Perception of Child-Directed Versus Adult-Directed Emotional Speech in Pediatric Cochlear Implant Users.
Cochlear implants (CIs) are remarkable in allowing individuals with severe to profound hearing loss to perceive speech. Despite these gains in speech understanding, however, CI users often struggle to perceive elements such as vocal emotion and prosody, as CIs are unable to transmit the spectro-temporal detail needed to decode affective cues. This issue becomes particularly important for children with CIs, but little is known about their emotional development. In a previous study, pediatric CI users showed deficits in voice emotion recognition with child-directed stimuli featuring exaggerated prosody. However, the large intersubject variability and differential developmental trajectory known in this population incited us to question the extent to which exaggerated prosody would facilitate performance in this task. Thus, the authors revisited the question with both adult-directed and child-directed stimuli. Vocal emotion recognition was measured using both child-directed (CDS) and adult-directed (ADS) speech conditions. Pediatric CI users, aged 7-19 years old, with no cognitive or visual impairments and who communicated through oral communication with English as the primary language participated in the experiment (n = 27). Stimuli comprised 12 sentences selected from the HINT database. The sentences were spoken by male and female talkers in a CDS or ADS manner, in each of the five target emotions (happy, sad, neutral, scared, and angry). The chosen sentences were semantically emotion-neutral. Percent correct emotion recognition scores were analyzed for each participant in each condition (CDS vs. ADS). Children also completed cognitive tests of nonverbal IQ and receptive vocabulary, while parents completed questionnaires of CI and hearing history. It was predicted that the reduced prosodic variations found in the ADS condition would result in lower vocal emotion recognition scores compared with the CDS condition. Moreover, it was hypothesized that cognitive factors, perceptual sensitivity to complex pitch changes, and elements of each child's hearing history may serve as predictors of performance on vocal emotion recognition. Consistent with our hypothesis, pediatric CI users scored higher on CDS compared with ADS speech stimuli, suggesting that speaking with an exaggerated prosody-akin to "motherese"-may be a viable way to convey emotional content. Significant talker effects were also observed in that higher scores were found for the female talker for both conditions. Multiple regression analysis showed that nonverbal IQ was a significant predictor of CDS emotion recognition scores while Years using CI was a significant predictor of ADS scores. Confusion matrix analyses revealed a dependence of results on specific emotions; for the CDS condition's female talker, participants had high sensitivity (d' scores) to happy and low sensitivity to the neutral sentences while for the ADS condition, low sensitivity was found for the scared sentences. In general, participants had higher vocal emotion recognition to the CDS condition which also had more variability in pitch and intensity and thus more exaggerated prosody, in comparison to the ADS condition. Results suggest that pediatric CI users struggle with vocal emotion perception in general, particularly to adult-directed speech. The authors believe these results have broad implications for understanding how CI users perceive emotions both from an auditory communication standpoint and a socio-developmental perspective.


[Comparative pharmacokinetics of moxalactam and other cephalosporins].
A comparative study of the pharmacokinetics of eleven cephalosporins, given in rapid intravenous injections and studied under identical conditions (sampling regimens, assays by high performance liquid chromatography, statistical analyses), is reported. The very low diffusibility of cephalosporins throughout the body typifies this family of antibiotics. Apparent volumes of distribution vary little from the mean volume which is 0.30 liter per kg body weight. Conversely, apparent elimination half-lifes show significant differences, with values ranging from 0.52 h (cephalotin) and 0.75 h (cefotaxim) to 2.74 h (Moxalactam) and 3.07 h (cefazolin). The consequences of the pharmacokinetic differences between cefotaxim and Moxalactam are exemplified by the comparison of dosage regimens capable of generating and maintaining equivalent concentrations in the various body fluids. Table I shows the main parameters which typify the pharmacokinetic patterns of eleven cephalosporins given intravenously (in young, healthy, adults). The relative values of renal clearance and total clearance demonstrate the part played by extrarenal elimination: metabolization for cephalotin, cefapirin and cefotaxim, and biliary excretion which may be inconsiderable, as is usually the case, or predominant for cefoperazone. Compartmental analysis of plasmatic data provides unequivocal confirmation of open pharmacokinetic models with three compartments whose equations, of the type O plasmatic = Ae-gamma t + Be-gamma t + Ce-gamma t, are shown in Table III.


Hantaviruses: a tale of two hemispheres.
Infectious febrile nephropathies, initially described as epidemics during military campaigns in Europe and Asia at the turn of the 20(th) century, were eventually all unified under the rubric of hemorrhagic fever with renal syndrome (HFRS) and ascribed to infection from rodent-borne hantaviruses. At the end of the century, hantavirus pulmonary syndrome (HPS) was described throughout the Americas as a consequence of infection with the New World hantaviruses. The epidemiology and clinical manifestations of these diseases are linked to the ecology of their associated rodent hosts. Murine rodents (Old World mice and rats) are associated with the severe forms of HFRS in Asia and the Balkans due to Hantaan, Dobrava, and Seoul viruses. Hantaan virus causes an estimated 50-100,000 infections a year in China alone. Arvicoline rodents (voles) are associated with a mild form of HFRS in Europe called nephropathia epidemica due to Puumala virus. Sigmodontine rodents (New World rats and mice) are associated with approximately 200 HPS cases per year throughout the Americas caused by over a dozen viruses. The viruses are mainly transmitted as small-particle aerosols of rodent excreta, and the subsequent infections share cardiovascular shock as a prominent feature, although HFRS causes predominantly renal disease, while HPS causes a predominantly non-cardiogenic pulmonary edema - hemorrhage involvement varies in the syndromes on the basis of virus subtypes. Efforts are underway to refine prevention strategies, understand the pathogenesis of the shock, and identify therapeutic modalities.


High throughput sequencing technology reveals alteration of lower respiratory tract microbiome in severe aspiration pneumonia and its association with inflammation.
Aspiration pneumonia is a common and severe clinical condition. The microbiome present in the lower respiratory tract plays a crucial role in regulating human inflammatory response. However, the relationship between the altered lower respiratory tract microbiome and inflammation in aspiration pneumonia remains inadequately explored. To investigate the alteration of the lower respiratory tract microbiome in severe aspiration pneumonia patients and explore the potential correlation between microbiome components and inflammatory response. Patients in the severe aspiration pneumonia group and control group were enrolled from the intensive care unit of Jinshan Hospital, Fudan University between December 31, 2020 and August 19, 2021. Sputum specimens were collected from all participants and subsequently subjected to 16S rDNA high throughput sequencing technology. The concentration of inflammatory cytokines in serum was measured using enzyme-linked immunosorbent assay (ELISA) kits, and collected data including patients' demographic information, clinical data, and laboratory examination results were recorded for further analysis. Alteration in the lower respiratory tract microbiome was observed in severe aspiration pneumonia. Compared to the control group, a significant decrease in the relative abundance of Firmicutes was found at the phylum level (P < 0.01). At the family level, the relative abundance of Corynebacteriaceae, Enterobacteriaceae and Enterococcaceae increased significantly (P < 0.001, P < 0.05, P < 0.01). There were no significant differences in community diversity of the lower respiratory tract between the two groups. Patients in the severe aspiration pneumonia group exhibited significantly higher levels of inflammation compared to those in the control group. Correlation analysis showed that the relative abundance of Corynebacteriaceae was positively correlated with the expression level of IL-1β and IL-18 (P = 0.002, P = 0.02); the relative abundance of Enterobacteriaceae was negatively correlated with IL-4 (P = 0.011); no other significant correlations have been identified between microbiome and inflammatory indicators thus far (P > 0.05). Alteration of the lower respiratory tract microbiome is critically involved in inflammation and disease progression in severe cases of aspiration pneumonia. The potential inflammation regulation properties of the microbiome hold promising value for developing novel therapeutic approaches aimed at mitigating the severity of the disease.


Autoimmune-induced damage of the midbrain dopaminergic system in lupus-prone mice.
Spontaneous development of lupus-like disease is accompanied by impaired dopamine catabolism and degenerating axon terminals in the mesencephalon of MRL-lpr mice. We presently examine the hypothesis that systemic autoimmunity affects the central dopaminergic system in behaviorally impaired animals. The functional damage of the nigrostriatal pathway was assessed from rotational behavior after a single injection of the D1/D2-receptor agonist apomorphine. Neurodegeneration in the midbrain was estimated by Fluoro Jade B (FJB) staining. The causal role of autoimmunity was tested by comparing asymptomatic and diseased MRL-lpr mice, and by employing the immunosuppressive drug cyclophosphamide. Damage of dopaminergic neurons was assessed by tyrosine-hydroxylase (TH) staining of the midbrain. Apomorphine induced significant asymmetry in limb use, which lead to increased circling in the diseased MRL-lpr group. While FJB-positive somas were not seen in the striatum, increased staining in the substantia nigra (SN) and ventral tegmental area (VTA) were detected in behaviorally impaired MRL-lpr mice, but not in age-matched controls. Reduced brain mass and increased levels of TNF-alpha in their cerebrospinal fluid (CSF) suggested cerebral atrophy and inflammation. In addition, CSF was neurotoxic to a dopaminergic progenitor cell line. Immunosuppression attenuated CSF cytotoxicity, TNF-alpha levels, and midbrain neurodegeneration. Supportive of the notion that dying neurons were dopaminergic, the SN of autoimmune mice showed approximately a 35% reduction in the number of TH-positive cells. A three-fold increase in serum brain-reactive antibodies accompanied this loss. Although the source of toxic mediator(s) remains unknown, present results are consistent with the hypothesis that autoimmunity-induced destruction of mesonigral and mesolimbic dopaminergic pathways contributes to the etiology of aberrant behavior in an animal model of neuropsychiatric lupus.


