Developing a toolkit for panel management: improving hypertension and smoking cessation outcomes in primary care at the VA.
As primary care practices evolve into medical homes, there is an increasing need for effective models to shift from visit-based to population-based strategies for care. However, most medical teams lack tools and training to manage panels of patients. As part of a study comparing different approaches to panel management at the Manhattan and Brooklyn campuses of the VA New York Harbor Healthcare System, we created a toolkit of strategies that non-clinician panel management assistants (PMAs) can use to enhance panel-wide outcomes in smoking cessation and hypertension. We created the toolkit using: 1) literature review and consultation with outside experts, 2) key informant interviews with staff identified using snowball sampling, 3) pilot testing for feasibility and acceptability, and 4) further revision based on a survey of primary care providers and nurses. These steps resulted in progressively refined strategies for the PMAs to support the primary care team. Literature review and expert consultation resulted in an extensive list of potentially useful strategies. Key informant interviews and staff surveys identified several areas of need for assistance, including help to manage the most challenging patients, providing care outside of the visit, connecting patients with existing resources, and providing additional patient education. The strategies identified were then grouped into 5 areas - continuous connection to care, education and connection to clinical resources, targeted behavior change counseling, adherence support, and patients with special needs. Although panel management is a central aspect of patient-centered medical homes, providers and health care systems have little guidance or evidence as to how teams should accomplish this objective. We created a toolkit to help PMAs support the clinical care team for patients with hypertension or tobacco use. This toolkit development process could readily be adapted to other behaviors or conditions. ClinicalTrials.gov, NCT01677533.


Self-Immolation of a Bacterial Dehydratase Enzyme by its Epoxide Product.
Disabling the bacterial capacity to cause infection is an innovative approach that has attracted significant attention to fight against superbugs. A relevant target for anti-virulence drug discovery is the type I dehydroquinase (DHQ1) enzyme. It was shown that the 2-hydroxyethylammonium derivative 3 has in vitro activity since it causes the covalent modification of the catalytic lysine residue of DHQ1. As this compound does not bear reactive electrophilic centers, how the chemical modification occurs is intriguing. We report here an integrated approach, which involves biochemical studies, X-ray crystallography and computational studies on the reaction path using combined quantum mechanics/molecular mechanics Umbrella Sampling Molecular Dynamics, that evidences that DHQ1 catalyzes its self-immolation by transforming the unreactive 2-hydroxyethylammonium group in 3 into an epoxide that triggers the lysine covalent modification. This finding might open opportunities for the design of lysine-targeted irreversible inhibitors bearing a 2-hydroxyethylammonium moiety as an epoxide proform, which to our knowledge has not been reported previously.


Dual Task Effects on Visual Attention Capacity in Normal Aging.
Older adults show higher dual task performance decrements than younger adults. While this is assumed to be related to attentional capacity reductions, the precise affected functions are not specified. Such specification is, however, possible based on the "theory of visual attention" (TVA) which allows for modeling of distinct attentional capacity parameters. Furthermore, it is unclear whether older adults show qualitatively different attentional effects or whether they show the same effects as younger adults experience under more challenging conditions. By varying the complexity of the secondary task, it is possible to address this question. In our study, participants performed a verbal whole report of briefly presented letter arrays. TVA-based fitting of report performance delivered parameters of visual threshold t0, processing speed C, and visual short-term memory (VSTM) storage capacity K. Furthermore, participants performed a concurrent motor task consisting of continuous tapping of a (simple or complex) sequence. Both TVA and tapping tasks were performed under single and dual task conditions. Two groups of 30 younger adults each performed either the simple or complex tapping, and a group of 30 older adults performed the simple tapping condition. In older participants, VSTM storage capacity declined under dual task conditions. While no such effect was found in younger subjects performing the simple tapping sequence under dual task conditions, the younger group performing the complex tapping task under dual task conditions also showed a significant VSTM capacity reduction. Generally, no significant effect on other TVA parameters or on tapping accuracy was found. Comparable goodness-of-fit measures were obtained for the TVA modeling data in single and dual tasks, indicating that tasks were executed in a qualitatively similar, continuous manner, although quantitatively less efficiently under dual- compared to single-task conditions. Taken together, our results show that the age-specific effects of motor-cognitive dual task interference are reflected by a stronger decline of VSTM storage capacity. They support an interpretation of VSTM as central attentional capacity, which is shared across visual uptake and concurrent motor performance. Capacity limits are reached earlier, and already under lower motor task complexity, in older compared to younger adults.


Evaluation of drug susceptibility in nontuberculous mycobacteria using the SLOMYCO and RAPMYCO sensititre plates.
Non-tuberculous Mycobacteria (NTM) cause different forms of diseases. According to recent guideline by ATS/ERS/ESCMID/IDSA, drug susceptibility test (DST) is an important requirement to choose adequate treatment. The minimum inhibitory concentration (MIC) test is the recommended method. Sensititre SLOMYCO and RAPMYCO commercial panels were developed to perform mycobacteria DST easier. However, there are only two comparative studies between SLOMYCO and the MIC method and none for the RAPMYCO panel. The present study aimed to evaluate the Sensititre SLOMYCO and RAPMYCO plates in determining drug susceptibility compared to the gold standard method (MIC). The tests were carried out with clinical isolates received in the diagnostic routine of the Tuberculosis Laboratory at Institute Adolfo Lutz from the most frequent species in the state of São Paulo, Brazil. Reference strains were tested for repeatability and reproducibility analyses. MIC and Sensititre plates readings were compared with and without resazurin stain. Agreement between results was defined as MIC within the same dilution or dilution variation resulting the same category in both tests. Results were classified by categorical errors. The RAPMYCO panel had 100% agreement for the drugs amikacin, doxycycline, ciprofloxacin and trimethoprim/sulfamethoxazole, 83.3% for clarithromycin and moxifloxacin and 60% for cefoxitin. The SLOMYCO panel had 80% agreement for amikacin and moxifloxacin and 60% for clarithromycin, rifabutin, rifampicin and ciprofloxacin. The repeatability and reproducibility with RAPMYCO and SLOMYCO plates showed a high level of agreement for the drugs tested, being higher with the use of resazurin. However, an evaluation on routine condition is needed. The present study found that the fewer steps in the tests with Sensititre plates and reading with resazurin allow its use with greater safety and efficiency in the laboratory routine. The results presented here will facilitate the execution of a validation for complete incorporation of Sensititre plates into a diagnostic routine.


Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry.
Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33-66% of PRS), men with low (0-33%) and high (66-100%) PRS had odds ratios (OR) for overall prostate cancer of 2.08 (95% confidence interval (CI)=0.58 to 7.49) and 18.06 (95% CI=4.24 to 76.84) among P/LP/D carriers and 0.57 (95% CI=0.46 to 0.71) and 3.02 (95% CI=2.53 to 3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI=0.24 to 30.54) and 28.99 (95% CI=4.39 to 191.43) among P/LP/D carriers and 0.54 (95% CI=0.31 to 0.95) and 3.22 (95% CI=2.20 to 4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.


Asthma and Chronic Obstructive Pulmonary Disease.
In the United States, asthma and chronic obstructive pulmonary disease (COPD) disproportionately affect African Americans, Puerto Ricans, and other minority groups. Compared with non-Hispanic whites, minorities have been marginalized and more frequently exposed to environmental risk factors such as tobacco smoke and outdoor and indoor pollutants. Such divergent environmental exposures, alone or interacting with heredity, lead to disparities in the prevalence, morbidity, and mortality of asthma and COPD, which are worsened by lack of access to health care. In this article, we review the burden and risk factors for racial or ethnic disparities in asthma and COPD and discuss future directions in this field.


A conjugated gold nanoparticle-azacyanine off-on-off fluorescence probe for sensitive and selective detection of G-quadruplexes.
G-quadruplex secondary structures have gained significant recognition due to the discovery of their involvement in regulation of gene expression and their association with many diseases such as cancer and neurological disorders. Consequently, the need for the recognition and characterization of G-quadruplex structures has increased considerably. Here, we present a rapid, facile and sensitive off-on-off in vitro platform for G-quadruplex detection, based on the gold nanoparticle-azacyanine5 (AuNP-Aza5) conjugated fluorescence probe. The conjugated probe is governed by Fluorescence Resonance Energy Transfer (FRET) mechanism between the fluorophore molecule, Aza5, and AuNPs. The fluorescence of Aza5 that was hindered by AuNPs (off), was restored in the presence of L-cysteine (on) until the addition of a G-quadruplex structure (off). The developed sensing platform selectively responds to G-quadruplex structures formed within the promoter regions of VEGF-Pu22, K-RAS, C-myc and BCL-2. It doesn't exhibit a similar response to the other secondary structures such as single, double or triple stranded nucleic acid structures. The detailed investigation of the probe with VEGF-Pu22 as a model G-quadruplex structure revealed a linear response between the concentration range of 0.032-0.347 μM with a detection limit of 12.66 nM.


