Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.
In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.


Exogenous factors in the immunotoxicity of oral PMN.
Current evidence indicates that periodontal disease is frequently due to inappropriate levels of gingival granulocyte functions. Reason of this failure may be the toxic effects of a number of local or systemic exogenous factors, capable of spreading through the gingival crevice environment, and strongly conditioning the granulocyte activities. The wide list includes bacteria and granulotoxic products, hedonistic drugs (mainly tobacco), and chemotherapeutic agents (especially antimicrobials used for preventing or reducing the accumulation of dental plaque). Almost always, their presence induces a time- and/or dose-dependent toxicity.


Cyclical variation of blood pressure and heart rate in neonates.
Using a computerised physiological monitoring system a cyclical variation in blood pressure (waves), with associated changes in heart rate and transcutaneous oxygen, was observed. Twenty five episodes were seen in 10 neonates, with a median gestation of 33 weeks (range 28-42 weeks). Eight neonates had an asphyxial injury. Blood pressure waves had a mean (SD) amplitude of 11.6 (5.6) mm Hg with a mean wavelength of 9.0 (5.2) minutes. Both amplitude and frequency were independent of gestation. In neonates of less than 34 weeks an inverse phase relation existed between heart rate and blood pressure waves (blood pressure rose as heart rate fell); in infants with a gestation greater than 34 weeks a direct phase relationship occurred (blood pressure and heart rate rose together). It is postulated that hypertensive blood pressure waves may cause or exacerbate cerebral pathology in neonates with a pressure passive cerebral circulation.


Advanced leiomyosarcoma of the stomach.
Retrospective studies of twelve patients with advanced gastric leiomyosarcomas were undertaken to evaluate radical surgical resection and combined modality treatment with regard to the patient survival and symptom palliation. All but one patient were found to have metastases or involvement of adjacent organs at the initial operation. Despite radical resection, multidrug chemotherapy, and radiation therapy, no patient survived beyond the third year. Patients with objective response to chemotherapy and radiation and chemotherapy had a mean survival of 27 months, while those who did not respond survived only 7 months. The longest survival among untreated group was 8 months. Successful palliation of advanced gastric leiomyosarcoma requires early diagnosis, surgical resection and multimodal therapy.


A Smart Detection System Based on Specific Magnetic and Rolling Cycle Amplification Signal-Amplified Dual-Aptamers to Accurately Monitor Minimal Residual Diseases in Patients with T-ALL.
It is a major clinical challenge for clinicians how to early find out minimal residual diseases (MRD) of leukemia. Here, we developed a smart detection system for MRD involving magnetic aptamer sgc8 probe (M-sgc8 probe) to capture CEM cells and rolling cycle amplification probe (RCA-sgc8 probe) to initiate RCA, producing a single-stranded tandem repeated copy of the circular template. The DNA products were hybridized with molecular beacon to generate the amplified fluorescence signal. An in vitro model to mimic MRD was established to evaluate the sensitivity of the smart detection system. The smart detection system was used to detect MRD in patients with T-ALL peri-chemotherapy, which could not only specifically captured T-ALL cells, but also significantly amplified fluorescence signals on them. The sensitivity was 1/20,000. These results indicate that the smart detection system with high specificity and sensitivity could more efficiently monitor the progress of T-ALL peri-chemotherapy.


Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice.
It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-kappaB activation, and attenuated serum levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 microg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.


Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.
Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.


Epidermal nevus.
A healthy 25-year-old man presented with a widespread, non-organoid, non-epidermolytic epidermal nevus. In addition to extensive hyperpigented patches and thin plaques following Blaschko lines, there were superimposed psoriasiform plaques on the elbows and warty plaques on the upper trunk. Striate palmar keraoderma also was evident. We review the clinical morphologies, sites of involvement, histopathologic findings (presence or absence of epidermolytic hyperkeratosis), and syndromal associations of non-organoid EN with underlying mutations in different genes.


A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.
Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.


Murine CXCR3+CXCR6+γδT Cells Reside in the Liver and Provide Protection Against HBV Infection.
Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3+CXCR6+ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3+CXCR6+ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3+CXCR6+ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3+CXCR6+ γδT cells into acute HBV-infected TCRδ-/- mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3+CXCR6+ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3+CXCR6+ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.


Surgical anatomy of the upper eyelid relating to upper blepharoplasty or blepharoptosis surgery.
Eyelid anatomy, including thickness measurements, was examined in numerous age groups. The thickest part of the upper eyelid is just below the eyebrow (1.127±238 µm), and the thinnest near the ciliary margin (320±49 µm). The thickness of skin at 7 mm above the eyelashes was 860±305 µm. The results revealed no significant differences among the age groups. Fast fibers (87.8±3.7%) occupied a significantly larger portion of the orbicularis oculi muscle (OOM) than nonfast fibers (12.2±3.7%). The frontalis muscle passed through and was inserted into the bundles of the OOM on the superior border of the eyebrow at the middle and medial portions of the upper eyelid. Laterally, the frontalis muscle inserted about 0.5 cm below the superior border of the eyebrow. Fast fibers occupied a significantly larger portion of the OOM than did non-fast fibers. The oculomotor nerve ends that extend forward to the distal third of the levator muscle are exposed and vulnerable to local anesthetics and may be numbed during blepharoplasty. The orbital septum consists of 2 layers. The outer layer of loose connective tissue descends to interdigitate with the levator aponeurosis and disperses inferiorly. The inner layer follows the outer layer, then reflects and continues posteriorly with the levator sheath. Widths of the tarsal plate at its lower border, mid-height, and upper border were 21.8±1.8, 16.2±1.6, and 8.3±1.0 mm, respectively. The widths of the levator aponeurosis were 32.0±2.2, 29.2±3.5, and 27.2±3.9 mm, respectively. Below the levator, the "conjoint fascial sheath" (CFS) is attached to the conjunctival fornix. The CFS was 12.2±2.0 mm anteroposterior length and 1.1±0.1 mm thick. The shape was equilateral trapezoid with a longer base anteriorly. The superior palpebral muscle was trapezoidal. The lengths of its sides were 15.58±1.82 and 22.30±5.25 mm, and its height was 13.70±2.74 mm. The width of the levator aponeurosis was approximately 4 mm wider than the superior palpebral muscle.


Polymorphisms within the HLA-DRw6 haplotype. III. DQ alpha and DQ beta polymorphism associated with HLA-D.
We have studied HLA-DQ encoded antigens from HLA-DRw6 homozygous cells and analyzed the DQ region at the DNA level. HLA-DQ molecules were isolated from EBV transformed B-cell lines and analyzed for DQ alpha and DQ beta polymorphism. From the same set of cells, DNA was isolated and analyzed for RFLP. Polymorphism could be detected by both techniques, i.e., on the protein level and on the DNA. The variation in pI of the DQ alpha and beta chains correlated with the polymorphism as detected by HTC typing, as did the variation in molecular weight of the bands hybridizing to DQ specific cDNA probes; identical patterns were detected for cells of one HLA-D specificity and different patterns for different HLA-D types. Additionally, DQ reactive PLT reagents were raised against DRw6 positive cells. Panel studies revealed that these DQ reactive proliferative T cells can discriminate between the polymorphic DQ antigens on cells with different HLA-D specificities.


Visualization of a high protein concentration in the cochlea of a patient with a large endolymphatic duct and sac, using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging.
To evaluate the inner ear of a patient with an enlarged vestibular aqueduct and acute hearing deterioration, using three-dimensional fluid-attenuated inversion recovery (3D FLAIR) magnetic resonance imaging (MRI). Three-dimensional fluid-attenuated inversion recovery MRI has been recently developed to detect haemorrhage and high concentrations of protein. Application of this method to inner-ear diseases has not been fully described. We used 3D FLAIR MRI to evaluate a patient with an enlarged vestibular aqueduct and acute hearing deterioration. On 3D FLAIR MRI, this patient had high signals in the endolymphatic duct and sac, the vestibule and the cochlea and was diagnosed as having a high protein concentration in the inner ear. These high signal areas were not detected by T1- and T2-weighted MRI. This is the first published case in which a high protein concentration in the cochlea of a patient with an enlarged vestibular aqueduct was detected by 3D FLAIR MRI. These findings strongly supported the theory of the pathophysiology of hearing deterioration in patients with an enlarged vestibular aqueduct, which states that hyperosmolar fluid in the enlarged endolymphatic sac refluxes into the cochlea, resulting in damage to the hair cells. Thus, these finding may help clarify the cause of hearing deterioration in the presence of a large endolymphatic duct and sac.


In vivo magnetic resonance imaging of orthotopic prostate cancer.
Methods for imaging orthotopic prostate tumors within the prostate or small tumors with extension outside the prostate are needed to more closely model human prostate tumors, which are most commonly located within the gland or may extend just through the gland. By comparing MR sequences, we found that the T2-based Dixon 'water only' sequence best visualized tumors within the prostate of mouse models in both young and old mice and that tumor weight derived from this sequence correlated highly with ex vivo tumor weight (r2 = 0.98, p < 0.001, n = 12). This should aid tumor detection, margin delineation and evaluation of tumor burden to enable studies including, but not limited to, evaluating the natural history of the disease, the mechanisms of action and the efficacy of therapeutic interventions.


