This study presents a new recombinant protein that acts as a powerful antiviral (rAVLO—recombinant Antiviral protein of Lonomia obliqua). It was able to reduce the replication by 106 fold for herpes virus and by 104 fold for rubella virus. RT-PCR of viral RNA rAVLO treated infected cells also showed similar rate of inhibition in replication. The analysis of this protein by bioinformatics suggests that this protein is globular, secreted with a signal peptide and has the ability to bind to MHC class I. It was found that there are several protein binding sites with various HLA and a prevalence of α-helices in the N-terminal region (overall classified as a α/β protein type). BLAST similarity sequence search for corresponding cDNA did not reveal a similar sequence in Genbank, suggesting that it is from a novel protein family. In this study we have observed that this recombinant protein and hemolymph has a potent antiviral action. This protein was produced in a baculovirus/Sf-9 system. Therefore, these analyses suggest that this novel polypeptide is a candidate as a broad spectrum antiviral.
Antiviral; Lonomia obliqua; Bioinformatics
Background. The survival of patients with cutaneous malignant melanoma (MM) depends on multiple factors whose role is continuously updated, as the molecular mechanisms underlying the disease progression are understood. This study intended to assess whether the patient’s gender and tumor location affect the disease outcome.
Methods. Between 2008 and 2012, 155 patients with cutaneous MM underwent various types of surgeries in our clinic. Patients were staged according to the 2009 TNM classification. There were 90 women and 65 men. Primary tumors were located as it follows head and neck region - 4.5%, limbs - 50.7% and trunk - 44.8%. The disease free and overall survival rates (DFS, OS) were estimated by using the Kaplan-Meier method.
Results. Metastases developed in 52.3% of the males and 31.1% of the females (p=0.008). In univariate analysis, distant metastasis risk was significantly higher in men (p = 0.0472 for stage II patients and p = 0.0288 for stage III). In multivariate analysis, male gender almost doubled the risk of relapse (p = 0.044) and death (p = 0.022). Consequently, DFS and OS were significantly higher among females. Primary tumor location seemed to influence the melanoma spreading ability. Half of the trunk MM developed metastases while only a third of limbs MM did. The association between MM location and the recurrence risk was not random (p = 0.033).
Conclusions. The patient gender represents an independent prognostic factor for both relapse and death. Although trunk MM had a significantly higher risk of metastasis than limbs MM, the location per se was not an independent prognostic factor for survival (p = 0.078).
Abbreviations: MM = malignant melanoma, DFS = disease free survival, OS = overall survival, p = p value, AJCC = American Joint Commission on Cancer, CI = confidence interval
malignant melanoma; patient gender; primary tumor location; disease free survival; overall survival
17β-estradiol (E2), the primary circulating estrogen hormone, mediates physiological and pathophysiological functions of breast tissue mainly through estrogen receptor α (ERα). Upon binding to E2, ERα modulates the expression of target genes involved in the regulation of cellular proliferation primarily through interactions with specific DNA sequences, estrogen response elements (EREs). Our previous microarray results suggested that E2-ERα modulates CXXC5 expression. Because of the presence of a zinc-finger CXXC domain (ZF-CXXC), CXXC5 is considered to be a member of the ZF-CXXC family, which binds to non-methylated CpG dinucleotides. Although studies are limited, CXXC5 appears to participate as a transcription factor, co-regulator and/or epigenetic factor in the regulation of cellular events induced by various signaling pathways. However, how signaling pathways mediate the expression of CXXC5 is yet unclear. Due to the importance of E2-ERα signaling in breast tissue, changes in the CXXC5 transcription/synthesis could participate in E2-mediated cellular events as well. To address these issues, we initially examined the mechanism whereby E2-ERα regulates CXXC5 expression. We show here that CXXC5 is an E2-ERα responsive gene regulated by the interaction of E2-ERα with an ERE present at a region upstream of the initial translation codon of the gene.
