Alcohol fixation of induced sputum samples for applications in rural communities.
Sputum induction is a tool recommended for the assessment of airway inflammation and disease management. Currently, its use is limited because samples need to be processed within 3 h of induction (ie, while cells are viable); therefore, this procedure is unavailable to most clinicians. To develop a fixation method for induced sputum samples that allows for a delay in processing while maintaining sample integrity and not altering the standard processing method. Sputum samples were collected and split into three portions: a fresh sample processed using the routine method (within 3 h, using dithiothreitol); fixation in alcohol followed by delayed processing using the routine method (within 48 h to 72 h, using dithiothreitol); and fixation in formaldehyde followed by delayed processing using an alternative method (within 48 h to 72 h, using proteolysis). For each method, cytospins were prepared and differential cell counts were performed. Fixation in alcohol provides accurate measures of eosinophils and macrophages, but not neutrophils. Formaldehyde fixation provides accurate measures of neutrophils and macrophages, but not eosinophils. Alcohol fixation is a superior method for eosinophil quantification. It requires alteration of standardized methods for sputum sample processing and should be recommended for monitoring eosinophilic airway disease in settings where immediate processing of a sputum sample is not possible.


Effects of Stereo and Screen Size on the Legibility of Three-Dimensional Streamtube Visualization.
We report the impact of display characteristics (stereo and size) on task performance in diffusion magnetic resonance imaging (DMRI) in a user study with 12 participants. The hypotheses were that (1) adding stereo and increasing display size would improve task accuracy and reduce completion time, and (2) the greater the complexity of a spatial task, the greater the benefits of an improved display. Thus we expected to see greater performance gains when detailed visual reasoning was required. Participants used dense streamtube visualizations to perform five representative tasks: (1) determine the higher average fractional anisotropy (FA) values between two regions, (2) find the endpoints of fiber tracts, (3) name a bundle, (4) mark a brain lesion, and (5) judge if tracts belong to the same bundle. Contrary to our hypotheses, we found the task completion time was not improved by the use of the larger display and that performance accuracy was hurt rather than helped by the introduction of stereo in our study with dense DMRI data. Bigger was not always better. Thus cautious should be taken when selecting displays for scientific visualization applications. We explored the results further using the body-scale unit and subjective size and stereo experiences.


CD1a presentation of endogenous antigens by group 2 innate lymphoid cells.
Group 2 innate lymphoid cells (ILC2) are effectors of barrier immunity, with roles in infection, wound healing, and allergy. A proportion of ILC2 express MHCII (major histocompatibility complex II) and are capable of presenting peptide antigens to T cells and amplifying the subsequent adaptive immune response. Recent studies have highlighted the importance of CD1a-reactive T cells in allergy and infection, activated by the presentation of endogenous neolipid antigens and bacterial components. Using a human skin challenge model, we unexpectedly show that human skin-derived ILC2 can express CD1a and are capable of presenting endogenous antigens to T cells. CD1a expression is up-regulated by TSLP (thymic stromal lymphopoietin) at levels observed in the skin of patients with atopic dermatitis, and the response is dependent on PLA2G4A. Furthermore, this pathway is used to sense Staphylococcus aureus by promoting Toll-like receptor-dependent CD1a-reactive T cell responses to endogenous ligands. These findings define a previously unrecognized role for ILC2 in lipid surveillance and identify shared pathways of CD1a- and PLA2G4A-dependent ILC2 inflammation amenable to therapeutic intervention.


One-step integration of metal nanoparticle in photonic crystal nanobeam cavity.
A single step process of integrating a resonantly tuned silver nanoparticle into photonic crystal nanobeam cavities fabricated by focused ion beam milling is presented. Even though the quality factor of the cavities is reduced by a factor of 20, the emission peak at the cavity resonance is enhanced by 5-fold with respect to the cavities without the metal nanoparticle. The fluorescence is also compared before and after etching away the nanoparticle. Experimental quality factors and wavelength shifts are found to agree reasonably well with simulation values. These results are promising for future single photon emission studies involving the incorporation of quantum dot or NV center emitters into hybrid plasmonic/photonic crystal cavities for enhanced emission rates while retaining reasonably high quality factors.


Developmental dyslexia and the dual route model of reading: simulating individual differences and subtypes.
Developmental dyslexia was investigated within a well-understood and fully specified computational model of reading aloud: the dual route cascaded model (DRC [Coltheart, M., Rastle, K., Perry, C., Langdon, R., & Ziegler, J.C. (2001). DRC: A dual route cascaded model of visual word recognition and reading aloud. Psychological Review, 108, 204-256.]). Four tasks were designed to assess each representational level of the DRC: letter level, orthographic lexicon, phonological lexicon, and phoneme system. The data showed no single cause of dyslexia, but rather a complex pattern of phonological, phonemic, and letter processing deficits. Importantly, most dyslexics had deficits in more than one domain. Subtyping analyses also suggested that both the phonological and surface dyslexics almost always had more than a single underlying deficit. To simulate the reading performance for each individual with the DRC, we added noise to the model at a level proportional to the underlying deficit(s) of each individual. The simulations not only accounted fairly well for individual reading patterns but also captured the different dyslexia profiles discussed in the literature (i.e., surface, phonological, mixed, and mild dyslexia). Thus, taking into account the multiplicity of underlying deficits on an individual basis provides a parsimonious and accurate description of developmental dyslexia. The present work highlights the necessity and merits of investigating dyslexia at the level of each individual rather than as a unitary disorder.


A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain.
Active adult neurogenesis occurs in discrete brain regions of all mammals and is widely regarded as a neuronal replacement mechanism. Whether adult-born neurons make unique contributions to brain functions is largely unknown. Here we systematically characterized synaptic plasticity of retrovirally labeled adult-born dentate granule cells at different stages during their neuronal maturation. We identified a critical period between 1 and 1.5 months of the cell age when adult-born neurons exhibit enhanced long-term potentiation with increased potentiation amplitude and decreased induction threshold. Furthermore, such enhanced plasticity in adult-born neurons depends on developmentally regulated synaptic expression of NR2B-containing NMDA receptors. Our study demonstrates that adult-born neurons exhibit the same classic critical period plasticity as neurons in the developing nervous system. The transient nature of such enhanced plasticity may provide a fundamental mechanism allowing adult-born neurons within the critical period to serve as major mediators of experience-induced plasticity while maintaining stability of the mature circuitry.


Cyclophilin A in cardiovascular homeostasis and diseases.
Vascular homeostasis is regulated by complex interactions between many vascular cell components, including endothelial cells, vascular smooth muscle cells (VSMCs), adventitial inflammatory cells, and autonomic nervous system. The balance between oxidant and antioxidant systems determines intracellular redox status, and their imbalance can cause oxidative stress. Excessive oxidative stress is one of the important stimuli that induce cellular damage and dysregulation of vascular cell components, leading to vascular diseases through multiple pathways. Cyclophilin A (CyPA) is one of the causative proteins that mediate oxidative stress-induced cardiovascular dysfunction. CyPA was initially discovered as the intracellular receptor of the immunosuppressive drug cyclosporine 30 years ago. However, recent studies have established that CyPA is secreted from vascular cell components, such as endothelial cells and VSMCs. Extracellular CyPA augments the development of cardiovascular diseases. CyPA secretion is regulated by Rho-kinase, which contributes to the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. We recently reported that plasma CyPA levels are significantly higher in patients with coronary artery disease, which is associated with increased numbers of stenotic coronary arteries and the need for coronary intervention in such patients. Furthermore, we showed that the vascular erythropoietin (Epo)/Epo receptor system plays an important role in production of nitric oxide and maintenance of vascular redox state and homeostasis, with a potential mechanistic link to the Rho-kinase-CyPA pathway. In this article, I review the data on the protective role of the vascular Epo/Epo receptor system and discuss the roles of the CyPA/Rho-kinase system in cardiovascular diseases.


Vitamin D receptor activators upregulate and rescue podocalyxin expression in high glucose-treated human podocytes.
Vitamin D is beneficial in human and experimental chronic kidney disease, the leading cause of which is diabetic nephropathy. Vitamin D through its receptor, VDR, provides renal protection in diabetic nephropathy, but limited data exist about its effect on podocytes. Renal podocytes form the main filtration barrier possessing a unique phenotype maintained by proteins including podocalyxin and nephrin, the expression of which is suppressed in pathological conditions. We used immortalized human podocytes (human glomerular epithelial cells, HGEC) to assess podocalyxin and nephrin expression after treatment with 1,25-dihydroxyvitamin D3 (calcitriol) and its analogue paricalcitol. The involvement of VDR was investigated by silencing with hVDR-siRNA and ChIP analysis. HGEC exhibit high glucose-mediated downregulation of podocalyxin and nephrin, loss of which has been linked with loss of the permselective renal barrier and proteinuria. Calcitriol and paricalcitol reversed high glucose-induced decrease of nephrin and significantly enhanced podocalyxin expression in podocytes cultured in high glucose. HGEC express VDR and retinoid X receptor (RXR). In the presence of calcitriol and paricalcitol, VDR expression was upregulated and VDR colocalized with RXR in the nucleus. VDR knockdown abolished the protective action of calcitriol and paricalcitol on podocalyxin expression indicating that podocalyxin activation of expression is partly mediated by VDR. Furthermore, VDR specifically regulates podocalyxin expression by bounding to a site upstream of the podocalyxin promoter. Vitamin D analogues maintain and, furthermore, re-activate the expression of specialized components of podocytes including podocalyxin, hence they provide protection against loss of the permselective renal barrier, with molecular mechanisms elucidated herein.


Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially.
Wharton's jelly derived stem cells (WJMSCs) are gaining attention as a possible clinical alternative to bone marrow derived mesenchymal stem cells (BMMSCs) owing to better accessibility, higher expansion potential and low immunogenicity. Usage of allogenic mesenchymal stem cells (MSC) could be permissible in vivo only if they retain their immune properties in an inflammatory setting. Thus the focus of this study is to understand and compare the immune properties of BMMSCs and WJMSCs primed with key pro-inflammatory cytokines, Interferon-gamma (IFNgamma) and Tumor Necrosis Factor-alpha (TNFalpha). Initially the effect of priming on MSC mediated suppression of alloantigen and mitogen induced lymphoproliferation was evaluated in vitro. Treatment with IFNgamma or TNFalpha, did not ablate the immune-suppression caused by both the MSCs. Extent of immune-suppression was more with WJMSCs than BMMSCs in both the cases. Surprisingly, priming BMMSCs enhanced suppression of mitogen driven lymphoproliferation only; whereas IFNgamma primed WJMSCs were better suppressors of MLRs. Further, kinetic analysis of cytokine profiles in co-cultures of primed/unprimed MSCs and Phytohematoagglutinin (PHA) activated lymphocytes was evaluated. Results indicated a decrease in levels of pro-inflammatory cytokines. Interestingly, a change in kinetics and thresholds of Interleukin-2 (IL-2) secretion was observed only with BMMSCs. Analysis of activation markers on PHA-stimulated lymphocytes indicated different expression patterns in co-cultures of primed/unprimed WJMSCs and BMMSCs. Strikingly, co-culture with WJMSCs resulted in an early activation of a negative co-stimulatory molecule, CTLA4, which was not evident with BMMSCs. A screen for immune suppressive factors in primed/unprimed WJMSCs and BMMSCs indicated inherent differences in IFNgamma inducible Indoleamine 2, 3-dioxygenase (IDO) activity, Hepatocyte growth factor (HGF) and Prostaglandin E-2 (PGE2) levels which could possibly influence the mechanism of immune-modulation. This study demonstrates that inflammation affects the immune properties of MSCs distinctly. Importantly different tissue derived MSCs could utilize unique mechanisms of immune-modulation.


Opioids, Pain Management, and Palliative Care in a Norwegian Nursing Home From 2013 to 2018.
In Norway, approximately 50% of older people die in nursing homes (NH). Holistic care and pharmacological management are key factors in quality at the end of life. The purpose of this longitudinal study was to describe the use of opioids in an NH during a 5-year period. We focused on palliative care, symptoms, and suffering during the last 3 days before death. Data were collected from spring 2013 to spring 2018. We used the interRAI assessment instrument annually and when the resident died. We conducted a semi-structured interview with nurses on duty at the deathbed. At the time of death, the residents had an average age of 88.9 years and an average stay of 2.9 years (N = 100). At the first assessment, 19% of the residents used 1 or more type of opioids. On the day of death, 55% had an active prescription for opioids, mainly as subcutaneous injections. The results illustrate the different uses of opioids, including managing pain, dyspnoea, sedation, for comfort, as a prophylaxis, or a combination of reasons. Cancer- and cardiovascular diagnoses were the strongest predictor for using morphine (P < 0.05). Identification of the residents' needs for opioids is a challenge for palliative care nurses, both ethically and legally.


The orchestration of occupation: the dance of mothers.
This article describes the relationship of mothers' orchestration of daily occupations, the specialized maternal work of parenting a child with a disability, and the mother's subjective well-being. Mothers' daily occupations and subjective well-being were studied using multiple in-depth interviews, participant observation of a day's round of occupations, and scales of well-being. Data were treated to a recursive analysis, which included theoretical notes generated during transcriptions that identified important themes and additional points of inquiry, line-by-line coding of transcripts, and theoretical sorting of codes and regrouping, recoding. To account for patterns in the data, a relational analysis was conducted that included the generation of metaphors. Emergent findings of this analysis identified the mothers' guiding occupational motif and eight processes of orchestration in their daily routines. The occupational motif, the embrace of paradox, directed the mother's orchestration of daily occupations. The orchestration processes included planning, organizing, balancing, anticipating, interpreting, forecasting, perspective shifting, and meaning making. Examples illustrate the maternally driven and child-sensitive nature of these processes. In their daily rounds, the mothers studied were attentive to the manner and method with which they interacted with their children to produce child-contingent occupations commensurate with their values of being a good mother. Using these orchestration processes, mothers made sense of their past, designed their present, and planned for their future within their daily occupational rounds for themselves and family members.


Osteopontin-immunoreactivity in the rat trigeminal ganglion and trigeminal sensory nuclei.
Osteopontin-immunoreactivity (OPN-ir) was examined in the oro-facial tissues and trigeminal sensory nuclei (principal sensory nucleus and spinal trigeminal nucleus) to ascertain the peripheral ending and central projection of OPN-containing primary sensory neurons in the trigeminal ganglion (TG). No staining was observed using mouse monoclonal anti-OPN antibody preabsorbed with recombinant mature OPN. OPN-immunoreactive (ir) peripheral endings were classified into two types: encapsulated and unencapsulated types. Unencapsulated endings were subdivided into two types: simple and complex types. Simple endings were characterized by the thin neurite that was usually devoid of ramification. These endings were seen in the hard plate and gingiva. The complex type was characterized by the thick ramified neurite, and observed in the vibrissa, hard palate, and molar periodontal ligament. Encapsulated endings were found only in the hard palate. The trigeminal sensory nuclei contained OPN-ir cell bodies and neuropil. The neuropil was devoid of ir in laminae I and II of the medullary dorsal horn (MDH), and had various staining intensities in other regions of the trigeminal sensory nuclei. Transection of the infraorbital and inferior alveolar nerves caused an increase of OPN-ir intensity in ipsilateral TG neurons. The staining intensity of the neuropil also increased in the trigeminal sensory nuclei ipsilateral to the neurotomy excepting laminae I and II of the MDH. The present study indicates that OPN-ir primary sensory neurons in the TG innervate encapsulated and unencapsulated corpuscular endings. Such neurons probably project their central terminals to the trigeminal sensory nuclei except for the superficial laminae of the MDH.


The effect of brief interventions on alcohol consumption among heavy drinkers in a general hospital setting.
(i) To evaluate the effect of receiving one of two brief interventions in reducing alcohol consumption among general hospital patients compared with usual care. (ii) To assess whether a brief intervention of self-efficacy enhancement was superior to a self-help booklet in reducing alcohol consumption. A three-arm cluster randomized controlled trial. Seven general medical, six general surgical, one dermatology and two otolaryngology wards of a large teaching hospital covering a large urban and rural area. A total of 215 of 789 in-patients aged 18-75 years, who screened positive for alcohol consumption in excess of national recommended limits according to a 7-day retrospective drinking diary. Participants were allocated to receive one of three interventions: (i) face-to-face self-efficacy enhancement; (ii) a self-help booklet; or (iii) usual care. The primary outcome measure was change in reported alcohol consumption at 6-month follow-up as measured by a 7-day retrospective drinking diary. Secondary outcomes were change in: number of alcohol drinking days in last week; the maximum units of alcohol consumed on any one day in last week; and Drinking Refusal Self-efficacy Expectancy Questionnaire score. Compared to the usual care group the self-efficacy enhancement group (-10.1 units 95% CI -16.1 to -4.1) and the self-help booklet group (-10.0 units 95% CI -16.0 to -3.9) had greater reductions in self-reported weekly alcohol consumption. There was no evidence that self-efficacy enhancement was superior to the self-help booklet (P = 0.96). Brief interventions delivered in hospital offer simple means of helping heavy drinkers to reduce their alcohol consumption.


Paracellin-1 gene mutation with multiple congenital abnormalities.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.


Estimation of Resting Energy Expenditure Using Predictive Equations in Critically Ill Children: Results of a Systematic Review.
Provision of adequate energy intake to critically ill children is associated with improved prognosis, but resting energy expenditure (REE) is rarely determined by indirect calorimetry (IC) due to practical constraints. Some studies have tested the validity of various predictive equations that are routinely used for this purpose, but no systematic evaluation has been made. Therefore, we performed a systematic review of the literature to assess predictive equations of REE in critically ill children. We systematically searched the literature for eligible studies, and then we extracted data and assigned a quality grade to each article according to guidelines of the Academy of Nutrition and Dietetics. Accuracy was defined as the percentage of predicted REE values to fall within ±10% or ±15% of the measured energy expenditure (MEE) values, computed based on individual participant data. Of the 993 identified studies, 22 studies testing 21 equations using 2326 IC measurements in 1102 children were included in this review. Only 6 equations were evaluated by at least 3 studies in critically ill children. No equation predicted REE within ±10% of MEE in >50% of observations. The Harris-Benedict equation overestimated REE in two-thirds of patients, whereas the Schofield equations and Talbot tables predicted REE within ±15% of MEE in approximately 50% of observations. In summary, the Schofield equations and Talbot tables were the least inaccurate of the predictive equations. We conclude that a new validated indirect calorimeter is urgently needed in the critically ill pediatric population.).


