Depot haloperidol decanoate for schizophrenia.
The mainstay of treatment for schizophrenia is the antipsychotic group of drugs. These are usually given orally but compliance with medication given by this route may be difficult to quantify. Problems with treatment adherence are common. The development of depot injections in the 1960s gave rise to their extensive use as a means of long-term maintenance treatment. Haloperidol decanoate is one depot drug available in clinical practice. To assess the effects of haloperidol decanoate versus oral anti-psychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. Relevant trials were identified by searching Biological Abstracts (1982-1998), Cochrane Library (Issue 2, 1998), Cochrane Schizophrenia Group's Register (June 1998), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). References of all identified trials were also inspected for more studies. All relevant randomised trials focusing on people with schizophrenia where haloperidol decanoate, oral anti-psychotics or other depot preparations were compared. Outcomes such as death, clinically significant change in global function, mental state, relapse, hospital admission, adverse effects and acceptability of treatment were sought. Studies were reliably selected, quality rated and data extracted. For dichotomous data Mantel-Haenszel odds ratios (OR) with the 95% confidence intervals (CI) were estimated. Where possible, the number needed to treat statistic (NNT) was calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. In a haloperidol decanoate versus placebo comparison, two small studies reported that significantly fewer people on depot left early (OR 0.09 CI 0.03-0.21, NNT 2 CI 1-3) or experienced no important improvement in mental state (OR 0. 04 CI 0.01-0.15). Zississ (1982) suggested that those taking haloperidol decanoate would need less additional antipsychotic medication (OR 0.14 Cl 0.04-0.55, NNT 2 CI 1-5). Haloperidol decanoate was compared to oral haloperidol in a single trial that showed no differences in global impression, mental state or side effects ( approximately approximately Zuardi 1983 approximately approximately , n=22). Compliance with medication was not reported in this study. Eight trials compared haloperidol decanoate to other depot neuroleptics and again no differences were found for the outcomes of death, global impression, mental state, behaviour, or side effects. Haloperidol decanoate may have a substantial effect in improving the symptoms and behaviour associated with schizophrenia in comparison to placebo, but data are remarkably sparse. There are no discernible differences between the depot form of haloperidol and its oral equivalent. For those needing and willing to take the drug, the means of administration is then a matter of individual choice and clinical judgement. As there are no clear differences between haloperidol decanoate and other depots, the choice of depot medication could also be individually tailored and patient preference exercised. Well-conducted and reported randomised trials are needed comparing haloperidol decanoate with other depots but the comparison of haloperidol decanoate to oral antipsychotics is a priority.


Association of life style and dietary habits with blood choline and cardiovascular outcome.
Whole-blood choline, plasma choline and serum choline are emerging biomarkers in cardiovascular diseases (CVD). To examine the association of Whole-blood choline is an early predictor for cardiac events. In case control study, we enrolled 240 individuals including 120 normal (39 females and 82 males) and 120 cases (49 females and 71 males) where age limit was >40 years) Information through interviews, family disease history, 24 recall diet assessment and blood sampling. Odds ratios express the associated risks with CVD and without CVD patients. In healthy populations, good dietary habits and active lifestyle were observed. The number of participants with CVD were smokers than normal. In men, and women the risk was observed highly significant. (p=0.0049) Different blood parameters like Triglycerides, Uric Acid, Urea, Creatinine, CRP and ESR were non-significant observed. In females the low carbohydrates and high protein and frequent salad vegetable consumption observed. On the other hand, men consume more carbohydrates. Body mass index was significantly with p= 0.036 (OD 1.12 95% 1.00-1.26). The total fats (p=0.017) (OD 1.3301 95% 1.05-1.69) total carbohydrate (p=0.076) (OD 1.1536 95% 0.98-1.35) and total proteins (p=0.287) (OD 1.1456 95% 0.89-1.47) effecting respectively. The Blood choline level was significant observed between cases (p=0.026) OD (0.944 95%0.89- 0.99).


Rat lung metabolism after 3 days of continuous exposure to 0.6 ppm ozone.
Continuous exposure of rats to low concentrations of ozone has previously been associated with enhanced metabolic enzyme activities, when measured in lung homogenates. In this study, metabolic rates were measured in intact perfused lungs with altered pathology brought about by 3 days continuous exposure to 0.6 ppm ozone. Increased metabolism of ozone-exposed lungs was indicated by a twofold enhancement in glucose utilization, associated with a 62% increase in lactate formation and a 166% increase in the rate of 14CO2 production from D-[U-14C]glucose from control values of 5.2 +/- 0.5 mumol lactate and 4.4 +/- 0.6 mumol 14CO2/h per lung (+/- SE, n = 4), respectively. Mitochondrial metabolism was separately assessed by measurements of 14CO2 production from [U-14C]-pyruvate, which was found not to be significantly altered by ozone exposure, although homogenate oxygen uptake in the presence of succinate was significantly enhanced by 57%. These changes in intermediary metabolism could be correlated with increased glucose carbon incorporation into lipid and elevated activity of glucose-6-phosphate dehydrogenase. The observed elevated metabolic rates were consistent with the energy and synthetic needs of a lung during repair of ozone-induced damage.


Synaptic integration in rat frontal cortex shaped by network activity.
Neocortical neurons in vivo are embedded in networks with intensive ongoing activity. How this network activity affects the neurons' integrative properties and what function this may imply at the network level remain largely unknown. Most of our knowledge regarding synaptic communication and integration is based on recordings in vitro, where network activity is strongly diminished or even absent. Here, we present results from two complementary series of experiments based on intracellular in vivo recordings in anesthetized rat frontal cortex. Specifically, we measured 1) the relationship between the excursions of a neuron's membrane potential and the spiking activity in the surrounding network and 2) how the summation of several inputs to a single neuron changes with the different levels of its membrane potential excursions and the associated states of network activity. The combination of these measurements enables us to assess how the level of network activity influences synaptic integration. We present direct evidence that integration of synaptic inputs in frontal cortex is linear, independent of the level of network activity. However, during periods of high network activity, the neurons' response to synaptic input is markedly reduced in both amplitude and duration. This results in a drastic shortening of its window for temporal integration, requiring more precise coordination of presynaptic spike discharges to reliably drive the neuron to spike under conditions of high network activity. We conclude that ongoing activity, as present in the active brain, emphasizes the need for neuronal cooperation at the network level, and cannot be ignored in the exploration of cortical function.


Pigment epithelial changes in a strain of pigmented rabbits with low ERG b-wave amplitudes.
Retinas from a strain of rabbits with low dark-adapted electroretinographic (ERG) b-wave amplitudes, and declining ERG responses with time, were examined by light and electron microscopy. Seven rabbits from the affected strain (13 months to 5 years old) and six control animals (6-26 months old) were included in the study. Small inclusions with an electron dense border, about 0.2-1.5 microm in diameter, were significantly (p<0.01) more numerous within the retinal pigment epithelial (RPE) cells in the affected rabbits than in the control animals. No morphological evidence of retinal degeneration was found. Further studies are needed to establish the functional defect in this strain of rabbits.


Physical and biological properties of influenza virus components obtained after ether treatment.
The Rostock strain of fowl plague, the swine, A, A', and Asian strains of influenza A as well as their hemagglutinin and internal s antigen subunits obtained after ether splitting, were found to be morphologically indistinguishable when examined simultaneously. Hemagglutinin fractions reacted in a highly strain specific manner when tested by hemagglutination inhibition or by complement fixation using sera obtained after infection. With the same sera internal s antigen fractions were shown to be serologically distinguishable by complement fixation. This observation may stimulate interest in the feasibility of employing immunologic techniques for the study of nucleoproteins. The significance of the findings reported is discussed.


Phase I study of carboplatin, cisplatin, and cyclophosphamide without and with lenograstim for the treatment of ovarian cancer.
Cisplatin and carboplatin are both active in ovarian cancer with different toxicity profiles; thus, dose intensification may be possible by combining them. The aim of the present study was to determine the maximum tolerated dose of carboplatin combined with fixed doses of cisplatin and cyclophosphamide without and with support of lenograstim. Cisplatin (60 mg/m(2)), cyclophosphamide (600 mg/m(2)) and carboplatin (starting dose 200 mg/m(2)) were given on day 1 every 3 weeks for 4 cycles. Escalated dose levels for carboplatin were planned by increments of 50 mg/m(2) per level. Lenograstim (L) (150 mu g/m(2)/day subcutaneously) was given in case of grade 4 leukopenia (levels without support) or from day 5 up to leukocyte >10,000/mm(3) after nadir (levels with support). Four levels were studied (200, 250, 250 + lenograstim, 300 + lenograstim) with 7, 7, 8, and 7 patients enrolled, respectively. Unacceptable toxicity was induced in 1 patient at the level I (grade 4 thrombocytopenia), in 4 patients at the level 2 (2 prolonged grade 2 leukopenia, 1 grade 4 leukopenia with concomitant grade 4 thrombocytopenia and 1 grade 4 thrombocytopenia), in 1 patient at the level 2 + L (grade 4 thrombocytopenia) and in 3 patients at the level 3 + L (3 grade 4 thrombocytopenia). Thus, 200 mg/m(2) and 250 mg/m(2) were defined as carboplatin MTDs without and with lenograstim support, respectively. Median total platinum (cisplatin + 1/4 carboplatin) delivered dose-intensities were 33, 32, 38 and 44 mg/m(2)/week at the four levels, respectively. Hematological toxicity was overall mild. In no case was febrile neutropenia recorded. Grade 4 thrombocytopenia was always transient and never symptomatic. Grade 3 vomiting was the only severe non-hematological toxicity reported in 5 patients. Out of 16 patients with measurable disease, 11 objective responses were obtained (5 complete and 6 partial) for an overall response rate of 69% (95% exact CL 41-89%). Recommended dose of carboplatin is 200 mg/m(2) without and 250 mg/m(2) with support of lenograstim when combined with cisplatin 60 mg/m(2) and cyclophosphamide 600 mg/m(2). Dose limiting toxicity is persistent leukopenia without and grade 4 thrombocytopenia with support of lenograstim.