The number of circulating CD34-positive cells is an independent predictor of coronary artery calcification progression: Sub-analysis of a prospective multicenter study.
Decreases in circulating CD34-positive cells are associated with increases in cardiovascular events. We investigated the association between the number of CD34-positive cells and the progression of coronary artery calcification (CAC), a marker of atherosclerosis, in patients with hypercholesteremia under statin therapy in a sub-analysis of a multicenter study. In the principal study, patients with CAC scores of 1-999 were treated with pitavastatin. Measurement of CAC by non-enhanced computed tomography and a blood test were performed at baseline and at 1-year follow-up. Patients were divided into two groups: CAC progression (change in CAC score > 0) and non-progression. The number of circulating CD34-positive cells was counted using flow cytometry. A total of 156 patients (mean age 67 years, 55% men) were included in this sub-analysis. CD34 positive cell numbers at baseline as a continuous variable was inversely correlated with annual change in the log-transformed CAC score (r = -0.19, p = 0.02). When patients were divided into high and low CD34 groups based on the median value of 0.8 cells/μL, the adjusted change in CAC score in the low-CD34 group was significantly greater than that in the high-CD34 group (54.2% vs. 20.8%, respectively, p = 0.04). In multiple logistic analysis, a low CD34-positive cell number was an independent predictor of CAC progression, with an odds ratio of 2.88 (95% confidence interval 1.28-6.49, p = 0.01). Low numbers of CD34-positive cells are associated with CAC progression in patients with hypercholesterolemia under statin therapy. The number of CD34-positive cells may help to identify patients at increased cardiovascular risk.


Gallionellaceae pangenomic analysis reveals insight into phylogeny, metabolic flexibility, and iron oxidation mechanisms.
The iron-oxidizing Gallionellaceae drive a wide variety of biogeochemical cycles through their metabolisms and biominerals. To better understand the environmental impacts of Gallionellaceae, we need to improve our knowledge of their diversity and metabolisms, especially any novel iron oxidation mechanisms. Here, we used a pangenomic analysis of 103 genomes to resolve Gallionellaceae phylogeny and explore their genomic potential. Using a concatenated ribosomal protein tree and key gene patterns, we determined Gallionellaceae has four genera, divided into two groups: iron-oxidizing bacteria (FeOB) Gallionella, Sideroxydans, and Ferriphaselus with iron oxidation genes (cyc2, mtoA) and nitrite-oxidizing bacteria (NOB) Candidatus Nitrotoga with the nitrite oxidase gene nxr. The FeOB and NOB have similar electron transport chains, including genes for reverse electron transport and carbon fixation. Auxiliary energy metabolisms, including S oxidation, denitrification, and organotrophy, were scattered throughout the FeOB. Within FeOB, we found genes that may represent adaptations for iron oxidation, including a variety of extracellular electron uptake mechanisms. FeOB genomes encoded more predicted c-type cytochromes than NOB genomes, notably more multiheme c-type cytochromes (MHCs) with >10 CXXCH motifs. These include homologs of several predicted outer membrane porin-MHC complexes, including MtoAB and Uet. MHCs efficiently conduct electrons across longer distances and function across a wide range of redox potentials that overlap with mineral redox potentials, which can expand the range of usable iron substrates. Overall, the results of pangenome analyses suggest that the Gallionellaceae genera Gallionella, Sideroxydans, and Ferriphaselus have acquired a range of adaptations to succeed in various environments but are primarily iron oxidizers.IMPORTANCENeutrophilic iron-oxidizing bacteria (FeOB) produce copious iron (oxyhydr)oxides that can profoundly influence biogeochemical cycles, notably the fate of carbon and many metals. To fully understand environmental microbial iron oxidation, we need a thorough accounting of iron oxidation mechanisms. In this study, we show the Gallionellaceae FeOB genomes encode both characterized iron oxidases as well as uncharacterized multiheme cytochromes (MHCs). MHCs are predicted to transfer electrons from extracellular substrates and likely confer metabolic capabilities that help Gallionellaceae occupy a range of different iron- and mineral-rich niches. Gallionellaceae appear to specialize in iron oxidation, so it would be advantageous for them to have multiple mechanisms to oxidize various forms of iron, given the many iron minerals on Earth, as well as the physiological and kinetic challenges faced by FeOB. The multiple iron/mineral oxidation mechanisms may help drive the widespread ecological success of Gallionellaceae.


Why do some jail inmates not engage in treatment and services?
Jail inmates represent a high-risk, multineed population. Why do some jail inmates not access available programs and services? Drawn from a longitudinal study, 261 adults were assessed shortly upon incarceration and reassessed prior to transfer or release from a county jail. Of the participants in need of treatment, 18.5% did not participate in any formal treatment programs or religious programs and services. Untreated inmates were disproportionately young and male and less likely to report preincarceration cocaine dependence. Treatment participation varied little as a function of race or symptoms of mental illness. The most common reason for nonparticipation was the belief that one would not be around long enough to participate in programs. Other reasons were both institution-related and person-related in nature, including doubts about treatment efficacy, stigma concerns, lack of motivation, and lack of programs, especially addressing mental illness.


Improved Radiotherapy Sensitivity of Nasopharyngeal Carcinoma Cells by miR-29-3p Targeting COL1A1 3'-UTR.
BACKGROUND Radio-resistance is an obstacle to the treatment of human nasopharyngeal carcinoma (NPC). However, how microRNAs (miRNA) are involved in this process remains unclear. In the present study we explored the role and possible molecular mechanism of miR-29a-3p, formerly known as tumor suppressors, in radio-sensitivity of NPC cells. MATERIAL AND METHODS A radio-resistant sub-cell line, CNE-2R, was established to detect the expression of miR-29a/b/c-3p using qRT-PCR. CCK-8 assay, colony formation assay, and single-cell gel electrophoresis (SCGE) assay were carried out to analyze the radio-sensitivity of NPC cells. qRT-PCR, luciferase reporter, and Western blot experiments were performed to validate the targeting of COL1A1 by miR-29a. Short interference RNAs (siRNAs) were used to investigate whether COL1A1 mediates the radio-sensitizer role of miR-29a. Expression of miR-29a and COL1A1 in radio-resistant NPC tissues was finally determined. RESULTS miR-29a was decreased in the radio-resistant CNE-2R cells. Following a time-course irradiation (IR) exposure, miR-29a exhibited a time-dependent decrease. Cellular experiments confirmed that miR-29a induced radio-sensitivity of CNE-2R cells via suppressing cell viability and enhancing cell apoptosis after IR. We confirmed that COL1A1 is a direct target of miR-29a and can exert radio-resistance effects in NPC cells. We also found that knockdown of COL1A1 inhibits NPC cell viability and sensitivity to IR. Finally, we observed a downregulation of miR-29a in radio-resistant NPC tissues and its decrease was associated with upregulation of COL1A1. CONCLUSIONS miR-29a is a critical determinant of NPC radio-response for NPC patients, and its induction provides a promising therapeutic choice to elevate NPC radio-sensitivity.


Acute and chronic B cell depletion disrupts CD4+ and CD8+ T cell homeostasis and expansion during acute viral infection in mice.
B cells provide humoral protection against pathogens and promote cellular immunity through diverse nonclassical effector functions. To assess B cell function in promoting T cell homeostasis, mature B cells were either acutely or chronically depleted in mice using CD20 mAb. Acute B cell depletion in either 2- or 4-mo-old mice significantly reduced spleen and lymph node CD4(+) and CD8(+) T cell numbers, including naive, activated, and Foxp3(+)CD25(+)CD4(+) regulatory T cell subsets. The numbers of IFN-γ- and TNF-α-producing T cells were also significantly reduced. Chronic B cell depletion for 6 mo in aged naive mice resulted in a 40-70% reduction in activated CD4(+) and CD8(+) T cell numbers and 20-50% reductions in IFN-γ-producing T cells. Therefore, B cells were necessary for maintaining naive CD4(+) and CD8(+) T cell homeostasis for subsequent optimal T cell expansion in young and old mice. To determine the significance of this finding, a week of B cell depletion in 4-mo-old mice was followed by acute viral infection with lymphocytic choriomeningitis virus Armstrong. Despite their expansion, activated and cytokine-producing CD4(+) and CD8(+) T cell numbers were still significantly reduced 1 wk later. Moreover, viral peptide-specific CD4(+) and CD8(+) T cell numbers and effector cell development were significantly reduced in mice lacking B cells, whereas lymphocytic choriomeningitis virus titers were dramatically increased. Thus, T cell function is maintained in B cell-depleted mice, but B cells are required for optimal CD4(+) and CD8(+) T cell homeostasis, activation, and effector development in vivo, particularly during responses to acute viral infection.


Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome-wide Association Studies.
Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells and optic nerve axons. According to its anatomical features, glaucoma is mainly subdivided into primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Exfoliation syndrome (XFS) and glaucoma (XFG) are characterized by the accumulation of extracellular materials in ocular tissues, particularly the lens surface and pupillary border. In addition to the two major forms of glaucoma, XFG is the most common cause of secondary open-angle glaucoma. Recent genome-wide association studies(GWASs) revealed genetic loci associated with each glaucoma subtype. Review of literatures regarding GWASs for POAG, PACG and XFS. Several genetic loci were found to be independently associated with POAG, PACG, and XFS by large-scale GWASs. Genetic studies may not only provide a better understanding of the pathophysiological mechanisms underlying the diseases, but also facilitate the development of new drugs or treatments.


Metastatic epidural spinal cord compression among elderly patients with advanced prostate cancer.
A recent randomized trial demonstrated that for metastatic epidural spinal cord compression (MESCC), a complication of advanced prostate cancer, surgical decompression may be more effective than external beam radiation therapy (RT). We investigated predictors of MESCC, its treatment, and its impact on hospital length of stay for patients with advanced prostate cancer. We used the SEER-Medicare database to identify patients >65 years with stage IV (n = 14,800) prostate cancer. We used polytomous logistic regression to compare those with and without MESCC and those hospitalized for treatment with surgical decompression and/or RT. MESCC developed in 711 (5 %) of patients, among whom 359 (50 %) received RT and 107 (15 %) underwent surgery ± RT. Median survival was 10 months. MESCC was more likely among patients who were black (OR 1.75, 95 %CI 1.39-2.19 vs. white) and had high-grade tumors (OR 3.01, 95 %CI 1.14-7.94), and less likely in those younger; with prior hormonal therapy (OR 0.73, 95 %CI 0.62-0.86); or with osteoporosis (OR 0.63, 95 %CI 0.47-0.83). Older patients were less likely to undergo either RT or surgery, as were those with ≥1 comorbidity. Patients with high-grade tumors were more likely to undergo RT (OR 1.92, 95 %CI 1.25-2.96). Those who underwent RT or surgery spent an additional 11 and 29 days, respectively, hospitalized. We found that black men with metastatic prostate cancer are more likely to develop MESCC than whites. RT was more commonly utilized for treatment than surgery, but the elderly and those with comorbidities were unlikely to receive either treatment.