Iron deficiency anemia associated with extracorporeal photopheresis: A retrospective analysis.
Extracorporeal photopheresis (ECP) is associated with few adverse effects. We have anecdotally noted patients treated with long-term ECP develop iron deficiency anemia (IDA). We performed a retrospective chart review of adult patients who received ECP for any indication at Mayo Clinic Rochester and Mayo Clinic Arizona. The primary objective was to describe the cumulative incidence of IDA at 1 year of ECP therapy. A total of 123 patients were eligible for analysis. Graft-vs-host disease was the most common indication for ECP (n = 76, 61.8%). At 1 year of ECP therapy, the cumulative incidence of IDA was 24.1% (95% CI, 14.2%-32.9%). At 5 years, the cumulative incidence of IDA was 68.3% (95% CI, 38%-83.8%). Risk factors for the development of IDA included: cumulative number of ECP sessions (HR 1.34, 95% CI, 1.05-1.73 per 10 additional sessions, P = .022), an indication for ECP of solid organ transplant rejection (compared to cutaneous T-cell lymphoma, HR 5.46, 95% CI, 2.06-14.49, P < .001), and proton pump inhibitor use at baseline (HR 2.15, 95% CI, 1.1-4.21, P = .03). Iron supplementation was initiated in 29 of 37 evaluable patients who developed IDA, with a cumulative incidence of supplementation in 77.2% patients within 3 months of recognition of IDA (95% CI, 55.8%-88.3%). Hemoglobin normalized in 50.1% of patients started on iron supplementation for IDA within 7 months (95% CI, 25.2%-66.7%). Iron deficiency anemia is common in patients receiving long-term ECP and occurs throughout ECP therapy. IDA resolved with iron supplementation in half of patients.


Northern blotting analysis of microRNAs, their precursors and RNA interference triggers.
Numerous microRNAs (miRNAs) have heterogeneous ends resulting from imprecise cleavages by processing nucleases and from various non-templated nucleotide additions. The scale of miRNA end-heterogeneity is best shown by deep sequencing data revealing not only the major miRNA variants but also those that occur in only minute amounts and are unlikely to be of functional importance. All RNA interference (RNAi) technology reagents that are expressed and processed in cells are also exposed to the same machinery generating end-heterogeneity of the released short interfering RNAs (siRNAs) or miRNA mimetics. In this study we have analyzed endogenous and exogenous RNAs in the range of 20-70 nt by high-resolution northern blotting. We have validated the results obtained with northern blotting by comparing them with data derived from miRNA deep sequencing; therefore we have demonstrated the usefulness of the northern blotting technique in the investigation of miRNA biogenesis, as well as in the characterization of RNAi technology reagents. The conventional northern blotting enhanced to high resolution may be a useful adjunct to other miRNA discovery, detection and characterization methods. It provides quantitative data on distribution of major length variants of abundant endogenous miRNAs, as well as on length heterogeneity of RNAi technology reagents expressed in cells.


The effects of fructose and other substances on acetaldehyde and ethanol metabolism in the rat.
The purpose of this study was to test the comparative effectiveness of fructose, glucose, sucrose and alanine in increasing the rates of ethanol and acetaldehyde clearance. Intravenously administered fructose was found to be most effective, followed by alanine in increasing the rate of blood alcohol clearance. Administration of any one of the test substances during ethanol metabolism did not result in a significant change in the levels of blood acetaldehyde. Fructose partially prevented the ethanol-mediated changes in the concentration ratios of lactate/pyruvate and beta-hydroxybutyrate/acetoacetate. Its administration also resulted in the reversal of acetaldehyde-mediated changes in the liver. Test substances resulted in an increase in hepatic glucose levels, however, a combination of these substances with ethanol resulted in decreased hepatic glucose levels. The most pronounced effect on glucose was observed when ethanol was given in combination with glucose. During the simultaneous metabolism of fructose and ethanol, hepatic and blood levels of sorbitol increased significantly. Fructose also exerted the most pronounced antiketogenic action.


Sarcopenia associated with portosystemic shunting is reversed by follistatin.
The distinct role of portosystemic shunting (PSS) in the pathogenesis of sarcopenia (skeletal muscle loss) that occurs commonly in cirrhosis is unclear. We have previously shown increased expression of myostatin (inhibitor of skeletal muscle mass) in the portacaval anastamosis (PCA) rat model of sarcopenia of PSS. The present study was performed to examine the mechanisms of sarcopenia following PCA. In PCA and sham operated pair fed control rats, the phenylalanine flooding dose method was used to quantify the fractional and absolute protein synthesis rates in the skeletal muscle over time and in response to follistatin, a myostatin antagonist. The expression of myostatin and markers of satellite cell (myocyte precursors) proliferation and differentiation were quantified by real-time PCR and Western blot analyses. The absolute synthesis rate (ASR) was lower at 2, 4, and 6 weeks (p<0.05) and the fractional synthesis rate (FSR) of skeletal muscle protein was significantly lower (p<0.05) at week 2 in the PCA rats compared to control rats. Expression of myostatin was elevated while markers of satellite cell proliferation and differentiation were lower at 4 and 6 weeks after PCA. Follistatin increased skeletal muscle mass, muscle FSR and ASR, decreased expression of myostatin protein, and increased expression of markers of satellite cell function. Sarcopenia associated with PSS is caused by impaired protein synthesis and reduced satellite cell function due to increased myostatin expression. Confirming these alterations in human patients with cirrhosis will provide novel therapeutic targets for sarcopenia of liver disease.


Association analysis of toluene exposure time with high-throughput mRNA expressions and methylation patterns using in vivo samples.
The emission of volatile organic compounds (VOCs) resulting from outdoor air pollution can contribute to major public health problems. However, there has been limited research on the health effects in humans from the inhalation of VOCs. Therefore, this study conducted an in vivo analysis of the effects of toluene, one of the most commonly used chemicals in many industries, on gene expression and methylation over time using the high-throughput technique of microarray analysis. We separated participants into three groups (control, short-term exposure, and long-term exposure) to investigate the influence of toluene exposure time on gene expression. We then comprehensively analyzed and investigated the correlation between variations in gene expression and the occurrence of methylation. Twenty-six genes were upregulated and hypomethylated, while 32 genes were downregulated and hypermethylated. The pathways of these genes were confirmed to be associated with cell survival and the immune system. Based on our findings, these genes can help predict the effects of time-dependent exposure to toluene on human health. Thus, observations from our data may have implications for the identification of biomarkers of toluene exposure.


Chinese Adults' Willingness to Pay for Mandatory Nutrients Reporting on Nutrition Facts Table.
The Chinese food industry has opposed the mandatory inclusion of increased nutrients in the Nutrition Facts Table (NFT), thus impeding its improvement. This poses a challenge to the endeavors aiming to assist consumers in cultivating healthy dietary habits that incorporate reduced saturated fatty acids and added sugars while ensuring the adequate intake of essential micronutrients. This study conducted a choice experiment to investigate Chinese consumers' preference for updated labeling schemes among 630 adults that were randomly selected from Central, North, East, South, Northwest, Southwest, and Northeast China. It revealed that respondents were willing to pay the highest premium for the most mandatory nutrients (22.575% of the food price per unit). Respondents preferred the NFT with the most mandatory nutrients if they met the following population characteristics: female; non-overweight or obese; without a college degree; possessed an annual household disposable income between 50,000 and 99,999 CNY; from North China; lived in rural areas and often cooked for family; cared about food nutrition. Two combinations of NFT information received the highest preference: (1) the NFT detailing the most mandatory nutrients and their content values and nutrient reference values (NRV%); (2) the NFT containing the most nutrients and the nutrients in 100 g/mL or a serving. The first and second combinations attracted a premium of 14.884% and 31.833% of the food price per unit, respectively.


[Reexcision and perioperative brachytherapy in the treatment of local relapse after breast conservation: a possible alternative to mastectomy].
Breast conserving surgery and postoperative radiotherapy became widely accepted in the last two decades for the treatment of early invasive breast cancer. In spite of adequate surgery and radiotherapy, the rate of ipsilateral breast tumor recurrence is approximately 10%. In such cases salvage mastectomy is the standard treatment, however wide reexcision of the recurrent tumor is also a reasonable option for selected patients. The risk of second local relapse is higher following further breast conservation compared to mastectomy. The authors report the technique of tumor reexcision combined with intraoperative implantation and perioperative high dose rate (HDR) bracytherapy of the tumor bed for the salvage of recurrence in a previously irradiated breast. One can perform two operative interventions at the same time with this method. Irradiation can be started safely within 48 hours after surgery. A review of the literature is also performed by the authors to demonstrate the role and indication of perioperative brachytherapy in the treatment of breast tumor relapse and other cancer recurrences. Reexcision is a practicable alternative to mastectomy for solitary, parenchymal breast tumor relapse measured 2 cm or less in diameter. Perioperative brachytherapy may decrease the risk of second relapse without increasing radiation side effects. Further prospective study is required to define the value of the prescribed method in comparison with salvage mastectomy.


Identification of Promotor and Exonic Variations, and Functional Characterization of a Splice Site Mutation in Indian Patients with Unconjugated Hyperbilirubinemia.
Mild unconjugated hyperbilirubinemia (UH), due to reduced activity of the enzyme uridine diphosphoglucuronate-glucuronosyltransferase family, polypeptide 1 (UGT1A1), is a common clinical condition. Most cases are caused by presence in homozygous form of an A(TA)7TAA nucleotide sequence instead of the usual A(TA)6TAA sequence in promoter region of the UGT1A1 gene. In some cases, other genetic variations have been identified which differ between populations. There is need for more data on such genetic variations from India. DNA from subjects with unexplained persistent or recurrent UH was tested for the presence of TA promoter insertions. In addition, all five exons and splicing site regions of UGT1A1 gene were sequenced. Several bioinformatics tools were used to determine the biological significance of the observed genetic changes. Functional analysis was done to look for effect of a splice site mutation in UGT1A1. Of 71 subjects with UH (68 male; median age [range], 26 [16-63] years; serum bilirubin 56 [26-219] μM/L, predominantly unconjugated) studied, 65 (91.5%) subjects were homozygous for A(TA)7TAA allele, five (7.0%) were heterozygous, and one (1.4%) lacked this change. Fifteen subjects with UH had missense exonic single nucleotide changes (14 heterozygous, 1 homozygous), including one subject with a novel nucleotide change (p.Thr205Asn). Bioinformatics tools predicted some of these variations (p.Arg108Cys, p.Ile159Thr and p.Glu463Val) to be deleterious. Functional characterization of an exonic variation (c.1084G>A) located at a splice site revealed that it results in frameshift deletion of 31 nucleotides and premature truncation of the protein. Our study revealed several single nucleotide variations in UGT1A1 gene in Indian subjects with UH. Functional characterization of a splice site variation indicated that it leads to disordered splicing. These variations may explain UH in subjects who lacked homozygous A(TA)7TAA promoter alleles.


