Consent for transfusion: is it informed?
Informed consent for transfusions presumes that the patient has been "informed," meaning they have been given sufficient information to make an intelligent choice, and that they "consent," meaning that the patient is competent and free to consent. Although this may be oral or written, the latter is preferable for documentation and legal proof. This may either be as a chart note, or form. In any case, the informed transfusion recipient should be given a description of the procedure in lay terms, told of the expected benefit, including the outcome without the transfusion, and what reasonably foreseeable adverse consequences may occur. The individual should have the opportunity to ask questions of the physician performing the informed consent process. There should be time to provide the information and a discussion; and the patient must be able to comprehend all of this. If this process is performed by the physician talking to his/her patient, then, the patient is likely to be informed about, and consent to, elective transfusions. Once obtained and documented, that consent should be presumed to be valid with a course of therapy for transfusions. If some event significantly changes some aspects of the information on which the patient relied in consenting and now should be aware of, then, the patient should again give consent for transfusion, after being informed of this new information.


Numerical study on flows of red blood cells with liposome-encapsulated hemoglobin at microvascular bifurcation.
Flow analysis at microvascular bifurcation after partial replacement of red blood cell (RBC) with liposome-encapsulated hemoglobin (LEH) was performed using the lattice Boltzmann method. A two-dimensional symmetric Y bifurcation model with a parent vessel diameter of 20 mum and daughter branch diameters of 20 microm was considered, and the distributions of the RBC, LEH, and oxygen fluxes were calculated. When only RBCs flow into the daughter branches with unevenly distributed flows, plasma separation occurred and the RBC flow to the lower-flow branch was disproportionately decreased. On the other hand, when half of RBC are replaced by LEH, the biasing of RBC flow was enhanced whereas LEH flowed favorably into the lower-flow branch, because many LEH within the parent vessel are suspended in the plasma layer, where no RBCs exist. Consequently, the branched oxygen fluxes became nearly proportional to flows. These results indicate that LEH facilitates oxygen supply to branches that are inaccessible to RBCs.


Infection-specific activation of the Medicago truncatula Enod11 early nodulin gene promoter during actinorhizal root nodulation.
The MtEnod11 gene from Medicago truncatula is widely used as an early infection-related molecular marker for endosymbiotic associations involving both rhizobia and arbuscular mycorrhizal fungi. In this article, heterologous expression of the MtEnod11 promoter has been studied in two actinorhizal trees, Casuarina glauca and Allocasuarina verticillata. Transgenic C. glauca and A. verticillata expressing a ProMtEnod11::beta-glucuronidase (gus) fusion were generated and the activation of the transgene investigated in the context of the symbiotic associations with the N-fixing actinomycete Frankia and both endo- and ectomycorrhizal fungi (Glomus intraradices and Pisolithus albus, respectively). ProMtEnod11::gus expression was observed in root hairs, prenodules, and nodules and could be correlated with the infection of plant cells by Frankia spp. However, no activation of the gus reporter gene was detected prior to infection or in response to either rhizobial Nod factors or the wasp venom peptide MAS-7. Equally, ProMtEnod11::gus expression was not elicited during the symbiotic associations with either ecto- or endomycorrhizal fungi. These observations suggest that, although there is a conservation of gene regulatory pathways between legumes and actinorhizal plants in cells accommodating endosymbiotic N-fixing bacteria, the events preceding bacterial infection or related to mycorrhization appear to be less conserved.


Cost-effectiveness analysis of sofosbuvir compared to current standard treatment in Swiss patients with chronic hepatitis C.
In clinical trials, sofosbuvir showed high antiviral activity in patients infected with hepatitis C virus (HCV) across all genotypes. We aimed to determine the cost-effectiveness of sofosbuvir-based treatment compared to current standard treatment in mono-infected patients with chronic hepatitis C (CHC) genotypes 1-4 in Switzerland. Cost-effectiveness was modelled from the perspective of the Swiss health care system using a lifetime Markov model. Incremental cost-effectiveness ratios (ICERs) used an endpoint of cost per quality-adjusted life year (QALY) gained. Treatment characteristics, quality of life, and transition probabilities were obtained from published literature. Country-specific model inputs such as patient characteristics, mortality and costs were obtained from Swiss sources. We performed extensive sensitivity analyses. Costs and effects were discounted at 3% (range: 0-5%) per year. Sofosbuvir-containing treatment in mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1-4 showed ICERs between CHF 10,337 and CHF 91,570 per QALY gained. In subgroup analyses, sofosbuvir dominated telaprevir- and boceprevir-containing treatment in treatment-naïve genotype 1 cirrhotic patients. ICERs of sofosbuvir were above CHF 100,000 per QALY in treatment-naïve, interferon eligible, non-cirrhotic patients infected with genotypes 2 or 3. In deterministic and probabilistic sensitivity analyses, results were generally robust. From a Swiss health care system perspective, treatment of mixed cohorts of cirrhotic and non-cirrhotic patients with CHC genotypes 1-4 with sofosbuvir-containing treatment versus standard treatment would be cost-effective if a threshold of CHF 100,000 per QALY was assumed.


Capturing single cell genomes of active polysaccharide degraders: an unexpected contribution of Verrucomicrobia.
Microbial hydrolysis of polysaccharides is critical to ecosystem functioning and is of great interest in diverse biotechnological applications, such as biofuel production and bioremediation. Here we demonstrate the use of a new, efficient approach to recover genomes of active polysaccharide degraders from natural, complex microbial assemblages, using a combination of fluorescently labeled substrates, fluorescence-activated cell sorting, and single cell genomics. We employed this approach to analyze freshwater and coastal bacterioplankton for degraders of laminarin and xylan, two of the most abundant storage and structural polysaccharides in nature. Our results suggest that a few phylotypes of Verrucomicrobia make a considerable contribution to polysaccharide degradation, although they constituted only a minor fraction of the total microbial community. Genomic sequencing of five cells, representing the most predominant, polysaccharide-active Verrucomicrobia phylotype, revealed significant enrichment in genes encoding a wide spectrum of glycoside hydrolases, sulfatases, peptidases, carbohydrate lyases and esterases, confirming that these organisms were well equipped for the hydrolysis of diverse polysaccharides. Remarkably, this enrichment was on average higher than in the sequenced representatives of Bacteroidetes, which are frequently regarded as highly efficient biopolymer degraders. These findings shed light on the ecological roles of uncultured Verrucomicrobia and suggest specific taxa as promising bioprospecting targets. The employed method offers a powerful tool to rapidly identify and recover discrete genomes of active players in polysaccharide degradation, without the need for cultivation.


Open randomized study of cefepime versus piperacillin-gentamicin for treatment of febrile neutropenic cancer patients.
An open-label randomized trial comparing the efficacy and safety of cefepime versus piperacillin plus gentamicin (P+G) given intravenously for the treatment of febrile episodes in neutropenic patients with underlying malignancy was conducted at two oncology centers. Over a 30-month period 111 patients were enrolled and 99 patients were found to be suitable for evaluation. At the 72-h time of evaluation, cefepime monotherapy and P+G combination therapy produced comparable clinical response rates (78% for both). P+G and cefepime produced comparable response rates in microbiologically documented (78 versus 71%), clinically documented (100 versus 100%), and possible (75 versus 79%) infections. The P+G and cefepime treatments achieved comparable microbiological eradication of gram-negative (100 versus 71%) (P = 0.09) and gram-positive (44 versus 70%) (P = 0.37) organisms. There were no statistically significant differences in the rates of superinfection between the groups; however, more superinfections of fungal origin were noted in the P+G group. Cefepime was demonstrated to be an effective and safe treatment for febrile episodes in neutropenic patients with malignancies, and its lack of nephrotoxicity compared to P+G was noteworthy. Cefepime appears to be a candidate for monotherapy in febrile neutropenic cancer patients.


Transformation of NIH 3T3 cells with cloned fragments of human cytomegalovirus strain AD169.
NIH 3T3 cells were transfected with restriction endonuclease and cloned human cytomegalovirus DNA fragments to identify the transforming region(s). Cleavage of human cytomegalovirus strain AD169 DNA with XbaI and HindIII left a transforming region intact whereas EcoRI inactivated this function. Transfection of cells with cosmids containing human cytomegalovirus DNA spanning the entire genome resulted in transformation by one cosmid, pCM1058, with the AD169 HindIII DNA fragments E, R, T, and a'. Cells were selected for their growth in 1.2% methylcellulose. The clones isolated had a significant replating efficiency and were oncogenic in BALB/c nu/nu mice. Transfection of cosmids and plasmids containing subsets of the viral sequences in pCM1058 identified a common region possessed by all of the transforming recombinant molecules. This region was in the HindIII E fragment with the left boundary defined by the EcoRI d-R junction and the right boundary defined by the HindIII E-T junction. Further mapping and transfection experiments determined that the transforming region was contained without a 2.9-kilobase fragment between map units 0.123 and 0.14 on the prototype molecule of the AD169 strain.


