Effects of 1-MHz Ultrasound on Epaxial Muscle Temperature in Horses.
Objective: The purpose of this study was to examine the tissue temperature changes that occur at various depths during 1.0-MHz ultrasound (US) treatments of the epaxial muscles in horses. Animals: Ten healthy adult mares with no lameness or orthopedic disease weighing between 465 and 576 kg were studied. Procedures: Two 1.0 MHz US treatments, one at an intensity of 1.0 W/cm2 and one at 2.0 W/cm2, were administered to the epaxial region. Needle thermistors were inserted in the epaxial muscles below the skin surface at depths of 1.0, 3.0, and 5.0 cm, directly under the US treatment area. Depths were verified with diagnostic ultrasound. Both intensities of US treatment were performed on each horse over a 20 cm2 area for 10 min using a sound head with an effective radiating area of 10 cm2. Treatments were administered in random order. Tissue temperature was measured before, during, and for an additional 10 min after the end of US treatment. Mean temperatures for each time point, location, and intensity was recorded at 30 s intervals. A mixed model analysis of variance (ANOVA) with repeated measures was used to test for differences in these means. Individual differences in the means was tested for by a Least Significant Difference (LSD) mean separation test. Results: At the completion of the 10 min US treatment, the temperature rise at an intensity of 1.0 W/cm2 was 1.55°C at the 1.0 cm depth, 1.18°C at 3.0 cm depth, and 1.29°C at 5.0 cm depth. At an intensity of 2.0 W/cm2, temperatures rose 2.48°C at the 1.0 cm depth, 1.24°C at 3.0 cm depth, and 1.95°C at 5.0 cm depth. Conclusion and Clinical Importance: The main findings of the study is that use of therapeutic ultrasound with a 1.0 MHz US for 10 min in horse's epaxial muscles when clipped creates the greatest heat at 1.0 cm. The heat in the tissues at 5 cm depth is more than at 3 cm depth.


High concentrations of amniotic fluid proinflammatory cytokines in healthy neonates are associated with low risk of respiratory syncytial virus bronchiolitis.
The burden of respiratory syncytial virus (RSV) bronchiolitis in individual children and their families, the medical system and society is considerable. Mechanisms underlying RSV bronchiolitis in healthy term infants are largely unknown. Sterile intraamniotic inflammation and chorioamnionitis have been associated with increased lung volume and compliance. The aim of this study was to determine whether high amniotic fluid interleukin-8 (IL-8), and tumor necrosis factor-α protect against RSV bronchiolitis in healthy term infants. We conducted a prospective birth cohort study of healthy term newborns, born after uncomplicated pregnancy. Amniotic fluid was collected during labor. In case of medical attention for respiratory symptoms during the first year of life, a nose-throat swab was taken to establish the presence of respiratory viruses by polymerase chain reaction. Physician-attended RSV infection was observed in 27 (9.3%) of 292 children at median age 6 months. Amniotic fluid concentrations of IL-8 were higher in children without physician-attended RSV infection than in children with physician-attended RSV infection (11.1 versus 5.5 ng/mL; P = 0.002). Similarly, in children without physician-attended RSV, the proportion of detectable amniotic fluid tumor necrosis factor-α was higher (159/265 [60%] versus 8/27 [30%]; P = 0.002). Among children with physician-attended RSV infection, amniotic fluid IL-8 was inversely correlated to the number of wheezing days during the first year of life (ρ = -0.38; P = 0.048). High concentrations of amniotic fluid IL-8 and tumor necrosis factor-α are associated with low risk of RSV bronchiolitis in healthy term infants. We hypothesize that direct exposure of fetal lungs to proinflammatory signals induces local protection against viral infection during infancy.


Thiol ligation of two zinc atoms to a class I tRNA synthetase: evidence for unshared thiols and role in amino acid binding and utilization.
Class I tRNA synthetases generally contain a characteristic N-terminal catalytic core joined to a C-terminal domain that is idiosyncratic to the enzyme. The closely related class I Escherichia coli methionyl- and isoleucyl-tRNA synthetases each have a single zinc atom coordinated to ligands contained in the catalytic domain. Isoleucyl-tRNA synthetase has a second, functionally essential, zinc bound to ligands at the C-terminal end of the 939 amino acid polypeptide. Recent evidence suggested that this structure curls back and interacts directly or indirectly with the active site. We show here by X-ray absorption spectroscopy that the average Zn environment contains predominantly sulfur ligands with a Zn-S distance of 2.33 A. A model with eight coordinated thiolates divided between two Zn(Cys)4 structures best fit the data which are not consistent with a thiolate-bridged Zn2(Cys)6 structure joining the C-terminal end with the N-terminal active site domain. We also show that zinc bound to the N-terminal catalytic core is important specifically for amino acid binding and utilization, although a direct interaction with zinc is unlikely. We suggest that, in addition to idiosyncratic sequences for tRNA acceptor helix interactions incorporated into the class-defining catalytic domain common to class I enzymes, the architecture of at least some parts of the amino acid binding sites may differ from enzyme to enzyme and include motifs that bind zinc.


Conjugated Protein Domains as Engineered Scaffold Proteins.
Assembly of proteins into higher-order complexes generates specificity and selectivity in cellular signaling. Signaling complex formation is facilitated by scaffold proteins that use modular scaffolding domains, which recruit specific pathway enzymes. Multimerization and recombination of these conjugated native domains allows the generation of libraries of engineered multidomain scaffold proteins. Analysis of these engineered proteins has provided molecular insight into the regulatory mechanism of the native scaffold proteins and the applicability of these synthetic variants. This topical review highlights the use of engineered, conjugated multidomain scaffold proteins on different length scales in the context of synthetic signaling pathways, metabolic engineering, liquid-liquid phase separation, and hydrogel formation.


Anomalous diffusion on the servosphere: A potential tool for detecting inherent organismal movement patterns.
Tracking animal movements such as walking is an essential task for understanding how and why animals move in an environment and respond to external stimuli. Different methods that implemented image analysis and a data logger such as GPS have been used in laboratory experiments and in field studies, respectively. Recently, animal movement patterns without stimuli have attracted an increasing attention in search for common innate characteristics underlying all of their movements. However, it is difficult to track the movements in a vast and homogeneous environment without stimuli because of space constraints in laboratories or environmental heterogeneity in the field, hindering our understanding of inherent movement patterns. Here, we applied an omnidirectional treadmill mechanism, or a servosphere, as a tool for tracking two-dimensional movements of small animals that can provide both a homogenous environment and a virtual infinite space for walking. To validate the use of our tracking system for assessment of the free-walking behavior, we compared walking patterns of individual pillbugs (Armadillidium vulgare) on the servosphere with that in two types of experimental flat arenas. Our results revealed that the walking patterns on the servosphere showed similar diffusive characteristics to those observed in the large arena simulating an open space, and we demonstrated that our mechanism provides more robust measurements of diffusive properties compared to a small arena with enclosure. Moreover, we showed that anomalous diffusion properties, including Lévy walk, can be detected from the free-walking behavior on our tracking system. Thus, our novel tracking system is useful to measure inherent movement patterns, which will contribute to the studies of movement ecology, ethology, and behavioral sciences.


Lag time structure of cardiovascular deaths attributed to ambient air pollutants in Ahvaz, Iran, 2008-2015.
There are few studies about the association between breathing polluted air and increased risk of cardiovascular diseases and cardiac death in the Middle East. This study aimed to investigate the relation between air pollutants and cardiovascular mortality (based on ICD-10) in Ahvaz. In this ecological study, the data about cardiovascular disease mortality and air pollutants from March 2008 until March 2015 was inquired from the Ahvaz City Authority and the Khuzestan Province Environmental Protection Agency. The quasi-Poisson, second degree polynomial constrained, distributed lag model; using single and cumulative lag structures, adjusted by trend, seasonality, temperature, relative humidity, weekdays and holidays was used for the data analysis purposes. Findings indicated a direct significant relation between an interquartile range (IQR) increase in ozone and cardiovascular deaths among men after 3 days' lag. There was also a significant relation between an IQR increase in particulate matter below 10 μm and cardiovascular deaths for all people, over 60 years old and under 18 years old after 3 and 13 days' lags. There was a significant relation between an IQR increase in nitrogen dioxide and carbon monoxide, and cardiovascular deaths in the case of under 18-year-olds (in the lag 11) and over 60-year-olds (in the lag 9), respectively. We finally found a significant association between an IQR increase in sulfur dioxide and cardiovascular deaths in the case of men, under 18-year-olds and from 18- to 60-year-olds in the lag 9, 0, and 11, respectively (p-values < 0.05). It appears that air pollution is significantly associated with cardiovascular deaths in Ahvaz City. Int J Occup Med Environ Health 2018;31(4):459-473.


Acute hepatitis A in an elderly patient after care worker travel to high endemicity country.
Hepatitis A virus (HAV) is considered one of the most important vaccine-preventable diseases in travelers. HAV spreads from person to person via the fecal-oral route and gives rise to an estimated 1.4 million cases worldwide each year. In developing countries with poor sanitary conditions people tend to be infected during childhood and have few symptoms, whereas in developed countries with good sanitary conditions fewer people develop immunity during childhood. This leads to susceptible populations of adults, who are also more prone to severe complications. Here we describe two confirmed cases of hepatitis A associated with a nursing home. The index case was a care worker who had recently traveled to a high-endemicity country, and the second case was a resident at the nursing home where the index case worked. Both cases had an identical genotype IIIA strain, consistent with a transmission event. Current policy does not include a requirement for hepatitis A vaccine in care workers who travel to high endemicity countries despite the fact that infected care workers can potentially spread the disease to elderly patients and other groups at risk of severe complications from HAV infection. We suggest that employers should consider hepatitis A vaccine upon employment; particularly in care workers who plan to visit areas where HAV is known to be endemic.


