First Report of Fusarium redolens as a Causal Agent of Aleppo Pine Damping-Off in Algeria.
Aleppo pine (Pinus halepensis Mill.) is a common native coniferous tree in the natural forests of the Mediterranean region. In 2008 and 2009, a survey of Aleppo pine seedling diseases was performed in three forest nurseries from Relizane, Sidi Bel Abbes, and Tlemcen departments in northwestern Algeria. Aleppo pine seedlings showed symptoms of pre- and post-emergence damping-off, resulting in severe crop losses. The problem was widespread with a disease incidence of 64 to 77%. Fusarium redolens Wollenw. was isolated from Relizane and Sidi Bel Abbes forest nurseries. Disinfested root and root collar segments, approximately 5 mm in length, were cultured on potato dextrose agar (PDA) and incubated at 25°C. Morphological identification was done according to Fusarium keys (2). PDA colonies consisted of flat mycelium with sparse white aerial hyphae. Macroconidia with three to five septa, 24 to 43.8 μm long, widest upper third, hooked apical cell, and foot shaped basal cell were observed. Microconidia with zero to one septa, 6.8 to 10.4 μm long, oval to cylindrical, and produced on monophialides were also observed. Chlamydospores were produced abundantly in terminal and intercalary chains, in 3- to 4-week-old cultures. To confirm the identity of the fungus, the internal transcribed spacer (ITS) of F5RS3, F91SR, F55RS1, F8RS3, and F09SS1 isolates of F. redolens were amplified and sequenced using ITS 1 and ITS 4 primers (3). GenBank Accession Nos. are JX051323 to 26, and JX114783, respectively. Those sequences bore 99% (JF311916) and 100% (U34565) similarity with sequences of F. redolens in GenBank. A Fusarium pathogenicity assay was used to complete Koch's postulates. Inoculum was produced by adding a 5 mm diam. agar disc from a 7-day-old CMA petri dish culture to a previously sterilized 500 ml flask (237.5 g of sand, 12.5 g of cornmeal, and 80 ml of deionized H2O). Isolates were allowed to colonize the medium for 9 days, and flasks were shaken every day. The inoculum was mixed with sterile soil at a rate of 3:1 (v:v). Infested soil was then transferred to 500 ml pots, and 10 Aleppo pine seeds were planted. A completely randomized design was used with three replicates. After 1 month, all tested isolates caused typical damping-off symptoms on seedlings. The percentage of the inoculated plants that became infected was 53 to 91%. To our knowledge, this is the first report of F. redolens being pathogenic on Aleppo pine in northwestern Algeria and throughout the world. In Algeria, F. redolens has been reported on tomato (Solanum lycopersicum L.) (1), suggesting that it is adapted to the conditions of this area and could become a major threat to regional plant production. The annual economic impact of this disease was estimated at approximately US$50,000 per forest nursery. References: (1) N. Hamini-Kadar et al. New Dis. Rep. 22:3, 2010. (2) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Ames, Iowa, 2006. (3) T. J. White et al. Pages 315-322 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Allobranchiibius huperziae gen. nov., sp. nov., a member of Dermacoccaceae isolated from the root of a medicinal plant Huperzia serrata (Thunb.).
A Gram-stain-positive, non-spore-forming actinobacterial strain, designated CPCC 204077T, was isolated from the surface-sterilized root of a medicinal plant Huperzia serrata (Thunb.) collected from Sichuan Province, south-west China. The peptidoglycan type of strain CPCC 204077T was detected as A4α with an l-Lys-l-Ser-d-Asp interpeptide bridge. Galactose, glucose, rhamnose and ribose were the sugar compositions in the whole-cell hydrolysates. MK-8(H4) was the only menaquinone. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, one unidentified phospholipid and one unidentified glycolipid. The major fatty acid was iso-C16 : 0. The genomic DNA G+C content was 71.0 mol%. The phylogenetic tree based on 16S rRNA gene sequences showed that strain CPCC 204077T stood for a distinct lineage within the family Dermacoccaceaealongside the genera Branchiibius, Demetria and Barrientosiimonas, with the highest 16S rRNA gene sequence similarities to Branchiibius hedensis Mer 29717T (95.0 %), Calidifontibacter indicus PC IW02T (95.0 %), Barrientosiimonas humi 39T (94.9 %) and Demetria terragena HKI 0089T (94.7 %), and less than 94.7 % sequence similarities to all other species. Signature nucleotides in the 16S rRNA sequence showed that the strain contained the Dermacoccaceaefamily-specific 16S rRNA signature nucleotides and a genus-specific diagnostic nucleotide signature pattern. Combining the genotypic and phenotypic analyses, we propose that strain CPCC 204077T represents a novel species of a new genus in the family Dermacoccaceae with the name Allobranchiibius huperziae gen. nov., sp. nov. Strain CPCC 204077T (=NBRC 110719T=DSM 29531T) is the type strain of the type species.


Plasticity of subcortical pathways promote recovery of skilled hand function in rats after corticospinal and rubrospinal tract injuries.
The corticospinal and rubrospinal tracts are the predominant tracts for controlling skilled hand function. Injuries to these tracts impair grasping but not gross motor functions such as overground locomotion. The aim of the present study was to determine whether or not, after damage to both the corticospinal and rubrospinal tracts, other spared subcortical motor pathway can mediate the recovery of skilled hand function. Adult rats received a bilateral injury to the corticospinal tract at the level of the medullar pyramids and a bilateral ablation of the rubrospinal axons at C4. One group of rats received, acutely after injury, two injections of chondroitinase-ABC at C7, and starting at 7days post-injury were enrolled in daily reaching and grasping rehabilitation (CHASE group, n=5). A second group of rats received analogous injections of ubiquitous penicillinase, and did not undergo rehabilitation (PEN group, n=5). Compared to rats in the PEN group, CHASE rats gradually recovered the ability to reach and grasp over 42days after injury. Overground locomotion was mildly affected after injury and both groups followed similar recovery. Since the reticulospinal tract plays a predominant role in motor control, we further investigated whether or not plasticity of this pathway could contribute to the animal's recovery. Reticulospinal axons were anterogradely traced in both groups of rats. The density of reticulospinal processes in both the normal and ectopic areas of the grey ventral matter of the caudal segments of the cervical spinal cord was greater in the CHASE than PEN group. The results indicate that after damage to spinal tracts that normally mediate the control of reaching and grasping in rats other complementary spinal tracts can acquire the role of those damaged tracts and promote task-specific recovery.


Boiler: lossy compression of RNA-seq alignments using coverage vectors.
We describe Boiler, a new software tool for compressing and querying large collections of RNA-seq alignments. Boiler discards most per-read data, keeping only a genomic coverage vector plus a few empirical distributions summarizing the alignments. Since most per-read data is discarded, storage footprint is often much smaller than that achieved by other compression tools. Despite this, the most relevant per-read data can be recovered; we show that Boiler compression has only a slight negative impact on results given by downstream tools for isoform assembly and quantification. Boiler also allows the user to pose fast and useful queries without decompressing the entire file. Boiler is free open source software available from github.com/jpritt/boiler.


Neuroprotective effects of acetyl-L-carnitine on neuropathic pain and apoptosis: a role for the nicotinic receptor.
Several pathologies related to nervous tissue alterations are characterized by a chronic pain syndrome defined by persistent or paroxysmal pain independent or dependent on a stimulus. Pathophysiological mechanisms related to neuropathic disease are associated with mitochondrial dysfunctions that lead to an activation of the apoptotic cascade. In a model of peripheral neuropathy obtained by the loose ligation of the rat sciatic nerve, acetyl-L-Carnitine (ALCAR; 100 mg/kg intraperitoneally [i.p.] twice daily for 14 days) was able to reduce hyperalgesia and apoptosis. In the present study, different mechanisms for the analgesic and the antineuropathic effect of ALCAR are described. The muscarinic blocker atropine (5 mg/kg i.p.) injected simultaneously with ALCAR did not antagonize the ALCAR antihyperalgesic effect on the paw-pressure test but significantly reduced the analgesic effect of ALCAR. Conversely, the antineuropathic effect of ALCAR was prevented by cotreatment with the nicotinic antagonist mecamylamine (2 mg/kg i.p. twice daily for 14 days). A pharmacological silencing of the nicotinic receptors significantly reduced the X-linked inhibitor of apoptosis protein-related protective effect of ALCAR on the apoptosis induced by ligation of the sciatic nerve. Taken together, these data highlight the relevance of nicotinic modulation in neuropathy treatment.


One Hundred Years of Psychiatry at Johns Hopkins: A Story of Meyer to McHugh.
This article describes a history of clinical methods and constructs that guide Psychiatry at Johns Hopkins Phipps Clinic today. The contributions of Adolf Meyer and Paul McHugh are central and closely connected. Both emphasize the clinical examination as the central practice of psychiatry as a specialty within medicine. Meyer's comprehensive examination of the patient became the centerpiece of his approach and was the standard for psychiatrists in the English-speaking world. McHugh, with Phillip Slavney, developed a pluralistic and practical framework for interpreting that history and examination. Both argued against the uncritical use of the modern disease construct. McHugh argues that the disease construct, although fundamental, is but one of four useful "perspectives of psychiatry" and is, thus, an insufficient basis for psychiatric practice. The perspectives could be used as an organizing framework by all physicians who seek a practical and truly personalized approach to the care of patients.