Hydrogen sulfide (H2S), the gas with the odor of rotten eggs, was formally discovered in 1777, over 239 years ago. For many years, it was considered an environmental pollutant and a health concern only in occupational settings. Recently, however, it was discovered that H2S is produced endogenously and plays critical physiological roles as a gasotransmitter. Although at low physiological concentrations it is physiologically beneficial, exposure to high concentrations of H2S is known to cause brain damage, leading to neurodegeneration and long‐term neurological sequelae or death. Neurological sequelae include motor, behavioral, and cognitive deficits, which are incapacitating. Currently, there are concerns about accidental or malicious acute mass civilian exposure to H2S. There is a major unmet need for an ideal neuroprotective treatment, for use in the field, in the event of mass civilian exposure to high H2S concentrations. This review focuses on the neuropathology of high acute H2S exposure, knowledge gaps, and the challenges associated with development of effective neuroprotective therapy to counteract H2S‐induced neurodegeneration.
brain; hydrogen sulfide; neuropathology; neurodegeneration; neuroprotection
The feasibility and validity of brief computerized cognitive batteries at the population-level are unknown.
Non-demented participants (n = 1660, age 50–97) in the Mayo Clinic Study on Aging completed the computerized CogState battery and standard neuropsychological battery. The correlation between tests was examined and comparisons between CogState performance on the personal computer (PC) and iPad (n = 331), and in the Clinic vs. at home (n = 194), were assessed.
We obtained valid data on >97% of participants on each test. Correlations between the CogState and neuropsychological tests ranged from −0.462 to 0.531. While absolute differences between the PC and iPad were small and participants preferred the iPad, performance on the PC was faster. Participants performed faster on Detection, One Card Learning, and One Back at home compared to the Clinic.
The computerized CogState battery, especially the iPad, was feasible, acceptable, and valid in the population.
Computerized cognitive battery; Epidemiology; Neuropsychology; Cognitively normal; Mild cognitive impairment; Population-based cohort study
The cancer epigenome exhibits global loss of DNA methylation, which contributes to genomic instability and aberrant gene expression by mechanisms that are yet to be fully elucidated. We previously discovered over 3300 long non-coding (lnc)RNAs in human cells and demonstrated that specific lncRNAs regulate gene expression via interactions with chromatin-modifying complexes. Here, we tested whether lncRNAs could also associate with DNA methyltransferases to regulate DNA methylation and gene expression. Using RIP-seq, we identified a subset of lncRNAs that interact with the DNA methyltransferase DNMT1 in a colon cancer cell line, HCT116. One lncRNA, TCONS_00023265, which we named DACOR1 (DNMT1-associated Colon Cancer Repressed lncRNA 1), shows high, tissue-specific expression in the normal colon (including colon crypts) but was repressed in a panel of colon tumors and patient-derived colon cancer cell lines. We identified the genomic occupancy sites of DACOR1, which we found to significantly overlap with known differentially methylated regions (DMRs) in colon tumors. Induction of DACOR1 in colon cancer cell lines significantly reduced their ability to form colonies in vitro, suggesting a growth suppressor function. Consistent with the observed phenotype, induction of DACOR1 led to the activation of tumor-suppressor pathways and attenuation of cancer-associated metabolic pathways. Notably, DACOR1 induction resulted in down-regulation of Cystathionine β-synthase, which is known to lead to increased levels of S-adenosyl methionine—the key methyl donor for DNA methylation. Collectively, our results demonstrate that deregulation of DNMT1-associated lncRNAs contributes to aberrant DNA methylation and gene expression during colon tumorigenesis.
Inflammatory mediators, such as PGE2 and IL-1β, are produced by osteoarthritic joint tissues, where they may contribute to disease pathogenesis. We examined whether inflammation, reflected in plasma and peripheral blood leukocytes (PBLs) reflected presence of osteoarthritis (OA), progression or symptoms in patients with symptomatic knee osteoarthritis (SKOA).
SKOA patients were enrolled in a 24-month prospective study of radiographic progression. Standardized knee radiographs were obtained at baseline and 24 months. Biomarkers assessed at baseline included plasma lipids PGE2 and 15-HETE, and transcriptome analysis of PBLs by microarray and qPCR.