The Network Structure of Tobacco Withdrawal in a Community Sample of Smokers Treated With Nicotine Patch and Behavioral Counseling.
Network theories of psychopathology highlight that, rather than being indicators of a latent disorder, symptoms of disorders can causally interact with one another in a network. This study examined tobacco withdrawal from a network perspective. Participants (n = 525, 50.67% female) completed the Minnesota Tobacco Withdrawal Scale four times (2 weeks prior to a target quit day, on the target quit day, and 4 and 8 weeks after the target quit day) over the course of 8 weeks of treatment with nicotine patch and behavioral counseling within a randomized clinical trial testing long-term nicotine patch therapy in treatment-seeking smokers. The conditional dependence among seven withdrawal symptoms was estimated at each of the four measurement occasions. Influential symptoms of withdrawal were identified using centrality indices. Changes in network structure were examined using the Network Comparison Test. Findings indicated many associations among the individual symptoms of withdrawal. The strongest associations that emerged were between sleep problems and restlessness, and associations among affective symptoms. Restlessness and affective symptoms emerged as the most central symptoms in the withdrawal networks. Minimal differences in the structure of the withdrawal networks emerged across time. The cooccurrence of withdrawal symptoms may result from interactions among symptoms of withdrawal rather than simply reflecting passive indicators of a latent disorder. Findings encourage greater consideration of individual withdrawal symptoms and their potential interactions and may be used to generate hypotheses that may be tested in future intensive longitudinal studies. This study provides a novel, network perspective on tobacco withdrawal. Drawing on network theories of psychopathology, we suggest that the cooccurrence of withdrawal symptoms may result from interactions among symptoms of withdrawal over time, rather than simply reflecting passive indicators of a latent disorder. Results indicating many associations among individual symptoms of withdrawal are consistent with a network perspective. Other results of interest include minimal changes in the network structure of withdrawal across four measurement occasions prior to and during treatment with nicotine patch and behavioral counseling.


The agrin gene codes for a family of basal lamina proteins that differ in function and distribution.
We isolated two cDNAs that encode isoforms of agrin, the basal lamina protein that mediates the motor neuron-induced aggregation of acetylcholine receptors on muscle fibers at the neuromuscular junction. Both proteins are the result of alternative splicing of the product of the agrin gene, but unlike agrin, they are inactive in standard acetylcholine receptor aggregation assays. They lack one (agrin-related protein 1) or two (agrin-related protein 2) regions in agrin that are required for its activity. Expression studies provide evidence that both proteins are present in the nervous system and muscle and that, in muscle, myofibers and Schwann cells synthesize the agrin-related proteins while the axon terminals of motor neurons are the sole source of agrin.


Mindfulness-based parent training: strategies to lessen the grip of automaticity in families with disruptive children.
Disagreements and conflicts in families with disruptive children often reflect rigid patterns of behavior that have become overlearned and automatized with repeated practice. These patterns are mindless: They are performed with little or no awareness and are highly resistant to change. This article introduces a new, mindfulness-based model of parent training and contrasts the model's assumptions with those of behavioral (operant) parent training. The new model informs 3 strategies to lessen the grip of automaticity in families with disruptive children: facilitative listening, distancing, and motivated action plans. The article does not oppose mindfulness to mindlessness or suggest that the former is always better than the latter but instead proposes that each is most useful at different times in the parenting process. I conclude by calling for empirical investigations of mindfulness-based parent training and, if those are successful, for the development of an integrated model that blends behavioral and mindfulness-based principles to inform all facets of intervention.


Anti-Gametocyte Antigen Humoral Immunity and Gametocytemia During Treatment of Uncomplicated Falciparum Malaria: A Multi-National Study.
Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates. In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pfs230 (Pfs230c and Pfs230D1M) and Pfs48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment. Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pfs230c, Pfs48/45 and Pfs230D1M varied across study sites at enrolment (p < 0.001), as did IgG seroprevalence for anti-Pfs230c and D1M IgG (p < 0.001), but not for anti-Pfs48/45 IgG (p = 0.159). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (Pfs230c OR [95% CI], p: 1.70 [1.10, 2.62], 0.017; Pfs48/45: 1.45 [0.85, 2.46], 0.174; Pfs230D1M: 1.70 [1.03, 2.80], 0.037), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pfs230c OR [95% CI], p: 1.09 [1.02, 1.17], 0.008; Pfs48/45: 1.05 [0.98, 1.13], 0.185; Pfs230D1M: 1.07 [0.99, 1.14], 0.071). Pfs230 and Pfs48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum.


Macular thickness profile and diabetic retinopathy: the Singapore Epidemiology of Eye Diseases Study.
To evaluate retinal thickness profiles in eyes with and without diabetic retinopathy (DR) using spectral-domain optical coherence tomography (SD-OCT) among individuals with diabetes. Participants were recruited from the Singapore Epidemiology of Eye Diseases Study, a population-based study among Chinese, Malays and Indians aged 40 years or older residing in Singapore. All participants underwent standardised systemic and ophthalmic examinations. Average thickness of the macula, ganglion cell-inner plexiform layer and outer retina layer (from the outer plexiform layer to the retinal pigment epithelium layer) were measured using SD-OCT. DR status and severity were graded based on fundus photographs using the modified Airlie House classification system. Participants with macular oedema were excluded. 2240 eyes from 1280 participants were included. Of these, 1764 (78.7%) eyes had no DR, 351 (15.7%) eyes had minimal or mild DR and 125 (5.6%) eyes had moderate or worse DR. After adjusting for age, gender, ethnicity, axial length, hypertension, glycated haemoglobin, body mass index, total cholesterol and diabetes duration, eyes with DR had thicker macula (245.44 µm vs 243.04 µm, P=0.03) and outer retina (124.26 µm vs 123.08 µm, P=0.01) than eyes without DR. When stratified by DR severity, thicker macula (250.24 µm vs 242.88 µm, P=0.011) and outer retina (126.4 µm vs 123.0 μm, P=0.006) were observed in eyes with moderate or worse, but not minimal or mild DR, compared with eyes without DR. Even in the absence of macular oedema, eyes with DR, particularly those with more severe DR, had thicker macular and outer retinal layers than eyes without DR.


Multiple complexes of nitrogen assimilatory enzymes in spinach chloroplasts: possible mechanisms for the regulation of enzyme function.
Assimilation of nitrogen is an essential biological process for plant growth and productivity. Here we show that three chloroplast enzymes involved in nitrogen assimilation, glutamate synthase (GOGAT), nitrite reductase (NiR) and glutamine synthetase (GS), separately assemble into distinct protein complexes in spinach chloroplasts, as analyzed by western blots under blue native electrophoresis (BN-PAGE). GOGAT and NiR were present not only as monomers, but also as novel complexes with a discrete size (730 kDa) and multiple sizes (>120 kDa), respectively, in the stromal fraction of chloroplasts. These complexes showed the same mobility as each monomer on two-dimensional (2D) SDS-PAGE after BN-PAGE. The 730 kDa complex containing GOGAT dissociated into monomers, and multiple complexes of NiR reversibly converted into monomers, in response to the changes in the pH of the stromal solvent. On the other hand, the bands detected by anti-GS antibody were present not only in stroma as a conventional decameric holoenzyme complex of 420 kDa, but also in thylakoids as a novel complex of 560 kDa. The polypeptide in the 560 kDa complex showed slower mobility than that of the 420 kDa complex on the 2D SDS-PAGE, implying the assembly of distinct GS isoforms or a post-translational modification of the same GS protein. The function of these multiple complexes was evaluated by in-gel GS activity under native conditions and by the binding ability of NiR and GOGAT with their physiological electron donor, ferredoxin. The results indicate that these multiplicities in size and localization of the three nitrogen assimilatory enzymes may be involved in the physiological regulation of their enzyme function, in a similar way as recently described cases of carbon assimilatory enzymes.


Relationship between addiction relapse and self-efficacy rates in injection drug users referred to Maintenance Therapy Center of Sari, 1391.
Self-efficacy is the belief that one has the ability to implement the behaviors needed to produce a desired effect. There has been growing interest in the role of self-efficacy as a predictor and/or mediator of treatment outcome in number of domains. In numerous studies of substance abuse treatment, self-efficacy has emerged as an important predictor of outcome, or as a mediator of treatment effects. In the event of a slip, highly self-efficacious persons are inclined to regard the slip as a temporary setback and to reinstate control, whereas those who have low self-efficacy are more likely to proceed to a full-blown relapse. This study was carried out to determine relationship between relapse and self-efficacy and other factors in injected drug users. We conducted this study in 200 addicts in the center of counseling behavioral disease in health center of sari city (methadone maintenance therapy center or MMTC). A cross-sectional study was carried out on all of these addicts. The average age in addictions was 38 and its range was 20-60.72%of them were married and the first drug used was opium. All of them had relapse at least one time .we found a relationship between relapse and self-efficacy as well as the relationship between self-efficacy with the age of the first of drug use, dose, and procrastination for treatment, marriage, employment and job was significant. This study found that there was a significant difference between relapse and self-efficacy as well as other related factors. It is important to include drug users and common society organizations representing them in every stage of the governmental policy and program development process to make them responsive to the needs of the community.


Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats.
The effect of two types of electrical stimulation designed to induce long-lasting plasticity of the Schaffer/commissural inputs to CA1 pyramidal neurons was investigated using in vitro hippocampal slices made from young (3-6 month) and old (24-27 month) Fischer 344 rats. The first stimulation paradigm, primed burst (PB) stimulation, consisted of a total of five physiologically patterned stimuli: a single priming pulse followed 170 ms later by a burst of four pulses at 200 Hz. The second stimulation paradigm, long-term potentiation (LTP) stimulation, consisted of a 200 Hz/1 second train (a total of 200 stimuli). Primed burst and LTP stimulation were equally effective at inducing a lasting increase in the population spike recorded from slices made from young rats. However, the enhancement of population spike amplitude produced by PB, but not LTP, stimulation was significantly less in slices made from old rats. These results suggest that the capacity of the hippocampus to demonstrate long-lasting synaptic plasticity is not altered with age, but that engaging plasticity-inducing mechanisms becomes more difficult. Furthermore, these data suggest that physiologically patterned paradigms for inducing long-lasting synaptic plasticity may more accurately assess the functional status of hippocampal memory encoding mechanisms than does conventional LTP stimulation.