Elucidating Drought-Tolerance Mechanisms in Plant Roots through 1H NMR Metabolomics in Parallel with MALDI-MS, and NanoSIMS Imaging Techniques.
As direct mediators between plants and soil, roots play an important role in metabolic responses to environmental stresses such as drought, yet these responses are vastly uncharacterized on a plant-specific level, especially for co-occurring species. Here, we aim to examine the effects of drought on root metabolic profiles and carbon allocation pathways of three tropical rainforest species by combining cutting-edge metabolomic and imaging technologies in an in situ position-specific 13C-pyruvate root-labeling experiment. Further, washed (rhizosphere-depleted) and unwashed roots were examined to test the impact of microbial presence on root metabolic pathways. Drought had a species-specific impact on the metabolic profiles and spatial distribution in Piper sp. and Hibiscus rosa sinensis roots, signifying different defense mechanisms; Piper sp. enhanced root structural defense via recalcitrant compounds including lignin, while H. rosa sinensis enhanced biochemical defense via secretion of antioxidants and fatty acids. In contrast, Clitoria fairchildiana, a legume tree, was not influenced as much by drought but rather by rhizosphere presence where carbohydrate storage was enhanced, indicating a close association with symbiotic microbes. This study demonstrates how multiple techniques can be combined to identify how plants cope with drought through different drought-tolerance strategies and the consequences of such changes on below-ground organic matter composition.


Ideology and COVID-19 Vaccination Intention: Perceptual Mediators and Communication Moderators.
Widespread COVID-19 vaccination is critical to slow the spread of the illness. This study investigates how political ideology is associated with COVID-19 vaccine intention via perceived effectiveness of the vaccine, perceived side effects, and perceived severity of the illness, three key aspects of the Health Belief Model (HBM). This study also examines how partisan information flow moderates the effects of ideology on these three HBM components. Using survey data collected from two battleground states in the 2020 election (N = 1849), regression, mediation and moderation analyses revealed that conservatives were less likely to intend to get vaccinated against COVID-19, and this association was significantly mediated by perceived effectiveness and perceived side effects of vaccination, as well as perceived severity of COVID-19. In addition, partisanship of news sources and discussion partners were significant moderators of ideology's association with perceived vaccine effectiveness, with conservatives viewing COVID-19 vaccination as less effective if they were frequently exposed to liberal news, and if they had frequent conversations with fellow conservatives. This suggests boomerang effects for cross-cutting mass media exposure, and reinforcement effect for interpersonal communication. Implications for efforts to promote COVID-19 vaccine uptake are discussed, including tailored and targeted campaign strategies.


Pseudotime Dynamics in Melanoma Single-Cell Transcriptomes Reveals Different Mechanisms of Tumor Progression.
Single-cell transcriptomics has been used for analysis of heterogeneous populations of cells during developmental processes and for analysis of tumor cell heterogeneity. More recently, analysis of pseudotime (PT) dynamics of heterogeneous cell populations has been established as a powerful concept to study developmental processes. Here we perform PT analysis of 3 melanoma short-term cultures with different genetic backgrounds to study specific and concordant properties of PT dynamics of selected cellular programs with impact on melanoma progression. Overall, in our setting of melanoma cells PT dynamics towards higher tumor malignancy appears to be largely driven by cell cycle genes. Single cells of all three short-term cultures show a bipolar expression of microphthalmia-associated transcription factor (MITF) and AXL receptor tyrosine kinase (AXL) signatures. Furthermore, opposing gene expression changes are observed for genes regulated by epigenetic mechanisms suggesting epigenetic reprogramming during melanoma progression. The three melanoma short-term cultures show common themes of PT dynamics such as a stromal signature at initiation, bipolar expression of the MITF/AXL signature and opposing regulation of poised and activated promoters. Differences are observed at the late stage of PT dynamics with high, low or intermediate MITF and anticorrelated AXL signatures. These findings may help to identify targets for interference at different stages of tumor progression.


Fusing functional signals by sparse canonical correlation analysis improves network reproducibility.
We contribute a novel multivariate strategy for computing the structure of functional networks in the brain from arterial spin labeling (ASL) MRI. Our method fuses and correlates multiple functional signals by employing an interpretable dimensionality reduction method, sparse canonical correlation analysis (SCCA). There are two key aspects of this contribution. First, we show how SCCA may be used to compute a multivariate correlation between different regions of interest (ROI). In contrast to averaging the signal over the ROI, this approach exploits the full information within the ROI. Second, we show how SCCA may simultaneously exploit both the ASL-BOLD and ASL-based cerebral blood flow (CBF) time series to produce network measurements. Our approach to fusing multiple time signals in network studies improves reproducibility over standard approaches while retaining the interpretability afforded by the classic ROI region-averaging methods. We show experimentally in test-retest data that our sparse CCA method extracts biologically plausible and stable functional network structures from ASL. We compare the ROI approach to the CCA approach while using CBF measurements alone. We then compare these results to the joint BOLD-CBF networks in a reproducibility study and in a study of functional network structure in traumatic brain injury (TBI). Our results show that the SCCA approach provides significantly more reproducible results compared to region-averaging, and in TBI the SCCA approach reveals connectivity differences not seen with the region averaging approach.


Drug-related deaths and the sales of needles through pharmacies.
Providing needles to people who inject drugs is a well-proven public health response to the transmission of HIV and other blood borne viruses. Despite over a quarter of a century of research, new concerns about potential unintended negative consequences of needle distribution continue to emerge. Specifically, a claim was recently made that the introduction of pharmacy sales of needles was followed by an increase in overdoses in pharmacy parking lots. If true, this would have serious implications for the design of needle access programs, particularly those involving pharmacy sales of needles. We examine spatial relationships between drug-related deaths and pharmacies in Los Angeles County (population 9.8 million) before and after the 2007 enactment of a California law allowing pharmacy sales of needles without a prescription. Seven thousand and forty-nine drugs related deaths occurred in Los Angeles county from 2000 to 2009 inclusive. Four thousand two hundred and seventy-five of these deaths could be geocoded, and were found to be clustered at the census tract level. We used three methods to examine spatial relationships between overdose death locations and pharmacy locations for two years on either side of the enactment of the pharmacy sales law, and found no statistically significant changes. Among the 711 geocodable deaths occurring in the two years following the change in law, no death was found to occur within 50m of a pharmacy which sold needles. These results are consistent with prior studies which suggest pharmacy sales of needles improve access to needles without causing increased harms to the surrounding community.


Conspiracies of immanence: Paul Tillich, Pierre Teilhard de Chardin and C.G. Jung.
Jung's psychology proffers a sustained reflection on the traditional religious question of the relation of divine transcendence to immanence. On this issue his psychology affirms a position of radical immanence in its contention that the experience of divinity is initially wholly from within. Though this position remains on the periphery of religious and theological orthodoxy Jung is not alone in holding it among moderns. Paul Tillich adopts a similar stance with his controlling symbols of the divine as 'Ground of Being' and 'Depth of Reason'. Pierre Teilhard de Chardin understands divinity as the experiential energy of evolution itself working within nature and humanity toward greater configurations of universal communion as the basis of community. All of Jung's master symbols of individuation assume such an understanding of immanence uniting individual and totality. His psychology strongly suggests and contributes to the current emergence of a new religious sensitivity based on the awareness of the intra-psychic origin of all religions. In his later writings he held out such a position as a significant alternative to genocide.


Catalytic asymmetric Nozaki-Hiyama reactions with a tridentate bis(oxazolinyl)carbazole ligand.
Nozaki-Hiyama reactions are powerful Cr(II)-mediated C--C bond-forming reactions conducted under mild conditions that show excellent compatibility with various functional groups. Therefore, Nozaki-Hiyama reactions have been utilized for many total syntheses of complex natural products, but at least two equivalents of Cr(II) salt are required to complete the reaction because Cr(II) salt is a one-electron donor. In 1996, however, the quantity of Cr(II) salts required was successfully reduced by a catalytic redox system reported by Fürstner and Shi. Since the report by Fürstner, the catalytic asymmetric Nozaki-Hiyama reactions have attracted attention because they would allow control over enantioselectivity, thereby further enhancing the versatility of Nozaki-Hiyama reactions. In this review, we describe the development of a tridentate bis(oxazolinyl)carbazole ligand for the catalytic asymmetric Nozaki-Hiyama allylation, methallylation, propargylation, and allenylation. Also described are their successful applications to the highly stereoselective construction of the side chain of calcitriol lactone, as well as structure elucidation and the enantioselective first total synthesis of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, FR901512 and FR901516.


Autoimmune acute liver failure: proposed clinical and histological criteria.
Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone.


Atomic and molecular layer deposition: off the beaten track.
Atomic layer deposition (ALD) is a gas-phase deposition technique that, by relying on self-terminating surface chemistry, enables the control of the amount of deposited material down to the atomic level. While mostly used in semiconductor technology for the deposition of ceramic oxides and nitrides on wafers, ALD lends itself to the deposition of a wealth of materials on virtually every substrate. In particular, ALD and its organic counterpart molecular layer deposition (MLD), have opened up attractive avenues for the synthesis of novel nanostructured materials. However, as most ALD processes were developed and optimized for semiconductor technology, these might not be optimal for applications in fields such as catalysis, energy storage, and health. For this reason, novel applications for ALD often require new surface chemistries, process conditions, and reactor types. As a result, recent developments in ALD technology have marked a considerable departure from the standard set by well-established ALD processes. The aim of this review is twofold: firstly, to capture the recent departure of ALD from its original development; and secondly, to pinpoint the unexplored paths through which ALD can advance further in terms of synthesis of novel materials. To that end, we provide a review of the recent developments of ALD and MLD of materials that are gaining increasing attention on various substrates, with particular emphasis on high-surface-area substrates. Furthermore, we present a critical review of the effects of the process conditions, namely, temperature, pressure, and time on ALD growth. Finally, we also give a brief overview of the recent advances in ALD reactors and energy-enhanced ALD processes.


