Histamine and histamine intolerance.
Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.


Old disease, new targets--part-I, solid malignancies.
Targeted agents are now an integral part of treatment regimens for some cancers. Trastuzumab is established in treatment of human epidermal receptor 2 (Her2) positive breast cancers, with improvements in both, the disease free and over all survival. Monoclonal antibody (MoAB) against vascular growth factor receptor (VEGF), bevacizumab and cetuximab a MoAB against epidermal growth factor receptor (EGFR) are establishing their role in a many cancers after making their mark in colorectal cancer. Sorafenib and sunitinib have success stories in renal carcinoma. The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial has established sorafenib role in advanced hepatocellular carcinoma, while in gastrointestinal tumors; imatinib and sunitinib have proven role. At this point in time side effect profile of all these agents appears relatively safe however cost for developing countries remains an issue.


Visual Impairment, Eye Diseases, and Dementia Risk: A Systematic Review and Meta-Analysis.
Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies. To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes. We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies. Thirty studies met our eligibility criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR] = 1.38, 95% confidence interval [CI]: 1.19-1.59, I2 = 28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio [HR] = 1.17, 95% CI: 1.00-1.38, I2 = 0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR = 1.34, 95% CI: 1.11-1.61, I2 = 63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR = 0.97, 95% CI: 0.90-1.04, I2 = 51.5%) or age-related macular degeneration (7,800,692 participants, > 2,559 cases, HR = 1.15, 95% CI: 0.88-1.50, I2 = 91.0%) and risk of dementia, respectively. As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation.


Genome-wide identification of TAL1's functional targets: insights into its mechanisms of action in primary erythroid cells.
Coordination of cellular processes through the establishment of tissue-specific gene expression programs is essential for lineage maturation. The basic helix-loop-helix hemopoietic transcriptional regulator TAL1 (formerly SCL) is required for terminal differentiation of red blood cells. To gain insight into TAL1 function and mechanisms of action in erythropoiesis, we performed ChIP-sequencing and gene expression analyses from primary fetal liver erythroid cells. We show that TAL1 coordinates expression of genes in most known red cell-specific processes. The majority of TAL1's genomic targets require direct DNA-binding activity. However, one-fifth of TAL1's target sequences, mainly among those showing high affinity for TAL1, can recruit the factor independently of its DNA binding activity. An unbiased DNA motif search of sequences bound by TAL1 identified CAGNTG as TAL1-preferred E-box motif in erythroid cells. Novel motifs were also characterized that may help distinguish activated from repressed genes and suggest a new mechanism by which TAL1 may be recruited to DNA. Finally, analysis of recruitment of GATA1, a protein partner of TAL1, to sequences occupied by TAL1 suggests that TAL1's binding is necessary prior or simultaneous to that of GATA1. This work provides the framework to study regulatory networks leading to erythroid terminal maturation and to model mechanisms of action of tissue-specific transcription factors.


Regulation of CCL2 expression by an upstream TALE homeodomain protein-binding site that synergizes with the site created by the A-2578G SNP.
CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity.


Mechanisms of oxidant-induced changes in erythrocytes.
There is an increasing body of experimental studies demonstrating the toxic effects of oxygen-derived free radicals. Evidence supports an important role for free radicals in ischemic injuries, inflammation, and chemical-induced tissue injury. Free radicals are involved in normal biochemical processes like oxidative reduction and cellular metabolism; however, they also mediate disease processes. The participation of oxygen free radicals in lysis of red cells is important in some situations of intravascular hemolysis. This article will review neutrophil-derived oxygen free radicals, emphasizing: (1) their effects on the erythrocyte and (2) how these effects may be attenuated.


Anterior lateral line nerve encoding to tones and play-back vocalisations in free-swimming oyster toadfish, Opsanus tau.
In the underwater environment, sound propagates both as a pressure wave and as particle motion, with particle motion dominating close to the source. At the receptor level, the fish ear and the neuromast hair cells act as displacement detectors, and both are potentially stimulated by the particle motion component of sound. The encoding of the anterior lateral line nerve to acoustic stimuli in freely behaving oyster toadfish, Opsanus tau, was examined. Nerve sensitivity and directional responses were determined using spike rate and vector strength analysis, a measure of phase-locking of spike times to the stimulus waveform. All units showed greatest sensitivity to 100 Hz stimulus. While sensitivity was independent of stimuli orientation, the neuron's ability to phase-lock was correlated with stimuli origin. Two different types of units were classified, type 1 (tonic), and type 2 (phasic). The type 1 fibres were further classified into two sub-types based on their frequency response (type 1-1 and type 1-2), which was hypothesised to be related to canal (type 1-1) and superficial (type 1-2) neuromast innervation. Lateral line units also exhibited sensitivity and phase locking to boatwhistle vocalisations, with greatest spike rates exhibited at the onset of the call. These results provide direct evidence that oyster toadfish can use their lateral line to detect behaviourally relevant acoustic stimuli, which could provide a sensory pathway to aid in sound source localisation.


Identification and characterization of the Spodoptera Su(var) 3-9 histone H3K9 trimethyltransferase and its effect in AcMNPV infection.
Histone H3-lysine(9) (H3K9) trimethyltransferase gene Su(var) 3-9 was cloned and identified in three Spodoptera insects, Spodopterafrugiperda (S. frugiperda), S. exigua and S. litura. Sequence analysis showed that Spodoptera Su(var) 3-9 is highly conserved evolutionarily. Su(var) 3-9 protein was found to be localized in the nucleus in Sf9 cells, and interact with histone H3, and the heterochromatin protein 1a (HP1a) and HP1b. A dose-dependent enzymatic activity was found at both 27 °C and 37 °C in vitro, with higher activity at 27 °C. Addition of specific inhibitor chaetocin resulted in decreased histone methylation level and host chromatin relaxation. In contrast, overexpression of Su(var) 3-9 caused increased histone methylation level and cellular genome compaction. In AcMNV-infected Sf9 cells, the transcription of Su(var) 3-9 increased at late time of infection, although the mRNA levels of most cellular genes decreased. Pre-treatment of Sf9 cells with chaetocin speeded up viral DNA replication, and increased the transcription level of a variety of virus genes, whereas in Sf9 cells pre-transformed with Su(var) 3-9 expression vector, viral DNA replication slow down slightly. These findings suggest that Su(var) 3-9 might participate in the viral genes expression an genome replication repression during AcMNPV infection. It provided a new insight for the understanding virus-host interaction mechanism.


Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages.
Ocular immune privilege (IP) limits the immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized the immune mechanisms responsible for rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. CD8(+) T cells, IFNγ, and FasL, but not perforin, or TNFα were required for the elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1(-/-) mice and Fas-defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras revealed that IFNγR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mϕ) within intraocular tumors in an IFNγ- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNγ and Fas. As depletion of Mϕs limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral Mϕs by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mϕs to limit the immunosurveillance of intraocular tumors.


Development of a Reading Accessibility Index Using the MNREAD Acuity Chart.
We define a Reading Accessibility Index for evaluating reading in individuals with normal and low vision. To compare the Reading Accessibility Index with data from the Impact of Cataracts on Mobility (ICOM) study. This investigation was a secondary data analysis from the ICOM study performed between July 1, 2014, and September 20, 2015, at 12 eye clinics in Alabama from October 1, 1994, through March 31, 1996. Participants were 321 adults with cataract (n = 92), pseudophakia (n = 131), or natural crystalline lenses without cataract (n = 98). The Reading Accessibility Index (hereafter referred to using the abbreviation ACC for the first 3 letters of Accessibility) is defined as an individual's mean reading speed measured across the 10 largest print sizes on the MNREAD Acuity Chart (Precision Vision) (0.4-1.3 logarithm of the minimum angle of resolution at 40 cm), normalized by 200 words per minute, which was the mean value for a group of 365 normally sighted young adults. The ACC is a single-value measure that captures an individual's range of accessible print sizes and reading fluency within this range. The study cohort comprised 321 participants. Their age range was 55 to 85 years, and 157 (48.9%) were female. The ACCs for the ICOM study participants ranged from 0.19 to 1.33, where 1.00 is the mean value for normally sighted young adults. The ACC for the cataract group (mean [SD], 0.65 [0.18]) was significantly lower than that for the pseudophakia group (mean [SD], 0.77 [0.16]) and the control group (mean [SD], 0.76 [0.19]) (P < .001 for both). The correlation between the ACC and Early Treatment Diabetic Retinopathy Study visual acuity (r = -0.22) and Pelli-Robson contrast sensitivity (r = 0.20) was weaker than that with a reading-related measure of instrumental activities of daily living (r = -0.60) (P < .001 for both). The ACC represents an individual's access to text across the range of print sizes found in everyday life. Its calculation does not rely on curve fitting and provides a direct comparison with the performance of normally sighted individuals. Changes in an individual's ACC might be used to evaluate the effect of ophthalmic treatment, rehabilitation programs, or assistive technology on reading accessibility. Data from the ICOM study show that the ACC reflects characteristics of reading performance in everyday life and is sensitive to improved reading accessibility for pseudophakic eyes.


Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis.
The Gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a nondiffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for Ab-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild-type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin to withstand Y. pestis encounters and effectively clear bacteria.


Psychological effects of Hurricane Andrew on an elementary school population.
To explore the prevalence and progression of posttraumatic symptomatology (PTS), using emotional and behavioral indices of psychopathology in school-age children in the pathway of Hurricane Andrew (HI-IMPACT) and in a comparison group north of Miami (LO-IMPACT). Pynoos' Posttraumatic Stress Disorder Reaction Index and Achenbach's Teacher's Report Form (TRF) were administered 8 weeks and 32 weeks after the hurricane. In addition, 21 measures of disruptive behavior cataloged by Dade County Public Schools were aggregated and compared by grading period between pre- and posthurricane school years. There were no statistically significant differences between the two schools in PTS at 8 weeks after the hurricane, although the children in the HI-IMPACT school were more likely to have severe PTS. TRF findings at 8 weeks revealed that children in the HI-IMPACT school evidenced lower means on the eight TRF scales and on the broader Internalizing and Externalizing measures. Analysis of the disruptive behavior revealed a drop in the marking period immediately after the hurricane in the HI-IMPACT area, but an opposite effect was observed in the LO-IMPACT area. After the hurricane there was an initial increase in PTS and a concomitant decrease in other measures of behavior and psychopathology. PTS remained relatively high throughout the school year, but there was a rebound and subsequent normalization of the measures of disruptive behavior.


Invasive fungal infections in acute leukemia.
Invasive fungal infection (IFI) is among the leading causes for morbidity, mortality, and economic burden for patients with acute leukemia. In the past few decades, the incidence of IFI has increased dramatically. The certainty of diagnosis of IFI is based on host factors, clinical evidence, and microbiological examination. Advancement in molecular diagnostic modalities (e.g. non-culture-based serum biomarkers such as β-glucan or galactomannan assays) and high-resolution radiological imaging has improved our diagnostic approach. The early use of these diagnostic tests assists in the early initiation of preemptive therapy. Nonetheless, the complexity of IFI in patients with leukemia and the limitations of these diagnostic tools still mandate astute clinical acumen. Its management has been further complicated by the increasing frequency of infection by non-Aspergillus molds (e.g. zygomycosis) and the emergence of drug-resistant fungal pathogens. In addition, even though the antifungal armamentarium has expanded rapidly in the past few decades, the associated mortality remains high. The decision to initiate antifungal treatment and the choice of anti-fungal therapy requires careful consideration of several factors (e.g. risk stratification, local fungal epidemiologic patterns, concomitant comorbidities, drug-drug interactions, prior history of antifungal use, overall cost, and the pharmacologic profile of the antifungal agents). In order to optimize our diagnostic and therapeutic management of IFI in patients with acute leukemia, further basic research and clinical trials are desperately needed.


Temporal grouping modulates ipsilateral capture in right visual neglect.
The current study assessed the performance of a patient with right neglect (M.A.H.) across various manipulations of the flanker paradigm. When required to identify a central target in the presence of a unilateral flanker, M.A.H. responded to the flanking distractor on the left (ipsilesional) side as if it were the target, even when the flanker appeared at left peripheral locations. A right (contralesional) flanker did not affect central identification performance (Experiment 1). The "ipsilesional capture" effect persisted when pretrial location markers were introduced to make the flanker and target locations more clearly defined (Experiment 2). However, when the ipsilesional flanker appeared simultaneously with a contralesional flanker, central target detection improved to ceiling (Experiment 3). Interestingly, with these three-stimulus displays, congruency effects in reaction time only occurred in relation to the flanker on the contralesional side (Experiment 3), suggesting impaired response selectivity to ipsilesional stimuli. Congruency effects were produced on both sides only when the two flanking distractors grouped together (by both onset and offset, Experiment 4) and when the ipsilesional flanking distractor grouped with the target by onset (lone contra offset, Experiment 4). The results are attributed to ipsilesional capture in central target detection, which is offset by temporal grouping processes when another stimulus appears on the contralateral side.


Patient analysis and selection in aging face surgery.
Advances in health, increased awareness of preventative medicine, and evolution have led to an increasingly older population worldwide. Surgical aesthetic facial rejuvenation has become increasingly popular, more accessible, and has lost much of the stigma that it once carried. This review will discuss proper patient analysis and selection for aging face surgery, including medical, anatomic, and psychosocial factors that are involved. Although the novice facial plastic surgeon typically focuses on facial analysis and operative techniques in aging face surgery, we caution that the patient's expectations, psychosocial comorbidities, and perioperative interpersonal experiences are the most important factors that yield patient satisfaction, which is the prime outcome that is meaningful in elective cosmetic surgery.


The power of support from companion animals for people living with mental health problems: a systematic review and narrative synthesis of the evidence.
There is increasing recognition of the therapeutic function pets can play in relation to mental health. However, there has been no systematic review of the evidence related to the comprehensive role of companion animals and how pets might contribute to the work associated with managing a long-term mental health condition. The aim of this study was to explore the extent, nature and quality of the evidence implicating the role and utility of pet ownership for people living with a mental health condition. A systematic search for studies exploring the role of companion animals in the management of mental health conditions was undertaken by searching 9 databases and undertaking a scoping review of grey literature from the earliest record until March 2017. To be eligible for inclusion, studies had to be published in English and report on primary data related to the relationship between domestic animal ownership and the management of diagnosable mental health conditions. Synthesis of qualitative and quantitative data was undertaken in parallel using a narrative synthesis informed by an illness work theoretical framework. A total of 17 studies were included in the review. Quantitative evidence relating to the benefits of pet ownership was mixed with included studies demonstrating positive, negative and neutral impacts of pet ownership. Qualitative studies illuminated the intensiveness of connectivity people with companion animals reported, and the multi-faceted ways in which pets contributed to the work associated with managing a mental health condition, particularly in times of crisis. The negative aspects of pet ownership were also highlighted, including the practical and emotional burden of pet ownership and the psychological impact that losing a pet has. This review suggests that pets provide benefits to those with mental health conditions. Further research is required to test the nature and extent of this relationship, incorporating outcomes that cover the range of roles and types of support pets confer in relation to mental health and the means by which these can be incorporated into the mainstay of support for people experiencing a mental health problem.


Novel quinuclidinone derivatives induced apoptosis in human breast cancer via targeting p53.
Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCF-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclin D1. Derivative 2e reduced expression levels of Mdm2, Akt and ERK1/2 by and increased expression level of p53. Moreover, the apoptosis induction by 2e was also inhibited by PFT-α as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both derivative 2e and PFT-α. In addition, docking study reveals that derivative 2e has a binding pattern close to the pattern observed in the structure of the lead fragment 5,6-dimethoxy-2-methylbenzothiazole bound to T-p53C-Y220C. The above findings demonstrate that derivative 2e induces apoptosis in MCF-7 cells via targeting p53 which merits further development.


The metal tin promoted cascade reaction of ketones in aqueous media for the construction of 2-bromo-4-aryl-1,3-pentadiene.
A novel type of transformation was discovered serendipitously during the Barbier-type allenylation reaction of aromatic ketones promoted by the metal, tin, in aqueous media. Additionally, a series of new, highly functionalized 2-bromo-4-aryl-1,3-pentadienes could be obtained with good yields in this reaction. This cascade reaction shows the unique properties of the metal, tin. Furthermore, it is actually a cascade reaction which involves two steps: one is the Barbier-type allenylation of the carbonyl compound, and the other is an SN2' type addition-elimination reaction. Notably, this reaction has the advantages of simple, mild conditions and is easy to operate. Furthermore, the corresponding product could be applied to various coupling reactions or other diversified transformations.


Characterization of the inflammatory and metabolic profile of adipose tissue in a mouse model of chronic hypoxia.
In both obesity and chronic obstructive pulmonary disease (COPD), altered oxygen tension in adipose tissue (AT) has been suggested to evoke AT dysfunction, subsequently contributing to metabolic complications. Studying the effects of chronic hypoxia on AT function will add to our understanding of the complex pathophysiology of alterations in AT inflammation, metabolism, and mass observed in both obesity and COPD. This study investigated the inflammatory and metabolic profile of AT after chronic hypoxia. Fifty-two-week-old C57Bl/6J mice were exposed to chronic hypoxia (8% O2) or normoxia for 21 days, after which AT and plasma were collected. Adipocyte size, AT gene expression of inflammatory and metabolic genes, AT macrophage density, and circulating adipokine concentrations were measured. Food intake and body weight decreased upon initiation of hypoxia. However, whereas food intake normalized after 10 days, lower body weight persisted. Chronic hypoxia markedly reduced AT mass and adipocyte size. AT macrophage density and expression of Emr1, Ccl2, Lep, and Tnf were decreased, whereas Serpine1 and Adipoq expression levels were increased after chronic hypoxia. Concomitantly, chronic hypoxia increased AT expression of regulators of oxidative metabolism and markers of mitochondrial function and lipolysis. Circulating IL-6 and PAI-1 concentrations were increased, and leptin concentration was decreased after chronic hypoxia. Chronic hypoxia is associated with decreased rather than increased AT inflammation, and markedly decreased fat mass and adipocyte size. Furthermore, our data indicate that chronic hypoxia is accompanied by significant alterations in AT metabolic gene expression, pointing toward an enhanced AT metabolic rate.


