Characteristics of the spatial pattern of the dengue vector, Aedes aegypti, in Iquitos, Peru.
We determine the spatial pattern of Aedes aegypti and the containers in which they develop in two neighborhoods of the Amazonian city of Iquitos, Peru. Four variables were examined: adult Ae. aegypti, pupae, containers positive for larvae or pupae, and all water-holding containers. Adults clustered strongly within houses and weakly to a distance of 30 meters beyond the household; clustering was not detected beyond 10 meters for positive containers or pupae. Over short periods of time restricted flight range and frequent blood-feeding behavior of Ae. aegypti appear to be underlying factors in the clustering patterns of human dengue infections. Permanent, consistently infested containers (key premises) were not major producers of Ae. aegypti, indicating that larvaciding strategies by themselves may be less effective than reduction of mosquito development sites by source reduction and education campaigns. We conclude that entomologic risk of human dengue infection should be assessed at the household level at frequent time intervals.


Novel, diverse RNA viruses from Mediterranean isolates of the phytopathogenic fungus, Rosellinia necatrix: insights into evolutionary biology of fungal viruses.
To reveal mycovirus diversity, we conducted a search of as-yet-unexplored Mediterranean isolates of the phytopathogenic ascomycete Rosellinia necatrix for virus infections. Of seventy-nine, eleven fungal isolates tested RNA virus-positive, with many showing coinfections, indicating a virus incidence of 14%, which is slightly lower than that (approximately 20%) previously reported for extensive surveys of over 1000 Japanese R. necatrix isolates. All viral sequences were fully or partially characterized by Sanger and next-generation sequencing. These sequences appear to represent isolates of various new species spanning at least 6 established or previously proposed families such as Partiti-, Hypo-, Megabirna-, Yado-kari-, Fusagra- and Fusarividae, as well as a newly proposed family, Megatotiviridae. This observation greatly expands the diversity of R. necatrix viruses, because no hypo-, fusagra- or megatotiviruses were previously reported from R. necatrix. The sequence analyses showed a rare horizontal gene transfer event of the 2A-like protease domain between a dsRNA (phlegivirus) and a positive-sense, single-stranded RNA virus (hypovirus). Moreover, many of the newly detected viruses showed the closest relation to viruses reported from fungi other than R. necatrix, such as Fusarium spp., which are sympatric to R. necatrix. These combined results imply horizontal virus transfer between these soil-inhabitant fungi.


Costs and process of in-patient tuberculosis management at a central academic hospital, Cape Town, South Africa.
South Africa reports more cases of tuberculosis (TB) than any other country, but an up-to-date, precise estimate of the costs associated with diagnosing, treating and preventing TB at the in-patient level is not available. To determine the costs associated with TB management among in-patients and to study the use of personal protective equipment (PPE) at a central academic hospital in Cape Town. Retrospective and partly prospective cost analysis of TB cases diagnosed between May 2008 and October 2009. The average daily in-patient costs were US$238; the average length of stay was 9.7 days. Mean laboratory and medication costs per stay were respectively US$26.82 and US$8.68. PPE use per day cost US$0.99. The average total TB management costs were US$2373 per patient. PPE was not always properly used. The costs of in-patient TB management are high compared to community-based treatment; the main reason for the high costs is the high number of in-patient days. An efficiency assessment is needed to reduce costs. Cost reduction per TB case prevented was approximately US$2373 per case. PPE use accounted for the lowest costs. Training is needed to improve PPE use.


Manuka honey synergistically enhances the chemopreventive effect of 5-fluorouracil on human colon cancer cells by inducing oxidative stress and apoptosis, altering metabolic phenotypes and suppressing metastasis ability.
The development of chemo-sensitizers is urgently needed to overcome 5-fluorouracil (5-FU) therapeutic resistance and adverse toxicity in colorectal cancer. This work aims to evaluate the synergic effects of 5-FU and Manuka honey (MH), a rich source of bioactive compounds, in enhancing the anticancer effects of this drug on human colon cancer HCT-116 and LoVo cells. Compared to 5-FU alone, MH synergistically enhanced the chemotherapeutic effects of 5-FU, by reducing cell proliferation through the suppression of EGFR, HER2, p-Akt and p-mTOR expression, and promoting apoptosis by the modulation pro-apoptotic (p53, Bax, Cyto c, FasL caspase-3, -8, -9 and cleave-PARP) and anti-apoptotic (Bcl-2) markers. The activations of p-p38MAPK and p-Erk1/2 pathways and ROS production were also involved in this process. Downregulation of transcription factor (NF-κB and Nrf2) and antioxidant enzyme activity (SOD, catalase, glutathione peroxidase and glutathione reductase) and expression (SOD, catalase and HO-1) were more evident after the combined treatment, leading to more cell death by oxidative stress. Moreover, additive effects were also observed by increasing lipid and protein oxidation and arresting cell cycle. All the parameters of mitochondrial respiration and glycolysis function decreased and both cells entered the quiescent stage after the combined treatments. MH also influenced the anti-metastasis effects of 5-FU by decreasing migration ability, suppressing the expression of MMP-2, MMP-9 and increasing N-cadherin and E-cadherin. In conclusion, MH could be a useful preventive or adjuvant agent in the treatment of colorectal cancer with 5-FU.


Elderly patients with acute coronary syndromes managed without revascularization: insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel versus standard-dose clopidogrel.
Dual antiplatelet therapy in older versus younger patients with acute coronary syndromes is understudied. Low-dose prasugrel (5 mg/d) is recommended for younger, lower-body-weight patients and elderly patients with acute coronary syndromes to mitigate the bleeding risk of standard-dose prasugrel (10 mg/d). A total of 9326 medically managed patients with acute coronary syndromes from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial (<75 years of age, n=7243; ≥75 years of age, n=2083) were randomized to prasugrel (10 mg/d; 5 mg/d for those ≥75 or <75 years of age and <60 kg in weight) or clopidogrel (75 mg/d) plus aspirin for ≤30 months. A total of 515 participants ≥75 years of age (25% of total elderly population) had serial platelet reactivity unit measurements in a platelet-function substudy. Cumulative risks of the primary end point (cardiovascular death/myocardial infarction/stroke) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding increased progressively with age and were ≥2-fold higher in older participants. Among those ≥75 years of age, TIMI major bleeding (4.1% versus 3.4%; hazard ratio, 1.09; 95% confidence interval, 0.57-2.08) and the primary end point rates were similar with reduced-dose prasugrel and clopidogrel. Despite a correlation between lower 30-day on-treatment platelet reactivity unit values and lower weight only in the prasugrel group, there was a nonsignificant treatment-by-weight interaction for platelet reactivity unit values among participants ≥75 years of age in the platelet-function substudy (P=0.06). No differences in weight were seen in all participants ≥75 years of age with versus without TIMI major/minor bleeding in both treatment groups. Older age is associated with substantially increased long-term cardiovascular risk and bleeding among patients with medically managed acute coronary syndromes, with no differences in ischemic or bleeding outcomes with reduced-dose prasugrel compared with clopidogrel in elderly patients. No significant interactions among weight, pharmacodynamic response, and bleeding risk were observed between reduced-dose prasugrel and clopidogrel in elderly patients. URL: http://www.clinicaltrials.gov/ct2/home. Unique identifier: NCT0069999.


Treatment stabilization in children and adolescents with attention-deficit/hyperactivity disorder: data from the Netherlands.
To evaluate the number of patients reaching stable treatment with a stimulant (methylphenidate or dexamphetamine) or non-stimulant (atomoxetine) attention-deficit/hyperactivity disorder (ADHD) medication approved for use in the Netherlands, and the time to treatment stabilization among children and adolescents aged 6-17 years. Prescription data from the PHARMO medical record linkage system from 48 geo-demographic areas in the Netherlands (2003-2006) were analyzed from newly treated patients with ADHD aged 6-17 years. Only patients with ≥ 5 dispensings for any ADHD drug during follow-up (at least 12 months) and no missing information on type of drug, strength, and number of pills per day were included. Attainment of a stable dosing regimen was defined as no change in type of drug (including a switch from an immediate release (IR) to a long-acting (LA) formulation), strength, and number of pills per day for five consecutive dispensings. Time to stable dosing regimen was defined as the number of days between the first dispensing for an ADHD drug and the first of five unchanged dispensings. Of 4909 children or adolescents initiating treatment, 3099 met selection criteria. More patients starting therapy with LA methylphenidate (82.4%) achieved treatment stabilization during follow-up than with IR methylphenidate (74.8%; p < 0.01) or atomoxetine (69.8%; p < 0.05). More patients initiated on LA methylphenidate patients (43.9%) achieved treatment stabilization without changing their index medication or dose compared to those initiated on IR methylphenidate (25.3%) or atomoxetine (8.1%; p < 0.0001 for both comparisons). Among patients achieving treatment stabilization, those initiating treatment with LA methylphenidate had a significantly shorter time to treatment stabilization (14 days) than patients initially treated with IR methylphenidate (56 days; p < 0.001) or atomoxetine (31 days; p < 0.05). Mean number of pills per day varied between 1.0 and 1.8 at initial treatment and 1.1 and 1.9 at treatment stabilization. Potential limitations of the study include the use of ADHD-medication dispensing as a proxy for an ADHD diagnosis and the impact of different titration schedules for the various ADHD medications. Overall, 2316 of the 3066 eligible patients (75.5%) achieved treatment stabilization during follow-up. Among children and adolescents with ADHD in the Netherlands, the time to treatment stabilization varied according to choice of initial treatment and was shortest for LA methylphenidate.