Occurrence of Squash yellow mild mottle virus and Pepper golden mosaic virus in Potential New Hosts in Costa Rica.
Leaf samples of Solanum lycopersicum, Capsicum annuum, Cucurbita moschata, Cucurbita pepo, Sechium edule and Erythrina spp. were collected. All samples were positive for begomoviruses using polymerase chain reaction and degenerate primers. A sequence of ∼1,100 bp was obtained from the genomic component DNA-A of 14 samples. In addition, one sequence of ∼580 bp corresponding to the coat protein (AV1) was obtained from a chayote (S. edule) leaf sample. The presence of Squash yellow mild mottle virus (SYMMoV) and Pepper golden mosaic virus (PepGMV) were confirmed. The host range reported for SYMMoV includes species of the Cucurbitaceae, Caricaceae and Fabaceae families. This report extends the host range of SYMMoV to include the Solanaceae family, and extends the host range of PepGMV to include C. moschata, C. pepo and the Fabaceae Erythrina spp. This is the first report of a begomovirus (PepGMV) infecting chayote in the Western Hemisphere.


Extended upstream A-T sequence increases T7 promoter strength.
Bacteriophage T7 promoters contain a consensus sequence from -17 to +6 relative to the transcription start site, +1. In addition, the strong class III promoters are characterized by an extended AT-rich region upstream of -17, which is often interrupted by one or more GC base pairs in the weaker class II promoters. Herein we studied the role of the AT-rich region upstream of -17 in transcription regulation of T7 RNA polymerase. Equilibrium DNA binding studies with promoter fragments of consensus sequence truncated at various positions between -17 and -27 showed that the polymerase-promoter complex is significantly stabilized as the upstream AT-rich sequence is extended to and beyond -22. Similarly, promoters in which the AT-rich region from -17 to -22 is interrupted by several GC base pairs showed weak binding. Kinetic studies indicated that the presence of extended AT-rich sequence slows the dissociation rate constant of the polymerase-promoter complex and slightly stimulates the association rate constant, thereby increasing the stability of the complex. Measurement of the transcription activity revealed that the extended AT-rich region does not affect the kinetics of abortive synthesis up to the formation of 8-nucleotide RNA but causes accumulation of longer abortive products between 9 and 13 nucleotides. The observed effects of the upstream DNA region were AT sequence-specific, and the results suggested a larger role for the extended AT-rich sequence that has been unappreciated previously. We propose that the AT-rich DNA sequence upstream of -17 plays a role in modulating the efficiency of transcription initiation by affecting both the affinity of T7 RNA polymerase for the promoter and the efficiency of promoter clearance.


Autologous Fat Grafting as a Last Resort for Unsustainable Pain in a Woman with Multiple Osteochondromas.
Multiple osteochondromas (MO) is characterized by the formation of osteochondromas throughout the entire body. Although the evidence regarding its pathogenesis is well understood, no curative treatment for the disorder is available. Patients can be treated symptomatically by surgical removal of painful osteochondromas. Unfortunately, some patients still suffer from severe pain, even after surgery. We report on a case concerning a 48-year-old woman with a history of MO who presented with persistent pain after surgical removal of a symptomatic osteochondroma of the left scapula and multiple symptomatic osteochondromas of the left foot and trochanteric region. Several interventions to reduce the pain did not have any lasting effect. Subsequently, she was treated with autologous fat grafting (AFG). After each session she was pain-free for at least one year and reported only partial recurrence of the pain. This is the first case report describing AFG for the treatment of pain after both surgical removal of an osteochondroma and symptomatic osteochondromas in a patient suffering MO with promising results. The treatment is more effective and clearly continues to remain active longer than injection therapy or pain medication. Future studies are necessary to confirm our results.


Brain training improves recovery after stroke but waiting list improves equally: A multicenter randomized controlled trial of a computer-based cognitive flexibility training.
Brain training is currently widely used in an attempt to improve cognitive functioning. Computer-based training can be performed at home and could therefore be an effective add-on to available rehabilitation programs aimed at improving cognitive functioning. Several studies have reported cognitive improvements after computer training, but most lacked proper active and passive control conditions. Our aim was to investigate whether computer-based cognitive flexibility training improves executive functioning after stroke. We also conducted within-group analyses similar to those used in previous studies, to assess inferences about transfer effects when comparisons to proper control groups are missing. We conducted a randomized controlled, double blind trial. Adults (30-80 years old) who had suffered a stroke within the last 5 years were assigned to either an intervention group (n = 38), active control group (i.e., mock training; n = 35), or waiting list control group (n = 24). The intervention and mock training consisted of 58 half-hour sessions within a 12-week period. Cognitive functioning was assessed using several paper-and-pencil and computerized neuropsychological tasks before the training, immediately after training, and 4 weeks after training completion. Both training groups improved on training tasks, and all groups improved on several transfer tasks (three executive functioning tasks, attention, reasoning, and psychomotor speed). Improvements remained 4 weeks after training completion. However, the amount of improvement in executive and general cognitive functioning in the intervention group was similar to that of both control groups (active control and waiting list). Therefore, this improvement was likely due to training-unspecific effects. Our results stress the importance to include both active and passive control conditions in the study design and analyses. Results from studies without proper control conditions should be interpreted with care.


Geoepidemiology and changing mortality in primary biliary cholangitis.
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.


Aramid Pulp Reinforced Clay Aerogel Composites: Mechanical, Thermal and Combustion Behavior.
In this work, we reported that aramid pulps (AP) reinforced clay aerogel composites with improved mechanical strength, good thermal insulation and fire resistance based on the combination of AP, Poly(vinyl alcohol) (PVA) and sodium montmorillonite (MMT), which present a promising prospect in the thermal insulation application. The PVA-MMT-APx (x: denotes the mass content of AP) aerogel composites present an isotropic "lamella-honeycomb" porous structure, which endows them with excellent comprehensive performance. With the AP content increasing, the extremely low density is kept, ranging between 67-73 mg/cm3, and the low thermal conductivity is maintained within 40.9-47.9 mW·m-1·K-1. The mechanical strength is significantly improved with the maximum compressive modulus increasing from 2.95 to 5.96 MPa and the specific modulus rising from 44.03 to 81.64 MPa∙cm3/g. Their detailed heat transfer process has been analyzed, which provides a deep understanding to the low thermal conductivity of the PVA-MMT-APx aerogel composites. Based on the combination of thermogravimetric analysis and combustion behavior, the PVA-MMT-APx aerogel composites are demonstrated to possess improved thermal stability and fire resistance. This study puts forward a facile approach to utilizing AP to reinforce clay aerogel composites, which provides new insight into the development of thermal-insulating, fire-safe and high-strength thermal insulation materials.


The psychosocial consequences of childhood infection with human immunodeficiency virus.
This article reviews the available medical literature on the psychosocial and neuropsychiatric implications of childhood infection by the human immunodeficiency virus. This information is supplemented by discussion of cases from our clinical experience. It is clear that different psychosocial issues are confronted by children of different ages (infants, young children or adolescents) and their families. The differences are due partly to the social correlates of different modes of transmission of the acquired immunodeficiency syndrome (AIDS), the psychosocial risk factors that are associated with certain family life-styles, whether other family members are infected, and the developmental stage and awareness of the child. Psychiatric assessments of these children and their families are recommended as a routine as they will identify potential ethical dilemmas, and will allow for the detection and management of the psychosocial and neuropsychiatric consequences of AIDS.


Normal masticatory function of girls and young women: mandibular masticatory movements.
Mandibular masticatory movements were evaluated in 10 young adult women and 12 young girls. All subjects had normal occlusion with minimal overjet. Masticatory movements of the incisors were recorded in three dimensions with an Optotrak® camera system while subjects chewed gum in a habitual manner for 20 seconds. A masticatory analysis program divided each masticatory cycle into four phases and averaged the duration, excursions, and velocities of all cycles for each subject. Duration of the total cycle was longer in women because they had longer slow opening and slow closing phases than girls. Women had a significantly larger vertical component of opening during slow opening and the power stroke than girls. Women also had a significantly larger posterior component of opening during slow opening and the power stroke than did girls. At maximum opening, women also tended to have the incisors in a more posterior position. There were no differences between the groups for the amount of maximum lateral excursion during chewing. Vertical velocity during fast opening and fast closing was slower for women, but there were no age-related differences during the slow open and slow close phases. Am. J. Human Biol. 10:53-62, 1998. © 1998 Wiley-Liss, Inc.


Interaction of the san jacinto and san andreas fault zones, southern california: triggered earthquake migration and coupled recurrence intervals.
Two lines of evidence suggest that large earthquakes that occur on either the San Jacinto fault zone (SJFZ) or the San Andreas fault zone (SAFZ) may be triggered by large earthquakes that occur on the other. First, the great 1857 Fort Tejon earthquake in the SAFZ seems to have triggered a progressive sequence of earthquakes in the SJFZ. These earthquakes occurred at times and locations that are consistent with triggering by a strain pulse that propagated southeastward at a rate of 1.7 kilometers per year along the SJFZ after the 1857 earthquake. Second, the similarity in average recurrence intervals in the SJFZ (about 150 years) and in the Mojave segment of the SAFZ (132 years) suggests that large earthquakes in the northern SJFZ may stimulate the relatively frequent major earthquakes on the Mojave segment. Analysis of historic earthquake occurrence in the SJFZ suggests little likelihood of extended quiescence between earthquake sequences.