Association of beta 1 integrin with phosphotyrosine in growth cone filopodia.
Filopodia of growth cones are key elements in the transduction of extracellular cues that guide axon growth during development. How they are specialized to carry out this role is poorly understood. We previously had found tyrosine phosphorylated protein to be heavily concentrated at the tips of many filopodia of Aplysia growth cones in certain culturing conditions, suggesting that tyrosine phosphorylation might be involved in filopodial specialization. Immunocytochemistry was used to analyze the protein composition of the tip aggregates to determine whether there was an association of the tip phosphorylation with any important extracellular cue. beta 1 integrin, a subunit of the receptor for laminin-type neurite growth promoters, coconcentrated with phosphotyrosine at filopodial tips of both Aplysia and mouse growth cones. Several observations indicated that the association of beta 1 integrin with phosphotyrosine is close. beta 1 integrin and phosphotyrosine are known to colocalize at focal contacts, sites of adhesion of cells to the extracellular matrix, but the composition and behavior of the tip aggregates mark them as distinct structures. Also found in the tip aggregates was a member of the ezrin-radixin-moesin family of proteins, which are thought to link membrane proteins to submembranous bundles of actin filaments. Use of an inhibitor of protein-tyrosine kinases to deplete tip phosphotyrosine also caused disappearance of beta 1 integrin from the tip, suggesting a role for tyrosine phosphorylation in facilitating interaction of growth cones with certain environmental cues by fostering the aggregation of receptors in filopodia.


An experimental study of the mechanical response of frozen biological tissues at cryogenic temperatures.
An experimental study of the mechanical response of frozen soft biological tissues to applied compressive stresses is presented. This study is related to the mechanical stresses that develop due to the contraction of frozen tissues in cryopreservation as well as in cryosurgical procedures. The main concept in this study is that the stresses associated with the constrained contraction of the frozen tissue, i.e., due to temperature variations within the frozen tissue, can be simulated by an external mechanical load which is applied to the frozen tissue while the tissue is maintained at a uniform temperature. A new apparatus for measuring compressive stresses and strains of frozen biological tissues in cryogenic temperature range is presented. A new technique for processing the fresh biological tissue into a cylindrical frozen sample for mechanical testing is introduced. Results of compression tests on rabbit liver, kidney, and brain are presented and are compared with available data from the literature on sea ice and single ice crystals. An unusual response of frozen biological tissues to compressive stress was observed: after the initial, roughly linear elastic portion there was a series of sudden stress drops at constant strain, each followed by a linear increase of stress with strain to the next drop. This phenomenon, which is attributed to the accumulation of microcracks, broadly resembles plastic deformation, and thus provides some support for simple mechanical models invoked in theoretical studies.


Structures and relative stability of medium- and large-sized silicon clusters. VI. Fullerene cage motifs for low-lying clusters Si(39), Si(40), Si(50), Si(60), Si(70), and Si(80).
We performed a constrained search, combined with density-functional theory optimization, of low-energy geometric structures of silicon clusters Si(39), Si(40), Si(50), Si(60), Si(70), and Si(80). We used fullerene cages as structural motifs to construct initial configurations of endohedral fullerene structures. For Si(39), we examined six endohedral fullerene structures using all six homolog C(34) fullerene isomers as cage motifs. We found that the Si(39) constructed based on the C(34)(C(s):2) cage motif results in a new leading candidate for the lowest-energy structure whose energy is appreciably lower than that of the previously reported leading candidate obtained based on unbiased searches (combined with tight-binding optimization). The C(34)(C(s):2) cage motif also leads to a new candidate for the lowest-energy structure of Si(40) whose energy is notably lower than that of the previously reported leading candidate with outer cage homolog to the C(34)(C(1):1). Low-lying structures of larger silicon clusters Si(50) and Si(60) are also obtained on the basis of preconstructed endohedral fullerene structures. For Si(50), Si(60), and Si(80), the obtained low-energy structures are all notably lower in energy than the lowest-energy silicon structures obtained based on an unbiased search with the empirical Stillinger-Weber potential of silicon. Additionally, we found that the binding energy per atom (or cohesive energy) increases typically >10 meV with addition of every ten Si atoms. This result may be used as an empirical criterion (or the minimal requirement) to identify low-lying silicon clusters with size larger than Si(50).


Closing the quality gap: revisiting the state of the science (vol. 5: public reporting as a quality improvement strategy).
The goal of this review was to evaluate the effectiveness of public reporting of health care quality information as a quality improvement strategy. We sought to determine if public reporting results in improvements in health care delivery and patient outcomes. We also considered whether public reporting affects the behavior of patients or of health care providers. Finally we assessed whether the characteristics of the public reports and the context affect the impact of public reports. Articles available between 1980 and 2011 were identified through searches of the following bibliographical databases: MEDLINE®, Embase, EconLit, PsychINFO, Business Source Premier, CINAHL, PAIS, Cochrane Database of Systematic Reviews, EPOC Register of Studies, DARE, NHS EED, HEED, NYAM Grey Literature Report database, and other sources (experts, reference lists, and gray literature). We screened citations based on inclusion and exclusion criteria developed based on our definition of public reporting. We initially did not exclude any studies based on study design. Of the 11,809 citations identified through title and abstract triage, we screened and reviewed 1,632 articles. A total of 97 quantitative and 101 qualitative studies were included, abstracted, entered into tables, and evaluated. The heterogeneity of outcomes as well as methods prohibited formal quantitative synthesis. Systematic reviews were used to identify studies, but their conclusions were not incorporated into this review. For most of the outcomes, the strength of the evidence available to assess the impact of public reporting was moderate. This was due in part to the methodological challenges researchers face in designing and conducting research on the impact of population-level interventions. Public reporting is associated with improvement in health care performance measures such as those included in Nursing Home Compare. Almost all identified studies found no evidence or only weak evidence that public reporting affects the selection of health care providers by patients or their representatives. Studies of health care providers' response to public reports suggest they engage in activities to improve quality when performance data are made public. Characteristics of public reports and the context, which are likely to be important when considering the diffusion of quality improvement activities, were rarely studied or even described. The heterogeneity of the outcomes and the moderate strength of evidence for most outcomes make it difficult to draw definitive conclusions. However, some observations were supported by existing research. Public reporting is more likely to be associated with changes in health care provider behaviors than with selection of health services providers by patients or families. Quality measures that are publicly reported improve over time. Although the potential for harms is frequently cited by commentators and critics of public reporting, the amount of research on harms is limited and most studies do not confirm the potential harm.


Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs.
Based on neonatal examination at birth, it has been estimated that epileptic women have a 2-3 times greater risk of giving birth to an infant with congenital anomalies. But anticonvulsant drugs may also have more subtle influences on the developing foetus which are not visible at birth but only emerge later in life. Evidence for these functional teratogenic influences has been provided by animal research and follow-up studies in young children. This article discusses these findings in human and animal studies. In addition, the outline of a study carried out at the Department of Obstetrics and Neonatology, Academic Medical Centre, Amsterdam, is described. In this study cognitive functioning, fertility and gender role behaviour of young adults, who had been prenatally exposed to barbiturates and/or hydantoins was examined.


The communication experience of tracheostomy patients with nurses in the intensive care unit: A phenomenological study.
To describe the experience and sources of comfort and discomfort in tracheostomy patients, when they communicate with nurses in the Intensive Care Unit. Benner's interpretive phenomenology. Data were collected through: a) semi-structured interviews conducted with the patients after leaving the intensive care unit; b) participant observation; c) situated interviews with intensive care nurses. The intensive care unit of a hospital in Northern Italy. Eight patients and seven nurses were included in this study. Two main themes were identified 1) feeling powerless and frustrated due to the impossibility to use voice to communicate; 2) facing continual misunderstanding, resignation, and anger during moments of difficulty and/or communication misunderstandings. The main communication discomfort factors were: struggling with not knowing what was happening, feeling like others had given up on me, living in isolation and feeling invisible. The main comfort factors were: being with family members, feeling reassured by having a call bell nearby and nurses' presence. This study highlights the important role of communication in tracheostomy patients in intensive care and how closely it is linked to all the aspects of a person's life, which cannot be underestimated as just not being able to use one's voice.