Modelling the executive components involved in processing false belief and mechanical/intentional sequences.
To understand the executive demands of the false-belief (FB) task relative to an alternative theory-of-mind (or mechanical causality) task, picture sequencing, the present study used path analyses. One hundred and sixty-six children between 3 and 6 years old completed the FB and picture-sequencing tasks, three executive function tasks (updating, inhibition, and shifting), and the receptive language test. The model with the best fit indicated that FB performance had a direct contribution from shifting of attention and inhibitory control, which was independent of the significant contribution made by picture sequencing. This model indicates that FB inference requires more executive processing than picture sequencing, which is used as an alternative task to measure theory of mind. Statement of contribution What is already known on this subject? The majority of researchers use the false-belief task to assess mentalizing ability in young children. Sources of information used in various different mentalizing tasks require different levels of cognitive demand. Many executive functions (EFs) are involved in children's judgements of false belief. What does this study add? A statistical model was created to compare processing requirements of false-belief and picture-sequencing tasks. The model supported the claim that the false-belief task involves considerably more than just mentalizing. Shifting the focus of attention was an EF that was found to be a key component of performance in the false-belief task.


Impacts of an Integrated Medicaid Managed Care Program for Adults with Behavioral Health Conditions: The Experience of Illinois.
This study assessed the impact of the Integrated Care Program (ICP), a new Medicaid managed care model in Illinois, on health services utilization and costs for adults with behavioral health conditions. Data sources included Medicaid claims, encounter records, and state payment data for 28,127 persons with a behavioral health diagnosis. Difference-in-differences models, in conjunction with propensity score weighting, were used to compare utilization and costs between ICP enrollees and a fee-for-service (FFS) comparison group. The model considered the impact of the SMART Act, which restricted access to care for the comparison group. Before the SMART Act, ICP was associated with 2.8 fewer all-cause primary care visits, 34.6 fewer behavioral health-specific outpatient visits, and 2.5 fewer all-cause inpatient admissions per 100 persons per month, and $228 lower total costs per member per month relative to the FFS group. After the SMART Act, ICP enrollees had increased outpatient and dental services utilization without significantly higher costs. The relative increase in utilization was due primarily to decreased utilization in the restricted FFS group after the SMART Act. By the end of the study period, the ICP group had 13.3 more all-cause primary care visits, 1.5 more emergency department visits, and 1.4 more dental visits per 100 persons per month relative to the FFS program. A fully-capitated, integrated managed care program has the potential to reduce overall Medicaid costs for people with behavioral health conditions without negative effects on service utilization.


Graded motor imagery and the impact on pain processing in a case of CRPS.
Graded motor imagery (GMI) shows promising results for patients with complex regional pain syndrome (CRPS). In a case with chronic unilateral CRPS type I, we applied GMI for 6 weeks and recorded clinical parameters and cerebral activation using functional magnetic resonance imaging (fMRI; pre-GMI, after each GMI block, and after 6 mo). Changes in fMRI activity were mapped during movement execution in areas associated with pain processing. A healthy participant served as a control for habituation effects. Pain intensity decreased over the course of GMI, and relief was maintained at follow-up. fMRI during movement execution revealed marked changes in S1 and S2 (areas of discriminative pain processing), which seemed to be associated with pain reduction, but none in the anterior insula and the anterior cingulate cortex (areas of affective pain processing). After mental rotation training, the activation intensity of the posterior parietal cortex was reduced to one third. Our case report develops a design capable of differentiating cerebral changes associated with behavioral therapy of CRPS type I study.


Patterns of impact resulting from a 'sit less, move more' web-based program in sedentary office employees.
Encouraging office workers to 'sit less and move more' encompasses two public health priorities. However, there is little evidence on the effectiveness of workplace interventions for reducing sitting, even less about the longer term effects of such interventions and still less on dual-focused interventions. This study assessed the short and mid-term impacts of a workplace web-based intervention (Walk@WorkSpain, W@WS; 2010-11) on self-reported sitting time, step counts and physical risk factors (waist circumference, BMI, blood pressure) for chronic disease. Employees at six Spanish university campuses (n=264; 42±10 years; 171 female) were randomly assigned by worksite and campus to an Intervention (used W@WS; n=129; 87 female) or a Comparison group (maintained normal behavior; n=135; 84 female). This phased, 19-week program aimed to decrease occupational sitting time through increased incidental movement and short walks. A linear mixed model assessed changes in outcome measures between the baseline, ramping (8 weeks), maintenance (11 weeks) and follow-up (two months) phases for Intervention versus Comparison groups. A significant 2 (group) × 2 (program phases) interaction was found for self-reported occupational sitting (F[3]=7.97, p=0.046), daily step counts (F[3]=15.68, p=0.0013) and waist circumference (F[3]=11.67, p=0.0086). The Intervention group decreased minutes of daily occupational sitting while also increasing step counts from baseline (446±126; 8,862±2,475) through ramping (+425±120; 9,345±2,435), maintenance (+422±123; 9,638±3,131) and follow-up (+414±129; 9,786±3,205). In the Comparison group, compared to baseline (404±106), sitting time remained unchanged through ramping and maintenance, but decreased at follow-up (-388±120), while step counts diminished across all phases. The Intervention group significantly reduced waist circumference by 2.1cms from baseline to follow-up while the Comparison group reduced waist circumference by 1.3cms over the same period. W@WS is a feasible and effective evidence-based intervention that can be successfully deployed with sedentary employees to elicit sustained changes on "sitting less and moving more".


Two large reciprocal translocations characterized in the disease resistance-rich burmannica genetic group of Musa acuminata.
Banana cultivars are derived from hybridizations involving Musa acuminata subspecies. The latter diverged following geographical isolation in distinct South-east Asian continental regions and islands. Observation of chromosome pairing irregularities in meiosis of hybrids between these subspecies suggested the presence of large chromosomal structural variations. The aim of this study was to characterize such rearrangements. Marker (single nucleotide polymorphism) segregation in a self-progeny of the 'Calcutta 4' accession and mate-pair sequencing were used to search for chromosomal rearrangements in comparison with the M. acuminata ssp. malaccensis genome reference sequence. Signature segment junctions of the revealed chromosome structures were identified and searched in whole-genome sequencing data from 123 wild and cultivated Musa accessions. Two large reciprocal translocations were characterized in the seedy banana M. acuminata ssp. burmannicoides 'Calcutta 4' accession. One consisted of an exchange of a 240 kb distal region of chromosome 2 with a 7.2 Mb distal region of chromosome 8. The other involved an exchange of a 20.8 Mb distal region of chromosome 1 with a 11.6 Mb distal region of chromosome 9. Both translocations were found only in wild accessions belonging to the burmannicoides/burmannica/siamea subspecies. Only two of the 87 cultivars analysed displayed the 2/8 translocation, while none displayed the 1/9 translocation. Two large reciprocal translocations were identified that probably originated in the burmannica genetic group. Accurate characterization of these translocations should enhance the use of this disease resistance-rich burmannica group in breeding programmes.


Tactile learning and the individual evaluation of the reward in honey bees (Apis mellifera L.).
Using the proboscis extension response we conditioned pollen and nectar foragers of the honey bee (Apis mellifera L.) to tactile patterns under laboratory conditions. Pollen foragers demonstrated better acquisition, extinction, and reversal learning than nectar foragers. We tested whether the known differences in response thresholds to sucrose between pollen and nectar foragers could explain the observed differences in learning and found that nectar foragers with low response thresholds performed better during acquisition and extinction than ones with higher thresholds. Conditioning pollen and nectar foragers with similar response thresholds did not yield differences in their learning performance. These results suggest that differences in the learning performance of pollen and nectar foragers are a consequence of differences in their perception of sucrose. Furthermore, we analysed the effect which the perception of sucrose reward has on associative learning. Nectar foragers with uniform low response thresholds were conditioned using varying concentrations of sucrose. We found significant positive correlations between the concentrations of the sucrose rewards and the performance during acquisition and extinction. The results are summarised in a model which describes the relationships between learning performance, response threshold to sucrose, concentration of sucrose and the number of rewards.