Symmetry as a new element to control molecular switches.
The isomerization properties of an azocarbazole macrocycle in solution were investigated utilizing NMR spectroscopy with in situ irradiation in combination with DFT calculations. It was demonstrated that the position of azo units in a rigid macrocyclic system influences the photoisomerization pathway even if the initial all-E isomer is highly symmetric. Furthermore, the effect of ring strain on lowering the rates of thermal isomerization was demonstrated and a mechanism via an inversion-rotation proposed. The herein presented results and methods give new insights into the general nature of the azobenzene unit. In particular we illustrate the effect of symmetry changes due to macrocyclic arrangement on the photochemical and thermal isomerization properties, which will stimulate future development towards multinary molecular switches.


Characterization of the first cultured representative of Verrucomicrobia subdivision 5 indicates the proposal of a novel phylum.
The recently isolated strain L21-Fru-ABT represents moderately halophilic, obligately anaerobic and saccharolytic bacteria that thrive in the suboxic transition zones of hypersaline microbial mats. Phylogenetic analyses based on 16S rRNA genes, RpoB proteins and gene content indicated that strain L21-Fru-ABT represents a novel species and genus affiliated with a distinct phylum-level lineage originally designated Verrucomicrobia subdivision 5. A survey of environmental 16S rRNA gene sequences revealed that members of this newly recognized phylum are wide-spread and ecologically important in various anoxic environments ranging from hypersaline sediments to wastewater and the intestine of animals. Characteristic phenotypic traits of the novel strain included the formation of extracellular polymeric substances, a Gram-negative cell wall containing peptidoglycan and the absence of odd-numbered cellular fatty acids. Unusual metabolic features deduced from analysis of the genome sequence were the production of sucrose as osmoprotectant, an atypical glycolytic pathway lacking pyruvate kinase and the synthesis of isoprenoids via mevalonate. On the basis of the analyses of phenotypic, genomic and environmental data, it is proposed that strain L21-Fru-ABT and related bacteria are specifically adapted to the utilization of sulfated glycopolymers produced in microbial mats or biofilms.


Innovative UVC light (185 nm) and radio-frequency-plasma pretreatment of Nylon surfaces at atmospheric pressure and their implications in photocatalytic processes.
Innovative pretreatment by UVC light (185 nm) and by radio-frequency (RF) plasma at atmospheric pressure to functionalize the Nylon surface, increasing its bondability toward TiO(2), is reported in this study. In the case of UVC light pretreatment in air, the molar absorption coefficient of O(2)/N(2) at 185 nm is very low and the air in the chamber absorbs very little light from the UVC source before reaching the Nylon sample. Nylon fabrics under RF plasma were also functionalized at atmospheric pressure because of the marked heating effect introduced in the Nylon by the RF plasma. This effect leads to intermolecular bond breaking and oxygenated surface groups in the topmost Nylon layers. Both pretreatments enhanced significantly the photocatalytic discoloration of the red-wine stain in Nylon-TiO(2) compared with samples without pretreatment. The UVC and RF methods in the absence of vacuum imply a considerable cost reduction to functionalize textile surfaces, suggesting a potential industrial application. Red-wine-stain discoloration under simulated sunlight was monitored quantitatively by diffuse-reflectance spectroscopy and by CO(2) evolution. X-ray photoelectron spectroscopy (XPS) was used to monitor the changes of the C, N, and S species on the Nylon topmost layers during the discoloration process. Significant changes in the XPS spectra of Ti 2p peaks were observed during discoloration of the wine spots. Wine stains attenuated the signal of the Ti 2p (458.4 eV) peak in the Nylon-TiO(2)-stained wine sample at time zero (from now on, the time before the discoloration process). Furthermore, a decrease of the wine-related O 1s signal at 529.7 eV and N 1s signal at 399.5 eV was observed during the discoloration process, indicating an efficient catalytic decomposition of the wine pigment on Nylon-TiO(2). X-ray diffraction detected the formation of anatase on the Nylon fibers. High-resolution transmission electron microscopy shows the formation of anatase particles with sizes between 8 and 20 nm.


Activation of Dioxygen at a Lewis Acidic Nickel(II) Complex: Characterization of a Metastable Organoperoxide Complex.
In metal-mediated O2 activation, nickel(II) compounds hardly play a role, but recently it has been shown that enzymes can use nickel(II) for O2 activation. Now a low-coordinate Lewis acidic nickel(II) complex has been synthesized that reacts with O2 to give a nickel(II) organoperoxide, as proposed for the enzymatic system. Its formation was studied further by UV/Vis absorption spectroscopy, leading to the observation of a short-lived intermediate that proved to be reactive in both oxygen atom transfer and hydrogen abstraction reactions, while the peroxide efficiently transfers O atoms. Both for the enzyme and for the functional model, the key to O2 activation is proposed to represent a concomitant electron shift from the substrate/co-ligand.


A multimodal dataset of spontaneous speech and movement production on object affordances.
In the longstanding effort of defining object affordances, a number of resources have been developed on objects and associated knowledge. These resources, however, have limited potential for modeling and generalization mainly due to the restricted, stimulus-bound data collection methodologies adopted. To-date, therefore, there exists no resource that truly captures object affordances in a direct, multimodal, and naturalistic way. Here, we present the first such resource of 'thinking aloud', spontaneously-generated verbal and motoric data on object affordances. This resource was developed from the reports of 124 participants divided into three behavioural experiments with visuo-tactile stimulation, which were captured audiovisually from two camera-views (frontal/profile). This methodology allowed the acquisition of approximately 95 hours of video, audio, and text data covering: object-feature-action data (e.g., perceptual features, namings, functions), Exploratory Acts (haptic manipulation for feature acquisition/verification), gestures and demonstrations for object/feature/action description, and reasoning patterns (e.g., justifications, analogies) for attributing a given characterization. The wealth and content of the data make this corpus a one-of-a-kind resource for the study and modeling of object affordances.


Does early-onset chronic or recurrent major depression impact outcomes with antidepressant medications? A CO-MED trial report.
Prior studies have suggested that major depressive disorder (MDD) with pre-adult onset represents a distinct subtype with greater symptom severity and higher rates of suicidal ideation. Whether these patients have poorer response to various types of antidepressant treatment than those with adult-onset MDD is unclear. Method A total of 665 psychiatric and primary care out-patients (aged 18-75 years) with non-psychotic chronic or recurrent MDD participated in a single-blind, randomized trial that compared the efficacy of escitalopram plus placebo, bupropion sustained-release plus escitalopram, or venlafaxine extended-release plus mirtazapine. We compared participants who self-reported MDD onset (before age 18) to those with a later onset (adult onset) with respect to baseline characteristics and treatment/outcome variables at 12 and 28 weeks. Early-onset chronic/recurrent MDD was associated with a distinct set of sociodemographic (female, younger age) and clinical correlates (longer duration of illness, greater number of prior episodes, greater likelihood of atypical features, higher rates of suicidality and psychiatric co-morbidity, fewer medical problems, poorer quality of life, greater history of child abuse/neglect). However, results from unadjusted and adjusted analyses showed no significant differences in response, remission, tolerability of medications, quality of life, or retention at 12 or 28 weeks. Although early-onset chronic/recurrent MDD is associated with a more severe clinical picture, it does not seem to be useful for predicting differential treatment response to antidepressant medication. Clinicians should remain alert to an increased risk of suicidality in this population.


Antigen-presenting genes and genomic copy number variations in the Tasmanian devil MHC.
The Tasmanian devil (Sarcophilus harrisii) is currently under threat of extinction due to an unusual fatal contagious cancer called Devil Facial Tumour Disease (DFTD). DFTD is caused by a clonal tumour cell line that is transmitted between unrelated individuals as an allograft without triggering immune rejection due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Here we report the characterization of the genomic regions encompassing MHC Class I and Class II genes in the Tasmanian devil. Four genomic regions approximately 960 kb in length were assembled and annotated using BAC contigs and physically mapped to devil Chromosome 4q. 34 genes and pseudogenes were identified, including five Class I and four Class II loci. Interestingly, when two haplotypes from two individuals were compared, three genomic copy number variants with sizes ranging from 1.6 to 17 kb were observed within the classical Class I gene region. One deletion is particularly important as it turns a Class Ia gene into a pseudogene in one of the haplotypes. This deletion explains the previously observed variation in the Class I allelic number between individuals. The frequency of this deletion is highest in the northwestern devil population and lowest in southeastern areas. The third sequenced marsupial MHC provides insights into the evolution of this dynamic genomic region among the diverse marsupial species. The two sequenced devil MHC haplotypes revealed three copy number variations that are likely to significantly affect immune response and suggest that future work should focus on the role of copy number variations in disease susceptibility in this species.


Can video consultations replace face-to-face interviews? Palliative medicine and the Covid-19 pandemic: rapid review.
During the Covid-19 pandemic, a strategy to minimise face-to-face (FtF) visits and limit viral spread is essential. Video consultations offer clinical assessment despite restricted movement of people.We undertook a rapid literature review to identify the highest currently available level of evidence to inform this major change in clinical practice. We present a narrative synthesis of the one international and one national guideline and two systematic reviews-all published within the last 18 months.The global evidence appears to support video consultations as an effective, accessible, acceptable and cost-effective method of service delivery. Organisations must ensure software is simple, effective, reliable and safe, with the highest level of security for confidentiality.Although video consultations cannot fully replace FtF, they can radically reduce the need for FtF and the risk of Covid-19 spread in our communities while maintaining high standards of care. For patient safety, it will be critical to follow the WHO guidance regarding: a standard operating procedure; clinical protocols for when video consultations can (and cannot) be used; policies to ensure equity of access in disadvantaged populations; adequate staff training; and administrative support to coordinate appointments.