Distinct cortical networks for hand movement initiation and directional processing: An EEG study.
Movement preparation and initiation have been shown to involve large scale brain networks. Recent findings suggest that movement preparation and initiation are represented in functionally distinct cortical networks. In electroencephalographic (EEG) recordings, movement initiation is reflected as a strong negative potential at medial central channels that is phase-locked to the movement onset - the movement-related cortical potential (MRCP). Movement preparation describes the process of transforming high level movement goals to low level commands. An integral part of this transformation process is directional processing (i.e., where to move). The processing of movement direction during visuomotor and oculomotor tasks is associated with medial parieto-occipital cortex (PO) activity, phase-locked to the presentation of potential movement goals. We surmised that the network generating the MRCP (movement initiation) would encode less information about movement direction than the parieto-occipital network processing movement direction. Here, we studied delta band EEG activity during center-out reaching movements (2D; 4 directions) in visuomotor and oculomotor tasks. In 15 healthy participants, we found a consistent representation of movement direction in PO 300-400 ms after the direction cue irrespective of the task. Despite generating the MRCP, sensorimotor areas (SM) encoded less information about the movement direction than PO. Moreover, the encoded directional information in SM was less consistent across participants and specific to the visuomotor task. In a classification approach, we could infer the four movement directions from the delta band EEG activity with moderate accuracies up to 55.9%. The accuracies for cue-aligned data were significantly higher than for movement onset-aligned data in either task, which also suggests a stronger representation of movement direction during movement preparation. Therefore, we present direct evidence that EEG delta band amplitude modulations carry information about both arm movement initiation and movement direction, and that they are represented in two distinct cortical networks.


Implementation of an extended ZINB model in the study of low levels of natural gastrointestinal nematode infections in adult sheep.
In this study, two traits related with resistance to gastrointestinal nematodes (GIN) were measured in 529 adult sheep: faecal egg count (FEC) and activity of immunoglobulin A in plasma (IgA). In dry years, FEC can be very low in semi-extensive systems, such as the one studied here, which makes identifying animals that are resistant or susceptible to infection a difficult task. A zero inflated negative binomial model (ZINB) model was used to calculate the extent of zero inflation for FEC; the model was extended to include information from the IgA responses. In this dataset, 64% of animals had zero FEC while the ZINB model suggested that 38% of sheep had not been recently infected with GIN. Therefore 26% of sheep were predicted to be infected animals with egg counts that were zero or below the detection limit and likely to be relatively resistant to nematode infection. IgA activities of all animals were then used to decide which of the sheep with zero egg counts had been exposed and which sheep had not been recently exposed. Animals with zero FEC and high IgA activity were considered resistant while animals with zero FEC and low IgA activity were considered as not recently infected. For the animals considered as exposed to the infection, the correlations among the studied traits were estimated, and the influence of these traits on the discrimination between unexposed and infected animals was assessed. The model presented here improved the detection of infected animals with zero FEC. The correlations calculated here will be useful in the development of a reliable index of GIN resistance that could be of assistance for the study of host resistance in studies based on natural infection, especially in adult sheep, and also the design of breeding programs aimed at increasing resistance to parasites.


Synthesis and reactivity of Li and TaMe3 complexes supported by N,N'-bis(2,6-diisopropylphenyl)-o-phenylenediamido ligands.
The dilithium complex of N,N'-bis(2,6-diisopropylphenyl)-o-phenylenediamide, [Li2L(thf)3], reacts with TaMe3Cl2 in THF/Et2O to yield [Li(Et2O)(thf)LTaMe3Cl] in which the phenylene backbone of (2-) is bound η(4) to the Ta centre. This dinuclear species reacts with MeLi to yield the tetramethyltantalum complex [Li(Et2O)(thf)LTaMe4]. Double deprotonation of N,N'-bis(2,6-diisopropylphenyl)(4,5-dimethyl)-o-phenylenediamine (H2L') in Et2O yielded the dilithium complex [Li2L'(OEt2)2]. The two additional methyl groups on L'(2-) change the observed reactivity towards TaMe3Cl2: rather than bridging between Ta and Li, ligand oxidation occurs to afford mononuclear [LiL'(OEt2)]. This monolithium radical species, which was characterized by EPR spectroscopy, can also be synthesized using the more conventional oxidant AgBF4. Double deprotonation of H2L with KCH2Ph in toluene followed by reaction with TaMe3Cl2 furnished [TaLMe3]. Preliminary reactivity studies show [TaLMe3] reacts with unsaturated substrates N,N'-dicyclohexylcarbodiimide and mesityl azide to undergo migratory insertion into one of the Ta-C bonds: the corresponding amidinate and triazenido ligands are generated. When subjected to UV irradiation, [TaLMe3] undergoes reduction accompanied by loss of a methyl group to yield the dimeric species [TaLMe2]2.


Zika virus infection histories in brain development.
An outbreak of births of microcephalic patients in Brazil motivated multiple studies on this incident. The data left no doubt that infection by Zika virus (ZIKV) was the cause, and that this virus promotes reduction in neuron numbers and neuronal death. Analysis of patients' characteristics revealed additional aspects of the pathology alongside the decrease in neuronal number. Here, we review the data from human, molecular, cell and animal model studies attempting to build the natural history of ZIKV in the embryonic central nervous system (CNS). We discuss how identifying the timing of infection and the pathways through which ZIKV may infect and spread through the CNS can help explain the diversity of phenotypes found in congenital ZIKV syndrome (CZVS). We suggest that intraneuronal viral transport is the primary mechanism of ZIKV spread in the embryonic brain and is responsible for most cases of CZVS. According to this hypothesis, the viral transport through the blood-brain barrier and cerebrospinal fluid is responsible for more severe pathologies in which ZIKV-induced malformations occur along the entire anteroposterior CNS axis.


A model of survival times for predator populations: the case of the army ants.
We develop a method to estimate the expected time of survival of a predator population as a function of the size of the habitat island on which it lives and the dynamic parameters of the population and its prey. The model may be thought of either as a patch occupancy model for a structured population or as a model of metapopulation type. The method is applied to a keystone predator species, the neotropical army ant Eciton burchelli. Predictions are made as to how many of the islands and habitat islands in and around Gatun Lake in the Panama Canal, most of which were formed when the canal was dug, can be expected to support such a population today, and these are compared with data.


Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States).
Multiple studies have noted that obese individuals are at a high risk of renal cell cancer. Similarly, numerous case-control and cohort studies have consistently reported that individuals with a history of hypertension experience an increased risk of renal cancer. In spite of this compelling body of epidemiologic data, no credible hypothesis has been advanced to explain this dual etiologic association. In this communication we propose that lipid peroxidation, which is increased in obese and hypertensive subjects, is the mechanism responsible, at least in part. for their increased risk of renal cell carcinoma. In experimental animals lipid peroxidation of the proximal renal tubules is a necessary mechanistic pathway in renal carcinogenesis induced by several different chemicals. Our hypothesis may also explain the roles of other risk (oophorectomy/hysterectomy, parity, smoking, diabetes) and protective factors (dietary antioxidants) for renal cell cancer.


A meta-analytic investigation of the potential for plant volatiles and sex pheromones to enhance detection and management of Lepidopteran pests.
Effective early detection, monitoring and management methods are critical for reducing the impacts of insect pests in agriculture and forestry. Combining host plant volatiles with sex pheromones could enhance trapping methodologies, whilst the use of non-host volatiles could improve the effectiveness of pest management through repellency effects. In this meta-analysis approach, we analysed 51 studies that used electroantennograms (EAG), wind tunnels and/or field traps to evaluate the antennal and behavioural responses of Lepidoptera to sex pheromones combined with attractant or repellent plant volatiles. Proposed attractant plant volatiles had a positive association with female Lepidoptera responses to sex pheromone, but effects on males were highly variable, with unexpected repellency reported in some studies. Proposed repellent plant volatiles were significantly or near-significantly negatively associated with male attraction to sex pheromones but were scarcely studied. Sub-group analysis identified that male responses to sex pheromone were reduced when the dose of attractant plant volatile relative to sex pheromone was increased. Green-leaf volatiles were associated with the strongest positive effects for males in field traps. Multiple-compound attractant plant volatile blends were less effective than single compounds in field studies. Our analysis demonstrates, (i) the potential value of combining host plant volatiles with sex pheromones to capture females rather than only males, (ii) the importance of identifying appropriate host plant volatiles and optimal relative doses, and (iii) the potential for non-host plant volatile use in pest management strategies.


Electrical coupling, receptive fields, and relative rod/cone inputs of horizontal cells in the tiger salamander retina.
Light responses, dendritic/axonal morphology, receptive field diameters, patterns of dye coupling, and relative rod/cone inputs of various types of horizontal cells (HCs) were studied using intracellular recording and Lucifer yellow/neurobiotin dye injection methods in the flatmount tiger salamander retina. Three physiologically and morphologically distinct types of HC entities were identified. 1) The A-type HCs are somas that do not bear axons, with average (+/-SE) soma diameters of 20.01 +/- 0.59 microm, relatively sparse and thick dendrites, and they resemble the A-type HC in mammals. The average receptive field diameter of these cells is 529.6 +/- 10.87 microm and they receive inputs predominantly from cones. 2) The B-type HCs are broad-field somas that bear thin and long axons, with average soma diameters of 17.67 +/- 0.38 microm, thinner dendrites of higher density, and they resemble the B-type HC in mammals. The average receptive field diameter of these cells is 1,633.55 +/- 37.34 microm and they receive mixed inputs from rods and cones. 3) The B-type HC axon terminals are broad-field, coarse axon terminal processes and they resemble the B-type HC axon terminal in rabbits. The average receptive field diameter of these axon terminals is 1,291.67 +/- 24.02 microm and they receive mixed inputs from rods and cones. All these types of HC are dye-coupled with adjacent HCs of the same type. Additionally, B-type HCs and axon terminals are dye-coupled with subpopulations of bipolar cells whose axon terminals ramify in the proximal half of the inner plexiform layer, raising the possibility that these HCs may send feedforward antagonistic surround responses to depolarizing bipolar cells through electrical synapses.