Harpagophytum procumbens extract potentiates morphine antinociception in neuropathic rats.
The association of opioids and non-steroidal anti-inflammatory drugs, to enhance pain relief and reduce the development of side effects, has been demonstrated. Given many reports concerning the antinociceptive and anti-inflammatory effects of Harpagophytum procumbens extracts, the aim of our study was to investigate the advantage of a co-administration of a subanalgesic dose of morphine preceded by a low dose of H. procumbens to verify this therapeutically useful association in a neuropathic pain model. Time course, registered with the association of the natural extract, at a dose that does not induce an antinociceptive effect, followed by a subanalgesic dose of morphine showed a well-defined antiallodynic and antihyperalgesic effect, suggesting a synergism as a result of the two-drug association. H. procumbens cooperates synergistically with morphine in resolving hyperalgesia and allodynia, two typical symptoms of neuropathic pain. The results support the strategy of using an adjuvant drug to improve opioid analgesic efficacy.


Efficiency and loss mechanisms of plasmonic Luminescent Solar Concentrators.
Using a hybrid nanoscale/macroscale model, we simulate the efficiency of a luminescent solar concentrator (LSC) which employs silver nanoparticles to enhance the dye absorption and scatter the incoming light. We show that the normalized optical efficiency can be increased from 10.4% for a single dye LSC to 32.6% for a plasmonic LSC with silver spheres immersed inside a thin dye layer. Most of the efficiency enhancement is due to scattering of the particles and not due to dye absorption/re-emission.


Access to subsidized ACT and malaria treatment--evidence from the first year of the AMFm program in six districts in Uganda.
To determine the effect of the Affordable Medicines Facility for malaria (AMFm) launched in April 2011 in Uganda on the use of Artemisinin Combination Therapies (ACTs) for malaria treatment. 2398 households across six districts in Eastern Uganda were monitored through monthly survey visits from April 2011 to April 2012. During each visit, health seeking modules were completed for any morbidity episode reported by the household. Additional surveys were conducted with 114 licensed drug shops in the same districts in April 2011 and April 2012. Changes in drug shops' stocking and pricing of ACTs, as well as changes in households' treatment behaviour and drug usage were analysed. The fraction of licensed drug shops reporting that an ACT was one of their top five bestselling antimalarial drugs increased from 32% to 84% (Δ=0.517, 95% Confidence Intervals (CI) [0.407, 0.628], P<0.001). The fraction of children under the age of 5 with fevers getting an ACT increased from 37% to 47% (Δ=0.103, 95% CI [0.070, 0.136], P<0.001), and the fraction of ACT treatments among patients getting any antimalarial increased from 51% to 65% (Δ=0.145, 95% CI [0.121, 0.169], P<0.001). The observed changes were particularly large among poorer households, and were smallest for households from the highest wealth quintile. The study results suggest that, during its first year of implementation in Uganda, the AMFm achieved its main objective of increasing the availability and use of ACTs. Estimates of the impact of the AMFm on ACT use for children under 5 imply that the program should be considered highly cost-effective under current World Health Organization (WHO) guidelines. The overall results look promising, but larger and longer term studies will be needed to assess the health impact and cost-effectiveness of the program.


Experimental Evaluation of the Effectiveness of Demineralized Bone Matrix and Collagenated Heterologous Bone Grafts Used Alone or in Combination with Platelet-Rich Fibrin on Bone Healing in Sinus Floor Augmentation.
The aim of this study was an experimental evaluation of the effectiveness of demineralized bone matrix (DBM) and collagenated heterologous bone graft (CHBG) used alone or in combination with platelet-rich fibrin on bone healing in sinus floor augmentation procedures. In this study, 36 New Zealand rabbits were used. The bilateral sinus elevation was performed, and 72 defects were obtained. The rabbit maxillary sinuses were divided into four groups according to the augmentation biomaterials obtained: demineralized bone matrix (Grafton DBM Putty, Osteotech; DBM group), DBM combined with platelet-rich fibrin (PRF; DBM + PRF group), collagenated heterologous bone graft (CHBG; Apatos Mix, OsteoBiol, Tecnoss; CHBG group), CHBG combined with PRF (CHBG + PRF group). All groups were sacrificed at 2, 4, and 8 weeks after surgery for histologic, histomorphometric, and immunohistochemical analyses. The inflammatory reaction was moderate to intense at the second week in all groups and declined from 2 to 8 weeks. New bone formation was started at the second week and increased from 2 to 8 weeks in all groups. There was no significant difference in bone formation between the experimental groups that used PRF mixed graft material and control groups that used only graft material. The percentage of new bone formation showed a significant difference in DBM groups and DBM + PRF groups compared with other groups. There were osteoclasts around all the bone graft materials used, but the percentage of residual graft particles was significantly higher in CHBG groups and CHBG + PRF groups at the eighth week. There is no beneficial effect of the application of PRF in combination with demineralized bone matrix or collagenated heterologous bone graft on bone formation in sinus floor augmentation. The results of this study showed that both collagenated heterologous bone graft and demineralized bone matrix have osteoconductive properties, but demineralized bone matrix showed more bone formation than collagenated heterologous bone graft.


A Randomized Trial of Social Media Versus Search Engine Advertising to Increase Awareness of Treatments for Female Stress Urinary Incontinence.
Outreach based on user characteristics through social media advertising is significantly more effective than outreach based on user interests with search engine advertising for female stress urinary incontinence. The aim of the study was to compare the effectiveness of 2 online outreach platforms to engage women at risk of stress urinary incontinence with a high-quality patient education website. A geographic randomized trial was performed comparing online advertising on Facebook, a social media site, versus Google Ads, a search engine, to direct viewers to VoicesForPFD.org. Advertisements were developed using health communication theory and pretested before the randomized trial. Counties in the Pacific Northwest were grouped into approximately equal populations, called "supercounties," and randomized to advertisement platforms. Educational website views resulting from each campaign, called sessions, were measured using Google Analytics; the primary outcome was the number of sessions per supercounty. County characteristics were obtained from national survey data. Effectiveness of the advertising platforms was compared between randomization arms using Welch's unequal variances t test, and crude and adjusted linear regression models. Mean user sessions were significantly higher in areas randomized to Facebook advertising (470 sessions) compared with areas randomized to Google Ads advertising [44 sessions; mean, 426 session difference (95% confidence interval, 199-653 sessions); P = 0.001]. After accounting for adult female population and rurality, randomization to Facebook instead of Google Ads still resulted in 409 additional sessions (95% confidence interval, 317-501 sessions; P < 0.001). Social media was 10 times more effective (470 versus 44 mean sessions per supercounty) than search engine outreach advertising and should be prioritized in outreach efforts. Future work is needed on engagement and behavior change with online outreach.


Factors related to number of present teeth in Korean elderly adults aged 55-84 years.
The aim of this study was to determine the associations between the number of present teeth (NT) and socio-economic, demographic and oral health behavioural factors among Korean adults aged 55-84 years. The total subjects comprised 3767 individuals who were examined and who answered the questions on socio-economic status and oral health behaviour from the fourth Korean National Health and Nutrition Examination Survey conducted from 2007 to 2009. The dependent variable was NT, with binary status divided by the median. Socio-economic and demographic factors included gender, educational level, parent's educational levels, region of residence, household income, type of health insurance and mother's economic activity. Oral health behaviours were as follows: daily toothbrushing frequency, smoking status, recent dental visit and illegal dental treatment. Multivariate logistic regression models were applied to explain the associations between NT and other variables. In a model adjusted by socio-economic, demographic and oral health behavioural variables, subjects who lived in urban areas were more likely to have larger NT compared to those in suburban areas (OR: 1.22, P = 0.025). Males were more likely to have larger NT (OR: 1.90, P < 0.001), and daily toothbrushing frequency was associated with NT (OR = 1.25, P = 0.023). Non-smokers (OR: 2.44, P < 0.001) and past smokers (OR: 1.70, P < 0.001) were more likely to have lager NT compared to current smokers. Subjects without illegal dental treatments were more likely to have lager NT compared to those with illegal dental treatments (OR = 2.21, P < 0.001). Interventions aiming to preserve present teeth in elderly adults should consider socio-economic, demographic and oral health behavioural factors.


Micro magnetofluidics: droplet manipulation of double emulsions based on paramagnetic ionic liquids.
The ability to control and manipulate discrete fluid droplets by magnetic fields offers new opportunities in microfluidics. A surfactant-free and easy to realize technique for the continuous generation of double emulsion droplets, composed of an organic solvent and a paramagnetic ionic liquid, is applied. The inner phase of the emulsion droplet consists of imidazolium-based ionic liquids with either iron, manganese, nickel or dysprosium containing anions which provide paramagnetic behaviour. The double emulsion droplets are dispersed in a continuous phase of FC-40. All substances - the organic phase, the paramagnetic ionic liquid and the continuous phase -are immiscible. The magnetic properties of ionic liquids allow, through the influence of external magnetic fields, the manipulation of individual emulsion droplets such as capture and release, rotation and distortion. Arrays of magnets allow a coalescence of emulsion droplets and their subsequent mixing by flowing through an alternating permanent magnetic field. In addition, the double emulsion droplets can be split and reunified, or continuously separated into their original phases.