En Bloc Resection of Solitary Functional Secreting Spinal Metastasis.
Study Design Literature review. Objective Functional secretory tumors metastatic to the spine can secrete hormones, growth factors, peptides, and/or molecules into the systemic circulation that cause distinct syndromes, clinically symptomatic effects, and/or additional morbidity and mortality. En bloc resection has a limited role in metastatic spine disease due to the current paradigm that systemic burden usually determines morbidity and mortality. Our objective is to review the literature for studies focused on en bloc resection of functionally active spinal metastasis as the primary indication. Methods A review of the PubMed literature was performed to identify studies focused on functional secreting metastatic tumors to the spinal column. We identified five cases of patients undergoing en bloc resection of spinal metastases from functional secreting tumors. Results The primary histologies of these spinal metastases were pheochromocytoma, carcinoid tumor, choriocarcinoma, and a fibroblast growth factor 23-secreting phosphaturic mesenchymal tumor. Although studies of en bloc resection for these rare tumor subtypes are confined to case reports, this surgical treatment option resulted in metabolic cures and decreased clinical symptoms postoperatively for patients diagnosed with solitary functional secretory spinal metastasis. Conclusion Although the ability to formulate comprehensive conclusions is limited, case reports demonstrate that en bloc resection may be considered as a potential surgical option for the treatment of patients diagnosed with solitary functional secretory spinal metastatic tumors. Future prospective investigations into clinical outcomes should be conducted comparing intralesional resection and en bloc resection for patients diagnosed with solitary functional secretory spinal metastasis.


Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis.
Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy. A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6 ± 0.3 years) compared to C9N ALS (3.8 ± 0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5 ± 1.3 words/year) than C9N FTLD (1.4 ± 0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD.


Differences in essential newborn care at birth between private and public health facilities in eastern Uganda.
In Uganda and elsewhere, the private sector provides an increasing and significant proportion of maternal and child health services. However, little is known whether private care results in better quality services and improved outcomes compared to the public sector, especially regarding care at the time of birth. To describe the characteristics of care-seekers and assess newborn care practices and services received at public and private facilities in rural eastern Uganda. Within a community-based maternal and newborn care intervention with health systems strengthening, we collected data from mothers with infants at baseline and endline using a structured questionnaire. Descriptive, bivariate, and multivariate data analysis comparing nine newborn care practices and three composite newborn care indicators among private and public health facilities was conducted. The proportion of women giving birth at private facilities decreased from 25% at baseline to 17% at endline, whereas overall facility births increased. Private health facilities did not perform significantly better than public health facilities in terms of coverage of any essential newborn care interventions, and babies were more likely to receive thermal care practices in public facilities compared to private (68% compared to 60%, p=0.007). Babies born at public health facilities received an average of 7.0 essential newborn care interventions compared to 6.2 at private facilities (p<0.001). Women delivering in private facilities were more likely to have higher parity, lower socio-economic status, less education, to seek antenatal care later in pregnancy, and to have a normal delivery compared to women delivering in public facilities. In this setting, private health facilities serve a vulnerable population and provide access to service for those who might not otherwise have it. However, provision of essential newborn care practices was slightly lower in private compared to public facilities, calling for quality improvement in both private and public sector facilities, and a greater emphasis on tracking access to and quality of care in private sector facilities.


Pro-inflammatory responses induced by A. fumigatus and A. versicolor in various human macrophage models.
Exposure to mold-contaminated indoor air has been associated with various respiratory diseases, and there is a need for experimental data to confirm these associations. The pro-inflammatory properties of well-characterized aerosolized spores and hyphal fragments from Aspergillus fumigatus and Aspergillus versicolor were examined and compared using various human macrophage cell models including phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages (THP-1 Ma), primary peripheral blood monocyte-derived macrophages (MDM), and primary airway macrophages (AM) from induced sputum. X-ray treated samples of the two mold species induced different responses with A. fumigatus displaying the most potent induction of pro-inflammatory responses. While hyphal fragments from A. fumigatus were more potent than spores, similar responses were produced by the two growth stages of A. versicolor. THP-1 Ma was the most sensitive model releasing a broad range of cytokines/chemokines. MDM exhibited a similar cytokine/chemokine profile as THP-1 Ma, except for a low-quantity release of interleukin-1β (IL-1β). In contrast, AM appeared to be nonresponsive and yielded a different pattern of pro-inflammatory markers. Toll-like receptor (TLR)4, but also to a certain degree TLR2, was involved in several responses induced by spores and aerosolized hyphal fragments of A. fumigatus in MDM. Taken together, MDM seems to be the most promising experimental macrophage model. Abbreviations: AF: A. fumigatus, Aspergillus fumigatus; AV: A. versicolor, Aspergillus versicolor; AM: Airway Macrophage; CBA: Cytometric Bead Array; CD: Cluster of Differentiation; DTT: dithiothreitol; ELISA: Enzyme Linked Immunosorbent Assay; FBS: fetal bovine serum; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-1β: Interleukin-1beta; MDM: Monocyte-Derived Macrophages; NF-κB: Nuclear Factor kappa light chain enhancer of activated B cells; NLR: NOD-like Receptor; PAMP: Pathogen Associated Molecular Pattern; PMA: Phorbol 12-myristate 13-acetate; PRR: Pattern Recognition Receptor; THP-1: Human leukemia monocyte cell line; TLR: Toll-like Receptor; TNF-α: Tumor Necrosis Factor- alpha.


Trends in cancer mortality in Brazil, 1980-2004.
Scanty information, limited to selected areas of the country, is available on cancer mortality in Brazil. Age-standardized (world population) mortality rates between 1980 and 2004, derived from the WHO database, were computed for all cancers and 24 major cancer sites in Brazil. Joinpoint regression analyses were used to identify the significant changes in trends and estimate annual percent change (APC) in rates. Total cancer mortality rates increased over the last decade in men (APC = 0.5) to reach 101.2/100 000, and in women (APC = 0.3) to reach 71.3/100 000. In men, upward trends were observed for cancers of the oral cavity and pharynx with a rate of 5.9/100 000 in 2000-2004, intestines (whose rate, however was low, i.e. 7.6), prostate (12.2), and leukemias (3.4). Male lung cancer increased until 1993 (APC = 1.39) and decreased thereafter (APC = -0.29), with a relatively low rate of 16.2/100 000 in 2000-2004. In women, there were steady upward trends for cancers of the lung (APC = 2.3), reaching 6.2/100 000 in 2000-2004, and leukemias (2.5). Breast cancer mortality leveled off at around 10/100 000 in the last decade, whereas declines were observed for cancers of the uterus, whose rate (8.3) however, remained comparatively high. Declines were observed for stomach cancer in both sexes, with rates of 11.1 in men and 4.6 in women. In conclusion, the key issues of cancer mortality in Brazil are the high rates of head and neck cancers in men and (cervix) uterine cancer in women, that is, in principle cancers that are largely avoidable through prevention, screening, and early diagnosis.


Contributions Of Public Health, Pharmaceuticals, And Other Medical Care To US Life Expectancy Changes, 1990-2015.
Life expectancy in the US increased 3.3 years between 1990 and 2015, but the drivers of this increase are not well understood. We used vital statistics data and cause-deletion analysis to identify the conditions most responsible for changing life expectancy and quantified how public health, pharmaceuticals, other (nonpharmaceutical) medical care, and other/unknown factors contributed to the improvement. We found that twelve conditions most responsible for changing life expectancy explained 2.9 years of net improvement (85 percent of the total). Ischemic heart disease was the largest positive contributor to life expectancy, and accidental poisoning or drug overdose was the largest negative contributor. Forty-four percent of improved life expectancy was attributable to public health, 35 percent was attributable to pharmaceuticals, 13 percent was attributable to other medical care, and -7 percent was attributable to other/unknown factors. Our findings emphasize the crucial role of public health advances, as well as pharmaceutical innovation, in explaining improving life expectancy.


On the sensitization of Eu3+ with Ce3+ and Tb3+ by composite structured Ca2LuHf2Al3O12 garnet phosphors for blue LED excitation.
This work deals with the photoluminescence of various composite structured Ca2LuHf2Al3O12 garnet type LED phosphors. It is well known that sensitization of Eu3+ with Ce3+ suffers from metal-to-metal charge transfer (MMCT) quenching. Spatial separation of the sensitizer and activator results in a reduced quenching mechanism and thus higher luminescence intensities, when Ce3+ is excited in the blue spectral range and transfers its energy to Eu3+. The phosphor particles were prepared via different synthesis techniques. The phase purity of the synthesized particles was determined by X-ray powder diffraction. Scanning electron microscopy images were obtained to study the particle morphology and composite formation. Photoluminescence properties were determined by recording the emission spectra, excitation spectra and diffuse reflectance spectra. Furthermore, the temperature dependent emission spectra and fluorescence lifetimes were recorded to compare thermal quenching and decay behavior of the samples. External quantum efficiencies (EQEs) were calculated to examine the MMCT quenching behavior. Since the EQE of Ca2LuHf2Al3O12:Ce3+,Tb3+,Eu3+ is lower than 1%, it could be demonstrated that the composite approach significantly increases the EQE due to the spatial separation of Ce3+ and Eu3+.


