Treg in the nasopharynx contributes to this persistence. We have investigated the numbers and activities of Foxp3+Treg in adenoidal tissues and their association with pneumococcal carriage in children. Expression of Treg cell-related markers including Foxp3, CD25, CD39, CD127 and CLTA4 were analysed by flow-cytometry in adenoidal mononuclear cells (MNC) and PBMC from children. Unfractionated MNC or Treg-depleted MNC were stimulated with a pneumococcal whole cell antigen (WCA) and T cell proliferation measured. Cytokine production by MNC was measured using a cytometric bead array. Higher numbers of CD25(high)Foxp3(high) Treg expressing higher CD39 and CTLA4 were found in adenoidal MNC than in PBMC. Children with pneumococcus positive nasopharyngeal cultures had higher proportions of Treg and expressed higher levels of CD39 and CTLA-4 than those who were culture negative (-). WCA induced adenoidal Treg proliferation which produce IL10 but not IL17, and CD4 T cell proliferation in Treg-depleted MNC was greater in pneumococcal culture positive than negative children. Significant numbers of Treg with an effector/memory phenotype which possess a potent inhibitory effect, exist in adenoidal tissue. The association of pneumococcal carriage with an increased frequency of adenoidal Treg suggests that Treg in nasal-associated lymphoid tissue (NALT) may contribute to the persistence of pneumococcus in children. Further studies to determine what component and mechanisms are involved in the promotion of Treg in NALT may lead to novel therapeutic or vaccination strategy against upper respiratory infection.


Integrating SMS Text Messages Into a Preventive Intervention for Postpartum Depression Delivered via In-Home Visitation Programs: Feasibility and Acceptability Study.
The Mothers and Babies (MB) Course is recognized by the US Preventive Services Task Force as an evidence-based preventive intervention for postpartum depression (PPD) that should be recommended to pregnant women at risk for PPD. This report examines the feasibility and acceptability of enhancing the MB 1-on-1 intervention by adding 36 SMS text messages that target 3 areas: reinforcement of skills, between-session homework reminders, and responding to self-monitoring texts (ie, MB Plus Text Messaging [MB-TXT]). In partnership with 9 home visiting programs, 28 ethnically and racially diverse pregnant women (mean 25.6, SD 9.0 weeks) received MB-TXT. Feasibility was defined by home visitors' adherence to logging into the HealthySMS platform to enter session data and trigger SMS text messages within 7 days of the in-person session. The acceptability of MB-TXT was measured by participants' usefulness and understanding ratings of the SMS text messages and responses to the self-monitoring SMS text messages. On average, home visitors followed the study protocol and entered session-specific data between 5.50 and 61.17 days following the MB 1-on-1 sessions. A high proportion of participants responded to self-monitoring texts (25/28, 89%) and rated the text message content as very useful and understandable. This report contributes to a growing body of research focusing on digital adaptations of the MB course. SMS is a low-cost, accessible digital tool that can be integrated into existing interventions. With appropriate resources to support staff, it can be implemented in community-based organizations and health care systems that serve women at risk for PPD. ClinicalTrials.gov NCT03420755; https://clinicaltrials.gov/ct2/show/NCT03420755.


Drug reaction with eosinophilia and systemic symptoms (DRESS): A histopathology based analysis.
The data on the histology of cutaneous lesions of drug reaction with eosinophilia and systemic symptoms (DRESS) is limited. To study the histopathology of cutaneous lesions of drug reaction with eosinophilia and systemic symptoms (DRESS) and to identify any features with diagnostic or prognostic significance. All patients admitted to the dermatology ward of government medical college, Kozhikode from January 1, 2014 to December 31, 2014 with probable or definite DRESS as per the RegiSCAR scoring system and who were willing to undergo skin biopsy were included in this prospective study. The study population comprised of nine patients. The consistent histological finding documented was the predominantly lymphocytic dermal inflammatory infiltrate. Four of the five patients whose histology revealed focal interface dermatitis and keratinocyte vacuolation with or without apoptotic keratinocytes, had elevated liver transaminases. Tissue eosinophilia was associated with disease flares. The presence of atypical lymphocytes in peripheral smear and histological evidence of dense dermal inflammatory infiltrate showed an association with hepatic involvement. The main limitations of our study were the small sample size and our inability to carry out a detailed immunohistochemistry work-up. In the appropriate setting, varying combinations of epidermal hyperplasia, spongiosis, parakeratosis and individually necrotic keratinocytes in the background of lymphocyte predominant dermal infiltrate (with some atypia) favor a diagnosis of drug reaction with eosinophilia and systemic symptoms. Female sex, the presence of atypical lymphocytes in peripheral smear, dense dermal inflammatory infiltrate, tissue eosinophilia and interface dermatitis with or without keratinocyte necrosis was associated with a poor prognosis.