Baseline PGE synthases (PGES) by PBL microarray gene expression, and plasma PGE2 distinguished SKOA patients from non-OA controls (AUCs 0.87 and 0.89 respectively, p<0.0001). Baseline plasma 15-HETE was significantly elevated in SKOA versus non-OA controls (p<0.019). In the 146 patients who completed the 24-month study, elevated baseline expression of IL-1β, TNFα and COX-2 mRNA in PBLs predicted higher risk for radiographic progression by joint space narrowing (JSN). In a multivariate model, AUC point estimates of models containing COX-2 in combination with demographic traits overlap the confidence interval of the base model in two out of the three JSN outcome measures (JSN >0.0mm, >0.2mm and >0.5mm, AUC=0.62–0.67).
Inflammatory plasma lipid biomarkers PGE2 and 15-HETE identify patients with SKOA. PBL inflammatory transcriptome identifies a subset of SKOA patients at higher risk for radiographic progression. These findings may reflect low-grade inflammation in OA and may be useful as diagnostic and prognostic biomarkers in clinical development of disease-modifying OA drugs.
interleukin; cyclooxygenase; prostaglandin; inflammation; joint space width; osteoarthritis
While it is clear that the maintenance of Bordetella pertussis-specific immunity evoked both after vaccination and infection is insufficient, it is unknown at which pace waning occurs and which threshold levels of sustained functional memory B and T cells are required to provide long-term protection. Longevity of human cellular immunity to B. pertussis has been studied less extensively than serology, but is suggested to be key for the observed differences between the duration of protection induced by acellular vaccination and whole cell vaccination or infection. The induction and maintenance of levels of protective memory B and T cells may alter with age, associated with changes of the immune system throughout life and with accumulating exposures to circulating B. pertussis or vaccine doses. This is relevant since pertussis affects all age groups. This review summarizes current knowledge on the waning patterns of human cellular immune responses to B. pertussis as addressed in diverse vaccination and infection settings and in various age groups. Knowledge on the effectiveness and flaws in human B. pertussis-specific cellular immunity ultimately will advance the improvement of pertussis vaccination strategies.
Waning and aging features of human B- and T-cell responses specific for Bordetella pertussis are discussed, and this knowledge may be instrumental in the development of improved vaccines and vaccination strategies for pertussis.
Graphical Abstract Figure.Waning and aging features of human B- and T-cell responses specific for Bordetella pertussis are discussed, and this knowledge may be instrumental in the development of improved vaccines and vaccination strategies for pertussis.
Bordetella pertussis; T cells; B cells; infection; vaccination; aging
Influenza is a vaccine-preventable contagious respiratory illness caused by influenza (flu) viruses which can lead to hospitalization and sometimes even death. Current flu vaccines delivered intramuscularly (IM) or intradermally (ID) are less effective at eliciting protective mucosal immune responses and vaccines delivered intranasally (IN) possess potential safety concerns. Sublingual (SL) vaccination is a promising alternative route for vaccine delivery which has been indicated as safe and effective at inducing protective immune responses in both systemic and mucosal compartments. We evaluated the efficacy of methylglycol chitosan (MGC) and a synthetic toll-like receptor 4 agonist (CRX-601), alone or in combination, for improving systemic and mucosal immune responses to a monovalent detergent-split flu virus vaccine delivered SL. SL vaccination of mice with split-flu vaccine formulated with either MGC or CRX-601 resulted in specific serum IgG and mucosal IgA titers that were significantly greater than titers from non-adjuvanted vaccination and equivalent to or greater than titers in mice vaccinated IM. Our results demonstrate that SL vaccination utilizing MGC or CRX-601 as adjuvants is a viable alternative route of vaccination for flu which can elicit systemic immune responses equivalent to or greater than IM vaccination with the added benefit of stimulating a robust specific mucosal immune response.
sublingual; TLR-4; chitosan; influenza; mucosal vaccination; CRX-601
In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.