A survey of veterinarian involvement in zoonotic disease prevention practices.
To determine the extent to which practicing veterinarians in King County, Washington, engaged in commonly recommended practices for the prevention of zoonotic diseases. Cross-sectional survey. Sample Population-Licensed veterinarians practicing clinical medicine in King County, Washington. A survey was sent between September and November 2006 to 454 licensed veterinarians practicing clinical medicine in King County. 370 valid responses were received. A high proportion (280/362 [77%]) of respondents agreed that it was very important for veterinarians to educate clients on zoonotic disease prevention, but only 43% (158/367) reported that they had initiated discussions about zoonotic diseases with clients on a daily basis, and only 57% (203/356) indicated that they had client educational materials on zoonotic diseases available in their practices. Thirty-one percent (112/360) of respondents indicated that there were no written infection-control guidelines for staff members in the practice, and 28% (105/371) reported having been infected with a zoonotic disease in practice. Results illustrated that veterinarians recognize their important role in zoonotic disease prevention and suggested that veterinarians would welcome stronger partnerships with public health agencies and other health professionals in this endeavor. Methods to increase veterinarians' involvement in zoonotic disease prevention include discussing zoonotic diseases more frequently with clients, physicians, and public health agencies; encouraging higher risk individuals to discuss zoonotic diseases; having educational materials on zoonotic diseases available for clients; improving infection-control practices; and ensuring that continuing education courses on zoonotic diseases are regularly available.


Combining genetic crosses and pool targeted DNA-seq for untangling genomic variations associated with resistance to multiple insecticides in the mosquito Aedes aegypti.
In addition to combating vector-borne diseases, studying the adaptation of mosquitoes to insecticides provides a remarkable example of evolution-in-action driving the selection of complex phenotypes. Actually, most resistant mosquito populations show multi-resistance phenotypes as a consequence of the variety of insecticides employed and of the complexity of selected resistance mechanisms. Such complexity makes the identification of alleles conferring resistance to specific insecticides challenging and prevents the development of molecular assays to track them in the field. Here we showed that combining simple genetic crosses with pool targeted DNA-seq can enhance the specificity of resistance allele's detection while maintaining experimental work and sequencing effort at reasonable levels. A multi-resistant population of the mosquito Aedes aegypti was exposed to three distinct insecticides (deltamethrin, bendiocarb and fenitrothion), and survivors to each insecticide were crossed with a susceptible strain to generate three distinct lines. F2 individuals from each line were then segregated based on their survival to two insecticide doses. Hundreds of genes covering all detoxifying enzymes and insecticide targets together with more than 7,000 intergenic regions equally spread over mosquito genome were sequenced from pools of F0 and F2 individuals unexposed or surviving insecticide. Differential coverage analysis identified 39 detoxification enzymes showing an increased gene copy number in association with resistance. Combining an allele frequency filtering approach with a Bayesian F ST-based genome scan identified multiple genomic regions showing strong selection signatures together with 50 nonsynonymous variations associated with resistance. This study provides a simple and cost-effective approach to improve the specificity of resistance allele's detection in multi-resistant populations while reducing false positives frequently arising when comparing populations showing divergent genetic backgrounds. The identification of novel DNA resistance markers opens new opportunities for improving the tracking of insecticide resistance in the field.


Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.
Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE(-/-) mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE(-/-) mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.


TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation.
CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4(+) T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4(+) T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4(+) T cell responses that produce normal levels of interferon gamma, suggesting a CD40L/CD40-independent mechanism of CD4(+) T cell priming that to date has not been elucidated. Here we show that CD4(+) T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4(+) T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4(+) T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention.


Experimental parameter estimation method for nonlinear viscoelastic composite material models: an application on arterial tissue.
This study is aimed at setting a method of experimental parameter estimation for large-deforming nonlinear viscoelastic continuous fibre-reinforced composite material model. Specifically, arterial tissue was investigated during experimental research and parameter estimation studies, due to medical, scientific and socio-economic importance of soft tissue research. Using analytical formulations for specimens under combined inflation/extension/torsion on thick-walled cylindrical tubes, in vitro experiments were carried out with fresh sheep arterial segments, and parameter estimation procedures were carried out on experimental data. Model restrictions were pointed out using outcomes from parameter estimation. Needs for further studies that can be developed are discussed.


Synaesthesia lost and found: two cases of person- and music-colour synaesthesia.
Synaesthesia is a developmental condition involving cross-communication between sensory modalities or substreams whereby an inducer (e.g. a sound) automatically evokes a concurrent percept in another modality (e.g. a colour). Whether this condition arises due to atypical structural connectivity (e.g., between normally unconnected cortical areas) or altered neurochemistry remains a central question. We report the exceptional cases of two synaesthetes - subjects AB and CD - both of whom experience coloured auras around individuals, as well as coloured perceptions in response to music. Both subjects have, in recent years, suffered a complete loss or reduction of their synaesthetic experiences, one (AB) through successive head traumas, including a lightning strike, followed by a number of medications, and the other (CD) while taking anxiolytic medications. Using semi-structured interviews and data from the Synaesthesia Battery and a colourpicker task, we characterize the phenomenological characteristics of their pre-loss synaesthesia, as well as the subsequent restoration of each subject's synaesthetic experiences (in the months post-trauma for AB, and after cessation of medication for CD). Even after years of suppression, the patterns of associations were highly consistent with those experienced pre-injury. The phenomenological experience of synaesthesia can, thus, like most conscious experiences, be modulated by pharmacologically diverse medications or head injury. However, the underlying neural substrates mediating specific synaesthetic pairings appear remarkably 'hard-wired' and can persist over very long periods even under conditions that alter or completely suppress the conscious synaesthetic experience itself.


Predicting mortality for patients with exacerbations of COPD and Asthma in the COPD and Asthma Outcome Study (CAOS).
Decisions about the intensity of treatment for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are influenced by predictions about survival and quality of life. Evidence suggests that these predictions are poorly calibrated and tend to be pessimistic. The aim of this study was to develop an outcome prediction model for COPD patients to support treatment decisions. A prospective multi-centre cohort study in Intensive Care Units (ICU) and Respiratory High Dependency Units (RHDU) in the UK recruited patients aged 45 years and older admitted with an exacerbation of obstructive lung disease. Data were collected on patients' characteristics prior to ICU admission, and on their survival and quality of life after 180 days. An outcome prediction model was developed using multivariate logistic regression and bootstrapping. Ninety-two ICUs (53% of those in the UK) and three RHDUs took part. A total of 832 patients were recruited. Cumulative 180-day mortality was 37.9%. Using data available at the time of admission to the units, a prognostic model was developed which had an estimated area under the receiver operating characteristic curve ('c') of 74.7% after bootstrapping that was more discriminating than the clinicians (P = 0.033) and was well calibrated. This study has produced an outcome prediction model with slightly better discrimination and much better calibration than the participating clinicians. It has the potential to support risk adjustment and clinical decision making about admission to intensive care.


Asymptomatic infection of the fungal pathogen Batrachochytrium salamandrivorans in captivity.
One of the most important factors driving amphibian declines worldwide is the infectious disease, chytridiomycosis. Two fungi have been associated with this disease, Batrachochytrium dendrobatidis and B. salamandrivorans (Bsal). The latter has recently driven Salamandra salamandra populations to extirpation in parts of the Netherlands, and Belgium, and potentially also in Germany. Bsal has been detected in the pet trade, which has been hypothesized to be the pathway by which it reached Europe, and which may continuously contribute to its spread. In the present study, 918 amphibians belonging to 20 captive collections in Germany and Sweden were sampled to explore the extent of Bsal presence in captivity. The fungus was detected by quantitative Polymerase Chain Reaction (qPCR) in ten collections, nine of which lacked clinical symptoms. 23 positives were confirmed by independent processing of duplicate swabs, which were analysed in a separate laboratory, and/or by sequencing ITS and 28 S gene segments. These asymptomatic positives highlight the possibility of Bsal being widespread in captive collections, and is of high conservation concern. This finding may increase the likelihood of the pathogen being introduced from captivity into the wild, and calls for according biosecurity measures. The detection of Bsal-positive alive specimens of the hyper-susceptible fire salamander could indicate the existence of a less aggressive Bsal variant or the importance of environmental conditions for infection progression.


