The effect of the kinesio taping and spiral taping on menstrual pain and premenstrual syndrome.
[Purpose] The purpose of this study was to compare the effects of Kinesio taping and spiral taping on menstrual pain and premenstrual syndrome, to investigate the efficacy of the two types of taping as methods for alleviating menstrual pain and premenstrual syndrome. [Subjects and Methods] The subjects of this study were 34 unmarried women. The subjects were randomly divided into a Kinesio taping group, a spiral taping group and a control group. Subjects with a regular menstrual cycle underwent taping a total of six times; twice a week for about three weeks, starting from 14 days before menstruation and continuing until its end. Degrees of menstrual pain and premenstrual syndrome were measured before the application of taping. [Results] The results revealed that Kinesio taping had significant effects on menstrual pain, while spiral taping was effective at alleviating both menstrual pain and premenstrual syndrome. [Conclusion] Both taping methods before menstruation brought significant relief to menstrual pain, which suggests that spiral taping is an effective method of alleviating premenstrual symptoms.


Percutaneous reduction and cannulated screw fixation assisted by 3D printing technology of calcaneal fractures in children.
Percutaneous reduction and cannulated screw fixation (PR + CSF) for treatment of calcaneal fractures in pediatric patients has been proven to achieve satisfactory outcomes with few complications. But it is also a difficult technology due to the limited exposure and surgeons are unable to reduce articular surface under direct vision. The purpose of this study was to analyze the outcomes of applying 3D printing technology to preoperative preparation and Intraoperative operating for the treatment of calcaneal fractures in children. Pediatric patients with calcaneal fractures from January 2010 to December 2018 were reviewed during study period. Preoperative radiographs and computed tomography scans were collected to classify the fractures, reconstruct 3D printed model and evaluate postoperative outcomes. The blood loss, operative time, number of fluoroscopies, surgeon and patient satisfaction were used to assess the effectiveness, feasibility and safety of 3D printing technology. Functional results were measured by American Orthopedic Foot and Ankle Society (AOFAS) hindfoot score. 12 patients (10 boys and 2 girls) with 17 fractures were involved in our study. There were significant differences in the average Böhler angle before operation compared with that after operation and at last follow-up (P < 0.001). Similarly, the calcaneal height and length postoperatively and at the end of follow-up time were proved to have significant difference (P < 0.05) compared to preoperative. CT scan showed good reduction of the posterior facet according to Goldzak index. The average subjective AOFAS hindfoot score was 94.1. Both patients and surgeon made sense of the 3D printed model that can help them getting more information about the factures and making preoperative plans. No wound complication was found in this study. This study indicated that percutaneous reduction and cannulated screw fixation (PR + CSF) assisted by 3D printing technology in the treatment of calcaneal fractures in pediatric patients achieve good outcomes, with specific preoperative preparation, satisfactory functional recovery and fewer complications. III.


Expression of CAP2, an APETALA2-family transcription factor from chickpea, enhances growth and tolerance to dehydration and salt stress in transgenic tobacco.
The APETALA2 (AP2) domain defines a large family of DNA-binding proteins that play important roles in plant morphology, development, and stress response. We describe isolation and characterization of a gene (CAP2) from chickpea (Cicer arietinum) encoding a novel AP2-family transcription factor. Recombinant CAP2 protein bound specifically to C-repeat/dehydration-responsive element in gel-shift assay and transactivated reporter genes in yeast (Saccharomyces cerevisiae) one-hybrid assay. CAP2 appeared to be a single/low copy intronless gene, and the protein product localized in the nucleus. Transcript level of CAP2 increased by dehydration and by treatment with sodium chloride, abscisic acid, and auxin, but not by treatment with low temperature, salicylic acid, and jasmonic acid. The 35S promoter-driven expression of CAP2 in tobacco (Nicotiana tabacum) caused drastic increase in the leaf cell size, and, thereby, in leaf surface area and number of lateral roots. Transgenic plants demonstrated more tolerance to dehydration and salt stress than the wild-type plants. Transgenic plants expressed higher steady-state transcript levels of abiotic stress-response genes NtERD10B and NtERD10C and auxin-response genes IAA4.2 and IAA2.5. Taken together, our results indicated a mutual interrelation between plant growth-development and abiotic stress-response pathways and a probable involvement of CAP2 in both the signaling pathways.