An in vitro morphological investigation of the endodontic spaces of third molars.
Aim of this paper was to investigate the particular anatomic features of the endodontic space of third molars in the general population of Croatia. A total of 106 fully developed third molars (56 maxillar and 50 mandibular) has been analyzed. The respective number of roots and of root canals, the structure of the roots, and the curvature and absolute length of the root-canals were analyzed. In most cases, upper third molars had three roots (83.9%), while most of the lower molars were single rooted (56.0%). Upper third molars had mostly three root canals (75.1%), lower third molars two (90.0%). In both jaws, most third molars had curved canals (60.7% in the upper and 84.0% in the lower jaw). 12.5% of upper third molars had lateral and accessory canals, whereas only 4.0% of the lower third molars were found to have them. The Student t-test showed statistically significant differences (p < 0.05) in the length of the root-canals, mesiobuccal and distobuccal canals being significantly shorter than palatinal canals. The same test showed that in the lower third molars the mesial root canals were significantly longer that the distal ones, although slightly. The results obtained are in compliance with similar results by other authors; however, they tend to show some specific population-related features.


Growth hormone receptor polymorphism and growth hormone therapy response in children: a Bayesian meta-analysis.
Recombinant human growth hormone (rhGH) therapy is used in the long-term treatment of children with growth disorders, but there is considerable treatment response variability. The exon 3-deleted growth hormone receptor polymorphism (GHR(d3)) may account for some of this variability. The authors performed a systematic review (to April 2011), including investigator-only data, to quantify the effects of the GHR(fl-d3) and GHR(d3-d3) genotypes on rhGH therapy response and used a recently established Bayesian inheritance model-free approach to meta-analyze the data. The primary outcome was the 1-year change-in-height standard-deviation score for the 2 genotypes. Eighteen data sets from 12 studies (1,527 children) were included. After several prior assumptions were tested, the most appropriate inheritance model was codominant (posterior probability = 0.93). Compared with noncarriers, carriers had median differences in 1-year change-in-height standard-deviation score of 0.09 (95% credible interval (CrI): 0.01, 0.17) for GHR(fl-d3) and of 0.14 (95% CrI: 0.02, 0.26) for GHR(d3-d3). However, the between-study standard deviation of 0.18 (95% CrI: 0.10, 0.33) was considerable. The authors tested by meta-regression for potential modifiers and found no substantial influence. They conclude that 1) the GHR(d3) polymorphism inheritance is codominant, contrasting with previous reports; 2) GHR(d3) genotypes account for modest increases in rhGH effects in children; and 3) considerable unexplained variability in responsiveness remains.


Genetic analysis of repair and damage tolerance mechanisms for DNA-protein cross-links in Escherichia coli.
DNA-protein cross-links (DPCs) are unique among DNA lesions in their unusually bulky nature. We have recently shown that nucleotide excision repair (NER) and RecBCD-dependent homologous recombination (HR) collaboratively alleviate the lethal effect of DPCs in Escherichia coli. In this study, to gain further insight into the damage-processing mechanism for DPCs, we assessed the sensitivities of a panel of repair-deficient E. coli mutants to DPC-inducing agents, including formaldehyde (FA) and 5-azacytidine (azaC). We show here that the damage tolerance mechanism involving HR and subsequent replication restart (RR) provides the most effective means of cell survival against DPCs. Translesion synthesis does not serve as an alternative damage tolerance mechanism for DPCs in cell survival. Elimination of DPCs from the genome relies primarily on NER, which provides a second and moderately effective means of cell survival against DPCs. Interestingly, Cho rather than UvrC seems to be an effective nuclease for the NER of DPCs. Together with the genes responsible for HR, RR, and NER, the mutation of genes involved in several aspects of DNA repair and transactions, such as recQ, xth nfo, dksA, and topA, rendered cells slightly but significantly sensitive to FA but not azaC, possibly reflecting the complexity of DPCs or cryptic lesions induced by FA. UvrD may have an additional role outside NER, since the uvrD mutation conferred a slight azaC sensitivity on cells. Finally, DNA glycosylases mitigate azaC toxicity, independently of the repair of DPCs, presumably by removing 5-azacytosine or its degradation product from the chromosome.


An otoprotective role for the apoptosis inhibitor protein survivin.
Hearing impairment caused by ototoxic insults, such as noise or gentamicin is a worldwide health problem. As the molecular circuitries involved are not yet resolved, current otoprotective therapies are rather empirical than rational. Here, immunohistochemistry and western blotting showed that the cytoprotective protein survivin is expressed in the human and guinea pig cochlea. In the guinea pig model, moderate noise exposure causing only a temporary hearing impairment transiently evoked survivin expression in the spiral ligament, nerve fibers and the organ of Corti. Mechanistically, survivin upregulation may involve nitric oxide (NO)-induced Akt signaling, as enhanced expression of the endothelial NO synthase and phosphorylated Akt were detectable in some surviving-positive cell types. In contrast, intratympanic gentamicin injection inducing cell damage and permanent hearing loss correlated with attenuated survivin levels in the cochlea. Subsequently, the protective activity of the human and the guinea pig survivin orthologs against the ototoxin gentamicin was demonstrated by ectopic overexpression and RNAi-mediated depletion studies in auditory cells in vitro. These data suggest that survivin represents an innate cytoprotective resistor against stress conditions in the auditory system. The pharmacogenetic modulation of survivin may thus provide the conceptual basis for the rational design of novel therapeutic otoprotective strategies.


[Anti-dementia drugs for Alzheimer disease in present and future].
Alzheimer disease(AD) is characterized as neurodegenerative disease showing impairment of cognitive function, death of neuronal cells, numerous numbers of senile plaques and tangle of neurofilaments. There are two different hypotheses that neurotoxicity of aggregated amyloid beta protein(A beta) and hyperphosphorylation of tau protein are the causes of AD. The dysfunction of cholinergic neuronal system is observed in the early stage of AD. Therefore, the strategy to increase of acetylcholine (ACh) level in brain by using ACh esterase inhibitor is mainstream in the present. We have tacrine, donepezil, rivastigmine and galantamine. Tacrine, the first drug for AD, is replaced by other drugs, because of its hepatic toxicity. Galantamine binds allosteric sites of nicotine receptor and stimulates it in addition to its inhibitory effect on ACh esterase. Metamantine was approved in EU in 2002. It is non-competitive inhibitor of NMDA receptors, and dopamine releaser, which has neuroprotective effect. All of the above drugs improve cognitive function of patients, and they could delay hospitalization for 7 months or more. In the present anti-inflammatory drugs, anti-oxidative drugs and estrogen are under investigation. As anti-A beta therapy, inhibitors of beta -and gamma-secretase, A beta aggregation inhibitors, A beta degradation stimulators and A beta vaccination are possible strategies. The inhibitors of tau protein phosphorylation and activators of phosphates could be that of anti-tau protein phosphorylation. Additionally, it is expected to have the strategies such as neuroregeneration by neurotorophic factors and immunopyline ligands, and supply of neuronal cells by gene therapy and human ES cells.


Effects of anisotropic diffractions on holographic polymer-dispersed liquid-crystal gratings.
Volume gratings fabricated by interferometric exposure using composite materials composed of nematic liquid crystals (LC) and LC diacrylate monomers are discussed in the effects of diffraction properties on different grating formations, such as varying LC content ratios, film thicknesses, and the surface conditions composed of alignment layers and rubbing directions. Diffraction properties are experimentally investigated in the viewpoints of anisotropic diffraction and LC orientation. The polarization-azimuth dependence of diffraction efficiencies as functions of the incident polarization states shows the controllability of anisotropic diffractions based on the effects of different surface conditions.


Children and Adolescents and Digital Media.
Today's children and adolescents are immersed in both traditional and new forms of digital media. Research on traditional media, such as television, has identified health concerns and negative outcomes that correlate with the duration and content of viewing. Over the past decade, the use of digital media, including interactive and social media, has grown, and research evidence suggests that these newer media offer both benefits and risks to the health of children and teenagers. Evidence-based benefits identified from the use of digital and social media include early learning, exposure to new ideas and knowledge, increased opportunities for social contact and support, and new opportunities to access health promotion messages and information. Risks of such media include negative health effects on sleep, attention, and learning; a higher incidence of obesity and depression; exposure to inaccurate, inappropriate, or unsafe content and contacts; and compromised privacy and confidentiality. This technical report reviews the literature regarding these opportunities and risks, framed around clinical questions, for children from birth to adulthood. To promote health and wellness in children and adolescents, it is important to maintain adequate physical activity, healthy nutrition, good sleep hygiene, and a nurturing social environment. A healthy Family Media Use Plan (www.healthychildren.org/MediaUsePlan) that is individualized for a specific child, teenager, or family can identify an appropriate balance between screen time/online time and other activities, set boundaries for accessing content, guide displays of personal information, encourage age-appropriate critical thinking and digital literacy, and support open family communication and implementation of consistent rules about media use.


De novo protein design, a retrospective.
Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.