Highlights of the Didymellaceae: A polyphasic approach to characterise Phoma and related pleosporalean genera.
Fungal taxonomists routinely encounter problems when dealing with asexual fungal species due to poly- and paraphyletic generic phylogenies, and unclear species boundaries. These problems are aptly illustrated in the genus Phoma. This phytopathologically significant fungal genus is currently subdivided into nine sections which are mainly based on a single or just a few morphological characters. However, this subdivision is ambiguous as several of the section-specific characters can occur within a single species. In addition, many teleomorph genera have been linked to Phoma, three of which are recognised here. In this study it is attempted to delineate generic boundaries, and to come to a generic circumscription which is more correct from an evolutionary point of view by means of multilocus sequence typing. Therefore, multiple analyses were conducted utilising sequences obtained from 28S nrDNA (Large Subunit - LSU), 18S nrDNA (Small Subunit - SSU), the Internal Transcribed Spacer regions 1 & 2 and 5.8S nrDNA (ITS), and part of the beta-tubulin (TUB) gene region. A total of 324 strains were included in the analyses of which most belonged to Phoma taxa, whilst 54 to related pleosporalean fungi. In total, 206 taxa were investigated, of which 159 are known to have affinities to Phoma. The phylogenetic analysis revealed that the current Boeremaean subdivision is incorrect from an evolutionary point of view, revealing the genus to be highly polyphyletic. Phoma species are retrieved in six distinct clades within the Pleosporales, and appear to reside in different families. The majority of the species, however, including the generic type, clustered in a recently established family, Didymellaceae. In the second part of this study, the phylogenetic variation of the species and varieties in this clade was further assessed. Next to the genus Didymella, which is considered to be the sole teleomorph of Phoma s. str., we also retrieved taxa belonging to the teleomorph genera Leptosphaerulina and Macroventuria in this clade. Based on the sequence data obtained, the Didymellaceae segregate into at least 18 distinct clusters, of which many can be associated with several specific taxonomic characters. Four of these clusters were defined well enough by means of phylogeny and morphology, so that the associated taxa could be transferred to separate genera. Aditionally, this study addresses the taxonomic description of eight species and two varieties that are novel to science, and the recombination of 61 additional taxa.


Intervention to Improve Compliance With National Guidelines on Venous Thromboembolism Chemoprophylaxis for Patients With Operatively Managed Ankle Fractures.
Background: Trauma and subsequent immobilization of the lower limb increase the risk of venous thromboembolism (VTE). Our aim was to evaluate compliance with national guidance on operatively managed ankle fractures and VTE chemoprophylaxis before and after implementation of a change in practice. Methods: We conducted an initial single-center audit of patients undergoing ankle fracture fixation. The primary outcome was quality of operation note documentation, and the secondary outcome was whether VTE chemoprophylaxis was prescribed on discharge. All stakeholders were educated on audit findings, new guidelines were synthesized, and the practice was re-audited. Results: A total of 137 patients were included in the initial audit, and 49 patients were included in the loop closure. The first audit highlighted that chemoprophylaxis prescription on discharge was significantly higher when both the agent and treatment duration were clearly stipulated in the operation note compared to when either treatment duration or both agent and treatment duration were omitted (97.2% vs 51.8% and 32.4%, respectively, P<0.001). Following our intervention, operation note documentation of agent and treatment duration improved from 29% to 90% (P<0.001). VTE chemoprophylaxis on discharge significantly improved from 57% to 98% (P<0.001). Conclusion: Our closed-loop audit identified suboptimal operation note documentation as the root cause of VTE noncompliance. The operation note is an important clinical interface between the operating theater and ward staff. We addressed these deficiencies with a basic intervention.


Efficient postprocessing technique for fabricating surface nanoscale axial photonics microresonators with subangstrom precision by femtosecond laser.
We demonstrated the subangstrom precise correction of surface nanoscale axial photonics (SNAP) micro-resonators by the femtosecond (fs) laser postprocessing technique for the first time. The internal stress can be induced by fs laser inscriptions in the fiber, causing nanoscale effective radius variation (ERV). However, the obtained ultraprecise fabrication usually undergoes multiple tries. Here, we propose a novel postprocessing technique based on the fs laser that significantly reduces the ERV errors and improves the fabrication precision without iterative corrections. The postexposure process is achieved at the original exposure locations using lower pulse energy than that in the initial fabrication process. The results show that the ERV is nearly proportional to the pulse energy of the postexposure process. The slope of the ERV versus the pulse energy is 0.07 Å/nJ. The maximum of the postprocessed ERV can reach 8.0 Å. The repeatability was experimentally verified by accomplishing the correction on three SNAP microresonators with the precision of 0.75 Å. The developed fabrication technique with fs laser enables SNAP microresonators with new breakthrough applications for optomechanics and filters.


Treating depression in nursing homes: practice guidelines in the real world.
Depression in nursing home residents is a common phenomenon, though there is a wide range in the severity of this disorder as experienced by elderly adults in the United States. Treating older patients for depression is costly in both human and financial terms. The authors review guidelines and recommendations for the diagnosis of depression and medical treatment of depressed elderly adults from the 1993 Clinical Practice Guidelines for Depression in Primary Care by the US Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality), making note also of similar guidelines provided by the American Medical Directors Association in 1996 and those provided by the American Psychiatric Association in 2000. In November 1999, the authors used a Delphi survey to gather data from prescreened panelists (N = 10) to have the panel review and clarify the importance and feasibility of each "A" rated item in the US Agency for Health Care Policy and Research guidelines. This research allows health care providers to evaluate the importance and feasibility of items related to the delivery of mental health services for the elderly in nursing homes.


Disrupted Sleep: From Molecules to Cognition.
Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of these different forms of sleep disruption show deranged physiology from subcellular levels to complex affective behavior. In keeping with the multifaceted influence of sleep on health and well-being, we illustrate how the duration of sleep, its timing, and continuity can affect cellular ultrastructure, gene expression, metabolic and hormone regulation, mood, and vigilance. Recent brain imaging studies provide some clues on mechanisms underlying the most common cause of disrupted sleep (insomnia). These insights should ultimately result in adequate interventions to prevent and treat sleep disruption because of their high relevance to our most prevalent health problems. Disruption of the duration, timing, and continuity of sleep affects cellular ultrastructure, gene expression, appetite regulation, hormone production, vigilance, and reward functions.


Cadmium Bioavailability, Uptake, Toxicity and Detoxification in Soil-Plant System.
This review summarizes the findings of the most recent studies, published from 2000 to 2016, which focus on the biogeochemical behavior of Cd in soil-plant systems and its impact on the ecosystem. For animals and people not subjected to a Cd-contaminated environment, consumption of Cd contaminated food (vegetables, cereals, pulses and legumes) is the main source of Cd exposure. As Cd does not have any known biological function, and can further cause serious deleterious effects both in plants and mammalian consumers, cycling of Cd within the soil-plant system is of high global relevance.The main source of Cd in soil is that which originates as emissions from various industrial processes. Within soil, Cd occurs in various chemical forms which differ greatly with respect to their lability and phytoavailability. Cadmium has a high phytoaccumulation index because of its low adsorption coefficient and high soil-plant mobility and thereby may enter the food chain. Plant uptake of Cd is believed to occur mainly via roots by specific and non-specific transporters of essential nutrients, as no Cd-specific transporter has yet been identified. Within plants, Cd causes phytotoxicity by decreasing nutrient uptake, inhibiting photosynthesis, plant growth and respiration, inducing lipid peroxidation and altering the antioxidant system and functioning of membranes. Plants tackle Cd toxicity via different defense strategies such as decreased Cd uptake or sequestration into vacuoles. In addition, various antioxidants combat Cd-induced overproduction of ROS. Other mechanisms involve the induction of phytochelatins, glutathione and salicylic acid.


Influence of electrolyte composition on liquid-gated carbon nanotube and graphene transistors.
Field-effect transistors based on single-walled carbon nanotubes (SWNTs) and graphene can function as highly sensitive nanoscale (bio)sensors in solution. Here, we compare experimentally how SWNT and graphene transistors respond to changes in the composition of the aqueous electrolyte in which they are immersed. We show that the conductance of SWNTs and graphene is strongly affected by changes in the ionic strength, the pH, and the type of ions present, in a manner that can be qualitatively different for graphene and SWNT devices. We show that this sensitivity to electrolyte composition results from a combination of different mechanisms including electrostatic gating, Schottky-barrier modifications, and changes in gate capacitance. Interestingly, we find strong evidence that the sensor response to changes in electrolyte composition is affected by a high density of ionizable groups on both the underlying substrate and the carbon surfaces. We present a model based on the (regulated) surface charge associated with these ionizable groups that explains the majority of our data. Our findings have significant implications for interpreting and optimizing sensing experiments with nanocarbon transistors. This is particularly true for complex biological samples such as cell extracts, growth media, or bodily fluids, for which the complete composition of the solution needs to be considered.


Biomarkers of oxidative stress in blood of workers exposed to non-cholinesterase inhibiting pesticides.
In occupational settings workers are often exposed to pesticides at relatively high doses compared to environmental exposures. Long-term exposure to pesticides has been associated with numerous adverse health effects in epidemiological studies, and oxidative stress is often claimed as one of the underlying mechanisms. In fact, different pesticides have been reported to induce oxidative stress due to the generation of free radicals and/or alteration in antioxidant defense enzymes. The present study examined greenhouse workers regularly exposed to diverse pesticides under integrated production system, and a group of controls of the same geographic area without any chemical exposure. Two different periods of the same crop season were assessed, one of high exposure (with greater use of pesticides) and other of low exposure (in which a less use of these compounds was made). Non-specific biomarkers of oxidative stress, e.g. thiobarbituric acid reactive substances (TBARS), ferric reducing ability of serum (FRAS), total thiol groups (SHT), gamma-glutamyl transpeptidase (GGT) and paraoxonase-1 (PON1) were measured in serum samples from all study subjects, alongside erythrocyte acetylcholinesterase (AChE). Results are suggestive of a mild increase in oxidative stress associated with pesticide exposure, which was compensated by an adaptive response to raise the antioxidant defenses and thus counter the detrimental effects of sustained oxidative stress. This response led to significantly increased levels of FRAS, SHT and PON1 in greenhouse workers relative to controls. Furthermore, AChE was decreased likely as a result of oxidative stress as workers did not use organophosphate insecticides.