Early changes in glomerular size selectivity in young adults with type 1 diabetes and retinopathy. Results from the Diabetes Incidence Study in Sweden.
To investigate the relationship between early-onset retinopathy and urinary markers of renal dysfunction. The Diabetes Incidence Study in Sweden (DISS) aims to register all new cases of diabetes in young adults (15-34 years). In 1987-1988, 806 patients were reported and later invited to participate in a follow-up study focusing on microvascular complications after approximately 10 years of diabetes. In the present study, 149 patients with type 1 diabetes, completed eye examination, and urine sampling were included. The patients with retinopathy (n=58, 39%) had higher HbA(1c) (P<.001) and urinary IgG2/creatinine (P<.05) and IgG2/IgG4 ratios (P<.05). Patients with maculopathy had the highest levels. No significant differences in urinary albumin/creatinine, glycosaminoglycans (GAGs)/creatinine, Tamm-Horsfall protein (THP)/creatinine, and IgG4/creatinine ratios were found. Women had higher urinary albumin/creatinine (P<.01) and urinary IgG2/creatinine ratios (P<.01) than men. Young adults with type 1 diabetes and early-onset retinopathy had higher IgG2/creatinine and IgG2/IgG4 ratios than patients without retinopathy indicating that retinopathy is associated with a change in glomerular size selectivity. This was found in association with normal urinary albumin and THP excretion and may be suspected to reflect early general vascular changes.


Good Outcome in a Patient with Massive Pontine Hemorrhage.
Massive pontine hemorrhage with comatose condition has a poor prognosis and bad outcome despite adequate surgical treatment. However, this case report gives a different result. Providing adequate prophylactic treatment to prevent secondary brain injury resulted in a very good recovery at the 6-month follow-up. A 42-year-old man with a history of heavy smoking and poorly controlled blood pressure (BP) developed acute loss of consciousness. He was then brought to the emergency room (ER) in 30 min. At the ER, his Glasgow coma scale score was E1M2V1 and the BP was high. An emergency computed tomography (CT) scan of the brain showed massive hematoma in the pons with intraventricular extension. He was admitted to the intensive care unit with close monitoring of both vital signs and neurosigns. External ventricular drainage was inserted to control intracranial pressure and then removed in only 5 days after adequate control. The patient returned to a good recovery status in 6 months with a modified Rankin scale score of 2 and the CT brain scan showed a small cavity-like lesion at the hemorrhage area. Massive hemorrhage and low consciousness may not truly indicate a poor prognosis in patients with pontine hematoma. Medical and surgical treatments are still needed to control intracranial pressure for prophylaxis of secondary brain injury. Restoration of neuronal functions was achieved after resolution of the hematoma.


N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer.
A step toward the molecular classification of prostate cancer was the discovery of recurrent erythroblast transformation-specific rearrangements, most commonly fusing the androgen-regulated TMPRSS2 promoter to ERG. The TMPRSS2-ERG fusion is observed in around 90% of tumors that overexpress the oncogene ERG. The goal of the current study was to complete the characterization of these ERG-overexpressing prostate cancers. Using fluorescence in situ hybridization and reverse transcription-polymerase chain reaction assays, we screened 101 prostate cancers, identifying 34 cases (34%) with the TMPRSS2-ERG fusion. Seven cases demonstrated ERG rearrangement by fluorescence in situ hybridization without the presence of TMPRSS2-ERG fusion messenger RNA transcripts. Screening for known 5' partners, we determined that three cases harbored the SLC45A3-ERG fusion. To discover novel 5' partners in these ERG-overexpressing and ERG-rearranged cases, we used paired-end RNA sequencing. We first confirmed the utility of this approach by identifying the TMPRSS2-ERG fusion in a known positive prostate cancer case and then discovered a novel fusion involving the androgen-inducible tumor suppressor, NDRG1 (N-myc downstream regulated gene 1), and ERG in two cases. Unlike TMPRSS2-ERG and SCL45A3-ERG fusions, the NDRG1-ERG fusion is predicted to encode a chimeric protein. Like TMPRSS2, SCL45A3 and NDRG1 are inducible not only by androgen but also by estrogen. This study demonstrates that most ERG-overexpressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions. Broader implications of this study support the use of RNA sequencing to discover novel cancer translocations.


Drinking water in South Africa: implications for fluoride supplementation.
During the extremely heavy rainfall period in the first half of 2000 in certain summer rainfall regions of South Africa a similar investigation as in 1983-1984/1985 was done but on a smaller scale, and compared to the previous results. A greater reduction (P < 0.05) of the fluoride levels in the drinking water than previously recorded has recently been demonstrated, thus strongly accentuating the effect of heavy rains. Presently, for fluoride prescription we recommend that the prescriber should decide whether it is a dry or wet period for his area and then read the fluoride content for that area, from the higher or lower end of the water fluoride content range from the tables published in 1988, 1991 or 1994. When in doubt the higher fluoride level should be used as a measure of safety against overprescribing. If only one value exists it should be used until further notification. An extended study is in process to set a single table for South Africa.


Prioritizing Surgical Care on National Health Agendas: A Qualitative Case Study of Papua New Guinea, Uganda, and Sierra Leone.
Little is known about the social and political factors that influence priority setting for different health services in low- and middle-income countries (LMICs), yet these factors are integral to understanding how national health agendas are established. We investigated factors that facilitate or prevent surgical care from being prioritized in LMICs. We undertook country case studies in Papua New Guinea, Uganda, and Sierra Leone, using a qualitative process-tracing method. We conducted 74 semi-structured interviews with stakeholders involved in health agenda setting and surgical care in these countries. Interviews were triangulated with published academic literature, country reports, national health plans, and policies. Data were analyzed using a conceptual framework based on four components (actor power, ideas, political contexts, issue characteristics) to assess national factors influencing priority for surgery. Political priority for surgical care in the three countries varies. Priority was highest in Papua New Guinea, where surgical care is firmly embedded within national health plans and receives significant domestic and international resources, and much lower in Uganda and Sierra Leone. Factors influencing whether surgical care was prioritized were the degree of sustained and effective domestic advocacy by the local surgical community, the national political and economic environment in which health policy setting occurs, and the influence of international actors, particularly donors, on national agenda setting. The results from Papua New Guinea show that a strong surgical community can generate priority from the ground up, even where other factors are unfavorable. National health agenda setting is a complex social and political process. To embed surgical care within national health policy, sustained advocacy efforts, effective framing of the problem and solutions, and country-specific data are required. Political, technical, and financial support from regional and international partners is also important.


Pharmacokinetics of N4-octadecyl-1-beta-D-arabinofuranosylcytosine in plasma and whole blood after intravenous and oral administration to mice.
N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) is a new cytotoxic derivative of cytosine arabinoside with improved cytotoxic activity and stability against deamination. Its pharmacokinetics were studied in mice. The drug was administered intravenously and orally to ICR mice to assess its pharmacokinetic parameters in plasma and whole blood. The lipophilic drug was administered in small unilamellar liposomes 100-400 nm in diameter. The concentrations of NOAC in plasma and erythrocytes were determined by high-performance liquid chromatography (HPLC). When given orally a rather low amount of the delivered NOAC was absorbed as the unchanged drug, resulting in a bioavailability of 1.1% from the plasma and 12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in human xenograft models after oral administration. The mean residence time of NOAC after intravenous administration was 3.5 h in plasma and 6 h in whole blood giving NOAC a terminal half-life in blood substantially longer than that of cytosine arabinoside. After oral administration the mean residence time was 18 h in plasma and whole blood. In summary, NOAC has a prolonged half-life after intravenous administration compared with cytosine arabinoside. The distribution of NOAC in blood is highly dependent on its mode of administration.


The local twitch response during trigger point dry needling: Is it necessary for successful outcomes?
Myofascial trigger point (MTrP) injection and trigger point dry needling (TrPDN) are widely accepted therapies for myofascial pain syndrome (MPS). Empirical evidence suggests eliciting a local twitch response (LTR) during needling is essential. This is the first review exploring the available literature, regardless of study design, on the neurophysiological effects and clinical significance of the LTR as it relates to reductions in pain and disability secondary to MTrP needling. PubMed, MEDLINE, Science Direct and Google Scholar were searched up until October 2016 using terms related to trigger point needling and the LTR. and Discussion: Several studies show that eliciting a LTR does not correlate with changes in pain and disability, and multiple systematic reviews have failed to conclude whether the LTR is relevant to the outcome of TrPDN. Post needling soreness is consistently reported in studies using repeated in and out needling to elicit LTRs and increases in proportion to the number of needle insertions. In contrast, needle winding without LTRs to MTrPs and connective tissue is well supported in the literature, as it is linked to anti-nociception and factors related to tissue repair and remodeling. Additionally, the positive biochemical changes in the MTrP after needling may simply be a wash out effect related to local vasodilation. While the LTR during TrPDN appears unnecessary for managing myofascial pain and unrelated to many of the positive effects of TrPDN, further investigation is required.


Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids.
Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.