UHMWPE Sublaminar Wires in Posterior Spinal Instrumentation: Stability and Biocompatibility Assessment in an Ovine Pilot Study.
An animal study. To explore ultra-high molecular weight polyethylene (UHMWPE) sublaminar wires in spinal surgery and to assess stability and biocompatibility of the UHMWPE instrumentation in an ovine model. Sublaminar wiring is a well-established technique in segmental scoliosis surgery. However, during introduction and/or removal of the metal sublaminar wires, neurological problems can occur. Abrasion after cutting metal wires for removal can lead to damage to the dural sac. Sublaminar wires have to withhold large forces and breakage of the wires can occur. Different types of sublaminar wires have been developed to address these problems. UHMWPE sublaminar wires can potentially substitute currently used metal sublaminar metal wires. In vivo testing and biocompatibility analysis of UHMWPE wires are recommended before clinical use in spinal surgery. In 6 immature sheep, pedicle screws were instrumented at lumbar level L4 and attached with titanium rods to 4 thoracolumbar vertebrae using 3- and 5-mm-wide UHMWPE sublaminar wiring constructions in 5 animals. Titanium sublaminar wires were applied in 1 animal to function as a control subject. After a follow-up period of 16 weeks, the animals were sacrificed and the spines were isolated. Radiographs and computed tomography (CT) scans were made to assess stability of the instrumentation. The vertebrae were dissected for macroscopic and histologic evaluation. None of the wires had loosened and the instrumentation remained stable. CT scans and radiographs showed no signs of failure of the instrumentation and no neurological complications occurred. Although several bony bridges were seen on CT, growth was observed at the operated levels. Biocompatibility was assessed by macroscopical and histologic analysis, showing no signs of dural or epidural inflammation. This pilot animal study shows that UHMWPE sublaminar wiring is a safe technique. The UHMWPE wires are biocompatible and provide sufficient stability in spinal instrumentation. Heterotopic ossification because of periost reactions in the ovine spine led to some restrictions in this study.


Emissivity of isothermal spherical cavity with gray lambertian walls.
An exact expression for the emissivity of an ideally diffuse, gray, isothermal, spherical cavity is derived directly, making no geometrical approximations, and is shown to agree with the results of DeVos, Gouffé, and Sparrow and Jonsson, as compared by Fecteau. It appears that, even under ideal conditions, the spherical configuration is the only one that will have uniform isotropic emissivity over a wide angle, approaching a full hemisphere, across the entire aperture.


Trait-mediated diversification in nematode predator-prey systems.
Nematodes are presumably the most numerous Metazoans in terrestrial habitats. They are represented at all trophic levels and are known to respond to nutrient limitation, prey availability, and microbial resources. Predatory nematodes reside at the highest trophic level, and as such their feeding habits could have a major impact on soil food web functioning. Here, we investigate the effects of gender and developmental stage on the nematode body sizes in coarse and loamy soils. Besides Neodiplogasteridae, our predators are much larger than other soil-dwelling nematodes from their early developmental stage onwards. From juvenile to adult, the predatory Aporcelaimellus (Kruskal-Wallis P < 0.001), Dorylaimoides, and Tripyla (both P < 0.01) show great length increases during their developmental growth, in contrast to their possible prey (almost all P < 0.001). Less than 4% of the prey exceeds the length of the predatory adults, but more than 30% of the prey exceeds the length of the predatory juveniles. Potential body size ratios and some physical problems experienced by small fluid feeders attacking large prey are discussed in an attempt to summarize different prey-searching mechanisms and aggregative predatory responses in the soil system.


Landscaping capacity-building initiatives in epidemiology in India: bridging the demand-supply gap.
India, the second most populous country in the world, has 17% of the world's population but its total share of global disease burden is 21%. With epidemiological transition, the challenge of the public health system is to deal with a high burden of noncommunicable diseases, while still continuing the battle against communicable diseases. To combat this progression, public health capacity-building initiatives for the health workforce are necessary to develop essential skills in epidemiology and competencies in other related fields of public health. This study is an effort to systematically explore the training programmes in epidemiology in India and to understand the demand-supply dynamics of epidemiologists in the country. A systematic, predefined approach, with three parallel strategies, was used to collect and assemble the data regarding epidemiology training in India and assess the demand-supply of epidemiologists in the country. The programmes offering training in epidemiology included degree and diploma courses offered by departments of preventive and social medicine/community medicine in medical colleges and 19 long-term academic programmes in epidemiology, with an estimated annual output of 1172 per year. The demand analysis for epidemiologists estimated that there is need for at least 3289 epidemiologists to cater for the demand of various institutions in the country. There is a wide gap in demand-supply of epidemiologists in the country and an urgent need for further strengthening of epidemiology training in India. More capacity-building and training initiatives in epidemiology are therefore urgently required to promote research and address the public health challenges confronting the country.


Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the α-Ketoglutarate Signaling Pathway.
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.Significance: These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. Cancer Res; 78(11); 2799-812. ©2018 AACR.


Surgical technology and operating-room safety failures: a systematic review of quantitative studies.
Surgical technology has led to significant improvements in patient outcomes. However, failures in equipment and technology are implicated in surgical errors and adverse events. We aim to determine the proportion and characteristics of equipment-related error in the operating room (OR) to further improve quality of care. A systematic review of the published literature yielded 19 362 search results relating to errors and adverse events occurring in the OR, from which 124 quantitative error studies were selected for full-text review and 28 were finally selected. Median total errors per procedure in independently-observed prospective studies were 15.5, interquartile range (IQR) 2.0-17.8. Failures of equipment/technology accounted for a median 23.5% (IQR 15.0%-34.1%) of total error. The median number of equipment problems per procedure was 0.9 (IQR 0.3-3.6). From eight studies, subdivision of equipment failures was possible into: equipment availability (37.3%), configuration and settings (43.4%) and direct malfunctioning (33.5%). Observed error rates varied widely with study design and with type of operation: those with a greater burden of technology/equipment tended to show higher equipment-related error rates. Checklists (or similar interventions) reduced equipment error by mean 48.6% (and 60.7% in three studies using specific equipment checklists). Equipment-related failures form a substantial proportion of all error occurring in the OR. Those procedures that rely more heavily on technology may bear a higher proportion of equipment-related error. There is clear benefit in the use of preoperative checklist-based systems. We propose the adoption of an equipment check, which may be incorporated into the current WHO checklist.


Referrals to a liaison psychiatry out-patient clinic in a UK general hospital: a report on 900 cases.
To describe the demographic and clinical characteristics of consecutive referrals to an out-patient liaison psychiatry clinic in a large university hospital in the UK. We studied 900 patients using a standardized proforma. Assessments of functional capacity were made using the Global Assessment of Functioning (GAF) scale, and each patient was assigned a psychiatric diagnosis using ICD-10 criteria. Four of five of all referrals presented with somatic complaints, and 41% had a concurrent physical illness. The most common psychiatric diagnoses were somatoform disorders (55%) and neurasthenia (11%). Although more than half (59%) had no previous psychiatric history, a surprisingly high number (35%) had significant functional impairment (scores of < 50 on the GAF scale). The lack of adequate psychological treatment services often provided a barrier to optimal management of some of the more disabled patients. The general hospital liaison psychiatry clinic provides an acceptable setting in which to assess and manage patients referred from non-psychiatric colleagues.


Feasibility of touch-less control of operating room lights.
Today's highly technical operating rooms lead to fairly complex surgical workflows where the surgeon has to interact with a number of devices, including the operating room light. Hence, ideally, the surgeon could direct the light without major disruption of his work. We studied whether a gesture tracking-based control of an automated operating room light is feasible. So far, there has been little research on control approaches for operating lights. We have implemented an exemplary setup to mimic an automated light controlled by a gesture tracking system. The setup includes a articulated arm to position the light source and an off-the-shelf RGBD camera to detect the user interaction. We assessed the tracking performance using a robot-mounted hand phantom and ran a number of tests with 18 volunteers to evaluate the potential of touch-less light control. All test persons were comfortable with using the gesture-based system and quickly learned how to move a light spot on flat surface. The hand tracking error is direction-dependent and in the range of several centimeters, with a standard deviation of less than 1 mm and up to 3.5 mm orthogonal and parallel to the finger orientation, respectively. However, the subjects had no problems following even more complex paths with a width of less than 10 cm. The average speed was 0.15 m/s, and even initially slow subjects improved over time. Gestures to initiate control can be performed in approximately 2 s. Two-thirds of the subjects considered gesture control to be simple, and a majority considered it to be rather efficient. Implementation of an automated operating room light and touch-less control using an RGBD camera for gesture tracking is feasible. The remaining tracking error does not affect smooth control, and the use of the system is intuitive even for inexperienced users.