Past, present and future targets for immunotherapy in ovarian cancer.
Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.


Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production.
The steroid hormone metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25D3), promotes osteogenic activity and regulates calcium and phosphate metabolism, which are actions regarded as classical vitamin D-regulated functions. Besides its role in these processes, 1,25D3 also seems implicated in the host defense against microbial/pro-inflammatory attacks. Low serum levels of vitamin D3 (vitamin D deficiency) are associated with osteoporosis and increased risk of fractures but also inflammatory diseases and their disease progression, presumably via mechanisms associated with 1,25D3-evoked modulation of the innate immune system. 1,25D3 has been reported to modulate many inflammatory responses, suggesting that it regulates multiple transcriptional targets within the inflammatory system. Experimental studies in various experimental systems show that 1,25D3 differentially regulates the production of pro-inflammatory cytokines and chemokines depending on cell type. Importantly, many reports show that 1,25D3 up-regulates expression of the human antimicrobial peptide hCAP-18/LL-37 gene. The hCAP-18/LL-37 gene seems indeed to be an important transcriptional target for 1,25D3. However, only limited evidence is presented showing that 1,25D3 consistently increases the amount of biologically active LL-37 peptide. In the present review, we discuss 1,25D3-induced down-regulation of cytokine/chemokine production and stimulation of hCAP-18/LL-37 gene expression which represent two very important pathways for 1,25D3-evoked regulation of the innate immune response.


Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks.
The inquisitiveness about what happens in the brain has been there since the beginning of humankind. Functional magnetic resonance imaging is a prominent tool which helps in the non-invasive examination, localisation as well as lateralisation of brain functions such as language, memory, etc. In recent years, there is an apparent shift in the focus of neuroscience research to studies dealing with a brain at 'resting state'. Here the spotlight is on the intrinsic activity within the brain, in the absence of any sensory or cognitive stimulus. The analyses of functional brain connectivity in the state of rest have revealed different resting state networks, which depict specific functions and varied spatial topology. However, different statistical methods have been introduced to study resting state functional magnetic resonance imaging connectivity, yet producing consistent results. In this article, we introduce the concept of resting state functional magnetic resonance imaging in detail, then discuss three most widely used methods for analysis, describe a few of the resting state networks featuring the brain regions, associated cognitive functions and clinical applications of resting state functional magnetic resonance imaging. This review aims to highlight the utility and importance of studying resting state functional magnetic resonance imaging connectivity, underlining its complementary nature to the task-based functional magnetic resonance imaging.


Phase II study of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037) in the treatment of brain tumors.
Thirty-eight patients with symptomatic recurrent primary or metastatic brain tumors were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) at an initial dose of 120-130 mg/m2 with subsequent doses determined by the degree of delayed toxicity. The interval between treatments was usually 6 weeks. Two groups of patients were treated: those who had received no prior chemotherapy and those who had previously received BCNU. The response rates were 33% and 0 respectively. The major dose-limiting toxic effect was delayed depression of the white blood cell and platelet counts; this depression was not cumulative with the schedule used. Significant toxicity was encountered more frequently in the patients who had received BCNU previously. We concluded (a) that CCNU was effective against recurrent brain tumors although the results were not any better than those attainable with BCNU in a similar group of patients, and (b) that cross resistance to CCNU occurred in patients treated previously with BCNU.


Genotoxicity of fixation devices analyzed by the frequencies of sister chromatid exchange.
Metal alloys utilized in the management of jaw fractures may exert genotoxic effects. Our purpose was to compare the genotoxicity of intermaxillary fixation devices containing nickel and chromium to that of titanium miniplates utilized in treatment of jaw fractures through the analysis of sister chromatid exchange. In this prospective study, in a total of 28 non-smoker patients (10 females, 18 males; mean age 33.43±10.76; range 15 to 60 years) with jaw fractures, 14 were treated with intermaxillary fixation by administration of nickel-chromium wire and arch bar and 14 with titanium miniplates to investigate the genotoxicity of different metal alloys. The outcome variable was the frequency of sister chromatide exchange in peripheral lymphoctyes, determined through the analysis of venous blood samples obtained preoperatively and 4 to 6 weeks postoperatively. The frequency of the average sister chromatid exchange was found to be significantly higher in patients treated with the nickel-chromium intermaxillary fixation devices than those treated by titanium miniplates (1.29±0.29 vs. 0.46±0.39, p<0.001). Although titanium miniplate osteosynthesis is an invasive technique in comparison with the nickel-chromium-containing intermaxillary fixation devices, titanium seems to exert less genotoxic effect than the nickel-chromium alloy. However, this finding should be supported in clinical studies with a larger sampling size.


Core Decompression and Bone Marrow Aspirate Concentrate in the Treatment of Femoral Head Avascular Necrosis in Pediatric Sickle Cell Disease: Can We Improve Natural History?
Femoral head avascular necrosis (AVN) affects between 10% and 41% of children with sickle cell disease (SCD), resulting in the development of proximal femoral deformity and residual hip pain in the majority of patients without treatment. There have been multiple adult studies published on the outcomes of core decompression with and without the use of bone marrow aspirate concentrate (BMAC) injection both in idiopathic and SCD-related AVN with promising results, however, few studies have reported on outcomes in skeletally immature patients. This study sought to report on a single surgeon's outcomes for core decompression with BMAC injection in pediatric patients with AVN of the femoral head secondary to underlying SCD. A single-center, retrospective review was performed for pediatric patients undergoing core decompression with BMAC injection for femoral head AVN in patients with SCD with a minimum of 12-month follow-up. Demographic, radiographic, and clinical variable were collected. Patients were subdivided based upon presence of open femoral physes at the time of surgery. Successful treatment was defined as the ability to return to activities without limitations. A total of 13 patients (average age 14.1±2.8 y, 84.6% male, 6 skeletally immature and 7 skeletally mature) with 18 affected extremities were identified. Open physes were present in 50% of operative extremities. Skeletally immature patient demonstrated reconstitution of the femoral head in 78% of cases and 89% demonstrated regression of at least 1 Steinberg grade and none had progression. Skeletally immature patients were significantly more likely to return to activities (100% vs. 55.6%, P=0.023) and achieve a final Tonnis grade <2 (89% vs. 44%, P=0.046). Core decompression appears to alter the natural history of AVN in skeletally immature patients with SCD. Skeletal immaturity was a positive prognostic factor for the ability to return to activities without pain and achieve a lower Tonnis grade at final follow-up.


Dengue in travellers: applicability of the 1975-1997 and the 2009 WHO classification system of dengue fever.
The aim of this study was to assess the applicability and benefits of the new WHO dengue fever guidelines in clinical practice, for returning travellers. We compared differences in specificity and sensitivity between the old and the new guidelines for diagnosing dengue and assessed the usefulness in predicting the clinical course of the disease. Also, we investigated whether hypertension, diabetes or allergies, ethnicity or high age influenced the course of disease. In our setting, the old classification, compared with the new, had a marginally higher sensitivity for diagnosing dengue. The new classification had a slightly higher specificity and was less rigid. Patients with dengue who had warning signs as postulated in the new classification were admitted more often than those who had no warning signs (RR, 8.09 [1.80-35.48]). We did not find ethnicity, age, hypertension, diabetes mellitus or allergies to be predictive of the clinical course. In our cohort of returned travellers, the new classification system did not differ in sensitivity and specificity from the old system to a clinically relevant degree. The guidelines did not improve identification of severe disease.


Japanese Babesia microti cytologically detected in salivary glands of naturally infected tick Ixodes ovatus.
Babesia microti protozoa were detected by light and electron microscopy in the salivary glands of field-collected Ixodes ovatus ticks; 6 of 85 adult ticks were demonstrated to be positive for B. microti DNA by polymerase chain reaction assays. In the salivary glands of unfed ticks, B. microti existed in the sporoblast stage in the granular acinus cells, and developed into the sporozoite stage during feeding on the host for 2 days. The present results indicated for the first time that I. ovatus can indeed carry B. microti and is not infected mechanically with the parasites by blood-sucking. This frequent infection of I. ovatus with B. microti demonstrates the significance of such a vector-pathogen relationship in Japan, and strongly suggests that I. ovatus is involved in the maintenance of B. microti in the fauna of Japanese rodents.


High-grade atrioventricular block in acute coronary syndrome: Portuguese experience.
The high-grade atrioventricular block (HAVB) occurrence in acute coronary syndrome (ACS) is a potentially life-threatening complication, that demands a rapid and efficient response regarding reperfusion time and rhythm stabilization. This study aimed to analyse the rate, clinical features, therapeutic approach, complications, in-hospital mortality and follow-up of HAVB in the setting of ACS. Multicenter retrospective study based on the Acute Coronary Syndrome Portuguese National Registry, including 32157 patients admitted for ACS between 1/10/2010-3/05/2020, classified according to the presence or absence of HAVB during the hospitalization for ACS. Comparison between the two groups was performed. Logistic regression was accomplished to assess predictors of HAVB in ACS patients. Patients with HAVB were older, and had higher rates of females, history of stroke and neoplasia. HAVB patients presented more frequently ST-segment elevation myocardial infarction, syncope as a major symptom, higher Killip-Kimball class and multivessel disease. Furthermore, HAVB patients had more major adverse cardiac events during the hospitalization for ACS, namely heart failure complication, cardiogenic shock complication, new-onset of atrial fibrillation, ACS mechanical complication, sustained ventricular tachycardia, cardiac arrest, stroke complication and in-hospital death. Logistic regression revealed that female gender, age ≥ 75 years old, heart rate < 60 and Killip-Kimball class > I were predictors of HAVB in ACS patients. Also, HAVB patients presented higher rates of all-causes of death at 1-year follow-up (p = 0.011). Using real-life data, patients with HAVB in the setting of ACS had a worse prognosis during hospitalization and in the short-term follow-up period.


