Substrate specificity and modifications of the active centre of elastase-like neutral proteinases from horse blood leucocytes.
Two proteinases (2A and 2B) purified from the granular fraction of horse blood leucocytes degrade casein (Km values 12.8 and 6mg/ml respectively) with maximum activity at pH 7.4 and in the presence of 2m-urea. Urea-denatured haemoglobin, fibrinogen, albumin and resorcin/fuchsin-stained elastin are digested at a slower rate. The enzymes hydrolyse synthetic substrates of elastase, N-benzyloxycarbonyl-L-alanine 4-nitrophenyl ester (Km 0.114 and 0.178 mM) and N-acetyl-tri-L-alanine methyl ester (Km 5.55 and 0.98 mM), but they do not hydrolyse synthetic substrates of trypsin, chymotrypsin and thrombin. The examined proteinases are completely inhibited by 2 mM-di-isopropyl phosphorfluoridate and show a sensitivity to butyl and octyl isocyanates similar to that of pancreatic elastase. The pH-dependence of their photoinactivation in the presence of Rose Bengal indicates the presence of histidine in the active centre. Proteinase 2A rather insensitive to iodination by IC1 as is pancreatic elastase, whereas proteinase 2B is totally inactivated after incorporation of five iodine atoms per enzyme molecule.


The relationship between shoulder alignment and elbow joint angle in cricket fast-medium bowlers.
The aim of this study was to examine the relationship between shoulder alignment and elbow angle during the delivery action of fast-medium bowlers. The elbow and upper trunk alignment were recorded for 13 high-performance bowlers (mean age 20 years) using a 12-camera Vicon motion analysis system operating at 250 Hz. The three highest velocity trials for "good" and "short" length deliveries were analysed. Results showed that bowlers with a more front-on shoulder alignment at back-foot impact and when the upper arm was horizontal to the ground experienced a significantly greater elbow flexion--extension range when compared with those who had a more side-on orientation at the same point in the delivery action. Bowlers with greater shoulder counter-rotation also recorded higher elbow flexion and subsequently extension during the period from upper arm horizontal to ball release. Shoulder alignment and elbow angles were similar for "short" and "good" length deliveries. It was concluded that bowlers with a more front-on shoulder orientation at back-foot impact demonstrated a higher elbow extension from upper arm horizontal to ball release and are therefore more likely to infringe International Cricket Council elbow tolerance levels, compared with those who adopt a more side-on shoulder orientation at back-foot impact.


Diversity Patterns of Dung Beetles along a Mediterranean Elevational Gradient.
Most studies of biodiversity-elevational patterns do not take species abundance into consideration. Hill numbers are a unified family of indices that use species abundance and allow a complete characterization of species assemblages through diversity profiles. Studies on dung beetle responses to elevation were essentially based on species richness and produced inconsistent results because of the non-distinction between different habitats and the use of gradients dispersed over wide areas. We analyzed dung beetle diversity in a Mediterranean mountain (central Italy) for different habitats (woodlands vs. grasslands) and taxonomic groups (scarabaeids and aphodiids). Scarabaeids were the most abundant. Since scarabaeids are able to construct subterranean nests, this indicates that the warm and dry summer climatic conditions of high elevations favor species capable of protecting their larvae from desiccation. Dung beetles were more abundant and diversified in grasslands than in woodlands, which is consistent with their preference for open habitats. In the woodlands, diversity increased with increasing elevation because of increasing tree thinning, whereas, in the grasslands, diversity decreased with elevation because of increasingly harsher environmental conditions. These results indicate a trade-off in the beetle response to elevation between the positive effects of increasing the availability of more suitable habitats and the decrease of optimal environmental conditions.


MicroRNA-140-5p is Downregulated in Osteosarcoma and Overexpression of MicroRNA-140-5p Inhibits Cancer Cell Proliferation by Downregulating GLUT-1.
MicroRNA-140-5p plays pivotal role in different types of human malignancies, while its involvement in osteosarcoma is unknown. Our study aimed to investigate the functionality of microRNA-140-5p in osteosarcoma. Plasma levels of microRNA-140-5p and glucose transporter 1 (GLUT-1) in both osteosarcoma and healthy controls were measured by qRT-PCR and ELISA, respectively. Correlation between plasma levels of microRNA-140-5p and GLUT-1 was analyzed by Pearson correlation coefficient. Correlation between plasma levels of microRNA-140-5p and clinical data of patients with osteosarcoma was analyzed by Chi-square test. MicroRNA-140-5p mimic and GLUT-1 expression vector were transfected into cells of human osteosarcoma cell lines, and the effects on microRNA-140-5p expression, GLUT-1 expression and cell proliferation were analyzed by qRT-PCR, Western-blot and CCK-8 assay, respectively. Plasma levels of microRNA-140-5p were significantly lower and plasma levels of GLUT-1 were significantly higher in osteosarcoma patients than that in healthy controls. Levels of plasma microRNA-140-5p and GLUT-1 were reversely correlated in osteosarcoma patients. Plasma levels of microRNA-140-5p were correlated with tumor size but not with other clinical data of patients. MicroRNA-140-5p mimic significantly inhibited cancer cell proliferation, while GLUT-1 overexpression significantly promoted cancer cell proliferation. MicroRNA-140-5p mimic significantly downregulated GLUT-1 expression. GLUT-1 overexpression showed no significant effect on microRNA-140-5p expression but attenuated the inhibitory effects of microRNA-140-5p mimic on cell proliferation. We therefore conclude that microRNA-140-5p is downregulated in osteosarcoma and overexpression of microRNA-140-5p may inhibit cancer cell proliferation by downregulating GLUT-1.


Epidemiological characteristics of multidrug-resistant Acinetobacter baumannii ST369 in Anhui, China.
Acinetobacter baumannii is a major health threat due to its antibiotic resistance and ability to cause nosocomial infections. Epidemiological studies indicated that the majority of globally prevalent ST369 clones originated from China, indicating a significant impact on public health in the country. In this study, we conducted whole-genome sequencing, comparative genomics, and Galleria mellonella infection model on eight A. baumannii ST369 isolates collected from a provincial hospital in China to comprehensively understand the organism. We identified two mutations (G540A and G667D) on the wzc gene that can affect bacterial virulence and viscosity. We confirmed their impact on resistance and virulence. We also investigated the potential involvement of AB46_0125 and AB152_03903 proteins in virulence. This finding provides a theoretical reference for further research on A. baumannii ST369 clinical isolates with similar mutations.


Antioxidant mediated protective effect of Parthenium hysterophorus against oxidative damage using in vitro models.
Parthenium hysterophorus L. (Asteraceae) is a common weed occurring throughout the globe. In traditional medicine its decoction has been used for treatment of many infectious and degenerative diseases. This work was therefore designed to assess the phytochemical constitution of P. hysterophorus flower and root extracts and to evaluate their reducing power, radical scavenging activity as well as protective efficacy against membrane lipid damage. Dried flower and root samples were sequentially extracted with non-polar and polar solvents using Soxhlet apparatus. The phytochemical screening was done using standard chemical methods and thin layer chromatography. Total phenolic content was determined spectrophotometrically. Reducing power and hydroxyl radical scavenging activity assays were used to measure antioxidant activity. Protection against membrane damage was evaluated by inhibition of lipid peroxidation (TBARS assay) in rat kidney homogenate. Flavonoids, terpenoids, alkaloids and cardiac glycosides were present in all the extract. The total phenol contents in flower and root extracts were found to be in the range 86.69-320.17 mg propyl gallate equivalent (PGE)/g and 55.47-253.84 mg PGE/g, respectively. Comparatively better reducing power was observed in hexane fractions of flower (0.405) and root (0.282). Benzene extract of flower and ethyl acetate fraction of root accounted for appreciable hydroxyl radical scavenging activity (75-77%). Maximum protection against membrane lipid peroxidative damage among flower and root extracts was provided by ethanol (55.26%) and ethyl acetate (48.95%) fractions, respectively. Total phenolic content showed positive correlations with reducing power and lipid peroxidation inhibition (LPOI) % in floral extracts as well as with hydroxyl radical scavenging activity and LPOI % in root extracts. Study established that phytochemicals present in P. hysterophorus extracts have considerable antioxidant potential as well as lipo-protective activity against membrane damage.


Inhibition of LPS-induced inflammatory mediators by 3-hydroxyanthranilic acid in macrophages through suppression of PI3K/NF-κB signaling pathways.
Many tryptophan metabolites have immunomodulatory effects on various immune cells. 3-Hydroxyanthranilic Acid (3-HAA) is a tryptophan metabolite reported to have anti-inflammatory activity. The mechanism of this activity is unclear. The present study examined the immunomodulatory effects and molecular mechanisms of 3-HAA on macrophages. Pretreatment of 3-HAA (0.1-10 μg mL(-1)) for 2 h markedly inhibited NO and cytokine production in LPS-stimulated Raw 264.7 cells. Moreover, translocation and activation of NF-κB by LPS in the nucleus were abrogated through the prevention of IκB degradation by 3-HAA treatment. 3-HAA significantly suppressed LPS-induced PI3K/Akt/mTOR activation, whereas MAPKs were not affected by 3-HAA treatment. Furthermore, the inhibition of mTOR by 3-HAA resulted in decreased production of inflammatory mediators and NF-κB activity. Similar results were also observed in primary peritoneal macrophages. Furthermore, 3-HAA modulated macrophage polarization. Collectively, the results suggest that 3-HAA has an immunomodulatory effect that may result from inhibition of PI3K/Akt/mTOR and NF-κB activation, thereby decreasing the production of pro-inflammatory mediators.