Mucosal human defensins 5 and 6 antagonize the anti-HIV activity of candidate polyanion microbicides.
Defensins are highly abundant antimicrobial peptides in the female genital mucosa. We have previously shown that human defensins 5 and 6 (HD5 and HD6), produced by cervicovaginal epithelial cells, significantly enhance HIV infectivity in vitro. Candidate polyanion microbicides, including PRO 2000, cellulose sulfate and carrageenan, failed to protect women against HIV infection in large-scale clinical trials, but the molecular basis of ineffectiveness was not clear. We hypothesized that mucosal host factors such as HD5 an HD6 may alter the activity of polyanion microbicides against HIV. Our results demonstrated that HD5 and HD6 but not their linear analogs antagonized the anti-HIV activity of PRO 2000, cellulose sulfate and carrageenan in vitro. Polyanion microbicides also reduced the HIV-enhancing effect of these defensins. We conclude that mucosal host factors could negatively impact the efficacy of topical microbicides against HIV, and their impact on the activity of candidate microbicides needs to be considered during the preclinical evaluation.


Predators drive community reorganization during experimental range shifts.
Increased global temperatures caused by climate change are causing species to shift their ranges and colonize new sites, creating novel assemblages that have historically not interacted. Species interactions play a central role in the response of ecosystems to climate change, but the role of trophic interactions in facilitating or preventing range expansions is largely unknown. The goal of our study was to understand how predators influence the ability of range-shifting prey to successfully establish in newly available habitat following climate warming. We hypothesized that fish predation facilitates the establishment of colonizing zooplankton populations, because fish preferentially consume larger species that would otherwise competitively exclude smaller-bodied colonists. We conducted a mesocosm experiment with zooplankton communities and their fish predators from lakes of the Sierra Nevada Mountains in California, USA. We tested the effect of fish predation on the establishment and persistence of a zooplankton community when introduced in the presence of higher- and lower-elevation communities at two experimental temperatures in field mesocosms. We found that predators reduce the abundance of larger-bodied residents from the alpine and facilitate the establishment of new lower-elevation species. In addition, fish predation and warming independently reduced the average body size of zooplankton by up to 30%. This reduction in body size offset the direct effect of warming-induced increases in population growth rates, leading to no net change in zooplankton biomass or trophic cascade strength. We found support for a shift to smaller species with climate change through two mechanisms: (a) the direct effects of warming on developmental rates and (b) size-selective predation that altered the identity of species' that could colonize new higher elevation habitat. Our results suggest that predators can amplify the rate of range shifts by consuming larger-bodied residents and facilitating the establishment of new species. However, the effects of climate warming were dampened by reducing the average body size of community members, leading to no net change in ecosystem function, despite higher growth rates. This work suggests that trophic interactions play a role in the reorganization of regional communities under climate warming.


Rhein induces apoptosis in HL-60 cells via reactive oxygen species-independent mitochondrial death pathway.
Rhein is an anthraquinone compound enriched in the rhizome of rhubarb, a traditional Chinese medicine herb showing anti-tumor promotion function. In this study, we first reported that rhein could induce apoptosis in human promyelocytic leukemia cells (HL-60), characterized by caspase activation, poly(ADP)ribose polymerase (PARP) cleavage, and DNA fragmentation. The efficacious induction of apoptosis was observed at 100 microM for 6h. Mechanistic analysis demonstrated that rhein induced the loss of mitochondrial membrane potential (DeltaPsi(m)), cytochrome c release from mitochondrion to cytosol, and cleavage of Bid protein. Rhein also induced generation of reactive oxygen species (ROS) and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinase. However, these actions seem not to be associated with the apoptosis induction because antioxidants including N-acetyl cysteine (NAC), Tiron, and catalase did not block rhein-induced apoptosis, although they could block the generation of ROS and the phosphorylation of JNK and p38 kinase. Our data demonstrate that rhein induces apoptosis in HL-60 cells via a ROS-independent mitochondrial death pathway.


Molecular and Dual-Isotopic Profiling of the Microbial Controls on Nitrogen Leaching in Agricultural Soils under Managed Aquifer Recharge.
Nitrate (NO3-) leaching is a serious health and ecological concern in global agroecosystems, particularly those under the application of agricultural-managed aquifer recharge (Ag-MAR); however, there is an absence of information on microbial controls affecting NO3- leaching outcomes. We combine natural dual isotopes of NO3- (15N/14N and 18O/16O) with metagenomics, quantitative polymerase chain reaction (PCR), and a threshold indicator taxa analysis (TITAN) to investigate the activities, taxon profiles, and environmental controls of soil microbiome associated with NO3- leaching at different depths from Californian vineyards under Ag-MAR application. The isotopic signatures demonstrated a significant priming effect (P < 0.01) of Ag-MAR on denitrification activities in the topsoil (0-10 cm), with a 12-25-fold increase of 15N-NO3- and 18O-NO3- after the first 24 h of flooding, followed by a sharp decrease in the enrichment of both isotopes with ∼80% decline in denitrification activities thereafter. In contrast, deeper soils (60-100 cm) showed minimal or no denitrification activities over the course of Ag-MAR application, thus resulting in 10-20-fold of residual NO3- being leached. Metagenomic profiling and laboratory microcosm demonstrated that both nitrifying and denitrifying groups, responsible for controlling NO3- leaching, decreased in abundance and potential activity rates with soil depth. TITAN suggested that Nitrosocosmicus and Bradyrhizobium, as the major nitrifier and denitrifier, had the highest and lowest tipping points with regard to the NO3- changes (P < 0.05), respectively. Overall, our study provides new insight into specific depth limitations of microbial controls on soil NO3- leaching in agroecosystems.


Luminal fillers in nerve conduits for peripheral nerve repair.
The use of nerve conduits as an alternative for nerve grafting has a long experimental and clinical history. Luminal fillers, factors introduced into these nerve conduits, were later developed to enhance the nerve regeneration through conduits. Though many luminal fillers have been reported to improve nerve regeneration, their use has not been subjected to systematic review. This review categorizes the types of fillers used, the conduits associated with fillers, and the reported performance of luminal fillers in conduits to present a preference list for the most effective fillers to use over specific distances of nerve defect.


Role of sulfoquinovosyl diacylglycerol for the maintenance of photosystem II in Chlamydomonas reinhardtii.
The physiological role of sulfoquinovosyl diacylglycerol (SQDG) in photosynthesis was investigated with a SQDG defective mutant (hf-2) of Chlamydomonas reinhardtii that did not have any detectable amount of SQDG. The mutant showed a lower rate of photosystem II (PSII) activity by approximately 40% and also a lower growth rate than those of the wild-type. Results of genetical analysis of hf-2 strongly suggest that the SQDG defect and the lowered PSII activity are due to a single gene mutation. The supplementation of SQDG to hf-2 cells restored the lowered PSII activity to the same level as that of wild-type cells, and also enabled the mutant to grow even in the presence of 135 nm 3-(3,4-dichlorophenyl)-1,1-dimethylurea. Moreover, the incubation of isolated thylakoid membranes of hf-2 with SQDG raised the lowered PSII activity. Chemical modifications of SQDG impaired the recovery of PSII activity. The results suggest that SQDG is indispensable for PSII activity in Chlamydomonas by maintaining PSII complexes in their proper state.


Nanomechanics of collagen microfibrils.
Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to organisms and is thus the prime construction material in biology. Collagen is also the dominating material in the extracellular matrix where its stiffness controls cell differentiation, growth and pathology. We use atomistic-based hierarchical multiscale modeling to describe this complex biological material from the bottom up. This includes the use and development of large-scale computational modeling tools to investigate several aspects related to collagen-based tissues, including source of visco-elasticity and deformation mechanisms at the nanoscale level. The key innovation of this research is that until now, collagen materials have primarily been described at macroscopic scales, without explicitly understanding the mechanical contributions at the molecular and fibrillar levels. The major impact of this research will be the development of fundamental models of collagenous tissues, important to the design of new scaffolding biomaterials for regenerative medicine as well as for the understanding of collagen-related diseases.


Exploring the Effect of Metformin to Lower Thyroid-Stimulating Hormone in Euthyroid and Hypothyroid Type-2 Diabetic Patients.
Introduction Metformin is one of the safest, first-line oral hypoglycemic agents used in type-2 diabetes mellitus patients. This study aims to study the effect of metformin on thyroid-stimulating hormone (TSH) in hypothyroid and euthyroid individuals, as both these diseases have an increased prevalence and coexistence. Method This hospital-based study was conducted in Jinnah Allama Iqbal Institute of Diabetes and Endocrinology (JAIDE), Allama Iqbal Medical College/Jinnah Hospital Lahore, Pakistan, from October 2019 to April 2020. One hundred and sixty type-2 diabetic participants, aged 25-60 years and meeting the inclusion criteria were enrolled in the study after informed consent. They were divided into two groups, the hypothyroid group who were already on levothyroxine therapy and had a stable TSH in the normal range, and a euthyroid group who had no thyroid dysfunction. Both the groups were started on metformin therapy for the control of type-2 diabetes mellitus and followed for six months. Their blood samples for TSH and free thyroid hormone (fT4) were drawn both prior to and after the study period. Results Out of the 160 type-2 diabetic patients, TSH levels showed a significant reduction in the hypothyroid patients (2.33 ± 0.70, p < 0.001) with no significant changes in the euthyroid patients (3.87 ± 0.40, p = 0.206) following six months of metformin therapy. However, there was no significant difference in the fT4 levels in either of the groups. Conclusion Metformin has the effect of significantly lowering TSH levels in hypothyroid individuals. However, no such effect was observed in euthyroid patients.


Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases.
There is a pressing need for antiviral agents that are effective against multiple classes of viruses. Broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. We reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. A chimeric antibody, bavituximab, was used to identify and target the exposed anionic phospholipids. Infection of cells with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent) led to the exposure of anionic phospholipids. Bavituximab treatment cured overt disease in guinea pigs lethally infected with Pichinde virus. Direct clearance of infectious virus from the blood and antibody-dependent cellular cytotoxicity of virus-infected cells seemed to be the major antiviral mechanisms. Combination therapy with bavituximab and ribavirin was more effective than either drug alone. Bavituximab also bound to cells infected with multiple other viruses and rescued mice with lethal mouse cytomegalovirus infections. Targeting exposed anionic phospholipids with bavituximab seems to be safe and effective. Our study demonstrates that anionic phospholipids on infected host cells and virions may provide a new target for the generation of antiviral agents.


Higher Triad Risk Scores Are Associated With Increased Risk for Trabecular-Rich Bone Stress Injuries in Female Runners.
Bone stress injuries (BSIs) in trabecular-rich bone are associated with greater biological risk factors compared with cortical-rich bone. We hypothesized that female runners with high Female Athlete Triad (Triad)-related risk would be at greater risk for trabecular-rich BSIs than runners with low Triad-related risk. Prospective cohort study. Two NCAA institutions. Female runners were followed prospectively for up to 5 years. The intervention consisted of team nutrition presentations focused on optimizing energy availability plus individualized nutrition sessions. Triad Cumulative Risk Assessment (CRA) categories were assigned yearly based on low-energy availability, menstrual status, age of menarche, low body mass index, low bone mineral density, and prior BSI. The outcome was the annual incidence of trabecular- and cortical-rich BSI. Generalized Estimating Equations (GEE, to account for the correlated nature of the observations) with a Poisson distribution and log link were used for statistical modeling. Cortical-rich BSI rates were higher than trabecular-rich BSI rates (0.32 vs 0.13 events per person-year). Female runners with high Triad-related risk had a significantly higher incidence rate ratio of trabecular-rich BSI (RR: 4.40, P = 0.025) and cortical-rich BSI (RR: 2.87, P = 0.025) than women with low Triad-related risk. Each 1-point increase in Triad CRA score was associated with a significant 26% increased risk of trabecular-rich BSI ( P = 0.0007) and a nonsignificant 14% increased risk of cortical-rich BSI ( P = 0.054). Increased Triad CRA scores were strongly associated with increased risk for trabecular-rich BSI. Incorporating Triad CRA scores in clinical care could guide BSI prevention.


Knowledge, perception and attitude towards human papillomavirus among pre-university students in Malaysia.
To evaluate the knowledge, perception and attitudes towards human papilloma virus (HPV) among pre-university students in Malaysia. In this cross sectional study, between November 2013 to March 2014, in a public university, a convenient sampling method was used. A total of 716 respondents were recruited and interviewed with a set of standard questionnaires for assessment of knowledge, perception and attitudes towards HPV and predictor variables associated with level of knowledge. Almost half (48.9%) of the respondents scored less than 5 and were categorised as having poor knowledge. Three hundred and twelve (43.6%) respondents had moderate knowledge and only 54 (7.5%) respondents exhibited good knowledge with the score of 11 and above. Only 142 (20%) students perceived themselves to be vulnerable to HPV infection though 560 (78.2%) students thought that HPV infection is a serious disease. Perceived benefits and desire to be vaccinated were significantly associated with gender (p=0.000) and knowledge of HPV vaccine and cervical cancer (p=0.000). The level of knowledge regarding HPV among the pre-university students was low. However, student intention for vaccination increased with increasing level of knowledge. Thus, efforts to improve knowledge and awareness should be prioritised to increase uptake of the HPV vaccination programme and hence reduce morbidity and mortality from consequences of HPV infection, including cervical carcinoma.


Enantioselective Trapping of Oxonium Ylides by 3-Hydroxyisoindolinones via a Formal SN1 Pathway for Construction of Contiguous Quaternary Stereocenters.
An enantioselective Rh(II)/chiral phosphoric acid co-catalyzed three-component reaction via trapping of oxonium ylides with 3-hydroxyisoindolinones by a formal SN1 pathway is described. This reaction allows for the efficient synthesis of isoindolinone derivatives with two contiguous quaternary stereogenic centers in high yields (up to 93%) with excellent enantioselectivities and moderate diastereoselectivities under mild reaction conditions.


Hexagonal Boron Nitride Functionalized with Au Nanoparticles-Properties and Potential Biological Applications.
Hexagonal boron nitride is often referred to as white graphene. This is a 2D layered material, with a structure similar to graphene. It has gained many applications in cosmetics, dental cements, ceramics etc. Hexagonal boron nitride is also used in medicine, as a drug carrier similar as graphene or graphene oxide. Here we report that this material can be exfoliated in two steps: chemical treatment (via modified Hummers method) followed by the sonication treatment. Afterwards, the surface of the obtained material can be efficiently functionalized with gold nanoparticles. The mitochondrial activity was not affected in L929 and MCF-7 cell line cultures during 24-h incubation, whereas longer incubation (for 48, and 72 h) with this nanocomposite affected the cellular metabolism. Lysosome functionality, analyzed using the NR uptake assay, was also reduced in both cell lines. Interestingly, the rate of MCF-7 cell proliferation was reduced when exposed to h-BN loaded with gold nanoparticles. It is believed that h-BN nanocomposite with gold nanoparticles is an attractive material for cancer drug delivery and photodynamic therapy in cancer killing.


Intravascular coagulation with use of human prothrombin complex concentrates.
Prothrombin complex concentrates are used in the treatment of the congenital bleeding disorders associated with Factors II, VII, IX, and X deficiencies. They have also been extensively used to treat acquired coagulation abnormalities secondary to vitamin K deficiency, warfarin ingestion, and various types of liver disease. The reported complications of prothrombin complex concentrates administration include hepatitis, anaphylaxis, and thrombosis. This paper documents the development of disseminated intravascular coagulation in association with the administration of prothrombin complex concentrates to patients with liver disease.


Positive clinical impact of an additional PET/CT scan before adjuvant radiotherapy or concurrent chemoradiotherapy in patients with advanced oral cavity squamous cell carcinoma.
The aim of this single-center study was to investigate whether obtaining an additional PET/CT scan before adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT) could meaningfully improve 2-y disease-free survival (DFS) and disease-specific survival (DSS) rates. Six hundred seventy-four patients with oral cavity squamous cell carcinoma who received adjuvant therapy after radical surgery were included. Of these, 152 patients were initially scheduled to receive an additional preradiotherapy/CCRT PET/CT scan within 1 wk of starting adjuvant therapy. However, 16 patients were excluded because of either medical problems or refusal. Therefore, 136 patients underwent a preradiotherapy/CCRT PET/CT scan (PET group), and 522 did not (NO-PET group). All of the participants were followed up for at least 2 y or censored at the last follow-up. The impact of preradiotherapy/CCRT PET/CT imaging was examined using Kaplan-Meier curves and Cox proportional hazards models. Two-year DFS (80% vs. 70%, P = 0.033) and DSS (84% vs. 75%, P = 0.010) rates were significantly higher in the PET than in the NO-PET group. In the PET group, both DFS and DSS were higher in patients with negative findings than in those without (88% vs. 22% and 91% vs. 36%, respectively; both P < 0.001). A prognostic scoring system based on the presence of the 2 independent risk factors in the PET group (extracapsular spread and lymphatic invasion) predicted both DFS (P = 0.001 and P < 0.001, respectively) and DSS (P = 0.001 and P < 0.001, respectively). Nineteen patients (14%) had their treatment modified by preradiotherapy/CCRT PET/CT findings. Of these, 15 were treated with curative intent due to the presence of locoregional disease, and 4 received palliative care due to distant metastases. Seven of the 15 patients are currently alive without disease. An additional preradiotherapy/CCRT PET/CT scan improves both DFS and DSS in patients with advanced oral cavity squamous cell carcinoma.