Acute changes in the renin-angiotensin system modify bradykinin and angiotensin reactivity and metabolism in conscious rats.
We have shown that angiotensin I (AI) conversion as well as bradykinin (BK) inactivation and reactivity are altered in chronic renal hypertensive rats. In the present experiments we tested the possibility that acute renal hypertension or AI and AII infusion cause alterations in both systems. Pulmonary inactivation of BK was estimated by comparing intravenous and intraaortic equipressor doses (20 mm Hg), and the extent of AI conversion was assessed by determining the equipressor doses of AI and AII that produced a 20 mm Hg rise in mean arterial pressure (MAP). Acute renal hypertension was produced by unclamping the renal pedicle (URP) occluded for 5 hours in conscious rats. Before URP, the MAP was already increased (131 +/- 2 mm Hg) and captopril (10 mg/kg, i.v.) produced a fall of 27 +/- 8 mm Hg, suggesting that the renin-angiotensin system was overactive. After URP, MAP rose to 151 +/- 3 mm Hg, and captopril completely abolished the hypertension. Before URP, reactivity to BK was increased [doses 6 times smaller than control (C), 34 +/- 5 ng], and URP produced no further elevation. Pulmonary BK inactivation (97.5% +/- 4%) was the same before and after URP. Before URP, doses of AII 5 times greater than C (2 +/- 4 pmol) were necessary, and hyporeactivity to AII was markedly increased after URP (doses 300 times larger than C). After URP, the conversion was maximal (104% +/- 2% vs 49% +/- 3% in C), and it was already elevated before URP (82% +/- 10%) when six of the nine rats studied had maximal extent of conversion.(ABSTRACT TRUNCATED AT 250 WORDS)


Brominated sesquiterpenes from the red alga Laurencia obtusa.
Four new sesquiterpenes, (8R)-8-bromo-10-epi-beta-snyderol (1), (8S)-8-bromo-beta-snyderol (2), 5-bromo-3-(3'-hydroxy-3'-methylpent-4'-enylidene)-2,4,4-trimethylcyclohexanone (3), and the epoxide 4, have been isolated from the chloroform-methanol extract of Laurencia obtusa, together with the three known compounds alpha-snyderol (5), alpha-snyderol acetate (6), and stigmasterol. The structures of the isolated compounds were elucidated through spectroscopic analyses. Compound 1 showed antimalarial activity, with IC(50) values of 2700 and 4000 ng/mL against the D6 and W2 clones of Plasmodium falciparum, respectively.


Spatio-temporal common pattern: A companion method for ERP analysis in the time domain.
Already used at the incept of research on event-related potentials (ERP) over half a century ago, the arithmetic mean is still the benchmark for ERP estimation. Such estimation, however, requires a large number of sweeps and/or a careful rejection of artifacts affecting the electroencephalographic recording. In this article we propose a method for estimating ERPs as they are naturally contaminated by biological and instrumental artifacts. The proposed estimator makes use of multivariate spatio-temporal filtering to increase the signal-to-noise ratio. This approach integrates a number of relevant advances in ERP data analysis, such as single-sweep adaptive estimation of amplitude and latency and the use of multivariate regression to account for ERP overlapping in time. We illustrate the effectiveness of the proposed estimator analyzing a dataset comprising 24 subjects involving a visual odd-ball paradigm, without performing any artifact rejection. As compared to the arithmetic average, a lower number of sweeps is needed. Furthermore, artifact rejection can be performed roughly using permissive automatic procedures. The proposed ensemble average estimator yields a reference companion to the arithmetic ensemble average estimation, suitable both in clinical and research settings. The method can be applied equally to event related fields (ERF) recorded by means of magnetoencephalography. In this article we describe all necessary methodological details to promote testing and comparison of this proposed method by peers. Furthermore, we release a MATLAB toolbox, a plug-in for the EEGLAB software suite and a stand-alone executable application.


2023 AAHA Management of Allergic Skin Diseases in Dogs and Cats Guidelines.
These guidelines present a systematic approach to diagnosis, treatment, and management of allergic skin diseases in dogs and cats. The guidelines describe detailed diagnosis and treatment plans for flea allergy, food allergy, and atopy in dogs and for flea allergy, food allergy, and feline atopic skin syndrome in cats. Management of the allergic patient entails a multimodal approach with frequent and ongoing communication with the client. Obtaining a comprehensive history is crucial for diagnosis and treatment of allergic skin diseases, and the guidelines describe key questions to ask when presented with allergic canine and feline patients. Once a detailed history is obtained, a physical examination should be performed, a minimum dermatologic database collected, and treatment for secondary infection, ectoparasites, and pruritus (where indicated) initiated. The process of diagnosing and managing allergic skin disease can be prolonged and frustrating for clients. The guidelines offer recommendations and tips for client communication and when referral to a dermatologist should be considered, to improve client satisfaction and optimize patient outcomes.


Automatic Sequence-Based Network for Lung Diseases Detection in Chest CT.
To develop an accurate and rapid computed tomography (CT)-based interpretable AI system for the diagnosis of lung diseases. Most existing AI systems only focus on viral pneumonia (e.g., COVID-19), specifically, ignoring other similar lung diseases: e.g., bacterial pneumonia (BP), which should also be detected during CT screening. In this paper, we propose a unified sequence-based pneumonia classification network, called SLP-Net, which utilizes consecutiveness information for the differential diagnosis of viral pneumonia (VP), BP, and normal control cases from chest CT volumes. Considering consecutive images of a CT volume as a time sequence input, compared with previous 2D slice-based or 3D volume-based methods, our SLP-Net can effectively use the spatial information and does not need a large amount of training data to avoid overfitting. Specifically, sequential convolutional neural networks (CNNs) with multi-scale receptive fields are first utilized to extract a set of higher-level representations, which are then fed into a convolutional long short-term memory (ConvLSTM) module to construct axial dimensional feature maps. A novel adaptive-weighted cross-entropy loss (ACE) is introduced to optimize the output of the SLP-Net with a view to ensuring that as many valid features from the previous images as possible are encoded into the later CT image. In addition, we employ sequence attention maps for auxiliary classification to enhance the confidence level of the results and produce a case-level prediction. For evaluation, we constructed a dataset of 258 chest CT volumes with 153 VP, 42 BP, and 63 normal control cases, for a total of 43,421 slices. We implemented a comprehensive comparison between our SLP-Net and several state-of-the-art methods across the dataset. Our proposed method obtained significant performance without a large amount of data, outperformed other slice-based and volume-based approaches. The superior evaluation performance achieved in the classification experiments demonstrated the ability of our model in the differential diagnosis of VP, BP and normal cases.


Whole-Genome Sequencing of Brachyspira hyodysenteriae Isolates From England and Wales Reveals Similarities to European Isolates and Mutations Associated With Reduced Sensitivity to Antimicrobials.
Brachyspira hyodysenteriae is the principal cause of swine dysentery, a disease that threatens economic productivity of pigs in many countries as it can spread readily within and between farms, and only a small number of antimicrobials are authorized for treatment of pigs. In this study, we performed whole-genome sequencing (WGS) of 81 B. hyodysenteriae archived at the Animal and Plant Health Agency (APHA) from diagnostic submissions and herd monitoring in England and Wales between 2004 and 2015. The resulting genome sequences were analyzed alongside 34 genomes we previously published. Multi-locus sequence typing (MLST) showed a diverse population with 32 sequence types (STs) among the 115 APHA isolates, 25 of them identified only in England; while also confirming that the dominant European clonal complexes, CC8 and CC52, were common in the United Kingdom. A core-genome SNP tree typically clustered the isolates by ST, with isolates from some STs detected only within a specific region in England, although others were more widespread, suggesting transmission between different regions. Also, some STs were more conserved in their core genome than others, despite these isolates being from different holdings, regions and years. Minimum inhibitory concentrations to commonly used antimicrobials (Tiamulin, Valnemulin, Doxycycline, Lincomycin, Tylosin, Tylvalosin) were determined for 82 of the genome-sequenced isolates; genomic analysis revealed mutations generally correlated well with the corresponding resistance phenotype. There was a major swine dysentery intervention program in 2009-2010, and antimicrobial survival curves showed a significant reduction in sensitivity to tiamulin and valnemulin in isolates collected in and after 2010, compared to earlier isolates. This correlated with a significant increase in post-2009 isolates harboring the pleuromutilin resistance gene tva(A), which if present, may facilitate higher levels of resistance. The reduction in susceptibility of Brachyspira from diagnostic submissions to pleuromutilins, emphasizes the need for prudent treatment, control and eradication strategies.