Hypertrophic cardiomyopathy; dilated cardiomyopathy; heart failure; calcium sensitizer; levosimendan; sarcomere modulators
Spontaneous deamidation of asparagine is a non-enzymatic post-translational modification of proteins. Residue Asn 321 is the main site of deamidation of the Drosophila melanogaster Hox transcription factor Sex Combs Reduced (Scr). Formation of iso-aspartate, the major deamidation product, is detected by HNCACB triple-resonance NMR spectroscopy. The rate of deamidation is quantified by fitting the decay of Asn NH2 side-chain signals in a time-series of 15N-1H HSQC NMR spectra. The deamidated form of Scr binds to specific DNA target sequences with reduced affinity as determined by an electrophoretic mobility shift assay.
asparagine deamidation; dissociation constant; DNA binding; Hox transcription factor; Sex Combs Reduced; NMR spectroscopy
The trypanosomatids Leishmania amazonensis and Trypanosoma cruzi are excellent models for the study of the cell biology of intracellular protozoan infections. After their uptake by mammalian cells, the parasitic protozoan flagellates L. amazonensis and T. cruzi lodge within acidified parasitophorous vacuoles (PVs). However, whereas L. amazonensis develops in spacious, phagolysosome-like PVs that may enclose numerous parasites, T. cruzi is transiently hosted within smaller vacuoles from which it soon escapes to the host cell cytosol. To investigate if parasite-specific vacuoles are required for the survival and differentiation of T. cruzi, we constructed chimeric vacuoles by infection of L. amazonensis amastigote-infected macrophages with T. cruzi epimastigotes (EPIs) or metacyclic trypomastigotes (MTs). These chimeric vacuoles, easily observed by microscopy, allowed the entry and fate of T. cruzi in L. amazonensis PVs to be dynamically recorded by multidimensional imaging of coinfected cells. We found that although T. cruzi EPIs remained motile and conserved their morphology in chimeric vacuoles, T. cruzi MTs differentiated into amastigote-like forms capable of multiplying. These results demonstrate that the large adaptive vacuoles of L. amazonensis are permissive to T. cruzi survival and differentiation and that noninfective EPIs are spared from destruction within the chimeric PVs. We conclude that T. cruzi differentiation can take place in Leishmania-containing vacuoles, suggesting this occurs prior to their escape into the host cell cytosol.
It is not well known what is the main mechanism causing lung heterogeneity in healthy lungs under mechanical ventilation. We aimed to investigate the mechanisms causing heterogeneity of regional ventilation and parenchymal densities in healthy lungs under anesthesia and mechanical ventilation.
In a small animal model, synchrotron imaging was used to measure lung aeration and regional‐specific ventilation (sV̇). Heterogeneity of ventilation was calculated as the coefficient of variation in sV̇ (CV
sV̇). The coefficient of variation in lung densities (CVD) was calculated for all lung tissue, and within hyperinflated, normally and poorly aerated areas. Three conditions were studied: zero end‐expiratory pressure (ZEEP) and FIO
2 0.21; ZEEP and FIO
2 1.0; PEEP 12 cmH2O and FIO
21.0 (Open Lung‐PEEP = OLP).
The mean tissue density at OLP was lower than ZEEP‐1.0 and ZEEP‐0.21. There were larger subregions with low sV̇ and poor aeration at ZEEP‐0.21 than at OLP: 12.9 ± 9.0 vs. 0.6 ± 0.4% in the non‐dependent level, and 17.5 ± 8.2 vs. 0.4 ± 0.1% in the dependent one (P = 0.041). The CV
sV̇ of the total imaged lung at PEEP 12 cmH2O was significantly lower than on ZEEP, regardless of FIO
2, indicating more heterogeneity of ventilation during ZEEP (0.23 ± 0.03 vs. 0.54 ± 0.37, P = 0.049). CVD changed over the different mechanical ventilation settings (P = 0.011); predominantly, CVD increased during ZEEP. The spatial distribution of the CVD calculated for the poorly aerated density category changed with the mechanical ventilation settings, increasing in the dependent level during ZEEP.