Randomized Study of Metoclopramide Plus Diphenhydramine for Acute Posttraumatic Headache.
To determine whether IV metoclopramide 20 mg + diphenhydramine 25 mg (M + D) was more efficacious than IV placebo for acute moderate or severe posttraumatic headache in the emergency room. We conducted this randomized, double-blind, placebo-controlled, parallel-group study in 2 urban emergency departments (EDs). Participants who experienced head trauma and presented to our EDs within 10 days with a headache fulfilling criteria for acute posttraumatic headache were included. We randomized participants in a 1:1 ratio to M + D or placebo. Participants, caregivers, and outcome assessors were blinded to assignment. The primary outcome was improvement in pain on a scale of 0 to 10 between baseline and 1 hour after treatment. This study was completed between August 2017 and March 2020. We screened 414 patients for participation and randomized 160: 81 to M + D and 79 to placebo. Baseline characteristics were comparable between the groups. All enrolled participants provided primary outcome data. Patients receiving placebo reported mean improvement of 3.8 (SD 2.6), while those receiving M + D improved by 5.2 (SD 2.3), for a difference favoring metoclopramide of 1.4 (95% confidence interval [CI] 0.7-2.2, p < 0.01). Adverse events were reported by 35 of 81 (43%) patients who received metoclopramide and 22 of 79 (28%) of patients who received placebo (95% CI 1-30 for difference of 15%, p = 0.04). M + D was more efficacious than placebo with regard to relief of posttraumatic headache in the ED. ClinicalTrials.gov Identifier: NCT03220958. This study provides Class I evidence that for patients with acute moderate or severe posttraumatic headache, IV M + D significantly improved pain compared to placebo.


The von Hippel-Lindau Chuvash mutation in mice causes carotid-body hyperplasia and enhanced ventilatory sensitivity to hypoxia.
The hypoxia-inducible factor (HIF) family of transcription factors coordinates diverse cellular and systemic responses to hypoxia. Chuvash polycythemia (CP) is an autosomal recessive disorder in humans in which there is impaired oxygen-dependent degradation of HIF, resulting in long-term systemic elevation of HIF levels at normal oxygen tensions. CP patients demonstrate the characteristic features of ventilatory acclimatization to hypoxia, namely, an elevated baseline ventilation and enhanced acute hypoxic ventilatory response (AHVR). We investigated the ventilatory and carotid-body phenotype of a mouse model of CP, using whole-body plethysmography, immunohistochemistry, and electron microscopy. In keeping with studies in humans, CP mice had elevated ventilation in euoxia and a significantly exaggerated AHVR when exposed to 10% oxygen, with or without the addition of 3% carbon dioxide. Carotid-body immunohistochemistry demonstrated marked hyperplasia of the oxygen-sensing type I cells, and the cells themselves appeared enlarged with more prominent nuclei. This hypertrophy was confirmed by electron microscopy, which also revealed that the type I cells contained an increased number of mitochondria, enlarged dense-cored vesicles, and markedly expanded rough endoplasmic reticulum. The morphological and ultrastructural changes seen in the CP mouse carotid body are strikingly similar to those observed in animals exposed to chronic hypoxia. Our study demonstrates that the HIF pathway plays a major role, not only in regulating both euoxic ventilatory control and the sensitivity of the response to hypoxia, but also in determining the morphology of the carotid body.


The electronic structure of a β-diketiminate manganese hydride dimer.
The electronic structure of a dimeric manganese hydride catalyst supported by β-diketiminate ligands, [(2,6-iPr2PhBDI)Mn(μ-H)]2, was investigated with density functional theory. A triple bond between the manganese centres was anticipated from simple electron-counting rules; however, calculations revealed Mn-Mn Mayer bond orders of 0.21 and 0.27 for the ferromagnetically-coupled and antiferromagnetically-coupled extremes, respectively. In accordance with experimentally determined Heisenberg exchange coupling constants of -15 ± 0.1 cm-1 (SQUID) and -10.2 ± 0.7 cm-1 (EPR), the calculated J0 value of -10.9 cm-1 confirmed that the ground state involves antiferromagnetic coupling between high spin Mn(ii)-d5 centres. The effect of steric bulk on the bond order was examined via a model study with the least sterically-demanding version of the β-diketiminate ligand and was found to be negligible. Mixing between metal- and β-diketiminate-based orbitals was found to be responsible for the absence of a metal-metal multiple bond. The bridging hydrides give rise to a relatively close positioning of the metal centres, while bridging atoms possessing 2p orbitals result in longer Mn-Mn distances and more stable dimers. The synthesis and characterization of the bridging hydroxide variant, [(2,6-iPr2PhBDI)Mn(μ-OH)]2, provides experimental support for these assessments.


Stochastic description of complex and simple spike firing in cerebellar Purkinje cells.
Cerebellar Purkinje cells generate two distinct types of spikes, complex and simple spikes, both of which have conventionally been considered to be highly irregular, suggestive of certain types of stochastic processes as underlying mechanisms. Interestingly, however, the interspike interval structures of complex spikes have not been carefully studied so far. We showed in a previous study that simple spike trains are actually composed of regular patterns and single interspike intervals, a mixture that could not be explained by a simple rate-modulated Poisson process. In the present study, we systematically investigated the interspike interval structures of separated complex and simple spike trains recorded in anaesthetized rats, and derived an appropriate stochastic model. We found that: (i) complex spike trains do not exhibit any serial correlations, so they can effectively be generated by a renewal process, (ii) the distribution of intervals between complex spikes exhibits two narrow bands, possibly caused by two oscillatory bands (0.5-1 and 4-8 Hz) in the input to Purkinje cells and (iii) the regularity of regular patterns and single interspike intervals in simple spike trains can be represented by gamma processes of orders, which themselves are drawn from gamma distributions, suggesting that multiple sources modulate the regularity of simple spike trains.


Energy expenditure assessed by heart rate and doubly labeled water in young athletes.
To compare total energy expenditure (TEE) estimated by the FLEX heart rate (HR) method with that measured by the doubly labeled water (DLW) technique in young speed skaters. We hypothesized that the accuracy of FLEX HR-estimated TEE would be affected by a) the definition of the FLEX HR and b) the type of training regimen. Eight young athletes (mean age 18.2 +/- 1.3 yr) underwent measurements during two 10-d training periods: an off-season period with voluntary training (predominantly running) and a preseason period mainly focused on skating technique training. TEE was measured simultaneously by the DLW and FLEX HR methods. FLEX HR1 was defined as the mean of the HRs during all resting calibration activities and the lowest HR during exercising calibration activities. FLEX HR2 was defined as the mean of the highest HR during resting activities and the lowest HR during exercising. ANOVA showed that FLEX HR1 was significantly lower than FLEX HR2 (mean of both periods; 77 +/- 5 vs 84 +/- 6 beats.min(-1); P = 0.004). TEE values obtained by DLW were 16.8 +/- 3.8 and 16.9 +/- 2.9 MJ.d(-1) in the two periods, respectively. TEE values calculated from FLEX HR1 were 17.8 +/- 3.6 and 17.4 +/- 2.6 MJ.d(-1), and those from FLEX HR2 17.1 +/- 3.1 and 17.0 +/- 2.7 MJ.d-1, respectively. No significant period (P = 0.83) or method (P = 0.44) effect on TEE was observed. FLEX HR-estimated TEE was not affected by the definition of the FLEX HR or by the type of training regimen as compared with TEE measured by the DLW method in young athletes.


StatAlign: an extendable software package for joint Bayesian estimation of alignments and evolutionary trees.
Bayesian analysis is one of the most popular methods in phylogenetic inference. The most commonly used methods fix a single multiple alignment and consider only substitutions as phylogenetically informative mutations, though alignments and phylogenies should be inferred jointly as insertions and deletions also carry informative signals. Methods addressing these issues have been developed only recently and there has not been so far a user-friendly program with a graphical interface that implements these methods. We have developed an extendable software package in the Java programming language that samples from the joint posterior distribution of phylogenies, alignments and evolutionary parameters by applying the Markov chain Monte Carlo method. The package also offers tools for efficient on-the-fly summarization of the results. It has a graphical interface to configure, start and supervise the analysis, to track the status of the Markov chain and to save the results. The background model for insertions and deletions can be combined with any substitution model. It is easy to add new substitution models to the software package as plugins. The samples from the Markov chain can be summarized in several ways, and new postprocessing plugins may also be installed.


HRT dependent performance and bacterial community population of granular hydrogen-producing mixed cultures fed with galactose.
The effects of hydraulic retention times (HRTs-6, 3 and 2 h) on H2 production, operational stability and bacterial population response in a continuously stirred tank reactor (CSTR) were evaluated using galactose. A peak hydrogen production rate (HPR) of 25.9 L H2/L-d was obtained at a 3 h HRT with an organic loading rate (OLR) of 120 g/L-d, while the maximum hydrogen yield (HY) of 2.21 mol H2/mol galactose was obtained at a 6 h HRT (60 g galactose/L-d). Butyrate was dominant and the lactate concentration increased as HRT decreased, which significantly affected the HY. Biomass concentration (VSS) decreased from 16 to 3g/L at a 2 h HRT, leading to failure. A 3 h HRT supported the favorable growth of Clostridium species, as indicated by an increase in their populations from 25.4% to 27%, while significantly reducing Bacilli populations from 61.6% to 54.2%, indicating that this was the optimal condition.


