Cognitive and other neuropsychiatric symptoms in COVID-19: analysis of person-generated longitudinal health data from a community-based registry.
To describe cognitive symptoms in people not hospitalised at study enrolment for SARS-CoV-2 infection and associated demographics, medical history, other neuropsychiatric symptoms and SARS-CoV-2 vaccination. Longitudinal observational study. Direct-to-participant registry with community-based recruitment via email and social media including Google, Facebook and Reddit, targeting adult US residents. Demographics, medical history, COVID-19-like symptoms, tests and vaccinations were collected through enrolment and follow-up surveys. Participants who reported positive COVID-19 test results between 15 December 2020 and 13 December 2021. Those with cognitive symptoms were compared with those not reporting such symptoms. Self-reported cognitive symptoms (defined as 'feeling disoriented or having trouble thinking' from listed options or related written-in symptoms) RESULTS: Of 3908 participants with a positive COVID-19 test result, 1014 (25.9%) reported cognitive symptoms at any time point during enrolment or follow-up, with approximately half reporting moderate/severe symptoms. Cognitive symptoms were associated with other neuropsychiatric symptoms, including dysgeusia, anosmia, trouble waking up, insomnia, headache, anxiety and depression. In multivariate analyses, female sex (OR, 95% CI): 1.7 (1.3 to 2.2), age (40-49 years (OR: 1.5 (1.2-1.9) compared with 18-29 years), history of autoimmune disease (OR: 1.5 (1.2-2.1)), lung disease (OR: 1.7 (1.3-2.2)) and depression (OR: 1.4 (1.1-1.7)) were associated with cognitive symptoms. Conversely, black race (OR: 0.6 (0.5-0.9)) and COVID-19 vaccination before infection (OR: 0.6 (0.4-0.7)) were associated with reduced occurrence of cognitive symptoms. In this study, cognitive symptoms among COVID-19-positive participants were associated with female gender, age, autoimmune disorders, lung disease and depression. Vaccination and black race were associated with lower occurrence of cognitive symptoms. A constellation of neuropsychiatric and psychological symptoms occurred with cognitive symptoms. Our findings suggest COVID-19's full health and economic burden may be underestimated. NCT04368065.


Efficacy and safety of ciprofloxacin oral suspension versus trimethoprim-sulfamethoxazole oral suspension for treatment of older women with acute urinary tract infection.
To compare the efficacy and safety of ciprofloxacin (CIP) oral suspension to trimethoprim/sulfamethoxazole (TMP/SMX) oral suspension among older women with acute urinary tract infections (UTIs). Prospective, randomized, open-label, multicenter study of older women (age 65 and older). Community and nursing home. A total of 261 older women were evaluable for safety. Of these, 172 (86 community, 86 nursing home) were evaluable for clinical and bacteriological efficacy. Patients were randomized to a 10-day regimen of either CIP (250 mg/5 mL twice daily) or TMP/SMX (160/800 mg/20 mL twice daily). Clinical response 4 to 10 days posttherapy. For the efficacy-valid population, posttherapy clinical resolution was statistically superior following CIP (97%) versus TMP/SMX (85%) (95% CI=2.0-21.3; P= .009). Eradication of pretreatment bacterial isolates posttherapy was also higher following CIP (95%) versus TMP/SMX (84%) (95% CI=2.7-21.3; P= .019). For the intent-to-treat population, posttherapy clinical resolution was significantly higher in the CIP group (96%) than in the TMP/SMX group (87%) (95% CI=0.2-16.7; P= .025). Safety was assessed in the intent-to-treat population and the incidence of drug-related adverse events were significantly lower following CIP (17%) than following TMP/SMX (27%) (P= .047). Premature discontinuation due to these events was also less prevalent with CIP than with TMP/SMX (2% vs 11%, respectively) (P= .004). CIP suspension showed higher clinical success and bacteriological eradication rates than did TMP/SMX for both community-based and nursing home-residing older women with acute UTIs. Furthermore, CIP suspension was associated with significantly lower rates of adverse events and premature discontinuations compared with TMP/SMX suspension.


X-ray crystallographic studies of the alanine-specific racemase from Bacillus stearothermophilus. Overproduction, crystallization, and preliminary characterization.
To facilitate large-scale purification and crystallographic study, we have subcloned the gene for the alanine racemase of Bacillus stearothermophilus from pICR401 (Inagaki, K., Tanizawa, K., Badet, B., Walsh, C. T., Tanaka, H., and Soda, K. (1986) Biochemistry 25, 3268-3274) and overproduced the enzyme in Escherichia coli W3110 lacIq using the tac promoter of PKK223-3. This system yields alanine racemase as 6% of the bacterial cytosolic protein. Purification by a modification of the procedure of Inagake et al. yielded 75 mg of homogeneous alanine racemase from 30 g of cells (wet weight). Large, well-formed crystals of alanine racemase have been grown from polyethylene glycol 8000 using vapor diffusion. These crystals have unit cell dimensions a = 85.3 A, b = 110.0 A, and c = 89.9 A. The crystals belong to space group P2(1), with beta fortuitously equal to 90 degrees within experimental error; however, they are frequently twinned by second order pseudomerohedry with twin fraction (the ratio of the volume of the smaller twin domain to the total volume of the crystal) ranging from about 0 to 0.5. Fortunately, for crystals with low twin fraction, computational methods have been developed for the analysis and correction of simple twinning (Fisher, R. G., and Sweet, R. M. (1980) Acta Crystallogr. A36, 755-760). The crystals contain two alpha 2 dimers of alanine racemase in the asymmetric unit. We have identified several potentially useful heavy atom derivatives in low resolution screening experiments and are proceeding with high resolution data collection.


Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial.
Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m2, day 1) and oral capecitabine (1 g/m2, day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment. This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).


Glycosphingolipids of cultured human colon carcinoma cells and their drug-resistant sublines.
Human colon carcinoma cells were analyzed for lipid phosphorus, cholesterol and glycosphingolipids. Ceramide mono-, di- and trihexosides and sulfatides were isolated by column and thin-layer chromatography and determined quantitatively on the basis of their hexose content. The complex lipid fractions so isolated were only partially resolved with the material available. Gangliosides GM2 and GM3 and globoside were major components of the fraction and were determined on the basis of their hexose, hexosamine and neuraminic acid content. The HCT 116, 116a and 116b cells contained no fucolipids. Cell lines resistant to mitomycin C, teniposide and etoposide were developed and analyzed. Over the 5 year period of the study sulfatides declined to about one-fourth of their original amounts in both parent and drug-adapted cells. HCT 116 cells adapted to mitomycin C and teniposide had 30% less ceramide monohexoside and a 45% greater cholesterol to lipid phosphorus ratio than the parent cells. Reductions in ceramide dihexoside in the drug-adapted cells were greater than those of the ceramide monohexoside. Galabiosyl ceramide was the major ceramide dihexoside in all the cells and accumulated in HCT 116a to levels 4-6-fold greater than that of the other lines as the only dihexoside.


[Isolation, morphological and biochemical characteristics of gram-positive bacteria metabolizing beta-caryophyllene].
Eleven strains of coryneform bacteria were isolated from soil samples by enrichment culture in a mineral medium containing beta-caryophyllene as the sole energy and carbon source. Ten of them could also metabolize longifolene. Numerical taxonomy, based on the use of 147 characteristics, revealed a large diversity. The DNA G + C content was found to be in the range of 62.5-68.3 mol%. Three strains were placed in "The National Collection of Industrial and Marine Bacteria".


Adherence to physical activity recommendations and the influence of socio-demographic correlates - a population-based cross-sectional study.
Current physical activity guidelines acknowledge the importance of total health enhancing physical activity (HEPA) compared to leisure time physical activity or exercise alone. Assessing total HEPA may result in different levels of adherence to these as well as the strength and/or direction of associations observed between total HEPA and socio-demographic correlates. The aim of this study was to estimate the proportion of the population adhering to the recommendation of at least 30 minutes of HEPA on most days, and to examine the influences of socio-demographic correlates on reaching this recommendation. Swedish adults aged 18-74 years (n = 1470) were categorized, based on population data obtained using the IPAQ, into low, moderately and highly physically active categories. Independent associations between the physical activity categories and socio-demographic correlates were studied using a multinomial logistic regression. Of the subjects, 63% (95% CI: 60.5-65.4) adhered to the HEPA recommendation. Most likely to reach the highly physical active category were those aged < 35 years (OR = 1.8; 95% CI: 1.1-3.3), living in small towns (OR = 1.8; 95% CI: 1.1-2.7) and villages (OR = 2.4; 95% CI: 1.6-3.7), having a BMI between 25.0-29.9 kg/m2 (OR = 2.7; 95% CI: 1.4-5.3) having a BMI < 25 kg/m2 (OR = 2.5; 95% CI: 1.3-4.9), or having very good (OR = 2.1; 95% CI: 1.3-3.3) or excellent self-perceived health (OR = 4.1; 95% CI: 2.4-6.8). Less likely to reach the high category were women (OR = 0.6; 95% CI: 0.5-0.9) and those with a university degree (OR = 0.5; 95% CI: 0.3-0.9). Similar, but less pronounced associations were observed for the moderate group. Gender-specific patterns were also observed. Almost two-thirds of the Swedish adult population adhered to the physical activity recommendation. Due to a large diversity in levels of physical activity among population subgroups, social-ecological approaches to physical activity promotion may be warranted.