Longitudinal trends using a point-of-care gelatin-based model for ultrasound-guided central venous catheter insertion.
Ultrasound (US)-guided central venous catheter (CVC) insertion is a procedure that carries the risk of significant complications. Simulation provides a safe learning atmosphere, but most CVC simulators are not available outside of simulation centers. To explore longitudinal trends in US-guided CVC insertion competency in internal medicine (IM) interns, we studied the use of a low-fidelity, gelatin-based, US-guided CVC insertion simulation model combined with a simulation curriculum. This prospective observational study of IM interns was performed over the course of one academic year. Interns (n = 56) underwent model-based, US-guided procedure simulation training program and a repeated training course prior to their intensive care unit (ICU) rotation. CVC insertion competency at different timepoints was recorded. Survey data about intern experience and attitudes were also collected. Out of the 56 interns initially trained, 40 were included in the final analysis. Across all outcomes, interns experienced skill atrophy between initial training and the beginning of their ICU month. However, by the end of the month, there was a significant improvement in competency as compared to initial procedural training, which then waned by the end of the intern year. Attitudes toward the model were generally positive and self-reported confidence improved throughout the course of the year and correlated with objective measures of competency. Over the course of their intern year, which included simulation training using a gelatin-based model, interns demonstrated consistent competency trends. The use of a gelatin-based CVC insertion simulation model warrants further study as an adjunctive aid to existing simulation training.


Tea Polyphenols in Parkinson's Disease.
Parkinson's disease (PD) is a common motor neurodegenerative disorder with multifactorial etiology that is an increasing burden on our aging society. PD is characterized by nigrostriatal degeneration which might involve oxidative stress, α-synuclein (αS) aggregation, dysregulation of redox metal homeostasis and neurotoxicity. Although the exact cause remains unknown, both genetic and environmental factors have been implicated. Among the various environmental factors tea consumption has attracted increasing interest, as besides being one of the most consumed beverages in the world, tea contains specific polyphenols which can play an important role in delaying the onset or halting the progression of PD. Green and black teas are rich sources of polyphenols, the most abundant being epigallocatechin-3-gallate (EGCG) and theaflavins. There is now consistent mechanistic data on the neuroprotective and neuroregenerative effects of tea polyphenols, indicating that they do not just possess anti-oxidant or anti-chelating properties but may directly interfere with aggregation of the αS protein and modulate intracellular signalling pathways, both in vitro and in animal models. EGCG in green tea has been by far the most studied compound and therefore future investigations should address more the effects of other polyphenols, especially theaflavins in black tea. Nevertheless, despite significant data on their potential neuroprotective effects, clinical studies are still very limited and to date only EGCG has reached phase II trials. This review collates the current knowledge of tea polyphenols and puts into perspective their potential to be considered as nutraceuticals that target various pathologies in PD.


The Use of HPLC-PDA in Determining Nicotine and Nicotine-Related Alkaloids from E-Liquids: A Comparison of Five E-Liquid Brands Purchased Locally.
E-liquid manufacturers are under scrutiny concerning the purity and concentration accuracy of nicotine and the minor nicotine-related alkaloids (NRAs) packaged in their products. In this communication we report concentrations of nicotine and five NRAs (nornicotine, cotinine, anabasine, anatabine, myosmine) from locally purchased E-liquids. Five brands of E-liquids (three bottles each) were purchased locally. Additionally, three bottles of reference E-liquid were prepared. Concentrations of nicotine and NRAs from each bottle were measured by HPLC. Concentrations of these alkaloids were also determined from electronic cigarette-generated aerosol and traditional cigarette smoke. Nicotine concentrations in E-liquid brands 1, 2, 3, 4, 5 and in the reference E-liquid were 17.8 ± 4.1, 23.2 ± 0.7, 24.0 ± 0.9, 24.9 ± 0.2, 19.7 ± 0.3 and 20.4 ± 0.1 mg/mL, respectively. Concentrations normalized to 100% of product label were 74%, 97%, 100%, 104%, 109% and 102%, respectively. E-liquid brand 1 showed significance (p < 0.001) between bottles, while the reference showed the least variability. Similar results were obtained for the NRAs. Results also indicated the NRAs in aerosol of the reference E-liquid are lower than in cigarette smoke. The amounts of NRAs present in E-liquids and E-liquid aerosol are less compared to cigarettes, however, inconsistencies and variation in nicotine concentrations supports the need for regulatory oversight.


A simple mathematical model helps to explain the immunodominance of CD8 T cells in influenza A virus infections.
Understanding immunodominance, the phenomenon of epitope-specific T cells expanding in an often distinctly hierarchical fashion, is important for the design of T-cell-based intervention strategies. Several recent studies have investigated immunodominance of H-2D(b)-restricted CD8(+) T cells specific for the nucleoprotein NP366 and acid polymerase PA224 epitopes during influenza A virus infection of C57BL/6 mice. CD8(+) T cells specific for these two epitopes are codominant during primary infection; NP366 dominates during secondary infection. While a number of explanations for this observation have been proposed, none of them can fully account for all the observed data. In this article, we use a simple mathematical model to explain the seemingly inconsistent data. We show that the dynamic interactions between CD8(+) T cells and antigen presentation lead to a situation where CD8(+) T cells are limiting during the initial response whereas antigen is limiting in the secondary response. This "numbers game" between antigen and CD8(+) T cells can reproduce the observed immunodominance of the NP336- and PA224-specific CD8(+) T cells, thereby explaining the reported experimental data.