Sporotrichosis in cats: ABCD guidelines on prevention and management.
Sporotrichosis is an important subcutaneous fungal infection of humans and animals in some endemic tropical and subtropical areas. Among domestic species, cats are the most frequently infected. The primary mode of transmission is traumatic inoculation of fungal conidia from plants and soil. Contact with infected cats is the major mode of transmission to humans, especially in endemic areas like Brazil, where a large epidemic has occurred in the past decade. Most cases in cats are cutaneous, presenting as multiple ulcerated nodules and draining tracts in the skin. Lymphadenopathy, respiratory signs and systemic dissemination may also occur. Diagnosis is based on fungal detection by cytology and/or histology, and confirmation by culture. Treatment consists of at least 2 months' systemic antifungal therapy, with itraconazole as the first-choice agent. The prognosis is favourable provided there is good owner compliance and adverse drug effects do not occur. Contact with infected cats carries a high zoonotic risk. Cat owners travelling to endemic areas should be warned and advised to keep their cats indoors to prevent infection. Professionals must wear gloves when handling cats with skin nodules and ulcers and dealing with diagnostic samples.


Flavor preference learning increases olfactory and gustatory convergence onto single neurons in the basolateral amygdala but not in the insular cortex in rats.
The basolateral amygdala (BLA) and the insular cortex (IC) represent two major areas for odor-taste associations, i.e. flavor integration. This learning may require the development of convergent odor and taste neuronal activation allowing the memory representation of such association. Yet identification of neurons that respond to such coincident input and the effect of flavor experience on odor-taste convergence remain unclear. In the present study we used the compartmental analysis of temporal activity using fluorescence in situ hybridization for Arc (catFISH) to visualize odor-taste convergence onto single neurons in the BLA and in the IC to assess the number of cells that were co-activated by both stimuli after odor-taste association. We used a sucrose conditioned odor preference as a flavor experience in rats, in which 9 odor-sucrose pairings induce a reliable odor-taste association. The results show that flavor experience induced a four-fold increase in the percentage of cells activated by both taste and odor stimulations in the BLA, but not in the IC. Because conditioned odor preference did not modify the number of cells responding selectively to one stimulus, this greater odor-taste convergence into individual BLA neurons suggests the recruitment of a neuronal population that can be activated by both odor and taste only after the association. We conclude that the development of convergent activation in amygdala neurons after odor-taste associative learning may provide a cellular basis of flavor memory.


Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics.
Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein-protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide-from a novel library of 8,988 sub-kilodalton macrocyclic peptides-in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle-protein molecular recognition studies.


[3H]Threo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters.
Saturable and stereoselective binding sites for [3H]threo-(+/-)-methylphenidate were characterized in rat brain membranes. The highest density of [3H]threo-(+/-)-methylphenidate binding sites was found in the synaptosomal fraction of corpus striatum. Scatchard analysis revealed a single class of noninteracting binding sites with an apparent dissociation constant (KD) of 235 nM and a maximum number of binding sites (Bmax) of 13.4 pmol/mg protein. Saturable, high-affinity binding of [3H]threo-(+/-)-methylphenidate to striatal synaptosomal membranes was dependent on the presence of sodium ions. A good correlation (r = 0.88; p less than 0.001) was observed between the potencies of various psychotropic drugs in displacing [3H]threo-(+/-)-methylphenidate from these sites and their potencies as inhibitors of [3H]3,4-dihydroxyphenylethylamine ( [3H]dopamine) uptake into striatal synaptosomes. A good correlation (r = 0.85; p less than 0.001) was also observed between the potencies of a series of ritalinic acid esters in inhibiting [3H]threo-(+/-)-methylphenidate binding to striatal synaptosomal membranes and their potencies as motor stimulants in mice. These observations suggest that the binding sites for [3H]threo-(+/-)-methylphenidate described here are associated with a dopamine uptake or transport complex, and that these sites may mediate the motor stimulant properties of ritalinic acid esters such as methylphenidate.