The alleviation of skin wound-induced intestinal barrier dysfunction via modulation of TLR signalling using arginine in gilthead seabream (Sparus aurata L).
The present study sought to investigate the effect of arginine on the involvement of toll-like receptors (TLRs) in skin wound-induced intestinal barrier dysfunction in gilthead seabream (Sparus aurata L.). Two replicates of fish (n = 8) were fed a commercial diet (CON, total 2.75% arginine), CON diet enriched with 1% arginine (ARG1, total 3.65% arginine) and 2% arginine (ARG2, total 4.53% arginine) for 30 days. Half of the fish were sampled, whereas the others were injured and sampled 7 days post-wounding. The intestinal histology results showed that a more intense infiltration of mixed leucocytes was evident in the wounded fish, which was remarkably reduced in fish that were fed the ARG1 diet. Serum IgM levels were significantly higher in the ARG1 group than levels in the CON group at 7 days post-wounding. Compared with the fish in the CON group after wounding, dietary administration of 1% arginine markedly downregulated the gene expression of TLRs (TLR2 and TLR5), MyD88, and proinflammatory cytokines (CSF1R, IL-1β, and TNFα), but significantly enhanced the gene expression of IκBα, the anti-inflammatory cytokine TGF-β1, and tight junction proteins (tricellulin and occludin) in wounded fish. Furthermore, the ARG2 diet demonstrated no additional benefits on intestinal cells, compared to both the ARG1 and the CON diets, and it even appeared to induce negative effects. In summary, dietary administration of 1% arginine significantly inhibited intestinal inflammatory response and tight junction disruption in skin-wounded gilthead seabream by modulating TLR signalling in the intestine.


Influences of inducers and inhibitors of the microsomal monooxygenase system on the alkylating intensity of dimethylnitrosamine in mice.
Male mice were pretreated with various drugs, which are known either induce or to inhibit cytochrome P 450 function. Five hours after the administration of 14C-dimethylnitrosamine (10 mg/kg) in pretreated and control mice, total and specific radioactivities of cellular macromolecules of the liver were determined. Various types of nucleic acids were extracted and hydrolyzed, and the bases and nucleotides separated by ion-exchange-chromatography. Radioactivity resulting from incorporation and alkylation was measured. Pretreatment of mice with the inducers phenobarbital and 3-Methylcholanthrene decreased the alkylation rates, while administration of the inhibitors SKF 525 A and CFT 1201 caused an increase. These results appear to contradict the accepted activation mechanism of nitrosamines if DMN demethylation as catalyzed by cyt. P 450 is influenced in the same way as other cyt. P 450 dependent reactions.


Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing.
Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing, primarily due to regulatory uncertainty. This paper aims to help address these concerns by introducing methods for batch definition, raw material traceability, and sensor frequency determination. All of the methods are based on established engineering and mathematical principles, especially the residence time distribution (RTD). This paper introduces a risk-based approach to address content uniformity challenges of continuous manufacturing. All of the detailed methods are discussed using a direct compaction manufacturing line as the main example, but the techniques can easily be applied to other continuous manufacturing methods such as wet and dry granulation, hot melt extrusion, capsule filling, etc.


Topological Invariants of Vapor-Liquid, Vapor-Liquid-Liquid and Liquid-Liquid Phase Diagrams.
The study of topological invariants of phase diagrams allows for the development of a qualitative theory of the processes being researched. Studies of the properties of objects in the same equivalence class may be carried out with the aim of predicting the properties of unexplored objects from this class, or predicting the behavior of a whole system. This paper describes a number of topological invariants in vapor-liquid, vapor-liquid-liquid and liquid-liquid equilibrium diagrams. The properties of some invariants are studied and illustrated. It is shown that the invariant of a diagram with a miscibility gap can be used to distinguish equivalence classes of phase diagrams, and that the balance equation of the singular-point indices, based on the Euler characteristic, may be used to analyze the binodal-surface structure of a quaternary system.


The role of provider supply and organization in reducing racial/ethnic disparities in mental health care in the U.S.
Racial and ethnic disparities in mental health care access in the United States are well documented. Prior studies highlight the importance of individual and community factors such as health insurance coverage, language and cultural barriers, and socioeconomic differences, though these factors fail to explain the extent of measured disparities. A critical factor in mental health care access is a local area's organization and supply of mental health care providers. However, it is unclear how geographic differences in provider organization and supply impact racial/ethnic disparities. The present study is the first analysis of a nationally representative U.S. sample to identify contextual factors (county-level provider organization and supply, as well as socioeconomic characteristics) associated with use of mental health care services and how these factors differ across racial/ethnic groups. Hierarchical logistic models were used to examine racial/ethnic differences in the association of county-level provider organization (health maintenance organization (HMO) penetration) and supply (density of specialty mental health providers and existence of a community mental health center) with any use of mental health services and specialty mental health services. Models controlled for individual- and county-level socio-demographic and mental health characteristics. Increased county-level supply of mental health care providers was significantly associated with greater use of any mental health services and any specialty care, and these positive associations were greater for Latinos and African-Americans compared to non-Latino Whites. Expanding the mental health care workforce holds promise for reducing racial/ethnic disparities in mental health care access. Policymakers should consider that increasing the management of mental health care may not only decrease expenditures, but also provide a potential lever for reducing mental health care disparities between social groups.


On a new generalized symmetric vector equilibrium problem.
In this paper, a new form of the symmetric vector equilibrium problem is introduced and, by mixing properties of the nonlinear scalarization mapping and the maximal element lemma, an existence theorem for it is established. We show that Ky Fan's lemma, as a usual technique for proving the existence results for equilibrium problems, implies the maximal element lemma, while it is useless for proving the main theorem of this paper. Our results can be viewed as an extension and improvement of the main results obtained by Farajzadeh (Filomat 29(9):2097-2105, 2015) and some corresponding results that appeared in this area by relaxing the lower semicontinuity, quasiconvexity on the mappings and being nontrivial of the dual cones. Finally, some examples are given to support the main results.


Lower-limb dynamics and clinical outcomes for habitually shod runners who transition to barefoot running.
Recent investigations have revealed lower vertical loading rates and knee energy absorption amongst experienced barefoot runners relative to those who rear-foot strike (RFS). Although this has led to an adoption of barefoot running amongst many recreational shoe runners, recent investigations indicate that the experienced barefoot pattern is not immediately realized. Therefore, the purpose this investigation was to quantify changes in lower-extremity dynamics and clinical outcomes measures for habitually shod runners who perform a transition to barefoot running. We examined lower-extremity dynamics and clinical outcomes for 26 RFS shod runners who performed an 8-10 week transition to barefoot running. Runners were evaluated at the University of Southern California's Musculoskeletal Biomechanics Research Laboratory. Foot-strike patterns, vertical load rates, and joint energetics were evaluated before and after the transition using inverse dynamics. Clinical assessments were conducted throughout the transition by two licensed clinicians. Eighteen of the 26 runners successfully completed the transition: 7 maintained a RFS, 8 adopted a mid-foot strike (MFS), and 3 adopted a forefoot strike (FFS) during novice barefoot running. Following the transition, novice MFS/FFS runners often demonstrated reversions in strike-patterns and associated reductions in ankle energetics. We report no change in loading rates and knee energy absorption across transition time points. Importantly, there were no adverse events other than transient pain and soreness. These findings indicate that runners do not innately adopt the biomechanical characteristics thought to lower injury risk in-response to an uninstructed barefoot running transition.


Neoadjuvant radiochemotherapy of oral cavity and oropharyngeal cancer: evaluation of tumor response by CT differs from histopathologic response assessment in a significant fraction of patients.
Our aim was to compare and assess the predictive value of CT and histopathologic grading of tumor regression at primary tumor sites in patients with squamous cell carcinoma of the oral cavity and oropharynx after neoadjuvant (preoperative) radiochemotherapy (RCT). We investigated 55 patients with carcinomas of the oral cavity and oropharynx who underwent RCT before curative surgery. Two blinded observers measured RCT-induced reduction of tumor volume in pretherapeutic and posttherapeutic CT scans. Volume changes were compared with histopathologic findings obtained at surgery. Histopathologic response evaluation revealed 31 complete remissions, 12 cases of partial response, and 12 nonresponders. We performed a logistic regression analysis to evaluate whether measured volume reduction could predict the likelihood of belonging to a certain response group. Taken together, we found 35 correct, 12 false-negative, and seven false-positive predictions. The extent of remission as assessed by CT scans 4 to 5 weeks after completion of neoadjuvant RCT leads to false predictions in a significant percentage of patients.


Optimal relative workload for managing low-injury risk in lower extremities of female field hockey players: A retrospective observational study.
Our study aimed to investigate the relative workload that is related to the injury in lower extremities of female field hockey players and to identify the optimal ratio of acute to chronic workloads (ACWR) depending on the playing position to manage low risk of sports-related injuries.Data were collected using a global positioning systems unit on a full-time basis and during competition among 52 players who were enrolled in Korea National Team. The ACWR was calculated by dividing the most recent 1 week workload by the prior 4 weeks workload. Injury risk was calculated for each category from very low to very high based on a z-score.In striker and midfielder, the injury risk was the lowest in the moderate-low category of total distance covered, meters per minute (MpM), repeated high-intensity effort bouts, and acceleration bouts, and the moderate-high category of high-intensity running distance (HID). The injury risk of a defender was the lowest in the moderate-low category of HID and MpM.The ACWR in total distance covered, MpM, repeated high-intensity effort bouts, and acceleration bouts should stay within the moderate-low category in striker and midfielder positions and HID and MpM in defender positions in order to manage low-risk of non-contact and soft tissue injuries in female field hockey players.


Comparative analysis of SARS-CoV-2 receptor ACE2 expression in multiple solid tumors and matched non-diseased tissues.
The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global public health emergency. SARS-CoV-2 employs the host cell receptor ACE2 for cellular entry. Nonetheless, the differences in ACE2 expression pattern in lung versus other normal and solid tumor tissues remain incompletely characterized. Here, we analyze a large data set comprising ACE2 mRNA expression for 7592 tissue samples across 22 types of primary solid tumor and 4461 samples across matched 18 non-diseased tissues. Our results unravel eight normal tissues and 10 primary solid tumors, which might be at high risk of SARS-CoV-2 infection. These findings may provide additional insight into the prevention and treatment of SARS-CoV-2 infection, in particular for patients with these 10 vulnerable cancer types.