Evaluation of the genus Thiothrix Winogradsky 1888 (Approved Lists 1980) emend. Aruga et al. 2002: reclassification of Thiothrix disciformis to Thiolinea disciformis gen. nov., comb. nov., and of Thiothrix flexilis to Thiofilum flexile gen. nov., comb nov., with emended description of Thiothrix.
Thiothrix is the type genus of the Thiotrichaceae in the Thiotrichales of the Gammaproteobacteria, comprising nine species of sulfur-oxidising filamentous bacteria, which are variously autotrophic, heterotrophic or have mixed metabolic modes. Within the genus, four species show 16S rRNA gene identities lower the Yarza threshold for the rank of genus (94.5 %) - Thiothrix disciformis, Thiothrix flexilis, Thiothrix defluvii and Thiothrix eikelboomii - as they show no affiliation to extant genera, a polyphasic study was undertaken including biochemical, physiological and genomic properties and phylogeny based on the 16S rRNA gene (rrs), recombination protein A (RecA), polynucleotide nucleotidyltransferase (Pnp), translation initiation factor IF-2 (InfB), glyceraldehyde-3-phosphate dehydrogenase (GapA), glutaminyl-tRNA synthetase (GlnS), elongation factor EF-G (FusA) and concatamers of 53 ribosomal proteins encoded by rps, rpl and rpm operons, all of which support the reclassification of these species. We thus propose Thiolinea gen. nov. and Thiofilum gen. nov. for which the type species are Thiolinea disciformis gen. nov., comb. nov. and Thiofilum flexile gen. nov., comb. nov. We also propose that these genera are each circumscribed into novel families Thiolinaceae fam. nov. and Thiofilaceae fam. nov., and that Leucothrix and Cocleimonas are circumscribed into Leucotrichaceaefam. nov. and provide emended descriptions of Thiothrix and Thiotrichaceae.


Microenvironment at tissue injury, a key focus for efficient stem cell therapy: A discussion of mesenchymal stem cells.
Stem cell therapy is not a new field, as indicated by the success of hematopoietic stem cell reconstitution for various hematological malignancies and immune-mediated disorders. In the case of tissue repair, the major issue is whether stem cells should be implanted, regardless of the type and degree of injury. Mesenchymal stem cells have thus far shown evidence of safety, based on numerous clinical trials, particularly for immune-mediated disorders. The premise behind these trials is to regulate the stimulatory immune responses negatively. To apply stem cells for other disorders, such as acute injuries caused by insults from surgical trauma and myocardial infarction, would require other scientific considerations. This does not imply that such injuries are not accompanied by immune responses. Indeed, acute injuries could accompany infiltration of immune cells to the sites of injuries. The implantation of stem cells within a milieu of inflammation will establish an immediate crosstalk among the stem cells, microenvironmental molecules, and resident and infiltrating immune cells. The responses at the microenvironment of tissue injury could affect distant and nearby organs. This editorial argues that the microenvironment of any tissue injury is a key consideration for effective stem cell therapy.


Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.
Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.


Ion chemistry in space.
We review the gas-phase chemistry in extraterrestrial space that is driven by reactions with atomic and molecular ions. Ions are ubiquitous in space and are potentially responsible for the formation of increasingly complex interstellar molecules. Until recently, positively charged atoms and molecules were the only ions known in space; however, this situation has changed with the discovery of various molecular anions. This review covers not only the observation, distribution and reactions of ions in space, but also laboratory-based experimental and theoretical methods for studying these ions. Recent results from space-based instruments, such as those on the Cassini-Huygens space mission and the Herschel Space Observatory, are highlighted.


A Review on Rhizosphere Microbiota of Tea Plant (Camellia sinensis L): Recent Insights and Future Perspectives.
Rhizosphere microbial colonization of the tea plant provides many beneficial functions for the host, But the factors that influence the composition of these rhizosphere microbes and their functions are still unknown. In order to explore the interaction between tea plants and rhizosphere microorganisms, we summarized the current studies. First, the review integrated the known rhizosphere microbial communities of tea tree, including bacteria, fungi, and arbuscular mycorrhizal fungi. Then, various factors affecting tea rhizosphere microorganisms were studied, including: endogenous factors, environmental factors, and agronomic practices. Finally, the functions of rhizosphere microorganisms were analyzed, including (a) promoting the growth and quality of tea trees, (b) alleviating biotic and abiotic stresses, and (c) improving soil fertility. Finally, we highlight the gaps in knowledge of tea rhizosphere microorganisms and the future direction of development. In summary, understanding rhizosphere microbial interactions with tea plants is key to promoting the growth, development, and sustainable productivity of tea plants.


Diet, physical activity and screen time but not body mass index are associated with the gut microbiome of a diverse cohort of college students living in university housing: a cross-sectional study.
Modifiable lifestyle factors (e.g. dietary intake and physical activity) are important contributors to weight gain during college. The purpose of this study was to evaluate whether associations exist between body mass index, physical activity, screen time, dietary consumption (fat, protein, carbohydrates, and fiber), and gut microbial diversity during the first year of college. Racially/ethnically diverse college students (n = 82; 61.0% non-white) at a large Southwestern university completed self-reported physical activity and 24-h recall dietary assessments, height and weight measurements, and provided one fecal sample for gut microbiome analysis. Fecal microbial community composition was assessed with Illumina MiSeq next-generation sequencing of PCR amplified 16S rRNA genes. Post-hoc analyses compared microbial diversity by groups of high and low physical activity and fiber intake using QIIME and LEfSe bioinformatics software. No statistically significant differences were observed between body mass index and gut microbiome abundance and diversity. Median daily consumption of dietary fiber was 11.2 (7.6, 14.9) g/d, while the median self-reported moderate-to-vigorous physical activity (MVPA) was 55.7 (27.9, 79.3) min/d and screen time 195.0 (195.0, 315.0) min/d. Microbial analysis by LEfSe identified Paraprevotellaceae, Lachnospiraceae, and Lachnospira as important phylotypes in college students reporting greater MVPA, while Enterobacteriaceae and Enterobacteriales were more enriched among students reporting less MVPA (p < 0.05). Barnesiellaceae, Alphaproteobacteria, and Ruminococcus were more abundant taxa among those consuming less than the median fiber intake (p < 0.05). Post-hoc analyses comparing weighted UniFrac distance metrics based on combined categories of high and low MVPA and fiber revealed that clustering distances between members of the high MVPA-low fiber group were significantly smaller when compared to distances between members of all other MVPA-fiber groups (p < 0.0001). Habitual fiber consumption and MVPA behaviors help explain the differential abundance of specific microbial taxa and overall gut microbial diversity differences in first-year college students.


Novel biosensor for the rapid measurement of estrogen based on a ligand-receptor interaction.
A bioaffinity sensor was developed aiming at the detection of estrogen. This biosensor system is based on the specific binding of estrogen to its receptor immobilized on a gold disk electrode. The recombinant DNA encoding human estrogen receptor ligand-binding domain was expressed in bacteria using the histidine-tag fusion system. The expression of the fusion protein was under control of a bacteriophage T7 promoter, and the protein was purified under native conditions by affinity chromatography, which is based on a specific interaction between a histidine-tag, located in the N-terminus of the protein, and the Ni(II) chelate adsorbent. The protein was immobilized on an Au-electrode with Ni(II)-mediated chemisorption using a histidine tag and thiol-modified iminodiacetic acid. Cyclic voltammetric measurements showed that the reversible electrochemical reaction of a ferrocyanide/ferricyanide redox couple was suppressed by the presence of estrogen in a concentration-dependent manner. It seems reasonable to suppose that the electrostatic property of the protein layer on the electrode surface was altered by complexation with estrogen. These data suggest that this biosensor is applicable to the evaluation binding activities of the chemicals toward the human estrogen receptor.


Inhibition of smooth muscle cell death by Angiotensin 1-7 protects against abdominal aortic aneurysm.
Abdominal aortic aneurysm (AAA) represents a debilitating vascular disease characterized by aortic dilatation and wall rupture if it remains untreated. We aimed to determine the effects of Ang 1-7 in a murine model of AAA and to investigate the molecular mechanisms involved. Eight- to 10-week-old apolipoprotein E-deficient mice (ApoEKO) were infused with Ang II (1.44 mg/kg/day, s.c.) and treated with Ang 1-7 (0.576 mg/kg/day, i.p.). Echocardiographic and histological analyses showed abdominal aortic dilatation and extracellular matrix remodeling in Ang II-infused mice. Treatment with Ang 1-7 led to suppression of Ang II-induced aortic dilatation in the abdominal aorta. The immunofluorescence imaging exhibited reduced smooth muscle cell (SMC) density in the abdominal aorta. The abdominal aortic SMCs from ApoEKO mice exhibited markedly increased apoptosis in response to Ang II. Ang 1-7 attenuated cell death, as evident by increased SMC density in the aorta and reduced annexin V/propidium iodide-positive cells in flow cytometric analysis. Gene expression analysis for contractile and synthetic phenotypes of abdominal SMCs showed preservation of contractile phenotype by Ang 1-7 treatment. Molecular analyses identified increased mitochondrial fission, elevated cellular and mitochondrial reactive oxygen species (ROS) levels, and apoptosis-associated proteins, including cytochrome c, in Ang II-treated aortic SMCs. Ang 1-7 mitigated Ang II-induced mitochondrial fission, ROS generation, and levels of pro-apoptotic proteins, resulting in decreased cell death of aortic SMCs. These results highlight a critical vasculo-protective role of Ang 1-7 in a degenerative aortic disease; increased Ang 1-7 activity may provide a promising therapeutic strategy against the progression of AAA.