Interactions between GA, auxin, and UNI expression controlling shoot ontogeny, leaf morphogenesis, and auxin response in Pisum sativum (Fabaceae): or how the uni-tac mutant is rescued.
Leaf morphogenesis, including that of compound leaves, provides the basis for the great diversity of leaf form among higher plants. Leaf form is an important character by which plants adapt to their environment. The common garden pea provides a developmental model system for understanding leaf development in the legumes and a contrasting one for other groups of plants. We used genetic, tissue culture, and physiological methods, as well as DR5::GUS expression and qRT-PCR, to explore the interactions between the hormones gibberellic acid (GA) and auxin and Unifoliata ( UNI ) gene expression that control leaf morphogenesis in pea. Rate of increase in leaf complexity during shoot ontogeny (i.e., heteroblasty) and adult leaf complexity are controlled by GA through UNI . Leaves on greenhouse-grown uni-tac mutants are rescued by weekly GA or auxin applications. Auxin responsiveness is reduced in uni-tac shoot and root tips and in wild-type shoot tips treated with auxin transport inhibitors. GA and auxin increase UNI mRNA levels in uni-tac as well as that of other transcription factors. GA and auxin positively promote leaf dissection during leaf morphogenesis in pea by prolonging the time during which acropetally initiated pinna pairs are produced. GA-generated elaboration of leaf morphogenesis is in distinct contrast to that in other species, such as tomato and Cardamine . Instead, GA and auxin play common and supportive roles in pea leaf morphogenesis as they do in many other aspects of plant development


Mandated empowerment: handing antipoverty policy back to the poor?
The current trend in antipoverty policy emphasizes mandated empowerment: the poor are being handed the responsibility for making things better for themselves, largely without being asked whether this is what they want. Beneficiary control is now being built into public service delivery, while microcredit and small business promotion are seen as better ways to help the poor. The clear presumption is that the poor are both able and happy to exercise these new powers. This essay uses two examples to raise questions about these strategies. The first example is about entrepreneurship among the poor. Using data from a number of countries, we argue that there is no evidence that the median poor entrepreneur is trying his best to expand his existing businesses, even if we take into account the many constraints he faces. While many poor people own businesses, this seems to be more a survival strategy than something they want to do. The second example comes from an evaluation of a program in India that aims to involve poor rural parents in improving local public schools. The data suggest that despite being informed that they now have both the right to intervene in the school and access to funds for that purpose, and despite being made aware of how little the children were learning, parents opt to not get involved. Both examples raise concerns about committing ourselves entirely to antipoverty strategies that rely on the poor doing a lot of the work.


Understanding the fate of the oxyallyl cation following Nazarov electrocyclization: sequential Wagner-Meerwein migrations and the synthesis of spirocyclic cyclopentenones.
A general reaction sequence is described that involves Nazarov cyclization followed by two sequential Wagner-Meerwein migrations, to afford spirocyclic compounds from divinyl ketones in the presence of 1 equiv of copper(II) complexes. A detailed investigation of this sequence is described including a study of substrate scope and limitations. It was found that after 4π electrocyclization, two different pathways are available to the oxyallyl cation intermediate: elimination of a proton can give the usual Nazarov cycloadduct, or ring contraction can give an alternative tertiary carbocation. After ring contraction, either [1,2]-hydride or carbon migration can occur, depending upon the substitution pattern of the substrate, to furnish spirocyclic products. The rearrangement pathway is favored over the elimination pathway when catalyst loading is high and the copper(II) counterion is noncoordinating. Several ligands were found to be effective for the reaction. Thus, the reaction sequence can be controlled by judicious choice of reaction conditions to allow selective generation of richly functionalized spirocycles. The three steps of the sequence are stereospecific: electrocyclization followed by two [1,2]-suprafacial Wagner-Meerwein shifts, the ring contraction and then a hydride, alkenyl, or aryl shift. The method allows stereospecific installation of adjacent stereocenters or adjacent quaternary centers arrayed around a cyclopentenone ring.


Carcinoid tumor of the larynx. A case report with a review of the literature.
A carcinoid tumor of the larynx is reported. The tumor was initially interpreted as a poorly differentiated squamous carcinoma and treated with irradiation. One year later a laryngectomy was performed and a carcinoid tumor was found in the resection specimen. The patient died after 2 years with disseminated disease. Carcinoid tumors in the larynx are rare. In the literature 45 cases of laryngeal carcinoid tumors have been reported. The diagnosis of this laryngeal tumor is difficult but important because irradiation is ineffective. Surgical treatment should be performed.


Prefrontal executive function associated coupling relates to Huntington's disease stage.
Huntington's disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD.


A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients.
This randomised, double-blind, fixed-dose study evaluated the efficacy of escitalopram and paroxetine in the long-term treatment of severely depressed patients with major depressive disorder (MDD). Patients with a primary diagnosis of MDD and baseline Montgomery-Asberg Depression Rating Scale (MADRS) >or= 30 were randomised to 24 weeks of double-blind treatment with fixed doses of either escitalopram (20 mg) (n = 232) or paroxetine (40 mg) (n = 227). The primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (Week 24) in MADRS total score (last observation carried forward, LOCF). MAIN OUTCOME MEASURES; At endpoint (24 weeks), the mean change from baseline in MADRS total score was -25.2 for patients treated with escitalopram (n = 228) and -23.1 for patients with paroxetine (n = 223), resulting in a difference of 2.1 points (p < 0.05). The difference in the change in the MADRS total score (LOCF) was significantly in favour of escitalopram from Week 8 onwards. The proportion of remitters (MADRS <or= 12) after 24 weeks was 75% for escitalopram and 67% for paroxetine (p < 0.05). The results on the primary efficacy scale were supported by significantly greater differences in favour of escitalopram on the Hamilton Anxiety, Hamilton Depression and Clinical Global Impression-Improvement and -Severity scales. For very severely depressed patients (baseline MADRS >or= 35), there was a difference of 3.4 points at endpoint in the MADRS total score in favour of escitalopram (p < 0.05). The overall withdrawal rate for patients treated with escitalopram (19%) was significantly lower than with paroxetine (32%) (p < 0.01). The withdrawal rate due to adverse events was significantly lower for escitalopram (8%) compared to paroxetine (16%) (p < 0.05). There were no significant differences in the incidence of individual adverse events during treatment. Escitalopram is significantly more effective than paroxetine in the long-term treatment of severely depressed patients.


[Functional state of the hepatobiliary system and immune status of pregnant women who have had viral hepatitis].
Hepatobiliary function and immune status were evaluated in 92 pregnant women who had had viral hepatitis A (group 1) and in 35 who had suffered from viral hepatitis B. A control group included 102 healthy pregnant women. In group 1 there appeared clinical symptoms suggesting impairment of hepatobiliary system. It is suggested that pregnant women with the history of hepatitis should consult specialist on infections or gastroenterologist to specify the pathological process in order to correct it adequately.


A recording viscometer for assaying mammalian collagenase.
A recording viscometer for monitoring the action of mammalian collagenase on soluble collagen is described. For this system, where only one peptide bond is cleaved per subunit, it is shown theoretically that the decrease in viscosity is proportional to the fraction of molecules cleaved. Experimental confirmation was obtained by parallel monitoring of hydrolysis by using the fluorescamine assay of liberated amino groups. The initial velocity of reaction is proportional to substrate concentration and enzyme concentration.


Match analysis of elite adolescent team handball players.
The purposes of this study were to examine the activity profile of elite adolescent players during regular team handball games and to compare the physical and motor performance of players between the first and second halves of a match. Activity patterns (video analysis) and heart-rate (HR) responses (telemetry) were monitored in top national-division adolescent players (18 men, aged 15.1 ± 0.6 years) throughout 6 regulation games (25-minute halves with a 10-minute interval). The total distance covered averaged 1,777 ± 264 m per game (7.4% less in the second than in the first half, p > 0.05). Players ran 170 ± 24 m at high intensity and 86 ± 12 m at maximal speed, with 32 ± 6 bouts of running (duration 2.3 ± 0.3 seconds) at speeds > 18 km·h(-1); they stood still for 16% of the playing time. The mean HR during play was 172 ± 2 b·min(-1) (82 ± 3% of maximal HR). Blood lactate concentrations at the end of the first and second halves were 9.7 ± 1.1 and 8.3 ± 0.9 mmol·L(-1), respectively (difference p < 0.05). We conclude that adolescent handball players cover less distance and engage in fewer technical actions in the second half of a match. This indicates that team handball is physiologically very demanding. The practical implication is that coaches should seek to sustain performance in the second period of a game by modifying playing tactics and maximizing both aerobic and anaerobic fitness during training sessions.


[Features of the receptors of the alar system of locusts which have lost their ability to fly].
Using two species of locusts, Romalia microptera Beavy and Podisma pedestris L., receptors of the wing apparatus are described: campaniform sensillas of the wing, hair receptors of the tegula, chordotonal organ and thorax stretch receptor. A comparative analysis of the receptors mentioned with the homologous sensitive organs, participating in the control of wing movements, is performed in well flying species (Locusta migratoria migratorioides and Schistocerca gregaria). Loss of ability to fly is accompanied with a sharp decrease in the wing campaniform sensillas and in the tegula proprioceptive hairs. Simultaneously, there is loss of connection between the thorax receptors and the wing elements that are present in good flyers. The thorax stretch receptor begins to innervate the longitudinal dorsal muscle, as it is observed in the abdominal segments. The data obtained make it possible to speak about homology of the tergal chordotonal organs and the thorax and abdomen stretch receptors and about the pathways of their evolution, when the insects obtain and loose their ability to fly.


Home and Community-Based Physical Therapist Management of Adults With Post-Intensive Care Syndrome.
More than 4 million adults survive a stay in the intensive care unit each year, with many experiencing new or worsening physical disability, mental health problems, and/or cognitive impairments, known as post-intensive care syndrome (PICS). Given the prevalence and magnitude of physical impairments after critical illness, many survivors, including those recovering from COVID-19, could benefit from physical therapist services after hospital discharge. However, due to the relatively recent recognition and characterization of PICS, there may be limited awareness and understanding of PICS among physical therapists practicing in home health care and community-based settings. This lack of awareness may lead to inappropriate and/or inadequate rehabilitation service provision. While this perspective article provides information relevant to all physical therapists, it is aimed toward those providing rehabilitation services outside of the acute and postacute inpatient settings. This article reports the prevalence and clinical presentation of PICS and provides recommendations for physical examination and outcomes measures, plan of care, and intervention strategies. The importance of providing patient and family education, coordinating community resources including referring to other health care team members, and community-based rehabilitation service options is emphasized. Finally, this perspective article discusses current challenges for optimizing outcomes for people with PICS and suggests future directions for research and practice.