Melatonin and sleep disorders associated with intellectual disability: a clinical review.
Melatonin is used to treat sleep disorders in both children and adults with intellectual disability (ID), although it has no product license for such use. The evidence for its efficacy, potential adverse effects and drug interactions are reviewed in the context of prescribing to people with ID. A literature search was performed using multiple electronic databases. More literature was obtained from the reference lists of papers gathered through the searches. Most of the studies were uncontrolled and the few controlled trials available were of small size. Melatonin appears effective in reducing sleep onset latency and is probably effective in improving total sleep time in children and adolescents with ID. It appears to be ineffective in improving night-time awakenings. Melatonin is relatively safe for short-term use. Its safety for long-term use is not established. Potential drug interactions, possible effects on puberty and concerns regarding the use of melatonin in epilepsy, asthma and depressive disorders are discussed. Melatonin appears to be an effective sleep-initiator for children and adolescents with ID and probably has a similar effect for adults. There may be heterogeneity of response depending on the nature of the sleep problem and cause of the ID or associated disabilities. Further studies are necessary before firm conclusions can be drawn and guidelines for the use of melatonin for people with ID formulated.


Urogenital involvement in the Klippel-Trenaunay-Weber syndrome. Treatment options and results.
Klippel-Trenaunay-Weber syndrome (KTWS) is a congenital condition characterized by vascular malformations of the capillary, venous and lymphatic systems associated to soft tissue and bone hypertrophy in the affected areas. This syndrome may involve bladder, kidney, urethra, ureter and genitals. We report the treatment of 7 KTWS patients with urogenital involvement. From 1995 to 2005, 7 patients with KTWS were evaluated and the charts of these patients were reviewed. Patients' median age was 19-years (range 4 to 46-years) and only 1 was female. The clinical presentation included genital deformities in 3 cases, hematuria in 2 and urethrorragia in 2, one of which associated with cryptorchidism and phimosis. Three patients had an association of pelvic and genital malformations, including 2 patients with hematuria due to vesical lesions and 1 patient with left ureterohydronephrosis due to a pelvic mass. Two patients had urethral lesions. Treatment included endoscopic laser coagulation for 1 patient with recurrent hematuria and 1 patient with urethrorrhagia, pelvic radiotherapy for 1 patient with hematuria and circumcision in 2 patients with genital deformities. One patient required placement of a double-J catheter to relieve obstruction. Hematuria and urethrorragia were safely and effectively controlled with laser applications. Circumcision was also effective. The patient treated with radiotherapy developed a contracted bladder and required a continent urinary diversion. Urogenital involvement in patients with KTWS is not rare and must be suspected in the presence of hematuria or significant cutaneous deformity of the external genitalia. Surgical treatment may be warranted in selected cases.


Chemical Consequences of Radioactive Decay and their Biological Implications.
The chemical effects of radioactive decay arise from (1) transmutation, (2) formation of charged daughter nuclei, (3) recoil of the daughter nuclei, (4) electron "shakeoff" phenomenon and (5) vacancy cascade in decays via electron capture and internal conversion. This review aims to reiterate what has been known for a long time regarding the chemical consequences of radioactive decay and gives a historical perspective to the observations that led to their elucidation. The energetics of the recoil process in each decay mode is discussed in relation to the chemical bond between the decaying nucleus and the parent molecule. Special attention is given to the biological effects of the Auger process following decay by electron capture and internal conversion because of their possible utility in internal radiotherapy.


Computer quantitated evaluation of cardiac arrhythmias.
The identification of a cardiac arrhythmia depends on the interpretation of both the QRS complexes and the P waves. P wave detection is unreliable and hence automated diagnostic systems are often imperfect. An alternative is a system which detects QRS only and which classifies the QRS events; the physician then has a detailed quantitated QRS analysis to aid in diagnosis. The ATREC system has an analog QRS detector, which suppresses the P wave and the T wave frequencies and feeds a minicomputer (Mitra 15/35) with signals for the RR interval, the QRS duration, and polarity. The computer classifies these signals as either narrow or wide complexes. The narrow complexes are analyzed for irregular rhythm, bradycardia, pauses, transient or continuous tachycardia, and fibrillation. The wide complexes are classed by their coupling interval, bi- or trigeminy, doublets, or salvos, and the number per hour. The system gives a trend of the 16 beat mean, and the minimum and maximum heart rate. The data is presented on several displays.


Is intraoperative ultrasonography useful in pancreatic cancer surgery?
Preoperative staging of pancreatic cancer represents a major challenge for a suitable surgical management of the disease. In a consistent number of patients laparotomy is still necessary in order to decide whether the tumor is resectable or not. In the present paper the Authors report their experience with intraoperative ultrasonography (IOU) in evaluating pancreatic cancer resectability. Very important data for intraoperative decision making were obtained in 37.9% of the patients, useful information in 31%, while in 31% IOU may be looked forward to as an important aid in decision making and for a safely guided dissection.


An Evaluation of the Accuracy of the Subtraction Method Used for Determining Platelet Counts in Advanced Platelet-Rich Fibrin and Concentrated Growth Factor Preparations.
Platelet concentrates should be quality-assured of purity and identity prior to clinical use. Unlike for the liquid form of platelet-rich plasma, platelet counts cannot be directly determined in solid fibrin clots and are instead calculated by subtracting the counts in other liquid or semi-clotted fractions from those in whole blood samples. Having long suspected the validity of this method, we herein examined the possible loss of platelets in the preparation process. Blood samples collected from healthy male donors were immediately centrifuged for advanced platelet-rich fibrin (A-PRF) and concentrated growth factors (CGF) according to recommended centrifugal protocols. Blood cells in liquid and semi-clotted fractions were directly counted. Platelets aggregated on clot surfaces were observed by scanning electron microscopy. A higher centrifugal force increased the numbers of platelets and platelet aggregates in the liquid red blood cell fraction and the semi-clotted red thrombus in the presence and absence of the anticoagulant, respectively. Nevertheless, the calculated platelet counts in A-PRF/CGF preparations were much higher than expected, rendering the currently accepted subtraction method inaccurate for determining platelet counts in fibrin clots. To ensure the quality of solid types of platelet concentrates chairside in a timely manner, a simple and accurate platelet-counting method should be developed immediately.


Adjuvants: Classification, Modus Operandi, and Licensing.
Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations.


Engaging youth in bullying prevention through community-based participatory research.
Few studies that engage youth in community-based participatory research (CBPR) focus on issues of safety/violence, include elementary school-aged youth, or quantitatively assess outcomes of the CBPR process. This article expands understanding of CBPR with youth by describing and evaluating the outcomes of a project that engaged fifth-grade students at 3 schools in bullying-focused CBPR. Results suggest that the project was associated with decreases in fear of bullying and increases in peer and teacher intervention to stop bullying. We conclude with implications for the engagement of elementary school-aged youth in CBPR to address bullying and other youth issues.


Wound Irrigation in Orthopedic Open Fractures: A Review.
Background: Management of open fractures remains a major clinical challenge because of the higher energy involved in the injury, the greater local trauma, tissue necrosis, and extensive contamination. Even though early surgical debridement was thought to be critical, limited available operative techniques have minimized surgery in favor of early antibiotic administration. No clear agreement on the surgical approach, debridement, or irrigation technique exists. Surgeons continue to argue about the use of various fluids, the appropriate pressure of irrigation, antiseptics, and other factors. The current work reviews the available data and summarizes the capabilities of modern orthopedic irrigation solutions. Methods: To delineate available research on the topic, the PubMed database was queried for the most common techniques, fluid variables, and chemical adjuvants utilized in current open fracture and wound irrigation methodologies. Modes of delivery, volume, pressure, temperature, timing, solution type, and additives are evaluated in the context of known outcomes to determine which solutions may be preferable. Results: Various methods have been described with their own advantages as well as limitations. Particular solutions may apply to specific clinical scenarios, presence of implants, and degree of tissue contamination. Desired irrigation solutions are isotonic, non-toxic, non-hemolytic, transparent, sterilizable, efficient in removing debris and pathogens, as well as affordable; however, no current irrigant achieves all these desired characteristics. Conclusions: Despite being crucial for the healing of open fractures, there is no clear gold standard for irrigation. Although there are some novel irrigation solutions, there has been a paucity of research on finding new, safer, and more effective irrigation solutions that will promote wound healing and reduce infection.


Supersonic air flow due to solid-liquid impact.
A solid object impacting on liquid creates a liquid jet due to the collapse of the impact cavity. Using visualization experiments with smoke particles and multiscale simulations, we show that in addition, a high-speed air jet is pushed out of the cavity. Despite an impact velocity of only 1 m/s, this air jet attains supersonic speeds already when the cavity is slightly larger than 1 mm in diameter. The structure of the air flow closely resembles that of compressible flow through a nozzle-with the key difference that here the "nozzle" is a liquid cavity shrinking rapidly in time.


SKULL-STRIPPING WITH DEFORMABLE ORGANISMS.
Segmenting brain from non-brain tissue within magnetic resonance (MR) images of the human head, also known as skull-stripping, is a critical processing step in the analysis of neuroimaging data. Though many algorithms have been developed to address this problem, challenges remain. In this paper, we apply the "deformable organism" framework to the skull-stripping problem. Within this framework, deformable models are equipped with higher-level control mechanisms based on the principles of artificial life, including sensing, reactive behavior, knowledge representation, and proactive planning. Our new deformable organisms are governed by a high-level plan aimed at the fully-automated segmentation of various parts of the head in MR imagery, and they are able to cooperate in computing a robust and accurate segmentation. We applied our segmentation approach to a test set of human MRI data using manual delineations of the data as a reference "gold standard." We compare these results with results from three widely used methods using set-similarity metrics.