Drying method effects on the antioxidant activity of quince (Cydonia oblonga Miller) tea.
Quince has many health benefits. Dried quince has been used as a tea for centuries. The aim of this study was to investigate the influences of two drying methods on the antioxidant activity of the quince. Fifty two fresh Iranian quinces (Cydonia oblonga) were obtained from different parts of Shiraz. Half of the quinces were peeled and both peel and flesh immediately frozen at -20°C individually. The remainder was divided in two groups, and dried with sun and oven drying methods. Proximate analysis, caloric, mineral and vitamin C contents were determined in the fresh quinces. The total phenolic, DPPH radical scavenging activity and reducing power analysis were done on flesh, peel, sun-dried and oven-dried quinces. The proximate and nutritional composition of the fresh quinces was similar to those reported by other researchers. Oven-dried and quince peel contained higher amounts of phenolics than the sun-dried and flesh quinces, respectively. Sun-dried and flesh samples showed lower radical scavenging effect and reducing antioxidant capacity than oven-dried and quince peel, respectively. Overall, oven drying can better preserve the antioxidative activity of the quince.


A new specific succinate-glutamate metabolomic hallmark in SDHx-related paragangliomas.
Paragangliomas (PGLs) are frequently associated with germline mutations in genes involved in energy metabolism. The purpose of the present study was to assess whether the tumor metabolomic profile of patients with hereditary and apparently sporadic PGLs enables the distinction of different subtypes of tumors. Twenty-eight unrelated patients with a histological diagnosis of PGLs were included in the present study. Twelve had germline mutations in SDHx genes (5 SDHB, 7 SDHD), 6 VHL, and 10 were apparently sporadic. Intact tumor samples from these patients (one per patient) were evaluated with (1)H high-resolution magic angle spinning (HRMAS) NMR spectroscopy. SDHx-related tumors were characterized by an increase in succinate levels in comparison to other tumor subtypes (p = 0.0001 vs VHL and p = 0.000003 vs apparently sporadic). Furthermore, we found significantly lower values of glutamate in SDHx-related tumors compared to other subtypes (p = 0.0007 vs VHL and p = 0.003 vs apparently sporadic). Moreover, SDHx-tumors also exhibited lower values of ATP/ADP/AMP (p = 0.01) compared to VHL. VHL tumors were found to have the highest values of glutathione (GSH) compared to other tumors. Based on 4 metabolites (succinate, glutamate, GSH, and ATP/ADP/AMP), tumors were accurately distinguished from the other ones on both 3- and 2-class PLS-DA models. The present study shows that HRMAS NMR spectroscopy is a very promising method for investigating the metabolomic profile of various PGLs. The present data suggest the existence of a specific succinate-glutamate hallmark of SDHx PGLs. The relevance of such a metabolomic hallmark is expected to be very useful in designing novel treatment options as well as improving the diagnosis and follow-up of these tumors, including metastatic ones.


[Percutaneous transluminal angioplasty in aortic coarctation. Report of a case].
We describe the first case in our hospital of percutaneous transluminal angioplasty in a 16 years old boy with congenital coarctation of the aorta. The technique, hemodynamic findings, angiography before and after dilation and the advantages in comparison with the conventional cardiac surgery were analyzed. In our case the gradient decreased from 60 mmHg to 28 mmHg. We conclude that this procedure is an alternative treatment for patients with congenital coarctation of the aorta.


Association of sleep-disordered breathing and disturbed cardiac repolarization in patients with ST-segment elevation myocardial infarction.
In patients with ST-segment elevation myocardial infarction (STEMI), disturbed cardiac repolarization before percutaneous coronary intervention (PCI) is a risk factor for malignant ventricular arrhythmia. We tested the hypothesis that sleep-disordered breathing (SDB) in patients with STEMI is associated with disturbed cardiac repolarization. Thirty-three patients with STEMI who underwent PCI were prospectively enrolled. To assess cardiac repolarization, the heart-rate corrected interval from the peak of the T wave to the end of the T wave (TpTec) and QTc intervals were assessed with 12-lead electrocardiography before PCI, within 24 h after PCI, and 12 weeks after PCI. SDB defined as an apnea-hypopnea index (AHI) ≥15 per hour was diagnosed by polysomnography. Before PCI, patients with SDB had a significantly prolonged TpTec interval compared to patients without SDB (133 vs 104 ms, p = 0.035). Within 24 h after PCI, the TpTec interval was 107 vs 92 ms (p = 0.178). QTc intervals showed a similar pattern (pre-PCI: 443 vs 423 ms, p = 0.199; post-PCI: 458 vs 432 ms, p = 0.115). In multiple linear regression analyses, AHI was significantly associated with prolonged TpTec intervals (pre-PCI: B-coefficient = 1.11, 95% confidence interval (CI) 0.48-1.74, p = 0.001; post-PCI: B = 0.97, 95% CI 0.29-1.65, p = 0.007), prolonged QTc intervals (pre-PCI: B = 1.05, 95% CI 0.20-1.91, p = 0.018; post-PCI: B = 1.37, 95% CI 0.51-2.24, p = 0.003), and higher TpTe/QT-ratios (pre-PCI: B = 0.16, 95% CI 0.05-0.27, p = 0.007; post-PCI: B = 0.13, 95% CI < 0.01-0.25, p = 0.036), independent of known risk factors for cardiac arrhythmia. In patients with STEMI, SDB was significantly associated with disturbed cardiac repolarization before and after PCI, independent of known risk factors. These findings suggest that SDB may contribute to the risk of developing malignant ventricular arrhythmia.


Clonal distribution of resistance plasmid-carrying Salmonella typhimurium, mainly in the Middle East.
Strains of Salmonella typhimurium of predominantly Middle Eastern origin, but distributed from England to India, were found to carry at least three types of resistance plasmid. The most important was initially identified as an F(I) plasmid by compatibility tests, but differs from the F factor on the one hand and the F(I) factors R162 and ColV on the other. The three groups of F(I) plasmids can be distinguished by their compatibility reactions with the MP10 plasmid of S. typhimurium (Smith, Humphreys, Grindley, Grindley & Anderson, 1973) and group H(1) factors: the F factor is unilaterally incompatible with group H(1) (Smith, Grindley, Humphreys & Anderson, 1973; Anderson, 1975b); the F(I) factors are compatible with MP10 and group H(1); and F(I)me factors are incompatible with MP10 but compatible with H(1). The majority of S. typhimurium cultures belonged to phage type 208; most of those that did not, belonged to types related to 208. Only a minority of their F(I)me plasmids were autotransferring. The remainder were mobilizable by F-like plasmids, and by group H(1) and H(2) factors, but not by the fi(-) I(1) factor Delta, or by plasmids of the I(2), B, P, W, N and com 7 groups. The compatibility reactions of the autotransferring F(I)me plasmids were identical with those of the non-transferring members of the group, and both were large, single-copy plasmids.The S. typhimurium strains of this series carried A or AK, and SSu resistance determinants: small, probably multicopy, non-transferring plasmids similar to those originally described in phage type 29 of S. typhimurium (Anderson & Lewis, 1965b).These S. typhimurium cultures probably represent a clone of wide geographical distribution. The accurate epidemiological study of such clonal outbreaks requires, in addition to phage typing, precise identification of the plasmids harboured by the epidemic strains, and may have to be carried to the molecular level.F(I)me plasmids were identified in other drug-resistant salmonellas, notably in a strain of S. wien which caused large outbreaks of mainly paediatric infection in Algeria, and also spread to Britain. An F(I)me plasmid was found in S. typhi phage type 44 from Algeria, in which the phage-restricting properties of the plasmid are responsible for the specificity of the type.


Effect of early iron deficiency in rat on the gamma-aminobutyric acid shunt in brain.
Early iron deficiency in rat does not affect the weight or the protein, DNA, and RNA content but results in a slight reduction in gamma-aminobutyric acid (GABA) (13%, p less than 0.01) and glutamic acid (20%, p less than 0.001) content of the brain. The activities of the two GABA shunt enzymes, glutamate dehydrogenase and GABA-transaminase, and of the NAD+-linked isocitrate dehydrogenase (ICDH) were inhibited whereas the glutamic acid decarboxylase, mitochondrial NADP+-linked ICDH, and succinic dehydrogenase activities remained unaltered in brain. On rehabilitation with the iron-supplemented diet for 1 week, these decreased enzyme activities in brain attained the corresponding control values. However, the hepatic nonheme iron content increased to about 80% of the control, after rehabilitation for 2 weeks. A prolonged iron deficiency resulting in decreased levels of glutamate and GABA may lead to endocrinological, neurological, and behavioral alterations.


Cystoid macular edema associated with iridocorneal endothelial syndrome: a case report.
Iridocorneal endothelial (ICE) syndrome occurs mainly in young and middle-aged women and typically presents as a unilateral disease characterized by abnormalities of the iris and corneal endothelium. While the ICE syndrome is known to be associated with glaucoma and bullous keratopathy, to our knowledge, only two cases of ICE syndrome complicated with cystoid macular edema (CME) have been reported to date. In this paper, we report a case of ICE syndrome complicated with CME treated at our institution. The subject was a 51-year-old woman. In October 2013, she was examined by a primary care physician for blurred vision in her left eye. Dyscoria and abnormality of the corneal endothelium were observed, and the patient was diagnosed with ICE syndrome. In November of the same year, she was referred to our institution with a decrease in visual acuity and CME, both in her left eye. At initial examination, her best corrected decimal visual acuity was 1.0 (Snellen equivalent: 20/20) in the right eye and 0.5 (20/40) in the left eye. Intraocular pressure was 12 mmHg in both eyes. She was diagnosed with Cogan-Reese syndrome based on marked ectropion uveae, peripheral anterior synechia, and abnormalities of the corneal endothelium. Marked CME was observed on ophthalmoscopy and optical coherence tomography. A topical non-steroidal anti-inflammatory drug (nepafenac 0.1 %) was applied to the left eye four times daily from January 2014. Four weeks later, the CME had resolved and her visual acuity was 1.0 (20/20). While non-steroidal anti-inflammatory drugs and steroids did not appear to be effective in two previously reported cases of ICE syndrome complicated with CME, topical nepafenac was effective in this case. However, more such cases are needed before concluding that topical nepafenac is effective in this situation.