The effects of parental diagnosis and changing family norms on alcohol use and related problems among urban American Indian adolescents.
This study investigated the role of parental diagnosis of alcohol abuse/dependence and perceived family norms for adolescent drinking on alcohol use and alcohol-related problems among urban American Indian youth. A total of 251 urban, American Indian youth and their parents/caregivers were followed from ages 13 to 18. Perceived family norms against alcohol decreased and alcohol use increased from ages 13 to 18. Relative to no parental diagnosis, youth with one or two parents diagnosed with alcohol abuse/dependence were less likely to perceive family norms against alcohol use. Youth with two parents diagnosed were more likely to report alcohol-related problems at age 18 compared to no parental diagnosis. Faster rates of decrease in perceived family norms against alcohol use were associated with faster increases in alcohol use over time. Higher rates of perceived family norms against alcohol use protected youth from high rates of use at age 13, but higher rates of alcohol use at age 13 predicted more alcohol-related problems at age 18. These results suggest that both family history and family behaviors in the form of communication of norms for adolescent alcohol use are likely to impact both rates of use and eventual alcohol-related problems.


Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas.
Unlike their malignant counterparts, low-grade gliomas are associated with prolonged survival. However, these tumors have a propensity to progress after resection and ultimately undergo malignant degeneration. The factors associated with recurrence and malignant degeneration remain relatively unknown. The authors set out to determine factors that were independently associated with recurrence and malignant degeneration in patients who underwent resection of a hemispheric low-grade glioma. Adult patients who underwent craniotomy and resection of a hemispheric low-grade glioma (WHO Grade II) at the Johns Hopkins Medical Institution's academic tertiary-care institution between 1996 and 2006 were retrospectively reviewed. Multivariate proportional hazards regression analyses were used to identify associations with tumor recurrence and malignant degeneration. Of the 191 consecutive patients with low-grade gliomas in this series (89 fibrillary astrocytomas, 89 oligodendrogliomas, and 13 mixed gliomas), 83 (43%) and 44 (23%) experienced tumor recurrence and malignant degeneration at last follow-up, respectively. The 5-year progression-free and malignancy-free survival rates were 44 and 74%, respectively. Independent predictors of recurrence were duration of longest lasting symptom (relative risk [RR] 0.978, 95% CI 0.954-0.996, p = 0.01), tumor size (RR 1.328, 95% CI 1.109-1.602, p = 0.002), and preoperative contrast enhancement (RR 2.558, 95% CI 1.241-5.021, p = 0.01). Independent factors associated with malignant degeneration were fibrillary astrocytoma pathology (RR 1.800, 95% CI 1.008-4.928, p = 0.04), tumor size (RR 1.086, 95% CI 1.044-1.358, p = 0.04), and gross-total resection (RR 0.526, 95% CI 0.221-1.007, p = 0.05). The identification and consideration of factors associated with recurrence and malignant progression may help guide treatment strategies aimed at delaying recurrence and preventing malignant degeneration for patients with hemispheric low-grade gliomas.


Bone Marrow-Derived Mesenchymal Stem Cells Repair Necrotic Pancreatic Tissue and Promote Angiogenesis by Secreting Cellular Growth Factors Involved in the SDF-1 α /CXCR4 Axis in Rats.
Acute pancreatitis (AP), a common acute abdominal disease, 10%-20% of which can evolve into severe acute pancreatitis (SAP), is of significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to have a potential therapeutic role on SAP, but the specific mechanism is unclear. Therefore, we conducted this experiment to shed light on the probable mechanism. We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100. The capacities of proliferation, migration, and repair of human umbilical vein endothelial cells were enhanced by BMSCs supernatant. Meanwhile, BMSCs supernatant could also promote angiogenesis, especially after the stimulation with SDF-1α. In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis. Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups. Taken together, the results showed that BMSCs ameliorated SAP and the SDF-1α/CXCR4 axis was involved in the repair and regeneration process.


When a physician marries a physician: effect of physician-physician marriages on professional activities.
To determine whether more Canadian family physicians are marrying other physicians and to examine the influence of physician-physician marriages on FPs' professional activities. Secondary analysis of a population survey (mailed questionnaire) using regression analysis. Canadian family medicine. Family physicians who responded to the 2001 National Family Physician Workforce Survey conducted by the College of Family Physicians of Canada (CFPC) (13 088 respondents; 51.3% response rate). The main outcome measure was self-reported hours spent on professional activities during a typical week. Other information used in this analysis included marital status (currently married or not), hours spent providing dependent care each week, age (65 and older or younger than 65), sex, practice location (rural or not), and age of youngest child (younger than 6 or not). These factors were previously reported to affect amount of time spent on professional activities. Decade of graduation was used descriptively; having a physician spouse was considered a variable in the regression. About 86% of FPs were married; 16% of these were married to other physicians. The proportion of physician-physician marriages increased over time, mainly because male physicians increasingly married female physicians. The youngest cohort had the highest proportion of physician-physician marriages (20%). Having a physician spouse significantly reduced the hours devoted to professional practice. After taking into account the effects of other factors known to influence extent of professional activities, on average, female FPs in physician-physician marriages worked about 5 hours less weekly than other female physicians, and male FPs worked about 3 hours less weekly than other male physicians. The effect of other factors was consistent with previous reports of their influence on professional activities. These findings have implications for medical human resource planning. The cumulative effect on physicians' work time that physician-physician marriages have must be considered. Two physicians married to each other might be a marker for a couple with high discretionary income that allows them to make a lifestyle choice of reducing work time. If this is the case, reduction in professional activities is more likely to be found among FPs whose spouses can command a high salary.


Management of extravasation of oxaliplatin by mimicking its biotransformation.
Although oxaliplatin (Oxali) plays a key role in the treatment of many types of cancer and has been reported to be an irritant, there is no specific and effective method for its extravasation and failure in Oxali extravasation management results in the need for plastic surgery. In the body, Oxali bio-transforms upon dilution in chloride-containing buffer salts to its di-chloro derivative and loses an oxalate molecule. Consequently, the chloride ions exchange with water molecules in the intracellular environment to produce the di-aqua derivative, which is the most active biotransformation product of Oxali in terms of forming the DNA adducts. Thus, inhibiting transformation of di-chloro to di-aqua derivatives by accumulating chloride ions at the site of extravasation and saturating the Oxali molecule with these ions is a strategy that could help manage extravasation. Injecting normal saline at this site is a simple yet effective way to achieve this goal.


Mechanoelectrical excitation by fluid jets in monolayers of cultured cardiac myocytes.
Although the prevailing view of mechanoelectric feedback (MEF) in the heart is in terms of longitudinal cell stretch, other mechanical forces are considerable during the cardiac cycle, including intramyocardial pressure and shear stress. Their contribution to MEF is largely unknown. In this study, mechanical stimuli in the form of localized fluid jet pulses were applied to neonatal rat ventricular cells cultured as confluent monolayers. Such pulses result in pressure and shear stresses (but not longitudinal stretch) in the monolayer at the point of impingement. The goal was to determine whether these mechanical stimuli can trigger excitation, initiate a propagated wave, and induce reentry. Cells were stained with the voltage-sensitive dye RH237, and multi-site optical mapping was used to record the spread of electrical activity in isotropic and anisotropic monolayers. Pulses (10 ms) with velocities ranging from 0.3 to 1.8 m/s were applied from a 0.4-mm diameter nozzle located 1 mm above the cell monolayer. Fluid jet pulses resulted in circular wavefronts that propagated radially from the stimulus site. The likelihood for mechanical stimulation was quantified as an average stimulus success rate (ASSR). ASSR increased with jet amplitude and time waited between stimuli and decreased with the application of gadolinium and streptomycin, blockers of stretch-activated channels, but not with nifedipine, a blocker of the L-type Ca channel. Absence of cellular injury was confirmed by smooth propagation maps and propidium iodide stains. In rare instances, the mechanical pulse resulted in the induction of reentrant activity. We conclude that mechanical stimuli other than stretch can evoke action potentials, propagated activity, and reentrant arrhythmia in two-dimensional sheets of cardiac cells.