A 10-year literature review of family caregiving for motor neurone disease: moving from caregiver burden studies to palliative care interventions.
There is growing awareness that different terminal diseases translate into different family caregiver experiences, and the palliative and supportive care needs of these families are both similar and unique. Family members caring for people with motor neurone disease may experience exceptional strain due to the usually rapid and progressive nature of this terminal illness. The purpose of this review is to synthesize contemporary research and provide a comprehensive summary of findings relevant to motor neurone disease family caregivers, as well as highlight some of the suggested interventions to alleviate burden and improve quality of life for this group. We conducted a comprehensive review of empirical research on family caregiving for people with motor neurone disease in peer-reviewed journals published in English, January 2000-April 2011. Fifty-nine studies met the inclusion criteria. This comprehensive literature review was consistent with previous research documenting the substantial burden and distress experienced by motor neurone disease family caregivers and revealed important points in the trajectory of care that have the potential for negative effects. The diagnosis experience, assisted ventilation, cognitive changes and end-of-life decision making create challenges within a short time. This review has also implicated the need for improvements in access to palliative care services and highlighted the absence of interventions to improve care. Caregiver burden and quality-of-life studies on motor neurone disease family caregivers have so far dominated the research landscape .The focus needs to be on developing interventions that provide direct practical and psychosocial supports for motor neurone disease family caregivers.


Somatic motoneurone specification in the hindbrain: the influence of somite-derived signals, retinoic acid and Hoxa3.
We have investigated the mechanisms involved in generating hindbrain motoneurone subtypes, focusing on somatic motoneurones, which are confined to the caudal hindbrain within rhombomeres 5-8. Following heterotopic transplantation of rhombomeres along the rostrocaudal axis at various developmental stages, we have found that the capacity of rhombomeres to generate somatic motoneurones is labile at the neural plate stage but becomes fixed just after neural tube closure, at stage 10-11. Grafting of somites or retinoic acid-loaded beads beneath the rostral hindbrain induced the formation of somatic motoneurones in rhombomere 4 only, and Hox genes normally expressed more caudally (Hoxa3, Hoxd4) were induced in this region. Targeted overexpression of Hoxa3 in the rostral hindbrain led to the generation of ectopic somatic motoneurones in ventral rhombomeres 1-4, and was accompanied by the repression of the dorsoventral patterning gene Irx3. Taken together, these observations suggest that the somites, retinoic acid and Hox genes play a role in patterning somatic motoneurones in vivo.


Effect of gestational weight gain on perinatal outcomes in women with type 2 diabetes mellitus using the 2009 Institute of Medicine guidelines.
We sought to examine associations between gestational weight gain according to the 2009 Institute of Medicine (IOM) guidelines and perinatal outcomes in overweight/obese women with type 2 diabetes mellitus (T2DM). This is a retrospective cohort study of 2310 women with T2DM enrolled in the California Diabetes and Pregnancy Program. Gestational weight gain was categorized by 2009 IOM guidelines. Perinatal outcomes were assessed using the χ(2) test and multivariable logistic regression analysis. With excessive gestational weight gain, the odds of having large-for-gestational age (adjusted odds ratio [aOR], 2.00; 95% confidence interval [CI], 1.33-3.00) or macrosomic (aOR, 2.59; 95% CI, 1.56-4.30) neonates and cesarean delivery (aOR, 1.47; 95% CI, 1.03-2.10) was higher. Women with excessive gestational weight gain per week had increased odds of preterm delivery (aOR, 1.57; 95% CI, 1.11-2.20). In overweight or obese women with T2DM, gestational weight gain greater than the revised IOM guidelines was associated with higher odds of perinatal morbidity, suggesting these guidelines are applicable to a diabetic population.


Optical Coherence Tomography Angiography in Mice: Quantitative Analysis After Experimental Models of Retinal Damage.
We implemented optical coherence tomography angiography (OCT-A) in mice to: (1) develop quantitative parameters from OCT-A images, (2) measure the reproducibility of the parameters, and (3) determine the impact of experimental models of inner and outer retinal damage on OCT-A findings. OCT-A images were acquired with a customized system (Spectralis Multiline OCT2). To assess reproducibility, imaging was performed five times over 1 month. Inner retinal damage was induced with optic nerve transection, crush, or intravitreal N-methyl-d-aspartic acid injection in transgenic mice with fluorescently labeled retinal ganglion cells (RGCs). Light-induced retinal damage was induced in albino mice. Mice were imaged at baseline and serially post injury. Perfusion density, vessel length, and branch points were computed from OCT-A images of the superficial, intermediate, and deep vascular plexuses. The range of relative differences measured between sessions across the vascular plexuses were: perfusion density (2.8%-7.0%), vessel length (1.9%-4.1%), and branch points (1.9%-5.0%). In mice with progressive RGC loss, imaged serially and culminating in around 70% loss in the fluorescence signal and 18% loss in inner retinal thickness, there were no measurable changes in any OCT-A parameter up to 4 months post injury that exceeded measurement variability. However, light-induced retinal damage elicited a progressive loss of the deep vascular plexus signal, starting as early as 3 days post injury. Vessel length and branch points were generally the most reproducible among the parameters. Injury causing RGC loss in mice did not elicit an early change in the OCT-A signal.


Neurocutaneous sural flap in paraplegic patients.
Neurocutaneous flaps have been demonstrated to be a reliable option in different groups of patients but it remains unclear if distally-based sural flaps can be safely used in paraplegic patients because they suffer from significant nervous system alterations. The aim of this proof-of-concept study is to demonstrate that these flaps are reliable in paraplegic patients. We prospectively analysed a group (n=6) of paraplegic patients who underwent reversed sural flap surgery for ulcers on the lateral malleolus. Measurement of area and photographic documentation techniques have been employed to quantify the defect area. Sural nerve biopsies have been analysed histologically with several different staining techniques to assess the neurovascular network and the myelinisation of the nerve. The patients showed uneventful wound healing, except one case that suffered a partial flap necrosis that healed by secondary intention. Histologic analysis revealed an intact neurovascular network and myelinated nerve fibres. In this small series of paraplegic patients that underwent a distally-based sural flap, the complication rate was low, with only one case of superficial partial necrosis demonstrating the reliability and safety of the flap in this subset of patients. Histologic evaluation of sural nerve biopsies revealed an almost normal morphology. A possible explanation of this phenomenon is that the dorsal root ganglia remain intact in paraplegic patients and can preserve neural characteristics in the peripheral sensory nerve system.


Aneurysmal SAH: cognitive outcome and structural damage after clipping or coiling.
Aneurysmal subarachnoid hemorrhage (SAH) and surgical clipping of intracranial aneurysms are associated with substantial morbidity and mortality. To compare cognitive outcome and structural damage in patients with aneurysmal SAH treated with surgical clipping or endovascular coiling. Forty case-matched pairs of patients with aneurysmal SAH treated by surgical clipping or endovascular coiling were prospectively assessed by use of a battery of cognitive tests. Twenty-three case-matched pairs underwent MRI 1 year after the procedure. Matching was based on grade of SAH on admission, location of aneurysm, age, and premorbid IQ. Both groups were impaired in all cognitive domains when compared with age-matched healthy control subjects. Comparison of cognitive outcome between the two groups indicated an overall trend toward a poorer cognitive outcome in the surgical group, which achieved significance in four tests. MRI showed focal encephalomalacia exclusively in the surgical group. This group also had a significantly higher incidence of single or multiple small infarcts within the vascular territory of the aneurysm, but both groups had similar incidence of large infarcts and global ischemic damage. Endovascular treatment may cause less structural brain damage than surgery and have a more favorable cognitive outcome. However, cognitive outcome appears to be dictated primarily by the complications of SAH.


Routine assessment of performance status during palliative chemotherapy when approaching end-of-life.
Palliative chemotherapy treatment (PCT) offered late in the cancer disease trajectory may be problematic. It is not easy to accurately calculate whether the potential benefits will outweigh the side-effects. This study investigates whether routine use of the Performance Status in Palliative Chemotherapy questionnaire (PSPC) affects the proportions of patients receiving PCT during the last month of life, care utilization, and documentation routines. A secondary aim was to gather registered nurses' experiences of the PSPC in routine use. Eighty incurable patients with cancer who had used the PSPC before PCT were compared to 160 matched controls, using non-parametric tests. Nurses' reflections on the PSPC were collected and reviewed. No significant differences were found between users and non-users of the PSPC in terms of proportions receiving PCT during the last month of life. Higher proportions of patients older than 74 years received PCT than in previous studies (40% versus 17%). Nurses considered the questionnaires to be a valuable complement to verbal information when trying to acquire an accurate picture of patients' performance status. At this point in the development of the PSPC we did not find any significant decreases in the proportion of patients receiving PCT during the last month in life. However, as the nurses valued the PSPC, it can be used as a complementary tool in assessment of performance status until further research is conducted.


Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease.
Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD.