Whipple's disease: pathogenetic considerations.
A typical case of Whipple's disease was manifested by malabsorption and nondeforming peripheral arthritis for five years. A definite diagnosis was made by duodenal mucosal biopsy which revealed the characteristic histologic features by light microscopy, intracellular and extracellular Whipple's bacilli by electron microscopy, and a typical immune cross-reactivity pattern by immunofluorescence technique. Whipple's bacilli apparently elicit no effective humoral and cellular immune response; macrophages thus play the key role in its pathogenesis. Antibiotic treatment resulted in a dramatic relief of symptoms and rapid restoration of body weight. We stress that in patients with nondeforming peripheral arthritis associated with malabsorption syndrome, Whipple's disease, despite its rarity, should be included in the differential diagnosis.


Effect of pentoxiphylline on the recovery of the preserved rat liver: 31P NMR and ultrastructural studies.
Hepatic failure often occurs following transplantation. This is primarily due to cold ischemia during preservation, warm ischemia during implantation, and finally reperfusion damage after transplantation and reflow. The possibility that this ischemia and reperfusion-induced damage can be reduced by preischemic application of a xanthine derivative (pentoxiphylline) was examined using 31P NMR spectroscopy and electron microscopy (EM) studies of bioenergetic and ultrastructural changes in oxygenated erythrocyte-perfused rat livers. EM illustrated that the hepatocytes and the mitochondria appeared to be relatively unaffected by cold preservation of the liver, whereas the endothelial cells lining the sinusoids became disrupted. After reperfusion, NMR spectroscopy showed a partial recovery of ATP levels, and EM indicated progressive mitochondrial injury. This progressive injury to the liver was probably due to endothelial cell damage which resulted in microcirculatory malfunction and free radical formation during reperfusion. Pentoxiphylline pretreated livers showed better preservation of the cell morphology and exhibited better ATP recovery than untreated livers. Pentoxiphylline is known to prevent the loss of precursors of ATP resynthesis by inhibiting AMP dephosphorylation during ischemia and improves the microcirculation via vasodilatory properties following ischemia. Thus, it is concluded that pentoxiphylline may ameliorate ischemia-induced cell damage during transplantation.


OGTT Glucose Response Curves, Insulin Sensitivity, and β-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve β-Cell Function.
We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSThis was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed.RESULTSAt randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect.CONCLUSIONSDespite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve.


Neurodevelopmental Outcomes in Preterm Infants Receiving a Multicomponent vs. a Soybean-Based Lipid Emulsion: 24 Month Follow-Up of a Randomized Controlled Trial.
Few studies in the literature have analyzed the long-term neurodevelopmental outcomes of the administration of a multicomponent versus a soybean-based lipid emulsion (LE) in preterm infants receiving parenteral nutrition (PN). A recent randomized controlled trial conducted in our unit provided evidence of better growth in head circumference during the hospital stay in those who received a multicomponent LE. This is a 24 month follow-up study of preterm infants, previously enrolled in a randomized trial, who received a multicomponent LE (SMOFlipid®) or a standard soybean-based one (Intralipid®). We evaluated neurodevelopmental outcomes at 24 months of corrected age (CA) in the two groups. Ninety-three children were followed up to the age of 24 months CA. Due to the peculiar time frame of the SARS-CoV-2 pandemic, neurodevelopmental outcomes were evaluated only in 77 children: 37 in the SMOFlipid® group and 40 in the Intralipid® group. No differences in major disability rates or in Griffith's evaluation were found between the two groups. In our population study, the administration of a multicomponent LE containing fish oil, compared to a soybean-based LE, had no significant effects on neurodevelopmental outcomes in preterm infants at 24 months CA.


Classification of cryo-electron sub-tomograms using constrained correlation.
Cryo-electron tomography (CET) is currently the only three-dimensional imaging technique capable of visualizing macromolecules in their cellular context at close-to-native conditions with a resolution in the nanometer range. An important component for the analysis of the data is their classification, which should discriminate among various macromolecules, conformational changes and interaction partners. Missing structure factors, typically in a wedge-shaped region in Fourier space if single-axis tilting is performed, hamper classification of cryo-electron tomographic data. Here, we describe a classification method for three-dimensional (3D) sub-tomograms extracted from cryo-electron tomograms, which takes the missing wedge into account and provides reliable results. The similarity of the individually aligned sub-tomograms is scored by constrained correlation. Subsequently, they are clustered based on their pairwise correlation values. In order to demonstrate the feasibility of this approach, we apply the proposed method to simulated tomographic data of the chaperone thermosome in different conformations. By comparison of the principal components of the resulting matrix we show that the proposed metric is significantly less prone to the orientation of the missing wedge compared to the unconstrained correlation. Moreover, we apply our classification method to an experimental dataset of GroEL with and without GroES, where we achieve a distinct discrimination between the putative GroEL and GroEL/GroES complexes.


Impact of titanium dioxide nanomaterials on nitrogen fixation rate and intracellular nitrogen storage in Anabaena variabilis.
This study comprehensively investigated the impact of titanium dioxide nanomaterials (nTiO(2)) exposure on cell growth, nitrogen fixation activity, and nitrogen storage dynamics in the primary producer cyanobacteria Anabaena variabilis at various dose concentrations and exposure time lengths. The results indicated that both growth rate (EC(50)-96 h of 0.62 mgTiO(2)/L) and nitrogen fixation activity (EC(50)-96 h of 0.4 mgTiO(2)/L) were inhibited by nTiO(2) exposure. The Hom's law (C(n)T(m)) was used as inactivation model to predict the concentration- and time-dependent inhibition of growth and nitrogen fixation activity. The kinetic parameters determined suggested that the time of exposure has a greater influence than the nTiO(2) concentration in toxicity. We observed, for the first time, that nTiO(2) induced a dose (concentration and time)-dependent increase in both the occurrence and intracellular levels of the nitrogen-rich cyanophycin grana proteins (CGPs). The results implied that CGPs may play an important role in the stress response mechanisms of nTiO(2) exposure and can serve as a toxicity assessment endpoint indicator. This study demonstrated that nitrogen-fixing activity could be hampered by the release of nTiO(2) in aquatic environments; therefore it potentially impacts important biogeochemical processes, such as carbon and nitrogen cycling.


Oral aspiration, type 1 laryngeal cleft, and respiratory tract infections in canadian inuit children.
Canadian Inuit infants suffer the highest rate of lower respiratory tract infections (LRTI's) in the world. The causes of this are incompletely understood. The primary objective of this study was to determine whether there exists an association between respiratory morbidity and oral aspiration in Inuit children. A retrospective chart review was conducted including children from Nunavut who underwent Video Fluoroscopic Swallowing Study between the years of 2001 to 2015. The primary outcome was hospitalization for LRTI. We hypothesized that infants found to have aspiration would experience a higher rate of admissions for LRTI than those with normal swallowing studies. One-hundred and twenty-seven patients were identified, of whom 94 were included. Fifty-six percent of patients had an abnormal swallowing study. Compared with patients with normal swallowing, the incidence rate of LRTI was higher in patients with aspiration (incidence rate ratio [IRR] = 1.51; 95% confidence interval [CI] = 1.23-1.87) and in patients with penetration (IRR = 1.40; 95% CI = 1.11-1.76). Fourteen percent of patients had confirmed laryngeal cleft; patients with confirmed presence of this also had a higher incidence rate of LRTI (IRR = 1.66; 95% CI = 1.32-2.07). The incidence of abnormal swallowing study showed an 11-fold variation across the five regions in Nunavut, with the highest prevalence in west Qikiqtani Region (Baffin Island). We conclude that swallowing dysfunction is not only prevalent amongst Canadian Inuit but clinically significant. This is the first study to demonstrate an association between swallowing dysfunction and respiratory morbidity in this population. Geographic distribution patterns and high rates of laryngeal cleft may point to a potential genetic etiology for what remains at this point, idiopathic swallowing dysfunction.


Long- and short-term results of children's and adolescents' therapy courses for stuttering.
It is widely known that most young children recover from stuttering. Evaluations of this spontaneous recovery vary from 40 to 80% of stuttering children. However, if the child is already older than 6 years of age, the spontaneous recovery will be less likely. The effectiveness of stuttering treatment, and especially fluency shaping methods, has been frequently studied. Good results in the treatment of stuttering for school-aged children have been accomplished by several treatment methods. However, stuttering modification treatments have not been studied so intensively. This study addresses the effects of intensive therapy courses on the stuttering behaviour of children and adolescents. The courses included speech therapy, where stuttering modification treatment was used, and also parental guidance. Taking part in the study were 21 children/adolescents who stutter, and 29 of their mothers/fathers took part in the study. The children were between the ages of 6.8 and 14.0 years. The effectiveness of therapy was evaluated in three ways. First, the speech of the children who stutter was videotaped at both the beginning and the end of the course and the samples were transcribed and analysed. Second, the parents and adolescents completed a feedback questionnaire at the end of the course. And third, the parents and adolescents completed a follow-up questionnaire 9 months after the course. The aim was to evaluate the changes in stuttering behaviour after the therapy course. The results indicate that stuttering severity became milder or did not change during the course. The percentage of syllables stuttered dropped with two-thirds of the participants. This result was replicated with avoidance behaviour and struggle behaviour. The quality of stuttering became milder, and by the end many children had shorter moments of stuttering and more repetitions and prolongation instead of blocks. Two participants did not complete the questionnaire. Of those who did, all but one adolescent, and all except one parent, reported that the positive changes in stuttering behaviour had continued during the follow-up period. The implication is that intensive therapy courses can be helpful to some participants who stutter.