The learning of resources of the unified health system in the radiology residency program.
To investigate the learning on the management of resources of the Unified Health System (Sistema Único de Saúde - SUS) and its interfaces with private institutions in the radiology residency program of Escola Paulista de Medicina - Universidade Federal de São Paulo, in order to improve radiologists' training. Exploratory research with quantitative and qualitative approach to residents, faculty staff and preceptors of the program, utilizing Likert questionnaires (46), deepening interviews (18) and categorization based upon meaning units (thematic analysis). Sixty-three per cent of the respondents claim the non-existence of an opportunity for the residents to be acquainted with the management of SUS resources, and were even more categorical (76%) regarding the knowledge about resources from private institutions in the intersection with SUS. The learning on the management of SUS resources represents a relevant challenge to be overcome by residency programs, considering the extensiveness and complexity of the Brazilian health system, that is not sufficiently approached during the program, even in its most basic aspects, with daily experiences involving an excessive number of patients and a busy agenda, besides the inadequate public health infrastructure. The present study indicates the need for a greater emphasis on the development of the learning on aspects related to the management of resources from the SUS, assimilating particularities and overcoming the frequent difficulties, thus improving the training of radiologists.


Hydration water mobility is enhanced around tau amyloid fibers.
The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide (306)VQIVYK(311) were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.


Severe muscle damage with myofiber necrosis and macrophage infiltrates characterize anti-Mi2 positive dermatomyositis.
The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2-). Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2- muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2- DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2- patients [median (IQR) creatine-kinase fold increment: 16 (7-37)vs 3.5 (1-9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2- patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2- DM [mean 0.4 (0.5), <0.01]. Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.


Statutory controls in the care of the aged.
Legislation for the control of care of the aged in South Africa is examined with a view to its applicability to its purposes. The cornerstone of a comprehensive service for the aged is undoubtedly Act No. 63 (The Health Act) of 1977, but a great deal of voluntary community activity and previous legislation have contributed to making this possible. The delegation of responsibility from the National Health Policy Council via the Health Matters Advisory Committee to its Subcommittee of Health Services for the Aged and, finally, to the Regional Coordinating Committees is described. Unfortunately community services have not yet been developed to a capacity to meet all current needs, and various models for the delivery of care of the aged within the community are briefly discussed in attempting to seek a meaningful role for the Regional Coordinating Committees. Improved pensions or the introduction of compulsory contributory comprehensive social security for the aged are, in conjunction with improved home care facilities, essential factors in making care for the aged a community responsibility as far as possible.


Surface-Induced Frustration in Solid State Polymorphic Transition of Native Cellulose Nanocrystals.
The presence of an interface generally influences crystallization of polymers from melt or from solution. Here, by contrast, we explore the effect of surface immobilization in a direct solid state polymorphic transition on individual cellulose nanocrystals (CNCs), extracted from a plant-based origin. The conversion from native cellulose I to cellulose III crystal occurred via a host-guest inclusion of ethylene diamine inside the crystal. A 60% reduction in CNC width (height) in atomic force microscopy images suggested that when immobilized on a flat modified silica surface, the stresses caused by the inclusion or the subsequent regeneration resulted in exfoliation, hypothetically, between the van der Waals bonded sheets within the crystal. Virtually no changes in dimensions were visible when the polymorphic transition was performed to nonimmobilized CNCs in bulk dispersion. With reservations and by acknowledging the obvious dissimilarities, the exfoliation of cellulose crystal sheets can be viewed as analogous to exfoliation of 2D structures like graphene from a van der Waals stacked solid. Here, the detachment is triggered by an inclusion of a guest molecule inside a host cellulose crystal and the stresses caused by the firm attachment of the CNC on a solid substrate, leading to detachment of molecular sheets or stacks of sheets.