Mediterranean dirty edge: High level of meso and macroplastics pollution on the Turkish coast.
It has become apparent that the coastal zones of aquatic environments are significantly affected by plastics pollution. The accumulation of marine plastic litter on beaches is an important problem due to their significant environmental impacts. In this study, 13 coastal areas in Iskenderun Bay (NE Levantine coast of Turkey) were sampled in May 2018 to investigate meso and macroplastic (0.5-123.4 cm) pollution. A total of 1424 meso and macroplastic items in five categories (filament, film, foam, fragments, and pellets) were collected. The average meso and macroplastic concentration was 12.2 ± 3.5 pcs m-2 (12.3 ± 3.5 g m-2) and the mean size for all stations was 3.7 ± 0.16 cm. The highest meso and macroplastic concentration was found in the Dörtyol location (46.2 ± 7.6 pcs m-2) and the lowest concentration was found in the Y. Lagün location (2.3 ± 0.2 pcs m-2). Plastics were separated into 14 different groups based on their origins. The most dominant type was hard plastics (broken, fragmented, and deformed) with 59.8% and greenhouse coverage films with 11%. Our results shows that regardless their source plastics fluxes at beaches from various pathways. Results of this study provide useful information for designing monitoring strategies and setting management goals.


Alpha-actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle.
Approximately one billion people worldwide are homozygous for a stop codon polymorphism in the ACTN3 gene (R577X) which results in complete deficiency of the fast fibre muscle protein alpha-actinin-3. ACTN3 genotype is associated with human athletic performance and alpha-actinin-3 deficient mice [Actn3 knockout (KO) mice] have a shift in the properties of fast muscle fibres towards slower fibre properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. alpha-Actinins have been shown to interact with a number of muscle proteins including the key metabolic regulator glycogen phosphorylase (GPh). In this study, we demonstrated a link between alpha-actinin-3 and glycogen metabolism which may underlie the metabolic changes seen in the KO mouse. Actn3 KO mice have higher muscle glycogen content and a 50% reduction in the activity of GPh. The reduction in enzyme activity is accompanied by altered post-translational modification of GPh, suggesting that alpha-actinin-3 regulates GPh activity by altering its level of phosphorylation. We propose that the changes in glycogen metabolism underlie the downstream metabolic consequences of alpha-actinin-3 deficiency. Finally, as GPh has been shown to regulate calcium handling, we examined calcium handling in KO mouse primary mouse myoblasts and find changes that may explain the slower contractile properties previously observed in these mice. We propose that the alteration in GPh activity in the absence of alpha-actinin-3 is a fundamental mechanistic link in the association between ACTN3 genotype and human performance.


Dog and human inflammatory bowel disease rely on overlapping yet distinct dysbiosis networks.
Inflammatory bowel disease (IBD) is an autoimmune condition that is difficult to diagnose, and animal models of this disease have questionable human relevance1. Here, we show that the dysbiosis network underlying IBD in dogs differs from that in humans, with some bacteria such as Fusobacterium switching roles between the two species (as Bacteroides fragilis switches roles between humans and mice)2. For example, a dysbiosis index trained on humans fails when applied to dogs, but a dog-specific dysbiosis index achieves high correlations with the overall dog microbial community diversity patterns. In addition, a random forest classifier trained on dog-specific samples achieves high discriminatory power, even when using stool samples rather than the mucosal biopsies required for high discriminatory power in humans2. These relationships were not detected in previously published dog IBD data sets due to their limited sample size and statistical power3. Taken together, these results reveal the need to train host-specific dysbiosis networks and point the way towards a generalized understanding of IBD across different mammalian models.


The impact of a 3-year after-school obesity prevention program in elementary school children.
Children tend to be sedentary during the after-school hours, and this has deleterious effects on their health. The objective of the present study was to determine the effects of a 3-year after-school physical activity (PA) program, without restriction of dietary energy intake, on percent body fat (%BF), cardiorespiratory fitness (CRF), and cardiometabolic markers in children. A cluster randomization design was employed. A total of 574 3rd grade children from 18 elementary schools in the southeastern United States participated. The intervention consisted of 80 minutes of age-appropriate moderate-to-vigorous PA each school day. The main outcomes of interest were %BF measured by dual-energy X-ray absorptiometry; CRF measured by heart rate in response to a submaximal step test; nonfasting total and high-density lipoprotein cholesterol (HDL-C); and resting blood pressure (BP). Intent-to-treat analyses showed significant treatment by time interactions for %BF (p = 0.009) and CRF (p = 0.0003). The change pattern of the means suggested that %BF and CRF in intervention children improved relative to control children during the school months, rebounding to the levels of control children over the summers following years 1 and 2. Year-by-year analyses of what occurred during the months when the program was offered revealed dose–response relations for %BF and CRF, such that the clearest beneficial effects were seen for those youth who attended at least 60% of the after-school sessions. No significant intervention effects were seen for cholesterol or BP. An after-school PA program was effective in reducing adiposity and improving CRF, especially in the children who attended the sessions at least 3 days/week. However, the favorable effects on %BF and CRF were lost over the summer. Thus, it is critical to incorporate strategies that attract and retain the children to receive an adequate dose of PA year-round.


Comparison of enteral nutrition with combined enteral and parenteral nutrition in post-pancreaticoduodenectomy patients: a pilot study.
Many clinical studies have demonstrated that early postoperative enteral nutrition (EN) improved the postroperative course. Post-pancreaticoduodenectomy (PD), patients tend to suffer from postoperative nausea, abdominal distention, and diarrhoea, causing difficulty in the introduction of EN. In this pilot study, we investigated the appropriate nutritional mode post-pancreatic surgery. Between October 2006 and March 2007 2 postoperative nutritional methods were implemented in 17 patients in a prospective single-centere study. Eight patients received only enteral nutrition (EN group) and 9 patients received enteral nutrition combined with parenteral nutrition (EN + PN group). There were no differences in the patient characteristics and postoperative morbidity between the 2 groups. The rate of discontinuance of enteral feeding was significantly high in the EN group, and the duration of enteral feeding was significantly longer in the EN + PN group. The central venous line was retained for a significantly longer period in the EN + PN group, but there was no difference in the frequency of catheter-related infection between the 2 groups. EN combined with PN is more adequate for patients after pancreatic surgery.


Analysis of blunt trauma injuries: vertical deceleration versus horizontal deceleration injuries.
There are several similarities found in blunt trauma injuries to humans sustained as a result of vertical deceleration (falling) and those sustained as a result of deceleration in a horizontal plane (automobile accidents). However, examination of the patterns of traumatic skeletal injuries can distinguish those injuries associated with falling from heights from those associated with automobile accidents. While there is considerable variation within each type of blunt trauma injury dependent on the angle at which one falls or is struck, there are several characteristic skeletal features associated with each type of trauma. In this study we review both the current literature and human skeletal remains from the University of New Mexico's Documented Collection known to have been subjected to blunt trauma. This collection is used to characterize and differentiate the pattern of skeletal injuries to various parts of the body for each type of trauma. These assessments are applied to investigate the traumatic skeletal lesions observed in a forensic case where the manner of death is unknown. Analyses suggest two possible scenarios that would explain the death of the individual investigated, with death most likely related to a vehicular-pedestrian accident.


Spinal afferent nerve endings in visceral organs: recent advances.
Spinal afferent neurons play a major role in detection and transduction of painful stimuli from internal (visceral) organs. Recent technical advances have made it possible to visualize the endings of spinal afferent axons in visceral organs. Although it is well known that the sensory nerve cell bodies of spinal afferents reside within dorsal root ganglia (DRG), identifying their endings in internal organs has been especially challenging because of a lack of techniques to distinguish them from endings of other extrinsic and intrinsic neurons (sympathetic, parasympathetic, and enteric). We recently developed a surgical approach in live mice that allows selective labeling of spinal afferent axons and their endings, revealing a diverse array of different types of varicose and nonvaricose terminals in visceral organs, particularly the large intestine. In total, 13 different morphological types of endings were distinguished in the mouse distal large intestine, originating from lumbosacral DRG. Interestingly, the stomach, esophagus, bladder, and uterus had less diversity in their types of spinal afferent endings. Taken together, spinal afferent endings (at least in the large intestine) appear to display greater morphological diversity than vagal afferent endings that have previously been extensively studied. We discuss some of the new insights that these findings provide.


Spike-timing-dependent Hebbian plasticity as temporal difference learning.
A spike-timing-dependent Hebbian mechanism governs the plasticity of recurrent excitatory synapses in the neocortex: synapses that are activated a few milliseconds before a postsynaptic spike are potentiated, while those that are activated a few milliseconds after are depressed. We show that such a mechanism can implement a form of temporal difference learning for prediction of input sequences. Using a biophysical model of a cortical neuron, we show that a temporal difference rule used in conjunction with dendritic backpropagating action potentials reproduces the temporally asymmetric window of Hebbian plasticity observed physio-logically. Furthermore, the size and shape of the window vary with the distance of the synapse from the soma. Using a simple example, we show how a spike-timing-based temporal difference learning rule can allow a network of neocortical neurons to predict an input a few milliseconds before the input's expected arrival.