Management of rhinosinusitis: an evidence based approach.
The most recent recommendations for the management of both acute (ARS) and chronic rhinosinusitis (CRS) based on the strongest data available for each treatment modality are summarized in this review. The clinical relationships between CRS and its comorbidities are also discussed. The most promising advances in rhinosinusitis management involve the use of mAbs (anti-IgE, anti-IL-5, anti-IL-4Rα) in trials of CRS with nasal polyposis. Otherwise, the mainstays of treatment for both ARS and CRS have largely remained the same over the past several years. The treatment of ARS primarily involves symptomatic control with intranasal corticosteroids and nasal saline irrigation; antibiotics should be reserved for the patients who are believed to have bacterial rhinosinusitis. Treating CRS effectively involves using intranasal corticosteroids and irrigation, systemic corticosteroids, and potentially systemic antibiotics. Biologics (mAbs) have shown benefit in clinical studies. Providers should also be aware of concomitant disease processes that may afflict patients with CRS.


Nucleolar trafficking is essential for nuclear export of intronless herpesvirus mRNA.
The nucleolus is the largest subnuclear structure and is plurifunctional in nature. Here, we demonstrate that nucleolar localization of a key herpesvirus regulatory protein is essential for its role in virus mRNA nuclear export. The herpesvirus saimiri ORF57 protein is a nucleocytoplasmic shuttle protein that is conserved in all herpesviruses and orchestrates the nuclear export of viral intronless mRNAs. We demonstrate that expression of the ORF57 protein induces nucleolar redistribution of human TREX (transcription/export) proteins that are involved in mRNA nuclear export. Moreover, we describe a previously unidentified nucleolar localization signal within ORF57 that is composed of two distinct nuclear localization signals. Intriguingly, point mutations that ablate ORF57 nucleolar localization lead to a failure of ORF57-mediated viral mRNA nuclear export. Furthermore, nucleolar retargeting of the ORF57 mutant was achieved by the incorporation of the HIV-1 Rev nucleolar localization signal, and analysis demonstrated that this modification was sufficient to restore viral mRNA nuclear export. This finding represents a unique and fundamental role for the nucleolus in nuclear export of viral mRNA.


Amino acid repeats avert mRNA folding through conservative substitutions and synonymous codons, regardless of codon bias.
A significant number of proteins in all living species contains amino acid repeats (AARs) of various lengths and compositions, many of which play important roles in protein structure and function. Here, I have surveyed select homopolymeric single [(A)n] and double [(AB)n] AARs in the human proteome. A close examination of their codon pattern and analysis of RNA structure propensity led to the following set of empirical rules: (1) One class of amino acid repeats (Class I) uses a mixture of synonymous codons, some of which approximate the codon bias ratio in the overall human proteome; (2) The second class (Class II) disregards the codon bias ratio, and appears to have originated by simple repetition of the same codon (or just a few codons); and finally, (3) In all AARs (including Class I, Class II, and the in-betweens), the codons are chosen in a manner that precludes the formation of RNA secondary structure. It appears that the AAR genes have evolved by orchestrating a balance between codon usage and mRNA secondary structure. The insights gained here should provide a better understanding of AAR evolution and may assist in designing synthetic genes.


Searching for Evidence of an Anti-Inflammatory Diet in Children: A Systematic Review of Randomized Controlled Trials for Pediatric Obesity Interventions With a Focus on Leptin, Ghrelin, and Adiponectin.
To address the complex phenomenon of pediatric obesity, one must understand the physiological mechanisms regulating energy intake and inflammation. The peptide hormones leptin, ghrelin, and adiponectin are involved in both, but their functions are dysregulated in obesity. The purpose of this systematic review is (1) to characterize studies of nutrition interventions for weight management in children who measure these peptides as outcomes, (2) to assess risk of bias in the studies, and (3) to determine the relationships between these peptides and body mass index (BMI). Eligibility Criteria: Peer-reviewed articles written in English, published in 2001-2016, and describing randomized controlled trials of pediatric interventions involving a nutrition component with the outcome measures leptin, ghrelin, and/or adiponectin were included. Articles were excluded if the intervention involved pharmaceuticals, supplements, infant formula, breastfeeding, or surgery. The 25 international studies represented 2,153 obese children. Ten diets were identified. Successful interventions included both structured exercise and hypocaloric dietary components, with or without counseling, resistance training, or medical components. Direct measures of adiposity were used in 69% of studies. Comparison group designs were disparate. Leptin levels decreased as BMI decreased. Evidence regarding the relationships of ghrelin and adiponectin with BMI was inconclusive. Despite known effects of maturation on hormones, studies did not consistently differentiate findings by maturational stage. Common anti-inflammatory and disease risk modification diets were missing or underrepresented. Studies that include children with comorbidities are needed. BMI and leptin levels have a positive relationship, but evidence on ghrelin and adiponectin was inconclusive.


Observation on the effect of platelet-rich plasma combined with drugs in the treatment of herpes zoster neuralgia.
To observe the effect of ultrasound-guided platelet-rich plasma (PRP) injection in the treatment of herpes zoster neuralgia (HZN). Eighty patients with HZN were randomly divided into observation group and control group, with 40 cases in each group. The observation group was treated with ultrasound-guided PRP injection of target nerves combined with drugs. The control group was treated with drugs alone. The pain scores of before treatment (T0), and 1 week (T1), 1 month (T2), 3 months (T3) and 6 months (T4) after treatment were recorded with Numerical Rating Scale (NRS). The sleep quality of patients was assessed with the Athens Insomnia Scale, and the dosage used at each time point, skin lesions, adverse reactions, and the occurrence of postherpetic neuralgia (PHN) were recorded. The NRS score of the two groups after treatment showed a downward trend. Compared with T0 at each time point, the difference was statistically significant (p < 0.05). And the NRS score of the observation group was lower than control group (p < 0.05). The sleep quality of the observation group was better. The dosage of the observation group was less, and the time of herpes dry-up, scab crusting and shedding in the observation group was significantly shorter (p < 0.05). The incidence of dizziness, lethargy, ataxia and PHN in the observation group was significantly reduced (p < 0.05). Compared with traditional drug treatment alone, the ultrasound-guided PRP injection has the advantages of better analgesia and fewer side effects, which provides a new idea for the treatment of HZN.


[PULMONARY FIBROSIS INDUCED BY ANTI־TNF-Αlpha TREATMENT].
TNFα-targeted therapies have emerged as a new class of drugs in the treatment of various inflammatory diseases, including psoriasis. With the increasing use and longer follow-up periods of TNFα targeted therapies, a spectrum of immunological adverse events have been described, ranging from asymptomatic immunological alterations to life-threatening systemic diseases such as pulmonary fibrosis. We present a case of a 66 year old man diagnosed with psoriasis who developed pulmonary fibrosis three years after initiation of Etanercept (Enbrel) for his skin disease. We presented a rare case of a patient who developed pulmonary fibrosis, possibly triggered by anti-TNFα treatment. We suggest that adverse effects related to anti-TNFα should be evaluated carefully, considering pulmonary fibrosis as a possible side effect, especially among patients with risk factors for its development. There are growing numbers of reports of the paradoxical induction of pulmonary interstitial disease due to TNFα blockers, yet most of them are uncontrolled studies in patients with rheumatoid arthritis or other autoimmune diseases that can involve the lungs. Therefore, definitive conclusions are not possible at this stage. Recent studies described the poor prognosis of pulmonary fibrosis secondary to anti-TNFα therapy, with the mortality rate of up to 60% among patients with previous pulmonary disease. Coexisting or previous therapy with Methotrexate had stronger association with the development of drug-induced pulmonary fibrosis.


Mouse strain and injection site are crucial for detecting linked suppression in transplant recipients by trans-vivo DTH assay.
Chemokine-driven accumulation of lymphocytes, mononuclear and polymorphonuclear proinflammatory cells in antigenic tissue sites is a key feature of several types of T-cell-dependent autoimmunity and transplant rejection pathology. It is now clear that the immune system expends considerable energy to control this process, exemplified by the sequential layers of regulatory cell input, both innate and adaptive, designed to prevent a classical Type IV or 'delayed-type' hypersensitivity (DTH) reaction from occurring in the visual field of the eye. Yet, despite an abundance of in vitro assays currently available to the human T-cell immunologist, none of them adequately models the human DTH response and its various control features. The theme of this article is that it is relatively easy to model the effector side of the human DTH response with xenogeneic adoptive transfer models. However, we show that in order to detect inhibition of a recall DTH in response to colocalized donor antigen (linked suppression)--a characteristic feature of peripheral tolerance to an organ transplant--both the challenge site and the immunocompetence of the mouse adoptive host are critical factors limiting the sensitivity of the trans-vivo DTH test.


AaPDR3, a PDR Transporter 3, Is Involved in Sesquiterpene β-Caryophyllene Transport in Artemisia annua.
Artemisinin, a sesquiterpenoid endoperoxide, isolated from the plant Artemisia annua L., is widely used in the treatment of malaria. Another sesquiterpenoid, β-caryophyllene having antibiotic, antioxidant, anticarcinogenic and local anesthetic activities, is also presented in A. annua. The role played by sesquiterpene transporters in trichomes and accumulation of these metabolites is poorly understood in A. annua and in trichomes of other plant species. We identified AaPDR3, encoding a pleiotropic drug resistance (PDR) transporter located to the plasma membrane from A. annua. Expression of AaPDR3 is tissue-specifically and developmentally regulated in A. annua. GUS activity is primarily restricted to T-shaped trichomes of old leaves and roots of transgenic A. annua plants expressing proAaPDR3: GUS. The level of β-caryophyllene was decreased in transgenic A. annua plants expressing AaPDR3-RNAi while transgenic A. annua plants expressing increased levels of AaPDR3 accumulated higher levels of β-caryophyllene. When AaPDR3 was expressed in transformed yeast, yeasts expressing AaPDR3 accumulated more β-caryophyllene, rather than germacrene D and β-farnesene, compared to the non-expressing control.