Chemotherapy-induced peripheral neuropathy.
The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy.


Hypobaric-ischemic conditions produce glutamate-like cytopathology in infant rat brain.
We present a new animal model of perinatal hypoxic/ischemic brain damage and compare this type of brain damage with the excitotoxic type of damage previously described in the brains of infant rats and monkeys treated systemically with glutamate (Glu). Ten-d-old rats with unilateral occlusion of the common carotid artery were subjected to hypobaric conditions for 75 min and sacrificed 0-4 hr later for light and electron microscopic brain examination. The mortality rate was relatively low (12%), and brain damage was evident ipsilateral to the ligated carotid in 94% of surviving animals 4 hr after termination of the hypobaric event. Regions most frequently affected were the medial habenulum, dentate gyrus, caudate nucleus, frontoparietal neocortices, olfactory tubercle, and several thalamic nuclei. The acute cytopathological changes, primarily edematous degeneration of neuronal dendrites and cell bodies, evolved very rapidly, with some neurons manifesting end-stage necrosis at 0 hr (immediately after hypobaric exposure) and others developing such changes over a 1-4-hr period. We conclude that the neurodegenerative reaction induced in infant rat brain by hypoxia/ischemia is indistinguishable from the excitotoxic type of damage exogenous Glu is known to cause. Moreover, in a companion study (Olney et al., 1989) we show that MK-801, a powerful antagonist of the N-methyl-D-aspartate receptor complex (subtype of Glu receptor), protects against neuronal degeneration in this hypobaric/ischemic model. Our results reinforce other recent evidence suggesting that hypoxic/ischemic brain damage is mediated by endogenous Glu or related excitotoxins.


Radiomic Profiling of Head and Neck Cancer: 18F-FDG PET Texture Analysis as Predictor of Patient Survival.
The accurate prediction of prognosis and pattern of failure is crucial for optimizing treatment strategies for patients with cancer, and early evidence suggests that image texture analysis has great potential in predicting outcome both in terms of local control and treatment toxicity. The aim of this study was to assess the value of pretreatment 18F-FDG PET texture analysis for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC) treated with concurrent chemoradiation therapy. We performed a retrospective analysis of 90 patients diagnosed with primary HNSCC treated between January 2010 and June 2017 with concurrent chemo-radiotherapy. All patients underwent 18F-FDG PET/CT before treatment. 18F-FDG PET/CT texture features of the whole primary tumor were measured using an open-source texture analysis package. Least absolute shrinkage and selection operator (LASSO) was employed to select the features that are associated the most with clinical outcome, as progression-free survival and overall survival. We performed a univariate and multivariate analysis between all the relevant texture parameters and local failure, adjusting for age, sex, smoking, primary tumor site, and primary tumor stage. Harrell c-index was employed to score the predictive power of the multivariate cox regression models. Twenty patients (22.2%) developed local failure, whereas the remaining 70 (77.8%) achieved durable local control. Multivariate analysis revealed that one feature, defined as low-intensity long-run emphasis (LILRE), was a significant predictor of outcome regardless of clinical variables (hazard ratio < 0.001, P=0.001).The multivariate model based on imaging biomarkers resulted superior in predicting local failure with a c-index of 0.76 against 0.65 of the model based on clinical variables alone. LILRE, evaluated on pretreatment 18F-FDG PET/CT, is associated with higher local failure in patients with HNSCC treated with chemoradiotherapy. Using texture analysis in addition to clinical variables may be useful in predicting local control.


Epizootic vacuolar myelinopathy of the central nervous system of bald eagles (Haliaeetus leucocephalus) and American coots (Fulica americana).
Unprecedented mortality occurred in bald eagles (Haliaeetus leucocephalus) at DeGray Lake, Arkansas, during the winters of 1994-1995 and 1996-1997. The first eagles were found dead during November, soon after arrival from fall migration, and deaths continued into January during both episodes. In total, 29 eagles died at or near DeGray Lake in the winter of 1994-1995 and 26 died in the winter of 1996-1997; no eagle mortality was noted during the same months of the intervening winter or in the earlier history of the lake. During the mortality events, sick eagles were observed overflying perches or colliding with rock walls. Signs of incoordination and limb paresis were also observed in American coots (Fulica americana) during the episodes of eagle mortality, but mortality in coots was minimal. No consistent abnormalities were seen on gross necropsy of either species. No microscopic findings in organs other than the central nervous system (CNS) could explain the cause of death. By light microscopy, all 26 eagles examined and 62/77 (81%) coots had striking, diffuse, spongy degeneration of the white matter of the CNS. Vacuolation occurred in all myelinated CNS tissue, including the cerebellar folia and medulla oblongata, but was most prominent in the optic tectum. In the spinal cord, vacuoles were concentrated near the gray matter, and occasional swollen axons were seen. Vacuoles were uniformly present in optic nerves but were not evident in the retina or peripheral or autonomic nerves. Cellular inflammatory response to the lesion was distinctly lacking. Vacuoles were 8-50 microns in diameter and occurred individually, in clusters, or in rows. In sections stained by luxol fast blue/periodic acid-Schiff stain, the vacuoles were delimited and transected by myelin strands. Transmission electron microscopy revealed intramyelinic vacuoles formed in the myelin sheaths by splitting of one or more myelin lamellae at the intraperiodic line. This lesion is characteristic of toxicity from hexachlorophene, triethyltin, bromethalin, isonicotinic acid hydrazide, and certain exotic plant toxins; however, despite exhaustive testing, no etiology was determined for the DeGray Lake mortality events. This is the first report of vacuolar myelinopathy associated with spontaneous mortality in wild birds.


Y chromosome and male infertility: update, 2006.
Male factor infertility accounts for about half the cases of couple infertility and in around 50% of cases its etiology remains unknown. Molecular genetic techniques have unveiled a number of etiopathogenetic factors, including microdeletions of the Yq. Y chromosome microdeletions removing the AZoospermia Factor (AZF) regions are the most frequent molecular genetic causes of oligo/azoospermia. The intense effort of many laboratories contributed to a better understanding of the clinical significance of this genetic anomaly and to the identification of fertility candidate genes in the AZF regions. Important progress has been made on the structure of the Y chromosome and the mechanism of deletion. Studies aimed to define a predisposing genetic background for Yq deletions were not successful, perhaps due to the low number of patients analyzed so far. The screening for Yq deletions became a routine diagnostic test that provides an etiology for spermatogenic disturbances, and assess in the prognosis for testicular sperm retrieval according to the type of deletion. Assisted reproductive techniques represent an efficient symptomatic therapy for men bearing Y microdeletions, however, this genetic defect is transmitted to the male offsprings, affecting their fertility. Future studies should focus on understanding the biological function of AZF genes which is an essential step for the development of more appropriate and knowledge-based therapies.


Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies.
The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.


Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel.
In recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed. The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome. Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19-9, and baseline serum bilirubin levels) were not significantly associated with survival. Serum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.


NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy.
Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.


Bone parameters of elite athletes with oligomenorrhea and prevalence seeking medical attention: a cross-sectional study.
Since the definition of secondary amenorrhea is cessation of regular menses for more than 3 months, it is likely that athletes with irregular menstrual cycles, including oligomenorrhea, do not consider the condition as serious. However, the consequences of untreated oligomenorrhea have not been investigated in elite track and field athletes. The cohort consisted of 91 elite-level track and field athletes. Body compositions, including bone parameters and bone turnover markers (BTMs), were measured. Among the 91 participants, 52 were eumenorrheic and 33 were oligomenorrheic. The eumenorrheic athletes had significantly higher bone mineral density (BMD) and bone mineral content (BMC) of the lumbar spine, lower extremities, and whole body than had the oligomenorrheic athletes (p < 0.01). There were no significant differences in BTMs between the two groups, but oligomenorrheic athletes had significantly lower percent body fat. More than 40% of the elite-level female track and field athletes in this study reported menstrual disorders with oligomenorrhea as the most common. However, none sought medical attention. As compared to the eumenorrheic athletes, the oligomenorrheic athletes had lower BMC and BMD. Hence, if an athlete is oligomenorrheic, bone parameter measurements are considerably important.