Singularities in primate orientation maps.
We report the results of an analysis of orientation maps in primate striate cortex with focus on singularities and their distribution. Data were obtained from squirrel monkeys and macaque monkeys of different ages. We find the approximately 80% of singularities that are nearest neighbors have the opposite sign and that the spatial distribution of singularities differs significantly from a random distribution of points. We do not find evidence for consistent geometric patterns that singularities may form across the cortex. Except for a different overall alignment of orientation bands and different periods of repetition, maps obtained from different animals and different ages are found similar with respect to the measures used. Orientation maps are then compared with two different pattern models that are currently discussed in the literature: bandpass-filtered white noise, which accounts very well for the overall map structure, and the field analogy model, which specifies the orientation map by the location of singularities and their properties. The bandpass-filtered noise approach to orientation patterns correctly predicts the sign correlations between singularities and accounts for the deviations in the spatial distribution of singularities away from a random dot pattern. The field analogy model can account for the structure of certain local patches of the orientation map but not for the whole map. Neither of the models is completely satisfactory, and the structure of the orientation map remains to be fully explained.


Satellite remote sensing of dust aerosol indirect effects on ice cloud formation.
We undertook a new approach to investigate the aerosol indirect effect of the first kind on ice cloud formation by using available data products from the Moderate-Resolution Imaging Spectrometer (MODIS) and obtained physical understanding about the interaction between aerosols and ice clouds. Our analysis focused on the examination of the variability in the correlation between ice cloud parameters (optical depth, effective particle size, cloud water path, and cloud particle number concentration) and aerosol optical depth and number concentration that were inferred from available satellite cloud and aerosol data products. Correlation results for a number of selected scenes containing dust and ice clouds are presented, and dust aerosol indirect effects on ice clouds are directly demonstrated from satellite observations.


[Data protection in telemedicine--legal aspects].
Recent developments in telemedicine have resulted in an increased flow of personalized medicinal data and therefore caused new in calculable risks and dangers to the right of privacy. This article discusses the particular problems of this issue: The patient's consent must be based on sufficient information about the intended data processing and data flow. Transmitting data into countries outside the European Community should prevail sufficient data protection according to the EC-Guideline. Particular attention mus be paid to the regulations of the new German Multimedia Legislature.


Adaptive phenotypic diversification along a temperature-depth gradient.
Theoretical models suggest that sympatric speciation along environmental gradients might be common in nature. Here we present the first data-based model of evolutionary diversification along a continuous environmental gradient. On the basis of genetic analyses, it has been suggested that a pair of coregonid fishes (Coregonus spp.) in a postglacial German lake originated by sympatric speciation. Within this lake, the two species segregate vertically and show metabolic adaptations to, as well as behavioral preferences for, correspondingly different temperatures. We test the plausibility of the hypothesis that this diversifying process has been driven by adaptations to different thermal microhabitats along the lake's temperature-depth gradient. Using an adaptive-dynamics model that is calibrated with empirical data and allows the gradual evolution of a quantitative trait describing optimal foraging temperature, we show that under the specific environmental conditions in the lake, evolutionary branching of a hypothetical ancestral population into two distinct phenotypes may have occurred. We also show that the resultant evolutionary diversification yields two stably coexisting populations with trait values and depth distributions that are in agreement with those currently observed in the lake. We conclude that divergent thermal adaptations along the temperature-depth gradient might have brought about the two species observed today.


Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect.
Leukocyte adhesion deficiency type II is a hereditary disorder of neutrophil migration caused by mutations in the guanosine diphosphate-fucose transporter gene (SLC35C1). In these patients, inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis and recurrent infections, in addition to short stature and developmental delay. We report two brothers with short stature and developmental delay who are compound heterozygotes for novel mutations in SLC35C1 resulting in partial in vivo defects in fucosylation. Specifically, plasma glycoproteins including immunoglobulin G demonstrated marked changes in glycoform distribution. While neutrophil rolling on endothelial selectins was partially impeded, residual adhesion proved sufficient to avoid leukocytosis or recurrent infection. These findings demonstrate a surprising degree of immune redundancy in the face of substantial alterations in adhesion molecule expression, and show that short stature and developmental delay may be the sole presenting signs in this disorder.


Do mothers-in-law matter? Family dynamics and fertility decision-making in urban squatter settlements of Karachi, Pakistan.
The perspectives of mothers-in-law about intra-household decision-making, family size and family planning are investigated, and their views compared with those of their sons and daughters-in-law. Women (717 daughters-in-law), their husbands (717 sons) and their 522 mothers-in-law were interviewed in eight squatter settlements in Karachi, Pakistan. Decisions about the schooling and health care of children, and the purchase of jewellery, are perceived to lie within the nuclear family domain (i.e. husband and wife). There was a difference in mothers-in-law's, daughters-in-law's and sons' desire to have more children. Twenty-eight per cent of mothers-in-law versus 58%, of daughters-in-law did not want more grandsons/sons and 36%, of mothers-in-law versus 66% of daughters-in-law did not want more granddaughters/daughters. The difference was markedly greater among the mother-in-law/daughter-in-law pairs than in the mother/son pairs. Overall, the mother-in-law's role seems to be somewhat overshadowed by that of her son (family male member), except for limiting family size. It is suggested that mothers-in-law should be included in Information-Education-Communication (IEC) campaigns about family planning.


An experimental test of parenting practices as a mediator of early childhood physical aggression.
Parenting practices predict early childhood physical aggression. Preventive interventions that alter parenting practices and aggression during early childhood provide the opportunity to test causal models of early childhood psychopathology. Although there have been several informative preventive intervention studies that test mediation models in older children, no such studies have been conducted with younger children at high risk for psychopathology. Within the context of a randomized controlled trial, we examined whether changes in parenting practices mediate the effects of a family intervention on observed physical aggression among African American and Latino younger siblings of adjudicated youths. Improved parenting practices partially mediated the intervention effect on physical aggression. Improvements in harsh parenting, responsive parenting, and stimulating parenting explained a significant amount of the intervention effect on child physical aggression observed in the context of parent-child interactions. Parenting practices accounted for 38% of the intervention effect on physical aggression. There was support for the hypothesized model of the prevention of physical aggression during early childhood. Intervention benefits on parenting practices partially accounted for intervention effects on physical aggression in young high-risk children.


Selective Vulnerabilities of N-methyl-D-aspartate (NMDA) Receptors During Brain Aging.
N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals.


New techniques for efficient sliding thin-slab volume visualization.
High-resolution three-dimensional (3-D) volumetric images obtained by today's radiologic imaging scanners are rich in detailed diagnostic information. Despite the many visualization techniques available to assess such images, there remains information that is challenging to uncover, such as the location of small structures (e.g., mediastinal lymph nodes, narrowed-airway regions). Recently, sliding thin-slab (STS) visualization was proposed to improve the visualization of interior structures. These STS techniques sometimes depend on user opacity specifications or extra preprocessing, and other rendering approaches that use the general STS mechanism are conceivable. We introduce two techniques for STS volume visualization. The first, a depth (perspective) rendering process, produces an unobstructed, high-contrast 3-D view of the information within a thin volume of image data. Results are a function of relative planar locations. Thus, rendered views accurately depict the internal properties that were initially captured as position and intensity. The second method produces a gradient-like view of the intensity changes in a thin volume. Results can effectively detect the occurrence and location of dramatic tissue variations, often not visually recognized otherwise. Both STS techniques exploit the concept of temporal coherence to form sequences of consecutive slabs, using information from previously computed slabs. This permits efficient real-time computation on a general-purpose computer. Further, these techniques require no preprocessing, and results are not dependent on user knowledge. Results using 3-D computed tomography chest images show the computational efficiency and visual efficacy of the new STS techniques.


Plant compensation to grazing and soil carbon dynamics in a tropical grassland.
The effects of grazing on soil organic carbon (SOC) dynamics, particularly in the tropics, are still poorly understood. Plant compensation to grazing, whereby plants maintain leaf area (C input capacity) despite consumption (C removal) by grazers, has been demonstrated in tropical grasslands but its influence on SOC is largely unexplored. Here, the effect of grazing on plant leaf area index (LAI) was measured in a field experiment in Serengeti National Park, Tanzania. LAI changed little for grazing intensities up to 70%. The response curve of LAI versus grazing intensity was used in a mass balance model, called SNAP, of SOC dynamics based on previous data from the Serengeti. The model predicted SOC to increase at intermediate grazing intensity, but then to decline rapidly at the highest grazing intensities. The SNAP model predictions were compared with observed SOC stocks in the 24 grazed plots of a 10-year grazing exclosure experiment at eight sites across the park that varied in mean annual rainfall, soil texture, grazing intensity and plant lignin and cellulose. The model predicted current SOC stocks very well (R (2) > 0.75), and suggests that compensatory plant responses to grazing are an important means of how herbivores might maintain or increase SOC in tropical grasslands.