Beneficial effect of hemodialysis on renal allograft survival.
The effect of the length of hemodialysis on the outcome of renal transplant was evaluated in 43 recipients of renal allograft. 22 out of 23 patients (95.7%) dialyzed for longer than one year had an excellent renal function at one year, while only 10 out of 20 patients (50%) dialyzed for less than one year had good renal function at one year. Only one kidney (4.3%) was lost due to rejection in the first group, while 10 kidneys (50%) failed to function because of severe rejection in the second group. The length of hemodialysis appears to have a beneficial effect on graft survival, but the mechanism by which it exerts this effect is not clear.


Evaluation of warm compresses and topical cyclosporine treatment in meibomian gland dysfunction by confocal scanning laser microscopy.
The aim of our study is to confirm the utility of warm compresses (WC) and artificial tears (AT) in meibomian gland dysfunction (MGD) management and to understand if its association with topical cyclosporine A (CsA) improves outcomes. Patients with diagnosis of MGD-related dry eye were evaluated. In this prospective, randomized, double-masked study, patients were randomized in two treatments: AT plus WC (group A), and AT plus WC plus CsA 0.05% ophthalmic emulsion (group B). At baseline and at 1, 3, and 6 months, Ocular Surface Disease Index (OSDI) questionnaire was completed, and tear evaluation (BUT, Schirmer and osmolarity test), ocular surface evaluation (fluorescein and lissamine green staining), clinical (Shimazaki grading) and in vivo confocal microscopy (IVCM) evaluation of rete ridges (RRs) were performed. A total of 40 eyes, 20 in each group, completed the study. Analysis of OSDI, tear test, ocular surface evaluation and clinical grading of MG showed significant improvement at 6 months, whereas no difference was found between the two groups at 6 months. The analysis of IVCM showed significant improvement in both groups, but significantly better results in group B were found compared to group A at 6 months. WC performed 3 times daily during the 1st month and once daily afterwards, in addition to AT, were useful to manage the obstruction of MG and related signs and symptoms. Additional effects of CsA were visible in IVCM only at 6 months. IVCM is an effective tool to monitor treatments in MGD.


Electropharmacological effects of antiarrhythmic drugs on atrial fibrillation termination. Part I: Molecular and ionic fundamentals of antiarrhythmic drug actions.
In the last few years many studies have been performed with the aim of gaining a better understanding of the pathophysiological nature of atrial fibrillation. These recent observations provide new insights into the initiation and perpetuation of atrial fibrillation, underlying the importance of the pulmonary veins as major sources of atrial triggers and introducing new concepts such as the atrial electrical remodeling and the spatial heterogeneity of the electrophysiological characteristics of this arrhythmia. The increasing knowledge about the cardiac ion channel structure and function and about the electrophysiological actions of the antiarrhythmic drugs may contribute to a better comprehension of the mechanisms of the pharmacological termination of the arrhythmia. In part I of the review we try to give a unified vision of the old models and new concepts about the molecular and ionic fundamentals of antiarrhythmic drug actions.


The prenatal diagnosis of intrauterine growth retardation in one fetus of a twin gestation.
The prenatal care of twin gestations is primarily concerned with attempts at preventing premature labor and the management of obstetric difficulties. Little data are available prior to delivery, apart from Rh-isoimmunized twin gestations, concerning an individual fetus' well-being in a twin gestation. Ultrasonography has been concerned with the single gestation, and has not been used extensively in the care and evaluation of twin gestations, apart from early diagnosis of the condition. This report involves a twin gestation in which a significant repeated difference in the ultrasonographic fetal biparietal diameter measurements clearly identifies a normal fetus and a fetus with intrauterine growth retardation. The management of this patient could have been more aggressive with the present knowledge available and so resulted in better perinatal outcome.


Structures of citrate synthase and malate dehydrogenase of Mycobacterium tuberculosis.
The tricarboxylic acid (TCA) cycle is a central metabolic pathway of all aerobic organisms and is responsible for the synthesis of many important precursors and molecules. TCA cycle plays a key role in the metabolism of Mycobacterium tuberculosis and is involved in the adaptation process of the bacteria to the host immune response. We present here the first crystal structures of M. tuberculosis malate dehydrogenase and citrate synthase, two consecutive enzymes of the TCA, at 2.6 Å and 1.5 Å resolution, respectively. General analogies and local differences with the previously reported homologous protein structures are described.


Variation of B cell subsets with age in healthy Malawians.
Although a number of previous studies have shown that different lymphocyte subsets, including B cells, vary with age, how different B cell subsets vary with age in Malawian population has not been shown before. We recruited Malawian participants of different ages and analyzed their venous blood samples for different B cell subsets. We found that both percentage and absolute counts of B cells varied with age peaking in the 7 to 12 months age group. Proportion of naïve B cells was highest in neonates and decreased with age whereas the percentage of memory B cells was lowest in neonates and increased with age. When we zeroed in on the age band within which the proportion of B cells was highest, both classical and activated memory B cells increased with age and the naïve followed the opposite trend. These results provide additional knowledge in our understanding of the dynamics of B cell subsets in individuals of a specific ethnicity as they age.


Pericytes secrete pro-regenerative molecules in response to platelet-derived growth factor-BB.
Brain pericytes not only maintain the anatomical, biochemical and immune blood-brain barrier, but display features of mesenchymal stem cells (MSCs) in vitro. MSCs have pro-regenerative properties attributed to their secretome. However, whether also brain pericytes possess such pro-regenerative capacities is largely unknown. Here we characterize the secretome and microvesicle (MV) release of human brain pericytes mediated by platelet-derived growth factor-BB (PDGF-BB)/PDGF receptor beta (PDGFRβ) signalling. Upon PDGF-BB, pericytes release not only a plethora of growth factors and a panel of cytokines, but also MVs containing BDNF, FGFb, βNGF, VEGF and PLGF, a response that is specific for PDGFRβ signalling and activation of the ERK 1/2 pathway. In contrast, lipopolysaccharide (LPS), an activator of the innate immune system, stimulates the secretion of much higher amounts of mainly inflammatory cytokines and activates the NFκB pathway. Pericytes change their morphology and undergo opposite changes in surface marker expression, respectively. Our findings provide evidence that the secretome of human brain pericytes varies greatly depending on the exogenous stimulus. The differential secretory functions of pericytes may play an important role in either regulating neuroinflammation or contributing to neurorestoration and identify a possible new target cell for neuroregeneration.


Characterization and profiling of bacteriocin-like substances produced by lactic acid bacteria from cheese samples.
Bacteriocins have become biological weapons against harmful food pathogens and have attracted interest as tools for biopreservation. The aim of this study was to isolate, identify and characterize lactic acid bacterial (LAB) strains from cheese samples, partially purify potential bacteriocins and characterize their antimicrobial activity against pathogens. Bacteriocin-producing organisms were screened by Agar spot assay test. Initially, 25 LAB isolates were isolated from the cheese samples and identified as Lactobacillius spp., among them five strains were able to produce bacteriocin whose antimicrobial activates were analysed by agar-well-diffusion assay test against pathogenic organisms. Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Streptococcus thermophillus and Listeria monocytogens were inhibited, while Enterococcus faecalis, Salmonella typhi, Escherichia coli and Pseudomonas aeruginosa were resistant to the antimicrobial substances from LAB isolates. For optimal production of bacteriocin, LAB broth cultures were harvested at exponential phase. The molecular weights of the bacteriocins are between 7.0-15.0 kDa. The bacteriocins were characterized on the basis of their sensitivity to heat, pH, enzymes, NaCl and treatments with organic solvents. These results revealed that the bacteriocins from Lactobacillius spp. isolated from the cheese might have potential antimicrobial properties and give new insight in the development of bio-preservative agents to prevent and control pathogenic bacterial infection.


The surface enhanced Raman spectroscopic study of the adsorption of C70 on the gold nanoparticles.
Surface enhanced Raman spectra (SERS) of C(70) adsorbed on the gold nanoparticles coated on the filter paper were obtained by employing pyridine molecule as medium. As a new SERS substrate, dried gold coated filter paper has a high SERS activity, of which enhancement factor can be up to 8.2x10(6). When the C(70) molecule is adsorbed on the gold nanoparticle surface, its symmetry is reduced. Different orientations on the surface of gold nanoparticles will lead to different symmetry lowering. Generally, symmetry lowering may lead to the splitting of the Raman bands due to the degenerate modes. It was demonstrated that the C(70) molecule was adsorbed on its pentagonal face with its long axis perpendicular to the gold nanoparticles surface. Its surface enhanced Raman spectral behavior is consistent with the analysis based on the group theory.


Plant Virus Epidemiology: Applications and Prospects for Mathematical Modeling and Analysis to Improve Understanding and Disease Control.
In recent years, mathematical modeling has increasingly been used to complement experimental and observational studies of biological phenomena across different levels of organization. In this article, we consider the contribution of mathematical models developed using a wide range of techniques and uses to the study of plant virus disease epidemics. Our emphasis is on the extent to which models have contributed to answering biological questions and indeed raised questions related to the epidemiology and ecology of plant viruses and the diseases caused. In some cases, models have led to direct applications in disease control, but arguably their impact is better judged through their influence in guiding research direction and improving understanding across the characteristic spatiotemporal scales of plant virus epidemics. We restrict this article to plant virus diseases for reasons of length and to maintain focus even though we recognize that modeling has played a major and perhaps greater part in the epidemiology of other plant pathogen taxa, including vector-borne bacteria and phytoplasmas.