Design of low-frequency ultrasonic sensors for the analysis of the draining stage of cheese production.
This work presents a new ultrasonic system with a transmission mode in the 100-200 kHz frequency range. The system, composed of ultrasonic point sources, is used to monitor the mechanical properties of cheese during the early phases of production. First, our specialized sensor system is presented, and then the results obtained with the system model are compared to the results of actual experiments using the system to monitor the evolution of the medium during draining. The results of a rheological compliance test and shock pulse ultrasonic amplitude measurements agree and correspond quite accurately to the mechanical properties of the evolving physical state of the medium. This method could be used in the future to study the effect on the final cheese quality of the process parameters that interfere with cheese grain consolidation during the draining process.


Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.
Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.


The relationship between fatigue and participation in spinal cord injury.
Cross-sectional national survey. To explore the association between fatigue and community participation frequency and provide an adjusted model of the relationship including important covariates. Canada; Community. Data were obtained from the Rick Hansen Spinal Cord Injury Registry Community Survey. We used multi-variable regression analyses with hierarchical backward elimination, including variable specification, interaction assessment and confounding assessment. Variables with statistically significant correlation with the primary-dependent variable (participation) were included for modeling. The crude model of association between fatigue and participation accounted for 7.2% of the variance in participation scores. The full model with all a priori selected variables accounted for 25.1% of variance in participation scores. The adjusted model, including the identified confounders (pain, depressive mood, comorbidities and level of injury), accounted for 21.1% of variance in participation scores. Depressive mood variables had the highest standardized beta coefficients, reflecting the largest contribution to this model. Fatigue has a statistically significant negative association with participation for individuals with spinal cord injury, when controlling for pain, depressive mood, comorbidities and level of injury. Multifaceted clinical interventions and research addressing fatigue, pain and depressive symptoms are warranted.


Cyclic AMP/cAMP-GEF pathway amplifies insulin exocytosis induced by Ca2+ and ATP in rat islet beta-cells.
Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis. Rat islets were permeabilized with alpha-toxin to measure insulin exocytosis in the fixed conditions of Ca(2+) and ATP. The effects of several agents on insulin exocytosis were observed in perifusion experiments. Cyclic AMP enhanced the Ca(2+)-induced insulin release by around 30%, independent of Ca(2+) concentrations between 10 and 3000 nmol/L. A cAMP-GEF selective cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, also amplified insulin release. The effect disappeared in the absence of ATP. Conversely, cAMP-independent gradual increase in insulin release was observed with ATP. These results suggested that the site of action of cAMP-GEF existed proximal to that of ATP. An analogue selective to PKA, N(6)-Benzoyladenosine-3',5'-cyclic monophosphate, had little effect. Also, a PKA-selective inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, reduced insulin releases induced by 1000 nmol/L Ca(2+), but did not influence the relative increase produced by Ca(2+) and cAMP. Cyclic AMP potentiated Ca(2+) and ATP-induced exocytosis to a similar relative extent independent of Ca(2+) concentrations. The process appeared to be mainly mediated by cAMP-GEF. In addition, the cAMP/cAMP-GEF pathway may enhance insulin release by replenishing the readily releasable pool.


Dynamics of field-driven domain-wall propagation in ferromagnetic nanowires.
Ferromagnetic nanowires are likely to play an important role in future spintronic devices. Magnetic domain walls, which separate regions of opposing magnetization in a nanowire, can be manipulated and used to encode information for storage or to perform logic operations. Owing to their reduced size and dimensionality, the characterization of domain-wall motion is an important problem. To compete with other technologies, high-speed operation, and hence fast wall propagation, is essential. However, the domain-wall dynamics in nanowires has only been investigated in the last five years and some results indicate a drastic slowing down of wall motion in higher magnetic fields. Here we show that the velocity-field characteristic of a domain wall in a nanowire shows two linear regimes, with the wall mobility at high fields reduced tenfold from that at low fields. The transition is marked by a region of negative differential mobility and highly irregular wall motion. These results are in accord with theoretical predictions that, above a threshold field, uniform wall movement gives way to turbulent wall motion, leading to a substantial drop in wall mobility. Our results help resolve contradictory reports of wall propagation velocities in laterally confined geometries, and underscore the importance of understanding and enhancing the breakdown field for practical applications.


Health care and life expectancy.
The four pictures of the moon accompanying the review by Ursula B. Marvin of To a Rocky Moon: A Geologist's History of Lunar Exploration by Don E. Wilhelms (9 July, p. 231) should have been in reverse order on the page.


Microcystin accumulation and biochemical responses in the edible clam Corbiculaleana P. exposed to cyanobacterial crude extract.
We investigated the accumulation and effects of cyanobacterial crude extract (CCE) containing microcystins (MCs) on the edible clam Corbiculaleana P. Toxic effects were evaluated through the activity of antioxidant and detoxification enzymes: catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferases (GSTs) from gills, foot, mantle and remaining soft tissues. Clams were exposed to CCE containing 400μg MC-LReq/L for 10days and were then kept in toxin-free water for 5days. Clam accumulated MCs (up to 3.41±0.63μg/g dry weight (DW) of unbound MC and 0.31±0.013μg/g DW of covalently bound MC). Detoxification and antioxidant enzymes in different organs responded differently to CCE during the experiment. The activity of SOD, CAT, and GST in the gills and mantle increased in MC-treated clams. In contrast, CAT and GST activity was significantly inhibited in the foot and mostly only slightly changed in the remaining tissues. The responses of biotransformation, antioxidant enzyme activity to CCE and the fast elimination of MCs during depuration help to explain how the clam can survive for long periods (over a week) during the decay of toxic cyanobacterial blooms in nature.


Sialoblastoma arising in ectopic salivary gland tissue.
Sialoblastoma is a rare, congenital or perinatal tumour predominately affecting the parotid or submandibular salivary glands. We report a case of sialoblastoma arising in ectopic salivary gland tissue in the anterior cheek of a female infant. This lesion clinically and on ultrasound mimicked a haemangioma. Following imaging and tissue diagnosis, the lesion was surgically excised with clear margins. The patient remained disease free at 6 months follow up.


Secretory stressors induce intracellular death receptor accumulation to control apoptosis.
Disruption of the Golgi apparatus can induce a distinct form of programmed cell death that has not been thoroughly characterized. We found that pharmacological application of Golgi stress leads to induction of death receptors (DRs) 4 and 5. DR4 appears to be primarily responsible for the initiation of cell death downstream of Golgi stress, whereas DR5 seems to be more important for cell death triggered by endoplasmic reticulum (ER) stress in specific cancer cell lines. DR induction downstream of either Golgi or ER stress mainly causes intracellular accumulation of DR4 presumably at the Golgi, rather than increased expression on the cell surface. Nevertheless, cells treated with secretory pathway stressors displayed an increased susceptibility to TRAIL (tumor necrosis factor related apoptosis inducing ligand), the endogenous ligand of DR4/5, probably due to intracellular sequestration of the caspase-8 regulator CFLAR (caspase-8 and FADD-like apoptosis regulator). These findings have implications for the treatment of cancer with DR agonists and our general understanding of DR signaling while highlighting the role of the Golgi apparatus as a cell death signaling platform.


Moderate to Deep Hypothermia in Patients Undergoing Thoracoabdominal Aortic Repair.
The aim of this study was to determine early and mid-term outcomes after open repair of thoracoabdominal aortic aneurysm, with moderate to deep hypothermia as part of proximal aortic management. Between April 2009 and March 2015, 44 patients underwent thoracoabdominal aortic repair by total cardiopulmonary bypass at our institute. Our strategy was to use deep (<25°C) hypothermic circulatory arrest when open proximal anastomosis is necessary (n = 18). Otherwise, proximal anastomosis with an aortic clamp was performed with moderate (25-30°C) hypothermia without circulatory arrest (n = 26). Early and mid-term outcomes were assessed in all patients. In-hospital mortality was observed in 1 patient (2.3%). Stroke was observed in 2 (4.5%) patients and a spinal cord ischemic injury in 4 (9.1%). Renal failure requiring new hemodialysis was observed in 5 patients (11.4%). There were 9 patients (20.5%) with early major adverse events (in-hospital death, stroke, spinal cord ischemic injury, renal failure requiring new hemodialysis, and prolonged intubation). Multivariable logistic regression analysis demonstrated that a history of abdominal aortic aneurysm repair (odds ratio 17.711, 95% confidence interval 1.274-246.426, P = 0.032) was the only independent predictor of early major adverse events. Deep hypothermic circulatory arrest was not an independent predictor of early major adverse events. At 5 years, overall freedom from death was 89.4 ± 6.1%. Moderate to deep hypothermia as a constituent of proximal aortic management was safe and effective in patients undergoing open repair of thoracoabdominal aortic aneurysm.