Area-selective formation of macropore array by anisotropic electrochemical etching on an n-Si(100) surface in aqueous HF solution.
A photoassisted anodization process to fabricate arrays of uniform and straight macropores at selected areas of a Si wafer surface was developed. The front- and backside surfaces of n-type Si(100) wafers were coated with a thin Si(3)N(4) layer, and the frontside layer was micro-patterned using photolithography and reactive ion etching to form an array of microscopic openings at selected areas. The inverted pyramid-shape micropits were formed at these openings by anisotropic etching using aqueous KOH solution; these pits act as the initiation sites for the anodization to form macropores. The electrochemical etching was carried out in aqueous HF solution under illumination from the backside of the wafer, on which Au/Cr electric contact was formed following removal of the Si(3)N(4) layer. To improve the uniformity of the formation condition of the macropores at the selected area, holes were area-selectively generated by controlling the illumination condition during the anodization. For this, micropatterns were formed on the Au/Cr layer at the backside surface, which were aligned to those at the frontside surface. The parameters, such as HF concentration, current density, and wafer thickness, i.e., hole diffusion length, were optimized, and the arrays of uniform and high-aspect-ratio macropores were formed at the selected area of the domain at the silicon surface.


Costs of using motivational interviewing for problem drinking in the U.S. Air Force.
Despite the popularity of motivational interviewing (MI) to address heavy drinking, limited evidence exists on the costs of using MI to address heavy drinking. This study examines the costs of using MI to address heavy drinking at four U.S. Air Force (USAF) bases. Clients were referred to and assessed at a base program to address their drinking as a result of an incident; those who were not alcohol dependent were invited to participate in the study. Participants consented and were randomly assigned to one of three intervention arms: individual MI (IMI), group MI (GMI), and Substance Abuse Awareness Seminar (SAAS). Three cost perspectives were taken: USAF, client, and the two combined. Data were collected from bases and public sources. The start-up cost per base ranged from $1340 to $2400 per provider staff member. Average implementation costs across bases were highest for the SAAS intervention ($148 per client).


Possible therapeutic potential of berberine in diabetic osteopathy.
Diabetic osteopathy is a complication that leads to decreased bone mineral density, bone formation and having high risk of fractures that heals slowly. Diabetic osteopathy is a result of increase in osteoclastogenesis and decrease in osteoblastogenesis. Various factors viz., oxidative stress, increased inflammatory markers, PPAR-γ activation in osteoblast, activation of apoptotic pathway, increased glucose levels and inhibitory effect on parathyroid hormone etc. are mainly responsible for decreased bone mineral density. Berberine is an isoquinoline alkaloid widely used in Asian countries as a traditional medicine. Berberine is extensively reported to be an antioxidant, anti-inflammatory, antidiabetic, and having potential to treat diabetic complications and glucocorticoid induced osteoporosis. The osteoclastogenesis decreasing property of berberine can be hypothesized for inhibiting diabetic osteopathy. In addition, chronic treatment of berberine will be helpful for increasing the osteoblastic activity and expression of the modulators that affect osteoblastic differentiation. The apoptotic pathways stimulated due to increased inflammatory markers and nucleic acid damages could be reduced due to berberine. Another important consideration that berberine is having stimulatory effect on glucagon like peptide release and insulin sensitization that will be helpful for decreasing glucose levels and therefore, may exerts osteogenesis. Thiazolidinediones show bone loss due to activation of PPAR-γ in osteoblasts, whereas berberine stimulates PPAR-γ only in adipocytes and not in osteoblasts, and therefore the decreased bone loss due to use of thiazolidinediones may not be observed in berberine treatment conditions. Berberine decreases the advanced glycation end-products (AGE) formation in diabetic condition which will be ultimately helpful to decrease the stiffness of collagen fibers due to AGE-induced cross linking. Lastly, it is also reported that berberine has inhibitory effect on parathyroid hormone and enhances marker genes like osteocalcin, which are responsible for the osteoblastic activity. From these evidences, we hypothesized that berberine may have potential in the treatment of diabetic osteopathy.


A trial comparing noninvasive ventilation strategies in preterm infants.
To reduce the risk of bronchopulmonary dysplasia in extremely-low-birth-weight infants, clinicians attempt to minimize the use of endotracheal intubation by the early introduction of less invasive forms of positive airway pressure. We randomly assigned 1009 infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks to one of two forms of noninvasive respiratory support--nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP)--at the time of the first use of noninvasive respiratory support during the first 28 days of life. The primary outcome was death before 36 weeks of postmenstrual age or survival with bronchopulmonary dysplasia. Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4%), as compared with 180 of 490 infants assigned to nasal CPAP (36.7%) (adjusted odds ratio, 1.09; 95% confidence interval, 0.83 to 1.43; P=0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. Among extremely-low-birth-weight infants, the rate of survival to 36 weeks of postmenstrual age without bronchopulmonary dysplasia did not differ significantly after noninvasive respiratory support with nasal IPPV as compared with nasal CPAP. (Funded by the Canadian Institutes of Health Research; NIPPV ClinicalTrials.gov number, NCT00433212; Controlled-Trials.com number, ISRCTN15233270.).


Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.
Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry. Recombinant LIF induced lipolysis in vitro. Peripheral LIF administered to mice caused >50% loss of adipose tissue and >10% reduction in body weight despite only transient hypophagia due to decreasing leptin. LIF-injected mice lacking leptin (ob/ob) resulted in persistent hypophagia and loss of adipose tissue and body weight. LIF's peripheral role of initiating lipolysis in adipose loss was confirmed in pair-fed ob/ob mouse studies. Our studies demonstrate that (a) LIF is a tumor-secreted factor that promotes cachexia-like adipose loss when administered peripherally, (b) LIF directly induces adipocyte lipolysis, (c) LIF has the ability to sustain adipose and body weight loss through an equal combination of peripheral and central contributions, and (d) LIF's central effect is counterbalanced by decreased leptin signaling, providing insight into cachexia's wasting, despite normophagia.


Investigation of the dynamics of growth of polymer materials obtained by combined pervaporation and micro-moulding.
We report an extensive study of the concentration process of aqueous polymer solutions confined within microfluidic channels, owing to the pervaporation of water through the matrix of the chip. Concentration of polymer continuously increases up to the formation of a dense material which eventually invades the channel. This technology can be used to fabricate micro-composites of different shapes starting from dilute inks. We use both theory and screening experiments to show that the dynamics of growth can be predicted by simple conservation equations. More precisely, we establish a quantitative prediction of the growth dynamics taking into account deformations of the soft channels of the moulds, and the solvent chemical activity of the polymer solution. The present results based on general transport equations for binary mixtures provide direct guidance for the design of micro-fabricated materials considering their shape, dimensions, time scale of fabrication, and chemical composition. This quantitative framework is indeed essential to engineer integrated polymer-based micro-devices by using combined pervaporation and microfluidic moulding.


Analysis of complications of radiofrequency pallidotomy.
To systematically report the complications of pallidotomy and to tentatively determine the incidences of complications of pallidotomy, possible influencing factors, and the acceptability of symptomatic hemorrhage rates for microelectrode-guided pallidotomy. Clinical events were analyzed for 1116 patients with Parkinson's disease who underwent microelectrode-guided pallidotomies at our center. Complications included visual field deficits, weakness, fatigue, hypersomnia, drooling, dysphagia, speech disorders, hiccups, hemorrhage, seizures, apraxia, coma, infection, mental confusion, and impaired memory. Complication rates for bilateral pallidotomy and double-lesion groups were compared with those for unilateral pallidotomy and single-lesion groups, respectively. Among the total of 1116 patients, the incidences of visual field deficits, weakness, fatigue, hypersomnia, drooling, dysphagia, and speech disorders were 0.4, 4.2, 19.9, 12.4, 7.0, 3.7, and 11.9%, respectively. Symptomatic hemorrhage was observed for 17 patients, apraxia for 3 patients, coma for 2 patients, mental confusion for 24 patients, and impaired memory for 18 of the 1116 patients. The incidences of fatigue, speech disorders, drooling, dysphagia, and hypersomnia were 18.1, 10.3, 5.2, 2.4, and 11.6%, respectively, in the unilateral pallidotomy group and 34.9, 25.5, 22.6, 14.2, and 17.0%, respectively, in the staged pallidotomy group. Of the three patients who underwent simultaneous bilateral pallidotomies (all <50 yr of age), all developed severe fatigue and two exhibited drooling and dysphagia. The incidences of weakness, fatigue, speech disorders, drooling, dysphagia, and hypersomnia were 8.7, 30.4, 18.8, 7.2, 2.9, and 20.3%, respectively, in the double-lesion group and 3.2, 17.2, 9.7, 5.0, 2.3, and 11.5%, respectively, in the single-lesion group. Staged bilateral pallidotomy should be carefully evaluated before decision-making, whereas simultaneous bilateral pallidotomy is undesirable. Our study suggests that the size of the final lesion should be limited, to minimize the risks of complications. The incidence of symptomatic hemorrhage in microelectrode-guided pallidotomy is low and acceptable, because of the benefits of microelectrode-guided pallidotomy.


Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice.
Patients with cystic fibrosis have a lesion in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which is associated with abnormal regulation of other ion channels, abnormal glycosylation of secreted and cell surface molecules, and vulnerability to bacterial infection and inflammation in the lung usually leading to the death of these patients. The exact mechanism(s) by which mutation in CFTR leads to lung infection and inflammation is not clear. Mice bearing different mutations in the murine homolog to CFTR (Cftr) (R117H, S489X, Y122X, and DeltaF508, all backcrossed to the C57BL/6J background) were compared with respect to growth and in their ability to respond to lung infection elicited with Pseudomonas aeruginosa-laden agarose beads. Body weights of mice bearing mutations in Cftr were significantly smaller than wild-type mice at most ages. The inflammatory responses to P. aeruginosa-laden agarose beads were comparable in mice of all four Cftr mutant genotypes with respect to absolute and relative cell counts in bronchoalveolar lavage fluid, and cytokine levels (TNF-alpha, IL-1beta, IL-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant) and eicosanoid levels (PGE2 and LTB4) in epithelial lining fluid: the few small differences observed occurred only between cystic fibrosis mice bearing the S489X mutation and those bearing the knockout mutation Y122X. Thus we cannot implicate either misprocessing of CFTR or failure of CFTR to reach the plasma membrane in the genesis of the excess inflammatory response of CF mice. Therefore, it appears that any functional defect in CFTR produces comparable inflammatory responses to lung infections with P. aeruginosa.


Exposure to household air pollution from wood combustion and association with respiratory symptoms and lung function in nonsmoking women: results from the RESPIRE trial, Guatemala.
With 40% of the world's population relying on solid fuel, household air pollution (HAP) represents a major preventable risk factor for COPD (chronic obstructive pulmonary disease). Meta-analyses have confirmed this relationship; however, constituent studies are observational, with virtually none measuring exposure directly. We estimated associations between HAP exposure and respiratory symptoms and lung function in young, nonsmoking women in rural Guatemala, using measured carbon monoxide (CO) concentrations in exhaled breath and personal air to assess exposure. The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) Guatemala study was a trial comparing respiratory outcomes among 504 women using improved chimney stoves versus traditional cookstoves. The present analysis included 456 women with data from postintervention surveys including interviews at 6, 12, and 18 months (respiratory symptoms) and spirometry and CO (ppm) in exhaled breath measurements. Personal CO was measured using passive diffusion tubes at variable times during the study. Associations between CO concentrations and respiratory health were estimated using random intercept regression models. Respiratory symptoms (cough, phlegm, wheeze, or chest tightness) during the previous 6 months were positively associated with breath CO measured at the same time of symptom reporting and with average personal CO concentrations during the follow-up period. CO in exhaled breath at the same time as spirometry was associated with lower lung function [average reduction in FEV1 (forced expiratory volume in 1 sec) for a 10% increase in CO was 3.33 mL (95% CI: -0.86, -5.81)]. Lung function measures were not significantly associated with average postintervention personal CO concentrations. Our results provide further support for the effects of HAP exposures on airway inflammation. Further longitudinal research modeling continuous exposure to particulate matter against lung function will help us understand more fully the impact of HAP on COPD.


Correlation of endometrial glycodelin expression and pregnancy outcome in cases with polycystic ovary syndrome treated with clomiphene citrate plus metformin: a controlled study.
Objective. The purpose of this study was to evaluate the relationship between clomiphene citrate (CC) plus metformin treatment and endometrial glycodelin expression and to then correlate this relationship with pregnancy outcomes. Material and Methods. A total of 30 patients diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria constituted our study group. All had been admitted to the gynecology outpatient clinic between June 1, 2011, and January 1, 2012, for infertility treatment. Our control group consisted of 20 patients admitted for routine Pap smear control. They had no history of infertility and were not using contraceptives and they were actively attempting pregnancy. Midluteal progesterone measurement and pipelle endometrial biopsies were performed with both groups. For PCOS patients, metformin treatment was initiated right after the biopsy and CC was added in the second menstrual cycle. Pipelle endometrial biopsies were repeated. Histological dating and immunohistochemistry for glycodelin were performed by a single pathologist who was blinded to the patients' clinical data. Result(s). The posttreatment ovulation rate in the study group was 93.3%. No pregnancies were achieved in either group when glycodelin expression was not present, even in the presence of ovulation. When glycodelin expression was high in PCOS group, the pregnancy rate was 60% and all pregnancies ended in live births. In weak expression group, however, three out of four pregnancies ended as early pregnancy losses. Conclusion(s). Endometrial glycodelin expression is an important predictor of pregnancy outcomes in both PCOS and fertile groups.


Normative Data for Interpreting the BREAST-Q: Augmentation.
The BREAST-Q is a rigorously developed, well-validated, patient-reported outcome instrument with a module designed for evaluating breast augmentation outcomes. However, there are no published normative BREAST-Q scores, limiting interpretation. Normative data were generated for the BREAST-Q Augmentation module by means of the Army of Women, an online community of women (with and without breast cancer) engaged in breast-cancer related research. Members were recruited by means of e-mail; women aged 18 years or older without a history of breast cancer or breast surgery were invited to participate. Descriptive statistics and a linear multivariate regression were performed. A separate analysis compared normative scores to findings from previously published BREAST-Q augmentation studies. The preoperative BREAST-Q Augmentation module was completed by 1211 women. Mean age was 54 ± 24 years, the mean body mass index was 27 ± 6 kg/m, and 39 percent (n = 467) had a bra cup size of D or greater. Mean scores were as follows: Satisfaction with Breasts, 54 ± 19; Psychosocial Well-being, 66 ± 20; Sexual Well-being, 49 ± 20; and Physical Well-being, 86 ± 15. Women with a body mass index of 30 kg/m or greater and bra cup size of D or greater had lower scores. In comparison with Army of Women scores, published BREAST-Q augmentation scores were lower before and higher after surgery for all scales except Physical Well-being. The Army of Women normative data represent breast-related satisfaction and well-being in women not actively seeking breast augmentation. These data may be used as normative comparison values for those seeking and undergoing surgery as we did, demonstrating the value of breast augmentation in this patient population.


Investigating the acoustic release of doxorubicin from targeted micelles.
The main problem associated with the administration of anti-cancer medication is that the drug is delivered throughout the body causing undesirable side effects. Therefore, it is important to synthesize drug carriers capable of minimizing the adverse side effects of chemotherapy by preferentially targeting tumor cells both actively (e.g. a folate receptor) and using external stimulus (e.g. ultrasound). In this paper, we report the synthesis of Pluronic P105 micelles with a folate targeting moiety (with a yield of 48%) containing doxorubicin (Dox). We applied low frequency ultrasound as an external stimulus and measured the amount of release of Dox from these folated micelles. The results showed that the percent drug release increases as the power intensity of ultrasound increases. The maximum amount of release (14%) was measured at 5.4 W/cm(2). A power density threshold at approximately 0.55 W/cm(2) exists below which no statistically significant release was observed. This lower threshold suggests that cavitation plays an important role in triggering drug release from targeted micelles.


Foreign direct investment in the United States and u.s. Interests.
Foreign direct investment entered the United States at unprecedented rates during the second half of the 1980s. The result has been much higher levels of foreign ownership of U.S. economic activities than those to which the nation has been accustomed. The reasons for this investment include loss of competitiveness of U.S. firms compared to international rivals as well as attractions to foreign investors of the United States itself. The economic effects of greater levels of foreign ownership are generally positive, although some problems with levels of competition could ensue. National security considerations might cause the United States to place some restrictions on this investment, but other restrictions at the present time appear to be unwarranted.


Women with atypical glandular cells: a long-term follow-up study in a high-risk population.
To determine the incidence of clinically significant lesions in high-risk patients with atypical glandular cells (AGCs) after 4 to 6 years of follow-up, we reviewed repeated Papanicolaou (Pap) test and surgical pathology results for a 3-year period for 337 patients; 62 (18.4%) had only repeated Pap smears; 84 had Pap smear and histologic evaluations. In a range of repeated Pap smears from 1 to 11 (mean, 4.2), 9 patients had persistent AGCs/atypical squamous cells; remaining Pap smears were judged normal. Histologic follow-up revealed a clinically significant lesion in 110 (40.1%) of 274 patients--low-grade squamous intraepithelial lesion (LSIL), 46; high-grade squamous intraepithelial lesion (HSIL), 47; endocervical adenocarcinoma in situ (AIS), 3; endometrial hyperplasia, 4; endocervical or endometrial adenocarcinoma, 10. Among patients with histologic follow-up, 14 lesions (12.7% of patients with clinically significant lesions) were diagnosed after a mean of 37 months (range, 21-59 months): LSIL, 7; HSIL, 4; AIS, 1; endometrial adenocarcinoma, 2. Seven patients had negative cytologic and/or histologic evaluations between the initial cytologic AGC diagnosis and the final histologic diagnosis. Patients with AGCs are at risk of harboring clinically significant uterine lesions and should be followed up for a substantial period despite initial negative findings.


Age related mitochondrial degenerative disorders in humans.
Disorders caused by mitochondrial respiratory chain deficiency due to mutations in mitochondrial DNA have varied phenotypes but many involve neurological features often associated with cell loss within specific brain regions. These disorders, along with the increasing evidence of decline in mitochondrial function with ageing, have raised speculation that primary changes in mitochondria could have an important role in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence supporting a role for mitochondria in common neurodegenerative diseases comes from studies with the toxin MPP+ and familial PD, which has been shown to involve proteins such as DJ-1 and Pink1 (both of which are predicted to have a role in mitochondrial function and oxidative stress). Mutations within the mitochondrial genome have been shown to accumulate with age and in common neurodegenerative diseases. Mitochondrial DNA haplogroups have also been shown to be associated with certain neurodegenerative conditions. This review covers the primary mitochondrial diseases but also discuss the potential role of mitochondria and mitochondrial DNA mutations in mitochondrial and neurodegenerative diseases, in particular in PD and in AD.