Microscopic theory of the jamming transition of harmonic spheres.
We develop a microscopic theory to analyze the phase behavior and compute correlation functions of dense assemblies of soft repulsive particles both at finite temperature, as in colloidal materials, and at vanishing temperature, a situation relevant for granular materials and emulsions. We use a mean-field statistical mechanical approach which combines elements of liquid state theory to replica calculations to obtain quantitative predictions for the location of phase boundaries, macroscopic thermodynamic properties, and microstructure of the system. We focus, in particular, on the derivation of scaling properties emerging in the vicinity of the jamming transition occurring at large density and zero temperature. The new predictions we obtain for pair correlation functions near contact are tested using computer simulations. Our work also clarifies the conceptual nature of the jamming transition and its relation to the phenomenon of the glass transition observed in atomic liquids.


Role of immune system modulation in prevention of type 1 diabetes mellitus.
An increased incidence of Type 1 diabetes mellitus (T1DM) is expected worldwide. Eventually, T1DM is fatal unless treated with insulin. The expansion of interventions to prevent diabetes and the use of alternative treatments to insulin is a dream to be fulfilled. The pathophysiology in T1DM is basically a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present. Individual risk factors can have separate patho-physiological processes to, in turn, cause this beta cell destruction. Currently, autoimmunity is considered the major factor in the pathophysiology of T1DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. Many components of the immune system have been implicated in autoimmunity leading to β-cell destruction, including cytotoxic and helper T-cells, B-cells, macrophages, and dendritic cells. The inflammatory process in early diabetes is thought to be initiated and propagated by the effect of Th1-secreted cytokines (e.g. g interferon) and suppressed by Th2-secreted antiinflammatory cytokines (interleukins). Structure and function of β-cell may be modulated by using Th1/Th2-secreted cytokines. Several experimental and clinical trials of applying GAD65, Hsp60, peptide-MHC, pepetide-277 immunization, anti-CD3 infusion, and interleukins to modulate immune response in T1DM were done. Applying such trials in patients with prediabetes, will most likely be the future key in preventing Type 1 autoimmune diabetes.


Orthogeriatric Combined Management of Elderly Patients With Proximal Femoral Fracture: Results of a 1-Year Follow-Up.
According to the expected demographical changes, the number of elderly trauma patients will increase exponentially over the next decades. Different models of an interdisciplinary orthogeriatric care have been developed. But there is only limited evaluation of their benefit without clear and evidence-based results. In 2011, we monitored the results of our orthogeriatric combined management by conducting a 1-year follow-up. We treated 231 patients presenting a proximal femoral fracture on our orthogeriatric ward. We obtained the epidemiological data and the geriatric assessments from all these patients. One year after discharge, we sent them a written questionnaire. Primary end points were the mortality and the functional outcome, measured by Barthel score, the requirement of care, and the residential status. One hundred sixty-seven (72%) of the 231 patients completed the follow-up. The average age at admission was 81.5 years (70-99 years). The mortality rate was 2.4% during hospital stay and 31.4% after 1 year. The average Barthel score was 44 points at the time of admission, 55 points at discharge, and 72 points after 1 year. Forty-five percent of the patients were in requirement of care at the time of their admission. At the 1-year follow-up, 63% of the patients had some form of care, thus showing an increase of 18%. At the moment of the fracture, 77% of the patients were living in their own home and 23% in a nursing home. After 1 year, the surviving patients show nearly unchanged conditions (75% own home vs 25% nursing home). Eighty-six percent of the patients coming from their own home were able to continue living there independently. The orthogeriatric care is successful in reducing the short-time mortality without showing any effect on 1-year mortality. But the surviving patients seem to benefit from an improved functional outcome.