Variational approach for electrolyte solutions: from dielectric interfaces to charged nanopores.
A variational theory is developed to study electrolyte solutions, composed of interacting pointlike ions in a solvent, in the presence of dielectric discontinuities and charges at the boundaries. Three important and nonlinear electrostatic effects induced by these interfaces are taken into account: surface charge induced electrostatic field, solvation energies due to the ionic cloud, and image-charge repulsion. Our variational equations thus go beyond the mean-field theory, or weak coupling limit, where thermal fluctuations overcome electrostatic correlations, and allows one to reach the opposite strong coupling limit, where electrostatic interactions induced by interfaces dominate. The influence of salt concentration, ion valency, dielectric jumps, and surface charge is studied in two geometries. (i) A single neutral dielectric interface (e.g., air-water or electrolyte-membrane) with an asymmetric electrolyte. A charge separation and thus an electrostatic field get established due to the different image-charge repulsions for coions and counterions. Both charge distributions and surface tension are computed and compared to previous approximate calculations. For symmetric electrolyte solutions close to a charged surface, two zones are characterized. In the first one, in contact with the surface and with size proportional to the logarithm of the coupling parameter, strong image forces and strong coupling impose a total ion exclusion, while in the second zone the mean-field approach applies. (ii) A symmetric electrolyte confined between two dielectric interfaces as a simple model of ion rejection from nanopores in membranes. The competition between image-charge repulsion and attraction of counterions by the membrane charge is studied. For small surface charge, the counterion partition coefficient decreases with increasing pore size up to a critical pore size, contrary to neutral membranes. For larger pore sizes, the whole system behaves like a neutral pore. For strong coupling and small pore size, coion exclusion is total and the counterion partition coefficient is solely determined by global electroneutrality. A quantitative comparison is made with a previous approach, where image and surface charge effects were smeared out in the pore. It is shown that the variational method allows one to go beyond the constant Donnan potential approximation, with deviations stronger at high ion concentrations or small pore sizes. The prediction of the variational method is also compared with MC simulations and good agreement is observed.


The role of novel biologics in biliary cancers.
Biliary tract cancers (BTC) are a rare, heterogenous group encompassing gallbladder cancers and cholangiocarcinomas that are most commonly diagnosed in the locally advanced or metastatic setting. While systemic chemotherapy provides modest clinical benefit, there is a clear need for the development of more effective treatment strategies. Advances in next generation sequencing assays have underscored the molecular heterogeneity within BTC and identified the potential to exploit potential vulnerabilities in signaling pathways offering a personalized approach to treatment. In this article we review key genetic alterations detected in BTC and provide an overview of prior, current and the emerging role of molecular therapeutics in BTC. We also discuss the evaluation of immunotherapy in completed and ongoing trials as a potential treatment modality in BTC. Overall, prior studies using targeted agents were undermined by assessment of such agents within an unselected patient population. In contrast current and planned novel treatment approaches in BTC are now more frequently using molecular profiling to select patients for a molecularly targeted approach or incorporating biomarkers to inform studies in unselected patients. Currently, no approved molecular therapy for BTC exists, however by incorporating molecular profiling in directing novel targeted therapy trial enrollment and assessment along with the ongoing appraisal of immunotherapy we anticipate significant incremental progress over the coming decade.


Therapeutic potential of hAECs for early Achilles tendon defect repair through regeneration.
Cell-based therapy holds great promise for tendon disorders, a widespread debilitating musculoskeletal condition. Even if the cell line remains to be defined, preliminary evidences have proven that amniotic-derived cells possess in vitro and in vivo a great tenogenic potential. This study investigated the efficacy of transplanted human amniotic epithelial cells (hAECs) by testing their early regenerative properties and mechanisms involved on a validated ovine Achilles tendon partial defect performed on 29 animals. The injured tendons treated with hAECs recovered rapidly, in 28 days, structural and biomechanical properties undertaking a programmed tissue regeneration, differently from the spontaneous healing tissues. hAECs remained viable within the host tendons establishing with the endogenous progenitor cells an active dialogue. Through the secretion of modulatory factors, hAECs inhibited the inflammatory cells infiltration, activated the M2 macrophage subpopulation early recruitment, and accelerated blood vessel as well as extracellular matrix remodelling. In parallel, some in situ differentiated hAECs displayed a tenocytelike phenotype. Both paracrine and direct hAECs stimulatory effects were confirmed analysing their genome profile before and after transplantation. The 49 human up-regulated transcripts recorded in transplanted hAECs belonged to tendon lineage differentiation (epithelial-mesenchymal transition, connective specific matrix components, and skeleton or muscle system development-related transcripts), as well as the in situ activation of paracrine signalling involved in inflammatory and immunomodulatory response. Altogether, these evidences support the hypothesis that hAECs are a practicable and efficient strategy for the acute treatment of tendinopathy, reinforcing the idea of a concrete use of amniotic epithelial cells towards the clinical practice.


Pea aphid as both host and vector for the phytopathogenic bacterium Pseudomonas syringae.
Aphids are widespread agricultural pests that are capable of disseminating plant viral diseases; however, despite coming into frequent contact with epiphytic bacteria, aphids are considered to have no role in bacterial transmission. Here, we demonstrate the ability of pea aphids to vector the phytopathogen Pseudomonas syringae pv. syringae B728a (PsyB728a). While feeding on plants colonized by epiphytic bacteria, aphids acquire the bacteria, which colonize the digestive tract, multiply, and are excreted in the aphid honeydew, resulting in inoculation of the phyllosphere with up to 10(7) phytopathogenic bacteria per cm(2). Within days of ingesting bacteria, aphids succumb to bacterial sepsis, indicating that aphids serve as an alternative, nonplant host for PsyB728a. The related strain Pseudomonas syringae pv. tomato DC3000 is >1,000-fold less virulent than PsyB728a in the pea aphid, suggesting that PsyB728a possesses strain-specific pathogenicity factors that allow it to exploit aphids as hosts. To identify these factors, we performed a mutagenesis screen and recovered PsyB728a mutants that were hypovirulent, including one defective in a gene required for flagellum formation and motility. These interactions illustrate that aphids can also vector bacterial pathogens and that even seemingly host-restricted pathogens can have alternative host specificities and lifestyles.


Clustering and re-clustering for pattern discovery in gene expression data.
The combined interpretation of gene expression data and gene sequences is important for the investigation of the intricate relationships of gene expression at the transcription level. The expression data produced by microarray hybridization experiments can lead to the identification of clusters of co-expressed genes that are likely co-regulated by the same regulatory mechanisms. By analyzing the promoter regions of co-expressed genes, the common regulatory patterns characterized by transcription factor binding sites can be revealed. Many clustering algorithms have been used to uncover inherent clusters in gene expression data. In this paper, based on experiments using simulated and real data, we show that the performance of these algorithms could be further improved. For the clustering of expression data typically characterized by a lot of noise, we propose to use a two-phase clustering algorithm consisting of an initial clustering phase and a second re-clustering phase. The proposed algorithm has several desirable features: (i) it utilizes both local and global information by computing both a "local" pairwise distance between two gene expression profiles in Phase 1 and a "global" probabilistic measure of interestingness of cluster patterns in Phase 2, (ii) it distinguishes between relevant and irrelevant expression values when performing re-clustering, and (iii) it makes explicit the patterns discovered in each cluster for possible interpretations. Experimental results show that the proposed algorithm can be an effective algorithm for discovering clusters in the presence of very noisy data. The patterns that are discovered in each cluster are found to be meaningful and statistically significant, and cannot otherwise be easily discovered. Based on these discovered patterns, genes co-expressed under the same experimental conditions and range of expression levels have been identified and evaluated. When identifying regulatory patterns at the promoter regions of the co-expressed genes, we also discovered well-known transcription factor binding sites in them. These binding sites can provide explanations for the co-expressed patterns.


Prolactin localization, binding, and effects on peroxidase release in rat exorbital lacrimal gland.
Prolactin immunoreactivity has been detected in human tears and in lacrimal glands, and it has been suggested that this hormone might be a modulator of lacrimal secretion as well as a component of lacrimal gland fluid. The present study was designed to confirm the immunocytochemical localization of prolactin in the rat lacrimal gland, to determine the source of the prolactin, and to evaluate the acute effects of prolactin on lacrimal secretory function. We have confirmed that prolactin-like immunoreactivity is present in secretory vesicles of acinar cells of male and female Sprague-Dawley rats. Prolactin message was present at detectable levels in RNA extracts of lacrimal glands from males, indicating that at least a component of the prolactin-like immunoreactivity was the product of synthesis within the lacrimal glands. Crude membrane fractions from acini isolated from males bound 43.1 +/- 3.2 femtomoles prolactin/mg protein (mean +/- standard error of the mean; n = 6), which was significantly (P less than 0.01) more than comparable fractions from females (15.4 +/- 2.4 fmoles/mg protein, n = 6). Preincubating membranes at 65 degrees for 20 min to release endogenous ligands increased prolactin binding to 84.8 +/- 20.8 fmoles/mg protein for males and 63.8 +/- 17.4 fmoles/mg protein for females (P greater than 0.1), suggesting that, on average, similar numbers of receptors are expressed in acinar cells of male and female rats but a larger fraction of the receptors is occupied by endogenous prolactin-like peptides in females. Because prolactin binding triggers prolactin receptor internalization in various cell types, we propose that the prolactin-like immunoreactivity in lacrimal acinar cells of females has been accumulated from the circulation, while the immunoreactivity seen in males results, at least in part, from de novo synthesis. Ovine prolactin at concentrations of 10-20 ng/ml inhibited carbachol-induced peroxidase release by 19.6% +/- 6.9% (n = 8, P less than 0.02) but failed to alter peroxidase release in the absence of carbachol. These observations suggest that prolactin might function as an endocrine, paracrine, or autocrine modulator in the lacrimal gland.