Temporal patterns in growth and survival of the round goby Neogobius melanostomus.
Monthly, overwinter and annual instantaneous growth rates for round goby Neogobius melanostomus were calculated with maximal growth occurring in July and August and almost no growth observed between ice appearance (October) and melt (March). Annual absolute growth rates averaged 27·3 ± 1·9 mm for males and 19·8 ± 2·4 mm for females. The most parsimonious Cormack-Jolly-Seber model indicated that both the survival and recapture probabilities were dependent on sampling date, but not sex. Survival estimates remained high throughout the 13 month study with a median weekly survival probability of 0·920 (25 and 75% quartiles: 0·767 and 0·991), an overwinter survival probability of 99% and an annual survival rate of 67%. Survival probabilities were lowest for both sexes near the completion of the N. melanostomus reproductive season in July and August which supports existing evidence of higher mortality after reproduction, while challenging the paradigm that male N. melanostomus suffer comparatively higher mortality as a result of reproduction than females. Evidence indicating that growth and mortality rates are highest at the end of the reproductive season not only highlights seasonal variability in N. melanostomus natural history, but may also guide the control of this invasive species to periods when they are most vulnerable.


Biotinylation of lysine method identifies acetylated histone H3 lysine 79 in Saccharomyces cerevisiae as a substrate for Sir2.
Although the biological roles of many members of the sirtuin family of lysine deacetylases have been well characterized, a broader understanding of their role in biology is limited by the challenges in identifying new substrates. We present here an in vitro method that combines biotinylation and mass spectrometry (MS) to identify substrates deacetylated by sirtuins. The method permits labeling of deacetylated residues with amine-reactive biotin on the ε-nitrogen of lysine. The biotin can be utilized to purify the substrate and identify the deacetylated lysine by MS. The biotinyl-lysine method was used to compare deacetylation of chemically acetylated histones by the yeast sirtuins, Sir2 and Hst2. Intriguingly, Sir2 preferentially deacetylates histone H3 lysine 79 as compared to Hst2. Although acetylation of K79 was not previously reported in Saccharomyces cerevisiae, we demonstrate that a minor population of this residue is indeed acetylated in vivo and show that Sir2, and not Hst2, regulates the acetylation state of H3 lysine 79. The in vitro biotinyl-lysine method combined with chemical acetylation made it possible to identify this previously unknown, low-abundance histone acetyl modification in vivo. This method has further potential to identify novel sirtuin deacetylation substrates in whole cell extracts, enabling large-scale screens for new deacetylase substrates.


Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases.
Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.


3D Printed Anchoring Sutures for Permanent Shaping of Tissues.
Sutures are one of the most widely used devices for adhering separated tissues after injury or surgery. However, most sutures require knotting, which can create a risk of inflammation, and can act as mechanically weak points that often result in breakage and slipping. Here, an anchoring suture is presented with a design that facilitates its propagation parallel to the suturing direction, while maximizing its resistive force against the opposite direction of external force to lock its position in tissues. Different microstructures of suture anchors are systematically designed using orthogonal arrays, and selected based on shape factors associated with mechanical strength. 3D printing is used to fabricate different types of hollow microstructured suture anchors, and optimize their structure for the effective shaping of tissues. To define the structural design for fixing tissues, the maximum force required to pull 3D printed anchors in different directions is examined with tissues. The tissue reshaping function of suture anchors is further simulated ex vivo by using swine ear, nose, and skin, and bovine muscle tendon. This study provides advantages for building functional sutures that can be used for permanently reshaping tissues with enhanced mechanical strength, eliminating the need for knotting to improve surgical efficiency.


Control of human mesothelin-expressing tumors by DNA vaccines.
Mesothelin has been implicated as a potential ideal target antigen for the development of antigen-specific cancer immunotherapy for the control of mesothelin-expressing cancers such as ovarian cancer, mesothelioma and pancreatic adenocarcinoma. In the current study, we utilized a DNA vaccine encoding human mesothelin (pcDNA3-Hmeso) to treat C57BL/6 mice challenged with luciferase-expressing, Hmeso-expressing ovarian cancer cell line, Defb29 Vegf-luc/Hmeso. The therapeutic effect of the tumor-challenged mice was followed by noninvasive bioluminescence imaging systems. The mechanism of the antitumor effect was characterized by depletion of subsets of lymphocytes as well as adopted transfer of serum from pcDNA3-Hmeso-vaccinated mice. We found that vaccination with pcDNA3-Hmeso DNA vaccine generates a significant antitumor effect and promotes survival in mice challenged with Defb29 Vegf-luc/Hmeso. Furthermore, we found CD4+ and CD8+ T-cell immune responses as well as the humoral immune responses are important for the observed antitumor effects in vaccinated mice. Our data indicated that vaccination with DNA vaccine targeting Hmeso could generate potent antitumor effects against mesothelin-expressing tumors through both T cell-mediated immunity as well as antibody-mediated immunity.


An inorganic geochemical argument for coupled anaerobic oxidation of methane and iron reduction in marine sediments.
Here, we present results from sediments collected in the Argentine Basin, a non-steady state depositional marine system characterized by abundant oxidized iron within methane-rich layers due to sediment reworking followed by rapid deposition. Our comprehensive inorganic data set shows that iron reduction in these sulfate and sulfide-depleted sediments is best explained by a microbially mediated process-implicating anaerobic oxidation of methane coupled to iron reduction (Fe-AOM) as the most likely major mechanism. Although important in many modern marine environments, iron-driven AOM may not consume similar amounts of methane compared with sulfate-dependent AOM. Nevertheless, it may have broad impact on the deep biosphere and dominate both iron and methane cycling in sulfate-lean marine settings. Fe-AOM might have been particularly relevant in the Archean ocean, >2.5 billion years ago, known for its production and accumulation of iron oxides (in iron formations) in a biosphere likely replete with methane but low in sulfate. Methane at that time was a critical greenhouse gas capable of sustaining a habitable climate under relatively low solar luminosity, and relationships to iron cycling may have impacted if not dominated methane loss from the biosphere.


FX: an RNA-Seq analysis tool on the cloud.
FX is an RNA-Seq analysis tool, which runs in parallel on cloud computing infrastructure, for the estimation of gene expression levels and genomic variant calling. In the mapping of short RNA-Seq reads, FX uses a transcriptome-based reference primarily, generated from ~160 000 mRNA sequences from RefSeq, UCSC and Ensembl databases. This approach reduces the misalignment of reads originating from splicing junctions. Unmapped reads not aligned on known transcripts are then mapped on the human genome reference. FX allows analysis of RNA-Seq data on cloud computing infrastructures, supporting access through a user-friendly web interface. FX is freely available on the web at (http://fx.gmi.ac.kr), and can be installed on local Hadoop clusters. Guidance for the installation and operation of FX can be found under the 'Documentation' menu on the website. Supplementary data are available at Bioinformatics online.


Baduanjin Qigong Improves Balance, Leg Strength, and Mobility in Individuals With Chronic Stroke: A Randomized Controlled Study.
Effective and sustainable exercise training methods for improving balance poststroke are needed. To evaluate the effect of Baduanjin Qigong for improving balance after stroke. This was a single-blinded randomized controlled study in which only the assessor was blinded. Fifty-eight people with chronic stroke (mean age: 62.5 ± 11.8 years) were randomly assigned to the experimental (n = 29) or control group (n = 29). The experimental group underwent 8 weeks of supervised Baduanjin training (3 sessions per week). This was followed by home-based practice of the same exercises 3 days a week for another 8 weeks. The control group underwent 2 sessions of supervised conventional fitness training in the first week, followed by home-based exercise practice 3 days a week until the end of week 16. All outcomes were measured at baseline, week 8, and week 16. Significantly greater improvements in the Mini-Balance Evaluation Systems Test (Mini-BESTest), composite equilibrium score (Sensory Organization Test), 5 Times Sit to Stand, and Timed Up and Go test were detected at week 8 in the experimental group than in the control group (P < .017). Further improvement in the Mini-BESTest was observed from week 8 to 16 in the experimental group (P < .001). Other outcomes (Limit of Stability, Fall-Efficacy Scale, Modified Barthel Index, Stroke-Specific Quality of Life) showed no significant results. Baduanjin is effective in improving balance, leg strength, and mobility and is a safe and sustainable form of home-based exercise for people with chronic stroke.


Mechanical efficiency of high versus moderate intensity aerobic exercise in coronary heart disease patients: A randomized clinical trial.
Mechanical efficiency (ME) refers to the ability of an individual to transfer energy consumed by external work. A decreased ME, could represent an increased energy cost during exercise and may, therefore, be limited in terms of physical activity. This study aimed to compare the influence of two different exercise protocols: moderate continuous training (MCT) versus high intensity interval training (HIIT), as part of a cardiac rehabilitation program on ME values among coronary patients. One hundred and ten coronary patients were assigned to either HIIT or MCT groups for 8 weeks. Incremental exercise tests in a cycle ergometer were performed to obtain VO2peak. Net energy expenditure (EE) and ME were obtained at intensities corresponding to the first (VT1) and second (VT2) ventilatory thresholds, and at VO2peak. Both exercise programs significantly increase VO2peak with a higher increase in the HIIT group (2.96 ± 2.33 mL/kg/min vs. 3.88 ± 2.40 mL/kg/min, for patients of the MCT and HIIT groups, respectively, p < 0.001). The ME at VO2peak and VT2 only significantly increased in the HIIT group. At VT1, ME significantly increased in both groups, with a greater increase in the HIIT group (2.20 ± ± 6.25% vs. 5.52 ± 5.53%, for patients of the MCT and HIIT groups, respectively, p < 0.001). The application of HIIT to patients with chronic ischemic heart disease of low risk re- sulted in a greater improvement in VO2peak and in ME at VT1, than when MCT was applied. Moreover, only the application of HIIT brought about a significant increase in ME at VT2 and at VO2peak.


New method of automated sleep quantification.
Since its discovery some 50 years ago, the electro-encephalogram (EEG) has formed the basis for classification of sleep into several stages, either laboriously performed by visual examination of the EEG and related signals or, more recently, by automated techniques. Both visual scoring and most automated analyses are highly subjective and rely on application of a predefined set of rules. A method of analysing the EEG which requires no such application of rules and aims to give some indication of the dynamics of sleep in humans is proposed in the paper.