Pulmonary bioassay studies with nanoscale and fine-quartz particles in rats: toxicity is not dependent upon particle size but on surface characteristics.
Pulmonary toxicology studies in rats demonstrate that nanoparticles are more toxic than fine-sized particles of similar chemistry. This study, however, provides evidence to contradict this theory. The aims of the study were (1) to compare the toxicity of synthetic 50 nm nanoquartz I particles versus (mined) Min-U-Sil quartz ( approximately 500 nm); the toxicity of synthetic 12 nm nanoquartz II particles versus (mined) Min-U-Sil ( approximately 500 nm) versus (synthetic) fine-quartz particles (300 nm); and (2) to evaluate the surface activities among the samples as they relate to toxicity. Well-characterized samples were tested for surface activity and hemolytic potential. In addition, groups of rats were instilled with either doses of 1 or 5 mg/kg of carbonyl iron (CI) or various alpha-quartz particle types in phosphate-buffered saline solution and subsequently assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation, and histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postexposure. Exposures to the various alpha-quartz particles produced differential degrees of pulmonary inflammation and cytotoxicity, which were not always consistent with particle size but correlated with surface activity, particularly hemolytic potential. Lung tissue evaluations of three of the quartz samples demonstrated "typical" quartz-related effects--dose-dependent lung inflammatory macrophage accumulation responses concomitant with early development of pulmonary fibrosis. The various alpha-quartz-related effects were similar qualitatively but with different potencies. The range of particle-related toxicities and histopathological effects in descending order were nanoscale quartz II = Min-U-Sil quartz > fine quartz > nanoscale quartz I > CI particles. The results demonstrate that the pulmonary toxicities of alpha-quartz particles appear to correlate better with surface activity than particle size and surface area.


[Left ventricular papillary fibroelastoma associated with chief complaints of palpitation, general fatigue, and feverish].
Papillary fibroelastoma is one of the commonest benign tumor in the heart. In almost all of cases, symptoms never develop and the tumors are usually discovered coincidentally. Even though papillary fibroelastoma is a benign tumor, surgical extirpation is usually indicated for reason of productive serious complications. The tumors may cause left ventricular outflow obstruction, cerebral embolic infarction, myocardial infarction and even sudden death. The case we reported here is unusual case, because the patient developed symptoms and complaints such as palpitation, feverish and general fatigue. We measured tumor markers, interleukin 6, serotonin and histamine, but none of those was elevated in the blood samples. Surgical removal of the tumor attached to the base of posterior papillary muscle was carried out without causing mitral incompetence, and the pathological findings were compatible with papillary fibroelastoma. After the operation, the both symptoms and complaints disappeared unexpectedly.


Context modulates the ERP signature of contour integration.
We investigated how the electrophysiological signature of contour integration is changed by the context in which a contour is embedded. Specifically, we manipulated the orientations of Gabor elements surrounding an embedded shape outline. The amplitudes of early visual components over posterior scalp regions were changed by the presence of a contour, and by the orientation of elements surrounding the contour. Differences in context type had an effect on the early P1 and N1 components, but not on the later P2 component. The presence of a contour had an effect on the N1 and P2 components, but not on the earlier P1 component. A modulatory effect of context on contour integration was observed on the N1 component. These results highlight the importance of the context in which contour integration takes place.


Deterministic sequential isolation of floating cancer cells under continuous flow.
Isolation of rare cells, such as circulating tumor cells, has been challenging because of their low abundance and limited timeframes of expressions of relevant cell characteristics. In this work, we devise a novel hydrodynamic mechanism to sequentially trap and isolate floating cells in biosamples. We develop a microfluidic device for the sequential isolation of floating cancer cells through a series of microsieves to obtain up to 100% trapping yield and >95% sequential isolation efficiency. We optimize the trappers' dimensions and locations through both computational and experimental analyses using microbeads and cells. Furthermore, we investigated the functional range of flow rates for effective sequential cell isolation by taking the cell deformability into account. We verify the cell isolation ability using the human breast cancer cell line MDA-MB-231 with perfect agreement with the microbead results. The viability of the isolated cells can be maintained for direct identification of any cell characteristics within the device. We further demonstrate that this device can be applied to isolate the largest particles from a sample containing multiple sizes of particles, revealing its possible applicability in isolation of circulating tumor cells in cancer patients' blood. Our study provides a promising sequential cell isolation strategy with high potential for rapid detection and analysis of general floating cells, including circulating tumor cells and other rare cell types.


Incidental encoding of goal irrelevant information is associated with insufficient engagement of the dorsal frontal cortex and the inferior parietal cortex.
Previous studies have shown that goal-irrelevant distractors are incidentally encoded into long-term memory. Neuroimaging studies have suggested that the medial temporal and visual association regions are involved in incidental encoding of goal-irrelevant information. However, few studies have investigated prefrontal/parietal influence during the incidental encoding. The present study performed whole brain analysis to identify the brain regions involved in the incidental encoding of goal-irrelevant information. A face working memory (WM) task was administered with insertion of face distractors during the delay period. Following the WM task, a surprise recognition task was given in an MRI scanner. Recognition rate of distractors was higher than that of novel fillers. Recognition time was also faster in distractors than in novel fillers. Neuroimaging results showed less activation to distractors subsequently remembered than those forgotten in the middle and superior frontal regions and the lateral inferior parietal lobe including the angular gyrus and the temporoparietal regions. However, the left anterior hippocampus and the right fusiform gyrus showed greater activation to distractors subsequently remembered. Those findings suggest that insufficient engagement of the dorsal frontal cortex which regulates attentional control and the inferior parietal lobe which functions to reorient attention may allow goal-irrelevant information access to working memory and to be encoded into long-term memory.


Assessing patient's care requirements: a comparison of instruments.
The purpose of this study was to compare two patient classification instruments developed in different countries, Perroca's (Brazil) and the Beakta (Sweden) systems and to investigate if both instruments equally assess patients' care requirements. The survey sample comprised 85 patients from a university hospital in southeast Sweden. Statistical analysis used Spearman's correlation and Kappa. The Spearman's correlation coefficient for total scores and classifications were 0.83 and 0.80, respectively (P-value < 0.01). The level of agreement between the instruments related to the different care categories pointed to an overall kw of 0.60 (95% CI: 0.50-0.71). The findings indicate a high degree of association between the total scores and patient classification assessment using the Beakta and Perroca systems and also a moderate level of agreement between the two instruments in the different care categories. There are few surveys that compare classification instruments between countries making it difficult to know to what extent cultural differences influence measurement approaches.


Characterization of NADH dehydrogenases of Pseudomonas fluorescens WCS365 and their role in competitive root colonization.
The excellent-root-colonizing Pseudomonas fluorescens WCS365 was selected previously as the parental strain for the isolation of mutants impaired in root colonization. Transposon mutagenesis of WCS365 and testing for root colonization resulted in the isolation of mutant strain PCL1201, which is approximately 100-fold impaired in competitive tomato root colonization. In this manuscript, we provide evidence that shows that the lack of NADH dehydrogenase I, an enzyme of the aerobic respiratory chain encoded by the nuo operon, is responsible for the impaired root-colonization ability of PCL1201. The complete sequence of the nuo operon (ranging from nuoA to nuoN) of P. fluorescens WCS365 was identified, including the promoter region and a transcriptional terminator consensus sequence downstream of nuoN. It was shown biochemically that PCL1201 is lacking NADH dehydrogenase I activity. In addition, the presence and activity of a second NADH dehydrogenase, encoded by the ndh gene, was identified to our knowledge for the first time in the genus Pseudomonas. Since it was assumed that low-oxygen conditions were present in the rhizosphere, we analyzed the activity of the nuo and the ndh promoters at different oxygen tensions. The results showed that both promoters are up-regulated by low concentrations of oxygen and that their levels of expression vary during growth. By using lacZ as a marker, it was shown that both the nuo operon and the ndh gene are expressed in the tomato rhizosphere. In contrast to the nuo mutant PCL1201, an ndh mutant of WCS365 appeared not to be impaired in competitive root tip colonization.


Estimated Age of First Exposure to Contact Sports and Neurocognitive, Psychological, and Physical Outcomes in Healthy NCAA Collegiate Athletes: A Cohort Study.
Collegiate football players who started playing tackle football before age 12 years did not show worse neuropsychological test performance than those who started playing tackle football after age 12 years. It is unknown if beginning other contact sports, such as lacrosse, at a younger age is associated with worse neurocognitive performance, greater psychological distress, or worse postural stability in collegiate student athletes. The purpose of this study was to examine the association between estimated age of first exposure (eAFE) to repetitive head impacts (RHI) and these outcome measures in collegiate student athletes. 1891 female and 4448 male collision/contact (i.e., football, ice hockey, lacrosse, wrestling, soccer) and non-contact (i.e., golf, rifle, rowing/crew, swimming, tennis) sport athletes completed baseline testing, including the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), Brief Symptom Inventory 18 (BSI-18), and Balance Error Scoring System (BESS). For women, the eAFE-by-sport interaction was associated with ImPACT Verbal Memory and Visual Memory, whereby earlier eAFE to contact sports was associated with higher composite scores (B = - 0.397, B = - 0.485, respectively). For men, the eAFE-by-sport interaction was associated with BSI-18 Depression and Global Severity Index and symptom severity scores, whereby earlier eAFE to football was associated with lower psychological distress and symptom severity [Depression, Exp(B) = 1.057; Global Severity Index, Exp(B) = 1.047; Symptom Severity, Exp(B) = 1.046]. Parameter estimates were small suggesting these results may have minimal practical relevance. Findings suggest that RHI during early adolescence is unrelated to brain health as measured by these specific outcome measures in collegiate student athletes.