Successful Treatment of Allergic Bronchopulmonary Aspergillosis Using a Combination of Inhaled Fluticasone Furoate/Vilanterol and Oral Voriconazole.
Systemic corticosteroids are considered to be the standard treatment for allergic bronchopulmonary aspergillosis (ABPA). However, there is controversy regarding use of inhaled corticosteroid (ICS) therapy for ABPA. Here we report a case of ABPA that was successfully treated with inhaled fluticasone furoate/vilanterol (FF/VI) and oral voriconazole (VRCZ). The patient was a 62-year-old Japanese man with bronchiectasis and diabetes mellitus who presented with fever, cough, and purulent sputum. Computed tomography scans of the chest showed consolidation in the left upper and lower lobes. Laboratory investigations revealed an abnormal increase in the number of eosinophils (3,340/mm3) and elevated levels of C-reactive protein (3.04 mg/dL) and serum immunoglobulin E (IgE) (763 U/mL). Eight days after admission, he experienced a sudden attack of asthma. Aspergillus-precipitating antibodies were positive and Aspergillus fumigatus was detected in sputum culture. These results were consistent with a diagnosis of ABPA, and he was started on inhaled FF/VI and oral VRCZ. Systemic corticosteroids were not used because of the patient's history of diabetes mellitus and left atrial thrombus. His symptoms and consolidation improved significantly after treatment. He has not experienced an exacerbation for more than 3 years. In mild cases of ABPA in which total IgE is relatively low, inhaled FF/VI in combination with oral VRCZ can be considered as an alternative treatment to systemic corticosteroids in patients with ABPA.


Healthcare-use for major infectious disease syndromes in an informal settlement in Nairobi, Kenya.
A healthcare-use survey was conducted in the Kibera informal settlement in Nairobi, Kenya, in July 2005 to inform subsequent surveillance in the site for infectious diseases. Sets of standardized questionnaires were administered to 1,542 caretakers and heads of households with one or more child(ren) aged less than five years. The average household-size was 5.1 (range 1-15) persons. Most (90%) resided in a single room with monthly rents of US$ 4.50-7.00. Within the previous two weeks, 49% of children (n=1,378) aged less than five years (under-five children) and 18% of persons (n = 1,139) aged > or = 5 years experienced febrile, diarrhoeal or respiratory illnesses. The large majority (> 75%) of illnesses were associated with healthcare-seeking. While licensed clinics were the most-frequently visited settings, kiosks, unlicensed care providers, and traditional healers were also frequently visited. Expense was cited most often (50%) as the reason for not seeking healthcare. Of those who sought healthcare, 34-44% of the first and/or the only visits were made with non-licensed care providers, potentially delaying opportunities for early optimal intervention. The proportions of patients accessing healthcare facilities were higher with diarrhoeal disease and fever (but not for respiratory diseases in under-five children) than those reported from a contemporaneous study conducted in a rural area in Kenya. The findings support community-based rather than facility-based surveillance in this setting to achieve objectives for comprehensive assessment of the burden of disease.


Influence of watershed characteristics on streambed hydraulic conductivity across multiple stream orders.
Streambeds are critical hydrological interfaces: their physical properties regulate the rate, timing, and location of fluxes between aquifers and streams. Streambed vertical hydraulic conductivity (Kv) is a key parameter in watershed models, so understanding its spatial variability and uncertainty is essential to accurately predicting how stresses and environmental signals propagate through the hydrologic system. Most distributed modeling studies use generalized Kv estimates from column experiments or grain-size distribution, but Kv may include a wide range of orders of magnitude for a given particle size group. Thus, precisely predicting Kv spatially has remained conceptual, experimental, and/or poorly constrained. This usually leads to increased uncertainty in modeling results. There is a need to shift focus from scaling up pore-scale column experiments to watershed dimensions by proposing a new kind of approach that can apply to a whole watershed while incorporating spatial variability of complex hydrological processes. Here we present a new approach, Multi-Stemmed Nested Funnel (MSNF), to develop pedo-transfer functions (PTFs) capable of simulating the effects of complex sediment routing on Kv variability across multiple stream orders in Frenchman Creek watershed, USA. We find that using the product of Kv and drainage area as a response variable reduces the fuzziness in selecting the "best" PTF. We propose that the PTF can be used in predicting the ranges of Kv values across multiple stream orders.


Clinical implications of local field potentials for understanding and treating movement disorders.
Deep brain stimulation (DBS) for the treatment of movement disorders has provided researchers with an opportunity to record electrical oscillatory activity from electrodes implanted in deep brain structures. Extracellular activity recorded from a population of neurons, termed local field potentials (LFPs), has shed light on the pathophysiology of movement disorders and holds the potential to lead to refinement in existing treatments. This paper reviews the clinical significance of LFPs recorded from macroelectrodes implanted in basal ganglia and thalamic targets for the treatment of Parkinson's disease, essential tremor and dystonia. Neural population dynamics and subthreshold events, which are undetectable by single-unit recordings, can be examined with frequency band analysis of LFPs (frequency range: 1-250 Hz). Of clinical relevance, reliable correlations between motor symptoms and components of the LFP power spectrum suggest that LFPs may serve as a biomarker for movement disorders. In particular, Parkinson's rigidity has been shown to correlate with the power of beta oscillations (13-30 Hz), and essential tremor coheres with oscillations of 8-27 Hz. Furthermore, evidence indicates that the optimal contacts for DBS programming can be predicted from the anatomic location of beta and gamma bands (48-200 Hz). LFP analysis has implications for improved electrode targeting and the development of a real-time, individualized, 'closed-loop' stimulation system.