Intracellular Mg2+ and magnesium depletion in isolated renal thick ascending limb cells.
Magnesium reabsorption and regulation within the kidney occur principally within the cortical thick ascending limb (cTAL) cells of the loop of Henle. Fluorometry with the dye, mag-fura-2, was used to characterize intracellular Mg2+ concentration ([Mg2+]i) in single cTAL cells. Primary cell cultures were prepared from porcine kidneys using a double antibody technique (goat anti-human Tamm-Horsfall and rabbit anti-goat IgG antibodies). Basal [Mg2+]i was 0.52 +/- 0.02 mM, which was approximately 2% of the total cellular Mg. Cells cultured (16 h) in high magnesium media (5 mM) maintained basal [Mg2+]i, 0.48 +/- 0.02, in the normal range. However, cells cultured in nominally magnesium-free media possessed [Mg2+]i, 0.27 +/- 0.01 mM, which was associated with a significant increase in net Mg transport, (control, 0.19 +/- 0.03 and low Mg, 0.35 +/- 0.01 nmol.mg-1 protein.min-1) as assessed by 28Mg uptake. Mg(2+)-depleted cells were subsequently placed in high Mg solution (5 mM) and the Mg2+ refill rate was assessed by fluorescence. [Mg2+]i returned to normal basal levels, 0.53 +/- 0.03 mM, with a refill rate of 257 +/- 37 nM/s. Mg2+ entry was not changed by 5.0 mM Ca2+ or 2 mM Sr2+, Cd2+, Co2+, nor Ba2+ but was inhibited by Mn2+ approximately La3+ approximately Gd3+ approximately Zn2+ approximately Be2+ at 2 mM. Intracellular Ca2+ and 45Ca uptake was not altered by Mg depletion or Mg2+ refill, indicating that the entry is relatively specific to Mg2+. Mg2+ uptake was inhibited by nifedipine (117 +/- 20 nM/s), verapamil (165 +/- 34 nM/s), and diltiazem (194 +/- 19 nM/s) but enhanced by the dihydropyridine analogue, Bay K 8644 (366 +/- 71 nM/s). These antagonists and agonists were reversible with removal and [Mg2+]i subsequently returned to normal basal levels. Mg2+ entry rate was concentration and voltage dependent and maximally stimulated after 4 h in magnesium-free media. Cellular magnesium depletion results in increases in a Mg2+ refill rate which is dependent, in part, on de novo protein synthesis. These data provide evidence for novel Mg2+ entry pathways in cTAL cells which are specific for Mg2+ and highly regulated. These entry pathways are likely involved with renal Mg2+ homeostasis.


Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.
There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. We are using the results of this analysis to develop a prospective sample collection protocol.


Finding rule groups to classify high dimensional gene expression datasets.
Microarray data provides quantitative information about the transcription profile of cells. To analyze microarray datasets, methodology of machine learning has increasingly attracted bioinformatics researchers. Some approaches of machine learning are widely used to classify and mine biological datasets. However, many gene expression datasets are extremely high dimensionality, traditional machine learning methods cannot be applied effectively and efficiently. This paper proposes a robust algorithm to find out rule groups to classify gene expression datasets. Unlike the most classification algorithms, which select dimensions (genes) heuristically to form rules groups to identify classes such as cancerous and normal tissues, our algorithm guarantees finding out best-k dimensions (genes) to form rule groups for the classification of expression datasets. Our experiments show that the rule groups obtained by our algorithm have higher accuracy than that of other classification approaches.


Two-year Clinical Outcomes Post Implantation of EpicTM Self-Expanding Nitinol Stents for the Aortoiliac Occlusive Disease in Patients with Peripheral Arterial Disease.
We investigated 2-year clinical outcomes after implantaton of EpicTM self-expanding nitinol stents for patients with peripheral artery disease (PAD) due to the aortoiliac occlusive disease (AIOD). This study was a multicenter and retrospective study. From February 2013 through October 2014, 292 lesions (chronic total occlusion, 21%; TASC Ⅱ C/D, 35%) in 217 consecutive patients (74±8 years; male, 81%; diabetes mellitus, 47%; dialysis, 21%; critical limb ischemia, 29%) who had undergone endovascular therapy (EVT) with EpicTM self-expanding nitinol stents for PAD with AIOD were analyzed. The primary endpoints were 2-year primary patency and target lesion revascularization (TLR)-free rate. The primary patency and freedom from TLR were determined by Kaplan-Meier analysis. Additionally, predictors for loss of patency were estimated by Cox proportional hazard model. The mean follow-up duration was 19.1±8.5 months. Primary patency was 87.3% at 2 years. Freedom from TLR rate was 94.1% at 2 years. Multivariate analysis revealed that the presence of diabetes mellitus was associated with a loss of patency. The EpicTM self-expanding nitinol stent was demonstrated to be safe and effectivene for AIOD when tested for two years in patients with PAD.


High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder.
Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.