Chlamydophila pneumoniae-associated community-acquired pneumonia in paediatric patients of a tertiary care hospital in Mexico: molecular diagnostic and clinical insights.
Chlamydophila pneumoniae is a cause of community-acquired pneumonia (CAP) and responsible for 1-2% of cases in paediatric patients. In Mexico, information on this microorganism is limited. The aim of this study was to detect C. pneumoniae using two genomic targets in a real-time PCR and IgM/IgG serology assays in paediatric patients with CAP at a tertiary care hospital in Mexico City and to describe their clinical characteristics, radiological features, and outcomes. A total of 154 hospitalized patients with diagnosis of CAP were included. Detection of C. pneumoniae was performed by real-time PCR of the pst and arg genes. Complete blood cell count, C-reactive protein measurement and IgM and IgG detection were performed. Clinical-epidemiological and radiological data from the patients were collected. C. pneumoniae was detected in 25 patients (16%), of whom 88% had underlying disease (P = 0.014). Forty-eight percent of the cases occurred in spring, 36% in girls, and 40% in children older than 6 years. All patients had cough, and 88% had fever. Interstitial pattern on chest-X-ray was the most frequent (68%), consolidation was observed in 32% (P = 0.002). IgM was positive in 7% and IgG in 28.6%. Thirty-six percent presented complications. Four percent died. A high proportion showed co-infection with Mycoplasma pneumoniae (64%). This is the first clinical report of C. pneumoniae as a cause of CAP in Mexican paediatric patients, using two genomic target strategy and serology. We found a frequency of 16.2% with predominance in children under 6 years of age. In addition; cough and fever were the most common symptoms. Early detection of this pathogen allows timely initiation of specific antimicrobial therapy to reduce development of complications. This study is one of the few to describe the presence of C. pneumoniae in patients with underlying diseases.


High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet.
Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR and histology of epididymal white adipose tissue (eWAT) were performed. Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.


The Measure of Population Aging in Different Welfare Regimes: A Bayesian Dynamic Modeling Approach.
Given a population at a specific time point, it is often of interest to identify the entry age into typical stages of life, such as being young, becoming adult and elderly. These age cutoffs are important because they influence the public opinion and have an impact on policy decisions. An issue of great social relevance is defining the threshold beyond which a person becomes elderly. Fixed cutoffs are debatable because of their conventional nature which disregards issues such as changing life expectancy and the evolving structure of the age distribution. The above shortcomings can be overcome if age cutoffs are defined endogenously, i.e., relative to the whole age distribution of each country at a specific time point. We pursue this line of research by presenting an analysis whose main features are: (1) establishing a relationship between a country's welfare regime and its age distribution and aging process, together with the identification of four clusters of countries corresponding to distinctive welfare models and (2) a Bayesian hierarchical dynamic model which accounts for the uncertainty in the time series of measurements of the endogenous cutoffs for the countries in the sample, as well as for their clustering structure. Our analysis leads to model-based estimates of country-specific endogenous age cutoffs and corresponding aging indicators. Additionally, we provide cluster-specific estimates, a novel contribution engendered by the use of hierarchical modeling, which widens the scope of our analysis beyond the countries which are present in the sample.


[Insulin binding by erythroid cells of swines].
Insulin binding by erythroid cells of newborn and 1-, 10-, 30-days pigs was investigated. The process intensity in piglets was found to decline in the period from birth to 30 days of life. The obtained changes were determined by the reduced receptors number in high affinity site in early postnatal ontogenesis as well as by decrease of receptor affinity constants in 30-days animals. During investigated period the level of insulin binding by erythrocytes was conditioned by hormone binding ability of "young" erythroid cells, which was found to be high in newborn and decreased considerably in 10-30 days pigs. It was established that postnatal decrease of insulin binding by erythrocytes occurred simultaneously with sharp increase of insulin concentration in animal during the 10-days period after birth. So, it is supposed that insulin may be involved in regulation of its own receptor number in erythrocytes.


Spotlight on dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation.
The need for safe, effective and easily administered and monitored antithrombotic treatments that do not have the issues common to warfarin treatment has led to the development of new anticoagulant drugs. Dabigatran etexilate (Pradaxa®, Pradax™) is a prodrug of the direct thrombin inhibitor dabigatran, a direct, reversible, potent inhibitor of thrombin. Dabigatran does not interact with food, and is associated with very few known drug interactions. Dabigatran etexilate, at dosages of 110 and 150 mg twice daily, was shown to be noninferior to warfarin with regard to the incidence of stroke or systemic embolism in a large, randomized, partially blinded, multicentre study in a wide spectrum of patients with atrial fibrillation. Moreover, the higher dosage was associated with significantly greater efficacy than warfarin in this regard. These results were supported by secondary endpoints and subgroup analyses. In general, dabigatran etexilate is well tolerated, although it is associated with a higher rate of dyspepsia than warfarin. Major bleeding was as common in recipients of the higher dosage as, and less common in recipients of the lower dosage of dabigatran etexilate than, that in recipients of warfarin, and intracranial bleeding, life-threatening major bleeding and total bleeding were less common in recipients of either dabigatran etexilate dosage than in warfarin recipients. However, the higher dosage of dabigatran etexilate was associated with a higher rate of gastrointestinal bleeding than warfarin was. The incidence of hepatotoxicity did not significantly differ across treatment groups. In conclusion, dabigatran etexilate 150 mg twice daily is more effective than warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and is generally well tolerated, particularly with regard to bleeding endpoints compared with warfarin. It requires more frequent administration than warfarin, but provides multiple improvements to various issues associated with warfarin administration. Direct comparisons with other new anticoagulant drugs would be beneficial, as would further investigation into the effects in different patient populations, long-term effects, and the gastrointestinal bleeding and dyspepsia observed with dabigatran etexilate treatment. Dabigatran etexilate is a promising new option for the prevention of stroke and systemic embolism in patients with atrial fibrillation.


Multiple sclerosis and gliomas. Clinical remarks on 10 cases and critical review of the literature.
The association between multiple sclerosis and tumours of the central nervous system is unusual. The authors analyzed the clinico-pathological elements of the correlation. The pertinent literature on this subject is critically reviewed. Ten cases of patients with an history of multiple sclerosis for more than 15 years and a clinical and radiological evidence of brain tumour were submitted to surgery in order to remove the lesion and/or to chemo- and radiotherapy. The various aspects of the association were studied in detail. A patient with multiple sclerosis, particularly with atypical symptoms, should be evaluated by an annual MRI investigation with intravenous paramagnetic contrast medium. The diagnostic work-up should be: clinical and radiological assessment; MRI in the event of atypical symptoms; Sstereotactic or neuronavigation-aided biopsy in any suspected lesions. Patients with multiple sclerosis and glioma present survival times identical to those observed in patients not suffering from multiple sclerosis. The coexistence of multiple sclerosis and brain tumours does not seem to influence the clinical evolution of either of these pathologies. We believe that it is important to achieve an early diagnosis of brain tumour in such patients with a clinical and neuroradiological follow up, so that they can be treated promptly.


Delays in request for pregnancy termination: comparison of patients in the first and second trimesters.
Despite the availability of first trimester abortion services in urban settings, many women request abortion in the second trimester. We identified protective and risk factors associated with women who delay requesting abortions until the second trimester. The study was a cross-sectional survey of 247 patients requesting surgical abortion at an urban family planning clinic. Survey and medical records data were analyzed for associations between 18 risk factors and incidence of second trimester request. Thirty-two percent of subjects presented in the second trimester. Chi-square analyses revealed that first trimester participants were more often employed (p<.0001), privately insured (p=.01), or had previous abortions (p=.04). Second trimester patients were younger (p<.0001), more often primigravid (p=.04), experienced more difficulty financing the procedure (p<.0001) and finding a surgeon (p<.0001), traveled longer distances (p=.005), and more often feared the procedure (p=.03). Using multiple logistic regression, women requesting second trimester abortions were more likely to report: obstacles financing the abortion (OR 2.34, 95% CI 1.28-4.28); traveling long distances (OR 2.88, 95% CI 1.31-6.31); and fear (OR 2.45, 95% CI 1.17-5.17). These women were less often employed outside the home (OR 0.35, 95% CI 0.19-0.64). Physicians and advocates must strive to reduce abortion costs, increase access to trained surgeons, and allay women's fears of abortion procedures.