Galactose-extended glycans of antibodies produced by transgenic plants.
Plant-specific N-glycosylation can represent an important limitation for the use of recombinant glycoproteins of mammalian origin produced by transgenic plants. Comparison of plant and mammalian N-glycan biosynthesis indicates that beta1,4-galactosyltransferase is the most important enzyme that is missing for conversion of typical plant N-glycans into mammalian-like N-glycans. Here, the stable expression of human beta1,4-galactosyltransferase in tobacco plants is described. Proteins isolated from transgenic tobacco plants expressing the mammalian enzyme bear N-glycans, of which about 15% exhibit terminal beta1,4-galactose residues in addition to the specific plant N-glycan epitopes. The results indicate that the human enzyme is fully functional and localizes correctly in the Golgi apparatus. Despite the fact that through the modified glycosylation machinery numerous proteins have acquired unusual N-glycans with terminal beta1,4-galactose residues, no obvious changes in the physiology of the transgenic plants are observed, and the feature is inheritable. The crossing of a tobacco plant expressing human beta1,4-galactosyltransferase with a plant expressing the heavy and light chains of a mouse antibody results in the expression of a plantibody that exhibits partially galactosylated N-glycans (30%), which is approximately as abundant as when the same antibody is produced by hybridoma cells. These results are a major step in the in planta engineering of the N-glycosylation of recombinant antibodies.


The Jack and Jill Adaptive Working Memory Task: Construction, Calibration and Validation.
Visuospatial working memory (VSWM) is essential to human cognitive abilities and is associated with important life outcomes such as academic performance. Recently, a number of reliable measures of VSWM have been developed to help understand psychological processes and for practical use in education. We sought to extend this work using Item Response Theory (IRT) and Computerised Adaptive Testing (CAT) frameworks to construct, calibrate and validate a new adaptive, computerised, and open-source VSWM test. We aimed to overcome the limitations of previous instruments and provide researchers with a valid and freely available VSWM measurement tool. The Jack and Jill (JaJ) VSWM task was constructed using explanatory item response modelling of data from a sample of the general adult population (Study 1, N = 244) in the UK and US. Subsequently, a static version of the task was tested for validity and reliability using a sample of adults from the UK and Australia (Study 2, N = 148) and a sample of Russian adolescents (Study 3, N = 263). Finally, the adaptive version of the JaJ task was implemented on the basis of the underlying IRT model and evaluated with another sample of Russian adolescents (Study 4, N = 239). JaJ showed sufficient internal consistency and concurrent validity as indicated by significant and substantial correlations with established measures of working memory, spatial ability, non-verbal intelligence, and academic achievement. The findings suggest that JaJ is an efficient and reliable measure of VSWM from adolescent to adult age.


The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location.
The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, well-differentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to tumor site, particularly regarding anti-EGFR targeted treatment.


DNA-binding properties of simian virus 40 T-antigen mutants defective in viral DNA replication.
Three simian virus 40 (SV40)-transformed monkey cell lines, C2, C6, and C11, producing T-antigen variants that are unable to initiate viral DNA replication, were analyzed with respect to their affinity for regulatory sequences at the viral origin of replication. C2 and C11 T antigens both bound specifically to sequences at sites 1 and 2 at the viral origin region, whereas C6 T antigen showed no specific affinity for any viral DNA sequences under all conditions tested. Viral DNA sequences encoding the C6 T antigen have recently been cloned out of C6 cells and used to transform an established rat cell line. T antigen from several cloned C6-SV40-transformed rat lines failed to bind specifically to the origin. C6 DNA contains three mutations: two located close to the amino terminus of T antigen at amino acid positions 30 and 51 and a third located internally at amino acid position 153. Two recombinant SV40 DNA mutants were prepared containing either the amino-terminal mutations at positions 30 and 51 (C6-1) or the internally located mutation at position 153 (C6-2) and used to transform Rat 2 cells. Whereas T antigen from C6-2-transformed cells lacked any specific affinity for these sequences. Therefore, the single mutation at amino acid position 153 (Asn leads to Thr) is sufficient to abolish the origin-binding property of T antigen. A T antigen-specific monoclonal antibody, PAb 100, which had been previously shown to immunoprecipitate an immunologically distinct origin-binding subclass of T antigen, recognized wild-type or C6-1 antigens, but failed to react with C6 or C6-2 T antigens. These results indicate that viral replication function comprises properties of T antigen that exist in addition to its ability to bind specifically to the SV40 regulatory sequences. Furthermore, it is concluded from these data that specific viral origin binding is not a necessary feature of the transforming function of T antigen.