Comparative study of the cutaneous sensation of leprosy-suspected lesions using Semmes-Weinstein monofilaments and quantitative thermal testing.
The objective of the present study was to compare the warm cold perception thresholds (WPT), cold perception thresholds (CPT) and the warm and cold perception interval (WCPI) determined in our previous study with the touch-pressure thresholds, in leprosy-suspected skin lesions ('patch'). Thermal testing was conducted using a thermal sensory analyser TSA-2001 (Medoc Ltd., Israel) and the method of levels. The touch-pressure thresholds were measured using Semmes-Weinstein monofilament (SWM) of 0-05 g, 0.2 g, 2 g, 4 g, 10 g and 300 g. A cross-sectional study of 112 patients presenting with leprosy-suspected skin lesions, with no clinical evidence of peripheral nerve damage, was conducted. Leprosy diagnoses were based on clinical dermato-neurological examinations. One-hundred-and-eight subjects (45 males, 63 females; average age 37.7 years) completed the tests: 82 were positively diagnosed with leprosy and 26 with diseases of different aetiologies. The SWM test showed a sensitivity of 81.7% and a specificity of 96.1%, while the warm and cold perception thresholds presented sensitivity of 90.2% and 92-2%, respectively (both with 100% specificity). In leprosy patients, lesions that exhibited pressure thresholds of 0.05 g typically showed significantly different WPT, CPT and WCPI values when compared with skin lesions of different aetiologies. Within the leprosy group, the mean values of WPT, CPT and WCPI increased according to the increase in touch-pressure thresholds. Some of the patients exhibiting leprosy lesions with touch-pressure thresholds of 0-05 and 0-2 g presented normal WPT or CPT values. However, all patients with SWM equal or above 2.0 g presented altered WPT and CPT. All patients with leprosy, including those that exhibited pressure thresholds of 0.05 g, presented altered WCPI in the skin lesions. Despite a higher sensitivity to thermal tests, the SWM has adequate validity as a screening tool in the diagnosis of cutaneous forms of leprosy and in the selection of patients who should be submitted to a more detailed examination.


Validation of the Sinhala translation of Edinburgh Postnatal Depression Scale.
To determine the validity and reliability of the Sinhalese translation of the Edinburgh Postnatal Depression Scale (EPDS) as a screening instrument to detect antenatal and postnatal depression. Two hundred and sixty five antenatal women and 204 postnatal women attending the field polyclinics of the Medical Officer of Health (MOH) area Kolonnawa participated in the study. Psychiatric diagnosis based on ICD 10 Classification of Mental and Behavioural Disorders was the 'gold standard' and the receiver operating characteristic (ROC) analysis was used to evaluate the test performance of the translated EPDS for antenatal and postnatal depression separately. Reliability was tested using test-retest method and computing intra-class correlation coefficients. A cut-off score of 9 was selected as the best to screen for depression, in antenatal (sensitivity 90.7% and specificity 86.8%) and postnatal women (sensitivity 89.9% and specificity 78.9%). The intra-class correlation coefficients of the instrument for antenatal and postnatal women were 0.95 (95% CI = 0.82 - 0.99) and 0.96 (95% CI = 0.86 - 0.99). The Sinhalese translation of the EPDS is a valid and a reliable instrument to screen for depression in antenatal and postnatal women in Sri Lanka.


Analysis of the cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation: results for Serbia.
Recent studies have shown that dronedarone is associated with significantly fewer adverse effects and treatment discontinuations, and a trend toward reduced all-cause mortality, compared with amiodarone. Introduction of dronedarone in clinical practice is limited by its higher cost than amiodarone, propafenone, and sotalol. To estimate cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation (AF). We constructed a Markov model, which was then simulated by Monte Carlo simulation using 1,000 virtual patients. Costs and outcomes were estimated from the societal perspective and discounted at 3% annually. A lifetime horizon and three-month cycle length were used. The main outcome measurement was the number of years spent without stroke. Values of transition probabilities and therapy outcomes were estimated from available literature. The prices of health services and drugs were obtained from the Republic Institute for Health Insurance Tariff Book and Drug List A and from the drug developer. Cost-effectiveness shows that the dronedarone treatment option has the most advantageous relationship, where, for one year without a stroke, the total cost is €1,779.23. In the case of the amiodarone therapy option, for one year without a stroke €3,845.10 is needed, for propafenone €4,674.20, while for sotalol the sum is €14,973.89. Estimated annual costs for patients with first-detected AF in Serbia were €610. The results of our model indicate that dronedarone is a cost-effective therapy compared with amiodarone, propafenone, and sotalol in patients with AF, if the outcome measurement is the number of years spent without stroke.


Effect of weight and age on respiratory complexity in premature neonates.
Very low-birth-weight premature infants often suffer from a variety of respiratory problems, including respiratory distress syndrome (RDS), hypopnea and periodic breathing, and apnea. These conditions are likely related to immaturity of the respiratory centers; yet how respiratory rhythms originating from these centers, including their complexity, relate to demographic measures of prematurity remains largely unknown. In 39 neonates with mild RDS (22 males, 28 +/- 2 wk gestational age, 1,036 +/- 234 g body wt), we derived the univariate association between complexity of two respiratory rhythms [respiratory rate (RR) and tidal volume (Vt)] and postmenstrual age, gestational age, postnatal age, and weight at time of study. RR and Vt rhythm complexities were assessed using approximate entropy, sample entropy, base scale entropy, and forbidden words entropy estimated for 300 consecutive breaths determined from respiratory inductance plethysmography, irrespective of breathing effort rate or amplitude, collected during sleep while the neonates were exposed to nasal continuous positive airway pressure (4-6 cmH(2)O). RR and Vt exhibited increased complexity with increased maturity, but only in terms of base scale entropy and forbidden words entropy, which are based on pattern matching, rather than approximate entropy and sample entropy, which are based on conditional probabilities. Specifically, RR complexity as measured by forbidden word entropy increased with increasing weight (r = 0.502), postconceptional age (r = 0.423), and gestational age (r = 0.493). As measured by base scale entropy, RR complexity increased with increasing weight (r = 0.488) and postconceptional age (r = 0.390). Vt complexity, measured by base scale entropy, was greater with increased postnatal age (r = 0.428). Our results indicate that respiratory rhythms become more complex with increasing levels of maturity, as indicated by increased weight and several age parameters. This emphasizes the importance of the later weeks of gestation in the maturation of respiratory centers in the brain and suggests a promising use of entropy measures in exploring respiratory maturation in infants.


Urea and oxalate inhibition of the serum lactate dehydrogenase.
The serum lactate dehydrogenase (LDH) of 16 normal subjects was inhibited by 55 to 68% by the incorporation into the reaction mixture of 0.2 mM-oxalate. Oxalate inhibited the serum LDH of 17 out of 19 patients with myocardial infarction to a greater extent, and that of 16 out of 18 patients with liver disease to a lesser extent than that of the controls. The serum LDH of all 16 patients with liver disease was inhibited by 2 M-urea to a greater degree and that of eight out of nine patients with myocardial infarction to a lesser extent than that of the normal controls (45-62%). The serum LDH of five patients with megaloblastic anaemia was also less sensitive to inhibition by urea than was that of the controls. The inhibitory effect of oxalate was greatest with those sera containing an excess of the electrophoretically fast LDH isoenzymes, while that of urea was most marked with those sera in which the slow LDH isoenzymes preponderated. The results of inhibition studies with urea or oxalate correlated well with other indices of isoenzyme composition. The use of oxalate or urea is recommended as an aid in the enzymatic diagnosis of heart and liver disease, especially when the results of other enzyme tests are equivocal.


Reward-Related Suppression of Neural Activity in Macaque Visual Area V4.
In order for organisms to survive, they need to detect rewarding stimuli, for example, food or a mate, in a complex environment with many competing stimuli. These rewarding stimuli should be detected even if they are nonsalient or irrelevant to the current goal. The value-driven theory of attentional selection proposes that this detection takes place through reward-associated stimuli automatically engaging attentional mechanisms. But how this is achieved in the brain is not very well understood. Here, we investigate the effect of differential reward on the multiunit activity in visual area V4 of monkeys performing a perceptual judgment task. Surprisingly, instead of finding reward-related increases in neural responses to the perceptual target, we observed a large suppression at the onset of the reward indicating cues. Therefore, while previous research showed that reward increases neural activity, here we report a decrease. More suppression was caused by cues associated with higher reward than with lower reward, although neither cue was informative about the perceptually correct choice. This finding of reward-associated neural suppression further highlights normalization as a general cortical mechanism and is consistent with predictions of the value-driven attention theory.


In vitro determination of myeloma cell resistance to melphalan using the 3H-thymidine incorporation technique.
Plasma cells derived from marrow aspirates of 21 untreated myeloma patients have been cultured in RPMI 1640 medium containing 3H-thymidine and melphalan. Thereafter plasma cell-labelling index was determined autoradiographically. In 20 patients melphalan caused a measurable decrease in the percentage of labelled plasma cells. Decreases in labelling index ranging from -4% to 3% have been considered as indicating the resistance of myeloma cells to melphalan in vitro. Decreases within this range have been found in 7 patients. In other 13 myelomas with chemosensitive marrow plasma cells, melphalan did reduce the labelling index to values ranging from 4% to 24%. Some clinical implications of the tests are discussed.