Motor imagery ability in stroke patients: the relationship between implicit and explicit motor imagery measures.
There is little consensus on how motor imagery ability should be measured in stroke patients. In particular it is unclear how two methods tapping different aspects of the motor imagery process relate to each other. The aim of this study was to investigate the relationship between implicit and explicit motor imagery ability by comparing performance of stroke patients and controls on a motor imagery questionnaire and a hand laterality judgment task (HLJT). Sixteen ischemic stroke patients (36 ± 13 weeks post-stroke) and 16 controls, matched by age (51 ± 10 years), gender (7 females) and handedness (3 left-handed), performed a HLJT and completed a motor imagery questionnaire. Our study shows that neither in the healthy controls nor in patients, a correlation is found between the HLJT and the motor imagery questionnaire. Although the patient group scored significantly lower than the control group on the visual motor imagery component (U = 60; p = 0.010) and the kinesthetic motor imagery component (U = 63.5; p = 0.015) of the questionnaire, there were no significant differences between patients and controls on accuracy scores of the HLJT. Analyses of the reaction time profiles of patients and controls showed that patient were still able to use an implicit motor imagery strategy in the HLJT task. Our results show that after stroke performance on tests that measure two different aspects of motor imagery ability, e.g., implicit and explicit motor imagery, can be differently affected. These results articulate the complex relation phenomenological experience and the different components of motor imagery have and caution the use of one tool as an instrument for use in screening, selecting and monitoring stroke patients in rehabilitation settings.


Dose-related biphasic effect of the Parkinson's disease neurotoxin MPTP, on the spread, accumulation, and toxicity of α-synuclein.
Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, is characterized by the abnormal accumulation of intraneuronal inclusions enriched in aggregated α-synuclein (α-syn), known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the brain. Recent evidence suggests that the intrastriatal inoculation of α-syn preformed fibrils (PFF) in mice brain triggers endogenous α-syn in interconnected brain regions. 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP), a mitochondrial neurotoxin, has been used previously to generate a PD mouse model. However, the common methods of MPTP exposure do not induce LB or α-syn aggregation in mice. In the present study, we evaluated the effect of different doses of MPTP (10 mg/kg.b.wt and/or 25 mg/kg.b.wt) on the spread, accumulation, and toxicity of endogenous α-syn in mice administered an intrastriatal injection of human α-syn PFF. We inoculated human WT α-syn PFF in mouse striatum. At 6 weeks post PFF injection, we challenged the animal with two different doses of MPTP (10 mg/kg.b.wt and 25 mg/kg.b.wt) once daily for five consecutive days. At 2 weeks from the start of the MPTP regimen, we collected the mice brain and performed immunohistochemical analysis, and Rotarod test to assess motor coordination and muscle strength before and after MPTP injection. A single injection of human WT α-syn PFF in the mice striatum induced the propagation of α-syn, occurring as phosphorylated α-synuclein (pS129), towards the SNpc, within a very short time. Injection of a low dose of MPTP (10 mg/kg.b.wt) at 6 weeks post α-syn PFF inoculation further enhanced the spread, whereas a high dose of MPTP (25 mg/kg.b.wt.) reduced the spread. Majority of the accumulated α-syn were proteinase K resistant, as recognized using a conformation-specific α-syn antibody. Injection of α-syn PFF alone caused 12 % reduction in the number of tyrosine hydroxylase positive neurons while α-syn PFF + a low dose of MPTP caused 33 % reduction (loss), compared to the control mice injected with saline. This combination also reduced the motor coordination. Interestingly, a low dose of MPTP alone did not cause any significant reduction in the number of tyrosine hydroxylase positive neurons compared to saline treatment. Animals that received α-syn PFF and a high dose of MPTP showed massive activation of glial cells and decreased spread of α-syn, majority of which were detected in the nucleus. Our results suggest that a combination of human WT α-syn PFF and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time. Our model can be used to study the mechanisms of α-syn propagation and screen for potential drugs against PD.


Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones.
Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a') show optimal GI50 values (1.0 ± 0.1 μM and 1.7 ± 0.3 μM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b'), 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 μM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 μM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.


Unresponsive Wakefulness Syndrome in Children after Near-Drowning: Long-Term Outcome and Impact on the Families.
Among 131 children admitted to our institution for early phase rehabilitation after freshwater near-drowning (ND) between the year 1986 and 2000, 87 were in unresponsive wakefulness syndrome (UWS) for at least 4 weeks after the accidents. An anonymous questionnaire was sent to the families after 0.5 to 15.0 years (median: 4.6) and 48 mothers and 51 fathers of 55 of these 87 children were interviewed after 6.6 to 23.8 years (median: 13.8) of ND. At the time of the interviews, 8/55 children were able to perform daily living activities independently, 36/55 children were not able to do so (many of them suffered from chronic medical conditions like spasticity or disorders of swallowing), and 11/55 children had died. Health-related quality of life (HRQoL) was, however, similar to the normal population for mothers, and even higher for fathers. Furthermore, the ND accident had apparently not lead to a higher rate of separations of parents but had increased their likelihood to have further children. Feelings of guilt were highly prevalent (23/47 mothers, 20/47 fathers), and correlated with lower HRQoL of the respective parent. We found correlations between duty of supervision and feelings of guilt and between outcome and HRQoL for only the fathers. In conclusion, we found that after 4 weeks in UWS, the long-term neurological outcome of pediatric ND victims is often but not always poor. Despite often severe disabilities or death of the child during long-term care, parents surprisingly report little impact on their HRQoL, on the stability of their partnership or on their wish to have further children. Our findings may help parents and physicians to choose the best treatment for a child in UWS due to different etiologies striking the balance between rehabilitation and palliative care.