Temporal pole activity during understanding other persons' mental states correlates with neuroticism trait.
Comprehension of other persons' mental states is one of the representative cognitive functions involved in social situations. It has been suggested that this function sometimes recruits emotional processes. The present fMRI study examined the neural mechanisms associated with understanding others' mental states, and the conditions that determine the recruitment of the emotional processes. The false belief paradigm, a traditional behavioral paradigm to investigate comprehension of others, was applied to an event-related fMRI analysis, allowing for the extraction of brain activity time-locked to successful understanding of others' mental states. Prominent brain activity was observed in multiple cortical regions including the medial prefrontal cortex, temporo-parietal junction, precuneus, and temporal pole. Then, correlational analyses were performed between the activations and individuals' scores of neuroticism, a personality trait that reflects emotional instability in daily life. It was revealed that the neuroticism scores were positively correlated with the activity in the temporal pole region, but not in the other regions. These results suggest that the emotional processes implemented in the temporal pole are recruited during successful understanding of other persons' mental states, and that the recruitment may be modulated by an emotional personality trait of individual subjects.


Safety and efficacy of balloon-mounted stent in the treatment of symptomatic intracranial atherosclerotic disease: a multicenter experience.
Randomized clinical trials have failed to prove that the safety and efficacy of endovascular treatment for symptomatic intracranial atherosclerotic disease (ICAD) is better than that of medical management. A recent study using a self-expandable stent showed acceptable lower rates of periprocedural complications. To study the safety and efficacy of a balloon-mounted stent (BMS) in the treatment of symptomatic ICAD. Prospectively maintained databases from 15 neuroendovascular centers between 2010 and 2020 were reviewed. Patients were included if they had severe symptomatic intracranial stenosis in the target artery, medical management had failed, and they underwent intracranial stenting with BMS after 24 hours of the qualifying event. The primary outcome was the occurrence of stroke and mortality within 72 hours after the procedure. Secondary outcomes were the occurrence of stroke, transient ischemic attacks (TIAs), and mortality on long-term follow-up. A total of 232 patients were eligible for the analysis (mean age 62.8 years, 34.1% female). The intracranial stenotic lesions were located in the anterior circulation in 135 (58.2%) cases. Recurrent stroke was the qualifying event in 165 (71.1%) while recurrent TIA was identified in 67 (28.9%) cases. The median (IQR) time from the qualifying event to stenting was 5 (2-20.75) days. Strokes were reported in 13 (5.6%) patients within 72 hours of the procedure; 9 (3.9%) ischemic and 4 (1.7%) hemorrhagic, and mortality in 2 (0.9%) cases. Among 189 patients with median follow-up time 6 (3-14.5) months, 12 (6.3%) had TIA and 7 (3.7%) had strokes. Three patients (1.6%) died from causes not related to stroke. Our study has shown that BMS may be a safe and effective treatment for medically refractory symptomatic ICAD. Additional prospective randomized clinical trials are warranted.


A closer look at the taxonomic and genetic diversity of endemic South African Marphysa Quatrefages, 1865.
The current study investigates the final unresolved cosmopolitan species of Marphysa in South Africa, Marphysa corallina, collected from KwaZulu Natal, Eastern and Western Cape provinces, together with another species collected from northern KwaZulu Natal. Morphological and genetic data prove that M. corallina, originally described from Hawaii, does not occur in South Africa. The curvature of the inner base on maxilla I, the elevated inner base of maxilla II, and the ventral cirrus as a transverse welt with a rounded tip allow us to identify it as a new species of Treadwellphysa, T. izinqa sp. nov. (common name: brown wonderworm). Characteristic traits include the basal reddish and distal golden colour of the subacicular hook, the ear-shaped postchaetal lobe, and tridentate falcigers which is reported for the first time for the genus. This species is harvested as bait on the south coast of SA, although less frequently than the more common blood wonderworm, Marphysa haemasona Quatrefages, 1866, and can be distinguished by its more uniform brown colouration and white-tipped antennae. A second species, Marphysa mzingazia sp. nov., is characterized by red eyes, six branchial filaments extending to the posterior end, the golden aciculae in posterior chaetigers, weakly bidentate yellow/brown subacicular hooks, and the presence of similar sized spinigers along the body. A molecular analysis based on cytochrome oxidase I fragments confirm both taxa as different species. A key for all South African species of Marphysa is included.


Modeling the impact of novel diagnostic tests on pediatric and extrapulmonary tuberculosis.
Extrapulmonary tuberculosis (EPTB) and most pediatric TB cannot be diagnosed using sputum-based assays. The epidemiological impact of different strategies to diagnose EPTB and pediatric TB is unclear. We developed a dynamic epidemic model of TB in a hypothetical population with epidemiological characteristics similar to India. We evaluated the impact of four alternative diagnostic test platforms on adult EPTB and pediatric TB mortality over 10 years: (1) Nucleic acid amplification test optimized for diagnosis of EPTB ("NAAT-EPTB"); (2) NAAT optimized for pediatric TB ("NAAT-Peds"); (3) more deployable NAAT for sputum-based diagnosis of adult pulmonary TB ("point-of-care (POC) sputum NAAT"); and (4) more deployable NAAT capable of diagnosing all forms of TB using non-invasive, non-sputum specimens ("POC non-sputum NAAT"). NAAT-EPTB lowered adult EPTB mortality by a projected 7.6% (95% uncertainty range [UR]: 6.5-8.8%). NAAT-Peds lowered pediatric TB mortality by 6.8% (UR: 4.9-8.4%). POC sputum NAAT, though only able to diagnose pulmonary TB, reduced projected pediatric TB deaths by 13.3% (UR: 4.6-15.7%) and adult EPTB deaths by 8.4% (UR 2.0-9.3%) simply by averting transmission of disease. POC non-sputum NAAT had the greatest effect, lowering pediatric TB mortality by 34.7% (UR: 26.8-38.7), and adult EPTB mortality by 38.5% (UR: 30.7-41.2). The relative impact of a POC sputum NAAT (i.e., enhanced deployability) versus NAAT-EPTB (i.e., enhanced ability to specifically diagnose TB-NSP) on adult EPTB mortality depends most strongly on factors that influence transmission, with settings of higher transmission (e.g., higher per-person transmission rate, lower diagnostic rate) favoring POC sputum NAAT. Although novel tests for pediatric TB and EPTB are likely to reduce TB mortality, major reductions in pediatric and EPTB incidence and mortality also require better diagnostic tests for adult pulmonary TB that reach a larger population.


Virus-infected avian cell lines established in vitro.
Four virus-infected avian cell lines have been established in culture. Two of these lines, infected with BAI strain A virus, liberate only small quantities of virus in the culture fluid. The cells retain the ability to induce myeloblastic leukemia when inoculated i.v. into 1- to 2-day-old chicks, but do so less efficiently than freshly obtained myeloblasts. These cells do not appear to be transplantable, since the disease produced is characterized by the presence of myeloblasts that liberate large quantities of virus. The other two cell lines, infected with the MC29 strain of avian leukosis virus, liberate normal levels of infectious virus in the culture fluid. When these cells are inoculated into the wing web of 1- to 2-day-old chicks, tumors develop at the site of inoculation which are detectable as early as 4 to 7 days after challenge. Chromosome studies demonstrate that the four cell lines have karyotypes typical of Gallus domesticus. The myeloblastic cell lines (D.U. 11157 and D.U. 1765) show a reduction in the number of microchromosomes. These cell lines have been carried in continuous culture for various lengths of time, can be frozen, are easily recovered in viable form, and appear to be capable of indefinite growth.


"HealthKick": formative assessment of the health environment in low-resource primary schools in the Western Cape Province of South Africa.
This study evaluated the primary school environment in terms of being conducive to good nutrition practices, sufficient physical activity and prevention of nicotine use, with the view of planning a school-based health intervention. A sample of 100 urban and rural disadvantaged schools was randomly selected from two education districts of the Western Cape Education Department, South Africa. A situation analysis, which comprised an interview with the school principal and completion of an observation schedule of the school environment, was done at all schools. Schools, on average, had 560 learners and 16 educators. Principals perceived the top health priorities for learners to be an unhealthy diet (50%) and to far lesser degree, lack of physical activity (24%) and underweight (16%). They cited lack of physical activity (33%) and non-communicable diseases (NCDs; 24%) as the main health priorities for educators, while substance abuse (66%) and tobacco use (31%) were prioritised for parents. Main barriers to health promotion programmes included lack of financial resources and too little time in the time table. The most common items sold at the school tuck shops were crisps (100%), and then sweets (96%), while vendors mainly sold sweets (92%), crisps (89%), and ice lollies (38%). Very few schools (8%) had policies governing the type of food items sold at school. Twenty-six of the 100 schools that were visited had vegetable gardens. All schools reported having physical activity and physical education in their time tables, however, not all of them offered this activity outside the class room. Extramural sport offered at schools mainly included athletics, netball, and rugby, with cricket and soccer being offered less frequently. The formative findings of this study contribute to the knowledge of key environmental and policy determinants that may play a role in the health behaviour of learners, their parents and their educators. Evidently, these show that school environments are not always conducive to healthy lifestyles. To address the identified determinants relating to learners it is necessary to intervene on the various levels of influence, i.e. parents, educators, and the support systems for the school environment including the curriculum, food available at school, resources for physical activity as well as appropriate policies in this regard.