Macular symmetry testing for glaucoma detection.
To evaluate structural asymmetry in the macula using optical coherence tomography (OCT) in glaucomatous eyes with visual field defects localized to one hemifield. Complete examination, standard automated perimetry (SAP), and OCT imaging (512 A-scans) of the peripapillary retina and macula were performed. Exclusion criteria were visual acuity <20/40, diseases other than glaucoma, and SAP defects localized to both hemifields. Macular OCT images were obtained using four 5-mm radial scans centered on the foveola and passing obliquely through the macula (15 degrees superotemporally and inferotemporally). Macular measurements temporal to the fovea (T) were sub-divided into nasal (T1) and temporal (T2) segments. Macular symmetry testing (MST) was performed in T, T1, and T2 segments by comparing the mean macular thickness of the perimetrically abnormal and perimetrically normal hemi-zones (macular thickness in perimetrically normal hemi-zone/macular thickness in perimetrically abnormal hemi-zone x 100), and superior and inferior hemi-zones in normal subjects (macular thickness in superior hemi-zone/macular thickness in inferior hemi-zone x 100). MST measurements were considered to be abnormal if they exceeded the 95% limits of normal variability. Forty eyes of 40 patients (20 normal, 20 glaucoma) were enrolled (mean age 60 +/- 19 years, range 21-89). All eyes with glaucoma had associated hemifield defect (average MD = -7.23 +/- 4.8 dB, range -0.9 to -15.4). In glaucomatous eyes, mean retinal thickness in T, T1, and T2 within the perimetrically abnormal hemi-zone (222 +/- 14 microm, 224+/- 17 microm, 221 +/-13 microm, respectively) was significantly less (P = 0.002, 0.008, 0.001, respectively) than the corresponding segments in the perimetrically normal hemi-zone (235 +/- 17 microm, 237 +/- 18 microm, 233 +/- 17 microm, respectively). Normal eyes showed no difference (P = 0.17, 0.20, 0.35) in T, T1, and T2 measurements within the superior hemi-zone (254 +/- 11, 249 +/- 14, 258 +/- 14) and inferior hemi-zone (252 +/- 11, 250 +/- 13, 255 +/- 13), respectively. MST values in glaucomatous eyes were outside 95% limits of normal variability in 17/20 (85%) T segments, 16 /20 (80%) T1 segments, and 16/20 (80%) T2 segments. Localized macular thickness changes exist in glaucomatous eyes with regional visual field loss. The MST may represent a novel strategy for glaucoma diagnosis.


An eye-movement analysis of the effects of scotopic sensitivity correction on parsing and comprehension.
Does scotopic sensitivity correction enhance parsing and, thus, comprehension? Twenty-two readers with scotopic sensitivity (mean age = 20.3 yrs.; 40.9% male) parsed sentences under scotopic correction and control conditions. Measures included eye-movement indices of parsing and comprehension questions. Although eye movements suggested enhanced parsing, comprehension scores were not significantly improved with correction.


The positive piezoconductive effect in graphene.
As the thinnest conductive and elastic material, graphene is expected to play a crucial role in post-Moore era. Besides applications on electronic devices, graphene has shown great potential for nano-electromechanical systems. While interlayer interactions play a key role in modifying the electronic structures of layered materials, no attention has been given to their impact on electromechanical properties. Here we report the positive piezoconductive effect observed in suspended bi- and multi-layer graphene. The effect is highly layer number dependent and shows the most pronounced response for tri-layer graphene. The effect, and its dependence on the layer number, can be understood as resulting from the strain-induced competition between interlayer coupling and intralayer transport, as confirmed by the numerical calculations based on the non-equilibrium Green's function method. Our results enrich the understanding of graphene and point to layer number as a powerful tool for tuning the electromechanical properties of graphene for future applications.


Hyperalgesia and the reduction of monoamines resulting from lesions of the dorsolateral funiculus.
Unilateral lesions of the dorsolateral funiculus (DLF) in the rat resulted in unilateral hyperalgesia as revealed by a hindpaw withdrawal test to heat. Larger lesions involving the dorsal column and ventrolateral quadrant did not cause hyperalgesia. The levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA) and dopamine (DA) were measured in the lumbar dorsal quadrant using high performance liquid chromatography (HPLC). In hyperalgesic animals DLF lesions caused an ipsilateral reduction of all the amines and a contralateral reduction of 5-HT and NA. This suggests that serotonergic and noradrenergic axons in the DLF give a contralateral innervation. A correlation was sought between the reduction of amine level and the degree of hyperalgesia shown by individual rats on lesioned and unlesioned sides of the cord. No consistent correlation was found with any of the amines.


Tracheal injury added to cervical bone destruction due to the impact of hitting the water surface: four immersed adult bodies.
In the forensic examinations of cases of falling, two properties of the water surface, namely its nature as a hard, flat object and as a soft and ungraspable substance must be appreciated. Namely, at the moment of impact, the water surface exerts a greater resistance against relatively broad areas like the head, face and trunk than against the extremities that have a small area. Therefore, total resistance against the whole body would promote flexure. We experienced 72 autopsy cases of immersed bodies during a 4-year period. The cause of death for 64 of these with or without cervical vertebra fracture was drowning. In these cases, the various heights of the falls could often be estimated at the scene. A characteristic pattern of cervical injury with involvement of hyoid bone and thyroid cartilage in addition to cervical vertebra fracture plus rare involvement of the trachea was identified. When a fall from a relatively low height is broken by the water surface, to a certain degree physical findings that differ from those seen in falls to the ground from extreme heights are left mediated by different underlying mechanisms.


A facile approach for grafting ion imprinted polymer onto magnetic multi-walled carbon nanotubes for selective removal and preconcentration of cadmium in food and wastewater samples prior to atomic spectrometric determination.
A 3D Fe3O4@MWCNT-CdIIP was synthesized by the oxidizing surface of multi-walled carbon nanotubes with carboxylic acid end groups and its subsequent termination with an ion imprinted polymer. An artificial neural network manifests better predictability than the central composite design methodology for optimising the adsorption procedure. The adsorption capacity was 109 mg g-1 (2.5 times more than non-imprinted polymer) under optimized conditions (pH; 5.6, time; 15 min, concentration; 800 μg mL-1 temperature; 25 °C), which was in accord with Toth isotherm. Fractal-like pseudo-second-order kinetics was found reasonably fast, with 66 % adsorption in 5 min. Solid phase extraction coupled Flame atomic absorption spectrometry method provides selective recognition towards Cd(II), with limit of detection; 1.13 µg/L, limit of quantification; 3.21 µg/L after preconcentration (preconcentration factor; 50) and good robustness. The developed method was applied for Cd(II) determination in food (tea, coffee, bread, tobacco, radish, spinach), water and wastewater (>99 % removal as well). Cd(II) loaded IIP was further utilized to remove anionic dyes with >95 % removal.


Methodologies for assessing exposures to metals: human host factors.
Many factors affect bioavailability of metals. Host factors can be defined as any attribute that can influence the amount and degree of metal exposure. In this series of articles, a wide range of aspects are discussed concerning the methodologies for assessing exposures to metals. These aspects include speciation, bioaccessibility, and bioavailability in the environment, in food, and in feed. This article complements the articles by Peakall and Burger and by Calderón et al., reviewing human host factors. In this article, measurement and assessment methods are discussed as they apply to risk assessment, with examples for arsenic, cadmium, chromium, and lead, as well as special consideration for source issues and children's risk. Finally, several examples from the current literature are cited to illustrate some of the approaches presently in use as well as areas of research that require further consideration, including longitudinal studies, as well as better biomonitoring and assessment strategies.


Cell density, dimethylsulfoxide concentration and needle gauge affect hydrogel-induced bone marrow mesenchymal stromal cell viability.
Mesenchymal stromal cells (MSCs) have shown potential therapeutic benefits for a range of medical disorders and continue to be a focus of intense scientific investigation. Transplantation of MSCs into injured tissue can improve wound healing, tissue regeneration and functional recovery. However, implanted cells rapidly lose their viability or fail to integrate into host tissue. Hydrogel-seeded bone marrow (BM)-MSCs offer improved viability in response to mechanical forces caused by syringe needles, cell density and dimethylsulfoxide (DMSO) concentration, which in turn, will help to clarify which factors are important for enhancing biomaterial-induced cell transplantation efficiency and provide much needed guidance for clinical trials. In this study, under the control of cell density (<2 × 107 cells/mL) and final DMSO concentration (<0.5%), hydrogel-induced BM-MSC viability remained >82% following syringe needle passage by 25- or 27-gauge needles, providing improved cell therapeutic approaches for regenerative medicine.


Quantitative Real-Time PCR and Platelia Galactomannan Assay for the Diagnosis of Invasive Pulmonary Aspergillosis: Bronchoalveolar Lavage Fluid Performs Better Than Serum in Non-neutropaenic Patients.
The diagnosis of invasive pulmonary aspergillosis (IPA) is still in challenge in clinical practice, particularly for those patients without an obvious neutropaenia. In this study, a well-validated qPCR method and Platelia galactomannan (GM) assay were compared for their diagnostic performance using paired samples of bronchoalveolar lavage (BAL) fluid and serum from predominantly non-neutropaenic patients. In the serum samples, qPCR showed a comparable performance with GM assay in terms of sensitivity and specificity. In the BAL samples, qPCR and GM assay both demonstrated a good sensitivity (90 vs. 90 %); however, the specificity of qPCR was higher than that of GM assay (92.5 vs. 68.8 %, P < 0.001) in these samples. A better sensitivity was obtained with BAL compared with serum samples for both GM assay (90 vs. 50 %) and qPCR (90 vs. 60 %). In conclusion, in non-neutropaenic patients, BAL appears to provide improved sensitivity for both GM and qPCR assays. BAL qPCR offers a better diagnostic value for IPA compared with BAL GM assay, significantly increasing the specificity without affecting the sensitivity.


Successful role of radiation therapy: Account for every single gray and make every single gray count.
Combined-modality treatment involving immuno-chemotherapy with or without radiation has become the mainstay of treatment for aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL). Long-term goals in the treatment of DLBCL are to keep improving the therapeutic ratio and to extend survival; these goals have been accomplished largely by (a) gaining insight into disease biology and developing biologically based criteria to guide choice of therapy, (b) avoiding unnecessarily long courses of chemotherapy, and (c) reducing both the size of the radiation fields and the radiation dose. Here I review the available literature on which clinical presentations can benefit the most from radiation; how the availability of advanced imaging has led to radical changes in the use of radiation therapy in DLBCL; and examples of best-practice radiation planning and delivery.