The community as an active part in the implementation of interventions for the prevention and control of tuberculosis: a scoping review.
Interventions involving direct community stakeholders include a variety of approaches in which members take an active role in improving their health. We evaluated studies in which the community has actively participated to strengthen tuberculosis prevention and control programs. A literature search was performed in Pubmed, Scopus, ERIC, Global Index Medicus, Scielo, Cochrane Library, LILACS, Google Scholar, speciality journals, and other bibliographic references. The primary question for this review was: what is known about tuberculosis control interventions and programs in which the community has been an active part?. Two reviewers performed the search, screening and selection of studies independently. In cases of discrepancies over the eligibility of an article, it was resolved by consensus. 130 studies were selected, of which 68.47% (n=89/130) were published after 2010. The studies were conducted in Africa (44.62%), the Americas (22.31%) and Southeast Asia (19.23%). It was found that 20% (n=26/130) of the studies evaluated the participation of the community in the detection/active search of cases, 20.77% (n=27/130) in the promotion/prevention of tuberculosis; 23.07% (n=30/130) in identifying barriers to treatment, 46.15% (n=60/130) in supervision during treatment and 3.08% (n=4/130) in social support for patient. Community participation not only strengthens the capacities of health systems for the prevention and control of tuberculosis, but also allows a better understanding of the disease from the perspective of the patient and the affected community by identifying barriers and difficulties through of the tuberculosis care cascade. Engaging key community stakeholders in co-creating solutions offers a critical pathway for local governments to eradicate TB.


Best-practice Indicators in Psoriatic Disease Care.
In 2016, members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), in collaboration with KPMG LLP (UK), conducted a study to measure care in psoriatic arthritis (PsA). A key finding was that centers do not usually have processes in place to measure the effect of improved quality of care. Our objectives were to identify and select best-practice indicators to enable PsA caregivers to assess and monitor the outcomes of specific initiatives aimed at improving care in 4 focus areas: (1) shortening time to diagnosis; (2) improving multidisciplinary collaboration; (3) optimizing disease management; and (4) improving disease monitoring. (1) Structured review of scientific and grey literature to obtain evidence for a long list of 100 potential indicators across the 4 focus areas; (2) survey expert rheumatologists and dermatologists to review the long list and identify the most meaningful and feasible indicators for use in day-to-day practice; (3) consensus discussion to identify a shortlist of indicators based on predefined selection criteria; (4) electronic group discussion to refine definitions of shortlisted indicators and targets; and (5) review of the shortlisted indicators at the annual GRAPPA meeting in July 2018 to ensure the indicators meet the preliminary criteria. The expert group arrived at a consensus with a shortlist of 8 best-practice indicators across 4 key focus areas aligned with the patient pathway. There were 8 evidence-based best-practice indicators and respective targets that were identified to enable the monitoring of quality of care and target improvements.


Fraction of boroxol rings in vitreous boron oxide from a first-principles analysis of Raman and NMR spectra.
We determine the fraction f of B atoms belonging to boroxol rings in vitreous boron oxide through a first-principles analysis. After generating a model structure of vitreous B2O3 by first-principles molecular dynamics, we address a large set of properties, including the neutron structure factor, the neutron density of vibrational states, the infrared spectra, the Raman spectra, and the 11B NMR spectra, and find overall good agreement with corresponding experimental data. From the analysis of Raman and 11B NMR spectra, we yield consistently for both probes a fraction f of approximately 0.75. This result indicates that the structure of vitreous boron oxide is largely dominated by boroxol rings.


Developmental control of telomere lengths and telomerase activity in plants.
Telomere lengths and telomerase activity were studied during the development of a model dioecious plant, Melandrium album (syn Silene latifolia). Telomeric DNA consisted of Arabidopsis-type TTTAGGG tandem repeats. The terminal positions of these repeats were confirmed by both Bal31 exonuclease degradation and in situ hybridization. Analysis of terminal restriction fragments in different tissues and ontogenetic stages showed that telomere lengths are stabilized precisely and do not change during plant growth and development. Telomerase activity tested by using a semiquantitative telomerase repeat amplification protocol correlated with cell proliferation in the tissues analyzed. Highest activity was found in germinating seedlings and root tips, whereas we observed a 100-fold decrease in telomerase activity in leaves and no activity in quiescent seeds. Telomerase also was found in mature pollen grains. Telomerase activity in tissues containing dividing cells and telomere length stability during development suggest their precise control during plant ontogenesis; however, the telomere length regulation mechanism could be unbalanced during in vitro dedifferentiation.


Antibodies for biodefense.
Potential bioweapons are biological agents (bacteria, viruses, and toxins) at risk of intentional dissemination. Biodefense, defined as development of therapeutics and vaccines against these agents, has seen an increase, particularly in the US following the 2001 anthrax attack. This review focuses on recombinant antibodies and polyclonal antibodies for biodefense that have been accepted for clinical use. These antibodies aim to protect against primary potential bioweapons, or category A agents as defined by the Centers for Disease Control and Prevention (Bacillus anthracis, Yersinia pestis, Francisella tularensis, botulinum neurotoxins, smallpox virus, and certain others causing viral hemorrhagic fevers) and certain category B agents. Potential for prophylactic use is presented, as well as frequent use of oligoclonal antibodies or synergistic effect with other molecules. Capacities and limitations of antibodies for use in biodefense are discussed, and are generally applicable to the field of infectious diseases.


Renal transplantation in adults with thrombotic thrombocytopenic purpura/haemolytic-uraemic syndrome.
Thrombotic thrombocytopenic purpura/haemolytic-uraemic syndrome (TTP/HUS) is a rare cause of renal failure in adults. There is little data concerning the outcome of adult patients who receive a renal transplant for TTP/HUS: We have carried out a survey of 22 transplant centres in the USA to determine the outcome of patients who developed ESRD from TTP/HUS and latter received a renal transplant. Twelve of the 22 centres responded to our inquiry. Seven centres had not transplanted any patients with TTP/HUS, and five centres had transplanted a total of 24 grafts in 17 patients with TTP/HUS: Thirty-three per cent of patients demonstrated definite clinical and pathological evidence of recurrence of TTP/HUS: An additional 16% of patients demonstrated pathological evidence of possible recurrence of TTP/HUS in the absence of clinical manifestations. The overall 1-year graft survival rate was 42% and the 2-year graft survival rate was 35%. In our experience recurrence TTP/HUS was associated with universal graft failure. Although cyclosporin A does occasionally cause a thrombotic angiopathy in patients with no history of TTP/HUS, we found no evidence that it should be avoided in patients with a previous history of ESRD from TTP/HUS who subsequently receive a renal transplant. TTP/HUS frequently recurres in adults who receive a renal transplant, with a 2-year graft survival rate of 35%.


On-chip optical interconnection by using integrated III-V laser diode and photodetector with silicon waveguide.
On-chip integration of III-V laser diodes and photodetectors with silicon nanowire waveguides is demonstrated. Through flip-chip bonding of GaInNAs/GaAs laser diodes directly onto the silicon substrate, efficient heat dissipation was realized and characteristic temperatures as high as 132K were achieved. Spot-size converters for the laser-to-waveguide coupling were used, with efficiencies greater than 60%. The photodetectors were fabricated by bonding of InGaAs/InP wafers directly to silicon waveguides and formation of metal-semiconductor-metal structures, giving responsivities as high as 0.74 A/W. Both laser diode and the photodetector were integrated with a single silicon waveguide to demonstrate a complete on-chip optical transmission link.


Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications.
The final section of this 3-part review analyzes published reports involving the acute treatment of migraine with opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and steroids in the emergency department (ED), urgent care, and headache clinic settings, as well as post-discharge medications. In the Conclusion, there is a general discussion of all the therapies presented in the 3 sections. Using the terms ("migraine" AND "emergency") AND ("therapy" OR "treatment"), the author searched MEDLINE for reports from ED and urgent care settings that involved all routes of medication delivery. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Seventy-five reports were identified that compared the efficacy and safety of multiple acute migraine medications for rescue. Of the medications reviewed in Part 3, opioids, NSAIDs, and steroids all demonstrated some effectiveness. When used alone, nalbuphine and metamizole were superior to placebo. NSAIDs were inferior to the combination of metoclopramide and diphenhydramine. Meperidine was arguably equivalent when compared with ketorolac and dihydroergotamine (DHE) but was inferior to chlorpromazine and equivalent to the other dopamine antagonists. Steroids afford some protection against headache recurrence after the patient leaves the treatment center. All 3 opioids most frequently studied - meperidine, tramadol, and nalbuphine - were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Opioid side effects included dizziness, sedation, and nausea. With ketorolac being the most frequently studied drug in the class, NSAIDs were generally well tolerated, and they may provide benefit even when given late in the migraine attack. The rate of headache recurrence within 24-72 hours after discharge from the ED can be greater than 50%. Corticosteroids can be useful in reducing headache recurrence after discharge. As discussed in Parts 1, 2, and 3, there are effective medications for provider-administered "rescue" in all the classes discussed. Prochlorperazine and metoclopramide are the most frequently studied of the anti-migraine medications in the emergent setting, and their effectiveness is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in migraine pain relief. Although there are fewer studies involving sumatriptan and DHE, relatively "migraine-specific" medications, they appear to be equivalent to the dopamine antagonists for migraine pain relief. Lack of comparisons with placebo and the frequent use of combinations of medications in treatment arms complicate the comparison of single agents to one another. When used alone, prochlorperazine, promethazine, metoclopramide, nalbuphine, and metamizole were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also are more likely to produce side effects that are difficult for a patient to tolerate (especially akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when only paired comparisons were considered. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to that observed with droperidol or prochlorperazine.