Heterogeneous terminal structure of Ty1 and Ty3 reverse transcripts.
A specific terminal structure of preintegrative DNA is required for transposition of retroviruses and LTR-retrotransposons. We have used an anchored PCR technique to map the 3'ends of DNA intermediates synthesized inside yeast Ty1 and Ty3 retrotransposon virus-like particles. We find that, unlike retroviruses, Ty1 replicated DNA does not have two extra base pairs at its 3'ends. In contrast some Ty3 preintegrative DNA molecules have two extra nucleotides at the 3'end of upstream and downstream long terminal repeats. Moreover we find that some molecules of replicated Ty3 DNA have more than two extra nucleotides at the 3'end of the upstream LTR. This observation could be accounted for by imprecise RNAse H cutting of the PPT sequence. The site of Ty1 and Ty3 plus-strand strong-stop DNA termination was also examined. Our results confirm that the prominent Ty1 and Ty3 plus-strand strong-stop molecules harbor 12 tRNA templated bases but also show that some Ty1 and Ty3 plus-strand strong-stop DNA molecules harbor less tRNA templated bases. We propose that these less than full length plus-strand molecules could be active intermediates in Ty retrotransposon replication.


Electronic structures of SiC nanoribbons.
Electronic structures of SiC nanoribbons have been studied by spin-polarized first-principles calculations. The armchair nanoribbons are nonmagnetic semiconductors, while the zigzag nanoribbons are magnetic metals. The spin polarization in the zigzag SiC nanoribbons is originated from the unpaired electrons localized on the ribbon edges. Interestingly, the zigzag nanoribbons narrower than approximately 4 nm present half-metallic behavior. Without the aid of external field or chemical modification, the metal-free half-metallicity predicted for narrow SiC zigzag nanoribbons opens a facile way for nanomaterial-based spintronics applications.


Large scale purification of human fibroblast interferon.
Human fibroblast interferon was partially purified, about 4,000-fold, on a chromatographic tandem of columns: concanavalin A-agarose leads to phenyl-agarose, to a specific activity of ca 4 x 10(7). The overall recovery of interferon activity was ca 60%.


Emerging roles of microglia cells in the regulation of adult neural stem cells.
Microglia cells were first described as a component for the brain with few beneficial functions. The classical point of view implied that these cells had inflammatory properties more than benefits for brain homeostasis. To date, this assumption has changed and new roles of microglia cells are continuously discovered. Although, the main function of microglia cells is to provide a cellular defense against harmful or pathogen agents (bacteria, viruses, fungi, toxins, etc.), recent evidence indicates that microglial cells are dynamic modulators of synaptic pruning, brain development and neurogenesis by maintaining a balance of local cell population. In this commentary, we summarized the emerging role of the relationship between microglia cells and the neural stem cells resident in the ventricular-subventricular zone (V-SVZ), the largest neurogenic niche in the adult brain.


Active noise experienced by a passive particle trapped in an active bath.
We study the properties of active noise experienced by a passive particle harmonically trapped in an active bath. The active bath is either explicitly simulated by an ensemble of active Brownian particles or abstractly represented by an active colored noise in theory. Assuming the equivalence of the two descriptions of the active bath, the active noise in the simulation system, which is directly extracted by fitting theoretical predictions to simulation measurements, is shown to depend on the constraint suffered by the passive tracer. This scenario is in significant contrast to the case of thermal noise that is independent of external trap potentials. The constraint dependence of active noise arises from the fact that the persistent force on the passive particle from the active bath can be influenced by the particle relaxation dynamics. Moreover, due to the interplay between the active collisions and particle relaxation dynamics, the effective temperature of the passive tracer quantified as the ratio of fluctuation to dissipation increases as the constraint strengthens, while the average potential and kinetic energies of the passive particle both decrease.


Simulated annealing and density functional theoretical prediction of macrocyclic ligand conformations, protonation sites and complex metal-ligand exchange reaction directions.
The prediction of conformations and protonation sites for the macrocyclic ligands H2DO2A (1,4,7,10-tetraazacyclododecane-1,7-diacetic acid) and H2ODO2A (1-oxa-4,7,10-triazacyclododecane-4,10-diacetic acid) has been performed employing the simulated annealing (SA) method and density functional theory (DFT) calculations using the B3LYP/6-31G* method in a vacuum and aqueous solution. These SA method/DFT calculations reveal that, in contrast to the H2ODO2A ligand system, the H2DO2A ligand system is (i) pre-organized for trivalent lanthanide (Ln) and other metal ion complexation, (ii) structurally more symmetrical and slightly more compact in aqueous solution (i.e. more and/or shorter intra-molecular hydrogen bonds), and (iii) with a greater degree of partial positive charge accumulation on the hydrogen atoms bonded to macrocyclic ring nitrogen atoms when protonated. The H2ODO2A ligand system is not pre-organized. These observations are in accord with the experimental findings that the LnODO2A(+) complexes are less thermodynamically stable and kinetically more labile as compared to those of the corresponding LnDO2A(+) complexes. The results on the prediction of the ligand protonation sites are consistent with those experimentally obtained via NMR spectroscopy. The calculations of the first and second protonation constants are, however, not as accurate as compared to those experimentally determined using either the thermodynamic cycle (TC) or the isodesmic reaction (IRn) methodology, although the latter gave relatively better results. The lowest energy structures of the LnL(+) and ZnL (Ln = Eu, Y; L = DO2A, ODO2A) complexes are also calculated using the same method. The Gibb's free energies (ΔGaq) for a number of ligand and/or metal ion exchange reactions such as LnDO2A(+) + HnODO2A((2-n)-) -->/<-- LnODO2A(+) + HnDO2A((2-n)-) (Ln = Eu, Y; n = 0, 1, 2), LnDO2A(+) + Ln'ODO2A(+) -->/<-- LnODO2A(+) + Ln'DO2A(+) (Ln = Eu, Ln' = Y), LnDO2A(+) + Ln'(3+) -->/<-- Ln'ODO2A(+) + Ln(3+) (Ln = Eu, Ln' = Y) and LnDO2A(+) + ZnODO2A -->/<-- LnODO2A(+) + ZnDO2A (Ln = Eu, Y) have been calculated in aqueous phase and the reaction directions in some cases could be predicted to be consistent with experimental or expected results. The errors between the calculated and experimental Gibb's free energy data are in the range ΔG(aq,calc) - ΔG(aq,exp) = -1.89 to +7.00 kcal mol(-1) in seven selected cases involving LnDO2A(+), LnODO2A(+) (Ln = Eu, Y), ZnDO2A and ZnODO2A complexes. The predicted reaction directions with the small core effective core potential (ECP) data are not necessarily better than those using large core ECP. However, the former takes much longer computer time to obtain the energy data.


Experimental Investigation for Determining an Ideal Algal Biodiesel-Diesel Blend to Improve the Performance and Mitigate Emissions Using a Response Surface Methodology.
The ongoing depletion of the world's fossil fuel sources and environmental damage has compelled the quest for alternative energy. Excellent characteristics of biodiesel include its renewable nature, safety, absence of sulfur, environmental advantages, and biodegradability, which can eradicate the above problems. In this study, algal oil was characterized to obtain the fatty acid profile, and the free fatty acid value of algal oil suggested a two-step process of esterification and transesterification for efficient biodiesel production. The performance and emission results of biodiesel and its blends (B10, B20, and B30) were investigated in a constant speed, single-cylinder, 4-stroke, 3.5 kW compression ignition engine at different loads for arriving at an appropriate fuel blend ratio. The response surface methodology technique is used to predict the ideal composition of microalgae-diesel using the experimental data with due weightage for the optimization criterion. The predicted blend ratio of B25 was tested on the engine and authenticated. The findings recorded an improvement in brake thermal efficiency to 31.42% and reduction in brake specific energy consumption to 9.82 MJ/kW h, unburned hydrocarbon to 85 ppm, carbon monoxide to 0.164% v/v, carbon dioxide to 4.115% v/v, nitrogen oxides to 691 ppm, and smoke opacity to 16.93%.


Lower Preterm Birth Rates but Persistent Racial Disparities in an Open-Access Health Care System.
The Military Health System (MHS) provides universal access to medical care to active duty service members, retirees, and their dependents. Observational data from small studies suggest lower preterm birth rates in the MHS compared with U.S. national averages. The objectives of this study are to determine the rate of preterm birth in the MHS from 2006 to 2012 compared with national rates and to analyze the impact of demographic factors on preterm birth in a universal access health care system. A cohort of infants born in 2006-2012 was formed from the MHS M2 database. International Classification of Disease - Ninth Revision (ICD-9) codes were used to define prematurity. Preterm births were linked to military parent's demographic data. Calculated MHS preterm birth rates were compared with U.S. national data using the Pearson chi-square test and comparison via standardized differences. Logistic regression analyses were used to determine the impact of demographic factors on prematurity. From 2006 to 2012, 564,920 infants were born in the MHS; 45,445 (8%) were born preterm. The preterm birth rate in the MHS peaked at 8.34% in 2008 and declined to 7.67% in 2012, which is significantly lower than the U.S. national average preterm birth rate over the same time period. In the 2008-2012 cohort, the odds of preterm birth were increased with Black race (adjusted odds ratio 1.30; 95% confidence interval 1.26-1.33) and with a parent of junior enlisted rank (adjusted odds ratio 1.08; 95% confidence interval 1.05-1.06), a surrogate for lower socioeconomic status. Odds of preterm birth were decreased in families with married parents and with an active duty mother. Preterm birth rates in the MHS have been consistently lower than national rates from 2006 to 2012, potentially due to universal access to health care. Black race increased odds of preterm birth despite universal access to health care. These findings support the need for further research examining racial disparities in health care outcomes related to preterm birth.