Dried leaves of Rosmarinus officinalis as a treatment for streptococcosis in tilapia.
Dietary application of dried Rosmarinus officinalis (rosemary) leaves as a treatment for streptococcal infection was studied in tilapia, Oreochromis sp. Feeding with dried rosemary leaves significantly reduced mortality following infection with Streptococcus iniae: 44% mortality in the group fed 8% rosemary, similar to oxytetracycline treatment (43% mortality), and significantly lower than the control (65%). Dietary administration of 16% rosemary significantly reduced mortality because of Streptococcus agalactiae infection in 44 g fish (62% and 76% in 16% rosemary and control, respectively), but not in a similar experiment conducted with 5.5 g fish. The antibacterial effect of rosemary on S. iniae was studied. Activity of rosemary cultivar Israel was reduced during the winter, but there was no significant change in cultivars Oranit and Star. Storage of powdered rosemary leaves at 50 degrees C resulted in fourfold and eightfold higher MIC(24 h) values after 3 and 4.5 months, respectively. Storage at -20 degrees C, 4 degrees C and 25 degrees C and autoclaving (120 degrees C) each resulted in a twofold increase in MIC(24 h). Repeated exposures of S. iniae to rosemary did not affect minimal inhibitory concentration, suggesting no development of resistance to rosemary.


LOIS in-stream water quality modelling. Part 1. Catchments and methods.
The catchment and river modelling undertaken within the UK Land Ocean Interaction Study (LOIS) programme represents the most extensive consistent exercise of this type undertaken in the UK. The calibrated model provides a quantitative assessment of the water and chemical fluxes transported by the rivers Derwent, Yorkshire Ouse, Wharfe, Aire, Don and Trent into the Humber estuary, i.e. a total drainage area of almost 18,000 km2 (almost 15% of the area of England) with 2,088 km of modelled river. The model simulated flow, temperature, pH, suspended sediment, dissolved oxygen, biochemical oxygen demand, particulate organic nitrogen, ammonium, ammonia, nitrite, nitrate, zinc (dissolved and particulate), lindane and atrazine. For all rivers, except the Trent, simulations were for the period 1985-1995; the simulation period for the Trent was 1998-1995. The modelling used routine monitoring data collect by the England and Wales Environment Agency, for both calibration and validation, with other data sets mainly collated by the LOIS River-Atmosphere Coastal Study (RACS) data centre (e.g. land use, soils, river network). A stepwise model development started with a basic water quality model driven by observed in-stream water quality, and resulted in the development of a LOIS specific version of the in-stream model Quality Evaluation and Simulation Tool for River-systems that could be used to explore scenarios. The performance of the model was demonstrated by the reproduction of long-term statistics describing loads and concentrations, together with graphical output in the form of time series and distributions. The simulations were subsequently used to drive a linked catchment-river-estuary-coast-sea model covering the full domain of the RACS area.


Human immunodeficiency virus reverse transcriptase. Expression in Escherichia coli, purification, and characterization of a functionally and structurally asymmetric dimeric polymerase.
Human immunodeficiency virus (HIV) reverse transcriptase isolated from viral particles contains two subunits, p51 and p66. We have produced both subunits in separate Escherichia coli strains using expression vectors. Stop codons were placed immediately after the codon for the carboxyl-terminal residue of the mature processed p51 and p66 subunits found in viral particles. Insertion of a methionine in front of the HIV protease cleavage site in the recombinant protein enabled synthesis of both subunits with the natural amino-terminal proline, since E. coli methionine aminopeptidase cleaves a Met-Pro amino-terminal linkage. That this occurred to an extent greater than 95% was confirmed by sequencing the purified subunits. Examination of the activities of the individual p51 and p66 subunits on a variety of templates and under solution conditions optimized for each subunit revealed a significant catalytic activity for the natural p51 subunit. This result contrasts to results reported earlier for many recombinant forms without the natural amino and/or carboxyl termini. As expected from earlier work, the optimal homopolymeric template for the p66 subunit was poly(rA). For the p51 subunit, poly(dC) was found to be the optimal template; its activity is 2- to 4-fold greater than p66 on poly(dC). The p51 subunit is 13- to 50-fold less active on poly(rC). These findings are discussed in the context of our earlier hypothesis (McHenry, C. S. (1989) in Molecular Biology of Chromosome Function (Adolph, K., ed) Chap. 5, Springer-Verlag, New York) that the HIV reverse transcriptase might be functionally asymmetric with distinct plus- and minus-strand polymerases.


SU-E-T-269: The Evaluation of Copper as an Alternative for Cerrobend Electron Shielding.
To evaluate the replacement of Cerrobend by copper for electron beam cutouts. The dosimetric comparisons for circular copper-and Cerrobend-cutouts with diameters (1.0, 2.0, 3.0, 5.0, 7.5, 10.0, and 12.5 cm) were made using electron beams with energies (6, 9, 12, 16, and 20 MeV) from 3 Varian accelerators. A PTW Farmer chamber (0.125cc-volume) was used for larger cutouts (diameters > 2cm), and an electron-diode for the 2 smallest cutouts. Also a Markus parallel plate chamber was used. (1) The tests showed little difference for the electron dosimetric characteristics, Eo, Eop, R50, Rp, and dmax. For larger cutout, the parameters were virtually the same for copper and Cerrobend. for smaller cutout (diameter = 3cm), small discrepancies were observed i.e. differences < 1mm for R50, Rp and dmax, =0.1MeV for Eop, and =0.3MeV for Eo. (2) The larger-cutout outputs at dmax were also virtually the same (difference = 0.6%). For smaller cutouts (diameters = 3cm), the copper outputs were 2.0%∼5.0% higher than Cerrobend. (3) For lower energy electrons (<12MeV), more larger-angle scattered electrons from higher-Z Cerrobend raise the Cerrobend percentage-depth-dose (PDD) curve at shallow-depths, and more forward scatter dose after dmax from lower-Z copper shifts the copper PDD slightly away from the one of Cerrobend. for higher energy electrons (= 12MeV), the shallow-dose difference becomes smaller for both cutouts, but even more forward-scattered dose from copper shifts copper's PDD further away from Cerrobend's. (4) The higher X-ray transmission through copper is also observable; i.e. 12%, 10%, and 7% for 20MeV, 16MeV, and 12MeV, respectively, but such small transmitted amount is clinically insignificant. Except for a higher x-ray transmission, other dosimetric differences brought in by the replacement of Cerrobend by copper cutout are negligible.


The interaction between the vastus medialis and vastus intermedius and its influence on the extensor apparatus of the knee joint.
Although the vastus medialis (VM) is closely associated with the vastus intermedius (VI), there is a lack of data regarding their functional relationship. The purpose of this study was to investigate the anatomical interaction between the VM and VI with regard to their origins, insertions, innervation and function within the extensor apparatus of the knee joint. Eighteen human cadaveric lower limbs were investigated using macro-dissection techniques. Six limbs were cut transversely in the middle third of the thigh. The mode of origin, insertion and nerve supply of the extensor apparatus of the knee joint were studied. The architecture of the VM and VI was examined in detail, as was their anatomical interaction and connective tissue linkage to the adjacent anatomical structures. The VM originated medially from a broad hammock-like structure. The attachment site of the VM always spanned over a long distance between: (1) patella, (2) rectus femoris tendon and (3) aponeurosis of the VI, with the insertion into the VI being the largest. VM units were inserted twice-once on the anterior and once on the posterior side of the VI. The VI consists of a complex multi-layered structure. The layers of the medial VI aponeurosis fused with the aponeuroses of the tensor vastus intermedius and vastus lateralis. Together, they form the two-layered intermediate layer of the quadriceps tendon. The VM and medial parts of the VI were innervated by the same medial division of the femoral nerve. The VM consists of multiple muscle units inserting into the entire VI. Together, they build a potential functional muscular complex. Therefore, the VM acts as an indirect extensor of the knee joint regulating and adjusting the length of the extensor apparatus throughout the entire range of motion. It is of clinical importance that, besides the VM, substantial parts of the VI directly contribute to the medial pull on the patella and help to maintain medial tracking of the patella during knee extension. The interaction between the VM and VI, with responsibility for the extension of the knee joint and influence on the patellofemoral function, leads readily to an understanding of common clinical problems found at the knee joint as it attempts to meet contradictory demands for both mobility and stability. Surgery or trauma in the anteromedial aspect of the quadriceps muscle group might alter a delicate interplay between the VM and VI. This would affect the extensor apparatus as a whole.


Shoulder strapping for stroke-related upper limb dysfunction and shoulder impairments: systematic review.
Shoulder impairments are common after stroke, resulting in reduced upper limb function. Shoulder strapping may be beneficial as an adjunct to conventional therapy and warrants further investigation. To determine i) the efficacy and ii) any adverse effects of shoulder strapping used to reduce stroke-related upper limb and shoulder impairments and to improve function. Three reviewers independently searched CINAHL, Ovid MEDLINE, EMBASE, AMED and PEDro databases and extracted data. Results were synthesized using descriptive methods and meta-analysis and interpreted in relation to potential risk of bias. Eight studies met inclusion criteria, recruiting 340 stroke participants. Studies predominantly included people with shoulder paralysis and examined shoulder strapping within four weeks of stroke onset for outcomes of increased upper limb function, reduced subluxation and pain. Strapping interventions, outcomes and measures were diverse, some studies encountered high risk of bias and findings were generally inconclusive with some indication of benefit in terms of delaying onset of shoulder pain. There is insufficient evidence of efficacy or inefficacy with shoulder paralysis but shoulder strapping demonstrated minimal adverse effects and should be rigorously tested with shoulder paresis as well as paralysis after stroke.