Clinical decision making with myocardial perfusion imaging in patients with known or suspected coronary artery disease.
Myocardial perfusion imaging (MPI) to diagnose coronary artery disease (CAD) is best performed in patients with intermediate pretest likelihood of disease; unfortunately, pretest likelihood is often overestimated, resulting in the inappropriate use of perfusion imaging. A good functional capacity often predicts low risk, and MPI for diagnosing CAD should be reserved for individuals with poor exercise capacity, abnormal resting electrocardiography, or an intermediate or high probability of CAD. With respect to anatomy-based testing, coronary CT angiography has a good negative predictive value, but stenosis severity correlates poorly with ischemia. Therefore decision making with respect to revascularization may be limited when a purely noninvasive anatomical test is used. Regarding perfusion imaging, the diagnostic accuracies of SPECT, PET, and cardiac magnetic resonance are similar, though fewer studies are available with cardiac magnetic resonance. PET coronary flow reserve may offer a negative predictive value sufficiently high to exclude severe CAD such that patients with mild to moderate reversible perfusion defects can forego invasive angiography. In addition, combined anatomical and perfusion-based imaging may eventually offer a definitive evaluation for diagnosing CAD, even in higher risk patients. Any remarkable findings on single-photon emission computed tomography and PET MPI studies are valuable for prognostication. Furthermore, assessment of myocardial blood flow with PET is particularly powerful for prognostication as it reflects the end result of many processes that lead to atherosclerosis. Decision making with respect to revascularization is limited for cardiac MRI and PET MPI. In contrast, retrospective radionuclide studies have identified an ischemic threshold, but randomized trials are needed. In patients with at least moderately reduced left ventricular systolic function, viable myocardium as assessed by PET or MRI, appears to identify patients who benefit from revascularization, but well-executed randomized trials are lacking.


A Simple Simulation Technique for Nonnormal Data with Prespecified Skewness, Kurtosis, and Covariance Matrix.
We present and investigate a simple way to generate nonnormal data using linear combinations of independent generator (IG) variables. The simulated data have prespecified univariate skewness and kurtosis and a given covariance matrix. In contrast to the widely used Vale-Maurelli (VM) transform, the obtained data are shown to have a non-Gaussian copula. We analytically obtain asymptotic robustness conditions for the IG distribution. We show empirically that popular test statistics in covariance analysis tend to reject true models more often under the IG transform than under the VM transform. This implies that overly optimistic evaluations of estimators and fit statistics in covariance structure analysis may be tempered by including the IG transform for nonnormal data generation. We provide an implementation of the IG transform in the R environment.


Conceptual and normative approaches to AI governance for a global digital ecosystem supportive of the UN Sustainable Development Goals (SDGs).
AI governance is like one of those mythical creatures that everyone speaks of but which no one has seen. Sometimes, it is reduced to a list of shared principles such as transparency, non-discrimination, and sustainability; at other times, it is conflated with specific mechanisms for certification of algorithmic solutions or ways to protect the privacy of personal data. We suggest a conceptual and normative approach to AI governance in the context of a global digital public goods ecosystem to enable progress on the UN Sustainable Development Goals (SDGs). Conceptually, we propose rooting this approach in the human capability concept-what people are able to do and to be, and in a layered governance framework connecting the local to the global. Normatively, we suggest the following six irreducibles: a. human rights first; b. multi-stakeholder smart regulation; c. privacy and protection of personal data; d. a holistic approach to data use captured by the 3Ms-misuse of data, missed use of data and missing data; e. global collaboration ('digital cooperation'); f. basing governance more in practice, in particular, thinking separately and together about data and algorithms. Throughout the article, we use examples from the health domain particularly in the current context of the Covid-19 pandemic. We conclude by arguing that taking a distributed but coordinated global digital commons approach to the governance of AI is the best guarantee of citizen-centered and societally beneficial use of digital technologies for the SDGs.


[The use of type A botulin toxin in the treatment of detrusor-sphincter dyssynergia].
The detrusor-sphincter dyssynergia (DSD) is a common and significant problem for patients with spinal cord lesions. If not treated, DSD can lead to severe and potentially lethal complications (urinary tract infections and renal damage). BTX inhibits acetylcholine release at the neuromuscular junction, producing muscle chemical denervation in the site of injection. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. Five patients (3 M, 2 F; mean age 43 years, range 22-56) with DSD entered the study. Videourodynamic parameters were controlled before BTX injection at 10 days, at 3 and 6 months after infiltration. The aim of this preliminary study was to test the safety and the effects of BTX injection in the spastic urethral rhabdosphincter in patients with DSD. The post void residual urine volume, the maximum pressure of emptying and the maximum pressure of urethral closure are reported in Tab. II-III-IV. Patients reported subjective improvement of bladder emptying and improved quality of life. No adverse effects related to pharmacological activity of BTX or to infiltration procedures were observed.


Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells.
The human epidermal clonal evolution, i.e. the transition from stem cells (SCs) to transient amplifying (TA)-cells and post-mitotic cells, is a continuous and tightly regulated process that ensures physiologic tissue homeostasis. The Ras family of small GTPases has a key role in skin homeostasis and tumorigenesis. Indeed, activating mutations in Ras genes have been found in human cutaneous squamous cell carcinomas (cSCCs) and in experimentally-induced murine cSCCs. In mouse models, the Ras signaling might lead to hyperproliferative phenotypes, including the development of cSCCs, depending on the nature of the founding cells. Tumor-initiating cells or Cancer Stem Cells (CSCs) have been demonstrated in murine and human cSCCs even if the mechanism of their development from normal SCs or TA-cells is not completely elucidated. Here, the relation between the Ras expression outcome and the clonogenic potential of the target keratinocyte is discussed.


KChAP as a chaperone for specific K(+) channels.
The concept of chaperones for K(+) channels is new. Recently, we discovered a novel molecular chaperone, KChAP, which increased total Kv2.1 protein and functional channels in Xenopus oocytes through a transient interaction with the Kv2.1 amino terminus. Here we report that KChAP is a chaperone for Kv1.3 and Kv4.3. KChAP increased the amplitude of Kv1.3 and Kv4.3 currents without affecting kinetics or voltage dependence, but had no such effect on Kv1.1, 1.2, 1.4, 1.5, 1.6, and 3.1 or Kir2.2, HERG, or KvLQT1. Although KChAP belongs to a family of proteins that interact with transcription factors, upregulation of channel currents was not blocked by the transcription inhibitor actinomycin D. A 98-amino acid fragment of KChAP binds to the channel and is indistinguishable from KChAP in its enhancement of Kv4.3 current and protein levels. Using a KChAP antibody, we have coimmunoprecipitated KChAP with Kv2.1 and Kv4.3 from heart. We propose that KChAP is a chaperone for specific Kv channels and may have this function in cardiomyocytes where Kv4.3 produces the transient outward current, I(to).


Ethical review of global short-term medical volunteerism.
Global short-term medical volunteerism is growing, and properly conducted, is a tool in the fight for greater global health equity. It is intrinsically "ethical" (i.e., it involves ethics at every step) and depends upon ethical conduct for its success. At present, ethical guidelines remain in their infancy, which presents a unique opportunity. This paper presents a set of basic ethical principles, building on prior work in this area and previously developed guidelines for international clinical research. The content of these principles, and the benchmarks used to evaluate them, remain intentionally vague and can only be filled by collaboration with those on-the-ground in local communities where this work occurs. Ethical review must additionally take into consideration the different obligations arising from the type of institution, type of intervention, and type of relationship involved. This paper argues that frequent and formalized ethical review, conducted from the beginning with the local community (where this community helps define the terms of debate), remains the most important ethical safeguard for this work.


Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using 64Cu-plerixafor PET.
Expression of the chemokine receptor CXCR4 by many cancers correlates with aggressive clinical behavior. As part of the initial studies in a project whose goal was to quantify CXCR4 expression on cancers non-invasively, we examined CXCR4 expression in cancer samples by immunohistochemistry using a validated anti-CXCR4 antibody. Among solid tumors, we found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. Microarrays of ACC metastases revealed correlations between expression of CXCR4 and other chemokine system genes, particularly CXCR7/ACKR3, which encodes an atypical chemokine receptor that shares a ligand, CXCL12, with CXCR4. A first-in-human study using 64Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient. Further studies are needed to understand better the role of CXCR4 in ACC and whether targeting it may be beneficial. In this regard, non-invasive methods for assessing CXCR4 expression, such as PET using 64Cu-plerixafor, should be important investigative tools.


Reliability, Usefulness, and Factorial Validity of Change-of-direction Speed Tests in Adolescent Basketball Players.
Stojanović, E, Aksović, N, Stojiljković, N, Stanković, R, Scanlan, AT, and Milanović, Z. Reliability, usefulness, and factorial validity of change-of-direction speed tests in adolescent basketball players. J Strength Cond Res 33(11): 3162-3173, 2019-The purposes of this study were to (1) determine the reliability, usefulness, and factorial validity of change-of-direction speed (CODS) tests in adolescent basketball players and (2) evaluate positional differences in test performances. Elite, adolescent male basketball players (n = 53; 17.3 ± 1.0 years) completed 6 CODS tests: "Lane Arrow Closeout," "Lane Agility Drill," "Reactive Shuttle Test," "Run-Shuffle-Run," "Compass Drill," and "Modified 505 Test." Players completed 3 trials of each test. All tests demonstrated acceptable reliability (intraclass correlation coefficient: 0.50-0.88; coefficient of variation: 5.1-7.9%). The typical error (TE) calculated for each test was above the smallest worthwhile change, rating the usefulness of all tests as marginal. The principal component factor analysis in all tests resulted in the extraction of one significant component that explained 74% of the total variance across tests. Positional comparisons showed that backcourt (guards) players performed better (small to moderate differences) in all CODS tests compared with frontcourt (forwards and centers) players. All tests were deemed reliable and valid in adolescent basketball players. The "Lane Agility Drill" and "Run-Shuffle-Run" tests seem the most appropriate to quantify changes in CODS possessing the lowest TE, whereas the "Lane Arrow Closeout" and "Lane Agility Drill" tests are the most sensitive in detecting positional differences.


Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians.
Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 μmol/L while each MTHFR 677T-allele contributed to 4.63 μmol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc.