[Effects of temperature and illumination on flag leaf photosynthetic characteristics and senescence of wheat cultivars with different grain quality].
Taking wheat cultivars Yumai 34 (high protein content in grain) and Yangmai 9 (low protein content in grain) as test materials, and by the method of growth chamber, this paper studied the effects of different combinations of temperature and illumination on the photosynthetic characteristics and senescence of their flag leaves at grain-filling stage. The results showed that both high temperature and low illumination had negative effects on the photosynthesis. They decreased the net photosynthetic rate (Pn), photochemical efficiency (Fv/Fm), and actual photochemical efficiency (PhiPSII) significantly, but their action mechanisms were differed. High temperature mainly decreased the chlorophyll content (SPAD value) and Pn, while low illumination mainly decreased the chlorophyll fluorescence parameters Fv,/Fm and PhiPSII, and thus, inhibited the activity of PS II. High temperature increased the MDA content and decreased the soluble protein content and SOD activity, resulting in the acceleration of senescence, while low illumination increased the SOD activity and slowed down the senescence. Yumai 34 was more sensitive to high temperature and low illumination than Yangmai 9.


Micro-well arrays for 3D shape control and high resolution analysis of single cells.
In addition to rigidity, matrix composition, and cell shape, dimensionality is now considered an important property of the cell microenvironment which directs cell behavior. However, available tools for cell culture in two-dimensional (2D) versus three-dimensional (3D) environments are difficult to compare, and no tools exist which provide 3D shape control of single cells. We developed polydimethylsiloxane (PDMS) substrates for the culture of single cells in 3D arrays which are compatible with high-resolution microscopy. Cell adhesion was limited to within microwells by passivation of the flat upper surface through 'wet-printing' of a non-fouling polymer and backfilling of the wells with specific adhesive proteins or lipid bilayers. Endothelial cells constrained within microwells were viable, and intracellular features could be imaged with high resolution objectives. Finally, phalloidin staining of actin stress fibers showed that the cytoskeleton of cells in microwells was 3D and not limited to the cell-substrate interface. Thus, microwells can be used to produce microenvironments for large numbers of single cells with 3D shape control and can be added to a repertoire of tools which are ever more sought after for both fundamental biological studies as well as high throughput cell screening assays.


Women's perceptions of chemotherapy-induced cognitive side affects on work ability: a focus group study.
To investigate women's awareness of chemotherapy-induced cognitive changes, their perception of cognitive limitations in carrying out daily tasks and subsequent return to work decisions and perceptions of work ability. Evidence suggests that women diagnosed with breast cancer experience cognitive changes as a consequence of chemotherapy treatment. Although these changes tend to be subtle deficits in memory, concentration and the ability to organise information, there has been no published research identifying how they can impact patient's ability to work and subsequent employment decisions. This was a qualitative study. Data were collected from breast cancer survivors using semi-structured interviews with two focus groups (n = 6, n = 7). Interviews were transcribed verbatim and analysed using template analysis. Data were categorised into four main themes: (1) awareness of cognitive changes during and following chemotherapy, (2) cognitive ability and confidence in return to work, (3) impact of cognitive changes on work ability and (4) information on the cognitive side effects of chemotherapy. The views and experiences of breast cancer survivors towards returning to work and subsequent work ability were affected by chemotherapy-induced cognitive impairment. More specifically the appraisal of returning to work and ability to manage work were influenced by three interrelated factors: (1) actual cognitive ability following chemotherapy, (2) awareness of cognitive failures by the women and their families and (3) the subsequent impact on their confidence in carrying out daily tasks including work tasks. More information and support is needed to help patients with cancer to manage chemotherapy-induced cognitive impairments in home and workplace. Nurses are increasingly asked about the impact of cancer and its treatment on work and are therefore well positioned to offer this advice. Subsequently, nurses require additional knowledge and guidance to provide this information and support.