APC controls asymmetric Wnt/β-catenin signaling and cardiomyocyte proliferation gradient in the heart.
Cardiomyocyte (CM) proliferation increases from the inner trabecular to outer compact myocardium in fetal hearts. We determined if canonical Wnt signaling has directional and graded activity to maintain this CM proliferation gradient. Moreover, we investigated whether perturbation of Wnt signaling intensity could modulate CM proliferative activity. With confocal microscopy and image analysis we found that the Wnt effector, β-catenin, formed a signaling gradient which positively correlated with CM proliferative activity across ventricular walls of wild type (WT) embryos at embryonic day (E) 13.5 and 17.5. Negative Wnt regulators, adenomatosis polyposis coli (APC), had a reverse distribution pattern. The activation of canonical Wnt/β-catenin signaling by deletion of Apc in CMs led to ventricular hyperplasia with no adverse effects on fetal survival or CM differentiation. In contrast, cardiac deletion of β-catenin resulted in ventricular hypoplasia and fetal demise by E14.5. We further revealed differential distribution and regulation of three cyclin Ds in fetal hearts. Cyclin D1 was mainly expressed in endothelial cells. Although both cyclin D2 and D3 were present in CMs, only cyclin D2 was regulated by Wnt signaling perturbation: downregulation by β-catenin deletion and upregulation by Apc knockout. Canonical Wnt signaling is asymmetrical and graded across ventricular walls and positively regulates CM proliferation via cyclin D2.


Safety assessment of bone marrow derived MSC grown in platelet-rich plasma.
The injection of endothelial progenitor cells and mononuclear cells derived from bone marrow at the ischemic region of peripheral artery disease patients is reported to be effective for therapeutic angiogenesis; however, these cell therapies require large amounts of bone marrow to obtain sufficient numbers of cells. To solve this problem, we attempted to culture bone-marrow-derived mesenchymal stem cells (BM-MSC), which are supposed to secrete several cytokines that promote angiogenesis. We also focused on using platelet-rich plasma (PRP) as a supplement for cell culture instead of fetal bovine serum. Human BM-MSC obtained from healthy volunteers expanded rapidly when cultured with 10% PRP prepared from their own blood. FACS analysis revealed that these cultured human MSC were homogeneous populations, and chromosomal analysis showed a normal karyotype. Moreover, the angiogenetic effect was apparent two weeks after human BM-MSC were injected into the ischemic muscle in SCID mice. Tumor formation was not detected three months after injection into SCID mice either subcutaneously or intramuscularly. To simulate clinical settings, canine BM-MSC were grown with canine PRP and injected into their ischemic muscles. We confirmed that donor cells existed in situ two and six weeks after operation without any side effects. These results suggest that cultured human BM-MSC can be a promising cell source for therapeutic angiogenesis.


Physical activity: associations with health and summary of guidelines.
The understanding of how physical activity and insufficient physical activity are associated with health outcomes has increased considerably over the past decades. Along with physical activity, the evidence on the associations between sedentary behavior and health has increased, which has resulted in the introduction of recommendations of sedentary behavior. In this article, we 1) present terminology for physical activity and sedentary behavior epidemiology, 2) show the relevant scientific evidence on associations of physical activity and sedentary behavior with selected health-related outcomes and 3) introduce the global guidelines for physical activity and sedentary behavior by the World Health Organization (WHO). Health-related outcomes include cardiovascular morbidity and mortality, total mortality, glucose regulation and type 2 diabetes, adiposity, overweight, obesity, cancer, musculoskeletal and bone health, brain health, and quality of life. These health-related outcomes are reflected across age groups and some population groups, such as pregnant and postpartum women. Furthermore, we discuss physical activity levels across Nordic countries and over time. For the Nordic Nutrition Recommendations, shared common physical activity guidelines were not developed. Instead, each country has created their own guidelines that are being referenced in the article, along with the global WHO guidelines.


The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma.
Cerebellar granule cells precursors are derived from the upper rhombic lip and migrate tangentially independent of glia along the subpial stream pathway to form the external germinal zone. Postnatally, granule cells migrate from the external germinal zone radially through the Purkinje cell layer, guided by Bergmann glia fibers, to the internal granular cell layer.Medulloblastomas (MBs) are the most common malignant childhood brain tumor. Many of these tumors develop from precursor cells of the embryonic rhombic lips. Four main groups of MB are recognized. The WNT group of MBs arise primarily from the lower rhombic lip and embryonic brainstem. The SHH group of MBs originate from cerebellar granule cell precursors in the external germinal zone of the embryonic cerebellum. The cellular origins of type 3 and type 4 MBs are not clear.Several ubiquitin ligases are revealed to be significant factors in development of the cerebellum as well as in the initiation and maintenance of MBs. Proteasome dysfunction at a critical stage of development may be a major factor in determining whether progenitor cells which are destined to become granule cells differentiate normally or become MB cells. We propose the hypothesis that proteasomal activity is essential to regulate the critical transition between proliferating granule cells and differentiated granule cells and that proteasome dysfunction may lead to MB. Proteasome dysfunction could also account for various mutations in MBs resulting from deficiencies in DNA checkpoint and repair mechanisms prior to development of MBs.Data showing a role for the ubiquitin ligases β-TrCP, FBW7, Huwe1, and SKP2 in MBs suggest the possibility of a classification of MBs based on the expression (over expression or under expression) of specific ubiquitin ligases which function as oncogenes, tumor suppressors or cell cycle regulators.


Plasma pharmacochemistry combined with microdialysis to screen potential bioactive components and their metabolites in Anemarrhena asphodeloides saponin extract using ultrahigh-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry.
Although various techniques have been employed to analyze drug metabolites, the metabolism of multicomponent herbal medicine has seldom been fully addressed. In contrast to chemical drugs, a number of compounds in herbal medicine could get into circulation and then be metabolized. Metabolism study on active constituents in herbal medicine is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of herbal medicine. The present work aims to elucidate the multicomponent metabolic characteristics of a herbal medicine by the combination of plasma pharmacochemistry and microdialysis sampling. Anemarrhena asphodeloides, a well-known traditional Chinese medicine, was chosen as a model. After oral administration of A. asphodeloides saponin extract to rats, microdialysis samples were collected continuously in the jugular vein and analyzed by ultrahigh-performance LC/quadrupole-TOF MS. The identification of compounds in biosamples was achieved by accurate mass measurement and detailed fragmentation pathway analysis. The results showed that unbound constituents in blood circulation of the rat included seven parent saponins and six metabolites, which might be the potential active components in vivo. Among which, three metabolites have not been previously reported and were identified in this study. It is the first report on systemic metabolism of total saponins of A. asphodeloides in mammalian plasma.


Specific Gene- and MicroRNA-Expression Pattern Contributes to the Epithelial to Mesenchymal Transition in a Rat Model of Experimental Colitis.
The aim of this study was to determine the gene- and microRNA-expression profile contributing to epithelial to mesenchymal transition in a rat model of experimental colitis. For this, inflammation was induced by injecting 2,4,6-trinitrobenzene sulphonic acid to the colon of male Wistar rats. Samples were taken from both inflamed and uninflamed regions of the same colon, total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that the expression of genes responsible for inducing mesenchymal phenotype, such as Egr1, Fgf2, Fgf7, Jak2, Notch2, Hif1α, Zeb2, Mmp9, Lox, and Vim, was all significantly induced in the inflamed regions of the affected colons while the epithelial marker E-cadherin (Cdh1) was downregulated. In contrast, the expression of microRNAs miR-192, miR-143, miR-375, miR-30a, miR-107, and miR-200b responsible for the regulation of the above mentioned genes was significantly downregulated in inflamed colon. Importantly, we detected moderate induction in the expression of five out of six tested microRNAs in the uninflamed regions. In summary, we identified numerous interacting genes and microRNAs with mutually exclusive expression pattern in inflamed regions of colitis-induced rats. These findings suggest that-among others-an important step in the epithelial to mesenchymal transition in experimental colitis is the dysregulated microRNA expression.


[Pars interarticularis reconstruction of spondylolysis using plates and screws with grafting without arthrodesis. Apropos of 78 cases].
Between 1978 and 1985, 78 reconstructions of the pars interarticularis were performed for painful spondylolysis in which there had been failure to respond to conservative methods and the subjacent disc was not degenerate. Sixty-five patients were reviewed with a follow-up greater than 2 years and a mean of 4.4 years. The concept of pars interarticularis reconstruction can be attributed to Kimura (1968), Buck (1970) and Nicol and Scott (1986). It consists of a posterior approach with freshening of the margins of the defect, the insertion of cancellous chips taken from the spinous processes, resection of the tips of the articular processes above the partes interarticulares and fixation with a butterfly plate and screws which was devised for this purpose. The plate was removed after 6 months. The rate of union after this procedure was 93.5 per cent and rose to 95.7 per cent after a secondary bone graft. Two bilateral non-unions required a lumbosacral arthrodesis. The results were excellent or good as regards pain in 86 per cent of cases. A return to heavy work and intensive sporting activity was possible in 88 per cent of cases. Movement of the lumbosacral spine was reduced by a mean of 41 per cent.


[The association of renalase single-nucleotide polymorphisms rs2576178 and rs10887800 with hypertension in patients with obstructive sleep apnea].
Objective: To evaluate the associations between the renalase single-nucleotide polymorphisms rs2576178 and rs10887800 and the risk of hypertension in OSA patients. Methods: A total of 3, 570 male OSA subjects diagnosed via standard polysomnography were included in this retrospective study. We recorded anthropometric, genomic, and polysomnographic parameters and blood pressure levels. All subjects were divided into four groups based on quartiles of the apnea-hypopnea index (AHI). The relationships between rs2576178 and rs10887800 and the risk of hypertension were evaluated using the binary logistic regression, and haplotype analysis. Results: In the bottom AHI quartile, rs10887800 was significantly associated with the risk of hypertension according to the dominant model [odds ratio(OR)=0.691, 95% confidence interval (CI)=0.483-0.990, P=0.044] even after adjustment for age, sex, and the body mass index. The G-A haplotype was associated with a co-effect of the two SNPs, namely, the risk of hypertension decreased (OR=0.879, 95%CI=0.784-0.986, P=0.028). Conclusions: We find no association between single rs2576178 or rs10887800 variants with the risk of hypertension in our OSA population. But, the synergistic effect of the two polymorphisms is associated with the risk of hypertension in OSA patients.