ZEEP together with low FIO
2 promoted heterogeneity of ventilation and lung tissue densities, fostering a greater amount of airway closure and ventilation inhomogeneities in poorly aerated regions.
Perception operates on an immense amount of incoming information that greatly exceeds the brain's processing capacity. Because of this fundamental limitation, the ability to suppress irrelevant information is a key determinant of perceptual efficiency. Here, I will review a series of studies investigating suppressive mechanisms in visual motion processing, namely perceptual suppression of large, background-like motions. These spatial suppression mechanisms are adaptive, operating only when sensory inputs are sufficiently robust to guarantee visibility. Converging correlational and causal evidence links these behavioral results with inhibitory center-surround mechanisms, namely those in cortical area MT. Spatial suppression is abnormally weak in several special populations, including the elderly and those with schizophrenia—a deficit that is evidenced by better-than-normal direction discriminations of large moving stimuli. Theoretical work shows that this abnormal weakening of spatial suppression should result in motion segregation deficits, but direct behavioral support of this hypothesis is lacking. Finally, I will argue that the ability to suppress information is a fundamental neural process that applies not only to perception but also to cognition in general. Supporting this argument, I will discuss recent research that shows individual differences in spatial suppression of motion signals strongly predict individual variations in IQ scores.
Spatial suppression; visual motion; surround suppression; intelligence; motion segregation; figure-ground segregation
The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration.
FGF8; cranial neural crest; cell fate; differentiation; tooth
Disease self-management is a critical component of maintaining clinical
stability for patients with chronic illness. This is particularly evident in the
context of heart failure (HF), which is the leading cause of hospitalization for
older adults. HF self- management, commonly known as HF self-care, is often
performed with the support of informal caregivers. However, little is known
about how HF dyads manage the patient’s care together. The purpose of
this study was to identify determinants of patient and caregiver contributions
to HF self-care maintenance (i.e., daily adherence and symptom monitoring) and
management (i.e., appropriate recognition & response to symptoms),
utilizing an approach that controls for dyadic interdependence. This was a
secondary analysis of cross-sectional data from 364 Italian HF patients and
caregivers. Multilevel modeling was used to identify determinants of HF
self-care within patient-caregiver dyads. Patients were 76.2
(SD=10.7) years, a slight majority (56.9%) was
male, while caregivers were 57.4 (SD=14.6) years, and fewer
than half (48.1%) were male. Most caregivers were adult children
(48.4%) or spouses (32.7%) of patients. Both patients and
caregivers reported low levels of HF maintenance and management behaviors.
Several significant individual and dyadic determinants of self-care maintenance
and self-care management were identified, including gender, quality of life,
comorbid burden, impaired ADLs, cognition, hospitalizations, HF duration,
relationship type, relationship quality, and social support. These comprehensive
dyadic models assist in elucidating the complex nature of patient-caregiver
relationships and their influence on HF self-care, leading to more effective
ways to intervene and maximize outcomes.
heart failure; self-care; caregivers; dyad; disease management
Local infiltration anesthesia (LIA) with anesthetics, steroids, NSAIDS, and epinephrine has been shown to be effective in reducing total knee arthroplasty (TKA) postoperative pain. This systematic review explores the functional outcomes of randomized control trials that have compared the use of LIA with and without steroids during TKA. Five studies with 412 patients met the inclusion criteria, 228 received local infiltration anesthesia with steroids (LIAS) and 184 received local infiltration anesthesia without steroids (LIAWS). The use of LIAS in management of postoperative TKA pain has been shown to decrease the length of hospital stay, time required to achieve straight leg raise, and pro-inflammatory signals in patients. Although there is no overwhelming data to suggest LIAS improves postoperative TKA pain, current literature does support its effectiveness in producing other favorable surgical outcomes.