Intracranial hemorrhage as the initial manifestation of a congenital disorder of glycosylation.
Intracranial hemorrhage in a term neonate is a rare event in the absence of an identifiable precipitating factor such as severe thrombocytopenia, mechanical trauma, asphyxia, infections, or congenital vascular malformations. Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of multisystem disorders characterized by the abnormal glycosylation of a number of glycoproteins. Although bleeding caused by abnormal glycosylation of various coagulation factors is a well-known clinical complication of several types of congenital disorders of glycosylation, intracranial hemorrhage has not been reported as an initial manifestation of this entity. Here we report the detailed history of a family with 2 consecutive male infants, both born at term with intracranial hemorrhage diagnosed within the first 24 hours of life. The diagnosis of a congenital disorder of glycosylation was established in the second infant by an abnormal glycosylation of serum transferrin detected by electrospray-ionization mass spectrometry. Both infants showed significant neurologic deterioration during the first month of life, and both died at 5 months of age. Intracranial hemorrhage in a term neonate without a potential precipitating factor represents yet another clinical feature that should raise the suspicion for a congenital disorder of glycosylation.


COMETARY SCIENCE. CHO-bearing organic compounds at the surface of 67P/Churyumov-Gerasimenko revealed by Ptolemy.
The surface and subsurface of comets preserve material from the formation of the solar system. The properties of cometary material thus provide insight into the physical and chemical conditions during their formation. We present mass spectra taken by the Ptolemy instrument 20 minutes after the initial touchdown of the Philae lander on the surface of comet 67P/Churyumov-Gerasimenko. Regular mass distributions indicate the presence of a sequence of compounds with additional -CH2- and -O- groups (mass/charge ratios 14 and 16, respectively). Similarities with the detected coma species of comet Halley suggest the presence of a radiation-induced polymer at the surface. Ptolemy measurements also indicate an apparent absence of aromatic compounds such as benzene, a lack of sulfur-bearing species, and very low concentrations of nitrogenous material.


Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors.
Palliative care is increasingly offered earlier in the cancer trajectory but rarely in Idiopathic Parkinson's Disease(IPD), Progressive Supranuclear Palsy(PSP) or Multiple System Atrophy(MSA). There is little longitudinal data of people with late stage disease to understand levels of need. We aimed to determine how symptoms and quality of life of these patients change over time; and what demographic and clinical factors predicted changes. We recruited 82 patients into a longitudinal study, consenting patients with a diagnosis of IPD, MSA or PSP, stages 3-5 Hoehn and Yahr(H&Y). At baseline and then on up to 3 occasions over one year, we collected self-reported demographic, clinical, symptom, palliative and quality of life data, using Parkinson's specific and generic validated scales, including the Palliative care Outcome Scale (POS). We tested for predictors using multivariable analysis, adjusting for confounders. Over two thirds of patients had severe disability, over one third being wheelchair-bound/bedridden. Symptoms were highly prevalent in all conditions - mean (SD) of 10.6(4.0) symptoms. More than 50% of the MSA and PSP patients died over the year. Over the year, half of the patients showed either an upward (worsening, 24/60) or fluctuant (8/60) trajectory for POS and symptoms. The strongest predictors of higher levels of symptoms at the end of follow-up were initial scores on POS (AOR 1.30; 95%CI:1.05-1.60) and being male (AOR 5.18; 95% CI 1.17 to 22.92), both were more predictive than initial H&Y scores. The findings point to profound and complex mix of non-motor and motor symptoms in patients with late stage IPD, MSA and PSP. Symptoms are not resolved and half of the patients deteriorate. Palliative problems are predictive of future symptoms, suggesting that an early palliative assessment might help screen for those in need of earlier intervention.


Identification of immunologic and pathologic parameters of death versus survival in respiratory tularemia.
Francisella tularensis can cause severe disseminated disease after respiratory infection. The identification of factors involved in mortality or recovery following induction of tularemia in the mouse will improve our understanding of the natural history of this disease and facilitate future evaluation of vaccine candidate preparations. BALB/c mice were infected intranasally with the live vaccine strain (LVS) of F. tularensis subsp. holarctica and euthanized at different stages of disease to analyze the induction of immune molecules, gross anatomical features of organs, bacterial burdens, and progression of the histopathological changes in lung and spleen. Tissue-specific interleukin-6 (IL-6), macrophage inflammatory protein 2, and monocyte chemotactic protein 1 were immune markers of mortality, while anti-LVS immunoglobulin M and IL-1beta were associated with survival. Moribund mice had enlarged spleens and lungs, while surviving mice had even more prominent splenomegaly and normal-appearing lungs. Histopathology of the spleens of severely ill mice was characterized by disrupted lymphoid follicles and fragmented nuclei, while the spleens of survivors appeared healthy but with increased numbers of megakaryocytes and erythrocytes. Histopathology of the lungs of severely ill mice indicated severe pneumonia. Lungs of survivors at early time points showed increased inflammation, while at late times they appeared healthy with peribronchial lymphoid aggregates. Our results suggest that host immune factors are able to affect bacterial dissemination after respiratory tularemia, provide new insights regarding the pathological characteristics of pulmonary tularemia leading to systemic disease, and potentially identify immune markers associated with recovery from the disease.


Iron deficiency and malaria among children living on the coast of Kenya.
Both iron deficiency and malaria are common in much of sub-Saharan Africa, and the interaction between these conditions is complex. To investigate the association between nutritional iron status, immunoglobulins, and clinical Plasmodium falciparum malaria, we determined the incidence of malaria in a cohort of children between the ages of 8 months and 8 years who were living on the Kenyan coast. Biochemical iron status and malaria-specific immune responses were determined during 2 cross-sectional surveys. We found that the incidence of clinical malaria was significantly lower among iron-deficient children (incidence-rate ratio [IRR], 0.70; 95% confidence interval [CI], 0.51-0.99; P<.05), that the incidence of malaria was significantly associated with plasma ferritin concentration (IRR for log ferritin concentration, 1.48; 95% CI, 1.01-2.17; P<.05), and that iron status was strongly associated with a range of malaria-specific immunoglobulins. We conclude that iron deficiency was associated with protection from mild clinical malaria in our cohort of children in coastal Kenya and discuss possible mechanisms for this protection.


Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn.
Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs) in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception.


[Validity of food and beverage intake data obtained by telephone survey].
To evaluate the reproducibility and validity of data on food and beverage intake obtained by means of a telephone-based surveillance system. Reproducibility and validity analyses were carried out in two random subsamples (n=112 and n=119, respectively) of the total sample (N=2,024) of adults (> or =18 years) studied by the system in 2005 in the municipality of São Paulo, Southeastern Brazil. Indicators evaluated included protective factors (daily or almost daily intake of fruit and vegetables) and risk factors (daily or almost daily intake of soft drinks, frequent intake of foods containing saturated animal fat, and abusive intake of alcoholic beverages) for the development of chronic diseases. Reproducibility was studied by comparing the results of the original telephonic interview with those of another interview carried out 7-15 days later. Validity was analyzed by comparing the results of the telephone interview with those of three 24-hour recalls (our gold-standard) carried out up to 5 days following the original interview. The frequency of the studied indicators remained relatively constant between the first and second telephone interviews, with kappa coefficients ranging from 0.57 to 0.80, indicating good reproducibility for all indicators. In relation to the gold standard, there was a trend towards overestimating the frequency of intake of protective foods, but of foods associated with increased risk of chronic diseases. Sensitivity and specificity were high for indicators of consumption of risk-associated foods (close to 80%), and variable in the case of protective foods (42% to 80%). The evaluation showed evidence of good reproducibility and adequate validity for most indicators employed in the system, which indicates that maintaining this system operational in coming years will provide a useful instrument for evaluating public policies for the promotion of a healthy diet and for control of non-communicable chronic diseases with a dietary component in Brazil.


Modeling intrinsically disordered proteins with bayesian statistics.
The characterization of intrinsically disordered proteins is challenging because accurate models of these systems require a description of both their thermally accessible conformers and the associated relative stabilities or weights. These structures and weights are typically chosen such that calculated ensemble averages agree with some set of prespecified experimental measurements; however, the large number of degrees of freedom in these systems typically leads to multiple conformational ensembles that are degenerate with respect to any given set of experimental observables. In this work we demonstrate that estimates of the relative stabilities of conformers within an ensemble are often incorrect when one does not account for the underlying uncertainty in the estimates themselves. Therefore, we present a method for modeling the conformational properties of disordered proteins that estimates the uncertainty in the weights of each conformer. The Bayesian weighting (BW) formalism incorporates information from both experimental data and theoretical predictions to calculate a probability density over all possible ways of weighting the conformers in the ensemble. This probability density is then used to estimate the values of the weights. A unique and powerful feature of the approach is that it provides a built-in error measure that allows one to assess the accuracy of the ensemble. We validate the approach using reference ensembles constructed from the five-residue peptide met-enkephalin and then apply the BW method to construct an ensemble of the K18 isoform of the tau protein. Using this ensemble, we indentify a specific pattern of long-range contacts in K18 that correlates with the known aggregation properties of the sequence.


Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review.
Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n = 108 studies) and stroke mortality rates (n = 3 countries). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17 nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25 nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Medical Research Council (UK) and British Heart Foundation.


Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy.
Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 September 2015), MEDLINE (January 1966 to 31 July 2015), EMBASE (January 1985 to 31 July 2015) and reference lists of retrieved studies. Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not eligible for inclusion. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two authors assessed the quality of the evidence using the GRADE approach. Overall, the quality of evidence is low for the primary outcomes. All of the included trials had small numbers of participants and few events. Preterm birth, the most important primary outcome, had wide confidence intervals crossing the line of no effect.Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo.Betamimetics reduced the incidence of preterm labour (two trials, 194 twin pregnancies, risk ratio (RR) 0.37; 95% confidence interval (CI) 0.17 to 0.78; low quality evidence). However, betamimetics did not reduce prelabour rupture of membranes (one trial, 144 twin pregnancies, RR 1.42; 95% CI 0.42 to 4.82; low quality evidence), preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10; low quality evidence), or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50; low quality evidence). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.21 to 200.24). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects), or small-for-gestational age neonates (two trials, 178 neonates, average RR 0.90; 95% CI 0.41 to 1.99, random-effects). Two trials showed that betamimetics significantly reduced the incidence of respiratory distress syndrome (388 neonates, RR 0.30; 95% CI 0.12 to 0.77), but the difference was not significant when the analysis was adjusted to account for the non-independence of twins (194 twins, RR 0.35; 95% CI 0.11 to 1.16). Three trials showed no evidence of an effect of betamimetics in reducing neonatal mortality, either with the unadjusted analysis, assuming twins are completely independent of each other (452 neonates, average RR 0.90; 95% CI 0.15 to 5.37, random-effects), or in the adjusted analysis, assuming non-independence of twins (226 twins, average RR 0.74; 95% CI 0.23 to 2.38, random-effects). A maternal death was reported in one trial without a significant difference between the groups (144 women, RR 2.84; 95% CI 0.12 to 68.57). There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy.


Concentration-dependent differing actions of the nonsteroidal anti-inflammatory drug, celecoxib, in distearoyl phosphatidylcholine multilamellar vesicles.
The interactions of the nonsteroidal anti-inflammatory drug, celecoxib, with 1,2-distearoyl-sn-glycero-3-phosphocholine multilamellar vesicles were studied as a function of temperature and different drug concentrations, using Fourier transform infrared spectroscopy, differential scanning calorimetry, and turbidity technique at 440 nm. Our studies reveal that celecoxib lowers the main phase-transition temperature and decreases the fluidity of the membranes at all concentrations. Celecoxib induced opposing effects on molecular order at different concentrations by increasing the ordering of the system at low concentrations and disordering it at high concentrations. Further, the drug increases the number of hydrogen bonds around the carbonyl groups at low concentrations in both phases, whereas the degree of dehydration increases at high concentrations in the gel phase. An evidence of phase separation has also been clearly observed at high concentrations. Thus, depending on the concentration used, celecoxib induces significant changes in the biophysical properties of membranes that may aid in understanding its mechanism of action.


Effects of repeated vibratory stimulation of wrist and elbow flexors on hand dexterity, strength, and sensory function in patients with chronic stroke: a pilot study.
[Purpose] The aim of this study was to investigate the effects of repeated vibratory stimulation to muscles related to hand functions on dexterity, strength, and sensory function in patients with chronic stroke. [Subjects and Methods] A total of 10 stroke patients with hemiplegia participated in this study. They were divided into two groups: a) Experimental and b) Control, with five randomly selected subjects for each group. The experimental group received vibratory stimulation, while the control group received the traditional physical therapy. Both interventions were performed for 30 minutes each session, three times a week for four weeks. [Results] There was a significant within-group improvement in the box and block test results in both groups for dexterity. Grip strength improved in both groups but the improvement was not statistically significant. [Conclusion] The vibratory stimulation activated the biceps brachii and flexor carpi radialis, which increased dexterity to grasp and lift the box and block from the surface. Therefore, repeated vibratory stimulation to muscles related to hand functions improved hand dexterity equality to the traditional physical therapy in patients with chronic stroke.


Histone deacetylase inhibitors and cancer therapy.
Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research and understanding epigenetic control has supplied a plethora of potential targets for intervention in cancer. Histone deacetylases (HDACs) have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. Here, we review HDAC inhibitors, together with their current status of clinical development and potential utility in cancer therapy.


Vestibular-related eye movements in the rat following selective electrical stimulation of the vestibular sensors.
Rats are the most commonly used species in the neurosciences; however, little is known about the effects of selective electrical stimulation of individual vestibular sensors, on their eye movements. This limits their use to study the effects of vestibular stimulation on the brain, and their use in further exploring novel technologies such as artificial vestibular implants. We describe the effects of electrical stimulation of each vestibular sensor on vestibular-related eye movement in rats and compared the results to other species. We demonstrated that each sensor is responsible for specific bilateral eye movements. We found that the eye movements in rats differed from other species. Although the results were similar when stimulating the horizontal canal ampulla, differences appeared when stimulating the vertical canal sensors. During utricular stimulation, the ipsilateral eye moved dorsally in most cases, while the contralateral eye usually moved either caudally, or in extorsion. Saccular stimulation usually moved the ipsilateral eye dorsally or ventrally, while the contralateral eye usually moved ventrally or caudally. This study provides the first data on the application of selective electrical vestibular stimulation in the rat to the study of vestibular-related eye movements.


Association of Socio-Environmental Determinants with Diabetes Prevalence in the Athens Metropolitan Area, Greece: A Spatial Analysis.
The aim of this study was to investigate the spatial variation of diabetes in relation to the geographical variability of socio-environmental characteristics in the urban districts of Athens. A sample of 2,445 individuals from the greater area of Athens was randomly enrolled in the ATTICA study between 2001 and 2002. Diabetes was defined according to American Diabetes Association criteria. Geographical and statistical analyses were applied to examine the relationship between diabetes prevalence and factors related to education, economic status, population density, immigrant status, and availability of urban green areas. Diabetes prevalence and socio-environmental factor mapping was based on the Geographic Information Systems (GIS) technology. Variograms and spatial quasi-Poisson regression analysis evaluated the associations of diabetes with the socio-environmental variables at the municipal level. According to the geographical analysis and mapping, the highest proportions of people with diabetes were found in the West sector and in one district of the East and South sector each. Regression analysis revealed that the proportion of inhabitants with higher education is negatively correlated with diabetes prevalence in the regional areas of Athens. The study revealed that socio-environmental status in residential areas, especially educational and economic levels, is correlated with diabetes prevalence at the aggregate level. These correlations may reflect socio-economic segregation patterns at the district level, and different prevalence rates of diabetes among individuals with higher income and educational levels.


Cohort analysis of mortality rates as an historical or narrative technique.
A history of cohort analysis has been given, and it has been pointed out that the bulk of the literature on the subject has dealt with concepts that assume either that graduation and possibly extrapolation are desirable, preferably in conformity with some formula expressing what is implicitly accepted as a "law of mortality", or that, whether or not a fixed pattern of mortality exists, the intensity of mortality risk is largely determined in early life. The view is advanced that either concept alone, is, or both concepts together are, inadequate and may lead to an improper assessment of the nature-nurture complex, since environment and therapeutic measures are constantly changing. The plea is made for the technique of cohort analysis to be used as a narrative or historical technique, and for a synthesis of knowledge derived from social history, medical history, and cohort analysis to be made to interpret the narrative. The effects of a changing rate on the mortality pattern as depicted by date-contour analysis and cohort analysis are outlined and the danger of basing biological theories on the mortality pattern revealed by date-contour analysis alone is indicated. This point is illustrated by reference to a recent theory that has been based on such an analysis.