Micromapping of Thalassemia and Hemoglobinopathies Among Laos, Khmer, Suay and Yer Ethnic Groups Residing in Lower Northeastern Thailand.
Northeastern (NE) Thailand is one of the areas with a prevalence of thalassemias and hemoglobinopathies. Data on the prevalence of the diseases in minorities in the region has been limited. This study aimed to survey the thalassemias and hemoglobinopathies that take into account ethnicity. Four ethnic groups, including Laos (n = 162), Khmer (n = 145), Suay (n = 134), and Yer (n = 101) inhabiting the lower region of NE Thailand, were selected to represent the study populations. The results demonstrated that an extremely high prevalence of Hb E (HBB: c.79G>A) (>50.0%) was observed in the Khmer, Suay and Yer ethnic groups. The highest prevalence of α+-thalassemia (α+-thal) [-α3.7 (rightward)] deletion was found in the Khmer ethnic group (48.28%). The -α4.2 (leftward) deletion (α+-thal) was restricted to the Yer ethnic group. Yer and Suay had a high incidence of Hb Constant Spring (Hb CS; HBA2: c.427T>C) as well as Hb Paksé (HBA2: c.429A>T). As the prevalence of α0-thalassemia (α0-thal) is relatively high in Suay (7.46%), couples who are members of Suay ethnic population should be urged to undergo hematological screening before planning a pregnancy to control the Hb Bart's hydrops fetalis. Micromapping of thalassemias and hemoglobinopathies herein described will be helpful in genetic counseling and public education campaigns, which should be carried out in appropriate languages, with exhibitions at the village levels. This information will be of benefit for the long-term effort to reduce the burden of severe thalassemia disease in the region.


How and when to manage respiratory infections out of hospital.
Lower respiratory infections include acute bronchitis, influenza, community-acquired pneumonia, acute exacerbation of COPD and acute exacerbation of bronchiectasis. They are a major cause of death worldwide and often affect the most vulnerable: children, elderly and the impoverished. In this paper, we review the clinical presentation, diagnosis, severity assessment and treatment of adult outpatients with lower respiratory infections. The paper is divided into sections on specific lower respiratory infections, but we also dedicate a section to COVID-19 given the importance of the ongoing pandemic. Lower respiratory infections are heterogeneous entities, carry different risks for adverse events, and require different management strategies. For instance, while patients with acute bronchitis are rarely admitted to hospital and generally do not require antimicrobials, approximately 40% of patients seen for community-acquired pneumonia require admission. Clinicians caring for patients with lower respiratory infections face several challenges, including an increasing population of patients with immunosuppression, potential need for diagnostic tests that may not be readily available, antibiotic resistance and social aspects that place these patients at higher risk. Management principles for patients with lower respiratory infections include knowledge of local surveillance data, strategic use of diagnostic tests according to surveillance data, and judicious use of antimicrobials.


Non-Antidepressant Pharmacologic Long-Term Treatment of Panic Disorder.
Panic disorder (PD) is a common anxiety disorder. Despite neurophysiological advances, its pathogenesis is still not well elucidated. Although the recommended pharmacological agents have demonstrated efficacy and a rather acceptable tolerability, yet many patients do not respond fully and still suffer from residual symptoms. There is a need for new pharmacological classes with better tolerability and efficacy, and faster onset of action. The purpose of this review is to illustrate the existing non-antidepressant treatment of PD as well as the recent advances in the treatment of PD. 38 articles discussing pharmacological treatment of PD were selected for this review. They were mainly openlabel studies, case-reports and review articles. We reviewed the studies on anticonvulsants, benzodiazepines, gamma amino butyric acid (GABAergic) products, atypical antipsychotics, clonidine, as well as emerging drugs in the treatment of PD such as metabotropic glutamate II agonists, and D-cycloserine. Although most of the drugs tested were proven effective and well tolerated, the studies on the nonconventional agents are restricted to open-label trials and case reports. Further studies are required to establish their efficacy and tolerability in the treatment of panic disorder.


The mind in the making: Developmental and neurobiological origins of mentalizing.
Tracing the development of mentalizing is central to understanding how we come to learn about the mind. Barring significant biological or developmental abnormalities, we all come to form an understanding of the mind and mental states. But how does this happen, and what accounts for individual differences in abilities to reason about mental states (i.e., desires, feelings, intentions)? The first section of the present article brings together relevant developmental research to outline the normative developmental trajectory of mentalizing. The second section delves into attachment research to drive home the point that this fundamental human capacity develops in tandem with early attachment relationships, and underscores the fact that suboptimal attachment contexts can hinder the developmental progression of mentalizing. Biobehavioral mechanisms that have been proposed to mediate this developmental process are discussed in the third section, with a particular focus on the neuropeptide oxytocin.


Synovial tissue research: a state-of-the-art review.
The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response.


Vivaria calvasensis-A new genus and species of Araceae (Araceae: Aroidea: Spathicarpeae) from southern Ecuador.
We describe a new genus with a new species belonging to Araceae, from southern Ecuador. Vivaria calvasensis gen. et sp. nov. inhabits semi-arid inter- Andean mountains at altitudes ranging between 1100-1300 m a.s.l. The species belongs to the tribe Spathicarpae, which in Ecuador is represented by two other genera, Incarum and Croatellia, both typical for humid environments such as montane forests. This new genus is clearly supported by molecular evidence based on the matK gene, and morphological traits that separate it from the closely-related genera included in this tribe. The analyzed material was collected during several field campaigns carried out during four years in two populations from Loja province (Calvas and Macará), southern Ecuador, near the border with Peru.


Alcohol Clustering Mechanisms in Supercritical Carbon Dioxide Using Pulsed-Field Gradient, Diffusion NMR and Network Analysis: Feedback on Stepwise Self-Association Models.
Co-solvent clustering in complex fluids is fundamental to solution phase processes, influencing speciation, reactivity, and transport. Herein, methanol (MeOH) clustering in supercritical carbon dioxide is explored with pulsed-field gradient, diffusion-ordered nuclear magnetic resonance spectroscopy (DOSY-NMR), and molecular dynamics (MD) simulations. Refinements on the application of self-association models to DOSY-NMR experiments on clustering species are presented. Network analysis of MD simulations reveals an elevated stability of cyclic tetrameric clusters across MeOH concentrations, which is consistent with experimental DOSY-NMR molecular cluster distributions calculated with self-association models that include both cooperative cluster assembly and entropic penalties for the formation of large clusters. Simulations also detail the emergence of cluster-assembly and cluster-disassembly reactions that deviate from stepwise monomer addition or removal. This combination of experiment, simulation, and novel analyses facilitates refinement of models that describe co-solvent aggregation with far-reaching impact on the prediction of solution phase properties of complex fluids.


Cyclic Peptide Extracts Derived From Pseudostellaria heterophylla Ameliorates COPD via Regulation of the TLR4/MyD88 Pathway Proteins.
We have explored the method of extraction and purification of cyclic-peptide extract (CPE) from Pseudostellaria heterophylla (Miq.) Pax. (Taizishen, TZS), characterized the structure about cyclic-peptide compounds and investigated the biological activity of CPE attenuating chronic obstructive pulmonary disease (COPD) in rats. The CPE from TZS was obtained by ethyl acetate, petroleum ether, hot water extraction, and alcohol-precipitation. Cyclic-peptide structures were distinguished using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Rats were induced by solid combustibles smoke (SCS) for the COPD model, and the anti-COPD activity of CPE was detected using lung airway resistance and dynamic lung compliance, as well as pulmonary tissue hematoxylin and eosin (HE) staining. The relevant inflammatory cytokines were assayed by enzyme-linked immunosorbent assay (ELISA). CPE obtained from TZS contained 12 cyclic-peptide constituents; the purity was up to 92.94%. CPE (200, 400, or 500 mg/kg/day) was given to SCS-induced COPD model rats orally for 15 days. The results showed that in rats given CPE (400 mg/kg/day) there was a sharp fall in lung airway resistance but a rise in dynamic lung compliance. The image analysis of lung tissue sections suggested that CPE could decrease the degree of alveolar destruction (p <0.05), alleviate lung inflammation, increase alveolar space, and improve the infiltration of inflammatory cells. CPE was found to reduce the levels of TNF-α, but increase IL-10, adjusting multiple cytokines in rat serum; the TLR4 mRNA, MyD88 mRNA and AP-1 mRNA levels, the expressing levels of p-JNK, p-p38 and p-TAK1 protein were significantly down regulated in rat alveolar macrophages. CPE intervention could improve the pulmonary ventilation function on COPD rats, which may be related to its effect in inhibiting the abnormal activation of the TLR4-MyD88-JNK/p38 pathway. This is the first report that the CPE of TZS lessens the severity of COPD episodes. The new preparation process of CPEs implements the anticipated goal, which is to refine CPE and actualize quality control.


A meta-analytic assessment of Wechsler's P>V sign in antisocial populations.
The dichotomy between Verbal IQ and Performance IQ was a hallmark of the Wechsler scales for over 60 years. Wechsler noted that adolescent delinquents tend to score higher on the Performance tests than the Verbal tests (P>V). A plethora of studies have examined the clinical utility of the P>V sign in juvenile delinquents. However, there have been few attempts to systematically quantify the size of this discrepancy in antisocial children and adults. A meta-analysis of 131 studies was conducted to examine whether the PIQ-VIQ discrepancy is found across different age groups as well as sex, race, and test instrument. Results indicated that the discrepancy is characteristic of antisocial females as well as males. The discrepancy is largest in adolescents (6 points), smaller in adults (3 points), and negligible in young children. Furthermore, the effect is moderated by race and instrument, such that the PIQ-VIQ discrepancy is smallest for African-Americans and for subjects administered the Wechsler Adult Intelligence Scale. Among adolescents administered the Wechsler Intelligence Scale for Children, the poorest subtests are Vocabulary and Information. It is argued that delinquency is intertwined with school failure, and that verbal-educational deficits accumulate over the course of childhood, eventually manifesting as P>V.