Local infiltration anesthesia; Steroid; Total knee arthroplasty; Systematic review; Periarticular injection
E-cigarette sales continue to increase in the United States. To date, little surveillance research has documented the specific product attributes driving growth. This study uses national market scanner data to describe sales trends in traditional U.S. tobacco retail channels between 2012 and 2013 and identifies product features associated with sales increases.
Data on e-cigarette sales in convenience stores, drug stores, grocery stores, and mass merchandisers in the United States were obtained from the Nielsen Company. Each product was coded for attributes such as brand, flavor, and unit size. Total sales volume, market share, and percent growth were calculated for various product attributes.
E-cigarette sales more than doubled between 2012 and 2013, from $273.6 million to $636.2 million, respectively. Growth was particularly strong in the convenience store channel. Blu eCigs quickly emerged as the best-selling brand and in 2013 constituted nearly half (44.1%) of overall sales. Although fruit-flavored and other flavored products experienced marked growth, unflavored and menthol e-cigarettes overwhelmingly dominated the market. Sales of single unit products (likely disposable e-cigarettes) increased by 216.4%, a much faster rate than multi-unit packs and cartridge refills.
In traditional U.S. retail channels, particularly the convenience store channel, sales of e-cigarettes continue to grow, with brands like blu and disposable products as the likely drivers. Given the rapidly-changing market, expanded surveillance is needed to monitor sales not only in traditional retail locations, but sales online and in specialty “vape shops,” as well.
Distracting stimuli in the environment can pull our attention away from our goal-directed tasks. fMRI studies have implicated regions in right frontal cortex as being particularly important for processing distractors (e.g., Demeter, Hernandez-Garcia, Sarter, & Lustig, 2011; de Fockert & Theeuwes, 2012). Less is known, however, about the timing and sequence of how right frontal or other brain regions respond selectively to distractors and how distractors impinge upon the cascade of processes related to detecting and processing behaviorally-relevant target stimuli. Here we used electroencephalography (EEG) and event-related potentials (ERPs) to investigate the neural consequences of a perceptually salient but task-irrelevant distractor on the detection of rare target stimuli embedded in a rapid, serial visual presentation (RSVP) stream. We found that distractors that occur during the presentation of a target interfere behaviorally with detection of those targets, reflected by reduced detection rates, and that these missed targets show a reduced amplitude of the long-latency, detection-related P3 component. We also found distractors elicited a right-lateralized frontal negativity beginning at 100 ms, whose amplitude negatively correlated across subjects with their distraction-related behavioral impairment. Finally, we also quantified the instantaneous amplitude of the steady-state visual evoked potentials (SSVEPs) elicited by the RSVP stream and found that the occurrence of a distractor resulted in a transient amplitude decrement of the SSVEP, presumably reflecting the pull of attention away from the RSVP stream when distracting stimuli occur in the environment.
attention; distraction; EEG; ERP; SSVEP
This paper presents our adaptation of Fryback and Thornbury’s hierarchical scheme for modeling the efficacy of diagnostic imaging systems. The original scheme was designed to evaluate new medical imaging systems but is less successful when applied to evaluate new radiopharmaceuticals. The proposed adaptation, which is specifically directed toward evaluating targeted imaging agents, has 6 levels: in vitro characterization, in vivo animal studies, initial human studies, impact on clinical care (change in management), impact on patient outcome, and societal efficacy. These levels, particularly the first four, implicitly define the sequence of studies needed to move an agent from the radiochemistry synthesis laboratory to the clinic. Completion of level 4 (impact on clinical care) should be sufficient for initial approval and reimbursement. We hope that the adapted scheme will help streamline the process and assist in bringing new targeted radiopharmaceuticals to approval over the next few years.
efficacy; evaluation; radiopharmaceutical; FDA approval process
Improving dyspnea and exercise performance are goals of COPD therapy. We tested the hypothesis that air current applied to the face would lessen dyspnea and improve exercise performance in moderate-severe COPD patients.