Regulation of pannexin and connexin channels and their functional role in skeletal muscles.
Myogenic precursor cells express connexins (Cx) and pannexins (Panx), proteins that form different membrane channels involved in cell-cell communication. Cx channels connect either the cytoplasm of adjacent cells, called gap junction channels (GJC), or link the cytoplasm with the extracellular space, termed hemichannels (HC), while Panx channels only support the latter. In myoblasts, Panx1 HCs play a critical role in myogenic differentiation, and Cx GJCs and possibly Cx HCs coordinate metabolic responses during later steps of myogenesis. After innervation, myofibers do not express Cxs, but still express Panx1. In myotubes and innervated myofibers, Panx1 HCs allow release of adenosine triphosphate and thus they might be involved in skeletal muscle plasticity. In addition, Panx1 HCs present in adult myofibers mediate adenosine triphosphate release and glucose uptake required for potentiation of muscle contraction. Under pathological conditions, such as upon denervation and spinal cord injury, levels of Panx1 are upregulated. However, Panx1(-/-) mice show similar degree of atrophy as denervated wild-type muscles. Skeletal muscles also express Cx HCs in the sarcolemma after denervation or spinal cord injury, plus other non-selective membrane channels, including purinergic P2X7 receptors and transient receptor potential type V2 channels. The absence of Cx43 and Cx45 is sufficient to drastically reduce denervation atrophy. Moreover, inflammatory cytokines also induce the expression of Cxs in myofibers, suggesting the expression of these Cxs as a common factor for myofiber degeneration under diverse pathological conditions. Inhibitors of skeletal muscle Cx HCs could be promising tools to prevent muscle wasting induced by conditions associated with synaptic dysfunction and inflammation.


Fused Brain Functional Connectivity Network and Edge-attention Graph Convolution Network for Fibromyalgia Syndrome Diagnosis.
Fibromyalgia syndrome (FMS) is a type of rheumatology that seriously affects the normal life of patients. Due to the complex clinical manifestations of FMS, it is challenging to detect FMS. Therefore, an automatic FMS diagnosis model is urgently needed to assist physicians. Brain functional connectivity networks (BFCNs) constructed by resting-state functional magnetic resonance imaging (rs-fMRI) to describe brain functions have been widely used to identify individuals with relevant diseases from normal control (NC). Therefore, we propose a novel model based on BFCN and graph convolutional network (GCN) for automatic FMS diagnosis. Firstly, a novel fused BFCN method is proposed by fusing Pearson's correlation (PC) and low-rank (LR) BFCN, which retains information and reduces data redundancy to construct BFCN. Then we combine the feature of BFCN with non-image information of subjects to obtain nodes and adjacency matrices, which builds a graph with edge attention. Finally, the graph is sent to the GCN layer for FMS diagnosis. Our model is evaluated on the in-house FMS dataset to achieve 82.48% accuracy. The experimental results show that our method outperforms the state-of-the-art competing methods.


Consequences of incomplete repair of acute type A aortic dissection.
During emergency repair of acute Stanford type A aortic dissections, surgical compromises in the form of incomplete arch replacement are made due to the unstable condition of the patient and safety issues of the performing team. We report a case of delayed reoperation after previous incomplete surgery for acute type A aortic dissection in a young patient with Marfan's syndrome. He presented again with repetitive chest pain five years after initial surgical treatment. Extensive aneurysmal dilatation of the aorta and remaining dissection led to the decision to replace the ascending aorta and the aortic arch. After a good progress during the first days after surgery, the patient died due to a ruptured thoraco-abdominal aneurysm on the fifth postoperative day. Extensive surgical reconstruction including aortic arch replacement should be considered in patients with Marfan's syndrome who present with aortic dissections type A to avoid unnecessary reoperations and their complications.


Chaperone-assisted assembly and molecular architecture of adhesive pili.
The assembly of bacterial pili as exemplified here by P and type 1 pili of E. coli is a complex process involving specific molecular interactions between structural and chaperone proteins. The assembly process occurs postsecretionally, i.e. after the subunits are translocated across the cytoplasmic membrane. In a single cell, hundreds of thousands of interactive subunits are typically surface localized and assembled into pili. Periplasmic chaperones are generally required to bind to the interactive subunits and partition them into assembly-competent complexes. The binding of the chaperone to the subunits apparently protects the interactive surfaces and prevents them from aggregating at the wrong time and place within the cell. Pili are most likely assembled into linear polymers that package into right-handed helices after their translocation through specific outer-membrane channels. Each pilus filament is a quaternary assembly of the structural subunit and several minor subunits including the adhesin moiety. Although the assembly and organization of P and type 1 pili are very similar, there are some notable differences. For example, the P pilus adhesin is located exclusively at the tips of the pilus filament and forms part of a morphologically distinct structure. In contrast, the adhesion moiety of type 1 pili is inserted into the pilus filament at intervals, but only the adhesin molecule exposed at the pilus tip is functional. The variability in isoreceptor recognition amongst P pili has been solely ascribed to structural differences in the respective adhesin molecules, whereas in type 1 pili, variability in binding specificity has been attributed to the pilus filament that influences the conformation of the adhesin moiety. Less is known about the structure or assembly of type 4 pili, which are a unique class of pili expressed by several different species of gram-negative bacteria. The phase variation of the pilC assembly gene in N. gonorrheae to the off state results in the accumulation of unassembled subunits toxic to the cells. This process exerts a strong selection pressure on the cells that triggers alterations in the pilin structural gene. Thus, antigenic variation of pili in this organism may be regulated at the level of assembly. Finally, the concept of periplasmic chaperones in postsecretional assembly is most likely a general phenomenon in the biology of gram-negative bacteria. The investigations of pilus assembly will continue to provide insight into the details of how macromolecular assembly reactions are coordinated in the bacterial cell and how the regulation of assembly genes can profoundly affect biological processes.


Fluid Dynamics and Biofilm Removal Generated by Syringe-delivered and 2 Ultrasonic-assisted Irrigation Methods: A Novel Experimental Approach.
Thorough understanding of fluid dynamics in root canal irrigation and corresponding antibiofilm capacity will support improved disinfection strategies. This study aimed to develop a standardized, simulated root canal model that allows real-time analysis of fluid/irrigation dynamics and its correlation with biofilm elimination. A maxillary incisor with an instrumented root canal was imaged with micro-computed tomography. The canal volume was reconstructed in 3 dimensions and replicated in soft lithography-based models microfabricated from polyethylene glycol-modified polydimethylsiloxane. Canals were irrigated by using a syringe (SI) and 2 ultrasonic-assisted methods, intermittent (IUAI) and continuous (CUAI). Real-time fluid movement within the apical 3 mm of canals was imaged by using microparticle image velocimetry. In similar models, canals were inoculated with Enterococcus faecalis to grow 3-week-old biofilms. Biofilm reduction by irrigation with SI, CUAI, and IUAI was assessed by using a crystal violet assay and compared with an untreated control. SI generated higher velocity and shear stress in the apical 1-2 mm than 0-1 and 2-3 mm. IUAI generated consistently low shear stress in the apical 3 mm. CUAI generated consistently high levels of velocity and shear stress; it was the highest of the groups in the apical 0-1 and 2-3 mm. Biofilm was significantly reduced compared with the control only by CUAI (two-sample permutation test, P = .005). CUAI exhibited the highest mechanical effects of fluid flow in the apical 3 mm, which correlated with significant biofilm reduction. The soft lithography-based models provided a novel model/method for study of correlations between fluid dynamics and the antibiofilm capacity of root canal irrigation methods.


[Disturbance of equilibrium between blood levels of antioxidant and prooxidant metalloproteins in pain stress in children].
Molecular mechanisms of the trauma stress of different origins in children to some extent is related to the quantitative changes of blood superoxide dismutase, catalase, ceruloplasmin, transferrin, cytochromes b5, b558III, b558IV and suprol. Non adequate changes of antioxidant (superoxide dismutase, catalase, ceruloplasmin, transferrin) and newly discovered prooxidant (cytochromes b5, b558III, b558IV, suprol) metalloproteins, as well as serum and erythrocyte cytochrome b5 depend on characteristic and duration of trauma stress caused by extremity fractures in children. This is due to the different mechanisms of adaptation to trauma stress.


Risk factor analysis of post-operative mortality in oesophagectomy.
Oesophagectomy for cancer is associated with a significant incidence of post-operative complications and death, and so this study sought to determine objective criteria which could better predict operative risk. Clinical risk factors for oesophagectomy and the results of objective investigations were assessed prospectively by independent surgical and intensive care specialists and a multivariate analysis was used to develop a scoring system for predicting operative risk. From September 1994 to June 1997, 32 patients from an overall experience of 70 oesophagectomy procedures for cancer at the Royal Adelaide Hospital were entered into this study. Hypertension, a history of previous cigarette smoking and FEV1/FVC were identified as independent predictors of the post-operative outcome. Age and FEV1/FVC were also significantly associated with the occurrence of cardiovascular and pulmonary complications respectively. The average risk score was 4.8 +/- 4.5 (mean +/- SD) for patients who died, 2.9 +/- 2.9 for patients who developed post-operative complications and 2.6 +/- 2.1 for patients who had an uncomplicated recovery. The likelihood of post-operative mortality and morbidity was highest in patients with a score of 5 or more. Mortality rates of different patient groups undergoing oesophagectomy by the same surgeons during the same time period were also compared, showing greatly different mortality rates. Important risk factors can be identified preoperatively, and a scoring system can be used to provide objective criteria which can be used to identify patients at an increased risk of post-operative complications and death. A prospective study of this scoring system is now needed to determine whether it proves useful in rejecting patients for surgery who would otherwise have undergone oesophagectomy.