Eupatilin inhibits xanthine oxidase in vitro and attenuates hyperuricemia and renal injury in vivo.
Uric acid (UA) is the final metabolite of purines in the liver that can cause hyperuricemia at high levels. The kidneys are the main excretory organs for UA. The excessive accumulation of UA in the kidneys causes the development of hyperuricemia that often leads to renal injury. Eupatilin (Eup) is a flavonoid natural product that possesses various pharmacological properties such as antioxidant, anti-cancer, and anti-inflammatory. We were interested in exploring the potential role of Eup in lowering UA and nephroprotective. We initially investigated the effects of Eup on xanthin oxidase (XOD) activity in vitro, followed by investigating its ability to lower UA levels, anti-inflammatory effects, nephroprotective effects, and the underlying mechanisms using hyperuricemia rats sustained at high UA level. The results showed that Eup had an inhibitory effect on XOD activity in vitro and significantly reduced serum UA, creatinine, BUN, IL-1β and IL-6 levels in hyperuricemic rats, ameliorating inflammation, renal oxidative stress and pathological injury. Furthermore, Eup inhibited ADA and XOD enzyme activities in the liver and serum and modulated GLUT9, URAT1 and ABCG2 protein expression in the kidneys and ileum. Our findings provide a scientific basis for suggesting Eup as an option for a potential treatment for hyperuricemia.


Cutting edge: the IgG response to the circumsporozoite protein is MHC class II-dependent and CD1d-independent: exploring the role of GPIs in NK T cell activation and antimalarial responses.
Biochemical analysis has suggested that self GPI anchors are the main natural ligand associated with mouse CD1d molecules. A recent study reported that Valpha14+ NK T cells responded to self as well as foreign (parasite-derived) GPIs in a CD1d-dependent manner. It further reported that the IgG response to the Plasmodium berghei malarial circumsporozoite (CS) protein was severely impaired in CD1d-deficient mice, leading to a model whereby NK T cells, upon recognition of CD1d molecules presenting the CS-derived GPI anchor, provide help for B cells secreting anti-CS Abs. We tested this model by comparing the anti-CS Ab responses of wild-type, CD1d-deficient, and MHC class II-deficient mice. We found that the IgG response to the CS protein was solely MHC class II-dependent. Furthermore, by measuring the response of a broad panel of CD1d-autoreactive T cells to GPI-deficient CD1d-expressing cells, we found that GPIs were not required for autoreactive responses.


Exercise training induces alteration of clock genes and myokines expression in tumor-bearing mice.
To investigate the impact of different exercise training schedules (following a fixed schedule or at random times of the day) on clock genes and myokine expression patterns in the skeletal muscle of tumor-bearing mice. Mice were divided into three groups: tumor (LLC), tumor + exercise training (LLC + T) always performed at the same time of the day (ZT2) and exercise training at random times of the day (ZTAlt). Mice were inoculated subcutaneously with Lewis lung carcinoma cells. The gastrocnemius muscle was dissected and the clock gene expression (Clock/Per1/Per2/Per3/Rev-Erbα/GAPDH) was investigated by quantitative reverse transcription polymerase chain reaction with SYBR® Green. Myokine content in muscle (tumour necrosis factor alpha/IL-10/IL-4) was assessed by enzyme-linked immunosorbent assay. At the end of the protocol, the trained groups showed a reduction in total weight, when compared to Lewis lung carcinoma. Tumor weight was lower in the LLC + T (ZTAlt), when compared to LLC. Clock gene mRNA expression showed a significant increase for ZT20 in the groups that performed physical exercise at LLC + T (ZTAlt), when compared with LLC. The Per family showed increased mRNA expression in ZT4 in both trained mice groups, when compared with LLC. LLC + T (ZTAlt) presented reduction of the expression of anti-inflammatory myokines (Il-10/IL-4) during the night, compared with LLC + T(ZT2). Exercise training is able to induce marked modification of clock gene expression and of the production of myokines, in a way that is dependent on schedule exercise training strategy. Taken together, the results show that exercise is a potent Zeitgeber and may thus contribute to change clock genes expression and myokines that are able to reduce the tumor weight.


Current practice in out-of-hospital cardiac arrest management: a European heart rhythm association EP network survey.
The purpose of this EP wire is to examine clinical practice in the field of out-of-hospital cardiac arrest (OHCA) management, with special focus on in-hospital diagnostic and therapeutic strategies. Fifty-three European centres, all members of the EHRA-EP Research network, completed the questions of the survey. A dedicated strategy for OHCA management is active in 85% of the centres. Shockable tachyarrhythmias such as initial OHCA rhythm are reported in >70% of the patients in 64% of the centres. In-hospital therapeutic hypothermia was applied in >50% of the patients in 53% of the centres and in <50% in 47% of the centres. In the year 2011 90% of the centres performed >10 primary percutaneous coronary angioplasties (PCI) in OHCA patients. The survival rate, when the initial documented rhythm was shockable, was >30% in 42% of the centres, and conversely, was significantly lower when asystole or pulseless electrical activity was the initial rhythm. A favourable neurological recovery was reported in >50% of the patients in 13 (26%) centres and in 21-50% of the patients in 21 (44%). This EP wire survey demonstrates a favourable implementation in OHCA of an invasive management strategy, including coronary angiography/PCI and implantable cardioverter defibrillator therapy, while therapeutic hypothermia appears to be underused.


"Future Patient" Telerehabilitation for Patients With Heart Failure: Protocol for a Randomized Controlled Trial.
Cardiovascular disease is the leading cause of mortality worldwide, accounting for 13%-15% of all deaths. Cardiac rehabilitation has poor compliance and adherence. Telerehabilitation has been introduced to increase patients' participation, access, and adherence with the help of digital technologies. The target group is patients with heart failure. A telerehabilitation program called "Future Patient" has been developed and consists of three phases: (1) titration of medicine (0-3 months), (2) implementation of the telerehabilitation protocols (3 months), and (3) follow-up with rehabilitation in everyday life (6 months). Patients in the Future Patient program measure their blood pressure, pulse, weight, number of steps taken, sleep, and respiration and answer questions online regarding their well-being. All data are transmitted and accessed in the HeartPortal by patients and health care professionals. The aim of this paper is to describe the research design, outcome measures, and data collection techniques in the clinical test of the Future Patient Telerehabilitation Program for patients with heart failure. A randomized controlled study will be performed. The intervention group will follow the Future Patient Telerehabilitation program, and the control group will follow the traditional cardiac rehabilitation program. The primary outcome is quality of life measured by the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes are development of clinical data; illness perception; motivation; anxiety and depression; health and electronic health literacy; qualitative exploration of patients', spouses', and health care professionals' experiences of participating in the telerehabilitation program; and a health economy evaluation of the program. Outcomes were assessed using questionnaires and through the data generated by digital technologies. Data collection began in December 2016 and will be completed in October 2019. The study results will be published in peer-reviewed journals and presented at international conferences. Results from the Future Patient Telerehabilitation program are expected to be published by the spring of 2020. The expected outcomes are increased quality of life, increased motivation and illness perception, reduced anxiety and depressions, improved electronic health literacy, and health economics benefits. We expect the study to have a clinical impact for future telerehabilitation of patients with heart failure. ClinicalTrials.gov NCT03388918; https://clinicaltrials.gov/ct2/show/NCT03388918. DERR1-10.2196/14517.


Diagnostic usefulness of a lumi-aggregometer adenosine triphosphate release assay for the assessment of platelet function disorders.
Platelet dense granule release assays are recommended for diagnosing platelet function disorders and are commonly performed by Lumi-Aggregometer (Chrono-Log, Havertown, PA) assays of adenosine triphosphate (ATP) release. We conducted a prospective cohort study of people tested for ATP release defects to assess bleeding symptoms. Reduced release, with 1 or more agonists, was more common among patients with bleeding disorders than among healthy control subjects (P < .001). The respective likelihood (odds ratio [95% confidence interval]) of a bleeding disorder or an inherited platelet function disorder were high when release was reduced with 1 or more agonists (17 [6-46]; 128 [30-545]), even if aggregation was normal (12 [4-34]; 105 [20-565]). ATP release had high specificity and moderate sensitivity for inherited platelet function disorders, with most abnormalities detected by the combination of 6 μmol/L epinephrine, 5.0 μg/mL collagen, and 1 μmol/L U46619. Platelet ATP release assays are useful for evaluating common bleeding disorders, regardless of aggregation findings.


Reducing Ambiguities in Line-based Density Plots by Image-space Colorization.
Line-based density plots are used to reduce visual clutter in line charts with a multitude of individual lines. However, these traditional density plots are often perceived ambiguously, which obstructs the user's identification of underlying trends in complex datasets. Thus, we propose a novel image space coloring method for line-based density plots that enhances their interpretability. Our method employs color not only to visually communicate data density but also to highlight similar regions in the plot, allowing users to identify and distinguish trends easily. We achieve this by performing hierarchical clustering based on the lines passing through each region and mapping the identified clusters to the hue circle using circular MDS. Additionally, we propose a heuristic approach to assign each line to the most probable cluster, enabling users to analyze density and individual lines. We motivate our method by conducting a small-scale user study, demonstrating the effectiveness of our method using synthetic and real-world datasets, and providing an interactive online tool for generating colored line-based density plots.


Epilepsia partialis continua as the presenting symptom in probable sporadic Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease (CJD) is a rare form of rapidly progressive neurodegenerative disorder. Literature survey reveals only four reported cases of CJD with epilepsia partialis continua. Here, we present a review and a case study, with video-EEG sequences and characteristic MRI findings, of a fifth patient who presented with epilepsia partialis continua in the very early stage of the disease and followed a fatal course which was faster than expected. [Published with video sequences].