Challenge of parents caring for children or adolescents with early-stage schizophrenia in China: A qualitative study.
To explore the challenges of parents caring for early-stage schizophrenia (ESS) children/adolescents in China. Thirteen parents of ESS subjects completed semi-structured interviews. Thematic analysis was used to analyze data. Seven themes emerged from the data: psychological shock and emotional burden; lack of disease knowledge and care skill; poor treatment compliance of the patient; difficulty getting along with the patient; conflict within the family or in the workplace; financial burden; and need sufficient social support. Each challenge was produced and influenced under the Chinese special social context. Professional support was needed to help patients with schizophrenia to cope with their situation promptly. Education initiatives should focus on mental health to prevent discrimination from society and enable people to recognize the early symptoms of schizophrenia in children. Telemedicine should be explored for application in the treatment of mental illness. Also, a broader nationwide healthcare policy would be needed to help to reduce the individual and societal financial burdens associated with schizophrenia.


Preimmigration Family Cohesion and Drug/Alcohol Abuse Among Recent Latino Immigrants.
Given the growing population of Latino immigrants in the United States, it is critical for counselors to understand pre- and postimmigration social contextual factors affecting the mental health of this heterogeneous ethnic population. The objective of our cross-sectional, retrospective study was to investigate the potential protective influence of preimmigration family cohesion on drug/alcohol abuse just prior to migration among 527 Latino young adults (age 18-34 years). Multivariate Poisson regression indicated that preimmigration family cohesion was inversely related with harmful/hazardous alcohol consumption, the frequency/quantity of alcohol use, and illicit drug use when controlling for the potentially confounding sociodemographic factors of gender, age, education, income, marital status, and immigration status (documented or undocumented). Associations between family cohesion and drug/alcohol use behaviors varied between Central American immigrants and Caribbean/South American regional groups. Preimmigration findings offer a fuller contextual understanding of the lives of Latino young adult immigrants and support the importance of family cohesion as a buffer against drug/alcohol abuse.


Induction of cytochrome P450 3A by paclitaxel in mice: pivotal role of the nuclear xenobiotic receptor, pregnane X receptor.
Paclitaxel, a taxane anti-microtubule agent, is known to induce CYP3A in rat and human hepatocytes. Recent studies suggest that a member of the nuclear receptor family, pregnane X Receptor (PXR), is a key regulator of the expression of CYP3A in different species. We investigated the role of PXR activation, in vitro and in vivo, in mediating Cyp3a induction by paclitaxel. Pregnenolone 16 alpha-carbonitrile (PCN), an antiglucocorticoid, was employed as a positive control for mouse PXR (mPXR) activation in vitro, and Cyp3a induction in vivo. In cell based reporter gene assays paclitaxel and PCN activated mPXR with an EC(50) of 5.6 and 0.27 microM, respectively. Employing PXR wild-type and transgenic mice lacking functional PXR (-/-), we evaluated the expression and activity of CYP3A following treatment with paclitaxel and PCN. Paclitaxel significantly induced CYP3A11 mRNA and immunoreactive CYP3A protein in PXR wild-type mice. Consistent with kinetics of CYP3A induction, the V(max) of testosterone 6 beta-hydroxylation in microsomal fraction increased 15- and 30-fold in paclitaxel- and PCN-treated mice, respectively. The Cyp3a induction response was completely abolished in paclitaxel- and PCN-treated PXR-null mice. This suggests that paclitaxel-mediated CYP3A induction in vivo requires an intact PXR-signaling mechanism. Our study validates the use of PXR activation assays in screening newer taxanes for potential drug interactions that may be related to PXR-target gene induction.


The Edinburgh Malawi Cancer Partnership: helping to establish multidisciplinary cancer care in Blantyre, Malawi.
In response to the growing incidence of cancer in Malawi, a new oncology unit was established at the Queen Elizabeth Central Hospital, Blantyre. The unit opened in 2010, the first in the country, and is led by a single consultant oncologist. In 2012, a healthcare partnership was formed between the oncology and palliative care unit at Queen Elizabeth Central Hospital and the Edinburgh Cancer Centre, UK. The principal objective of the partnership is to help develop high quality multidisciplinary cancer care in Malawi. Methods A needs assessment identified three priority areas for further improvement of cancer services: nurse-led treatment delivery; management of clinical data; and multidisciplinary working. The partnership received grant funding from the Scottish Government Malawi Development Programme in 2013 and a three year project plan was implemented. This has been conducted through a series of reciprocal training visits. Results Key achievements have been completion of a programme of oncology nursing education attended by 32 oncology nurses and other healthcare professionals, which has resulted in increased experience in cancer practice and standardisation of chemotherapy delivery procedures; development of a clinical database that enables prospective collection of data of all new patients with cancer and which links to the Malawi Cancer Registry; development of weekly multidisciplinary meetings involving oncology, gynaecology and surgery that has enabled a cross-specialty approach to patient care. Conclusion The Edinburgh Malawi Cancer Partnership is supporting nursing education, data use and cross-specialty collaboration that we are confident will improve cancer care in Malawi. Future work will focus on the further development of multidisciplinary breast cancer care and the development of a radiotherapy service for patients in Malawi.


Resolving single fluorophores within dense ensembles: contrast limits of tip-enhanced fluorescence microscopy.
We investigate the limits of one-photon fluorescence as a contrast mechanism in nanoscale-resolution tip-enhanced optical microscopy. Specifically, we examine the magnitude of tip-induced signal enhancement needed to resolve individual fluorophores within densely-packed ensembles. Modulation of fluorescence signals induced by an oscillating tip followed by demodulation with a lock-in amplifier increases image contrast by nearly two orders of magnitude. A theoretical model of this simple modulation/ demodulation scheme predicts an optimal value for the tip-oscillation amplitude that agrees with experimental measurements. Further, as an important step toward the eventual application of tip-enhanced fluorescence microscopy to the nanoscale structural analysis of biomolecular systems, we show that requisite signal enhancement factors are within the capabilities of commercially available silicon tips.


Strategies for the treatment of antidepressant-related sexual dysfunction.
Sexual dysfunction and dissatisfaction are common symptoms associated with depression. Optimal antidepressant treatment should result in remission of the symptoms of the underlying illness and minimize the potential for short- and long-term adverse effects, including sexual dysfunction. Sexual dysfunction and dissatisfaction are frequently persistent or worsen with the use of some antidepressant medications; this sexual dysfunction and dissatisfaction can have negative impact on adherence to treatment, quality of life, and the possibility of relapse. Successful management of sexual complaints during antidepressant treatment should begin with a systematic approach to determine the type of sexual dysfunction, potential contributing factors, and finally management strategies that should be tailored to the individual patient. The basic physiologic mechanisms of the normal sexual phases of libido, arousal, and orgasm and how these mechanisms may be interrupted by some antidepressants provide a framework for the clinician to utilize in order to minimize sexual complaints when initiating and continuing antidepressant treatment. This article provides guidelines, based upon this type of model, for the assessment, management, and prevention of sexual side effects associated with antidepressant treatment.


Preparative separation of alpha- and beta-naphthols catalyzed by immobilized sulfatase.
It has been found that sulfatase from Helix pomatia hydrolyzes beta-naphthyl sulfate much faster than alpha-naphthyl sulfate; e.g., at pH 7.8, while the former is readily hydrolyzed, the latter undergoes no appreciable hydrolysis. Kinetic investigations of both enzymatic and acid hydrolysis of naphthyl sulfates and their analogs indicate that in the enzymatic reaction the difference in reactivities is due to steric hindrances exerted in alpha-naphthyl sulfate by the benzene ring adjacent to the one bearing the sulfate group. (In the beta-ester this ring is remote from the site of hydrolysis.) The enzyme was immobilized and employed for the preparative resolution of alpha- and beta-naphthols: a mixture of the isomers was first sulfated with chlorosulfonic acid and then incubated with sulfatase covalently attached to alumina. The beta-naphthol produced was extracted with benzene, followed by acid hydrolysis of alpha-naphthyl sulfate in the remaining aqueous solution and extraction of the alpha-naphthol formed. Helix pomatia sulfatase also expresses a marked regiospecificity in the hydrolysis of ortho and para substituted phenyl sulfates. Therefore, the enzyme can be used for the preparative separation of naphthols as well as a variety of isomeric phenols.


Aminoacyl-tRNA synthetase-interacting multi-functional protein 1/p43: an emerging therapeutic protein working at systems level.
Drug discovery programs are based on the presumption of one drug-one action-one disease, which is frustrated by the complexity of biological systems. Because the aberration of a single gene often leads to multiple pathological symptoms, we should understand the functional network of the disease-related proteins to develop effective therapy. To describe how activities of proteins are reflected in phenotypes and their pathological implications using aminoacyl-tRNA synthetase-interacting multi-functional protein 1 (AIMP1). The physiological activities of AIMP1 are unveiled through in vitro approaches and in vivo phenotyptic investigation. Bioinformatics tool was used to combine all AIMP1-target proteins. Although a cytosolic protein, AIMP1 can be secreted as a cytokine to control immune response, angiogenesis and wound healing, and as a glucagon-like hormone for glucose homeostasis. It is involved in the regulation of autoimmune control and TGF-β signaling within the cells. AIMP1-deficient mice developed multiple phenotypes in immune systems, metabolism and body growth. The therapeutic potential of this multi-functional protein with associated biological activities are discussed.