Effects of time of estrogen deprivation on anxiety-like behavior and GABAA receptor plasticity in ovariectomized rats.
Ovariectomized animals have frequently been used to study the effects of estrogen deficiency on mood disorders, particularly anxiety disorder. However, a range of results including anxiolytic, anxiogenic, and no behavioral effects have been reported. One discrepancy was the different in behavioral testing time following ovariectomized; therefore, the aim of this study was to examine the effects of time of estrogen deprivation on anxiety-like behavior and on GABAA receptor subunit gene expressions in ovariectomized rats. The GABAA receptor was of special interest as it had been shown to be influenced by estrogen. In this study, adult female Wistar rats were ovariectomized and randomly assigned into 2 groups: ovariectomized-rat (Ovx) and ovariectomized-rat treated with estrogen (E2) at the dosage of 1μg/kg BW. At 7, 14, 21 and 28 days after ovariectomy, the rats were tested with elevated T-maze (ETM) and open field. We found that after ovariectomy, the Ovx showed signs of anxiety as demonstrated by the increased in inhibitory avoidance latency in the ETM with significant effect at day 21 and even higher at day 28. On the other hand, the escape latency was not differed between each time point. These behavioral data implied that the anxiety in term of generalized anxiety disorder as interpreted from impaired inhibitory avoidance in the ETM was affected by estrogen depletion; while, the anxiety disorder in term of panic disorder as shown by escape latency was unaffected. For gene expression analysis, the GABAA receptor α2-, α3- and α4-subunits in Ovx groups were significantly increased in the midbrain compared to E2 groups; whereas, in the amygdala, the gene expressions were not different between Ovx and E2 groups. In conclusion, these results indicated that ovariectomized as early as 21 day can induce anxiety and the altered GABAA receptor subunit may be partially responsible for anxiety following estrogen deprivation.


Potential therapeutic effects and applications of Eucommiae Folium in secondary hypertension.
Eucommiae Folium (EF), a traditional Chinese medicine, has been used to treat secondary hypertension, including renal hypertension and salt-sensitive hypertension, as well as hypertension caused by thoracic aortic endothelial dysfunction, a high-fat diet, and oxidized low-density lipoprotein. The antihypertensive components of EF are divided into four categories: flavonoids, iridoids, lignans, and phenylpropanoids, such as chlorogenic acid, geniposide acid and pinoresinol diglucoside. EF regulates the occurrence and development of hypertension by regulating biological processes, such as inhibiting inflammation, regulating the nitric oxide synthase pathway, reducing oxidative stress levels, regulating endothelial vasoactive factors, and lowering blood pressure. However, its molecular antihypertensive mechanisms are still unclear and require further investigation. In this review, by consulting the relevant literature on the antihypertensive effects of EF and using network pharmacology, we summarized the active ingredients and pharmacological mechanisms of EF in the treatment of hypertension to clarify how EF is associated with secondary hypertension, the related components, and underlying mechanisms. The results of the network pharmacology analysis indicated that EF treats hypertension through a multi-component, multi-target and multi-pathway mechanism. In particular, we discussed the role of EF targets in the treatment of hypertension, including epithelial sodium channel, heat shock protein70, rho-associated protein kinase 1, catalase, and superoxide dismutase. The relevant signal transduction pathways, the ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/eNOS/NO/Ca2+ pathways, are also discussed.


Assessment of Reward-Related Brain Function After a Single Dose of Oxytocin in Autism: A Randomized Controlled Trial.
Autism spectrum disorder (ASD) is characterized by difficulties in social communication and interaction, which have been related to atypical neural processing of rewards, especially in the social domain. As intranasal oxytocin has been shown to modulate activation of the brain's reward circuit, oxytocin might ameliorate the processing of social rewards in ASD and thus improve social difficulties. In this randomized, double-blind, placebo-controlled, crossover functional magnetic resonance imaging study, we examined effects of a 24-IU dose of intranasal oxytocin on reward-related brain function in 37 men with ASD without intellectual impairment and 37 age- and IQ-matched control participants. Participants performed an incentive delay task that allows the investigation of neural activity associated with the anticipation and receipt of monetary and social rewards. Nonsignificant tests suggested that oxytocin did not influence neural processes related to the anticipation of social or monetary rewards in either group. Complementary Bayesian analyses indicated moderate evidence for a null model, relative to an alternative model. Our results were inconclusive regarding possible oxytocin effects on amygdala responsiveness to social rewards during reward consumption. There were no significant differences in reward-related brain function between the two groups under placebo. Our results do not support the hypothesis that intranasal oxytocin generally enhances activation of reward-related neural circuits in men with and without ASD.


Acetaminophen and hepatic dysfunction in infectious mononucleosis.
Two family members developed severe hepatitic dysfunction in association with infectious mononucleosis and acetaminophen administration. Since severe hepatitis is an extremely rare complication of infectious mononucleosis, we postulate that the hepatic dysfunction was induced by acetaminophen.


Duration of cART Before Delivery and Low Infant Birthweight Among HIV-Infected Women in Lusaka, Zambia.
To estimate the association between duration of combination antiretroviral therapy (cART) during pregnancy and low infant birthweight (LBW), among women ≥37 weeks of gestation. We conducted a retrospective cohort study of HIV-infected women who met eligibility criteria based on CD4 count ≤350 but had not started cART at entry into antenatal care. Our cohort was restricted to births that occurred ≥37 weeks of gestation. We used Poisson models with robust variance estimators to estimate risk ratios (RRs) and 95% confidence intervals (CIs). Of 50,765 HIV-infected women with antenatal visits between January 2009 and September 2013, 4474 women met the inclusion criteria. LBW occurred in 302 pregnancies (7%). Nearly two-thirds of women (62%) eligible to initiate cART never started treatment. Overall, 14% were on cART for ≤8 weeks, 22% for 9-20 weeks, and 2% for 21-36 weeks. There was no evidence of an increased risk of LBW for women receiving cART for ≤8 weeks (RR = 1.22; 95% CI: 0.77 to 1.91), 9-20 weeks (RR = 1.23; 95% CI: 0.82 to 1.83), or 21-36 weeks (RR = 0.87; 95% CI: 0.22 to 3.46), compared with women who never initiated treatment. These findings were consistent across several sensitivity analyses. Longer duration of cART was not associated with poor fetal growth among term pregnancies in our cohort. However, the relationship between cART and adverse pregnancy outcomes remains complicated. Continued work is required to investigate causality. An understanding cART's impact on adverse pregnancy outcomes is essential as cART becomes the cornerstone of preventing mother-to-child transmission programs globally.


Abundant porewater Mn(III) is a major component of the sedimentary redox system.
Soluble manganese(III) [Mn(III)] can potentially serve as both oxidant and reductant in one-electron-transfer reactions with other redox species. In near-surface sediment porewater, it is often overlooked as a major component of Mn cycling. Applying a spectrophotometric kinetic method to hemipelagic sediments from the Laurentian Trough (Quebec, Canada), we found that soluble Mn(III), likely stabilized by organic or inorganic ligands, accounts for up to 90% of the total dissolved Mn pool. Vertical profiles of dissolved oxygen and dissolved and solid Mn suggest that soluble Mn(III) is primarily produced via oxidation of Mn(II) diffusing upwards from anoxic sediments with lesser contributions from biotic and abiotic reductive dissolution of MnO2. The conceptual model of the sedimentary redox cycle should therefore explicitly include dissolved Mn(III).


Production of an ovine monoclonal antibody to testosterone by an interspecies fusion.
Hybridomas were made between NS1/1-Ag4-1 mouse myeloma cells and peripheral blood lymphocytes from a sheep immunized with a testosterone-protein conjugate. ELISAs were developed to detect ovine IgG and specific ovine anti-testosterone and these were used to screen the colonies. Although the cells fused acceptably only 3% of colonies secreted detectable quantities of antibody. The antibody was secreted at low levels (2.5 ng/ml) but was of high affinity (KD = 7.63 x 10(-12) M/1). One line, O/M 4.22, continued to secrete in culture for four months until the termination of the experiment.


Combination therapy for portopulmonary hypertension with intravenous iloprost and oral bosentan.
Severe portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis and carries a poor prognosis. In the last years, intravenous (IV) epoprostenol has been suggested to be the optimal medical treatment for PPHTN, and recently oral bosentan has been shown to be efficacious and safe in selected patients with PPHTN. We report a case of PPHTN suffering from recurrent right heart failure while on treatment with IV iloprost, which was successfully managed by combination therapy with IV iloprost plus oral bosentan, providing sustained cardiopulmonary stabilization for at least two years. This report documents the first case of a patient with PPHTN successfully treated with the combination of IV iloprost and oral bosentan over an extended period. Thus, combination therapy with IV iloprost and oral bosentan might be a promising new option for selected patients suffering from PPHTN and recurrent right heart failure.


Analysis of cutaneous lymphomas in a medical center in Bahia, Brazil.
To evaluate the frequency of the different types of cutaneous lymphoma (CL) in 1 university hospital in Brazil and compare this frequency with those observed in other countries. After review, 72 (84.7%) cases of primary cutaneous T-cell lymphoma (CTCL) and 13 (15.3%) cases of primary cutaneous B-cell lymphoma (CBCL) were included. Of the CTCLs, 40.3% were mycosis fungoides (MF); 26.4% were adult T-cell leukemias/lymphomas (ATLs); 23.6% were peripheral T-cell lymphomas, unspecified; and 8.3% were anaplastic large cell lymphomas. Of the MF cases, 17.2% progressed to transformed MF. Five-year survival for primary human T-cell lymphotropic virus type 1-negative CTCL, ATL, and CBCL was 64.0%, 42.1%, and 62.5%, respectively. MF and ATL were the most frequent primary CTCLs. The frequencies observed here are close to those observed in Peru but different from those of European countries. Unfortunately, the World Health Organization/European Organization of Research and Treatment of Cancer classification does not include primary cutaneous ATL.