Dental status of 12-year-olds treated in private practice and a school dental service.
Different ways of service provision frequently lead to different services being provided. In the School Dental Service (SDS) in Western Australia, all 5-15-yr-olds are eligible for care free of charge and most avail themselves of the service. The parents of some children choose to use private dentists (typically copaying about 50% of the cost) and their children do not attend the SDS. This study aimed to compare the dental status of 12-yr-olds who attended private dentists with that of matched children enrolled in the SDS. Non-enrolled 12-yr-olds in Perth (F- 0.8 mg/l) were identified and asked to provide background information and participate in clinical examinations. Each non-enrolled participant was matched with a classmate of the same sex. Of 184 non-enrolled children, 100 actually participated. Data on caries experience (DMFT and DMFS), fissure sealants and gingival health (CPITN) were collected by clinical examination. Analyses used Wilcoxon's signed rank, categorical and t-tests and simple linear regression. Caries prevalence was lower in non-enrolled children (0.31) than in enrolled (0.47). Caries experience was also lower in non-enrolled children (mean DMFT 0.71 vs. 0.95, ns). Enrolled children had more FT than non-enrolled (Wilcoxon, P = 0.059) but the mean number of DT in each group was 0.14. Enrolled children had somewhat fewer fissure sealants than non-enrolled children but in enrolled children there was an apparent (P = 0.056) inverse relationship between number of fissure sealants and DMFT scores; this was not the case in the non-enrolled group, suggesting better targeting of fissure sealants in the SDS.(ABSTRACT TRUNCATED AT 250 WORDS)


Relative permeability experiments of carbon dioxide displacing brine and their implications for carbon sequestration.
To mitigate anthropogenically induced climate change and ocean acidification, net carbon dioxide emissions to the atmosphere must be reduced. One proposed option is underground CO2 disposal. Large-scale injection of CO2 into the Earth's crust requires an understanding of the multiphase flow properties of high-pressure CO2 displacing brine. We present laboratory-scale core flooding experiments designed to measure CO2 endpoint relative permeability for CO2 displacing brine at in situ pressures, salinities, and temperatures. Endpoint drainage CO2 relative permeabilities for liquid and supercritical CO2 were found to be clustered around 0.4 for both the synthetic and natural media studied. These values indicate that relative to CO2, water may not be strongly wetting the solid surface. Based on these results, CO2 injectivity will be reduced and pressure-limited reservoirs will have reduced disposal capacity, though area-limited reservoirs may have increased capacity. Future reservoir-scale modeling efforts should incorporate sensitivity to relative permeability. Assuming applicability of the experimental results to other lithologies and that the majority of reservoirs are pressure limited, geologic carbon sequestration would require approximately twice the number of wells for the same injectivity.


Collagenous colitis with spondyloarthropathy presenting as fibromyalgia syndrome.
Collagenous colitis is a newly recognized clinicopathologic entity that presents with diarrhea and weight loss. In some patients arthropathy may be a concomitant feature. We describe a patient whose initial presentation masqueraded as fibromyalgia with associated bowel symptoms, but who was finally diagnosed as having collagenous colitis and inflammatory spondyloarthropathy.


Perceptual quality prediction on authentically distorted images using a bag of features approach.
Current top-performing blind perceptual image quality prediction models are generally trained on legacy databases of human quality opinion scores on synthetically distorted images. Therefore, they learn image features that effectively predict human visual quality judgments of inauthentic and usually isolated (single) distortions. However, real-world images usually contain complex composite mixtures of multiple distortions. We study the perceptually relevant natural scene statistics of such authentically distorted images in different color spaces and transform domains. We propose a "bag of feature maps" approach that avoids assumptions about the type of distortion(s) contained in an image and instead focuses on capturing consistencies-or departures therefrom-of the statistics of real-world images. Using a large database of authentically distorted images, human opinions of them, and bags of features computed on them, we train a regressor to conduct image quality prediction. We demonstrate the competence of the features toward improving automatic perceptual quality prediction by testing a learned algorithm using them on a benchmark legacy database as well as on a newly introduced distortion-realistic resource called the LIVE In the Wild Image Quality Challenge Database. We extensively evaluate the perceptual quality prediction model and algorithm and show that it is able to achieve good-quality prediction power that is better than other leading models.


Infection rates of pentastomids on lizards in urban habitats in the Brazilian northeast.
The rates of pentastomid infections in the syntopic lizards Hemidactylus mabouia and Tropidurus hispidus inhabiting buildings at the Federal University of Paraiba, in João Pessoa, NE Brazil were examined. A total of 30 specimens of Hemidactylus mabouia and 55 specimens of Tropidurus hispidus were examined. The animals were sacrificed by freezing and then fixed and conserved in 70% alcohol. Analyses of the respiratory tract of Hemidactylus mabouia demonstrated that these lizards were infected by Raillietiella frenatus at a rate of 20% (6/30) with an average infection intensity of 1.33 +/- 0.21, 1-2. None of the specimens of T. hispidus analyzed were infected. Hemidactylus mabouia and R. frenatus are of African origin and it is possible that there are specific relationships, or preferences, between these two species.


Cofilin Activation Is Temporally Associated with the Cessation of Growth in the Developing Hippocampus.
Dendritic extension and synaptogenesis proceed at high rates in rat hippocampus during early postnatal life but markedly slow during the third week of development. The reasons for the latter, fundamental event are poorly understood. Here, we report that levels of phosphorylated (inactive) cofilin, an actin depolymerizing factor, decrease by 90% from postnatal days (pnds) 10 to 21. During the same period, levels of total and phosphorylated Arp2, which nucleates actin branches, increase. A search for elements that could explain the switch from inactive to active cofilin identified reductions in β1 integrin, TrkB, and LIM domain kinase 2b, upstream proteins that promote cofilin phosphorylation. Moreover, levels of slingshot 3, which dephosphorylates cofilin, increase during the period in which growth slows. Consistent with the cofilin results, in situ phalloidin labeling of F-actin demonstrated that spines and dendrites contained high levels of dynamic actin filaments during Week 2, but these fell dramatically by pnd 21. The results suggest that the change from inactive to constitutively active cofilin leads to a loss of dynamic actin filaments needed for process extension and thus the termination of spine formation and synaptogenesis. The relevance of these events to the emergence of memory-related synaptic plasticity is described.


Rationing human life: health care reform and people with disabilities.
Peter Singer has proposed health care rationing that includes an invidious discrimination against people with disabilities. Unfortunately, Congress has codified the potential for such discrimination in the 2010 Patient Protection and Affordable Care Act. But why should any public official have the discretion to treat the lives of people with disabilities as of "lower value" than the lives of anyone else. There must be a comprehensive limitation in the law against the misuse of comparative clinical effectiveness research to support the rationing of human life.


Echocardiographic Measurements in a Preclinical Model of Chronic Chagasic Cardiomyopathy in Dogs: Validation and Reproducibility.
Background: The failure to translate preclinical results to the clinical setting is the rule, not the exception. One reason that is frequently overlooked is whether the animal model reproduces distinctive features of human disease. Another is the reproducibility of the method used to measure treatment effects in preclinical studies. Left ventricular (LV) function improvement is the most common endpoint in preclinical cardiovascular disease studies, while echocardiography is the most frequently used method to evaluate LV function. In this work, we conducted a robust echocardiographic evaluation of LV size and function in dogs chronically infected by Trypanosoma cruzi. Methods and Results: Echocardiography was performed blindly by two distinct observers in mongrel dogs before and between 6 and 9 months post infection. Parameters analyzed included end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and fractional shortening (FS). We observed a significant LVEF and FS reduction in infected animals compared to controls, with no significant variation in volumes. However, the effect of chronic infection in systolic function was quite variable, with EF ranging from 17 to 66%. Using the cut-off value of EF ≤ 40%, established for dilated cardiomyopathy (DCM) in dogs, only 28% of the infected dogs were affected by the chronic infection. Conclusions: The canine model of CCC mimics human disease, reproducing the percentage of individuals that develop heart failure during the chronic infection. It is thus mandatory to establish inclusion criteria in the experimental design of canine preclinical studies to account for the variable effect that chronic infection has on systolic function.


Alkaptonuria: a very rare metabolic disorder.
Alkaptonuria (AKU) is a very rare autosomal recessive disorder of tyrosine metabolism in the liver due to deficiency of homogentisate 1,2 dioxygenase (HGD) activity, resulting in the accumulation of homogentisic acid (HGA). Circulating HGA pass into various tissues through-out the body, mainly in cartilage and connective tissues, where its oxidation products polymerize and deposit as a melanin-like pigment. Gram quantities of HGA are excreted in the urine. AKU is a progressive disease and the three main features, according the chronology of appearance, are: darkening of the urine at birth, then ochronosis (blue-dark pigmentation of the connective tissue) clinically visible at around 30 yrs in the ear and eye, and finally a severe ochronotic arthropathy at around 50 yrs with spine and large joints involvements. Cardiovascular and renal complications have been described in numerous case report studies. A treatment now is available in the form of a drug nitisinone, which decreases the production of HGA. The enzymatic defect in AKU is caused by the homozygous or compound heterozygous mutations within the HGD gene. This disease has a very low prevalence (1:100,000-250,000) in most of the ethnic groups, except Slovakia and Dominican Republic, where the incidence has shown increase up to 1:19,000. This review highlights classical and recent findings on this very rare disease.