Simultaneous scalp recorded EEG and local field potentials from monkey ventral premotor cortex during action observation and execution reveals the contribution of mirror and motor neurons to the mu-rhythm.
The desynchronization of alpha and beta oscillations (mu rhythm) in the central scalp EEG during action observation and action execution is thought to reflect neural mirroring processes. However, the extent to which mirror neurons (MNs) or other populations of neurons contribute to such EEG desynchronization is still unknown. Here, we provide the first evidence that, in the monkey, the neuronal activity recorded from the ventral premotor cortex (PMv) strongly contributes to the EEG changes occurring in the beta band over central scalp electrodes, during executed and observed actions. We simultaneously recorded scalp EEG and extracellular activity, Multi Unit Activity (MUA) and Local Field Potentials (LFP), from area F5 of two macaques executing and observing grasping actions. We found that MUA highly correlates with an increase in high gamma LFP power and, interestingly, such LFP power increase also correlates to EEG beta - and in part also to alpha - desynchronization. In terms of timing of signal changes, the increase in high gamma LFP power precedes the EEG desynchronization, during both action observation and execution, thus suggesting a causal role of PMv neuronal activity in the modulation of the alpha and beta mu-rhythm. Lastly, neuronal signals from deeper layers of PMv exert a greater contribution than superficial layers to the EEG beta rhythm modulation, especially during the motor task. Our findings have clear implications for EEG studies in that they demonstrate that the activity of different populations of neurons in PMv contribute to the generation of the mu-rhythm.


Paediatrics: how to manage pediculosis capitis.
Pediculosis capitis is a common human parasitic infestation in childhood. This article aims to provide a narrative updated review on the management of pediculosis capitis. A PubMed search was performed with Clinical Queries using the key terms "pediculosis capitis" OR "head lice" OR "head louse". The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews published within the past 10 years. The search was restricted to articles published in English literature. The information retrieved from the search was used in the compilation of the present article. Topical permethrin and pyrethrin formulated with piperonyl butoxide are the pediculicides of choice in areas where resistance to these products is low. When resistance to these products is suspected based on local levels of resistance or when treatment with these products fails despite their correct use, and reinfestation does not seem to be responsible, other topical treatment options include malathion, benzyl alcohol, dimethicone, spinosad and ivermectin. Wet combing should be considered for children younger than 2 years. Oral ivermectin and trimethoprim/sulfamethoxazole should be reserved for patients who do not respond to appropriate topical pediculicides. Many topical pediculicides are effective for the treatment of pediculosis capitis. The use of some of these pediculicides is limited for safety reasons, especially in children younger than 2 years. Resistance to pediculicides, especially those with a neurotoxic mode of action, is another concern which may limit the use of some of these pediculicides. New products should be evaluated for effectiveness and safety. Wet combing is time-consuming and should not be used as the sole intervention in the general population.


Precision Medicine: The New Frontier in Idiopathic Pulmonary Fibrosis.
Precision medicine is defined by the National Institute of Health's Precision Medicine Initiative Working Group as an approach to disease treatment that takes into account individual variability in genes, environment, and lifestyle. There has been increased interest in applying the concept of precision medicine to idiopathic pulmonary fibrosis, in particular to search for genetic and molecular biomarker-based profiles (so called endotypes) that identify mechanistically distinct disease subgroups. The relevance of precision medicine to idiopathic pulmonary fibrosis is yet to be established, but we believe that it holds great promise to provide targeted and highly effective therapies to patients. In this manuscript, we describe the field's nascent efforts in genetic/molecular endotype identification and how environmental and behavioral subgroups may also be relevant to disease management.


A case of granulocytic sarcoma of the breast and review of the literature.
This article discusses a case of granulocytic sarcoma of the breast, presenting prior to the onset of acute myeloid leukaemia. There has only been six reported cases of such a presentation in the breast. In view of the rarity of the tumour, it is often misdiagnosed as a high grade non-Hodgkin's lymphoma. Its treatment is still controversial and includes a proposal to use anti-leukaemic drug combinations for all cases.


Optimizing tylosin dosage for co-infection of Actinobacillus pleuropneumoniae and Pasteurella multocida in pigs using pharmacokinetic/pharmacodynamic modeling.
Formulating a therapeutic strategy that can effectively combat concurrent infections of Actinobacillus pleuropneumoniae (A. pleuropneumoniae) and Pasteurella multocida (P. multocida) can be challenging. This study aimed to 1) establish minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time kill curve, and post-antibiotic effect (PAE) of tylosin against A. pleuropneumoniae and P. multocida pig isolates and employ the MIC data for the development of epidemiological cutoff (ECOFF) values; 2) estimate the pharmacokinetics (PKs) of tylosin following its intramuscular (IM) administration (20 mg/kg) in healthy and infected pigs; and 3) establish a PK-pharmacodynamic (PD) integrated model and predict optimal dosing regimens and PK/PD cutoff values for tylosin in healthy and infected pigs. The MIC of tylosin against both 89 and 363 isolates of A. pleuropneumoniae and P. multocida strains spread widely, ranging from 1 to 256 μg/mL and from 0.5 to 128 μg/mL, respectively. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) ECOFFinder analysis ECOFF value (≤64 µg/mL), 97.75% (87 strains) of the A. pleuropnumoniae isolates were wild-type, whereas with the same ECOFF value (≤64 µg/mL), 99.72% (363 strains) of the P. multicoda isolates were considered wild-type to tylosin. Area under the concentration time curve (AUC), T1/2, and Cmax values were significantly greater in healthy pigs than those in infected pigs (13.33 h × μg/mL, 1.99 h, and 5.79 μg/mL vs. 10.46 h × μg/mL, 1.83 h, and 3.59 μg/mL, respectively) (p < 0.05). In healthy pigs, AUC24 h/MIC values for the bacteriostatic activity were 0.98 and 1.10 h; for the bactericidal activity, AUC24 h/MIC values were 1.97 and 1.99 h for A. pleuropneumoniae and P. multocida, respectively. In infected pigs, AUC24 h/MIC values for the bacteriostatic activity were 1.03 and 1.12 h; for bactericidal activity, AUC24 h/MIC values were 2.54 and 2.36 h for A. pleuropneumoniae and P. multocida, respectively. Monte Carlo simulation lead to a 2 μg/mL calculated PK/PD cutoff. Managing co-infections can present challenges, as it often demands the administration of multiple antibiotics to address diverse pathogens. However, using tylosin, which effectively targets both A. pleuropneumoniae and P. multocida in pigs, may enhance the control of bacterial burden. By employing an optimized dosage of 11.94-15.37 mg/kg and 25.17-27.79 mg/kg of tylosin can result in achieving bacteriostatic and bactericidal effects in 90% of co-infected pigs.


Phonological therapy in jargon aphasia: effects on naming and neologisms.
Jargon aphasia is one of the most intractable forms of aphasia with limited recommendation on amelioration of associated naming difficulties and neologisms. The few naming therapy studies that exist in jargon aphasia have utilized either semantic or phonological approaches, but the results have been equivocal. Moreover, the effect of therapy on the characteristics of neologisms is less explored. This study investigates the effectiveness of a phonological naming therapy (i.e., phonological component analysis-PCA) on picture-naming abilities and on quantitative and qualitative changes in neologisms for an individual with jargon aphasia (FF). FF showed evidence of jargon aphasia with severe naming difficulties and produced a very high proportion of neologisms. A single-subject multiple probe design across behaviours was employed to evaluate the effects of PCA therapy on the accuracy for three sets of words. In therapy, a phonological components analysis chart was used to identify five phonological components (i.e. rhymes, first sound, first sound associate, final sound and number of syllables) for each target word. Generalization effects-change in per cent accuracy and error pattern-were examined comparing pre- and post-therapy responses on the Philadelphia Naming Test, and these responses were analysed to explore the characteristics of the neologisms. The quantitative change in neologisms was measured by change in the proportion of neologisms from pre- to post-therapy and the qualitative change was indexed by the phonological overlap between target and neologism. As a consequence of PCA therapy, FF showed a significant improvement in his ability to name the treated items. His performance in maintenance and follow-up phases remained comparable with his performance during the therapy phases. Generalization to other naming tasks did not show a change in accuracy, but distinct differences in error pattern (an increase in proportion of real word responses and a decrease in proportion of neologisms) were observed. Notably, the decrease in neologisms occurred with a corresponding trend for increase in the phonological similarity between the neologisms and the targets. This study demonstrated the effectiveness of a phonological therapy for improving naming abilities and reducing the amount of neologisms in an individual with severe jargon aphasia. The positive outcome of this research is encouraging, as it provides evidence for effective therapies for jargon aphasia and also emphasizes that use of the quality and quantity of errors may provide a sensitive outcome measure to determine therapy effectiveness, in particular for client groups who are difficult to treat.


Spectroscopic Insights into Carbon Dot Systems.
The controversial nature of the fluorescent properties of carbon dots (CDs), ascribed either to surface states or to small molecules adsorbed onto the carbon nanostructures, is an unresolved issue. To date, an accurate picture of CDs and an exhaustive structure-property correlation are still lacking. Using two unconventional spectroscopic techniques, fluorescence correlation spectroscopy (FCS) and time-resolved electron paramagnetic resonance (TREPR), we contribute to fill this gap. Although electron micrographs indicate the presence of carbon cores, FCS reveals that the emission properties of CDs are based neither on those cores nor on molecular species linked to them, but rather on free molecules. TREPR provides deeper insights into the structure of carbon cores, where C sp2 domains are embedded within C sp3 scaffolds. FCS and TREPR prove to be powerful techniques, characterizing CDs as inherently heterogeneous systems, providing insights into the nature of such systems and paving the way to standardization of these nanomaterials.