Body, Brain, Life for Cognitive Decline (BBL-CD): protocol for a multidomain dementia risk reduction randomized controlled trial for subjective cognitive decline and mild cognitive impairment.
With no cure for dementia and the number of people living with the condition predicted to rapidly rise, there is an urgent need for dementia risk reduction and prevention interventions. Modifiable lifestyle risk factors have been identified as playing a major role in the development of dementia; hence, interventions addressing these risk factors represent a significant opportunity to reduce the number of people developing dementia. Relatively few interventions have been trialed in older participants with cognitive decline (secondary prevention). This study evaluates the efficacy and feasibility of a multidomain lifestyle risk reduction intervention for people with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). This study is an 8-week, two-arm, single-blind, randomized controlled trial (RCT) of a lifestyle modification program to reduce dementia risk. The active control group receives the following four online educational modules: dementia literacy and lifestyle risk, Mediterranean diet (MeDi), cognitive engagement and physical activity. The intervention group also completes the same educational modules but receives additional practical components including sessions with a dietitian, online brain training and sessions with an exercise physiologist to assist with lifestyle modification. Primary outcome measures are cognition (The Alzheimer's Disease Assessment Scale-Cognitive-Plus [ADAS-Cog-Plus]) and a composite lifestyle risk factor score for Alzheimer's disease (Australian National University - Alzheimer's Disease Risk Index [ANU-ADRI]). Secondary outcome measures are motivation to change lifestyle (Motivation to Change Lifestyle and Health Behaviour for Dementia Risk Reduction [MCLHB-DRR]) and health-related quality of life (36-item Short Form Health Survey [SF-36]). Feasibility will be determined through adherence to diet (Mediterranean Diet Adherence Screener [MEDAS] and Australian Recommended Food Score [ARFS]), cognitive engagement (BrainHQ-derived statistics) and physical activity interventions (physical activity calendars). Outcomes are measured at baseline, immediately post-intervention and at 3- and 6-month follow-up by researchers blind to group allocation. If successful and feasible, secondary prevention lifestyle interventions could provide a targeted, cost-effective way to reduce the number of people with cognitive decline going on to develop Alzheimer's disease (AD) and other dementias.


Evaluation of an elliptical area technique for calculating mitral blood flow by Doppler echocardiography.
To evaluate a method for measuring blood flow through the mitral valve 18 normal subjects and 19 patients with cardiac disease in whom mitral and aortic blood flows were identical were studied. Initially the mitral ring area was planimetered from the echocardiographic image, but the results of area calculation using the mathematical formula for the area of an ellipse were found to approximate to within 8% of the planimetered result in most cases. The formula was therefore used if the ring appeared elliptical on the cross sectional echo image, and other shapes were planimetered. Mitral velocity, aligned with flow in three planes, was recorded just distal to the ring. Mitral flow calculated using the elliptical technique correlated closely with flow measured in the ascending aorta by the Doppler technique and also with systemic flow measured by the Fick method at cardiac catheterisation in 10 patients. The mitral flow technique that assumed a circular orifice correlated almost as well with Doppler aortic flow and with Fick flow but overestimated flow by a mean of 1446 ml, whereas the elliptical method had a mean error of only 138 ml. Both methods correlated well with standards, but the elliptical method was easy to apply and gave a better correlation with comparison reference values.


A review of recent neurochemical data on inert gas narcosis.
Nitrogen narcosis occurs in humans at around 0.4 MPa (4 ATA). Hydrogen narcosis occurs between 2.6 and 3.0 MPa. In rats, nitrogen disturbances occur from 1 MPa and a loss of righting reflex around 4 MPa. Neurochemical studies in striatum of rats with nitrogen at 3 MPa (75% of anesthesia threshold) with differential pulse voltammetry have demonstrated a decrease in dopamine (DA) release by neurons originated from the substantia nigra pars compacta (SNc). Such a decrease is found also with compressed argon, which is more narcotic than nitrogen and with the anesthetic gas nitrous oxide. Inversely, compressed helium with its very low narcotic potency induces DA increase. Microdialysis studies in the striatum have indicated that nitrogen also induces a decrease of glutamate concentration. Nitrogen pressure did not modify NMDA glutamate receptor activities in SNc or striatum but enhanced GABAA receptors activities in SNc. Repetitive exposures to nitrogen narcosis suppressed the DA decrease and induced an increase. This fact and the lack of improvement of motor disturbances did not support the hypothesis of a physiological adaptation. The desensitization of the GABAA receptors on DA cells during recurrent exposures and the parallel long-lasting decrease of glutamate coupled to the increase in NMDA receptor sensitivity suggest a nitrogen neurotoxicity or addiction induced by recurrent exposures. The differential changes produced by inert gases indifferent neurotransmitter receptors would support the binding protein theory.