Presentation delay in breast cancer patients, identifying the barriers in North Pakistan.
There is strong evidence that delayed diagnosis of breast cancer is associated with poor survival. Our objectives were to determine the frequency of breast cancer patients with delayed presentation, the reasons of delay and its association with different socio-demographic variables in our North Pakistan setting. We interviewed 315 histologically confirmed breast cancer patients. Delay was defined as more than 3 months from appearance of symptoms to consultation with a doctor. Questions were asked from each patient which could reflect their understanding about the disease and which could be the likely reasons for their delayed presentation. 39.0 % (n=123) of patients presented late and out of those, 40.7% wasted time using alternative medicines; 25.2 % did not having enough resources; 17.1 % presented late due to painless lump; 10.6% felt shyness and 6.5% presented late due to other reasons. Higher age, negative family history, < 8 school years of education and low to middle socio-economic status were significantly associated with delayed presentation (p< 0.05). Education and socioeconomic status were two independent variables related to the delayed presentation after adjustment for others (OR of 2.26, 2.29 and 95%CI was 1.25-4.10, 1.06-4.94 respectively). Significant numbers of women with breast cancer in North Pakistan experience presentation delay due to their misconceptions about the disease. Coordinated efforts with public health departments are needed to educate the focused groups and removing the barriers identified in the study. Long term impact will be reduced overall burden of the disease in the region.


Importance of Trauma-Informed Practice in Evaluation of Children Diagnosed with Autism Spectrum Disorder.
As part of a multidisciplinary adoption support clinic, Erin, a 5-year-old girl, adopted approximately 6 months before the clinic visit, presents for postadoption evaluation. Erin was born at full term. Her birth history was significant for reported maternal treatment for liver failure during pregnancy. Her previous medical history included hospitalization for a viral illness at age 2 months, recurrent ear infections, and a fractured forearm. Family history was significant for a maternal history of bipolar disorder, depression, anxiety, borderline personality disorder, and concern for substance abuse; a paternal history of attention-deficit/hyperactivity disorder (ADHD) and depression; and full biological brother with a history of ADHD and oppositional defiant disorder. Erin and her brother lived with their parents until she was approximately 3 years old. At that time, there were concerns for poor hygiene, inconsistent medical care, poor school attendance for her brother, financial instability, and significant neglect. Erin was reportedly confined to her crib for hours at a time. She and her older brother were removed from the home because of concerns for significant neglect and placed into foster care. Approximately 3 months after foster placement, Erin underwent testing because of concerns for abnormal behaviors and possible developmental delays. Symptoms included poor sleep, repetitive behaviors such as head banging, delayed speech that primarily involved grunting, and lack of toilet training. She was hyperactive and aggressive and had poor caregiver attachment. On evaluation, she was small for age, poorly groomed, and easily distracted with poor eye contact and did not tolerate interactions with examiners. Neuropsychological testing consisted of symptom checklists and caregiver interview only because she did not tolerate diagnostic testing. She was diagnosed with autism spectrum disorder and global developmental delay with intellectual and language impairments. Over the following year, Erin was transitioned to a second foster family and was subsequently adopted. She received speech, occupational, and physical therapy, along with trauma-informed therapy. She made significant gains in multiple domains and was able to graduate from trauma-informed therapy after 1 year. On examination, Erin greets you with appropriate eye contact and reports that she is feeling "good." She is verbal and interactive with her brother and parents. She looks to parents for support when asked to participate in the physical examination. She does not display any significant repetitive behaviors. Erin's parents are concerned that her initial diagnoses of autism spectrum disorder and global developmental delay do not accurately reflect her current level of functioning and are afraid she may have been misdiagnosed. How would you proceed with next steps to address these diagnoses?


NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol.
Macrophages induce the innate immunity by recognizing pathogens through Toll-like receptors (TLRs), which sense pathogen-associated molecular patterns. Myeloid differentiation factor 88 (MyD88), which is an essential adaptor molecule for most TLRs, mediates the induction of inflammatory cytokines through nuclear factor κB (NF-κB). Trichothecene mycotoxin deoxynivalenol (DON) shows immunotoxic effects by interrupting inflammatory mediators produced by activated macrophages. The present study investigates the effect of DON on NF-κB in activated macrophages through MyD88-dependent pathways. DON inhibited NF-κB-dependent reporter activity induced by MyD88-dependent TLR agonists. In addition, lipopolysaccharide-induced phosphorylation of interleukin-1 receptor-associated kinase 1 and inhibitor κBα were attenuated by DON. Furthermore, DON downregulated the expression level of MyD88. These results suggest that DON inhibits NF-κB activation in macrophages stimulated with TLR ligands via MyD88-dependent TLR signals. Therefore exposure to DON may lead to the inhibition of MyD88-dependent pathway of TLR signaling.


Explaining variation in the premorbid adjustment of schizophrenia patients: the role of season of birth and family history.
Several studies have shown that patients with schizophrenia are more likely to be born in the winter and early spring than at any other time of the year. Furthermore, some studies have reported that winter-born patients differ from non-winter-born patients in terms of risk factors, symptoms, sensory abnormalities and brain morphology. Associations between season of birth and premorbid adjustment (PMA), however, are still unclear. The main purpose of this study was to determine whether winter-born and non-winter-born schizophrenia patients differ in terms of PMA and to examine how family history of schizophrenia-spectrum disorders may influence the association. Data on four PMA dimensions (attention, internalizing, externalizing and social problems) and family history were gathered from 37 schizophrenia patients (26 males and 11 females) and their mothers. Non-winter-birth and a positive family history of schizophrenia-spectrum disorders were associated with worse PMA. Results suggest that, although no significant interaction was found, season of birth and family history appear to work together in explaining distinct dimensions of PMA.


Spectroscopy of Solids in the Far-Infrared: Studies of superconductors, magnetic materials, and ferroelectrics in this spectral region are rewarding.
The far-infrared spectral region (10-100 cm(-1)) is a fruitful one for studies of solids. The experimental obstacle of weak sources has been partially overcome in recent years by the introduction of very sensitive bolometric radiation detectors cooled by liquid helium to temperatures near 1 degrees K. Used with a mercury arc source and a simple grating monochromator, these detectors have made work in a number of areas of solid-state physics possible. Important examples of such work are, (i) demonstration of the energy gap in superconductors and measurement of gap widths in various metals; (ii) observation of magnetic resonances in ordered magnetic materials, from which precise information about exchange fields and anisotropy energies can be obtained; and (iii) demonstration of the existence of a temperature-dependent low-frequency vibrational mode associated with the Curie-law dielectric constant in certain types of ferroelectric crystals.


MicroRNAs associated with mitogen-activated protein kinase in human pancreatic cancer.
Aberrant expression of microRNAs (miRNA) is associated with phenotypes of various cancers, including pancreatic cancer. However, the mechanism of the aberrant expression is largely unknown. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in gene expression related to the malignant phenotype of pancreatic cancer. Hence, we studied the role of MAPK in the aberrant expression of miRNAs in pancreatic cancer cells. The alterations in expression of 183 miRNAs induced by activation or inactivation of MAPK were assayed in cultured pancreatic cancer cells and HEK293 cells by means of the quantitative real-time PCR method. We found that four miRNAs, namely, miR-7-3, miR-34a, miR-181d, and miR-193b, were preferentially associated with MAPK activity. Among these miRNAs, miR-7-3 was upregulated by active MAPK, whereas the others were downregulated. Promoter assays indicated that the promoter activities of the host genes of miR-7-3 and miR-34a were both downregulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured pancreatic cancer cells; miR-193b was found to exhibit the most remarkable inhibition. A search for target genes of miR-193b led to identification of CCND1, NT5E, PLAU, STARD7, STMN1, and YWHAZ as the targets. Translational suppression of these genes by miR-193b was confirmed by reporter assay. These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer.


Concomitant analysis of arterial, venous, and CSF flows using phase-contrast MRI: a quantitative comparison between MS patients and healthy controls.
Venous dysfunction has recently been hypothesized to contribute to the pathophysiology of multiple sclerosis (MS). 2D phase-contrast (PC) magnetic resonance imaging (MRI) is a non-invasive and innocuous technique enabling reliable quantification of cerebrospinal fluid (CSF) and blood flows in the same imaging session. We compared PC-MRI measurements of CSF, arterial and venous flows in MS patients to those from a normative cohort of healthy controls (HC). Nineteen MS patients underwent a standardized MR protocol for cerebral examination on a 3T system including Fast cine PC-MRI sequences with peripheral gating in four acquisition planes. Quantitative data were processed using a homemade software to extract CSF and blood flow regions of interest, animate flows, and calculate cervical and intracranial vascular flow curves during the cardiac cycle (CC). Results were compared with values obtained in 21 HC using multivariate analysis. Venous flow patterns were comparable in both groups without signs of reflux. Arterial flows (P=0.02) and cervical CSF dynamic oscillations (P=0.01) were decreased in MS patients. No significant differences in venous cerebral and cervical outflows were observed between groups, thereby contradicting the recently proposed theory of venous insufficiency. Unexpected decrease in arterial perfusion in MS patients warrants further correlation to volumetric measurements of the brain.


Evolution of the herpes thymidine kinase: identification and comparison of the equine herpesvirus 1 thymidine kinase gene reveals similarity to a cell-encoded thymidylate kinase.
We have identified the equine herpesvirus 1 (EHV-1) thymidine kinase gene (TK) by DNA-mediated transformation and by DNA sequencing. Alignment of the amino acid sequence of the EHV-1 TK with the TKs from 3 other herpesviruses revealed regions of homology, some of which correspond to the previously identified substrate binding sites, while others have as yet, no assigned function. In particular, the strict conservation of an aspartate within the proposed nucleoside binding site suggests a role in ATP binding for this residue. Comparison of 5 herpes TKs with the thymidylate kinase of yeast revealed significant similarity which was strongest in those regions important to catalytic activity of the herpes TKs, and, therefore we propose that the herpes TK may be derived from a cellular thymidylate kinase. The implications for the evolution of enzyme activities within a pathway of nucleotide metabolism are discussed.