Use of gene expression studies to investigate the human immunological response to malaria infection.
Transcriptional profiling of the human immune response to malaria has been used to identify diagnostic markers, understand the pathogenicity of severe disease and dissect the mechanisms of naturally acquired immunity (NAI). However, interpreting this body of work is difficult given considerable variation in study design, definition of disease, patient selection and methodology employed. This work details a comprehensive review of gene expression profiling (GEP) of the human immune response to malaria to determine how this technology has been applied to date, instances where this has advanced understanding of NAI and the extent of variability in methodology between studies to allow informed comparison of data and interpretation of results. Datasets from the gene expression omnibus (GEO) including the search terms; 'plasmodium' or 'malaria' or 'sporozoite' or 'merozoite' or 'gametocyte' and 'Homo sapiens' were identified and publications analysed. Datasets of gene expression changes in relation to malaria vaccines were excluded. Twenty-three GEO datasets and 25 related publications were included in the final review. All datasets related to Plasmodium falciparum infection, except two that related to Plasmodium vivax infection. The majority of datasets included samples from individuals infected with malaria 'naturally' in the field (n = 13, 57%), however some related to controlled human malaria infection (CHMI) studies (n = 6, 26%), or cells stimulated with Plasmodium in vitro (n = 6, 26%). The majority of studies examined gene expression changes relating to the blood stage of the parasite. Significant heterogeneity between datasets was identified in terms of study design, sample type, platform used and method of analysis. Seven datasets specifically investigated transcriptional changes associated with NAI to malaria, with evidence supporting suppression of the innate pro-inflammatory response as an important mechanism for this in the majority of these studies. However, further interpretation of this body of work was limited by heterogeneity between studies and small sample sizes. GEP in malaria is a potentially powerful tool, but to date studies have been hypothesis generating with small sample sizes and widely varying methodology. As CHMI studies are increasingly performed in endemic settings, there will be growing opportunity to use GEP to understand detailed time-course changes in host response and understand in greater detail the mechanisms of NAI.


Functional connectivity in islets of Langerhans from mouse pancreas tissue slices.
We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.


Melatonin receptors in the spinal cord.
The pineal hormone, melatonin, plays an important role in the regulation of diurnal and seasonal rhythms in animals. In addition to the well established actions on the brain, the possibility of a direct melatonin action on the spinal cord has to be considered. In our laboratory, we have obtained data suggesting that melatonin receptors are present in the spinal cords of birds and mammals. Using radioreceptor binding and quantitative autoradiography assays with 2-[125I]iodomelatonin as the specific melatonin agonist, melatonin binding sites have been demonstrated in the rabbit and chicken spinal cords. These sites are saturable, reversible, specific, guanosine nucleotide-sensitive, of picomolar affinity and femtomolar density. The linearity of Scatchard plots of saturation data and the unity of Hill coefficients indicate that a single class of melatonin binding sites is present in the spinal cord membranes studied. The picomolar affinity of these sites is in line with the circulating levels of melatonin in these animals suggesting that these sites are physiologically relevant. Autoradiography studies in the rabbit spinal cord show that melatonin binding sites are localized in the central gray substance (lamina X). In the chicken spinal cord, these binding sites are localized in dorsal gray horns (laminae I-V) and lamina X. As lamina X and laminae I-II have similar functions, melatonin may have comparable roles in the chicken and rabbit spinal cords. Moreover, in the chicken spinal cord, the density of 2-[125I]iodomelatonin binding in the lumbar segment was significantly higher than those of the cervical and thoracic segments. The densities of these binding sites changed with environmental manipulations. When chickens were adapted to a 12L/12D photoperiod and sacrificed at mid-light and mid-dark, there was a significant diurnal variation in the density (maximum number of binding sites; Bmax) of melatonin binding sites in the spinal cord. After constant light treatment or pinealectomy, the Bmax of melatonin receptors in the chicken spinal cord increased significantly in the subjective mid-dark period. Moreover, there was an age-related decrease in the 2-[125I]iodomelatonin binding to the chicken spinal cord. Our results suggest that melatonin receptors in the chicken spinal cord are regulated by environmental lighting and change with development. These receptors may play an important role in the chronobiology of spinal cord function. The biological responses of melatonin on spinal cords have also been demonstrated in vitro. Melatonin decreased the forskolin-stimulated cAMP production in the chicken spinal cord explant. Preincubation with pertussis toxin blocked the melatonin effect. Our results suggest that melatonin receptors in the chicken spinal cord are linked to the adenylate cyclase via a pertussis toxin-sensitive G protein and that melatonin binding sites in spinal cords are melatonin receptors with biological functions. These receptors may be involved in the regulation of spinal cord functions related to sensory transmission, visceral reflexes and autonomic activities.


Moral thought-action fusion and OCD symptoms: the moderating role of religious affiliation.
The empirical literature on the relationship between moral thought-action fusion (TAF) and obsessive-compulsive disorder (OCD) is characterized by mixed findings. Previous studies have reported religious group differences in moral TAF and the relationship between moral TAF and religiosity. In light of those studies and considering the apparent role of moral TAF in scrupulosity, the purpose of this investigation was to evaluate the possible role of religion as a moderator of the relationship between moral TAF and OCD symptoms. The results revealed that (a) Christians endorsed higher levels of moral TAF than did Jews independent of OCD symptoms; (b) religiosity was correlated with moral TAF in Christians but not in Jews, suggesting that Christian religious adherence is related to beliefs about the moral import of thoughts; and (c) moral TAF was related to OCD symptoms only in Jews. That is, for Christians, moral TAF was related to religiosity but not OCD symptoms, and for Jews, moral TAF was related to OCD symptoms but not religiosity. These results imply that moral TAF is only a marker of pathology when such beliefs are not culturally normative (e.g., as a function of religious teaching or doctrine).


Redefining outcome of first seizures by acute illness.
Seizures are common in children, but the causes and recurrence risk for children with a nonfebrile first seizure remain poorly understood. In a prospective longitudinal study of children who presented with a first-time seizure, we investigated the viral etiology of associated infectious illnesses and sought to determine the risk of recurrent seizures stratified by fever and type of illness. Children (aged 6 months to 6 years) were enrolled at the time of evaluation for their first seizure and followed monthly for up to 5 years. Seizure and illness data were collected through parent interviews and medical-record reviews. Stool, serum, and cerebrospinal fluid collected within 48 hours of the first seizure were evaluated for viral gastrointestinal pathogens. Of the 117 children enrolled, 78 (67%) had febrile seizures, 34 (29%) had nonfebrile-illness seizures, and 5 (4%) had unprovoked seizures. Children with nonfebrile-illness seizures were more likely than those with febrile seizures to have acute gastroenteritis (47% and 28%, respectively; P = .05). No significant differences in seizure recurrence were found between children with or without a fever at first seizure. Children with acute gastroenteritis at first seizure, regardless of fever, had a lower risk of seizure recurrence compared with children with other acute illnesses (hazard ratio: 0.28; 95% confidence interval: 0.09-0.80). Our results confirm the role of gastrointestinal illness as a distinguishing feature in childhood seizures. Children with this distinct presentation have a low rate of seizure recurrence and few neurologic complications.


Pattern of maxillofacial and associated injuries in road traffic accidents.
Road Traffic Accidents (RTAs) are a major cause of morbidity and mortality in Kenya. Victims may suffer multiple injuries including maxillofacial injuries. In most developing countries RTAs are the leading cause of maxillofacial injuries. In an attempt to reduce RTAs, the government of Kenya has enacted a legislation requiring mandatory fitting of speed governors and safety belts by passenger service vehicles. To describe the characteristics and pattern of maxillofacial and associated injuries sustained in road traffic accidents. A cross-sectional study. Kenyatta National Hospital (KNH). All patients involved in RTAs brought to casualty and the dental department of KNH as well as accident victims admitted to the KNH mortuary over a four- month period from September 2004 to December 2004. Four hundred and thirteen (85.7%) had non-fatal injuries whereas 69 (14.3%) had sustained fatal injuries. Males in the 21-30-year age group were the most affected. Most accidents occurred during weekends with pedestrians being the leading casualties in 59.5% and 71.4% of non-fatal and fatal cases respectively. Most accidents were caused by passenger service vehicles (matatus) which were responsible for 62% and 40.6% of non-fatal and fatal injuries respectively. Non-use of safety belts was reported in 56.6% of the cases who suffered non-fatal injuries. In the non-fatal category 89.6% of the casualties had soft tissue injuries (STIs) involving the craniofacial region with facial cuts being the majority (69.2%). Two hundred and seventy three (66.1%) incidents of other STIs than those of the head region were noted, the lower limbs accounting for 45.4% of these. Only 5.1% of the casualties with non-fatal injuries had fractures involving the maxillofacial skeleton. Skeletal injuries other than those involving the maxillofacial region were found in 142 (34.1%) incidents. In the fatal category head injury alone was the leading cause of death accounting for 37.7% of the cases followed by head and chest injuries combined which were responsible for 13% of the cases. Injuries to the maxillofacial skeleton appear to be uncommon in this series. Pedestrians in their third decade of life are most affected with passenger service vehicles being responsible in the majority of the cases. Interventional programmes targeting pedestrians and those in the third and fourth decades of life should be enacted.