The effects of array structure and secondary cognitive task demand on processes of visual search.
Many aspects of our everyday behaviour require that we search for objects. However, in real situations search is often conducted while internal and external factors compete for our attention resources. Cognitive distraction interferes with our ability to search for targets, increasing search times. Here we consider whether effects of cognitive distraction interfere differentially with three distinct phases of search: initiating search, overtly scanning through items in the display, and verifying that the object is indeed the target of search once it has been fixated. Furthermore, we consider whether strategic components of visual search that emerge when searching items organized into structured arrays are susceptible to cognitive distraction or not. We used Gilchrist & Harvey's (2006) structured and unstructured visual search paradigm with the addition of Savage, Potter, and Tatler's (2013) secondary puzzle task. Cognitive load influenced two phases of search: 1) scanning times and 2) verification times. Under high load, fixation durations were longer and re-fixations of distracters were more common. In terms of scanning strategy, we replicated Gilchrist and Harvey's (2006) findings of more systematic search for structured arrays than unstructured ones. We also found an effect of cognitive load on this aspect of search but only in structured arrays. Our findings suggest that our eyes, by default, produce an autonomous scanning pattern that is modulated but not completely eliminated by secondary cognitive load.


[Update on current care guideline: diagnostics of acute myocardial infarction].
In a patient with acute chest pain or other symptoms suggestive of acute myocardial infarction (MI), a 12-lead electrocardiogram with at least two additional leads (V4R and V8), should be immediately recorded and evaluated. Telemedicine transmission of prehospital electrocardiograms for diagnostic evaluation should be part of regional systems of care. Troponin T and I are the recommended biomarkers for MI diagnosis. Implementation of uniform diagnostic criteria for acute MI is a prerequisite for high quality epidemiological studies and for the development of proper performance indicators to assess quality of care.


Updated evidence of the association between toxocariasis and epilepsy: Systematic review and meta-analysis.
To gain further insight on the association between human toxocariasis and epilepsy in light of the new evidence in the last years. A systematic review was conducted without date and language restriction in the following electronic databases: MEDLINE (PubMed), Ingenta Connect, Science Direct (Elsevier), RefDoc, Scopus, HighWire, Scielo and the database of the Institute of Neuroepidemiology and Tropical Neurology of the Limoges University (IENT). Two investigators independently conducted the search up to November 2017. A pooled odds ratio (OR) was estimated using a random effects model. Meta-regression was conducted to investigate potential sources of heterogeneity. Database search produced 204 publications. Eleven case-control studies were included that were carried out in 13 countries worldwide. A total number of 4740 subjects were considered (2159 people with epilepsy and 2581 people without epilepsy). The overall pooled OR was 1.69 (95% CI 1.42-2.01) for the association between epilepsy and Toxocara spp. seropositivity. A positive association was constantly reported in the restricted analysis (WB as confirmatory or diagnostic test, younger population, and population-based studies). Meta-regression showed no statistically significant association between covariates and outcome. The updated meta-analysis provides epidemiological evidence of a positive association between Toxocara seropositivity and epilepsy. New surveys supported the association, mainly population-based studies. On this basis, health strategies to reduce the impact of Toxocara spp are strongly advised. Further research should be performed to understand the physiopathological mechanisms of toxocara-associated epileptogenesis.


Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy.
Dendritic cells (DCs) are the main professional antigen-presenting cells for induction of T-cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by nonsynonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to DCs and their surrogate presentation on major histocompatibility complex class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity. Of the great diversity of DCs, BATF3/IRF8-dependent conventional DCs type 1 (cDC1) excel at cross-presentation of tumor cell-associated antigens. Location of cDC1s in the tumor correlates with improved infiltration by CD8+ T cells and tumor-specific T-cell immunity. Indeed, cDC1s are crucial for antitumor efficacy using checkpoint inhibitors and anti-CD137 agonist monoclonal antibodies in mouse models. Enhancement and exploitation of T-cell cross-priming by cDC1s offer opportunities for improved cancer immunotherapy, including in vivo targeting of tumor antigens to internalizing receptors on cDC1s and strategies to increase their numbers, activation and priming capacity within tumors and tumor-draining lymph nodes.


Endocrine-disrupting effects of cattle feedlot effluent on an aquatic sentinel species, the fathead minnow.
Over the last decade, research has examined the endocrine-disrupting action of various environmental pollutants, including hormones, pharmaceuticals, and surfactants, in sewage treatment plant effluent. Responding to the growth of concentrated animal feeding operations (CAFOs) and the pollutants present in their wastewater (e.g., nutrients, pharmaceuticals, and hormones), the U.S. Environmental Protection Agency developed a new rule that tightens the regulation of CAFOs. In this study, we collected wild fathead minnows (Pimephales promelas) exposed to feedlot effluent (FLE) and observed significant alterations in their reproductive biology. Male fish were demasculinized (having lower testicular testosterone synthesis, altered head morphometrics, and smaller testis size). Defeminization of females, as evidenced by a decreased estrogen:androgen ratio of in vitro steroid hormone synthesis, was also documented. We did not observe characteristics in either male or female fish indicative of exposure to environmental estrogens. Using cells transfected with the human androgen receptor, we detected potent androgenic responses from the FLE. Taken together, our morphologic, endocrinologic, and in vitro gene activation assay data suggest two hypotheses: a) there are potent androgenic substance(s) in the FLE, and/or b) there is a complex mixture of androgenic and estrogenic substances that alter the hypothalamic-pituitary-gonadal axis, inhibiting the release of gonadotropin-releasing hormone or gonadotropins. This is the first study demonstrating that the endocrine and reproductive systems of wild fish can be adversely affected by FLE. Future studies are needed to further investigate the effects of agricultural runoff and to identify the biologically active agents, whether natural or pharmaceutical in origin.


A longitudinal study of the relationship between health behavior risk factors and dependence in activities of daily living.
The purpose of this study was to shed further light on the effect of modifiable health behavior risk factors on dependence in activities of daily living, defined in a multidimensional fashion. The study participants were 10,278 middle aged Americans in a longitudinal health study, the Health and Retirement Survey (HRS). A multi-stage probability sampling design incorporating the effect of population sizes (Metropolitan and non-metropolitan), ethnicity (the non-Hispanic White, the Hispanic, and the Black), and age (age 51-61) was utilized. Basic Activities of Daily Living (ADL) were measured using five activities necessary for survival (impairment in dressing, eating, bathing, sleeping, and moving across indoor spaces). Explanatory variables were four health behavior risk factors included smoking, exercise, Body Mass Index (BMI), and alcohol consumption. Most participants at baseline were ADL independent (1992). 97.8% of participants were independent in all ADL's at baseline and 78.2% were married. Approximately 27.5% were current smokers at baseline, and the subjects reported moderate or heavy exercise were 74.8%. All demographic characteristics and behavioral risk factors were significantly associated with the ADL status at Wave 4 except alcohol consumption. Risk behaviors such as current smoking, sedentary life style and high BMI at Wave 1 were associated with ADL status deterioration; however, moderate alcohol consumption tended to be more related to better ADL status than abstaining at Wave 4. ADL status at Wave 1 was the strongest factor and the next was exercise and smoking affecting ADL status at Wave 4. People who were in ADL dependent at Wave 1 were 15.17 times more likely to be ADL dependent at Wave 4 than people who were in ADL independent at Wave 1. Concerning smoking cigarettes, people who kept only light exercise or sedentary life style at Wave 1 were 1.70 times more likely to be died at Wave 4 than the people who did not smoke at Wave 1. All demographics and health behaviors at wave 1 had consistently similar OR trends for ADL status to each other except alcohol consumption. Smoking and exercise in health behaviors, and age and gender in demographics at Wave 1 were significant factors associated with ADL group separation at Wave 4.


Livin, a novel inhibitor of apoptosis protein family member.
A novel human inhibitor of apoptosis protein (IAP) family member termed Livin was identified, containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. The mRNA for livin was not detectable by Northern blot in most normal adult tissues with the exception of the placenta, but was present in developmental tissues and in several cancer cell lines. Highest levels were observed in two melanoma-derived cell lines, G361 and SK-Mel29. Transfection of livin in HeLa cells resulted in protection from apoptosis induced by expression of FADD, Bax, RIP, RIP3, and DR6. Similar to other IAP family members, the anti-apoptotic activity of Livin was dependent on the BIR domain. Livin was also capable of inhibiting DEVD-like caspase activity triggered by tumor necrosis factor-alpha. In vitro binding studies demonstrated a direct interaction between Livin and the active form of the downstream caspases, caspase-3 and -7, that was dependent on the BIR domain of Livin. In addition, the unprocessed and cleaved forms of caspase-9 co-immunoprecipitated with Livin in vivo, and recombinant Livin could inhibit the activation of caspase-9 induced by Apaf-1, cytochrome c, and dATP. The subcellular distribution of the transfected Livin was analyzed by immunofluorescence. Both Livin and Survivin were expressed in the nucleus and in a filamentous pattern throughout the cytoplasm. In contrast to the apoptotic activity, the COOH-terminal RING domain mediated its subcellular localization patterning. Further studies found that transfection of an antisense construct against livin could trigger apoptosis specifically in cell lines expressing livin mRNA. This was associated with an increase in DNA fragmentation and in DEVD-like caspase activity. Thus, disruption of Livin may provide a strategy to induce apoptosis in certain cancer cells.


Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats.
Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered neurological aging and the ambiguous link between repetitive mTBI and progressive neurodegeneration, the current study was designed to examine the effect of a high fat diet (HFD), developmental age, and repetitive mTBI on behavioral outcomes following a mTBI. In addition, telomere length was examined before and after experimental mTBI. Sprague Dawley rats were maintained on a HFD or standard rat chow throughout life (including the prenatal period) and then experienced an mTBI/concussion at P30, P30 and P60, or only at P60. Behavioral outcomes were examined using a test battery that was administered between P61-P80 and included; beam-walking, open field, elevated plus maze, novel context mismatch, Morris water task, and forced swim task. Animals with a P30 mTBI often demonstrated lingering symptomology that was still present during testing at P80. Injuries at P30 and P60 rarely produced cumulative effects, and in some tests (i.e., beam walking), the first injury may have protected the brain from the second injury. Exposure to the high fat diet exacerbated many of the behavioral deficits associated with concussion. Finally, telomere length was shortened following mTBI and was influenced by the animal's dietary intake. Diet, age at the time of injury, and the number of prior concussion incidents differentially contribute to behavioral deficits and may help explain individual variations in susceptibility and resilience to poor outcomes following an mTBI.


Complete Genome Sequence of Desulfovibrio desulfuricans IC1, a Sulfonate-Respiring Anaerobe.
We report the complete genome sequence of the anaerobic, sulfonate-respiring, sulfate-reducing bacterium Desulfovibrio desulfuricans IC1. The genome was assembled into a single 3.25-Mb circular chromosome with 2,680 protein-coding genes identified. Sequencing of sulfonate-metabolizing anaerobes is key for understanding sulfonate degradation and its role in the sulfur cycle.


A tractography analysis of two deep brain stimulation white matter targets for depression.
Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) or anterior limb of the internal capsule (ALIC) may be effective in treating depression. Connectivity patterns of these regions may inform on mechanisms of action for DBS of these targets. Diffusion tensor imaging (DTI) and probabilistic tractography were performed in 13 nondepressed subjects to determine connectivity patterns of SCCwm and ALIC. Tract maps were generated for each target in each subject, and tract voxels were coded as being unique to either target or shared. Group level tract maps were generated by including only those voxels common to at least 10 of 13 (>75%) subjects. The two targets have distinct patterns of connectivity with regions of overlap. The SCCwm showed consistent ipsilateral connections to the medial frontal cortex, the full extent of the anterior and posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and the dorsal brainstem. The ALIC seed, in contrast, demonstrated widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem. Common to both targets, albeit through distinct white matter bundles, were connections to frontal pole, medial temporal lobe, nucleus accumbens, dorsal thalamus, and hypothalamus. Connectivity patterns of these two DBS white matter targets suggest distinct neural networks with areas of overlap in regions implicated in depression and antidepressant response.


Advantages of Using Blend Cultures of Native L. plantarum and O. oeni Strains to Induce Malolactic Fermentation of Patagonian Malbec Wine.
The malolactic fermentation (MLF) of Patagonian Malbec wine inoculated with blend cultures of selected native strains of Lactobacillus plantarum and Oenococcus oeni was monitored during 14 days, analyzing the strains ability to modify the content of some organic acids and to change the volatile compounds profile. The performance of the LAB strains was tested as single and blends cultures of both species. An implantation control by RAPD PCR was also carried out to differentiate among indigenous and inoculated strains. The L. plantarum strains UNQLp11 and UNQLp155 and the O. oeni strain UNQOe73.2 were able to remain viable during the monitoring time of MLF, whereas the O. oeni strain UNQOe31b showed a decrease of five log CFU at day 14. The four strains assayed showed a similar behavior in wine whether they were inoculated individually or as blend cultures. All strains were able to consume L-malic acid, particularly the L. plantarum strains, which showed the highest consumption values at day 14, both as single or blend cultures. The changes in the volatile compounds profile of Malbec wine samples, before and after MLF, were determined by HS-SPME and GC-MS technique. Wines inoculated with blend cultures containing strain UNQLp155 showed a decrease in the total alcohols content and an increase in the total esters content. On the other hand, wines inoculated with single cultures of strains UNQLp155, UNQOe31b or UNQOe73.2 showed no significant decrease in the total alcohols concentration but a significant increase in the total esters content. When strain UNQLp11 was inoculated as single or as blend culture with strain UNQOe31b, wines exhibited an increase in the total alcohols content, and a decrease in the total esters content. The content of diethyl succinate showed the greatest increase at final of MLF, and a particular synergistic effect in its synthesis was observed with a blend culture of strains UNQLp155 and UNQOe73.2. These results suggest that the use of blend cultures formulated with strains belonging to L. plantarum and O. oeni species could offer an interesting advantage to induce MLF in Malbec wines, contributing to diversify their aromatic profiles.


The factors associated with the burnout syndrome and fatigue in Cypriot nurses: a census report.
Fatigue and burnout are two concepts often linked in the literature. However, regardless of their commonalities they should be approached as distinct concepts. The current and ever-growing reforms regarding the delivery of nursing care in Cyprus, stress for the development of ways to prevent burnout and effectively manage fatigue that can result from working in stressful clinical environments. To explore the factors associated with the burnout syndrome in Cypriot nurses working in various clinical departments. A random sampling method taking into account geographical location, specialty and type of employment has been used. A total of 1,482 nurses (80.4% were females) working both in the private and public sectors completed and returned an anonymous questionnaire that included several aspects related to burnout; the MBI scale, questions related to occupational stress, and questions pertaining to self reported fatigue. Two-thirds (65.1%) of the nurses believed that their job is stressful with the majority reporting their job as stressful being female nurses (67.7%). Twelve point eight percent of the nurses met Maslach's criteria for burnout. The prevalence of fatigue in nurses was found 91.9%. The prevalence of fatigue was higher in females (93%) than in males (87.5%) (p = 0.003). As opposed to the burnout prevalence, fatigue prevalence did not differ among the nursing departments (p = 0.166) and among nurses with a different marital status (p = 0.553). Burnout can be associated adequately knowing if nurses find their job stressful, their age, the level of emotional exhaustion and depersonalization. It has been shown that the fatigue may be thought of as a predictor of burnout, but its influence is already accounted by emotional exhaustion and depersonalization. The clinical settings in Cyprus appear as stress generating environment for nurses. Nurses working both in the private and public sector appear to experience low to severe burnout. Self-reported fatigue interferes to the onset of emotional exhaustion and depersonalization.


Clinical yield of fetal echocardiography for suboptimal cardiac visualization on obstetric ultrasound.
Suboptimal cardiac imaging on obstetric ultrasound is a frequent referral indication for fetal echocardiography, even in the absence of typical risk factors for fetal cardiac disease. The clinical profile of patients and findings of examinations performed for such an indication are not well defined. Given the increased cost, time and resource utilization of fetal echocardiography, we sought to determine the clinical findings of such referrals. We performed a single-center review of such referrals from January 2010 to June 2016. Patients with commonly accepted indications for fetal echocardiography were excluded. Demographic variables and echocardiogram findings were collected. Findings were classified as (1) "normal," (2) "probably normal," if minor pathology could not confidently be excluded, or if minor findings were noted that were expected to resolve, or (3) "abnormal." Rates of pathology were determined with comparison of nonobese and obese populations. A total of 583 gestations in 562 women were included (median gestational age 23.3 weeks, range 19.0-38.4). The median body mass index (BMI) was 34.6 kg/m2 (range 17.2-66.3 kg/m2 ). The majority of women were obese (BMI ≥ 30 kg/m2 in 74.6%). Overall, 574 of 583 examinations (98.5%) were normal or "probably normal." Pathology was noted in 9 fetuses (1.5%), 3 of whom required intervention (0.5%). No ductal dependent lesions were diagnosed. There was no significant difference in pathology rates between nonobese and obese mothers. We found a low fetal cardiac anomaly rate in studies performed for suboptimal views on obstetric ultrasound. The majority of women referred for this indication were obese. The practice of routine referral for this indication deserves further evaluation.


Vibrotactile feedback to control the amount of weight shift during walking - A first step towards better control of an exoskeleton for spinal cord injury subjects.
People with Spinal Cord Injury do not only lack the ability to control their muscles, but also miss the sensory information from below the level of their lesion. Therefore, it may become difficult for them to perceive the state of the body during walking, which is however often used to control wearable exoskeletons. In the present study the possibilities of providing vibrotactile feedback about the Center of Mass (CoM) during walking were investigated. The results showed that healthy subjects could successfully interpret the provided vibrotactile cues and change their walking pattern accordingly. Vibrotactile stimulation was either provided in a concurrent (over the complete CoM movement) or terminal (only when the desired CoM displacement was reached) way. The latter led to a better accuracy and can be easily implemented in a wearable exoskeleton where a certain amount of CoM displacement is needed to initiate stepping.