We recruited 10 COPD patients (5 men, age 62 ± 6 years, FEV1 0.93 ± 0.11 L (34 ± 3 % predicted), TLC 107 ± 6 %, RV 172 ± 18 %) naïve to the study hypothesis. Each patient was randomized in a crossover fashion to lower extremity ergometry at constant submaximal workload with a 12-diameter fan directed at the patients face or exposed leg. Each patients’ studies were separated by at least 1 week. Inspiratory capacity and Borg dyspnea score were measured every 2 min and at maximal exercise.
Total exercise time was longer when the fan was directed to the face (14.3 ± 12 vs. 9.4 ± 7.6 min, face vs. leg, respectively, p = 0.03). Inspiratory capacity tended to be greater with the fan directed to the face (1.4 (0.6–3.25) vs. 1.26 (0.56–2.89) L, p = 0.06). There was a reduction in dynamic hyperinflation, as reflected by higher IRV area in the fan on face group (553 ± 562 a.u. vs. 328 ± 319 a.u., p = 0.047). There was a significant improvement in the Borg dyspnea score at maximal exercise (5.0 (0–10) vs. 6.5 (0–10), p = 0.03), despite exercising for 34 % longer with the fan directed to the face.
Air current applied to the face improves exercise performance in COPD. Possible mechanisms include an alteration in breathing pattern that diminishes development of dynamic hyperinflation or to a change in perception of breathlessness.
COPD; Dynamic hyperinflation; Emphysema; Exercise physiology
In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson’s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain.
ER stress; Proteasome; Parkinson’s disease; Ischemia; Hormesis; Autophagy; Wolfram syndrome; Glioblastoma
Background: The number of studies available on the performance of on-site medical waste treatment facilities is rare, to date. The aim of this study was to evaluate the performance of onsite medical waste treatment equipment in hospitals of Tabriz, Iran.
Methods: A various range of the on-site medical waste disinfection equipment (autoclave, chemical disinfection, hydroclave, and dry thermal treatment) was considered to select 10 out of 22 hospitals in Tabriz to be included in the survey. The apparatus were monitored mechanically, chemically, and biologically for a six months period in all of the selected hospitals.
Results: The results of the chemical monitoring (Bowie-Dick tests) indicated that 38.9% of the inspected autoclaves had operational problems in pre-vacuum, air leaks, inadequate steam penetration into the waste, and/or vacuum pump. The biological indicators revealed that about 55.55% of the samples were positive. The most of applied devices were not suitable for treating anatomical, pharmaceutical, cytotoxic, and chemical waste.
Conclusion: Although on-site medical waste treating facilities have been installed in all the hospitals, the most of infectious-hazardous medical waste generated in the hospitals were deposited into a municipal solid waste landfill, without enough disinfection. The responsible authorities should stringently inspect and evaluate the operation of on-site medical waste treating equipment. An advanced off-site central facility with multi-treatment and disinfection equipment and enough capacity is recommended as an alternative.
Medical waste; Hospitals; Disinfection; On-site; Equipment; Evaluation
This study examined differences in self-regulation among college-age expert, moderately expert, and non-expert video game players in playing video games for fun. Winne's model of self-regulation (Winne, 2001) guided the study. The main assumption of this study was that expert video game players used more processes of self-regulation than the less-expert players. We surveyed 143 college students about their game playing frequency, habits, and use of self-regulation. Data analysis indicated that while playing recreational video games, expert gamers self-regulated more than moderately expert and non-expert players and moderately expert players used more processes of self-regulation than non-experts. Semi-structured interviews also were conducted with selected participants at each of the expertise levels. Qualitative follow-up analyses revealed five themes: (1) characteristics of expert video gamers, (2) conditions for playing a video game, (3) figuring out a game, (4) how gamers act and, (5) game context. Overall, findings indicated that playing a video game is a highly self-regulated activity and that becoming an expert video game player mobilizes multiple sets of self-regulation related skills and processes. These findings are seen as promising for educators desiring to encourage student self-regulation, because they indicate the possibility of supporting students via recreational video games by recognizing that their play includes processes of self-regulation.
self-regulation; video game; expertise; mixed-methods; a sequential explanatory design