Comparison of two alcohol hand rubbing techniques regarding hand surface coverage among hospital workers: a quasi-randomized controlled trial.
The adapted 6-step without interlock (A6Sw/oI) hand rub technique, commonly practiced in Japan, adds the "wrist" but omits the "interlock" step compared to the WHO 6-step technique (WHO6S). The first objective of this study was to assess the differences of the two techniques regarding surface coverage. The second objective was to analyze the coverage differences between hand sizes. Hospital workers went under stratified quasi-randomization by glove size. The overall mean coverage, and the coverage of the sections of the hands were evaluated by fluorescent dye-based coverage assessment using a digital device with artificial intelligence technology. Total of 427 workers were randomly allocated to WHO6S (N = 215) or the A6Sw/oI (N = 212). The overall mean dorsum coverage by WHO6S and A6Sw/oI was 90.6% versus 88.4% (p < 0.01), and the percentage of the participants with insufficient coverage of the backs of the four fingers ranged from 0.0-7.4% versus 28.2-51.4% (p < 0.001). Dorsum coverage varied largely between hand size for both techniques, and significant differences were found between small and large hands. The WHO6S was superior to the locally adapted technique regarding hand surface coverage. Hand size should be considered when assessing coverage differences between procedures. No trial registrations or fundings.


Induction of virus specific and H-2 restricted cytotoxic T cells by UV inactivated murine cytomegalovirus.
Infection of C3H mice with live or UV-inactivated murine cytomegalovirus (MCMV) was able to generate population(s) of lymphocytes in the spleen (CTL) which could exert a lytic effect against L cells infected with MCMV but not against uninfected or those infected with HSV-1. The effector cells proved to be theta-bearing T cells and the lysis of target cells was H-2 restricted. Data presented show that early viral protein synthesis but not viral DNA synthesis was necessary for the appearance of relevant antigenic determinant(s) on target cells. The results of co-capping experiments suggest that H-2 molecules may have close association with MCMV induced product(s) as also with murine leukemia virus glycoprotein (gp70) which is carried by normal L cells. Despite this observation, anti-H-2 serum effectively blocked the cytolysis whereas anti-gp70 and anti-MCMV sera failed. Anti-MCMV serum was effective in blocking cytolysis, only if the L cells were infected for 24 hours and then used as targets. MCMV infected L cells which were coated externally with inactivated Sendai virus could be effectively recognised by MCMV as also by sendai specific CTL. That the cytotoxicity exerted on such targets was of specific nature was revealed by the results of competitive blocking experiments with unlabelled targets.


A Proposal for an Out-of-Range Glycemic Population Health Safety Measure for Older Adults With Diabetes.
To evaluate patient-level glycemic control and facility variation of a proposed out-of-range (OOR) measure (overtreatment [OT] [HbA1c <7% (53 mmol/mol)] or undertreatment [UT] [>9% (75 mmol/mol)]) compared with the standard measure (SM) (HbA1c <8% [64 mmol/mol]) in high-risk older adults. Veterans Health Administration patients ≥65 years of age in 2012 who were taking antihyperglycemic agents in 2013 were identified. Patient-level rates and facility-level rates/rankings were calculated by age and comorbid illness burden. We identified 303,097 patients who were taking antiglycemic agents other than metformin only. The study population comprised 193,689 patients with at least one significant medical, neurological, or mental health condition; 98.2% were taking a sulfonylurea and/or insulin; 55.2% were aged 65-75 years; and 44.8% were aged >75 years. The 47.4% of patients 65-75 years met the OOR measure (33.4% OT, 14% UT), and 65.7% met the SM. For patients aged >75 years, rates were 48.1% for OOR (39.2% OT; 8.9% UT) and 73.2% for SM. Facility-level rates for OOR for patients aged 65-75 years ranged from 33.7 to 60.4% (median 47.4%), with a strong inverse correlation (ρ = -0.41) between SM and OOR performance rankings. Among the best-performing 20% facilities on the SM, 14 of 28 ranked in the worst-performing 20% on the OOR measure; 12 of 27 of the worst-performing 20% facilities on the SM ranked in the best-performing 20% on the OOR measure. Facility rankings that are based on an SM (potential benefits) and OOR measure (potential risks) differ substantially. An OOR for high-risk populations can focus quality improvement on individual patient evaluation to reduce the risk for short-term harms.


A 14-year nationwide epidemiological analysis of delayed endolymphatic hydrops in Japan.
Delayed endolymphatic hydrops (DEH) is an inner ear disease that causes recurrent vertigo in the ipsilateral ear or fluctuating hearing in the contralateral ear due to endolymphatic hydrops secondary to preceding deafness. There are few reports of large, multicentre studies investigating the clinical-epidemiological characteristics of DEH. This study aimed to clarify the characteristics of DEH in Japan. Clinical data on 662 patients with DEH were analysed by nationwide, multicentre surveys conducted by the Peripheral Vestibular Disorders Research Group of Japan. The proportion of ipsilateral DEH (IDEH) was slightly higher than that of contralateral DEH (CDEH) at 55.4%. The time delay between onset of precedent deafness and onset of DEH was significantly longer for CDEH than for IDEH. The most common cause of precedent deafness was a disease of unknown cause with onset in early childhood (33.1%). Epidemiological characteristics were not significantly different between CDEH with and without vertigo. DEH appearing to be caused by viral labyrinthitis has a high rate of onset within 40 years of precedent deafness. Clinical and epidemiological characteristics of IDEH, CDEH with vertigo, and CDEH without vertigo were very similar. The clinical-epidemiological characteristics of DEH in Japan were clarified.


Biomarkers in infection and sepsis: Can they really indicate final outcome?
Infectious diseases are among the most common reasons for admission to hospital and can easily lead to sepsis. Sepsis is globally associated with increased mortality, and although biomarkers could help clinicians in the early diagnosis of sepsis and immediate onset of antibiotics, there are always questions to be answered about their usefulness in the prognosis of infectious diseases. This article reviews some of the available biomarkers used in infectious diseases and sepsis in order to evaluate their utility to predict mortality and unfavourable outcome. Several studies present the pros and cons of each compound, but it is obvious that the ideal biomarker, with high sensitivity and specificity, cost effectiveness and with definite cut-off ranges and time of blood sampling, is yet to be found.


How can attending physicians be more attentive? On being attentive versus producing attentiveness.
This article is about caregivers being attentive to patients in healthcare. From earlier work on the understanding of the other, we know that it is impossible to completely understand the experiences of others. By the sharing of subjectivity-intersubjectivity-we may try to 'grasp' the other's point of view. However, we can never assume that the same experience produces the same experience. Now, if it is principally impossible to understand the experience of one another, and if paying attention always implies an understanding of what to pay attention to, then how is it possible to be attentive to the experiences of those who are entirely at the mercy of our care? How can caregivers perceive the impossibility of understanding the experiences of patients as an appeal to be attentive to their experiences? This is discussed in this article. It departs from the authors being confronted with inexplicabilities in the empirical study of attentiveness in healthcare. It presents two examples and discusses the meaning of these emergent properties. This leads to a discussion of the existent literature on the indefiniteness and openness of attentiveness. It becomes clear why, although we can understand and predict much of it, attentiveness will always be characterized by a certain uncontrollability as well.


Trial of labor compared to repeat cesarean section in women with no other risk factors than a prior cesarean delivery.
To compare outcomes with trial of labor after cesarean (TOLAC) or elective repeat cesarean delivery on maternal request (ERCD-MR). Prospective cohort study. Danish university hospital. Women with TOLAC (n = 1161) and women with ERCD-MR (n = 622) between 2003 and 2010. Exclusion criteria were diabetes, two prior cesarean sections, index cesarean at a different hospital, a delivery after the index cesarean, twin gestation, gestational age <37(+0) weeks and stillbirth. Data were obtained from the Aarhus Birth Cohort database, which comprised prospective registration of the deliveries. Adverse neonatal outcomes, risk factors for emergency cesarean, and uterine rupture in case of TOLAC. TOLAC was associated with an increased risk of neonatal depression [odds ratio (OR) 3.6, 95% confidence interval (CI) 1.1-19.1] and neonatal intensive care unit admission (adjusted OR 1.9, 95% CI 1.3-2.8). Within the TOLAC group 67% delivered vaginally. In the TOLAC group 1.3% (n = 15) of the women had a complete uterine rupture. None of these infants had sequelae after 12 months. Significant risk factors for emergency cesarean were no prior vaginal delivery (adjusted OR 1.8, 95% CI 1.1-3.0), index emergency cesarean during labor (adjusted OR 3.0, 95% CI 2.3-4.1), maternal age ≥35 years (adjusted OR 1.9, 95% CI 1.3-2.8), pre-pregnancy body mass index ≥30 (adjusted OR 2.1, 95% CI 1.3-3.3), and birthweight 4000-4499 g (adjusted OR 1.5, 95% CI 1.1-2.1). Uterine rupture was associated with the use of epidural analgesia (OR 2.2, 95% CI 1.1-4.9) and no prior vaginal delivery (p = 0.03). TOLAC is an acceptable individualized option for women without major risk factors.


Postnastal changes in the concentration of carnitine and acylcarnitines in the rat brain.
The concentration of total and free carnitine (TC and FC) together with short-chain and long-chain acylcarnitines (SCAC and LCAC) has been determined in whole brain of female rats from birth to maturity. The concentration of TC and SCAC increases postnatally to reach a peak 10 days after birth. The concentration of LCAC is high relative to adult brain between 1 and 10 days of age before falling to a low level. The change in LCAC concentration correlates with previously described developmental changes of palmitoyl-CoA: carnitine acyl transferase activity and fatty acid oxidation. The ratio of LCAC/FC declines postnatally while the SCAC/FC ratio is high at birth and increases further in adult brain. The results are consistent with the concepts of carnitine participating in exchange of short-chain acyl groups and in the transfer of fatty acids into mitochondria as an alternative energy supply in neonatal rat brain.