Human Cytomegalovirus UL7, miR-US5-1, and miR-UL112-3p Inactivation of FOXO3a Protects CD34+ Hematopoietic Progenitor Cells from Apoptosis.
Human cytomegalovirus (HCMV) infection of myeloid lineage cells, such as CD34+ hematopoietic progenitor cells (HPCs) or monocytes, results in the upregulation of antiapoptotic cellular proteins that protect the newly infected cells from programmed cell death. The mechanisms used by HCMV to regulate proapoptotic cellular proteins upon infection of CD34+ HPCs have not been fully explored. Here, we show that HCMV utilizes pUL7, a secreted protein that signals through the FLT3 receptor, and miR-US5-1 and miR-UL112-3p to reduce the abundance and activity of the proapoptotic transcription factor FOXO3a at early times after infection of CD34+ HPCs. Regulation of FOXO3a by pUL7, miR-US5-1, and miR-UL112 results in reduced expression of the proapoptotic BCL2L11 transcript and protection of CD34+ HPCs from virus-induced apoptosis. These data highlight the importance of both viral proteins and microRNAs (miRNAs) in protecting CD34+ HPCs from apoptosis at early times postinfection, allowing for the establishment of latency and maintenance of viral genome-containing cells.IMPORTANCE Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals and is a significant problem during transplantation. The virus can establish a latent infection in CD34+ hematopoietic progenitor cells (HPCs) and periodically reactivate to cause disease in the absence of an intact immune system. What viral gene products are required for successful establishment of latency is still not fully understood. Here, we show that both a viral protein and viral miRNAs are required to prevent apoptosis after infection of CD34+ HPCs. HCMV pUL7 and miRNAs miR-US5-1 and miR-UL112-3p act to limit the expression and activation of the transcription factor FOXO3a, which in turn reduces expression of proapoptotic gene BCL2L11 and prevents virus-induced apoptosis in CD34+ HPCs.


[Successful treatment of neuroborreliosis with combined administration of antibiotics and steroids: a case report].
A 66-year-old woman developed bilateral facial paralysis as well as sensory and motor disturbances of extremities. Two months after the onset of paralysis, she also developed sensory disturbance of her trunk and vesicorectal disturbance, and her symptoms worsened gradually. Because the interferon-γ level in the cerebrospinal fluid was elevated, we suspected that her symptoms were caused by polyneuropathy and myelitis associated with infection. Her serum IgM and IgG antibodies against Borrelia garinii and B. afzelli were positive. Therefore, we diagnosed her as having neuroborreliosis. Her symptoms gradually improved after the combined administration of antibiotics and steroids. The present case report showed that it might be better to consider the possibility of neuroborreliosis when there are increasing concentrations of cytokine and chemokine, and that combination treatment with antibiotics and steroids can be used for the treatment of this disease.


Epigallocatechin gallate stimulates the neuroreactive salivary secretomotor system in autoimmune sialadenitis of MRL-Fas(lpr) mice via activation of cAMP-dependent protein kinase A and inactivation of nuclear factor κB.
The water channel aquaporin 5 (AQP5) plays a crucial role in regulating salivary flow rates. Xerostomia is often observed in patients with Sjögren's syndrome, and this is attributed to reduced AQP5 expression in the salivary glands. Recently, anti-type 3 muscarinic cholinergic receptors (M3R) autoantibodies and nuclear factor κB (NF-κB) have been found to be negative regulators of AQP5 expression in the salivary gland. Anti-M3R autoantibodies desensitize M3R to salivary secretagogues in Sjögren's syndrome, while activated NF-κB translocates to nuclei and binds to the AQP5 gene promoter, resulting in the suppression of AQP5 expression. We previously documented that epigallocatechin gallate (EGCG), which is a robust antioxidant contained in green tea, ameliorates oxidative stress-induced tissue damage to the salivary glands of MRL/MpJ-lpr/lpr (MRL-Fas(lpr)) mice, which are widely used as a model of Sjögren's syndrome. Reactive oxygen species (ROS) can activate NF-κB and inactivate protein kinase A (PKA), which is a key driver of AQP5 expression. In this study, we examined the effects of administering EGCG to MRL-Fas(lpr) mice with autoimmune sialadenitis on the levels of AQP5, activated NF-κB p65 subunit, activated PKA, activated c-Jun N-terminal kinase (JNK) (an activator of NF-κB), inhibitor κB (IκB) and histone deacetylase 1 (HDAC1) (an inhibitor of NF-κB). In EGCG-treated mice, intense aster-like immunostaining for AQP5 was observed on the apical plasma membranes (APMs) of submandibular gland acinar cells. Likewise, PKA, IκB and HDAC1 were highly expressed in salivary gland tissues, whereas the expression of JNK and NF-κB p65 was negligible. Rank correlation and partial correlation analyses revealed that treatment with EGCG upregulated AQP5 expression on the APM of acinar cells through activation of PKA and inactivation of NF-κB, while IκB and HDAC1 played a pivotal role in the induction of AQP5 expression by PKA. Our study indicates that EGCG may have therapeutic potential for Sjögren's syndrome patients.


The role of polyphenolic antioxidants in health, disease, and aging.
Polyphenolic antioxidants from dietary sources are frequently a topic of interest due to widespread scientific agreement that they may help lower the incidence of certain cancers, cardiovascular and neurodegenerative diseases, and DNA damage and even may have antiaging properties. On the other hand, questions still remain as to whether some antioxidants could be potentially harmful to health, because an increase in glycation-mediated protein damage (carbonyl stress) has been reported in some cases. Nevertheless, the quest for healthy aging has led to the extensive use of phytochemically derived antioxidants to disrupt age-associated deterioration in physiological function and to prevent many age-related diseases. Although a diet rich in the polyphenolic forms of antioxidants does seem to offer hope in delaying the onset of age-related disorders, it is still too early to define their exact clinical benefit for treating age-related disease. This review critically examines polyphenolic antioxidants, such as flavonoids, curcumene, and resveratrol in health, disease, and aging with the hope that a better understanding of the many mechanisms involved with these diverse compounds may lead to better health and novel treatment approaches for age-related diseases.


Dual-target inhibitors based on COX-2: a review from medicinal chemistry perspectives.
Inhibitors of COX-2 constitute a class of anti-inflammatory analgesics, showing potential against certain types of cancer. However, such inhibitors are associated with cardiovascular toxicity. Moreover, although single-target molecules possess specificity for particular targets, they often lead to poor safety, low efficacy and drug resistance due to compensatory mechanisms. A new generation of dual-target drugs that simultaneously inhibit COX-2 and another target is showing strong potential to treat cancer or reduce adverse cardiac effects. The present perspective focuses on the structure and functions of COX-2, and its role as a therapeutic target. It also explores the current state and future possibilities for dual-target strategies from a medicinal chemistry perspective.


Stability of employment after brain injury: a 7-year follow-up study.
Forty-three patients with severe traumatic brain injury (n = 24), cerebrovascular diseases (n = 15), or other acquired brain damage (n = 4) were followed-up 7-8 years after neuropsychological rehabilitation including a vocational re-entry programme. Current vocational status and work history since rehabilitation were investigated by means of a structured interview. Before interview, the patients were classified on the basis of medical records into four groups: (A) patients with minor residual neuropsychological impairments, (B) patients with minor impairments but psychopathological symptoms, (C) patients with persistent neuropsychological impairments showing no psychopathological symptoms, and (D) patients with persistent impairments and psychopathological symptoms. For patients in group A, a good, and for those in group D, a poor long-term employment outcome was predicted, while no predictions were made for the intermediate groups. Of the 43 interviewed subjects, 16 (37%) reported a stable return to work at pre-morbid level and seven (16%) at a lower level. In eight patients (19%), persisting difficulties in maintaining work were documented. Twelve subjects (28%) had retired within a period of 2 years after work trial. The relationship between patient classification and long-term employment outcome was only weak. Four out of 11 patients with a good prognosis (group A) experienced vocational adjustment problems or had retired. Three out of 10 patients with a poor prognosis (group D) were able to continue successfully with their previous jobs. These cases are described in detail. The employment outcome of the intermediate groups was very heterogeneous. The results suggest that particular attention should be paid to the long-term consequences of a reduced capacity for work, even if minor in degree. The success of patients despite a poor prognosis illustrate unsolved problems in relation to the ecological validity of neuropsychological measures of executive dysfunctions.


FragGeneScan: predicting genes in short and error-prone reads.
The advances of next-generation sequencing technology have facilitated metagenomics research that attempts to determine directly the whole collection of genetic material within an environmental sample (i.e. the metagenome). Identification of genes directly from short reads has become an important yet challenging problem in annotating metagenomes, since the assembly of metagenomes is often not available. Gene predictors developed for whole genomes (e.g. Glimmer) and recently developed for metagenomic sequences (e.g. MetaGene) show a significant decrease in performance as the sequencing error rates increase, or as reads get shorter. We have developed a novel gene prediction method FragGeneScan, which combines sequencing error models and codon usages in a hidden Markov model to improve the prediction of protein-coding region in short reads. The performance of FragGeneScan was comparable to Glimmer and MetaGene for complete genomes. But for short reads, FragGeneScan consistently outperformed MetaGene (accuracy improved ∼62% for reads of 400 bases with 1% sequencing errors, and ∼18% for short reads of 100 bases that are error free). When applied to metagenomes, FragGeneScan recovered substantially more genes than MetaGene predicted (>90% of the genes identified by homology search), and many novel genes with no homologs in current protein sequence database.


Heat transfer in protein-water interfaces.
We investigate using transient non-equilibrum molecular dynamics simulation the temperature relaxation process of three structurally different proteins in water, namely; myoglobin, green fluorescence protein (GFP) and two conformations of the Ca(2+)-ATPase protein. By modeling the temperature relaxation process using the solution of the heat diffusion equation we compute the thermal conductivity and thermal diffusivity of the proteins, as well as the thermal conductance of the protein-water interface. Our results indicate that the temperature relaxation of the protein can be described using a macroscopic approach. The protein-water interface has a thermal conductance of the order of 100-270 MW K(-1) m(-2), characteristic of water-hydrophilic interfaces. The thermal conductivity of the proteins is of the order of 0.1-0.2 W K(-1) m(-1) as compared with approximately 0.6 W K(-1) m(-1) for water, suggesting that these proteins can develop temperature gradients within the biomolecular structures that are larger than those of aqueous solutions. We find that the thermal diffusivity of the transmembrane protein, Ca(2+)-ATPase is about three times larger than that of myoglobin or GFP. Our simulation shows that the Kapitza length of these structurally different proteins is of the order of 1 nm, showing that the protein-water interface should play a major role in defining the thermal relaxation of biomolecules.