[Spontaneous bleeding in musculus rectus can be stopped by coil embolisation].
Spontaneous non-traumatic bleeding could be a fatal condition and the most frequent site of bleeding is the rectus sheath or psoas muscle. Successful coil embolisation of bleeding epigastric inferior artery and significantly clinical improvement in the following days is described.


Ultrastructure of medial smooth muscle and myofibroblasts in human arterial dysplasia.
Ultrastructural characteristics of 20 dysplastic human renal arteries were documented. Loss of smooth muscle with collection of fibrous connective tissue predominated in medical fibrodysplasia, whereas excessive accumulations of elastic fibrils typified perimedial dysplasia. Myofibroblasts were a unique feature of both forms of arterial dysplasia. These modified smooth muscle cells seemed to be the source of abnormal connective tissue synthesis. Transformation of medial smooth muscle cells to myofibroblasts represented a morphologic continuum. Intramedial vasa vasorum were often isolated from surrounding cellular elements by unusual amounts of mural ground substances. The results of this study lend further support to the hypothesis that ischemia and direct physical forces effect hormonally altered cells in the pathogenesis of arterial dysplasia.


Current american practice in color measurement.
Current Aimerienn practice in color measurement is reviewed from the standpoint of instrumentation practice, measurement concepts, and computational methods. Instrumentation practice is described for spectrophotometers, abridged spectrophotometers, and tristimulus colorimeters. Measurement variables discussed include photometric and wavelength scales, standards and standardization, illuminating and viewing geometry, and instrument sources simulating standard illuminants. Computation-methods practiced for obtaining color coordinates and color differences are discussed. Topics indirectly related to the measurement step, such as the basis of colorimetry, color mixing laws, and computer color matching, are specifically excluded from this paper.


Choice of airway devices for 12,020 cases of nontraumatic cardiac arrest in Japan.
This retrospective study was designed to determine the choice of airway devices used for nontraumatic, out-of-hospital cardiac arrest patients and to evaluate the success and failure of insertion and airway control/ventilation by three airway adjuncts, the Combitube, the esophageal gastric tube airway (EGTA), and the laryngeal mask (LM), which were used in conjunction with the bag-valve-mask (BVM) by emergency life-saving technicians (ELSTs) in Japan. A survey of 1,085 ELSTs was performed to identify the type of airway devices, the success rates of airway insertion, the effectiveness of airway control/ventilation in comparison with the BVM prior to each airway insertion, and associated complications. The type of education for airway skills was also surveyed. 1,079 surveys were returned and 12,020 cases of cardiac arrest were studied. Choice of airway devices: BVM, 7,180 cases; EGTA, 545 cases; Combitube, 1,594 cases; and LM, 2,701 cases. Successful insertion rates on the first attempt: EGTA, 82.7%; Combitube, 82.4%; and LM, 72.5% (p < 0.0001). Failed insertions: EGTA, 8.2%; Combitube, 6.9%; and LM, 10.5% (p < 0.0001). Successful ventilation: EGTA, 71.0%; Combitube, 78.9%; and LM, 71.5% (p < 0.0004). Six cases of aspiration were reported in the LM group, whereas nine cases of soft-tissue injuries, including esophageal perforation, were reported in the Combitube group. 17.8% had vomited either prior or during airway placement. The Combitube appears to be the most appropriate choice among the airway devices examined. However, serious injuries to the tissues, though they rarely occurred in the study, remain a major concern.


Adhesion-independent alpha6beta4 integrin clustering is mediated by phosphatidylinositol 3-kinase.
Clustering of cell-surface integrins is known to augment integrin-mediated signal transduction, but mechanisms of integrin clustering are poorly understood. Here we report that adhesion-independent clustering of alpha6beta4 integrin, known to be important in mediating tumor cell motility, is driven by phosphatidylinositol 3-kinase (PI3K) but does not require activation of the PI3K-Akt pathway. We observed clustering of alpha6beta4 in breast carcinoma cells after adhesion-independent cross-linking of the beta4 integrin subunit. Clustering was significantly blocked when cross-linking was performed in the presence of PI3K inhibitors LY294002 and wortmannin. In contrast, no significant inhibition of clustering was observed with protein kinase C inhibitor GF109203X, rapamycin, or heparin. Although alpha6beta4 clustering was blocked by PI3K inhibitors, clustering was not associated with increased PI3K lipid kinase activity or increased phosphorylation of Akt. A novel role for PI3K in alpha6beta4 integrin clustering is proposed.


The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): An Overview of Its Impact on Obesity and Early Progression of Renal Pathology.
Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients' everyday lives.


Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.
G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin-biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs.


Electron Microscopy Studies of Local Structural Modulations in Zeolite Crystals.
Zeolites are widely used in catalysis, gas separation, ion exchange, etc. due to their superior physicochemical properties, which are closely related to specific features of their framework structures. Although more than two hundred different framework types have been recognized, it is of great interest to explore from a crystallographic perspective, the atomic positions, surface terminations, pore connectivity and structural defects that deviate from the ideal framework structures, namely local structural modulation. In this article, we review different types of local modulations in zeolite frameworks using various techniques, especially electron microscopy (EM). The most recent advances in resolving structural information at the atomic level with aberration corrected EM are also presented, commencing a new era of gaining atomic structural information, not only for all tetrahedral atoms including point vacancies in framework but also for extra-framework cations and surface terminations.


Aromatic amino acid metabolism of neonatal piglets receiving TPN: effect of tyrosine precursors.
Low tyrosine solubility in total parenteral nutrition (TPN) solutions complicates meeting the aromatic amino acid needs of infants. This study compared the effectiveness of two tyrosine precursors to supply the aromatic amino acid needs of TPN-fed neonatal piglets with a control group in which total aromatic acid needs were met by the addition of phenylalanine (Phe). Eighteen 3-day-old male Yorkshire piglets (6/group) received TPN for 8 days by central line. The solution was supplemented with Phe or one of the following two tyrosine precursors: N-acetyltyrosine (N-AcTyr) or glycyltyrosine (GlyTyr). Aromatic amino acid metabolism, growth, and nitrogen utilization were measured. Average amino acid and energy intakes were 14.6 g.kg-1.day-1 and 1,050 kJ.kg-1.day-1. Nitrogen balance and utilization were significantly higher (P < 0.05) in piglets in the control Phe group and on the GlyTyr regimen. The high urinary excretion of N-AcTyr (65%) confirms its low bioavailability. Flux and oxidation were significantly higher (P < 0.05) in the Phe group. High plasma Phe levels and excretion of Phe catabolites, as well as the high plasma tyrosine in the GlyTyr group, indicate that current strategies employed to meet the aromatic amino acid needs of neonates on TPN need further refinement.


Exploring weak ligand-protein interactions by long-lived NMR states: improved contrast in fragment-based drug screening.
Ligands that have an affinity for protein targets can be screened very effectively by exploiting favorable properties of long-lived states (LLS) in NMR spectroscopy. In this work, we describe the use of LLS for competitive binding experiments to measure accurate dissociation constants of fragments that bind weakly to the ATP binding site of the N-terminal ATPase domain of heat shock protein 90 (Hsp90), a therapeutic target for cancer treatment. The LLS approach allows one to characterize ligands with an exceptionally wide range of affinities, since it can be used for ligand concentrations [L] that are several orders of magnitude smaller than the dissociation constants K(D). This property makes the LLS method particularly attractive for the initial steps of fragment-based drug screening, where small molecular fragments that bind weakly to a target protein must be identified, which is a difficult task for many other biophysical methods.


Effect of adding a sleep dimension to the EQ-5D descriptive system: a "bolt-on" experiment.
The generic preference-based measures (GPBMs) of health have been widely used to obtain health utility scores for calculating quality-adjusted life-years (QALYs) for economic evaluations. It has been recognized that GPBMs may miss relevant or important dimensions of health for some specific medical conditions. The objective of this study is to explore the effect of extending the current EQ-5D descriptive system by adding a sleep dimension. A new instrument, EQ-5D+Sleep, is proposed by adding a sleep dimension to the EQ-5D. Based on an orthogonal design, 18 EQ-5D+Sleep states and EQ-5D states were selected and a valuation study was undertaken whereby 160 members of the generic public in South Yorkshire, UK, were interviewed using time tradeoff (TTO). Econometric models have been fitted to the data. Two null hypotheses were tested: 1) the coefficient for the sleep dimension is not significant; and 2) the inclusion of the sleep dimension has no impact on the way people value the original dimensions of EQ-5D. and The results support these two null hypotheses. There seems to be no benefit to adding a sleep dimension to the EQ-5D. Research is required to explore the method of adding dimensions to existing descriptive systems of health.