[The use of dry-air radon baths in the treatment of patients with reactive arthritis].
66 patients with reactive arthritis took dry air radon baths. Radon concentration was 1.5 kBq/l (40 nCi/l), temperature regimens 27 +/- 3 and 37 +/- 3 degrees C. The procedures produced analgetic, anti-inflammatory and immunocorrective effects.


Ventricular Septal Defect in a 66-Year-Old Man.
A 66-year-old man presented with a moderate-sized ventricular septal defect and severe pulmonary hypertension that was responsive to vasodilator therapy. His electrocardiogram demonstrated biatrial enlargement and biventricular hypertrophy. Presentation at this age is unusual for this type of shunt.


Defining characteristics and risk indicators for diagnosing nursing home-acquired pneumonia and aspiration pneumonia in nursing home residents, using the electronically-modified Delphi Method.
In nursing home residents, it is not possible to distinguish pneumonia and aspiration pneumonia clinically. International literature reveals no consensus on which and how many characteristics and risk indicators must be present to diagnose (nursing home-acquired) pneumonia and aspiration pneumonia. The aim of this survey was to reach consensus among a panel of clinical medical experts in geriatrics and pulmonology about the characteristics required for diagnosing pneumonia, and about the risk indicators needed to consider the diagnosis aspiration pneumonia in nursing home residents with pneumonia. Literature review and three expert-rating iterations using the electronically-modified Delphi Method were carried out. After each expert rating iteration, data analysis was performed. Qualitative responses and additional (nursing home-acquired) pneumonia characteristics which were mentioned in reply to structured open-ended questions were summarised, whilst similar responses were combined and these combinations were ordered by frequency in order to use them in the next iteration. Characteristics which failed to reach consensus were considered as inconclusive and eliminated. Consensus was reached when at least 70 % of the participants agreed. Literature review revealed 16 currently used common characteristics for diagnosing (nursing home-acquired) pneumonia. No consensus was reached about characteristics and the number of characteristics required for diagnosing (nursing home-acquired) pneumonia. However, 57 % agreed that dyspnea, fever, deterioration of general functioning, tachypnea and crepitation with auscultation are the most important characteristics and the responses by the participants suggested that two or three characteristics should be present. Subsequently, 80 % of the participants agreed on the risk indicators dysphagia, choking incident, (history of) tube feeding, neurological disease and cognitive impairment for considering the diagnosis aspiration pneumonia in nursing home residents with pneumonia. No final consensus could be reached about which and how many characteristics are required for diagnosing pneumonia in nursing home residents. However, the results indicated that dyspnea, fever, deterioration of general functioning, tachypnea and crepitation with auscultation are characteristics of some importance and that at least two or three characteristics should be present. With regard to considering aspiration pneumonia in nursing home residents with pneumonia, final consensus was reached about the risk indicators dysphagia, choking incident, (history of) tube feeding, neurological disease and cognitive impairment.


Heated, humidified, high-flow nasal oxygen usage in the adult Emergency Department.
The aim of this study was to determine the role that heated, humidified high-flow nasal oxygen (HHHFNO) plays in the adult ED with particular focus on the indications and outcomes of use. An explorative study was undertaken using retrospective chart review to identify characteristics of adult patients who received HHHFNO in a tertiary adult ED between January and December 2014. Thirty-nine patients were identified as having received HHHFNO during the study period with a range of indications for this use. No clear guidelines existed for initiation of this use. Two patients failed on HHHFNO therapy, requiring increased respiratory support; twenty-seven patients were admitted to hospital with HHHFNO still being delivered and seven patients were successfully treated with HHHFNO in the ED. The use of HHHFNO was associated with a 4.91bpm (95% CI 2.23-7.59; P=0.001) decrease in mean RR and an 11.26bpm (95% CI 4.62-17.90; P=0.002) decrease in mean HR from baseline at 120min of use. Hypercapnic patients showed a significant decrease in mean PaCO2 levels after one hour of HHHFNO use (70.33mmHg (SD 19.63) vs. 55.00mmHg (SD 13.28), P=0.041) with no change in PaCO2 levels in patients who were not hypercapnic prior to HHHFNO use (PaCO2 32.71mmHg (SD 5.28) vs. 32.38mmHg (SD 3.70), P=0.919). HHHFNO is currently being used as a device for supplemental oxygen delivery within the adult Emergency Department; however, further research is needed in this area to quantify its use in many of the indications seen.


Nerve growth factor in normal and psoriatic skin equivalent models.
Our objective was to determine the pattern and time course of nerve growth factor expression in an established skin equivalent model that we have used in the past to study wound healing and psoriasis phenotypes. Skin equivalents were constructed in triplicate using normal neonatal foreskin keratinocytes plated on collagen gels containing fibroblast lines. These lines were derived from five specimens of psoriatic lesions, three specimens of normal skin from patients with psoriasis, and three specimens of eyelid skin from normal donors. Immunohistochemistry and a monoclonal nerve growth factor-b antibody were used to determine the pattern of protein staining over 2 weeks. We looked at the wound healing phenotype using the skin equivalent model for 7-14 days. When keratinocytes invaginate into the dermis of skin equivalents (beginning at around 7 days of growth), dark staining of nerve growth factor was seen under the basal membrane zone, suggesting that nerve growth factor serves in the development of the basal membrane zone and the epidermis, and may influence the migration of nerves through the basal membrane zone into the regenerated skin.


Age-dependent changes of the periodontal ligament in rats.
Even after the end of the natural tooth eruption, there is a continuous renewal of the periodontal collagenous fiber system, depending on functional demands. The aim of this study was to analyse the age-dependent changes and regional differences of the collagen renewal rate of the periodontal ligament in healthy rats. The study was performed by autoradiography of the molars of rats aged 1, 8, and 18 months, where collagen was labelled by intravenously applied 3H-proline. After an 8-hour incorporation period, the animals were killed. For comparative examinations, molar roots were subdivided into cervical, middle, and apical thirds. Structural and quantitative analyses were performed by light microscopy and autoradiography, using an image-analysing computer-assisted operating unit that determined the 3H-proline-labelled collagen by photometry based on extinction measurement. With increasing age of the animals, the number of silver grains (3H-proline-blackened collagen) was reduced and the quantitative evaluation indicated a reduction of 3H-proline in the periodontal ligament. The lowest level of 3H-proline activities was observed in the middle, and the highest level in the apical root third, independent of age. All preparations revealed condensations of silver grains, which were located in the region of the periodontal ligament adjacent to the alveolar bone, but did not reveal any preferred position with regard to the dental topography. With progressive age, the uptake of 3H-proline in the periodontal ligament was reduced by about 20 to 30%, a result that corresponds to a decrease in collagenous fiber production. Collagen was mainly formed in the apical and cervical root third, starting from the alveolar bone side, presumably in response to functional strain.


[Ascites as a complication of hepatic storage of hydroxyethyl starch in long-term dialysis].
Three adult dialysis patients developed ascites after having received repeatedly the plasma substitute hydroxyethyl starch (HES 40/0.5). In two cases (total dose 180, and 330 g HES, respectively) the ascites was reversible after discontinuation of the HES administration. In the third case (total dose 915 g HES) the ascites could be controlled only by implantation of a Denver shunt. In this latter case it was shown by histological, electron microscopical, and biochemical findings that the ascites was caused by hepatic sinusoidal obstruction due to an extreme storage of HES in the sinusoidal lining cells. Additional storage was detected in hepatocytes, bile duct epithelia, endothelial cells, and fibroblasts in the portal tracts. Biochemically HES was found in liver tissue at a concentration of 4% (w/w). Although in renal impairment plasma clearance of HES is not significantly different from normal individuals, long-term administration of HES must be regarded inadvisable because of tissue storage which apparently is especially significant in this condition.


Tracing geochemical sources and health risk assessment of uranium in groundwater of arid zone of India.
Water quality degradation and metal contamination in groundwater are serious concerns in an arid region with scanty water resources. This study aimed at evaluating the source of uranium (U) and potential health risk assessment in groundwater of the arid region of western Rajasthan and northern Gujarat. The probable source of vanadium (V) and fluorine (F) was also identified. U and trace metal concentration, along with physicochemical characteristics were determined for 265 groundwater samples collected from groundwater of duricrusts and palaeochannels of western Rajasthan and northern Gujarat. The U concentration ranged between 0.6 and 260 μg L-1 with a mean value of 24 μg L-1, and 30% of samples surpassed the World Health Organization's limit for U (30 μg L-1). Speciation results suggested that dissolution of primary U mineral, carnotite [K2(UO2)2(VO4)2·3H2O] governs the enrichment. Water-rock interaction and evaporation are found the major hydrogeochemical processes controlling U mineralization. Groundwater zones having high U concentrations are characterized by Na-Cl hydrogeochemical facies and high total dissolved solids. It is inferred from geochemical modelling and principal component analysis that silicate weathering, bicarbonate complexation, carnotite dissolution, and ion exchange are principal factors controlling major solute ion chemistry. The annual ingestion doses of U for all the age groups are found to be safe and below the permissible limit in all samples. The health risk assessment with trace elements manifested high carcinogenic risks for children.