[Routine determination of both hemoglobin and hematocrit is not necessary].
It is a well known fact that the haemoglobin concentration and haematocrit vary in proportion to one another in most clinical situations. Therefore routine, simultaneous measurement should not be necessary. In 400 consecutive patients' blood samples, a strong correlation between the two variables is demonstrated. Routine, simultaneous measurement of the haemoglobin concentration and haematocrit increases the workload and should be avoided.


The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer.
Wild-type p53 protein has been shown to inhibit angiogenesis through thrombospondin in the preclinical setting. Here, we determined the associations between the expression of the angiogenic factor vascular endothelial growth factor (VEGF) and the p53 status, including different mutation sites and types, in primary breast cancer. Cytosols from 224 primary breast cancer patients were analyzed with an enzyme immunoassay for determination of human VEGF165 protein content. p53 status was determined by cDNA-based sequencing of the entire coding region, by immunohistochemistry (IHC), and by a p53 luminometric immunoassay (LIA) method. Statistically significant associations was found between higher VEGF content and non-wild-type p53 status for all methods; sequence-based data (P = 0.0019), IHC data (P = 0.0068), and the LIA method (r = 0.427; P > 0.001). Highest VEGF values were detected in tumors with p53 insertions, deletions, and stop codon mutations (P = 0.0043). Combining p53 status and VEGF content resulted in additional prognostic information, relapse-free survival (RFS; P = 0.0377), overall survival (OS; P = 0.0319), and breast cancer corrected survival (BCCS; P = 0.0292). In multivariate analysis, the relative hazard increased when the VEGF data were added to the p53 status, with a relative hazard of 1.7 for RFS and 3.0 for BCCS, compared with 1.1 for RFS and 1.4 for BCCS among the patients with either high VEGF content or p53 mutation. Higher VEGF content was statistically significantly correlated with a worse outcome for patients with estrogen receptor-positive tumors receiving adjuvant tamoxifen: RFS (P = 0.0471), OS (P = 0.0134), BCCS (P = 0.0064), as well as in multivariate analysis with point estimates of 3.4 and 2.1 for BCCS and RFS, respectively. VEGF expression is related to p53 status in human breast cancer patients. Combining VEGF with p53 status resulted in better prognostic prediction.


Precision Control of Fingertip Force by a Biorealistic Hand with a Pair of Neuromorphic Muscles.
In this paper, the ability of precision control of fingertip forces was investigated in an antagonistic cable-driven prosthetic hand with neuromorphic twin of muscles. Surface electromyography (sEMG) signals collected from able-bodied subjects' forearm were processed and used as alpha motor commands to drive the neuromorphic muscle models. A pair of antagonistic muscles were cascaded by two servo motors to control the index finger. Force control performance was tested by pressing a spring with a fixed stiffness using the fingertip, where forces with varying target levels were regulated with visual feedback. Two able-bodied subjects performed the precision force control task with the prosthetic index finger by sEMG signals and the intact hand. One subject was tested with force level changes of 0.1N, and another subject with force level changes of 0.2N. The ability of force regulation by the prosthetic finger was compared to that of the intact finger. Results showed that the overall root-mean-squares (RMS) error of the prosthetic finger was low, although significantly higher than the intact finger, 75% higher in subject 1 and 57% in subject 2. However, the correlation coefficient between the forces of prosthetic finger and intact finger was high, 75% for subject 1 and 84% for subject 2, respectively. This preliminary study is encouraging, illustrating the feasibility of accurate and stable control of different levels of fingertip forces by the prosthetic finger, which is comparable to that of the intact finger. This capability may allow the prosthetic hand for fine manipulation tasks, such as grasping brittle objects, or response to object slip during grasp.Clinical Relevance-This work attempts to restore the ability of a prosthetic hand for precision fingertip force control that may enrich the functionality for users in activities of daily living.


[Early diagnosis of dementia].
Therapeutic interventions for dementia are crucially dependent on the early diagnosis of the case. The question is, how an early diagnosis on the symptom-, the syndrome- and the disease level can be accomplished. The data from epidemiological and clinical studies are described. On the symptom level a disorder of episodic memory, language and visuo-spatial functions have to be assessed in contrast to normal ageing effects and premorbid low cognitive functioning. Simple, clinically practical tests are described like an 10-word learning-test with encoding fascilitation, the semantic fluency (animals) and the clock drawing test. At the syndrome level the dementia syndrome of Alzheimer type has to be differentiated from other dementia syndromes, the senile amnestic syndrome and the delirium syndrome. At the disease level, the attempt to identify clinically the etiological entity is at most not possible with reasonable reliability in senile dementia cases. An improvement of the early diagnosis by prospective longitudinal investigations of the cases seems to be possible in the future.


Phenotypical and functional characterization of the CD8+ T cell repertoire of HLA-A2.1 transgenic, H-2KbnullDbnull double knockout mice.
Homozygous HLA-A2.1 transgenic H-2KbnullDbnull double knockout (KO) mice were created. Their potential to develop HLA-A2. 1-restricted cytolytic responses was compared with that of their classical transgenic counterparts, which still express H-2Kb, Db molecules. On cell surfaces, both strains express similar amounts of chimeric (alpha 1 alpha 2 domains of human, alpha 3 cytoplasmic domains of mouse) HLA-A2.1 molecules in noncovalent association with mouse beta 2-microglobulin. Compared with mice that are totally deprived of histocompatibility class Ia molecules (H-2KbnullDbnull double KO), the expression of HLA-A2.1 in transgenic/double KO mice resulted in sizeable increase in the periphery of CD8+ T cells with a normally diversified TCR repertoire. A biased education in favor of HLA-A2.1, ascribable to the absence of H-2 class Ia molecules, was evidenced in these transgenic/double KO mice by their improved capacity to mount HLA-restricted cytolytic responses, regardless of whether they were virally infected or injected with synthetic epitopic peptide. HLA class I transgenic, H-2 class Ia KO mice should represent useful animal models for the preclinical evaluation of vaccine formulations aiming at the induction of HLA class I-restricted CTL responses.


Arthroplasty of the second toe.
The pathology, pathophysiology, and clinical anatomy of claw, hammer, and crossover toe deformities are presented. Emphasis is placed on the deforming role of the collateral ligaments and intrinsic tendons. A sequential approach to soft-tissue releases about the metatarsophalangeal joint for correction of deformity is presented. In addition to these static deformities, instability of the second metatarsophalangeal joint, including subluxation and dislocation, is discussed.


Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen Cryptococcus neoformans.
Cryptococcus neoformans is one of the most important human fungal pathogens and causes life-threatening meningoencephalitis in immunocompromised patients. The current gold standard therapy for C. neoformans meningoencephalitis is based on medications that are over 50 years old and is not readily available in regions with high disease burden. Here, we report the mycologic, mechanistic, and pharmacologic characterization of a set of benzothioureas with highly selective fungicidal activity against C. neoformans. In addition, to direct antifungal activity, benzothioureas inhibit C. neoformans virulence traits. On the basis of a set of phenotypic, biochemical, and biophysical assays, the benzothioureas (BTUs) inhibit the late secretory pathway (post-Golgi), possibly through a direct interaction with Sav1, an orthologue of the Sec4-class small GTPase. Importantly, pharmacological characterization of the BTUs indicates it readily penetrates the blood-brain barrier. Together, our data support the further development of this scaffold as an antifungal agent with a novel mechanism of action against C. neoformans.


Interaction of human polyomavirus BK with the tumor-suppressor protein p53.
We have been studying the interaction of the oncogenic human polyomavirus BK (BKV) with the tumor-suppressor protein p53 to understand the biology of this virus as well as to understand the basic mechanisms of p53 transactivation. We here demonstrate that p53 binds specifically to the viral promoter at two different sites, S-I (np 361-383) and S-II (np 314-336) in the late region. Site S-I is a 23 bp domain comprising an unique combination of a 10 bp consensus monomer binding site (Pu Pu Pu C (A/T) (T/A) G Py Py Py) which is contiguous with a GC-rich Sp-1 motif that binds p53 in the SV40 promoter. Site S-II also spans a 23 bp sequence containing two tandem consensus binding sites with three base pair mismatches in each and a one base pair deletion. A dimer of a 100 bp region spanning both the binding sites or the site S-I alone induced p53 responsiveness to a basal promoter when cloned upstream from the TATA box, but a similar construct using S-II did not. One tumor-derived mutant protein, p53-175 H, which is defective in DNA binding, also failed to transactivate the reporter gene. We further show that p53 binding-dependent transactivation is abrogated by BKV large T antigen, thereby suggesting an interaction between these two proteins in vivo. In contrast to the isolated p53 binding site, viral early promoter is repressed by p53 in H 1299 cells and the mutants are defective in this function to varying extent. This is suggestive of an involvement of cellular factors in modulating p53's function in the context of the whole promoter. p53 binding sites in BKV are flanked by the binding sites for transcription factors Sp-1 and NF-1 and we show that these transcription factors are present in the immunocomplex with purified p53, implicating modification of p53's transactivation function by protein-protein interaction. Thus, oncoprotein synthesis in this virus might be modulated by p53 in vivo by a complex mechanism other than simple DNA binding and sequestration of the TATA binding protein. Together with SV40 and polyomavirus, which also harbor p53 binding sites, this viral system will serve as a model to understand the role of p53 in viral infection.


Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis.
Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification. Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.