Cervical Cannulation for Surgical Repair of Congenital Cardiac Defects in Infants and Small Children.
The biggest challenge faced in minimally invasive pediatric cardiac surgery is cannulation for cardiopulmonary bypass. Our technique and experience of cervical cannulation in infants and small children for repair of congenital cardiac defects is reported in this study. From January 2013 to June 2015, 37 children (22 males) with mean age of 17.97±8.63 months and weight of 8.06±1.59 kg were operated on for congenital cardiac defects through right lateral thoracotomy. The most common diagnosis was ventricular septal defect (18 patients). In all patients, right common carotid artery, right internal jugular vein and inferior vena cava were cannulated for institution of cardiopulmonary bypass and aorta was cross clamped through right 2nd intercostal space. There were no deaths or any major complications related to cervical cannulation. Common carotid artery cannulation provided adequate arterial inflow while internal jugular vein with inferior vena cava provided adequate venous return in all patients. No patient required conversion to sternotomy or developed vascular, neurological or wound related complications. Three patients had residual lesions (small leak across ventricular septal defect patch-2, Grade II left atrio-ventricular valve regurgitation-1) and one patient had mild left ventricular dysfunction. At discharge, both common carotid artery and internal jugular vein were patent on color Doppler ultrasonography in all patients. In a mean follow-up period of 11.4±2.85 months, all patients were doing well. No patient had any wound related, neurological or vascular complication. No patient had residual leak across ventricular septal defect patch. Cervical cannulation of common carotid artery and internal jugular vein is a safe, reliable, efficient and quick method for institution of cardiopulmonary bypass in minimally invasive pediatric cardiac surgery.


Targeting Olokizumab-Interleukin 6 interaction interface to discover novel IL-6 inhibitors.
The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID: 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structure‑based pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors.Communicated by Ramaswamy H. Sarma.


School-based physical activity programs for promoting physical activity and fitness in children and adolescents aged 6 to 18.
Physical activity among children and adolescents is associated with lower adiposity, improved cardio-metabolic health, and improved fitness. Worldwide, fewer than 30% of children and adolescents meet global physical activity recommendations of at least 60 minutes of moderate to vigorous physical activity per day. Schools may be ideal sites for interventions given that children and adolescents in most parts of the world spend a substantial amount of time in transit to and from school or attending school. The purpose of this review update is to summarise the evidence on effectiveness of school-based interventions in increasing moderate to vigorous physical activity and improving fitness among children and adolescents 6 to 18 years of age. Specific objectives are: • to evaluate the effects of school-based interventions on increasing physical activity and improving fitness among children and adolescents; • to evaluate the effects of school-based interventions on improving body composition; and • to determine whether certain combinations or components (or both) of school-based interventions are more effective than others in promoting physical activity and fitness in this target population. We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, BIOSIS, SPORTDiscus, and Sociological Abstracts to 1 June 2020, without language restrictions. We screened reference lists of included articles and relevant systematic reviews. We contacted primary authors of studies to ask for additional information. Eligible interventions were relevant to public health practice (i.e. were not delivered by a clinician), were implemented in the school setting, and aimed to increase physical activity among all school-attending children and adolescents (aged 6 to 18) for at least 12 weeks. The review was limited to randomised controlled trials. For this update, we have added two new criteria: the primary aim of the study was to increase physical activity or fitness, and the study used an objective measure of physical activity or fitness. Primary outcomes included proportion of participants meeting physical activity guidelines and duration of moderate to vigorous physical activity and sedentary time (new to this update). Secondary outcomes included measured body mass index (BMI), physical fitness, health-related quality of life (new to this update), and adverse events (new to this update). Television viewing time, blood cholesterol, and blood pressure have been removed from this update. DATA COLLECTION AND ANALYSIS: Two independent review authors used standardised forms to assess each study for relevance, to extract data, and to assess risk of bias. When discrepancies existed, discussion occurred until consensus was reached. Certainty of evidence was assessed according to GRADE. A random-effects meta-analysis based on the inverse variance method was conducted with participants stratified by age (children versus adolescents) when sufficient data were reported. Subgroup analyses explored effects by intervention type. Based on the three new inclusion criteria, we excluded 16 of the 44 studies included in the previous version of this review. We screened an additional 9968 titles (search October 2011 to June 2020), of which 978 unique studies were potentially relevant and 61 met all criteria for this update. We included a total of 89 studies representing complete data for 66,752 study participants. Most studies included children only (n = 56), followed by adolescents only (n = 22), and both (n = 10); one study did not report student age. Multi-component interventions were most common (n = 40), followed by schooltime physical activity (n = 19), enhanced physical education (n = 15), and before and after school programmes (n = 14); one study explored both enhanced physical education and an after school programme. Lack of blinding of participants, personnel, and outcome assessors and loss to follow-up were the most common sources of bias. Results show that school-based physical activity interventions probably result in little to no increase in time engaged in moderate to vigorous physical activity (mean difference (MD) 0.73 minutes/d, 95% confidence interval (CI) 0.16 to 1.30; 33 studies; moderate-certainty evidence) and may lead to little to no decrease in sedentary time (MD -3.78 minutes/d, 95% CI -7.80 to 0.24; 16 studies; low-certainty evidence). School-based physical activity interventions may improve physical fitness reported as maximal oxygen uptake (VO₂max) (MD 1.19 mL/kg/min, 95% CI 0.57 to 1.82; 13 studies; low-certainty evidence). School-based physical activity interventions may result in a very small decrease in BMI z-scores (MD -0.06, 95% CI -0.09 to -0.02; 21 studies; low-certainty evidence) and may not impact BMI expressed as kg/m² (MD -0.07, 95% CI -0.15 to 0.01; 50 studies; low-certainty evidence). We are very uncertain whether school-based physical activity interventions impact health-related quality of life or adverse events. Given the variability of results and the overall small effects, school staff and public health professionals must give the matter considerable thought before implementing school-based physical activity interventions. Given the heterogeneity of effects, the risk of bias, and findings that the magnitude of effect is generally small, results should be interpreted cautiously.


Modeling metal bioaccumulation and tissue distribution in killifish (Fundulus heteroclitus) in three contaminated estuaries.
The present study experimentally assessed the uptake, loss, and resulting tissue distribution of As(V), Cd, Cr(III), Hg(II), and methylmercury (MeHg) in killifish (Fundulus heteroclitus) following aqueous exposure in water collected from 3 contaminated field sites-Baltimore Harbor and Elizabeth River (Chesapeake Bay), and Mare Island (San Francisco Bay)-using a radiotracer technique. Uptake rate constants (L g-1 d-1) were highest for MeHg (0.370-0.781) and lowest for As (0.00028-0.00065). Loss rate constants (d-1) were highest for As (0.046-0.096) and lowest for MeHg (0.006-0.009). Tissue distribution data showed that MeHg was redistributed around the body throughout the 9-d depuration period, and drinking may be an uptake mechanism for Cd from the aqueous phase in higher-salinity water. The kinetic parameters calculated in the present study were entered into a bioaccumulation model to calculate the predicted body burden of each metal at steady state and the percentage body burden attributable to dietary exposure on a site-specific basis. Calculated body burdens varied between field sites for all metals except Cr. The predicted values for Cd, Hg(II), and MeHg matched independent field data from contaminated estuaries, indicating that the model can account for the major processes governing metal concentration in killifish. The diet accounted for >97% of the body burden of Cd and MeHg and was the predominant exposure route for As and Cr.


Parenting and family stress treatment outcomes in attention deficit hyperactivity disorder (ADHD): an empirical analysis in the MTA study.
Parenting and family stress treatment outcomes in the MTA study were examined. Male and female (579), 7-9-year-old children with combined type Attention Deficit Hyperactivity Disorder (ADHD), were recruited at six sites around the United States and Canada, and randomly assigned to one of four groups: intensive, multi-faceted behavior therapy program alone (Beh); carefully titrated and monitored medication management strategy alone (MedMgt); a well-integrated combination of the two (Comb); or a community comparison group (CC). Treatment occurred over 14 months, and assessments were taken at baseline, 3, 9, and 14 months. Parenting behavior and family stress were assessed using parent-report and child-report inventories. Results showed that Beh alone, MedMgt alone, and Comb produced significantly greater decreases in a parent-rated measure of negative parenting, Negative/Ineffective Discipline, than did standard community treatment. The three MTA treatments did not differ significantly from each other on this domain. No differences were noted among the four groups on positive parenting or on family stress variables. Results are discussed in terms of the theoretical and empirically documented importance of negative parenting in the symptoms, comorbidities and long-term outcomes of ADHD.


Non-invasive quantification of white and brown adipose tissues and liver fat content by computed tomography in mice.
Obesity and its distribution pattern are important factors for the prediction of the onset of diabetes in humans. Since several mouse models are suitable to study the pathophysiology of type 2 diabetes the aim was to validate a novel computed tomograph model (Aloka-Hitachi LCT-200) for the quantification of visceral, subcutaneous, brown and intrahepatic fat depots in mice. Different lean and obese mouse models (C57BL/6, B6.V-Lep(ob), NZO) were used to determine the most adequate scanning parameters for the detection of the different fat depots. The data were compared with those obtained after preparation and weighing the fat depots. Liver fat content was determined by biochemical analysis. The correlations between weights of fat tissues on scale and weights determined by CT were significant for subcutaneous (r(2) = 0.995), visceral (r(2) = 0.990) and total white adipose tissue (r(2) = 0.992). Moreover, scans in the abdominal region, between lumbar vertebrae L4 to L5 correlated with whole-body fat distribution allowing experimenters to reduce scanning time and animal exposure to radiation and anesthesia. Test-retest reliability and measurements conducted by different experimenters showed a high reproducibility in the obtained results. Intrahepatic fat content estimated by CT was linearly related to biochemical analysis (r(2) = 0.915). Furthermore, brown fat mass correlated well with weighted brown fat depots (r(2) = 0.952). In addition, short-term cold-expose (4 °C, 4 hours) led to alterations in brown adipose tissue attributed to a reduction in triglyceride content that can be visualized as an increase in Hounsfield units by CT imaging. The 3D imaging of fat by CT provides reliable results in the quantification of total, visceral, subcutaneous, brown and intrahepatic fat in mice. This non-invasive method allows the conduction of longitudinal studies of obesity in mice and therefore enables experimenters to investigate the onset of complex diseases such as diabetes and obesity.