Effect of transmission intensity on hotspots and micro-epidemiology of malaria in sub-Saharan Africa.
Malaria transmission intensity is heterogeneous, complicating the implementation of malaria control interventions. We provide a description of the spatial micro-epidemiology of symptomatic malaria and asymptomatic parasitaemia in multiple sites. We assembled data from 19 studies conducted between 1996 and 2015 in seven countries of sub-Saharan Africa with homestead-level geospatial data. Data from each site were used to quantify spatial autocorrelation and examine the temporal stability of hotspots. Parameters from these analyses were examined to identify trends over varying transmission intensity. Significant hotspots of malaria transmission were observed in most years and sites. The risk ratios of malaria within hotspots were highest at low malaria positive fractions (MPFs) and decreased with increasing MPF (p < 0.001). However, statistical significance of hotspots was lowest at extremely low and extremely high MPFs, with a peak in statistical significance at an MPF of ~0.3. In four sites with longitudinal data we noted temporal instability and variable negative correlations between MPF and average age of symptomatic malaria across all sites, suggesting varying degrees of temporal stability. We observed geographical micro-variation in malaria transmission at sites with a variety of transmission intensities across sub-Saharan Africa. Hotspots are marked at lower transmission intensity, but it becomes difficult to show statistical significance when cases are sparse at very low transmission intensity. Given the predictability with which hotspots occur as transmission intensity falls, malaria control programmes should have a low threshold for responding to apparent clustering of cases.


Putting a value on the avoidance of false positive results when screening for inherited metabolic disease in the newborn.
Despite the increase in the number of inherited metabolic diseases that can be detected at birth using a single dried blood spot sample, the impact of false positive results on parents remains a concern. We used an economic approach - the contingent valuation method - which asks parents to give their maximum willingness to pay for an extension in a screening programme and the degree to which the potential for false positive results diminishes their valuations. 160 parents of a child or children under the age of 16 years were surveyed and given descriptions of the current screening programme in the UK, an extended programme and an extended programme with no false positives. 148 (92.5%) respondents said they would accept the screen for the five extra conditions in an expanded screening programme whilst 10 (6.3%) said they would not and two were unsure. When asked to indicate if they would choose to be screened under an expanded screening programme with no false positive results, 152 (95%) said they would, five (3.1%) said they would not, two were unsure, and there was one non-response. 151 (94.4%) said they preferred the hypothetical test with no false-positives. The mean willingness to pay for the expanded programme was £178 compared to £219 for the hypothetical expanded programme without false positives (p > 0.05). The results suggest that there is widespread parental support for extended screening in the UK and that the number of false-positives is a relatively small issue.


Autoimmunity to type II collagen an experimental model of arthritis.
We have found that intradermal injection of native type II collagen extracted from human, chick or rat cartilage induces an inflammatory arthritis in approximately 40% of rats of several strains whether complete Freund's adjuvant or incomplete Freund's adjuvant is used. Type I or III collagen extracted from skin, cartilage proteoglycans and alpha1(II) chains were incapable of eliciting arthritis, as was type II collagen injected without adjuvant. The disease is a chronic proliferative synovitis, resembling adjuvant arthritis in rats and rheumatoid arthritis in humans. Native type II co-lagen modified by limited pepsin digestion still produces arthritis, suggesting that type-specific determinants residing in the helical region of the molecule are responsible for the induction of disease. Since homologous type II collagen emulsified in oil without bacterial preparations regularly causes the disease, this new animal model of arthritis represents a unique example of experimentally-inducible autoimmunity to a tissue component.


Copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues.
Copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase form the primary enzymic defense against toxic oxygen reduction metabolites. Such metabolites have been implicated in the damage brought about by ionizing radiation, as well as in the effects of several cytostatic compounds. These enzymes were analyzed in 31 different human normal diploid and neoplastic cell lines and for comparison in 15 normal human tissues. The copper- and zinc-containing superoxide dismutase appeared to be slightly lower in malignant cell lines in general as compared to normal tissues. The content of manganese superoxide dismutase was more variable than the content of the copper- and zinc-containing enzyme. Contrary to what has been suggested before, this enzyme did not appear to be generally lower in malignant cells compared to normal cells. One cell line, of mesothelioma origin (P27), was extremely abundant in manganese-containing superoxide dismutase; the concentration was almost an order of magnitude larger than in the richest normal tissue. Catalase was very variable both among the normal tissues and among the malignant cells, whereas glutathione peroxidase was more evenly distributed. In neither case was a general difference between normal cells and tissues and malignant cells apparent. The myocardial damage brought about by doxorubicin has been linked to toxic oxygen metabolites; particularly, an effect on the glutathione system has been noted. The heart is one of the tissues which have a low concentration of enzymes which protect against hydroperoxides. However, the deviation from other tissues is probably not large enough to provide a full explanation for the high doxorubicin susceptibility. In the present survey, no obvious relationship between generally assumed resistance to ionizing radiation or to radical-producing drugs and cellular content of any of the enzymes could be demonstrated.


Costs and utilities of manual therapy and orthopedic standard care for low-prioritized orthopedic outpatients of working age: a cost consequence analysis.
Treatment for musculoskeletal disorders in primary care in Sweden is generally initiated with advice and medication. Second-line therapy is physiotherapy and/or injection and radiography; third-line therapy is referral to an orthopedist. Manual therapy is not routine. It is a challenge to identify patients who benefit from treatment by different specialists. The current referral strategy probably contributes to long waiting lists in orthopedic departments, which is costly and implies prolonged suffering for the patients. The aim of this health economic evaluation was to compare costs and outcomes from naprapathic manual therapy (NMT) with orthopedic standard care for common, low-prioritized, nonsurgical musculoskeletal disorders, after second-line treatment. Diagnose Related Groups were used to define the costs, and the SF-36 was encoded to evaluate the outcomes in cost per quality adjusted life years gained. Results from a 12 months' follow-up showed significantly larger improvement for the NMT than for orthopedic standard care, significantly lower mean cost per patient; 5427 SEK (*Price level 2009; 1 Euro=106,213 SEK; 1 US Dollar=76,457 SEK) (95% confidence interval, 3693-7161) compared to14298 SEK (95% confidence interval, 8322-20,274), and more gains in outcomes in cost per quality adjusted life years per patient (0.066 compared with 0.026). Thus the result is "dominant." It is plausible that improved outcomes and reasonable cost savings for low-prioritized nonsurgical outpatients would be attainable if NMT were available as an additional standard care option in orthopedic outpatient clinics.


The seasonality of nonpolio enteroviruses in the United States: Patterns and drivers.
Nonpolio enteroviruses are diverse and common viruses that can circulate year-round but tend to peak in summer. Although most infections are asymptomatic, they can result in a wide range of neurological and other diseases. Many serotypes circulate every year, and different serotypes predominate in different years, but the drivers of their geographical and temporal dynamics are not understood. We use national enterovirus surveillance data collected by the US Centers for Disease Control and Prevention during 1983-2013, as well as demographic and climatic data for the same period, to study the patterns and drivers of the seasonality of these infections. We find that the seasonal pattern of enterovirus cases is spatially structured in the United States and similar to that observed for historical prevaccination poliomyelitis (1931-1954). We identify latitudinal gradients for the amplitude and the timing of the peak of cases, meaning that those are more regularly distributed all year-round in the south and have a more pronounced peak that arrives later toward the north. The peak is estimated to occur between July and September across the United States, and 1 month earlier than that for historical poliomyelitis. Using mixed-effects models, we find that climate, but not demography, is likely to drive the seasonal pattern of enterovirus cases and that the dew point temperature alone explains ∼30% of the variation in the intensity of transmission. Our study contributes to a better understanding of the epidemiology of enteroviruses, demonstrates important similarities in their circulation dynamics with polioviruses, and identifies potential drivers of their seasonality.


An integrated model-driven method for in-treatment upper airway motion tracking using cine MRI in head and neck radiation therapy.
For the first time, MRI-guided radiation therapy systems can acquire cine images to dynamically monitor in-treatment internal organ motion. However, the complex head and neck (H&N) structures and low-contrast/resolution of on-board cine MRI images make automatic motion tracking a very challenging task. In this study, the authors proposed an integrated model-driven method to automatically track the in-treatment motion of the H&N upper airway, a complex and highly deformable region wherein internal motion often occurs in an either voluntary or involuntary manner, from cine MRI images for the analysis of H&N motion patterns. Considering the complex H&N structures and ensuring automatic and robust upper airway motion tracking, the authors firstly built a set of linked statistical shapes (including face, face-jaw, and face-jaw-palate) using principal component analysis from clinically approved contours delineated on a set of training data. The linked statistical shapes integrate explicit landmarks and implicit shape representation. Then, a hierarchical model-fitting algorithm was developed to align the linked shapes on the first image frame of a to-be-tracked cine sequence and to localize the upper airway region. Finally, a multifeature level set contour propagation scheme was performed to identify the upper airway shape change, frame-by-frame, on the entire image sequence. The multifeature fitting energy, including the information of intensity variations, edge saliency, curve geometry, and temporal shape continuity, was minimized to capture the details of moving airway boundaries. Sagittal cine MR image sequences acquired from three H&N cancer patients were utilized to demonstrate the performance of the proposed motion tracking method. The tracking accuracy was validated by comparing the results to the average of two manual delineations in 50 randomly selected cine image frames from each patient. The resulting average dice similarity coefficient (93.28% ± 1.46%) and margin error (0.49 ± 0.12 mm) showed good agreement between the automatic and manual results. The comparison with three other deformable model-based segmentation methods illustrated the superior shape tracking performance of the proposed method. Large interpatient variations of swallowing frequency, swallowing duration, and upper airway cross-sectional area were observed from the testing cine image sequences. The proposed motion tracking method can provide accurate upper airway motion tracking results, and enable automatic and quantitative identification and analysis of in-treatment H&N upper airway motion. By integrating explicit and implicit linked-shape representations within a hierarchical model-fitting process, the proposed tracking method can process complex H&N structures and low-contrast/resolution cine MRI images. Future research will focus on the improvement of method reliability, patient motion pattern analysis for providing more information on patient-specific prediction of structure displacements, and motion effects on dosimetry for better H&N motion management in radiation therapy.