Dosimetric characteristics of the Novoste Beta-Cath 90Sr/Y source trains at submillimeter distances.
Measurements were performed on the 30, 40, and 60 mm 90Sr/Y beta-emitter source trains used in the Novoste Beta-Cath system to determine their dosimetric characteristics at submillimeter distances and provide the necessary TG-60 parameters for mapping their dose distributions. These measurements were carried out in a Solid Water phantom where MD55-2 Gafchromic films were placed in direct contact with a 5 French (F) catheter used for the 30 and 60 mm source trains and a 3.5F catheter used for thinner 30 and 40 mm source trains. A data set consisted of three pieces of Gafchromic film irradiated for periods of 1.5, 5, and 10 minutes, respectively. This 3-film irradiation technique provided reliable dose data at short, intermediate and long distances from a source train. Three data sets per source train were collected in this study. For the 30 mm source train with a 5F catheter, data were collected with the source axis at proximal (0.41 mm) and distal (1.19 mm) positions to the film surface in order to investigate dosimetric effects due to the off centering of the source train lumen within the catheter. Absolute doses were determined by calibrating the Gafchromic film in a high-energy electron beam from a radiotherapy accelerator. The absolute dose rates at a distance of 2 mm along the source trains transverse axis were found to be within 13.7% of the values provided by Novoste. Radial dose functions were within 13% compared to 90Sr/Y source train data constructed from Soares' 90Sr/Y single seed data and within 17% and 25% compared to Monte Carlo data by Ye et al., and Wang et al., respectively. Discrepancies of 33% and 19% were observed at short radial distances (< or = 1 mm) between the Novoste Monte Carlo and the 3.5F and 5F catheter measured data, respectively. The source off centering data showed higher dose contribution from the source train at its distal rather than proximal position. Radial dose function comparisons between the Novoste Monte Carlo and the measured data, calculated as a function of radial distance from the catheter's center showed good agreement (< or = 10%).


Increasing instruction time in school does increase learning.
Increasing instruction time in school is a central element in the attempts of many governments to improve student learning, but prior research-mainly based on observational data-disputes the effect of this approach and points out the potential negative effects on student behavior. Based on a large-scale, cluster-randomized trial, we find that increasing instruction time increases student learning and that a general increase in instruction time is at least as efficient as an expert-developed, detailed teaching program that increases instruction with the same amount of time. These findings support the value of increased instruction time.


Dietary Sodium/Potassium Intake Does Not Affect Cognitive Function or Brain Imaging Indices.
Dietary sodium may influence cognitive function through its effects on cerebrovascular function and cerebral blood flow. The aim of this study was to evaluate the association of dietary sodium intake with cognitive decline in community-dwelling older adults. We also evaluated the associations of dietary potassium and sodium:potassium intake with cognitive decline, and associations of these nutrients with micro- and macro-structural brain magnetic resonance imaging (MRI) indices. In all, 1,194 participants in the Health Aging and Body Composition study with measurements of dietary sodium intake (food frequency questionnaire [FFQ]) and change in the modified Mini Mental State Exam (3MS) were included. The age of participants was 74 ± 3 years with a mean dietary sodium intake of 2,677 ± 1,060 mg/day. During follow-up (6.9 ± 0.1 years), 340 (28%) had a clinically significant decline in 3MS score (≥1.5 SD of mean decline). After adjustment, dietary sodium intake was not associated with odds of cognitive decline (OR 0.96, 95% CI 0.50-1.84 per doubling of sodium). Similarly, potassium was not associated with cognitive decline; however, higher sodium:potassium intake was associated with increased odds of cognitive decline (OR 2.02 [95% CI 1.01-4.03] per unit increase). Neither sodium or potassium alone nor sodium:potassium were associated with micro- or macro-structural brain MRI indices. These results are limited by the use of FFQ. In community-dwelling older adults, higher sodium:potassium, but not sodium or potassium intake alone, was associated with decline in cognitive function, with no associations observed with micro- and macro-structural brain MRI indices. These findings do not support reduction dietary sodium/increased potassium intake to prevent cognitive decline with aging.


Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells.
Adenosine is an important signaling molecule that regulates multiple physiologic processes and exerts major anti-inflammatory actions. Tumors have high concentrations of adenosine, which could inhibit the function of tumor-infiltrating lymphoid cells. We investigated the ability of adenosine and its stable analogue 2-chloroadenosine (CADO) to inhibit cytokine production and cytotoxic activity of lymphokine-activated killer (LAK) cells and determined whether both these effects are initiated via a common pathway. CADO strongly inhibited cytotoxic activity of LAK cells and attenuated the production of IFN-gamma, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, and macrophage inflammatory protein-1alpha by LAK cells stimulated by cross-linking of the Ly49D receptor. These inhibitory effects were associated with the ability of CADO to stimulate cyclic AMP (cAMP) production and activate protein kinase A (PKA). Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKA types I and II, we found that activation of PKA I, but not PKA II, mimicked the inhibitory effects of CADO on LAK cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKI(14-22) peptide) failed to abrogate the inhibitory effects of CADO whereas Rp-8-Br-cAMPS, an antagonist of the RI subunit, blocked the inhibitory effects of CADO. We conclude that the inhibitory effects of adenosine are probably mediated via cAMP-dependent activation of the RI subunits of PKA I but are independent of the catalytic activity of PKA. Tumor-produced adenosine could be a potent tumor microenvironmental factor inhibiting the functional activity of tumor-infiltrating immune cells.


Immunopathology and immunogenetics of allergic bronchopulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1%-2% of asthmatic and 7%-9% of CF patients develop ABPA. ABPA is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis. The inflammatory response is characterized by Th2 responses to Aspergillus allergens, increased serum IgE, and eosinophilia. A number of genetic risks have recently been identified in the development of ABPA. These include HLA-DR and HLA-DQ, IL-4 receptor alpha chain (IL-4RA) polymorphisms, IL-10 -1082GA promoter polymorphisms, surfactant protein A2 (SP-A2) polymorphisms, and cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations. The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses to A. fumigatus antigens. These genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and CF patients who are at risk to the development of ABPA. Furthermore, these studies suggest that immune modulation with medications such as anti-IgE, anti-IL-4, and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA.


Low-dose radiation therapy for coronavirus disease-2019 pneumonia: Is it time to look beyond apprehensions?
Coronavirus disease-2019 (COVID-19) has become a global health crisis. Mortality associated with COVID-19 is characterized mainly by acute respiratory distress syndrome (ARDS), sepsis, pneumonia, and respiratory failure. The pathogenesis of the disease is known to be associated with pro-inflammatory processes after virus infection. Hence, various therapeutic strategies are being developed to control the inflammation and cytokine storm in COVID-19 patients. Recently, low-dose radiation therapy (LDRT) has been suggested for the treatment of pneumonia/ADRS in COVID-19 patients through irradiation of lungs by gamma/X-ray. In this direction, a few clinical trials have also been initiated. However, a few recent publications have raised some concerns regarding LDRT, especially about possibilities of activation/aggressiveness of virus (severe acute respiratory syndrome coronavirus 2 in case of COVID-19), lung injury and risk of second cancer after low-dose therapy. The present manuscript is an attempt to analyze these apprehensions based on cited references and other available literature, including some from our laboratory. At this point, LDRT may be not the first line of therapy. However, based on existing anti-inflammatory evidence of LDRT, it needs encouragement as an adjuvant therapy and for more multi-centric clinical trials. In addition, it would be worth combining LDRT with other anti-inflammatory therapies, which would open avenues for multi-modal therapy of pneumonia/ARDS in COVID-19 patients. The mode of irradiation (local lung irradiation or whole-body irradiation) and the window period after infection of the virus, need to be optimized using suitable animal studies for effective clinical outcomes of LDRT. However, considering ample evidence, it is time to look beyond the apprehensions if a low dose of radiation could be exploited for better management of COVID-19 patients.


Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay.
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection. Microscopic diagnosis, including diagnosis using the Merifluor-Pneumocystis direct fluorescent antigen (MP-DFA) test, has limitations. Real-time PCR may assist in diagnosis, but no commercially validated real-time PCR assay has been available to date. MycAssay Pneumocystis is a commercial assay that targets the P. jirovecii mitochondrial large subunit (analytical detection limit, ≤ 3.5 copies/μl of sample). A multicenter trial recruited 110 subjects: 54 with transplants (40 with lung transplants), 32 with nonmalignant conditions, 13 with leukemia, and 11 with solid tumors; 9 were HIV positive. A total of 110 respiratory samples (92% of which were bronchoalveolar lavage [BAL] specimens) were analyzed by PCR. Performance was characterized relative to investigator-determined clinical diagnosis of PCP (including local diagnostic tests), and PCR results were compared with MP-DFA test results for 83 subjects. Thirteen of 14 subjects with PCP and 9/96 without PCP (including 5 undergoing BAL surveillance after lung transplantation) had positive PCR results; sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were 93%, 91%, 59%, and 99%, respectively. Fourteen of 83 subjects for whom PCR and MP-DFA test results were available had PCP; PCR sensitivity, specificity, PPV, and NPV were 93%, 90%, 65%, and 98%, respectively, and MP-DFA test sensitivity, specificity, PPV, and NPV were 93%, 100%, 100%, and 98%. Of the 9 PCR-positive subjects without PCP, 1 later developed PCP. The PCR diagnostic assay compares well with clinical diagnosis using nonmolecular methods. Additional positive results compared with the MP-DFA test may reflect low-level infection or colonization.