Microsatellite instability in cancer of the proximal colon.
Colorectal tumor DNA was examined for somatic instability at (CA)n repeats on human chromosomes 5q, 15q, 17p, and 18q. Differences between tumor and normal DNA were detected in 25 of the 90 (28 percent) tumors examined. This instability appeared as either a substantial change in repeat length (often heterogeneous in nature) or a minor change (typically two base pairs). Microsatellite instability was significantly correlated with the tumor's location in the proximal colon (P = 0.003), with increased patient survival (P = 0.02), and, inversely, with loss of heterozygosity for chromosomes 5q, 17p, and 18q. These data suggest that some colorectal cancers may arise through a mechanism that does not necessarily involve loss of heterozygosity.


The effects of dynamic compression on the development of cartilage grafts engineered using bone marrow and infrapatellar fat pad derived stem cells.
Bioreactors that subject cell seeded scaffolds or hydrogels to biophysical stimulation have been used to improve the functionality of tissue engineered cartilage and to explore how such constructs might respond to the application of joint specific mechanical loading. Whether a particular cell type responds appropriately to physiological levels of biophysical stimulation could be considered a key determinant of its suitability for cartilage tissue engineering applications. The objective of this study was to determine the effects of dynamic compression on chondrogenesis of stem cells isolated from different tissue sources. Porcine bone marrow (BM) and infrapatellar fat pad (FP) derived stem cells were encapsulated in agarose hydrogels and cultured in a chondrogenic medium in free swelling (FS) conditions for 21 d, after which samples were subjected to dynamic compression (DC) of 10% strain (1 Hz, 1 h d(-1)) for a further 21 d. Both BM derived stem cells (BMSCs) and FP derived stem cells (FPSCs) were capable of generating cartilaginous tissues with near native levels of sulfated glycosaminoglycan (sGAG) content, although the spatial development of the engineered grafts strongly depended on the stem cell source. The mechanical properties of cartilage grafts generated from both stem cell sources also approached that observed in skeletally immature animals. Depending on the stem cell source and the donor, the application of DC either enhanced or had no significant effect on the functional development of cartilaginous grafts engineered using either BMSCs or FPSCs. BMSC seeded constructs subjected to DC stained less intensely for collagen type I. Furthermore, histological and micro-computed tomography analysis showed mineral deposition within BMSC seeded constructs was suppressed by the application of DC. Therefore, while the application of DC in vitro may only lead to modest improvements in the mechanical functionality of cartilaginous grafts, it may play an important role in the development of phenotypically stable constructs.


Pharmacological and Non-Pharmacological Interventions for Depression after Moderate-to-Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.
The objective of this study was to systematically review the literature and perform a meta-analysis of randomized controlled trials (RCTs) on the effectiveness of pharmacological and non-pharmacological interventions for depression in patients with moderate-to-severe traumatic brain injury. Databases searched were: Embase, PubMed, PsycInfo, Cochrane Central, Web of Science, and Google Scholar. Depression score on a self-report questionnaire was the outcome measure. Outcomes were collected at baseline and at the first follow-up moment. Data extraction was executed independently by two researchers. Thirteen RCTs were identified: five pharmacological and eight non-pharmacological. Although not all individual studies had significant results, the overall standardized mean difference (SMD) was -0.395, p ≤ 0.001, indicating that interventions improved the depression scores in patients with TBI. The difference in effectiveness between pharmacological interventions and non-pharmacological interventions was not significant (ΔSMD: 0.203, p = 0.238). Further subdivision into methylphenidate, sertraline, psychological, and other interventions showed a significant difference in effectiveness between methylphenidate (ΔSMD: -0.700, p = 0.020) and psychological interventions (reference). This difference was not found if other depression outcomes in four of the included studies were analyzed. The SMD of low-quality studies did not differ significantly from moderate- and high-quality studies (ΔSMD: 0.321, p = 0.050). Although RCTs targeting interventions for depression after TBI are scarce, both pharmacological and non-pharmacological interventions appear to be effective in treating depressive symptoms/depression after moderate-to-severe TBI. There is a need for high-quality RCTs in which the add-on effects of pharmacological and non-pharmacological interventions are investigated.


A randomized trial of ribavirin and interferon-alpha vs. interferon-alpha alone in patients with chronic hepatitis C who were non-responders to a previous treatment. Multicenter Study Group under the coordination of the Necker Hospital, Paris, France.
Fifty percent of patients infected with hepatitis C virus (HCV) show no response to alpha-interferon, and no alternative therapy has thus far proven to be effective. Therapeutic combination with ribavirin and alpha-interferon has shown promising results in naive patients and in relapsers, but based on limited series, it was reported to be inefficient in non-responders. The aim of our study was therefore to explore and compare, in a randomized trial, the tolerance and potential efficacy of alpha-interferon alone with a sequential combination of ribavirin and the same alpha-interferon regimen in those patients. Sixty-four non-responder patients were randomized in the alpha2b-interferon group (a 6-month course at a dosage of 6 MU followed by a 6-month course of 3 MU three times weekly subcutaneously) and 62 in the "combination" group (sequential combination of the same alpha2b-interferon therapy preceded by a 2-month course of ribavirin which was then associated for 2 months with alpha2b-interferon at a daily dosage of 1.0 or 1.2 g). Treatment withdrawal was necessary for six patients from the alpha-interferon and eight patients from the combination group. Normalization of aminotransferase activities was significantly more frequent after the 4-month course of ribavirin with 2 months of interferon than after 2 months of interferon alone (52.8 vs. 26.2%, p<0.01), but this difference was not maintained after ribavirin withdrawal. Disappearance of serum HCV RNA (PCR) was significantly more frequent at the end of treatment in the combination group (24.5 vs. 7.7%, p=0.02), but did not differ 6 months after the end of therapy (9.8 and 8.3%, respectively). The long-term response was not associated with liver status (cirrhosis vs. absence of cirrhosis) or genotype. Mean viremia was significantly lower in long-term responders than in non-responders or relapsers in both groups (p<0.001 for the interferon group and p<0.05 for the combination group), but the large extent of viral load precluded reliable prediction. The pre- and post-treatment hepatitis activity index did not differ between the two groups. While a crude histopathological improvement in the hepatitis activity index for a given patient was more frequently observed in the combination group (69.2 vs. 35.9%, p<0.01), improvement as defined by a decrease of at least 2 in the hepatitis activity index was significant only for lobular necrosis and degeneration. This study demonstrates the efficacy of the combination of ribavirin/alpha-interferon in non-responders. Indeed, (i) it is fairly tolerated; (ii) it increases the rate of the initial biological response, and of the virological response by decreasing breakthrough, though this benefit is not sustained; and (iii) it induces a significant histological improvement in necrosis. A simultaneous and prolonged combination of ribavirin/alpha-interferon should be further evaluated in non-responders.


Combination therapy with molecular hydrogen and hyperoxia in a murine model of polymicrobial sepsis.
Sepsis is the most common cause of death in intensive care units. Some studies have found that hyperoxia may be beneficial to sepsis. However, the clinical use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. Recently, it has been suggested that molecular hydrogen (H2) at low concentration can exert a therapeutic antioxidant activity and effectively protect against sepsis by reducing oxidative stress. Therefore, we hypothesized that combination therapy with H2 and hyperoxia might afford more potent therapeutic strategies for sepsis. In the present study, we found that inhalation of H2 (2%) or hyperoxia (98%) alone improved the 14-day survival rate of septic mice with moderate cecal ligation and puncture (CLP) from 40% to 80% or 70%, respectively. However, combination therapy with H2 and hyperoxia could increase the 14-day survival rate of moderate CLP mice to 100% and improve the 7-day survival rate of severe CLP mice from 0% to 70%. Moreover, moderate CLP mice showed significant organ damage characterized by the increases in lung myeloperoxidase activity, lung wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters (alanine aminotransferase, aspartate aminotransferase, creatinine, and blood urea nitrogen), and organ histopathological scores (lung, liver, and kidney), as well as the decrease in PaO2/FIO2 ratio at 24 h, which was attenuated by either H2 or hyperoxia alone. However, combination therapy with H2 and hyperoxia had a more beneficial effect against lung, liver, and kidney damage of moderate or severe CLP mice. Furthermore, we found that the beneficial effect of this combination therapy was associated with the decreased levels of oxidative product (8-iso-prostaglandin F2α), increased activities of antioxidant enzymes (superoxide dismutase and catalase) and anti-inflammatory cytokine (interleukin 10), and reduced levels of proinflammatory cytokines (high-mobility group box 1 and tumor necrosis factor α) in serum and tissues. Therefore, combination therapy with H2 and hyperoxia provides enhanced therapeutic efficacy via both antioxidant and anti-inflammatory mechanisms and might be potentially a clinically feasible approach for sepsis.