On the clubionid spiders (Araneae, Clubionidae) from Xishuangbanna, China, with descriptions of two new genera and seven new species.
Clubionid spiders from Xishuangbanna, Yunnan Province, China are studied. A total of seven genera and 13 species have been found, including two new genera with one new species each, i.e., Ramosatidia Yu & Li, gen. nov., with R.situ Yu & Li, sp. nov. (♂♀) as the type species and Sinostidia Yu & Li, gen. nov., with S.shuangjiao Yu & Li, sp. nov. (♂♀) as the type species. Five additional new species are Sinostidiadujiao Yu & Li, sp. nov. (♂♀), Matidiaxieqian Yu & Li, sp. nov. (♂♀), Nusatidiachangao Yu & Li, sp. nov. (♂♀), N.mianju Yu & Li, sp. nov. (♀), and N.subjavana Yu & Li, sp. nov. (♀). The following genera and species are reported from China for the first time: Malamatidia Deeleman-Reinhold, 2001, Pteroneta Deeleman-Reinhold, 2001, Malamatidiazu Jäger & Dankittipakul, 2010, Nusatidiaaeria (Simon, 1897), N.camouflata Deeleman-Reinhold, 2001, Porrhoclubionapteronetoides (Deeleman-Reinhold, 2001), and Pteronetaultramarina (Ono, 1989). Malamatidiachristae Jäger & Dankittipakul, 2010 syn. nov. is a junior synonym of Malamatidiazu. Nusatidiarama Deeleman-Reinhold, 2001 syn. nov. is synonymised with N.aeria (Simon, 1897).


Hemobilia Caused by Arterioportal Fistula Following Percutaneous Liver Biopsy Complicated by Acute Cholecystitis and Review of the Literature.
We present a case of a 44-year-old male with chronic hepatitis B that visited the Emergency Department due to epigastric pain after a liver biopsy. The ultrasonography revealed signs of bleeding in the bile ducts. and angiography visualized an arterioportal fistula. Selective right hepatic artery branch embolization was performed, and the bleeding was controlled. Although, the clinical picture was initially improved, the patient presented later with acute abdomen, obstructive jaundice and fever. The patient underwent cholecystectomy with bile duct exploration and placement of a Kehr's T tube in the common bile duct. The postoperative course was uneventful. We also review the relevant literature concerning arterioportal fistula manifested as hemobilia as well as acute cholecystitis occurring after hemobilia.


AAV1.NT-3 gene therapy in the SOD1KO mouse model of accelerated sarcopenia.
Sarcopenia, an age-related loss of muscle mass, is a critical factor that affects the health of the older adults. The SOD1KO mouse is deficient of Cu/Zn superoxide dismutase, used as an accelerated aging model. We previously showed that NT-3 improves muscle fibre size by activating the mTOR pathway, suggesting a potential for attenuating age-related muscle loss. This study assessed the therapeutic efficacy of AAV1.NT-3 in this accelerated aging model. Twelve 6 months old SOD1KO mice were injected intramuscularly with a 1 × 1011 vg dose of AAV1.tMCK.NT-3, and 13 age-matched SOD1KO mice were used as controls. The treatment effect was evaluated using treadmill, rotarod and gait analyses as well as histological studies assessing changes in muscle fibre, and fibre type switch, in tibialis anterior, gastrocnemius, and triceps muscles, and myelin thickness by calculating G ratio in sciatic and tibial nerves. Molecular studies involved qPCR experiments to analyse the expression levels of mitochondrial and glycolysis markers and western blot experiments to assess the activity of mTORC1 pathway. Treatment resulted in a 36% (154.9 vs. 114.1; P < 0.0001) and 76% increase (154.3 vs. 87.6; P < 0.0001) in meters ran, with treadmill test at 3 and 6 months post gene delivery. In addition, the treated cohort stayed on rotarod 30% (52.7 s vs. 40.4 s; P = 0.0095) and 54% (50.4 s vs. 32.7 s; P = 0.0007) longer, compared with untreated counterparts at 3 and 6 months post injection. Gait analysis, performed at endpoint, showed that stride width was normalized to wild type levels (29.3 mm) by an 11% decrease, compared with untreated cohort (28.6 mm vs. 32.1 mm; P = 0.0014). Compared with wild-type, SOD1KO mice showed 9.4% and 11.4% fibre size decrease in tibialis anterior and gastrocnemius muscles, respectively, which were normalized to wild type levels with treatment. Fibre diameter increase was observed prominently in FTG fibre type. G ratio analysis revealed hypomyelination in the tibial (0.721) and sciatic (0.676) nerves of SOD1KO model, which was reversed in the NT-3 cohort (0.646 and 0.634, respectively). Fibre size increase correlated with the increase in the p-S6 and p-4E-BP1 levels, and in the glycolysis markers in tibialis anterior. Alterations observed in the mitochondrial markers were not rescued with treatment. Overall, response to NT-3 was subdued in gastrocnemius muscle. This study shows that AAV1.NT-3 gene therapy protected SOD1KO mouse from accelerated aging effects functionally and histologically. We further confirmed that NT-3 has potential to activate the mTOR and glycolytic pathways in muscle.


Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.
Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease. We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease. We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.


The influence of the non-dialysable sugar-peptide fraction from bovine blood plasma on the amino acid incorporation of BHK-21 normal and RSV transformed cells.
The non-dialysable sugar-peptide rich fraction of bovine blood plasma has been studied with regard to its influence on the amino acid incorporation of BHK-21 and BHK/RSV cells in vitro. The results indicate that the Nsp fraction contains a peptide factor(s) causing changes in activity for the protein and DNA synthethizing system in both the cell cultures examined. The biological activity of the factor(s) is regulated by interaction with blood serum components and this fact may play a leading role in its regulatory function.


Hepatitis C virus envelope glycoprotein signatures are associated with treatment failure and modulation of viral entry and neutralization.
A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.


HLA-A and HLA-B antigens in transitional cell carcinoma of the bladder.
A possible association between HLA-A and HLA-B loci alleles and bladder carcinoma has been investigated in 44 patients with biopsy proved transitional cell carcinoma of the bladder. The patients were compared to 400 healthy controls and matched for ethnic origin. Typing was done by the standard National Institutes of Health microlymphocytotoxicity technique. Comparison between the HLA-A and HLA-B series of the patients and the controls, and the different stages of disease did not yield any significant difference.


Management of penetrating abdominal trauma in the conflict environment: the role of computed tomography scanning.
Computed tomography (CT) scanning is a vital imaging technique in selecting patients for nonoperative management of civilian penetrating abdominal trauma. This has reduced the rate of nontherapeutic laparotomies and associated complications. Battlefield abdominal injuries conventionally mandate laparotomy, and with the advent of field deployable CT scanners it is unclear whether some ballistic injuries can be managed conservatively. A retrospective 12 month cohort of patients admitted to a forward surgical facility in Afghanistan who sustained penetrating abdominal injury severe enough to warrant laparotomy or CT scan were studied. Patient details were retrieved from a prospectively maintained operative log and CT logs. Case notes were then reviewed and data pertaining to injury pattern, operative intervention, and survival were collected. A total of 133 patients were studied: 73 underwent immediate laparotomy (Lap group) and 60 underwent CT scanning (CT group). Of those undergoing CT scanning 17 underwent laparotomy and 43 were selected for nonoperative management. There were 15 deaths in the Lap group and none in the CT group. The median New Injury Severity and Revised Trauma Score was 29 and 7.55 in the Lap group and 9 and 7.8408 in the CT group, which is statistically significantly different (p < 0.001). Five patients in the CT-Lap group had nontherapeutic laparotomies and 1 patient failed nonoperative management. Computed tomography scanning can be used in stable patients who have sustained penetrating battlefield abdominal injury to exclude peritoneal breach and identify solid abdominal organ injury that can be safely managed nonoperatively.


Quantitative metrics of spinal cord injury recovery in the rat using motion capture, electromyography and ground reaction force measurement.
Toward improving the quantitative tools available for evaluation of locomotion after a spinal cord injury, we characterized selected biomechanical and physiological parameters that could be used to assess the level of recovery of locomotion after a mid-thoracic spinal cord lateral hemisection. Specifically we defined quantitative measures of muscle activation and coordination, body weight support, propulsive force, and pre-toe contact activation. Generation of this ensemble of recovery measures was based on kinematics, ground reaction forces, and EMG in rats from the hindlimb ipsilateral to the hemisection during quadrupedal running on a trackway. We derived muscle activation levels using inverse dynamics and static optimization applied to a model of the hindlimb musculoskeletal system. Rats exhibited a phased recovery pattern: progressive recovery of general muscle activity beginning within 2-3 days post-injury, followed by recovery of propulsive force and intralimb coordination of antagonistic muscles 12-13 days post-injury. Even at 12-13 days post-injury however, body weight support and the normal pre-paw contact EMG burst were significantly impaired. These data are consistent with a differential rate of recovery of general motor pool recruitment, and coordination among motor pools. The results demonstrate the discriminative potential of these physiologically based measures in quantifying the progressive recovery of gait performance after a lateral spinal cord hemisection.


The yields of diacetoxyscirpenol produced byFusarium sambucinum cultures isolated from potato tubers and their toxicity to brine shrimps (Artemia salina).
The amount of diacetoxyscirpenol (DAS) produced by 14 isolates ofFusarium sambucinum under laboratory conditions has been examined. The isolates were obtained from potato tubers with dry rot symptoms. Yields of DAS ranged from 20 to 330 mg/kg of wheat grain culture (chemical analysis -TLC). Chemical analysis and biological tests showed very similar results.


Optimization of [11C]CO2 trapping efficiencies from nitrogen gas streams.
Three new systems were developed for trapping [11C]CO2 from high flow rate nitrogen gas streams and the trapping efficiency was determined for each trap design. The results of this study indicate that both the stainless steel shot and stainless steel frit systems yield high trapping efficiencies under the range of flow rates evaluated (400-3600 sccm) and may prove to be alternatives to the traditional stainless steel/copper coiled tubing or molecular sieve trapping systems in common use.