Fermentative butanol production by Clostridia.
Butanol is an aliphatic saturated alcohol having the molecular formula of C(4)H(9)OH. Butanol can be used as an intermediate in chemical synthesis and as a solvent for a wide variety of chemical and textile industry applications. Moreover, butanol has been considered as a potential fuel or fuel additive. Biological production of butanol (with acetone and ethanol) was one of the largest industrial fermentation processes early in the 20th century. However, fermentative production of butanol had lost its competitiveness by 1960s due to increasing substrate costs and the advent of more efficient petrochemical processes. Recently, increasing demand for the use of renewable resources as feedstock for the production of chemicals combined with advances in biotechnology through omics, systems biology, metabolic engineering and innovative process developments is generating a renewed interest in fermentative butanol production. This article reviews biotechnological production of butanol by clostridia and some relevant fermentation and downstream processes. The strategies for strain improvement by metabolic engineering and further requirements to make fermentative butanol production a successful industrial process are also discussed.


Exploration of the academic lives of students with disabilities at South African universities: Lecturers' perspectives.
A decade has passed since South Africa signed and ratified the Convention on the Rights of Persons with Disabilities, a human rights treaty that protects the rights and dignity of people with disabilities. However, not much have changed for students with disabilities. The aim of this study was to explore lecturers' experiences with, and perspectives on, disability as well as with students with disabilities. It was hoped that this would contribute to the ongoing policy debates about diversity, inclusion and support for students with disabilities at universities. In an effort to understand the lives of students with disabilities better, a study which included students with disabilities, lecturers and disability supporting staff was conducted at two South African universities - University of the Free State and University of Venda. The paper takes a snapshot view of four lecturers and their perceptions of the lives of students with disabilities at their respective universities. Although most disability literature report students with disabilities blaming lecturers for their failure to advance their needs, this paper highlights that the education system needs to be supportive to lecturers for the inclusive agenda to be realised. An argument is made for a more comprehensive approach towards a national disability policy in higher education involving many stakeholders. Without a broader understanding of disability, it will be difficult to engage with the complex ways in which inequalities emerge and are sustained.


Assessment of cardiovascular risk factors in a rural community in the Brazilian state of Bahia.
To assess the frequency of cardiovascular risk factors in the rural community of Cavunge, in the Brazilian state of Bahia. A cross-sectional study was carried out with 160 individuals (age>19 years) randomly drawn from those listed in the population census of the Cavunge Project. The following parameters were studied: arterial hypertension, dyslipidemia, diabetes, obesity, smoking, waist-hip ratio (WHR), physical activity, and overall cardiovascular risk classified according to the Framingham score. The assessing parameters used were those established by the III Brazilian Consensus on Hypertension and the II Brazilian Consensus on Dyslipidemia. Of the randomly drawn individuals, 126 with a mean age of 46.6 +/- 19.7 years were included in the study, 43.7% of whom were males. The frequency of arterial hypertension was 36.5%; 20.4% of the individuals had cholesterol levels > or =240 mg/dL; 31.1% of the individuals had LDL-C levels >130 mg/dL; 4% were diabetic; and 39.7% had a high-risk Framingham score. Abdominal obesity was observed in 41.3% of the population and in 57.7% of the females. High caloric-expenditure (HCE) physical activities were performed by 56.5% of the individuals. The HCE group had a greater frequency of normal triglyceride levels (63% vs 44%; P=0.05), no diabetes, and WHR tending towards normal (46% vs 27%, P=0.08) as compared with those in the low caloric-expenditure group. Cardiovascular risk factors, such as hypertension and hypercholesterolemia, are frequently found in rural communities. The greatest frequency of normal triglyceride levels and normal WHR in the HCE group reinforces the association between greater caloric expenditure and a better risk profile.


[Specificities of intracellular metabolism in agricultural workers].
The purpose of the study was to identify and assess specific features of intracellular metabolism under the conditions of combined impact of biological and chemical work environment factors in agricultural workers. We have detected an activation of energetic and hydrolytic processes, suppression of antioxidant protection mechanisms in blood cells in workers of basic occupations. A most marked disorder of intracellular metabolism has been identified in poultry female workers. More significant activity deviations of acid phosphatase and glycogen in neutrophils and lymphocytes, myeloperoxidase in neutrophils have diagnosed in these workers.


Mitochondria at the interface between danger signaling and metabolism: role of unfolded protein responses in chronic inflammation.
Inflammatory bowel diseases (IBDs), like many other chronic diseases, feature multiple cellular stress responses including endoplasmic reticulum (ER) unfolded protein response (UPR). Maintaining protein homeostasis is indispensable for cell survival and, consequently, distinct signaling pathways have evolved to transmit organelle stress. While the ER UPR, aiming to restore ER homeostasis after challenges to ER function, has been extensively studied in the context of chronic diseases, only recently the related mitochondrial UPR (mtUPR), induced by disturbances of mitochondrial proteostasis, has drawn some attention. ER and mitochondria are in close contact and interact physically and functionally. Accumulating data have placed mitochondria at the center of diverse cellular functions and suggest mitochondria as integrators of signaling pathways such as autophagy and inflammation. Consequently, it is likely that mitochondrial stress and ER stress cannot be regarded separately and that mitochondrial stress, as well as ER stress, participates in the pathology of IBD. Protein homeostasis is particularly sensitive toward infections, oxidative stress, and energy deficiency. Thus, environmental disturbances impacting organelle function lead to the concerted activation of distinct UPRs. The metabolic status might therefore serve as an innate mechanism to sense the epithelial environment, including luminal-derived and host-derived factors. This review highlights mtUPR and its interrelation with ER UPR, focuses on recent studies identifying mitochondria as integrators of cellular danger signaling, and, furthermore, illustrates the importance ER UPR and mitochondrial dysfunction in IBD.


MHC studies in nonmodel vertebrates: what have we learned about natural selection in 15 years?
Elucidating how natural selection promotes local adaptation in interaction with migration, genetic drift and mutation is a central aim of evolutionary biology. While several conceptual and practical limitations are still restraining our ability to study these processes at the DNA level, genes of the major histocompatibility complex (MHC) offer several assets that make them unique candidates for this purpose. Yet, it is unclear what general conclusions can be drawn after 15 years of empirical research that documented MHC diversity in the wild. The general objective of this review is to complement earlier literature syntheses on this topic by focusing on MHC studies other than humans and mice. This review first revealed a strong taxonomic bias, whereby many more studies of MHC diversity in natural populations have dealt with mammals than all other vertebrate classes combined. Secondly, it confirmed that positive selection has a determinant role in shaping patterns of nucleotide diversity in MHC genes in all vertebrates studied. Yet, future tests of positive selection would greatly benefit from making better use of the increasing number of models potentially offering more statistical rigour and higher resolution in detecting the effect and form of selection. Thirdly, studies that compared patterns of MHC diversity within and among natural populations with neutral expectations have reported higher population differentiation at MHC than expected either under neutrality or simple models of balancing selection. Fourthly, several studies showed that MHC-dependent mate preference and kin recognition may provide selective factors maintaining polymorphism in wild outbred populations. However, they also showed that such reproductive mechanisms are complex and context-based. Fifthly, several studies provided evidence that MHC may significantly influence fitness, either by affecting reproductive success or progeny survival to pathogens infections. Overall, the evidence is compelling that the MHC currently represents the best system available in vertebrates to investigate how natural selection can promote local adaptation at the gene level despite the counteracting actions of migration and genetic drift. We conclude this review by proposing several directions where future research is needed.


Identifying causes of poor water quality in a Polish agricultural catchment for designing effective and targeted mitigation measures.
The Gowienica Miedwiańska catchment is a small agricultural catchment located in the NW of Poland draining into Lake Miedwie, on which a drinking water source for the city of Szczecin is located. The catchment is characterized by very rich soils. Subsequently, agriculture is intensive and this is thought to influence the poor water quality in the local area. Despite more than 20 years since first programmes of measures towards protection of water quality have been introduced into the catchment, these have not been produced the expected results, and the local farming community cites other sources such as poor sewage management rather that agricultural activity, as responsible for this problem. Evaluation of flow pathways in the catchment and identification of the areas responsible for the highest impact on local water quality was therefore conducted within the EU funded project Waterprotect. The aim of this study was to clarify sources of pollution precisely in space and time, in order to increase trust from stakeholders, so that targeted measures can be used effectively to improve water quality. The study included water quality monitoring, isotopic analysis and numerical flow modelling. Results showed that water quality in the catchment is spatially and temporally variable. 93% of nitrogen loadings into the Miedwie lake have been attributed to agriculture and only 7% to wastewater inputs. The local hydrology and hydrogeology play an important role in the distribution of the impacts from these inputs. As a result, three sub-catchments were identified which are differentiated by dominant pollution source, land use, and hydraulic characteristics. The highest inputs from agriculture have been identified in the most upper sub-catchment and this area have been pointed out as most suitable for implementation of agricultural best management practices towards protection of water quality at a local level.


Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.
Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.


Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients.
Objectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers. Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 y.o.; ZLM abuse/dependence; high-dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l. Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6-16.5%); one patient (0.9%, 95% CI 0.0-2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found. Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.


Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues.
An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden.


COVID-19 in Renal Transplant Recipients - A Single Center Experience from India.
The information on the clinical outcome of renal transplant recipients getting COVID-19 infection is sparse. The aim of this study is to report a single-center experience of renal transplant recipients with COVID-19 from India. This was a retrospective study of 23 consecutive renal transplant recipients with COVID-19 infection presenting to our center from May 2020 to August 2020. Clinical parameters, laboratory values, imaging characteristics, and outcome of the patients were collected and analyzed. Median follow-up duration was 36 (range: 10-110) days. Median age of patients was 54 (23-70) years, and 87% were male. Median duration since transplant was 69 (range: 15-132) months. The most common presenting feature was fever (82.6%), followed by breathlessness (43.5%) and cough (30.4%). Hospitalization rate was 52.2%, while 34.8% required ICU care. Severe to critical disease was seen in 39.1% of patients, and 17.4% required mechanical ventilation. Patients with severe disease had a higher incidence of lymphopenia (P = 0.005) when compared to the ones with mild to moderate disease. Acute kidney injury was seen in 39.1% of patients, and 13% required dialysis. Mortality rate was 13% overall, and 25% in those hospitalized. Renal transplant recipients with COVID-19 have a poor outcome. Although not all of them need hospitalization, they should be monitored closely. Immunosuppression minimization is an important part of the treatment strategy.


Two distinct Ca(2+)-dependent signaling pathways regulate the motor output of cochlear outer hair cells.
The outer hair cells (OHCs) of the cochlea have an electromotility mechanism, based on conformational changes of voltage-sensitive "motor" proteins in the lateral plasma membrane. The translocation of electrical charges across the membrane that accompanies electromotility imparts a voltage dependency to the membrane capacitance. We used capacitance measurements to investigate whether electromotility may be influenced by different manipulations known to affect intracellular Ca(2+) or Ca(2+)-dependent protein phosphorylation. Application of acetylcholine (ACh) to the synaptic pole of isolated OHCs evoked a Ca(2+)-activated apamin-sensitive outward K(+) current. It also enhanced electromotility, probably because of a phosphorylation-dependent decrease of the cell's axial stiffness. However, ACh did not change the voltage-dependent capacitance either in conventional whole-cell experiments or under perforated-patch conditions. The effects produced by the Ca(2+) ionophore ionomycin mimicked those produced by ACh. Hyperpolarizing shifts of the voltage dependence of capacitance and electromotility were induced by okadaic acid, a promoter of protein phosphorylation, whereas trifluoperazine and W-7, antagonists of calmodulin, caused opposite depolarizing shifts. Components of the protein phosphorylation cascade-IP(3) receptors and calmodulin-dependent protein kinase type IV-were immunolocalized to the lateral wall of the OHC. Our results suggest that two different Ca(2+)-dependent pathways may control the OHC motor output. The first pathway modulates cytoskeletal stiffness and can be activated by ACh. The second pathway shifts the voltage sensitivity of the OHC electromotile mechanism and may be activated by the release of Ca(2+) from intracellular stores located in the proximity of the lateral plasma membrane.


Delayed neuronal death after global incomplete ischemia in dogs is accompanied by changes in phospholipase C protein expression.
Activation of phospholipase C (PLC) increases intracellular Ca2+ and may play a role in delayed neuronal death after ischemia. Because changes in intracellular Ca2+ are believed to participate in ischemic neuronal injury, we tested the hypothesis that PLC beta protein levels are temporally altered in brain regions that undergo neurodegeneration after global incomplete ischemia. Dogs (n = 12) were subjected to 20 minutes of global incomplete ischemia followed by recovery of either 1 (n = 5) or 7 days (n = 7). Six sham-operated animals were used as nonischemic controls. In hematoxylin and eosin-stained brain sections, neuronal density at 1 day after ischemia was unchanged relative to nonischemic controls in hippocampus CA1, caudate, and cerebellar cortex (anterior lobule). However, at 7 days after ischemia, neuronal densities were decreased to 56 +/- 15% (mean +/- SD) and 75 +/- 17% of control in CA1 and caudate, respectively. At 1 and 7 days after ischemia, the percentage of neurons showing ischemic injury increased from 13 +/- 10 to 40 +/- 35% in CA1, 24 +/- 25 to 59 +/- 16% in cerebellum, and 4 +/- 2 to 18 +/- 12% in caudate. Densitometric analysis of immunocytochemically stained brain sections from controls (n = 3). 1 day after ischemia (n = 3), and 7 days after ischemia (n = 5) revealed that PLC beta immunoreactivity was increased in cerebellum at 1 day (0.274 +/- 0.013 v 0.295 +/- 0.005 optical density units [OD] in control and 1 day, respectively) and 7 days (0.108 +/- 0.009 v 0.116 +/- 0.005 O.D. in control and 7 days, respectively). PLC beta immunoreactivity was unchanged after ischemia in caudate and hippocampus. Western blot analysis of PLC beta immunoreactivity in the cerebellar cortex and hippocampus in the control (n = 3), 1 day (n = 2), and 7 days after ischemia (n = 2) groups showed that PLC beta levels were increased after ischemia in cerebellum 266% and 227% above control at 1 and 7 days, respectively. However, in hippocampus, PLC expression after ischemia was unchanged at 97% and 84% of control at 1 and 7 days, respectively. These results show that delayed neuronal degeneration after global incomplete ischemia is accompanied by regional abnormalities in PLC levels. Elevated PLC levels early may represent an aberrant signal transduction mechanism resulting in delayed cell damage, whereas decreased PLC levels later after ischemia may reflect ongoing neurodegeneration.


Predicting treatment response in adolescents and young adults with major depressive episodes from fMRI using graph isomorphism network.
Major depressive episode (MDE) is the main clinical feature of mood disorders (major depressive disorder and bipolar disorder) in adolescents and young adults and accounts for most of the disease course. However, 30%-40% of MDE patients not responding to clinical first-line interventions. It is crucial to predict treatment response in the early stages and identify biomarkers associated with treatment response. Graph Isomorphism Network (GIN), a deep learning method, is promising for predicting treatment response for individual MDE patients with more powerful representation ability to capture the features of brain functional connectivity. In this study, GIN was used to predict individual treatment response in 198 adolescents and young adults with MDE. The most discriminating regions were also identified for the treatment response prediction. Using GIN approach, the baseline functional connectivity could predict 79.8% responders and 67.4% non-responders to treatment (accuracy 74.24%). Furthermore, the most discriminating brain regions were mainly involved in paralimbic and subcortical areas. GIN has shown potential in predicting treatment response for individual patients, which may enable personalized treatment decisions. Furthermore, targeted interventions focused on modulating the activity and connectivity within paralimbic and subcortical regions could potentially improve treatment outcomes and enable personalized interventions for adolescents and young adults with MDE.


The effects of multimodal rehabilitation on pain-related sickness absence - an observational study.
The aim of the current study was to examine the effects on sickness absence of multimodal rehabilitation delivered within the framework of a national implementation of evidence based rehabilitation, the rehabilitation guarantee for nonspecific musculoskeletal pain. This was an observational matched controlled study of all persons receiving multimodal rehabilitation from the last quarter of 2009 until the end of 2010. The matching was based on age, sex, sickness absence the quarter before intervention start and pain-related diagnosis. The participants were followed by register data for 6 or 12 months. The matched controls received rehabilitation in accordance with treatment-as-usual. Of the participants, 54% (N = 3636) were on registered sickness absence at baseline and the quarter before rehabilitation. The average difference in number of days of sickness absence between the participants who received multimodal rehabilitation and the matched controls was to the advantage of the matched controls, 14.7 days (CI 11.7; 17.7, p ≤ 0.001) at 6-month follow-up and 9.5 days (CI 6.7; 12.3, p ≤ 0.001) at 12-month follow-up. A significant difference in newly granted disability pensions was found in favor of the intervention. When implemented nationwide, multimodal rehabilitation appears not to reduce sickness absence compared to treatment-as-usual. Implications for Rehabilitation A nationwide implementation of multimodal rehabilitation was not effective in reducing sickness absence compared to treatment-as-usual for persons with nonspecific musculoskeletal pain. Multimodal rehabilitation was effective in reducing the risk of future disability pension for persons with nonspecific musculoskeletal pain compared to treatment-as-usual. To be effective in reducing sick leave multimodal rehabilitation must be started within 60 days of sick leave. The evidence for positive effect of multimodal rehabilitation is mainly for sick listed patients. Prevention of sick leave for persons not being on sick leave should not be extrapolated from evidence for multimodal rehabilitation.


Postnatal craniofacial skeleton development following a pushback operation of patients with cleft palate.
A longitudinal growth study of the craniofacial skeleton in 52 (19 males, 33 females) Danish individuals with cleft palates was performed. Thirty (13 males, 17 females) had clefts of the soft palate only or clefts extending into the posterior third of the hard palate. Twenty-two (6 males, 16 females) had more extensive clefts including up to two-thirds of the hard palate. The cleft was closed with a pushback operation at 22 months of age. Orthodontic treatment was included in the early mixed dentition. Lateral cephalometries were obtained at 5, 8, 12, 16, and 21 years of age. Twenty-four variables were digitized and analyzed. The results indicated that patients with more extensive clefts demonstrated significantly smaller anterior cranial base length (N-S), total cranial base length (N-Ba), maxillary dentoalveolar base length (A-PMP), mandibular length (Cd-Pgn), upper anterior and posterior facial heights (N-ANS and P-PMP), and total facial height (N-Gn). Patients with the more extensive clefts reached maximum growth spurt later than patients with less extensive clefts in all dimensions except the A-PMP and the lower and total facial heights.