How many to sample? Statistical guidelines for monitoring animal welfare outcomes.
There is increasing scrutiny of the animal welfare impacts of all animal use activities, including agriculture, the keeping of companion animals, racing and entertainment, research and laboratory use, and wildlife management programs. A common objective of animal welfare monitoring is to quantify the frequency of adverse animal events (e.g., injuries or mortalities). The frequency of such events can be used to provide pass/fail grades for animal use activities relative to a defined threshold and to identify areas for improvement through research. A critical question in these situations is how many animals should be sampled? There are, however, few guidelines available for data collection or analysis, and consequently sample sizes can be highly variable. To address this question, we first evaluated the effect of sample size on precision and statistical power in reporting the frequency of adverse animal welfare outcomes. We next used these findings to assess the precision of published animal welfare investigations for a range of contentious animal use activities, including livestock transport, horse racing, and wildlife harvesting and capture. Finally, we evaluated the sample sizes required for comparing observed outcomes with specified standards through hypothesis testing. Our simulations revealed that the sample sizes required for reasonable levels of precision (i.e., proportional distance to the upper confidence interval limit (δ) of ≤ 0.50) are greater than those that have been commonly used for animal welfare assessments (i.e., >300). Larger sample sizes are required for adverse events with low frequency (i.e., <5%). For comparison with a required threshold standard, even larger samples sizes are required. We present guidelines, and an online calculator, for minimum sample sizes for use in future animal welfare assessments of animal management and research programs.


Nitrogen deficiency system is helpful in characterizing regulation mechanisms of ectopic triacylglycerol accumulation in Arabidopsis seedlings.
Triacylglycerol (TAG) is the major storage component accumulated in seed. However the regulatory mechanism of TAG synthesis and accumulation in non-seed tissues remains unknown. Recently, we found that nitrogen (N) deficiency (0.1mM N) caused an inducement of TAG biosynthesis in Arabidopsis seedlings. ABSCISIC ACID INSENSITIVE 4 (ABI4) was essential for the activation of Acyl-CoA:diacylglycerol acyltransferase1(DGAT1) expression during N deficiency in Arabidopsis seedlings. In this addendum, we further discussed the approaches to provide a net increase in total oil production in higher plants by using the low N platform. First, the N-deficient seedlings can be used to determine the key factors that regulate the ectopic expression of key genes in TAG metabolism. Second, the research on the relationship between TAG homeostasis and cell division will be helpful to find the key factors that specifically regulate TAG accumulation under the nutrient-limited condition.


[Analysis of parasitic communities in fishes from Lake Baikal].
Analysis of infracommunities and component communities of fish parasites in Lake Baikal has been conducted for the first time. It has been revealed that parasite infracommunities for the majority of Baikal fishes are weakly balanced and impoverished (the Berger-Parker Index is > 0.5; Evension is < 0.5; the Brillouin Index is < 1). The highest diversity and balance of the communities are characteristic for carnivorous fishes (Brachymystax lenok, Hucho taimen, Thymallus arcticus, Esox lucius, and Percafluviatilis). The component parasitic communities of Leuciscus leuciscus baicalensis, Rutilus rutilus, and Leocottus kesslerii are the most diverse in Lake Baikal since the Shennon index for L. leuciscus baicalensis, R. rutilus, and L. kesslerii is 2.4, for Paracotlus knerii--2.2, Limnocoitus godlewskii--2.3, Phoxinus phoxinus--2.1, Lota lota and Limnocuttus pallidus--1.9, P. fluviatilis--1.8, Leuciscus idus--1.8. The component parasitic communities of other fishes in Lake Baikal have low indices of biological diversity (H = 0.5-1.05, Smp is close to 1). A classification of mature and immature components of parasitic communities based on the ratio of specialist species and generalist species has been proposed. It is established that the component parasitic communities in sublitoral, profundal, and pseudoabyssal zones are mature, while in the littoral zone they are immature (impoverished and weakly balanced). The component parasitic communities in benthophagous fishes and predators are mature, in planktivorous fishes they are immature. The component parasitic communities are mature in the family Cyprinidae and immature in the families Coregonidae and Cottidae. The component parasitic communities of the Boreal Plain and Boreal Submountain faunal complexes are mature, but they are immature in Lake Baikal and Arctic freshwater complexes.


[The effect of hemolysate and calcium ions on transport ATPase activity in guinea pig erythrocytes].
Influence of 0.1, 0.3 and 1.0 microM Ca++ on Na,K-ATPases in different membrane preparations of guinea pig erythrocytes was studied both in presence and in absence of haemolysate. The incubation with the haemolysate and 0.1 or 0.3 microM Ca++ increased significantly the activity of the Na,K-ATPase in all membrane preparations used. The increasing Ca++ concentrations (up to 1 microM) led to the loss of the activating effect of the haemolysate in membrane preparations with lack of a part of the cytoskeleton proteins, and also decreased sharply its activity in all the preparations in absence of haemolysate. The latter also increased the Ca-ATPase activity irrespectively of the integrity of cytoskeleton structures (may be because of calmodulin action). The results obtained suggest that the cytoskeleton structures mediate the intracellular Na,K-ATPase activator action.


Poly(ferrocenylsilane) electrolytes as a gold nanoparticle foundry: "two-in-one" redox synthesis and electrosteric stabilization, and sensing applications.
Gold nanoparticles (AuNPs) coated with responsive polymers gained considerable interest due to their controllable size, good stability, and fast environmental response suitable for biological applications and sensing. Here we report on a simple and efficient method for the synthesis of stable and redox responsive AuNPs using organometallic polyelectrolytes in aqueous solutions of HAuCl4. In the redox reaction, positively or negatively charged poly(ferrocenylsilanes) (PFS+/PFS-) served as reducing agents, and also as stabilizing polymers. Due to their unique tunable electrostatic and electrosteric protection, AuNPs coated with PFS-, (PFS+)@AuNPs, possess high redox sensitivity, with reversible, repetitive, sustainable color switching between the assembled (purple color) and disassembled (red color) states as evidenced by UV-Vis absorption and TEM measurements. Feasibility studies reported here indicate that the particles described can be applied as a colorimetric probe for the detection of redox molecules, e.g. vitamin C, in a controlled and facile manner.


Metabolic reduction of chromium by alveolar macrophages and its relationships to cigarette smoke.
Pulmonary alveolar macrophages (PAM), obtained by bronchoalveolar lavage from 47 individuals, reduced hexavalent chromium [Cr(VI)] and decreased its mutagenicity. Their specific activity--mostly mediated by cytosolic, enzyme-catalyzed mechanisms--was significantly higher than in corresponding preparations of mixed-cell populations from human peripheral lung parenchyma or bronchial tree, or from rat lung or liver. At equivalent number of PAM, Cr(VI) reduction, total protein, and some oxidoreductase activities were significantly increased in smokers. No appreciable variation could be detected between lung cancer and noncancer patients. In rats, the Cr(VI)-reducing activity of PAM preparations was induced by Aroclor 1254. Thus, alveolar macrophages provide crucial defense mechanisms not only by phagocytizing metals, but also by metabolically reducing Cr(VI). The epithelial-lining fluid (ELF) also displayed some Cr(VI) reduction. Together with already investigated metabolic processes occurring inside lung cells, these mechanisms are expected to determine thresholds in the pulmonary carcinogenicity of chromium.


Use of transition probabilities to estimate the effect of smoking on the duration of episodes of respiratory symptoms in diary data: the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA).
Incompletely documented symptom episodes pose methodological problems in the analysis of diary data. The aim of this study was to develop a method of estimating the average durations of symptomatic and nonsymptomatic episodes, respectively, coping with the problem of bias due to undocumented days and censored episodes that is found in most diary studies. The authors derived their outcome variables from a Markov model using transition probabilities. To evaluate this method, the authors assessed the impact of active smoking on the duration of episodes of bronchitis symptoms and the corresponding nonsymptomatic periods, respectively, using diary data (1992-1993) obtained from 801 participants in the Swiss Study on Air Pollution and Lung Diseases in Adults. Covariate-adjusted distribution curves for the mean durations of individual episodes were estimated by Cox regression. Median values for light smokers (<10 cigarettes/day) were 60.0 symptom-free days (95% confidence interval (CI) 42.0-78.5) and 4.0 symptomatic days (95% CI 3.0-6.0), respectively, compared with medians of only 21.0 days (95% CI 16.2-29.8) for periods without bronchitis symptoms and 6.0 days (95% CI 4.9-9.0) for episodes of bronchitis symptoms in heavy smokers (> or =30 cigarettes/day). The authors suggest that the Markov method is a feasible approach to the assessment of long term effects of smoking and environmental risk factors on the average duration of symptomatic and nonsymptomatic respiratory episodes.


In search of the functional neuroanatomy of sociality: MRI subdivisions of orbital frontal cortex and social cognition.
We examined social cognition in a sample of healthy participants who had prior magnetic resonance imaging (MRI) gray matter volume studies of the orbital frontal cortex (OFC) that was parcellated into three regions: gyrus rectus, middle orbital gyrus and lateral orbital gyrus. These subjects also completed a self-report measure of Machiavelli personality traits, along with psychometric tests of social comprehension and declarative episodic memory, all of which we used as proxy measures to examine various features of social cognition. The data pointed to distinct functional-anatomical relationships highlighted by strong correlations of left lateral orbital gyrus and Machiavellian scores and right middle orbital gyrus with social comprehension and declarative episodic memory. In addition, hierarchical regression analyses revealed statistical evidence of a double dissociation between Machiavellian scores and left lateral orbital gyrus on one hand, and social comprehension with right middle orbital gyrus, on the other hand. To our knowledge, these findings are the first to show evidence linking normal variation in OFC subregions and different aspects of social cognition.