Transcriptional Truncation of the Long Coding Imprinted Gene Usp29.
Usp29 (Ubiquitin-specific protease 29) is a paternally expressed gene located upstream of another imprinted gene Peg3. In the current study, the transcription of this long coding gene spanning a 250-kb genomic distance was truncated using a knockin allele. According to the results, paternal transmission of the mutant allele resulted in reduced body and litter sizes whereas the maternal transmission caused no obvious effects. In the paternal mutant, the expression levels of Usp29 were reduced to 14-18% level of the wild-type littermates due to the Poly-A signal included in the knockin cassette. Expression analyses further revealed an unusual female-specific up-regulation of the adjacent imprinted gene Zfp264 in the mutant. Consistent with this, the promoter of Zfp264 was hypomethylated only in the female mutant. Interestingly, this female-specific hypomethylation by the knockin allele was not detected in the offspring of an interspecific crossing, indicating its sensitivity to genetic background. Overall, the results suggest that the transcription of Usp29 may be involved in DNA methylation setting of Zfp264 promoter in a sex-specific manner.


Application of 2021 American Diabetes Association Glycemic Treatment Clinical Practice Recommendations in Primary Care.
We aimed to identify the proportion of primary care patients meeting criteria for sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for cardiorenal comorbidities per 2021 American Diabetes Association (ADA) Standards of Care recommendations using readily available electronic health record (EHR) characteristics. We applied 2021 ADA recommendations to a primary care cohort of 13,350 adults with type 2 diabetes (T2D). We found that 33% of patients with diabetes would be eligible for an SGLT2i or GLP-1 RA based on cardiorenal comorbidities, 13% of patients met criteria for an SGLT2i based on heart failure or albuminuric chronic kidney disease (CKD), and 18% of patients met criteria for either agent based on atherosclerotic cardiovascular disease or CKD with an albumin-to-creatinine ratio of ≤300 mg/g. This EHR algorithm identified one-third of primary care patients with T2D as meeting criteria for SGLT2i and GLP-1 RA based on strict comorbidity definitions according to 2021 ADA recommendations.


The diagnosis, burden and prognosis of dementia: A record-linkage cohort study in England.
Electronic health records (EHR) might be a useful resource to study the risk factors and clinical care of people with dementia. We sought to determine the diagnostic validity of dementia captured in linked EHR. A cohort of adults in linked primary care, hospital, disease registry and mortality records in England, [CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records)]. The proportion of individuals with dementia, Alzheimer's disease, vascular and rare dementia in each data source was determined. A comparison was made of symptoms and care between people with dementia and age-, sex- and general practice-matched controls, using conditional logistic regression. The lifetime risk and prevalence of dementia and mortality rates in people with and without dementia were estimated with random-effects Poisson models. There were 47,386 people with dementia: 12,633 with Alzheimer's disease, 9540 with vascular and 1539 with rare dementia. Seventy-four percent of cases had corroborating evidence of dementia. People with dementia were more likely to live in a deprived area (conditional OR 1.26;95%CI:1.20-1.31 most vs least deprived), have documented memory impairment (cOR = 11.97;95%CI:11.24-12.75), falls (cOR = 2.36;95%CI:2.31-2.41), depression (cOR = 2.03; 95%CI:1.98-2.09) or anxiety (cOR = 1.27; 95%CI:1.23-1.32). The lifetime risk of dementia at age 65 was 9.2% (95%CI:9.0%-9.4%), in men and 14.9% (95%CI:14.7%-15.1%) in women. The population prevalence of recorded dementia increased from 0.3% in 2000 to 0.7% in 2010. A higher mortality rate was observed in people with than without dementia (IRR = 1.56;95%CI:1.54-1.58). Most people with a record of dementia in linked UK EHR had some corroborating evidence for diagnosis. The estimated 10-year risk of dementia was higher than published population-based estimations. EHR are therefore a promising source of data for dementia research.


Population structure of indigenous inhabitants of Arabia.
Modern day Saudi Arabia occupies the majority of historical Arabia, which may have contributed to ancient waves of migration out of Africa. This ancient history has left a lasting imprint in the genetics of the region, including the diverse set of tribes that call Saudi Arabia their home. How these tribes relate to each other and to the world's major populations remains an unanswered question. In an attempt to improve our understanding of the population structure of Saudi Arabia, we conducted genomic profiling of 957 unrelated individuals who self-identify with 28 large tribes in Saudi Arabia. Consistent with the tradition of intra-tribal unions, the subjects showed strong clustering along tribal lines with the distance between clusters correlating with their geographical proximities in Arabia. However, these individuals form a unique cluster when compared to the world's major populations. The ancient origin of these tribal affiliations is supported by analyses that revealed little evidence of ancestral origin from within the 28 tribes. Our results disclose a granular map of population structure and have important implications for future genetic studies into Mendelian and common diseases in the region.


Current-Controlled Electrical Point-Source Stimulation of Embryonic Stem Cells.
Stem cell therapy is emerging as a promising clinical approach for myocardial repair. However, the interactions between the graft and host, resulting in inconsistent levels of integration, remain largely unknown. In particular, the influence of electrical activity of the surrounding host tissue on graft differentiation and integration is poorly understood. In order to study this influence under controlled conditions, an in vitro system was developed. Electrical pacing of differentiating murine embryonic stem (ES) cells was performed at physiologically relevant levels through direct contact with microelectrodes, simulating the local activation resulting from contact with surrounding electroactive tissue. Cells stimulated with a charged balanced voltage-controlled current source for up to 4 days were analyzed for cardiac and ES cell gene expression using real-time PCR, immunofluorescent imaging, and genome microarray analysis. Results varied between ES cells from three progressive differentiation stages and stimulation amplitudes (nine conditions), indicating a high sensitivity to electrical pacing. Conditions that maximally encouraged cardiomyocyte differentiation were found with Day 7 EBs stimulated at 30 microA. The resulting gene expression included a sixfold increase in troponin-T and a twofold increase in beta-MHCwithout increasing ES cell proliferation marker Nanog. Subsequent genome microarray analysis revealed broad transcriptome changes after pacing. Concurrent to upregulation of mature gene programs including cardiovascular, neurological, and musculoskeletal systems is the apparent downregulation of important self-renewal and pluripotency genes. Overall, a robust system capable of long-term stimulation of ES cells is demonstrated, and specific conditions are outlined that most encourage cardiomyocyte differentiation.


A MicroRNA feedback circuit in midbrain dopamine neurons.
MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.


Walking sagittal balance correction by pedicle subtraction osteotomy in adults with fixed sagittal imbalance.
Pedicle subtraction osteotomy (PSO) is widely used to treat severe fixed sagittal imbalance. However, the effect of PSO on balance has not been fully documented. The aim of this study was to assess dynamic walking balance after PSO to treat fixed sagittal imbalance. Gait and balance were assessed in 15 consecutive adult female patients who had been treated by PSO for a fixed sagittal imbalance and compare patients' preop and postop dynamic walking balance with that of 15 age- and gender-matched healthy volunteers (HV). Each patient's chart, X-rays, pre and postop SRS22 outcome scores, and ODI were reviewed. Means were compared by Mann-Whitney U test and Chi-square test. The mean age was 66.3 years (51-74 years). The mean follow-up was 2.7 years (2-3.5 years). The C7PL and GL, measured on the force platform, were both improved from 24.2 ± 7.3 cm and 27.6 ± 9.4 to 5.4 ± 2.6 cm and 7.2 ± 3.4 cm, respectively. The baseline hip ROM was significantly smaller in patients compared to HV, whereas no significant difference was observed in the knee or ankle ROM. The pelvic tilt (preop -0.4° ± 1.4°, postop 8.9° ± 1.0°), and maximum hip-extension angle (preop -1.2° ± 14.2°, postop -11.2° ± 7.2°) were also improved after surgery. Cadence (116 s/min), stance-swing ratio (stance 63.2 % vs. swing 36.8 %), and stride (98.0 cm) were all increased after surgery. On the other hand, gait velocity was significantly slower in the PSO group at both pre and postop than in HV (PSO 53.3 m/min at preop and 58.8 m/min at postop vs. HV 71.1 m/min, p = 0.04). Despite a mild residual spinal-pelvic malalignment, PSO restored sagittal alignment and balance satisfactorily and has improved the gait pattern.


Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior.
Human genetic variation in the nicotinic receptor gene cluster CHRNA5/A3/B4, in particular the non-synonymous and frequent CHRNA5 variant rs16969968 (α5SNP), has an important consequence on smoking behavior in humans. A number of genetic association studies have additionally implicated the CHRNA5 gene in addictions to other drugs, and also body mass index (BMI). Here, we model the α5SNP, in a transgenic rat line, and establish its role in alcohol dependence, and feeding behavior. Rats expressing the α5SNP consume more alcohol, and exhibit increased relapse to alcohol seeking after abstinence. This high-relapsing phenotype is reflected in altered activity in the insula, linked to interoception, as established using c-Fos immunostaining. Similarly, relapse to food seeking is increased in the transgenic group, while a nicotine treatment reduces relapse in both transgenic and control rats. These findings point to a general role of this human polymorphism in reward processing, and multiple addictions other than smoking. This could pave the way for the use of medication targeting the nicotinic receptor in the treatment of alcohol use and eating disorders, and comorbid conditions in smokers.


La Untadita: a procedure for maintaining washbasins and drums free of Aedes aegypti based on modification of existing practices.
Chlorine bleach and detergent are routinely used by householders in El Progreso, Honduras in the process of cleaning washbasins and drums, the two most important larval habitats of Aedes aegypti in the city. The efficacy of these materials in eliminating eggs, larvae, and pupae of Ae. aegypti was assessed under controlled conditions. The promising results obtained led to trials using a combination of chlorine bleach and detergent to apply to the walls of washbasins and drums as a method for eliminating eggs. The bleach maintained its ovicidal properties when mixed with detergent, and the detergent gave the mixture consistency so that it could be applied as a thin film to the walls. This new procedure was named the little dab (Untadita in Spanish) and allows households to direct their efforts against a stage of the mosquito life cycle that has been ignored in the past: the egg.


Does the change in season affect disease activity in patients with psoriatic arthritis?
To determine whether there is seasonal variation in disease activity of patients with psoriatic arthritis (PsA). The authors identified the first available set of consecutive summer and winter visits for every patient from the prospective cohort of PsA. Comparison between summer and winter visits, and comparison of the repeated summer/winter visits, from 1978 until 2011 for the same identified patients was conducted for demographics, disease activity outcomes, laboratory results and treatment. The authors categorised disease activity into high, moderate and low states, and improvement versus flare/worsening. Descriptive statistics were computed and multivariate analyses using logistic regression and generalised estimating equations were conducted. The first available summer and winter visit were identified for 253 patients, and 1789 observations were analysed. There was no statistically significant difference in patients' demographics, disease activity outcomes, laboratory results and treatment between summer and winter visits. Bath Ankylosing Spondylitis Disease Activity Index scores were greater for summer visits and patients graded their disease as being worse in winter as compared with summer in the univariate analysis, but this difference did not hold in the multivariate analysis. The change in season does not affect PsA patients' characteristics and disease activity outcomes as determined by the physicians and patients.


Immunochemical analysis of a cytochrome P-450IA1 homologue in human lung microsomes.
The monoclonal antibody MAb 1-7-1, which specifically binds to cytochromes P-450IA1 and P-450IA2 in 3-methylcholanthrene-induced rat liver microsomes, was used to identify a cytochrome P-450IA1 homologue in human lung microsomes. Although MAb 1-7-1 had similar affinity constants for human and rat microsomes, the amount bound to human lung microsomes was severalfold lower than that bound to microsomes from untreated rat or rabbit lung and much lower than the amount bound to 3-methylcholanthrene-induced rat lung or liver microsomes. The amount bound to untreated baboon lung microsomes was similar to that bound to human lung microsomes. Three cytochrome P-450IA1-catalyzed activities, 7-ethoxyresorufin O-deethylase, 7-ethoxycoumarin, O-deethylase, and aryl hydrocarbon hydroxylase, were measurable in human lung microsomes, but the cytochrome P-450IA2-dependent activity acetanilide 4-hydroxylase was not. MAb 1-7-1 inhibited, and its binding correlated strongly with, 7-ethoxyresorufin O-deethylase activity (r = 0.92, p less than 0.01) in human lung microsomes. 7-Ethoxyresorufin O-deethylase activities in human lung were similar to those measured in untreated baboon lung but considerably lower than those present in untreated rabbit lung, untreated or 3-methylcholanthrene-induced rat lung and liver, or human liver. We conclude that MAb 1-7-1 recognizes a cytochrome P-450IA1 homologue in human lung and that no cytochrome P-450IA2 homologue is detected. Cytochrome P-450IA1 is expressed in human lung at relatively low levels, similar to those observed in untreated primate (baboon) lung. The majority of the 19 human lung samples examined do not exhibit a permanent polycyclic aromatic hydrocarbon-induced state with respect to this isozyme.


Ppm1b negatively regulates necroptosis through dephosphorylating Rip3.
The auto-phosphorylation of murine receptor-interacting protein 3 (Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how Rip3 phosphorylation is regulated is still largely unknown. Here we identified protein phosphatase 1B (Ppm1b) as a Rip3 phosphatase and found that Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by Rip3 auto-phosphorylation in resting cells, and tumour necrosis factor-α (TNF)-induced necroptosis in cultured cells. We revealed that Ppm1b selectively suppresses necroptosis through the dephosphorylation of Rip3, which then prevents the recruitment of mixed lineage kinase domain-like protein (Mlkl) to the necrosome. We further showed that Ppm1b deficiency (Ppm1b(d/d)) in mice enhanced TNF-induced death in a Rip3-dependent manner, and the role of Ppm1b in inhibiting necroptosis was evidenced by elevated Rip3 phosphorylation and tissue damage in the caecum of TNF-treated Ppm1b(d/d) mice. These data indicate that Ppm1b negatively regulates necroptosis through dephosphorylating Rip3 in vitro and in vivo.


Novel immune response to gluten in individuals with schizophrenia.
A link between celiac disease and schizophrenia has been postulated for several years, based primarily on reports of elevated levels of antibody to gliadin in patients. We sought to examine the proposed connection between schizophrenia and celiac disease by characterizing the molecular specificity and mechanism of the anti-gliadin immune response in a subset of individuals with schizophrenia. Blood samples from individuals with schizophrenia and elevated anti-gliadin antibody titer were examined for celiac disease-associated biomarkers, including antibodies to transglutaminase 2 (TG2) enzyme and deamidated gliadin peptides, as well as the HLA-DQ2 and -DQ8 MHC genes. The anti-gliadin antibody response was further characterized through examination of reactivity towards chromatographically separated gluten proteins. Target proteins of interest were identified by peptide mass mapping. In contrast to celiac disease patients, an association between the anti-gliadin immune response and anti-TG2 antibody or HLA-DQ2 and -DQ8 markers was not found in individuals with schizophrenia. In addition, the majority of individuals with schizophrenia and anti-gliadin antibody did not exhibit antibody reactivity to deamidated gliadin peptides. Further characterization of the antibody specificity revealed preferential reactivity towards different gluten proteins in the schizophrenia and celiac disease groups. These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8. Meanwhile, the presence of elevated levels of antibodies to specific gluten proteins points to shared immunologic abnormalities in a subset of schizophrenia patients. Further characterization and understanding of the immune response to gluten in schizophrenia may provide novel insights into the etiopathogenesis of specific disease phenotypes.


Correlation between computer-assisted measurements of mandibular opening and closing movements and clinical symptoms of temporomandibular dysfunction.
197 subjects (74 male, 123 female) were evaluated in this Study of Health in Pomerania associated project (SHIP 0). Both a clinical functional status and an instrumental analysis of functional movement patterns of the mandible were performed in each subject, in the latter case using an ultrasonic jaw motion analysis system. Correlations between instrumental movement pattern features and clinical signs and symptoms of temporomandibular joint dysfunction (TMD), such as joint sounds, palpable impairment of jaw movement, and the termination of opening movement at the incisal point, were particularly significant (p <0.005). Correlations for TMJ crepitation sounds and joint pain on palpitation from the lateral or posterior aspect tended to be less significant (p < 0.1). No association was found for pain on jaw movement or muscle tenderness in response to pressure. A multivariate logistic regression model showed a significant correlation between Helkimo Clinical Dysfunction grades 2 and 3 and the following independent variables: frequent headaches (odds ratio [OR] 4.12; p = 0.032), frequent popping sounds in the jaw joints (OR 5.79; p = 0.012), incisal paths showing conspicuous signs of dysfunction such as deviation or deflection (OR 4.35; p = 0.05), and condylar path anomalies such as jumpy, straight/inverse or irregular tracings (OR 28.59; p = 0.006). Instrumental functional analysis of condylar path tracings allows one to draw statistically valid conclusions about the occurrence of TMD symptoms. It can be helpful to perform condylar path analysis when performing risk assessments for temporomandibular dysfunction in certain situations, particularly before prosthetic rehabilitation.