Pelvic fractures: part 1. Evaluation, classification, and resuscitation.
Pelvic fractures range in severity from low-energy, generally benign lateral compression injuries to life-threatening, unstable fracture patterns. Initial management of severe pelvic fractures should follow Advanced Trauma Life Support protocols. Initial reduction of pelvic blood loss can be provided by binders, sheets, or some form of external fixation, which serve to reduce pelvic volume, stabilize clot formation, and reduce ongoing tissue damage. Persistently unstable patients may benefit from angiography with selective embolization, pelvic packing, or a combination of these interventions. Open pelvic fractures involving the perineum or bowel injury benefit from fecal diversion by colostomy. Trauma team coordination facilitates efficient resuscitative efforts and may affect definitive management by optimizing incision, ostomy, or catheter placement. Established protocols for both open and closed pelvic fractures help to standardize care.


Light-induced shift current vortex crystals in moiré heterobilayers.
Transition metal dichalcogenide (TMD) moiré superlattices provide an emerging platform to explore various light-induced phenomena. Recently, the discoveries of novel moiré excitons have attracted great interest. The nonlinear optical responses of these systems are however still underexplored. Here, we report investigation of light-induced shift currents (a second-order response generating DC current from optical illumination) in the WSe2/WS2 moiré superlattice. We identify a striking phenomenon of the formation of shift current vortex crystals-i.e., two-dimensional periodic arrays of moiré-scale current vortices and associated magnetic fields with remarkable intensity under laboratory laser setup. Furthermore, we demonstrate high optical tunability of these current vortices-their location, shape, chirality, and magnitude can be tuned by the frequency, polarization, and intensity of the incident light. Electron-hole interactions (excitonic effects) are found to play a crucial role in the generation and nature of the shift current intensity and distribution. Our findings provide a promising all-optical control route to manipulate nanoscale shift current density distributions and magnetic field patterns, as well as shed light on nonlinear optical responses in moiré quantum matter and their possible applications.


Time series identification and Kalman filtering techniques for Doppler lidar velocity estimation.
The use of recursive techniques based on Kalman filter algorithms for identification of time series system models for Doppler lidar returns and the subsequent filtering and smoothing of measured data is explored. The form of possible stochastic system models is reviewed, and reiterative maximum likelihood and innovation spectral tests are used for identification. It is found that a random walk model is adequate for the returns here, and possible explanations for this are considered. Examples are given to illustrate the extension of our method to real-time applications and on-line outlier rejection.


Regulator of G-protein signaling-10 negatively regulates NF-κB in microglia and neuroprotects dopaminergic neurons in hemiparkinsonian rats.
Microglia are the brain-resident macrophages responsible for immune surveillance that become activated in response to injury, infection, environmental toxins, and other stimuli that threaten neuronal survival. Previous work from our group demonstrated that mice deficient in Regulator of G-protein Signaling 10 (RGS10), a microglia-enriched GTPase activating protein (GAP) for G-protein α subunits, displayed increased microglial burden in the CNS at birth and developed a parkinsonian phenotype after exposure to chronic systemic inflammation, implicating a neuroprotective role for RGS10 in the nigrostriatal pathway. While it is known that RGS10 is expressed in both microglia and certain subsets of neurons, it is not known whether RGS10 functions similarly in both cells types. In this study we sought to delineate the specific role of RGS10 in microglia and identify the molecular pathway(s) required for RGS10 to exert its actions in microglia. Here, we identify RGS10 as a negative regulator of the nuclear factor κB(NF-κB) pathway in microglia and demonstrate that the proinflammatory and cytotoxic phenotype of Rgs10-null microglia can be reversed by lentiviral-mediated restoration of RGS10 expression. In vivo gene transfer of RGS10 into the substantia nigra pars compacta (SNpc) of rats reduced microgliosis and protected against 6-OHDA neurotoxin-induced death of dopaminergic (DA) neurons. Together, our findings suggest that modulation of RGS10 activity in microglia may afford therapeutic benefit in the treatment of chronic neuroinflammatory conditions as well as neuroprotection against inflammation-related degeneration in Parkinson's disease (PD), the second most common neurodegenerative disorder affecting individuals over age 65.