Systemic evaluation and localization of resistin expression in normal human tissues by a newly developed monoclonal antibody.
Resistin and resistin-like molecules are pleiotropic cytokines that are involved in inflammatory diseases. Our previous work suggested that resistin has the potential to be used as a biomarker and therapeutic target for human pulmonary arterial hypertension. However, data are limited on the distribution of resistin in healthy human organs. In this study, we used our newly developed anti-human resistin (hResistin) antibody to immunohistochemically detect the expression, localization, and intracellular/extracellular compartmentalization of hResistin in a full human tissue panel from healthy individuals. The potential cross reactivity of this monoclonal anti-hResistin IgG1 with normal human tissues also was verified. Results showed that hResistin is broadly distributed and principally localized in the cytoplasmic granules of macrophages scattered in the interstitium of most human tissues. Bone marrow hematopoietic precursor cells also exhibited hResistin signals in their cytoplasmic granules. Additionally, hResistin labeling was observed in the cytoplasm of nervous system cells. Notably, the cytokine activity of hResistin was illustrated by positively stained extracellular material in most human tissues. These data indicate that our generated antibody binds to the secreted hResistin and support its potential use for immunotherapy to reduce circulating hResistin levels in human disease. Our findings comprehensively document the basal expression patterns of hResistin protein in normal human tissues, suggest a critical role of this cytokine in normal and pathophysiologic inflammatory processes, and offer key insights for using our antibody in future pharmacokinetic studies and immunotherapeutic strategies.


Use of the Sequential Intercept Model as an approach to decriminalization of people with serious mental illness.
The Sequential Intercept Model provides a conceptual framework for communities to use when considering the interface between the criminal justice and mental health systems as they address concerns about criminalization of people with mental illness. The model envisions a series of points of interception at which an intervention can be made to prevent individuals from entering or penetrating deeper into the criminal justice system. Ideally, most people will be intercepted at early points, with decreasing numbers at each subsequent point. The interception points are law enforcement and emergency services; initial detention and initial hearings; jail, courts, forensic evaluations, and forensic commitments; reentry from jails, state prisons, and forensic hospitalization; and community corrections and community support. The model provides an organizing tool for a discussion of diversion and linkage alternatives and for systematically addressing criminalization. Using the model, a community can develop targeted strategies that evolve over time to increase diversion of people with mental illness from the criminal justice system and to link them with community treatment.


Structural analysis of a Vibrio phospholipase reveals an unusual Ser-His-chloride catalytic triad.
Phospholipases can disrupt host membranes and are important virulence factors in many pathogens. VvPlpA is a phospholipase A2 secreted by Vibrio vulnificus and essential for virulence. Its homologs, termed thermolabile hemolysins (TLHs), are widely distributed in Vibrio bacteria, but no structural information for this virulence factor class is available. Herein, we report the crystal structure of VvPlpA to 1.4-Å resolution, revealing that VvPlpA contains an N-terminal domain of unknown function and a C-terminal phospholipase domain and that these two domains are packed closely together. The phospholipase domain adopts a typical SGNH hydrolase fold, containing the four conserved catalytic residues Ser, Gly, Asn, and His. Interestingly, the structure also disclosed that the phospholipase domain accommodates a chloride ion near the catalytic His residue. The chloride is five-coordinated in a distorted bipyramid geometry, accepting hydrogen bonds from a water molecule and the amino groups of surrounding residues. This chloride substitutes for the most common Asp/Glu residue and forms an unusual Ser-His-chloride catalytic triad in VvPlpA. The chloride may orient the catalytic His and stabilize the charge on its imidazole ring during catalysis. Indeed, VvPlpA activity depended on chloride concentration, confirming the important role of chloride in catalysis. The VvPlpA structure also revealed a large hydrophobic substrate-binding pocket that is capable of accommodating a long-chain acyl group. Our results provide the first structure of the TLH family and uncover an unusual Ser-His-chloride catalytic triad, expanding our knowledge on the biological role of chloride.


Epidemiology of Vertebral Fractures.
Vertebral fractures are one of the most common fractures associated with skeletal fragility and can cause as much morbidity as hip fractures. However, the epidemiology of vertebral fractures differs from that of osteoporotic fractures at other skeletal sites in important ways, largely because only one quarter to one-third of vertebral fractures are recognized clinically at the time of their occurrence and otherwise require lateral spine imaging to be recognized. This article first reviews the prevalence and incidence of clinical and radiographic vertebral fractures in populations across the globe and secular trends in the incidence of vertebral fracture over time. Next, associations of vertebral fractures with measures of bone mineral density and bone microarchitecture are reviewed followed by associations of vertebral fracture with various textural measures of trabecular bone, including trabecular bone score. Finally, the article reviews clinical risk factors for vertebral fracture and the association of vertebral fractures with morbidity, mortality, and other subsequent adverse health outcomes.


The effect of Maras powder and smoking on the microRNA deregulation of oral mucosa.
This study aimed to investigate the effects of Maras powder (a type of smokeless tobacco obtained from Nicotiana rustica Linn and mixed with the ashes of wood, especially from oak, walnut or grapevine) on the microRNA (miRNA) deregulation of oral mucosa, and it compares these effects with those of smoking. Oral mucosal samples were collected from 74 patients, consisting of 16 nonusers, 26 smokers, and 32 Maras powder users. Genes associated with oral cancer were selected and 90 microRNAs targeting these genes were identified. MicroRNA were isolated and purified using the microRNA isolation kit. MicroRNA were expressed using Fluidigm RT-PCR. A positive correlation between the duration of Maras powder use with miR-31 expression levels, and a negative correlation between the Maras powder chewing time and miR-372 expression levels was found. In addition, there is a negative correlation between the amount of Maras powder consumed and expression levels of miR-375, miR-378a, miR-145, and miR-10b; moreover, another negative correlation is observed between the number of cigarettes consumed and the expression levels of miR-23a, miR-23b, miR-203a, miR-200b, and miR-375. However, miR-200b and miR-92a levels were downregulated significantly more in Maras powder users when compared with smokers and nonusers (p<0.05). The results show both chewing Maras powder and smoking have an effect on deregulation of miR-200b and miR-92a expressions. This leads to the belief that assessing the expression of these two miRNAs is a promising noninvasive method of analysis, especially in mutagen exposures. Finally, large-scale and high-throughput studies may help to identify an extensive miRNA expression profile associated with tobacco use and improve the understanding of oral malignancies.


The pathology of Q fever as seen on liver biopsy.
Granulomatous inflammation was seen in liver biopsy specimens from five patients with Q fever. All patients had a fever of unknown origin with mild abnormalities of liver function. The granulomatous process in the liver was very distinctive, with fibrinoid ring formation seen in four of the five cases. A diagnosis of Q fever was suggested in the five cases on the basis of the characteristic granulomatous inflammation. Results of subsequent complement fixation tests were positive in all five patients.


Pathogenicity of autoantibodies in anti-p200 pemphigoid.
Recently, the C-terminus of laminin γ1 has been identified as target antigen in anti-p200 pemphigoid and the disease was renamed as anti-laminin γ1 pemphigoid. However, the pathogenic relevance of these autoantibodies has not yet been demonstrated. Therefore, we employed an ex vivo model of autoantibody-mediated leukocyte-dependent neutrophil activation and dermal-epidermal separation (DES) using cryosections of human skin. We showed that anti-p200 pemphigoid sera (n = 7) induced DES in a time-dependent manner, in contrast to sera from healthy controls. Furthermore, laminin γ1-specific IgG and serum depleted from anti-laminin γ1 reactivity were generated using the recombinant C-terminus of laminin γ1 (LAMC1-term; amino acids 1364 to 1609). Interestingly, both fractions labeled the dermal-epidermal-junction (DEJ) by indirect immunofluorescence microscopy on human foreskin and recognized a 200 kDa protein by immunoblotting with dermal extract. Human and rabbit IgG against LAMC1-cterm failed to attract neutrophils at the DEJ and to induce DES. In contrast, patient serum depleted from LAMC1-cterm reactivity led to the same extent of DES as non-depleted IgG. Repeated injection of rabbit anti-murine LAMC1-cterm IgG into both neonatal and adult C57BL/6mice as well as repetitive immunization of various mouse strains with murine LAMC1-cterm failed to induce macro- and microscopic lesions. In all mice, circulating anti-LAMC1-cterm antibodies were present, but only in some mice, IgG deposits were seen at the DEJ. We conclude that autoantibodies in anti-p200 pemphigoid sera are pathogenic while pathogenicity is not mediated by autoantibodies against laminin γ1. Further studies are needed to identify the pathogenically relevant autoantigen in anti-p200 pemphigoid.


[The organization of public health in the USA: a federal model].
The present article analyzes the structure of public health services in the USA. It aims to describe the perspective of 200 years of a federal organization of public health services, which could be useful in the current context in Spain. Information was obtained by interviews with key informants from the three levels of government (federal, state, and local) and with academics (many of whom had previous experience as public health officers). Special attention is paid to the organization, financing and activities of local and state health departments, as well as to the relationships between these departments. The implications for a country like Spain, which has evolved in a short period from a highly centralized system to a decentralized system based on 17 Autonomous Communities, is discussed.