Efficient quality assurance programs in radiology and nuclear medicine in Ostergotland, Sweden.
Owners of imaging modalities using ionising radiation should have a documented quality assurance (QA) program, as well as methods to justify new radiological procedures to ensure safe operation and adequate clinical image quality. This includes having a system for correcting divergences, written imaging protocols, assessment of patient and staff absorbed doses and a documented education and training program. In this work, how some aspects on QA have been implemented in the County of Ostergötland in Sweden, and efforts to standardise and automate the process as an integrated part of the radiology and nuclear medicine QA programs were reviewed. Some key performance parameters have been identified by a Swedish task group of medical physicists to give guidance on selecting relevant QA methods. These include low-contrast resolution, image homogeneity, automatic exposure control, calibration of air kerma-area product metres and patient-dose data registration in the radiological information system, as well as the quality of reading stations and of the transfer of images to the picture archive and communication system. IT-driven methods to automatically assess patient doses and other data on all examinations are being developed and evaluated as well as routines to assess clinical image quality by use of European quality criteria. By assessing both patient absorbed doses and clinical image quality on a routine basis, the medical physicists in our region aim to be able to spend more time on imaging optimisation and less time on periodic testing of the technical performance of the equipment, particularly on aspects that show very few divergences. The role of the Medical Physics Expert is rapidly developing towards a person doing advanced data-analysis and giving scientific support rather than one performing mainly routine periodic measurements. It is concluded that both the European Council directive and the rapid development towards more complex diagnostic imaging systems and procedures support this changing role of the medical physics professional.


Knowledge-Based Planning for Identifying High-Risk Stereotactic Ablative Radiation Therapy Treatment Plans for Lung Tumors Larger Than 5 cm.
Stereotactic ablative body radiation therapy (SABR) for lung tumors ≥5 cm can be associated with more toxicity than that for smaller tumors. We investigated the relationship between dosimetry and toxicity and used a knowledge-based planning solution to retrospectively perform individualized treatment plan quality assurance (QA) with the aim of identifying where planning could have been improved. Previous retrospective analysis of 53 patients with primary or recurrent non-small cell lung cancer ≥5 cm, treated with 5- or 8-fraction volumetric modulated arc therapy SABR between 2008 and 2014, showed 30% with grade ≥3 toxicity. During this period, several improvements were made to departmental planning protocols. RapidPlan was used to compare dosimetry of patients with or without grade ≥3 toxicity. A model comprising plans from patients without toxicity and compliant with the current planning protocol was used to provide QA for the plans from patients who had toxicity. Sixteen of 53 patients had grade ≥3 toxicity, including 10 with radiation pneumonitis (RP), 3 with lung hemorrhage (1 of these also had RP), and 1 with airway stenosis/atelectasis. RP was again shown to be significantly correlated with contralateral and total-lung V5 and mean lung dose. The 4 highest contralateral-lung doses belonged to patients with RP. Five of 10 clinical plans in patients with RP had a contralateral-lung mean dose up to 2.5 times higher than that of the knowledge-based plan. For 2 of 3 patients with lung hemorrhage and 1 with airway stenosis/atelectasis, the clinical plans had the highest proximal bronchial tree doses, which was also higher than in plans from the model. In 8 patients with grade ≥3 toxicity, clinical plans had dosimetry similar to that in the predictions from the model. A "no-toxicity" RapidPlan model identified the potential for dosimetric improvement in nearly 50% of historical treatment plans from patients with grade ≥3 toxicity after SABR for lung tumors ≥5 cm. Model-based QA may be useful for benchmarking treatment planning protocols in routine practice and in clinical studies.


Antibodies against neutralization epitopes of human cytomegalovirus gH/gL/pUL128-130-131 complex and virus spreading may correlate with virus control in vivo.
Recently, human cytomegalovirus (HCMV) UL128-131 locus gene products have been found to be associated with glycoprotein H (gH) and glycoprotein L (gL) to form a pentameric glycoprotein complex gH/gL/pUL128-130-131, which is present in the virus envelope and elicits production of neutralizing antibodies. Purpose of this study was to verify whether in vitro activities of these antibodies may correlate with protection in vivo. By using potently neutralizing human monoclonal antibodies (mAbs) targeting 10 different epitopes of the pentameric complex, a competitive ELISA assay was developed, in which the pentamer bound to the solid-phase was reacted competitively with human sera and murinized human mAbs. In addition, inhibition of virus spreading (plaque formation and leukocyte transfer) by neutralizing human mAbs and sera was investigated. In the absence of any reactivity of sera from HCMV-seronegative subjects, antibodies to all 10 epitopes were detected in HCMV-seropositive individuals. During primary HCMV infection in pregnancy antibodies to some epitopes showed a trend towards an earlier appearance in mothers not transmitting the virus to the fetus as compared to transmitting mothers. In addition, the activity of neutralizing human mAbs and sera in blocking virus cell-to-cell spreading and virus transfer to leukocytes from infected endothelial cells was shown to develop during the convalescent phase of primary infection. Dissection of the neutralizing/inhibiting activities of human sera may be helpful in the study of their protective role in vivo. In particular, neutralizing antibodies to the pentamer may be a surrogate marker of protection in vivo.


Frizzled-7 is required for Xenopus heart development.
Wnt signalling regulates cardiogenesis during specification of heart tissue and the morphogenetic movements necessary to form the linear heart. Wnt11-mediated non-canonical signalling promotes early cardiac development whilst Wnt11-R, which is expressed later, also signals through the non-canonical pathway to promote heart development. It is unclear which Frizzled proteins mediate these interactions. Frizzled-7 (fzd7) is expressed during gastrulation in the mesodermal cells fated to become heart, and then in the primary heart field. This expression is complementary to the expression of wnt11 and wnt11-R We further show co-localisation of fzd7 with other early- and late-heart-specific markers using double in situ hybridisation. We have used loss of function analysis to determine the role of fzd7 during heart development. Morpholino antisense oligonucleotide-mediated knockdown of Fzd7 results in effects on heart development, similar to that caused by Wnt11 loss of function. Surprisingly, overexpression of dominant-negative Fzd7 cysteine rich domain (Fzd7 CRD) results in a cardia bifida phenotype, similar to the loss of wnt11-R phenotype. Overexpression of Fzd7 and activation of non-canonical wnt signalling can rescue the effect of Fzd7 CRD. We propose that Fzd7 has an important role during Xenopus heart development.


Dynamics of equilibrium folding and unfolding transitions of titin immunoglobulin domain under constant forces.
The mechanical stability of force-bearing proteins is crucial for their functions. However, slow transition rates of complex protein domains have made it challenging to investigate their equilibrium force-dependent structural transitions. Using ultra stable magnetic tweezers, we report the first equilibrium single-molecule force manipulation study of the classic titin I27 immunoglobulin domain. We found that individual I27 in a tandem repeat unfold/fold independently. We obtained the force-dependent free energy difference between unfolded and folded I27 and determined the critical force (∼5.4 pN) at which unfolding and folding have equal probability. We also determined the force-dependent free energy landscape of unfolding/folding transitions based on measurement of the free energy cost of unfolding. In addition to providing insights into the force-dependent structural transitions of titin I27, our results suggest that the conformations of titin immunoglobulin domains can be significantly altered during low force, long duration muscle stretching.


Mitigating Cybersecurity Risks.
Cybersecurity issues and their impact on compliance with the Health Insurance Portability and Accountability Act (HIPAA) and the Health Information Technology for Economic and Clinical Health (HITECH) Act are becoming more of an enforcement focus for a variety of government agencies, including the US Department of Health and Human Services, the Federal Trade Commission, and the Department of Justice. In the case presented in this article, a nurse in a neurology practice opted to speak with a patient about human immunodeficiency virus testing procedures in a manner audible to others in the waiting room. Computer screens with patient information were visible to anyone approaching a desk, the staff had not been trained on cybersecurity issues, and malware infected the computers used in the practice. In light of these circumstances and the launch of Phase 2 of the HIPAA Audit Program by the US Department of Health and Human Services Office for Civil Rights, the neurology practice must consider the following questions. First, could the gaps in the technical, administrative, and physical requirements of HIPAA and the HITECH Act result in an adverse audit and penalties? Second, what course of action does the law mandate in response to a ransomware attack?


Advantages of rhythmic movements at resonance: minimal active degrees of freedom, minimal noise, and maximal predictability.
Using time delay embedding, the authors applied phase space reconstruction to the time series of rhythmic movements of a hand-held pendulum. Subjects (N = 6) produced the manual oscillations about the wrist at the pendulum's resonant frequency and at a higher and a lower frequency. The number of active degrees of freedom required to capture the dynamics of the rhythmic behavior was 3 for the resonant frequency and 4 for each of the nonresonant frequencies. The residual high-dimensional noise was similarly lowest for the resonant frequency. Whereas 33% and 20%, respectively, of the vectors in the phase spaces of the dynamics higher and lower than resonance were unpredictable, only 12% were unpredictable at resonance. Finally, the predictability of the evolving dynamics extended farther into the future for oscillations at the resonant frequency. At resonance, the prediction horizon was 5 times farther than the prediction horizon for the higher than resonance behavior and 2.5 times farther than that for the lower than resonance behavior. The results suggest that, in pendular oscillations of a limb or limb segment, attunement of the central nervous system to the resonant frequency minimizes the variables to be controlled and maximizes the predictability of the rhythmic movement's chaotic dynamics.


PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.
Unabated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1β production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.