Coagulative Disorders in Critically Ill COVID-19 Patients with Acute Distress Respiratory Syndrome: A Critical Review.
In critically ill patients with acute respiratory distress syndrome (ARDS) coronavirus disease 2019 (COVID-19), a high incidence of thromboembolic and hemorrhagic events is reported. COVID-19 may lead to impairment of the coagulation cascade, with an imbalance in platelet function and the regulatory mechanisms of coagulation and fibrinolysis. Clinical manifestations vary from a rise in laboratory markers and subclinical microthrombi to thromboembolic events, bleeding, and disseminated intravascular coagulation. After an inflammatory trigger, the mechanism for activation of the coagulation cascade in COVID-19 is the tissue factor pathway, which causes endotoxin and tumor necrosis factor-mediated production of interleukins and platelet activation. The consequent massive infiltration of activated platelets may be responsible for inflammatory infiltrates in the endothelial space, as well as thrombocytopenia. The variety of clinical presentations of the coagulopathy confronts the clinician with the difficult questions of whether and how to provide optimal supportive care. In addition to coagulation tests, advanced laboratory tests such as protein C, protein S, antithrombin, tissue factor pathway inhibitors, D-dimers, activated factor Xa, and quantification of specific coagulation factors can be useful, as can thromboelastography or thromboelastometry. Treatment should be tailored, focusing on the estimated risk of bleeding and thrombosis. The aim of this review is to explore the pathophysiology and clinical evidence of coagulation disorders in severe ARDS-related COVID-19 patients.


Comparison of guanfacine and clonidine as antihypertensive agents.
1. The antihypertensive effects and side-effects of guanfacine and clonidine were compared in a single-blind, cross-over study. 2. The study consisted of two active treatment periods of 6 weeks each, which were both preceded by a 2 weeks placebo period. Thirty ambulatory, hypertensive patients (blood pressure WHO severity grades I-II) were admitted to the study. The results are based on the 24 patients who completed the study. 3. The optimal daily dose of guanfacine was in over half of the patients 3-4 mg, and of clonidine correspondingly 0.3-0.45 mg. A similar and statistically significant decrease in blood pressure was achieved with both drugs. 4. The most common side-effects with both drugs were tiredness and dryness of the mouth.


Pretreatment plasma fibrinogen level as a prognostic biomarker for patients with lung cancer.
Many researchers have shown that pretreatment plasma fibrinogen levels are closely correlated with the prognosis of patients with lung cancer (LC). In this study, we thus performed a meta-analysis to systematically assess the prognostic value of pretreatment plasma fibrinogen levels in LC patients. A computerized systematic search in PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) was performed up to March 15, 2018. Studies with available data on the prognostic value of plasma fibrinogen in LC patients were eligible for inclusion. The pooled hazard ratios (HRs) and odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the correlation between pretreatment plasma fibrinogen levels and prognosis as well as clinicopathological characteristics. A total of 17 studies with 6,460 LC patients were included in this meta-analysis. A higher pretreatment plasma fibrinogen level was significantly associated with worse overall survival (OS) (HR: 1.57; 95% CI: 1.39-1.77; p=0.001), disease-free survival (DFS) (HR: 1.53; 95% CI: 1.33-1.76; p=0.003), and progression-free survival (PFS) (HR: 3.14; 95% CI: 2.15-4.59; p<0.001). Furthermore, our subgroup and sensitivity analyses demonstrated that the pooled HR for OS was robust and reliable. In addition, we also found that a higher fibrinogen level predicted advanced TNM stage (III-IV) (OR=2.18, 95% CI: 1.79-2.66; p<0.001) and a higher incidence of lymph node metastasis (OR=1.74, 95% CI: 1.44-2.10; p=0.02). Our study suggested that higher pretreatment plasma fibrinogen levels predict worse prognoses in LC patients.


Epidemiology and the inference of cancer mechanisms.
Through the use of molecular methods and mathematical models, epidemiologists are contributing to the improved understanding of the mechanisms of cancer. Multistage models with their mechanistic basis have been useful in descriptions of initiator-promoter type behavior of some carcinogens as well as genetic predisposition to rare tumors and reproductive risk factors in breast cancer. The use of biochemical and molecular laboratory techniques on tissue and fluid samples should provide important information in the near future concerning the basic mechanisms of human cancer. The potential of these methods is not only to describe exposure to carcinogens but also to indicate various host factors and their relevance to the risk of cancer.