Postcopulatory fertilization bias as a form of cryptic sexual selection.
Males and females share most of their genetic material yet often experience very different selection pressures. Some traits that are adaptive when expressed in males may therefore be maladaptive when expressed in females. Recent studies demonstrating negative correlations in fitness between parents and their opposite-sex progeny suggest that natural selection may favor a reduction in trait correlations between the sexes to partially mitigate intralocus sexual conflict. We studied sex-specific forms of selection acting in Anolis lizards in the Greater Antilles, a group for which the importance of natural selection has been well documented in species-level diversification, but for which less is known about sexual selection. Using the brown anole (Anolis sagrei), we measured fitness-related variation in morphology (body size), and variation in two traits reflecting whole animal physiological condition: running endurance and immune function. Correlations between body size and physiological traits were opposite between males and females and the form of natural selection acting on physiological traits significantly differed between the sexes. Moreover, physiological traits in progeny were correlated with the body-size of their sires, but correlations were null or even negative between parents and their opposite-sex progeny. Although results based on phenotypic and genetic correlations, as well as the action of natural selection, suggest the potential for intralocus sexual conflict, females used sire body size as a cue to sort sperm for the production of either sons or daughters. Our results suggest that intralocus sexual conflict may be at least partly resolved through post-copulatory sperm choice in A. sagrei.


Genetic study of dentinal growth in mandibular first molars of mice.
The dentinal growth of mandibular molars of mice could be determined by genetic and environmental factors as are other quantitative characters, such as crown size and craniofacial size. To study the relative contribution of genetic and environmental factors to dentinal growth, a partial diallel cross was carried out by the mating of one pair from each of six strains of mice. In each F1 offspring, the total amount of dentinal formation in the first molar of the right mandible was quantified as a volume by the time-marking method, using nitrilotri-acetate lead with the computerized image scanning system, and then analyzed by a quantitative genetic method. The result obtained was as follows: In either sex, both additive genetic and nonadditive genetic variance components of the accumulative volume of dentinal formation in the first molar were relatively large throughout the experimental period, while the environmental variance component was much smaller. Thus it could be concluded that the genetic factor contributed more to the whole process of dentinal growth in the first molar rather than the environmental one in this F1 population.


The contribution of area-level walkability to geographic variation in physical activity: a spatial analysis of 95,837 participants from the 45 and Up Study living in Sydney, Australia.
Individual-level studies support a positive relation between walkable built environments and participation in moderate-intensity walking. However, the utility of this evidence for population-level planning is less clear as it is derived at much finer spatial scales than those used for regional programming. The aims of this study were to: evaluate if individual-level relations between walkability and walking to improve health manifest at population-level spatial scales; assess the specificity of area-level walkability for walking relative to other moderate and vigorous physical activity (MVPA); describe geographic variation in walking and other MVPA; and quantify the contribution of walkability to this variation. Data on sufficient walking, sufficient MVPA, and high MVPA to improve health were analyzed for 95,837 Sydney respondents to the baseline survey of the 45 and Up Study between January 2006 and April 2010. We used conditional autoregressive models to create smoothed MVPA "disease maps" and assess relations between sufficient MVPA to improve health and area-level walkability adjusted for individual-level demographic, socioeconomic, and health factors, and area-level relative socioeconomic disadvantage. Within-cohort prevalence of meeting recommendations for sufficient walking, sufficient MVPA, and high MVPA were 31.7 (95% CI 31.4-32.0), 69.4 (95% CI 69.1-69.7), and 56.1 (95% CI 55.8-56.4) percent. Prevalence of sufficient walking was increased by 1.20 (95% CrI 1.12-1.29) and 1.07 (95% CrI 1.01-1.13) for high and medium-high versus low walkability postal areas, and for sufficient MVPA by 1.05 (95% CrI 1.01-1.08) for high versus low walkability postal areas. Walkability was not related to high MVPA. Postal area walkability explained 65.8 and 47.4 percent of residual geographic variation in sufficient walking and sufficient MVPA not attributable to individual-level factors. Walkability is associated with area-level prevalence and geographic variation in sufficient walking and sufficient MVPA to improve health in Sydney, Australia. Our study supports the use of walkability indexes at multiple spatial scales for informing population-level action to increase physical activity and the utility of spatial analysis for walkability research and planning.


Missing productivity gains in the Medicare physician Fee Schedule: where are they?
The Medicare Fee Schedule with payments for thousands of visits and procedures is updated periodically for the work component of changes in physician relative work. Three 5-year reviews of physician work by Medicare have been biased against finding productivity gains and reductions in physician work relative values. The authors present four studies showing shorter physician times with patients in their offices and in the operating room, increases in surgeons' self-reported total work in spite of declining operating room times, and growing numbers of costly handoffs to nonsurgeons, while surgeons receive full payment for postoperative follow-up with patients. Substantial savings exist in the fee schedule if productivity gains from greater delegation to ancillary staff and specialists, reengineering of services, and rapid learning by experience with new technologies were integrated into the periodic reviews.