Theophylline alters distribution of blood flow to respiratory muscles.
This study was designed to examine the effects of theophylline on respiratory muscle blood flow in 11 lightly anesthetized and spontaneously breathing dogs using the radioactive microsphere tracer technique. During quiet breathing, blood flow to the costal diaphragm (25.1 +/- 13.9 ml/100 g/min) exceeded blood flow to the parasternal intercostals (18.0 +/- 10.2 ml/100 g/min, p < 0.05). Inspiratory resistive loading abolished these differences by increasing blood flow to the parasternal intercostals more than to the diaphragm. Aminophylline (40 mg/kg) significantly increased minute ventilation and tidal transdiaphragmatic pressure (Pdi) swing during quiet breathing but not during inspiratory resistive loading. Theophylline did not affect diaphragmatic blood flow during inspiratory resistive loading while the same Pdi swing and tension-time index (TTdi) were reached. During quiet breathing, however, theophylline significantly (p < 0.05) increased blood flow to the triangularis sterni from 7.9 +/- 5.6 to 18.1 +/- 25.6 ml/100 g/min and to the transversus abdominis from 10.8 +/- 8.4 to 14.6 +/- 10.5 ml/100 g/min and tended to increase blood flow to the costal diaphragm and the parasternals. We conclude that (1) during quiet breathing, but not during inspiratory resistive loading, blood flow to the costal diaphragm exceeded flow to the parasternal intercostals; (2) during quiet breathing, theophylline increased blood flow to the expiratory muscles as it promoted recruitment of expiratory muscles; and (3) theophylline did not affect diaphragmatic blood flow for a given TTdi.


[Expression and mutagenesis of genes coding for protein synthesis in the influenza virus].
Double-stranded cDNA copies of the neuraminidase genes of influenza viruses A/Tokyo/3/67 (N2), A/tern/Australia/G70C/75 (N9), and B/Lee/40, and the hemagglutinin genes of A/Memphis/1/71 (H3) and B/Hong Kong/8/73 were cloned into a SV40 vector in which the late region was replaced by the influenza sequences. Thus the influenza genes were expressed in transfected cells under the control of the SV40 late promoter. The Tokyo/67 neuraminidase gene was modified by oligonucleotide-directed site-specific in vitro mutagenesis. Several of the amino acid residues which are conserved in all known neuraminidases and which line the sialic acid binding pocket were changed, and the mutant gene ligated back into the SV40 vector. Five mutations which have been fully characterized resulted in synthesis of a protein which had totally lost neuraminidase enzyme activity.


Managing Lymphedema in Fracture Care: Current Concepts and Treatment Principles.
Lymphatic flow plays a notable role in the regulation of bone formation and remodeling. Chronic accumulation of the lymph fluid within tissues may lead to issues with proper bone healing after fractures, emphasizing the importance of proper management of lymphedema after trauma. Many associated risk factors place patients at risk for lymphedema, including previous surgery with nodal dissection, radiation therapy, infection, malignancy, family history of congenital lymphedema, and trauma. The benchmark imaging technique for the diagnosis of lymphedema is lymphoscintigraphy. Other modalities include duplex ultrasonography, CT, and MRI. First-line conservative treatment of lymphedema is compression. Complete decongestive therapy or complex physical therapy, also known as decongestive lymphatic therapy (DLT), has shown positive results in reducing lymphedema. Surgical interventions aim to either reconstruct and restore function of the lymphatic system or debulk and reduce tissues and fluids. Understanding the significance of lymphedema on bone healing and techniques available to recognize it are important factors in preventing delay in diagnosis and ensuring proper management of lymphedema after trauma.


Metabolism of luteinizing hormone by the pseudopregnant rat ovary.
Ovarian metabolism of highly purified human LH (hLH) was studied in pseudopregnant rats. The animals were injected with 1.0 microgram (11.1 IU) hLH, iv, and groups of animals were killed between 15 and 300 min. The hLH present in ovarian cytosol and sera and eluted from ovarian membrane was determined by RIA. Ovarian membrane-bound LH increased rapidly for 1 h, after which it plateaued and then decreased 4 h after the injection. Cytosolic LH peaked at 1 h, but concentrations declined thereafter. When ovarian cytosol obtained from rats injected with 10 micrograms hLH was chromatographed on a Sephadex G-100 column, the major immunoreactive fraction cochromatographed with the LH used for injection. Cytosol harvested 15 min after LH stimulation contained a small peak which coeluted with LH alpha. No LH beta was detected. No evidence for extensive dissociation of the LH subunits was found. When hLH present in serum and ovarian cytosol or bound to ovarian membrane was chromatographed on Concanavalin A-Sepharose, different patterns of binding and elution with that lectin were observed and were consistent with differential modification of the oligosaccharide side chains of LH present in serum and associated with the ovary. The biological to immunological ratio of cytosolic LH decreased from 1.7 15 min after LH injection to 0.8 at 5 h. Compared to our previous studies with hCG, LH was metabolized more rapidly. Whether that difference in the rates of ovarian metabolism of the two gonadotropins contributes to the marked disparity in their quantitative biochemical effects induced by those hormones should be examined.


Prevention of hypothermia in cats during routine oral hygiene procedures.
While thermally supported cats experienced a drop in body temperature during dental procedures, the drop was significantly greater in cats without thermal support. As cats are at risk of developing clinical hypothermia during dental procedures, steps should be taken to minimize the loss of body heat.


Screening of pediatric sleep-disordered breathing: a proposed unbiased discriminative set of questions using clinical severity scales.
Identification of sleep-disordered breathing (SDB) using questionnaires is critical from a clinical and research perspective. However, which questions to use and how well such questionnaires perform has thus far been fraught with substantial uncertainty. We aimed at delineating the usefulness of a set of questions for identifying pediatric SDB. Random prospective sampling of urban 5- to 9-year-old children from the community and enriched for habitual snoring underwent overnight sleep study. Subjective indicators or questions were evaluated to further characterize and discriminate SDB. Of 1,133 subjects, 52.8% were habitual snorers. This sample was analyzed based on a clinical grouping (ie, established apnea-hypopnea index cutoffs). Several statistical steps were performed and indicated that complaints can be ranked according to a severity hierarchy: shake child to breathe, apnea during sleep, struggle breathing when asleep, and breathing concerns while asleep, followed by loudness of snoring and snoring while asleep. With a posteriori cutoff, a predictive score > 2.72 on the severity scale was found (ie, area under the curve, 0.79 ± 0.03; sensitivity, 59.03%; specificity, 82.85%; positive predictive value, 35.4; negative predictive value, 92.7), making this cutoff applicable for confirmatory purposes. As a result, the set of six hierarchically arranged questions will aid the screening of children at high risk for SDB but cannot be used as the sole diagnostic approach.


Tickborne Diseases: Diagnosis and Management.
Tickborne diseases that affect patients in the United States include Lyme disease, Rocky Mountain spotted fever (RMSF), ehrlichiosis, anaplasmosis, babesiosis, tularemia, Colorado tick fever, and tickborne relapsing fever. Tickborne diseases are increasing in incidence and should be suspected in patients presenting with flulike symptoms during the spring and summer months. Prompt diagnosis and treatment can prevent complications and death. Location of exposure, identification of the specific tick vector, and evaluation of rash, if present, help identify the specific disease. Lyme disease presents with an erythema migrans rash in 70% to 80% of patients, and treatment may be initiated based on this finding alone. RMSF presents with a macular rash starting on the wrists, forearms, and ankles that becomes petechial. RMSF has a higher rate of mortality than other tickborne diseases; therefore, empiric treatment with doxycycline is recommended for all patients, including pregnant women and children, when high clinical suspicion is present. Testing patient-retrieved ticks for infections is not recommended. Counseling patients on the use of protective clothing and tick repellents during outdoor activities can help minimize the risk of infection. Prophylactic treatment after tick exposure in patients without symptoms is generally not recommended but may be considered within 72 hours of tick removal in specific patients at high risk of Lyme disease.


Three-dimensional echocardiographic features of unicuspid aortic valve stenosis correlate with surgical findings.
A unicuspid aortic valve (UAV) is a rare congenital defect that may manifest clinically as severe aortic stenosis or regurgitation in the third to fifth decade of life. This report describes two cases of UAV stenosis in adult patients diagnosed by transesophageal echocardiography (TEE). The utility of three-dimensional TEE in confirming valve morphology and its relevance to transcatheter valve replacement are discussed.


Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α.
C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson's trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.


Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo.
Conjugates based on nanostructured, superparamagnetic particles, a thermolabile linker and a cytotoxic maytansinoid were developed to serve as a model for tumour-selective drug delivery and release. It combines chemo- with thermal therapy. The linker-modified toxin was prepared by a combination of biotechnology and semisynthesis. Drug release was achieved by hyperthermia through an external oscillating electromagnetic field that induces heat inside the particles. Efficacy of this release concept was demonstrated both for cancer cell proliferation in vitro, and for tumour growth in vivo, in a xenograft mouse model. Biocompatibility studies for these magnetic-nanoparticle/ansamitocin conjugates complement this work.


Anal tuberculosis complicating anti-TNFα therapy.
A 42-year-old man receiving anti-tumour necrosis factor α (anti-TNFα) therapy with adalimumab due to psoriatic arthritis presented with a 2-month-old anal ulcer. An apical right lung infiltrate was found in his chest X-ray, although he had no pulmonary symptoms. Two biopsies of the ulcer were taken and reported as granulomatous, necrotising, with chronic inflammation (first), and as hyperplasic epidermis with linfocitary infiltrate and the presence of plenty of plasmatic cells (second). Histochemical techniques, including Ziehl-Neelsen, Grocott and periodic acid-Schiff stains, and PCR for Mycobacterium tuberculosis on both biopsies were negative. Serology for HIV, syphilis and hepatitis were also negative. In the second biopsy culture, moderate colonies of M. tuberculosis finally grew. The patient started a four-drug antituberculosis regimen. Adalimumab was discontinued and etanercept introduced after 2 months of antituberculosis therapy. The patient remained on therapy for 9 months with complete ulcer resolution.


Comparison of two European paediatric emergency departments: does primary care organisation influence emergency attendance?
To compare paediatric Emergency Department (ED) attendances and admission outcomes in two European hospitals with different paediatric primary care set-up. This is a retrospective prevalence study comparing all paediatric ED attendances during calendar years 2013 in two EDs with similar catchment area: one in Italy (Trieste) where paediatric primary care is provided by office paediatricians, the other, in the UK (Cambridge), where paediatric primary care is provided by general practitioners. Data on reason for presentation, discharge diagnosis and admission rate were collected and sub-group analysis for specific age groups (<1 year, 1-4 years, 5-15 years) was performed. Over 12 months, 20.331 children (0-15 years old) were seen in Cambridge and 18.646 in Trieste, with a very similar age distribution in both centres, except for the youngest age group: the percentage of infants seen in comparison with the total number of children attending ED was 1/3 higher in England than in Italy (15.4% vs 11.4%). The reasons for attendance were similar: under 1 year of age, the chief complaints were fever, breathing difficulties and gastrointestinal problems while in the older age groups trauma represented the commonest reason. Among discharge diagnoses, no differences were found between the two hospitals, except for faltering growth and "well child", more frequently diagnosed in English children under 5 years. The proportion of admissions was three times higher in Cambridge (14.1% vs 4.8%) with most children being admitted for infectious diseases. ED attendances in infants are more common in a primary care setting provided by general practicioner and, moreover, admission rates in all age groups are 1/3 reduced by primary care based paediatricians. Due to the methodological limits of this study, it isn't possible to evaluate whether these results depend only on paediatric primary care set-up or be determined by other confounding factors. New studies are needed to confirm this preliminary evidence.


Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.
The G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT). Our aim was to develop unique CXCR4-targeted therapeutics using lipopeptide GPCR modulators called pepducins. A pepducin is a synthetic molecule composed of a peptide derived from the amino acid sequence of one of the intracellular (IC) loops of a target GPCR coupled to a lipid tether. We prepared and screened a small CXCR4-targeted pepducin library and identified several pepducins with in vitro agonist activity, including ATI-2341, whose peptide sequence derives from the first IC loop. ATI-2341 induced CXCR4- and G protein-dependent signaling, receptor internalization, and chemotaxis in CXCR4-expressing cells. It also induced dose-dependent peritoneal recruitment of PMNs when administered i.p. to mice. However, when administered systemically by i.v. bolus, ATI-2341 acted as a functional antagonist and dose-dependently mediated release of PMNs from the bone marrow of both mice and cynomolgus monkeys. ATI-2341-mediated release of granulocyte/macrophage progenitor cells from the bone marrow was confirmed by colony-forming assays. We conclude that ATI-2341 is a potent and efficacious mobilizer of bone marrow PMNs and HSPCs and could represent a previously undescribed therapeutic approach for the recruitment of HSPCs before ABMT.


The physiology of tooth eruption.
Tooth eruption is a complex phenomenon that involves numerous biologic activities of the bone and the soft tissue surrounding teeth. While the exact mechanisms of eruption are not clearly understood, numerous experiments of nature, including many of the inborn errors of metabolism, should prove useful in their study. Nutritional studies may also prove useful, but will always be problematic [56]. Studies on endocrinologic changes such as puberty, pregnancy, menopause, and diseases such as diabetes, have already shown that the periodontium may not be able to accommodate to changes in the body's equilibrium [51].


A combined AgNOR-Feulgen staining technique.
We describe a new staining technique (H-Ag-S) which allows observation and counting of active nucleolus organizer regions (NORs) and evaluation of the amount of DNA in the same cell nucleus. The procedure consists of combining a modified AgNOR staining method with the Feulgen reaction. A sequential procedure is proposed, based on the determination of optimal staining conditions. The technique, which was designed to allow studies of correlations between the transcriptional activity of rDNA genes and the cell ploidy, was primarily developed for rat liver smears. It should be applicable to most biological preparations, but the optimal conditions might be variable.


Determinants of multidrug-resistant tuberculosis in São Paulo-Brazil: a multilevel Bayesian analysis of factors associated with individual, community and access to health services.
Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health problem worldwide. Accordingly, this study sought to identify individual, community and access to health services risk factors for MDR-TB. Retrospective cohort of all TB cases diagnosed between 2006 and 2016 in the state of São Paulo. A Bayesian spatial hierarchical analysis with a multilevel design was carried out. It was identified that the history of previous TB treatment (Odds Ratios [OR]:13.86, 95% credibility interval [95% CI]:12.06-15.93), positive sputum culture test (OR: 5.26, 95% CI: 4.44-6.23), diabetes mellitus (OR: 2.34, 95% CI: 1.87-2.91), residing at a standard address (OR: 2.62, 95% CI: 1.91-3.60), positive sputum smear microscopy (OR: 1.74, 95% CI: 1.44-2.12), cavitary pulmonary TB (OR: 1.35, 95% CI: 1.14-1.60) and diagnosis performed due to spontaneous request (OR: 1.26; 95% CI: 1.10-1.46) were associated with MDR-TB. Furthermore, municipalities that performed HIV tests in less than 42.65% of patients with TB (OR: 1.50, 95% CI: 1.25-1.79), that diagnosed TB cases only after death (OR: 1.50, 95% CI: 1.17-1.93) and that had more than 20.16% of their population with income between ¼ and ½ of one minimum wage (OR: 1.56, 95% CI: 1.30-1.87) were also related to the MDR-TB. Knowledge of these predictive factors may help to develop more comprehensive disease prevention strategies for MDR-TB, avoiding the risks expressed regarding drug resistance expansion.


Collective vortical motion and vorticity reversals of self-propelled particles on circularly patterned substrates.
The collective behavior of self-propelled particles (SPPs) under the combined effects of a circularly patterned substrate and circular confinement is investigated through coarse-grained molecular dynamics simulations of polarized and disjoint ring polymers. The study is performed over a wide range of values of the SPPs packing fraction ϕ[over ¯], motility force F_{D}, and area fraction of the patterned region. At low packing fractions, the SPPs are excluded from the system's center and exhibit a vortical motion that is dominated by the substrate at intermediate values of F_{D}. This exclusion zone is due to the coupling between the driving force and torque induced by the substrate, which induces an outward spiral motion of the SPPs. For high values of F_{D}, the SPPs exclusion from the center is dominated by the confining boundary. At high values of ϕ[over ¯], the substrate pattern leads to reversals in the vorticity, which become quasiperiodic with increasing ϕ[over ¯]. We also found that the substrate pattern is able to separate SPPs based on their motilities.


[Vasculitis-related acute abdomen in systemic lupus erythematosus--ultrasound appearances in lupus patients with intra-abdominal vasculitis].
Although an acute abdomen often occurs in lupus patients, definitive treatment is commonly delayed due to the difficulty in diagnosis. We performed an abdominal ultrasound (US) in two patients with severe abdominal pain and recognized mural thickenings of intestinal walls. In the first case high dose prednisone was given for severe abdominal pain, with subsequent perforation of sigmoid colon. Pathological specimens showed a thrombotic vasculitis in the mesenteric artery and arteriole of intestinal walls. In the second case physical examination elicited a rebound tenderness. An abdominal X-ray demonstrated a gasless ileus and US also showed marked thickening of intestinal walls, 16 mm in thickness. A CT scan revealed the same findings in the entire bowel. After high dose methylprednisolone was administered, her symptoms markedly improved. The mural thickenings disappeared within 10 days as seen by abdominal ultrasound examination. The US is very useful in order to make an early diagnosis of intestinal vasculitis, showing as edema (but non-specific) of intestinal wall and we can use it safely and repetitively without exposure to radiation, compared with other examinations, such as CT scan and gastrointestinal contrast study etc. The US is not only useful in diagnosis, but also helpful for follow up of patients after the initiation of treatment.