Cannabinoid-dopamine interaction in the pathophysiology and treatment of CNS disorders.
Endocannabinoids and their receptors, mainly the CB(1) receptor type, function as a retrograde signaling system in many synapses within the CNS, particularly in GABAergic and glutamatergic synapses. They also play a modulatory function on dopamine (DA) transmission, although CB(1) receptors do not appear to be located in dopaminergic terminals, at least in the major brain regions receiving dopaminergic innervation, e.g., the caudate-putamen and the nucleus accumbens/prefrontal cortex. Therefore, the effects of cannabinoids on DA transmission and DA-related behaviors are generally indirect and exerted through the modulation of GABA and glutamate inputs received by dopaminergic neurons. Recent evidence suggest, however, that certain eicosanoid-derived cannabinoids may directly activate TRPV(1) receptors, which have been found in some dopaminergic pathways, thus allowing a direct regulation of DA function. Through this direct mechanism or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with DA transmission in the CNS and this has an important influence in various DA-related neurobiological processes (e.g., control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes like basal ganglia disorders, schizophrenia, and drug addiction. The present review will address the current literature supporting these cannabinoid-DA interactions, with emphasis in aspects dealing with the neurochemical, physiological, and pharmacological/therapeutic bases of these interactions.


Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level.
This paper presents age-specific reference ranges for hearing level and change in hearing level for men and women at 500, 1000, 2000, and 4000 Hz. The percentiles are constructed from data obtained from persons in the Baltimore Longitudinal Study of Aging who were rigorously screened for otological disorders and evidence of noise-induced hearing loss. The resulting percentile curves represent norms for changes in hearing level in the absence of any known otologic disease. These percentile curves provide a reference for detecting when a person deviates from a normal pattern of change, thus helping in diagnosing problems with hearing or in monitoring hearing in occupational settings. The smoothed means and standard deviations of the hearing levels were used to construct the longitudinal percentiles. The percentiles for cross-sectional change were constructed using the skew normal distribution to allow for the percentiles to be asymmetric on either side of the median level. These percentiles are the first reference curves that (1) provide standards for hearing level changes over periods of up to 15 years, (2) account for age differences in the distribution of hearing levels, and (3) are based on data from persons who have been systematically screened for otological disorders and evidence of noise-induced hearing loss.


CircularRNA circ_0071269 knockdown protects against from diabetic cardiomyopathy injury by microRNA-145/gasdermin A axis.
Circular RNAs (circRNAs) are involved in the development and progression of diabetic cardiomyopathy (DCM). However, the specific function and underlying mechanism of circ_0071269 in DCM remains unclear. In our study, mRNA and miRNA expression was detected by real-time quantitative PCR (qRT-PCR). RNase R and actinomycin D treatment were applied to test the characteristics of circ_0071269. Cell Counting Kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) and enzyme-linked immunosorbent assay (ELISA) kits were performed to determine the cell viability, cell LDH content and interleukin (IL)-1β and IL-18 levels, respectively. Cell death rate was determined by Flow cytometry, and Western blotting was for the protein expression levels. In addition, luciferase reporter and RNA pull-down assays were performed to confirm the binding relationship between miR-145 and circ_0071269 or gasdermin A (GSDMA). Echocardiography, Hematoxylin and Eosin (HE) Staining, and Immunohistochemical (IHC) Staining were performed to evaluate myocardial damage in vivo. We found that circ_0071269 was significantly overexpressed in H9c2 cells upon treatment with high glucose. Knockdown of circ_0071269 promoted cell viability and inhibited the inflammatory response, cytotoxicity, and pyroptosis of H9c2 cells in vitro. Moreover, circ_0071269 sponges miR-145 to upregulate GSDMA. A miR-145 inhibitor antagonized the effects of circ_0071269 knockdown on the cellular functions of H9c2 cells, while the effects of miR-145 were abrogated by the overexpression of GSDMA. Meanwhile, knockdown of circ_0071269 attenuated cardiac dysfunction of DM mice. Hence, circ_0071269 may promote the development of DCM through the miR-145/GSDMA axis and thus provide a novel marker for the treatment of DCM.


Reversible Endoscopic Medial Maxillectomy: Endonasal Approach to Diseases of the Maxillary Sinus.
Introduction The endoscopic access has reduced the morbidity associated with external approaches in diseases of the maxillary sinus. A reversible endoscopic medial maxillectomy (REMM) is presented as an alternative for treatment of benign maxillary diseases. Objective To describe the REMM technique and report four cases of patients with benign maxillary sinus conditions treated through this approach. Methods The present study was divided into two parts: anatomical and case series. Two cadaveric dissections confirmed the feasibility of the REMM approach. The same technique was performed on four consecutive patients with benign maxillary sinus disease. Results The cadaveric dissections confirmed wide exposure to the maxillary cavity, preserving the anatomy of the maxillary sinus. In the patient series, one patient presented with an antrochoanal polyp, one had a silent sinus syndrome, one had a chronic maxillary sinusitis secondary to a gunshot, and the last one had an inverted papilloma in the maxillary sinus. In all of the cases, the REMM approach provided excellent access and adequate resection, as well as preservation of the inferior turbinate, nasolacrimal duct, and lateral wall of the nose (including its osteomucosal component). Finally, all of the patients had an uneventful postoperative course. Conclusion The REMM technique is an excellent surgical approach to benign conditions of the maxillary sinus. It has few limitations and appears to be associated with less morbidity than conventional techniques.


Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston Study.
To determine whether alterations in cerebral blood flow regulation are associated with slow gait speed and falls in community-dwelling elderly individuals. The study sample consisted of 419 individuals from the MOBILIZE Boston Study (MBS) who had transcranial Doppler ultrasound measures of cerebral blood flow velocity. The MBS is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We measured beat-to-beat blood flow velocity in the middle cerebral artery in response to 1) changes in end-tidal CO(2) (cerebral vasoreactivity) and 2) blood pressure changes during a sit-to-stand protocol (cerebral autoregulation). Gait speed was measured during a 4-meter walk. Falls were tracked by monthly calendars, and demographic and clinical characteristics were assessed at baseline. A multivariate linear regression analysis showed that cerebral vasoreactivity was cross-sectionally related to gait speed (p = 0.039). Individuals in the lowest quintile of vasoreactivity had lower gait speeds as compared to those in the highest quintile (p = 0.047). In a negative binomial regression analysis adjusted for relevant covariates, the relationship between cerebral vasoreactivity and fall rate did not reach significance. However, when comparing individuals in the lowest to highest quintile of cerebral vasoreactivity, those in the lowest quintile had a higher fall rate (p = 0.029). Impaired cerebral blood flow regulation, as measured by cerebral vasoreactivity to CO(2), is associated with slow gait speed and may lead to the development of falls in elderly people.


Identification of the oriI-binding site of poliovirus 3C protein by nuclear magnetic resonance spectroscopy.
Replication of picornaviral genomes requires recognition of at least three cis-acting replication elements: oriL, oriI, and oriR. Although these elements lack an obvious consensus sequence or structure, they are all recognized by the virus-encoded 3C protein. We have studied the poliovirus 3C-oriI interaction in order to begin to decipher the code of RNA recognition by picornaviral 3C proteins. oriI is a stem-loop structure that serves as the template for uridylylation of the peptide primer VPg by the viral RNA-dependent RNA polymerase. In this report, we have used nuclear magnetic resonance (NMR) techniques to study 3C alone and in complex with two single-stranded RNA oligonucleotides derived from the oriI stem. The (1)H-(15)N spectra of 3C recorded in the presence of these RNAs revealed site-specific chemical shift perturbations. Residues that exhibit significant perturbations are primarily localized in the amino terminus and in a highly conserved loop between residues 81 and 89. In general, the RNA-binding site defined in this study is consistent with predictions based on biochemical and mutagenesis studies. Although some residues implicated in RNA binding by previous studies are perturbed in the 3C-RNA complex reported here, many are unique. These studies provide unique site-specific insight into residues of 3C that interact with RNA and set the stage for detailed structural investigation of the 3C-RNA complex by NMR. Interpretation of our results in the context of an intact oriI provides insight into the architecture of the picornavirus VPg uridylylation complex.


Chernobyl and Fukushima nuclear accidents: what has changed in the use of atmospheric dispersion modeling?
The threat of a major accidental or deliberate event that would lead to hazardous materials emission in the atmosphere is a great cause of concern to societies. This is due to the potential large scale of casualties and damages that could result from the release of explosive, flammable or toxic gases from industrial plants or transport accidents, radioactive material from nuclear power plants (NPPs), and chemical, biological, radiological or nuclear (CBRN) terrorist attacks. In order to respond efficiently to such events, emergency services and authorities resort to appropriate planning and organizational patterns. This paper focuses on the use of atmospheric dispersion modeling (ADM) as a support tool for emergency planning and response, to assess the propagation of the hazardous cloud and thereby, take adequate counter measures. This paper intends to illustrate the noticeable evolution in the operational use of ADM tools over 25 y and especially in emergency situations. This study is based on data available in scientific publications and exemplified using the two most severe nuclear accidents: Chernobyl (1986) and Fukushima (2011). It appears that during the Chernobyl accident, ADM were used few days after the beginning of the accident mainly in a diagnosis approach trying to reconstruct what happened, whereas 25 y later, ADM was also used during the first days and weeks of the Fukushima accident to anticipate the potentially threatened areas. We argue that the recent developments in ADM tools play an increasing role in emergencies and crises management, by supporting stakeholders in anticipating, monitoring and assessing post-event damages. However, despite technological evolutions, its prognostic and diagnostic use in emergency situations still arise many issues.


Estrogen receptor based imaging agents. 2. Synthesis and receptor binding affinity of side-chain halogenated hexestrol derivatives.
We have synthesized as potential imaging agents for human breast tumors a series of hexestrol analogues bearing the halogens fluorine, chlorine, bromine, and iodine at the terminus of the hexane chain. The binding affinity of these compounds for the estrogen receptor from uterine tissues forms a monotonically decreasing series, starting at 129% of that of estradiol for the fluoro analogue and decreasing to 60% for the iodo analogue. Such a modest decrease in binding affinity is thought to reflect the preference of the receptor for lipophilic groups and for substituents of moderate steric size at this site, parameters which change in opposite directions in the halogen sequence going from fluorine to iodine. Three estrogenic bis(trifluoromethyl)diphenylethylenes, prepared by DuPont, also showed substantial binding affinities for the estrogen receptor. In terms of ease of radiolabeling and high receptor binding selectivity, the compound that appears to be the most promising candidate for a breast tumor imaging agent in these series is the chain terminal fluorohexestrol.