Public education materials about Vascular Composite Allotransplantation and donation in the United States: Current scope and limitations.
As the field of Vascular Composite Allotransplantation (VCA) grows, demand for VCA donations will increase. The public should be made aware of this treatment option to support patients' informed decision-making and authorization for deceased donation. We assessed the availability and quality of existing VCA public education materials from organ procurement organizations (OPOs), transplant centers, the Organ Procurement and Transplant Network, Veterans Affairs, and the Department of Defense. A content analysis was performed to identify topics covered and important gaps. In total, 1314 public education materials were analyzed, including OPO Facebook posts (61.6%), OPO Twitter posts (29.9%), websites (6.4%), and written documents (eg, fact sheets, research reports) (2.1%). Upper extremity (34.7%) and face (34.5%) transplants were more commonly covered than reproductive (6.4%) or other VCA types (2.8%). Most materials (76.6%) referenced a specific VCA story. However, few materials described which patient population could benefit from VCA (eg, Veterans, amputees, burn victims, 16.4%), the authorization requirements for VCA donation (6.6%), or the appearance of transplanted VCA organs (1.2%). Current VCA public education materials do not adequately educate the public. More comprehensive education materials are needed to prepare the public to authorize VCA donation, become potential donors, or learn about transplant options.


[Neurofibromatosis type 1. Splicing mutation detected by MLPA and DNA sequencing in Argentina].
Neurofibromatosis type 1 (NF1) is a dominant autosomic genetic disorder, with a birth incidence of 1 in 2500-3000. Diagnosis is difficult because of the size of gene NF1 that has few hot-spots sites, the absence of a clear genotype-phenotype relation, and a heterogeneous clinical manifestation. A NF1 suspected case from Jujuy province was analyzed by multiplex ligation-dependent probe amplification (MLPA). Mestizo female teenage (Amerindian/European), with a maxilar osteoma, lumbar lordosis, cutaneous neurofibromas and café au lait spots. MLPA detected an alteration in exon 13 of the NF1 gene. By sequencing of exon 13, a missense mutation (NM_000267.3:c.1466A>G) was found which introduces an aberrant splicing site and is registered as pathogenic in the clinical variants database of NCBI. As far as we are aware, this is the first report of a NF1 mutation in mestizo population of Northwest Argentina. 1466A>G has been described before in patients of European origin, suggesting that the affected site could be a hot-spot site of the gene. For countries as Argentina, with limited availability of molecular diagnostic methods, we propose a diagnosis algorithm by starting the mutational analysis of NF1 with MLPA. This methodology is relatively simple and of low cost, avoiding to send samples abroad for genetic analyses.


Bone remodeling as a spatial evolutionary game.
Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes. To address these issues, we developed a novel model of spatial remodeling based on the principles of evolutionary game theory. The analytically tractable framework describes the spatial interactions between zones of bone resorption, bone formation and quiescent bone, and explicitly accounts for regulation of remodeling by bone-embedded, mechanotransducing osteocytes. Using tools from the theory of interacting particle systems we systematically classified the different dynamic regimes of the spatial model and identified regions of parameter space that allow for global coexistence of resorption, formation and quiescence, as observed in physiological remodeling. In coexistence scenarios, three-dimensional simulations revealed the emergence of sponge-like bone clusters. Comparison between spatial and non-spatial dynamics revealed substantial differences and suggested a stabilizing role of space. Our findings emphasize the importance of accounting for spatial structure and bone-embedded osteocytes when modeling the process of bone remodeling. Thanks to the lattice-based framework, the proposed model can easily be coupled to a mechanical model of bone loading.


Multicomponent cleaning verification of stainless steel surfaces for the removal of dairy residues using infrared microspectroscopy.
The application of infrared microspectroscopy (IRMS) technology, combined with multivariate analysis, was evaluated to develop sensitive and robust methods to assess cleanability of stainless steel surfaces for the removal of dairy food residues. UHT milk samples (skim, 1%, 2%, and whole) were analyzed for total nitrogen (Kjeldahl) and fat (Babcock) contents. The coupons were manually soiled with serially diluted milk samples resulting in soils ranging from 0.1 to 428.1 μg/cm(2) for protein and 0.1 to 374.17 μg/cm(2) for fat, and then autoclaved to simulate a heated equipment surface. Reflectance spectra were collected from stainless steel coupons by using IRMS, and multivariate analysis was used to develop calibration models based on cross-validated partial least squares regression (PLSR). Statistical analysis for the prediction of protein and fat showed a standard error of cross-validation (SECV) of 0.5 and 0.4 μg/cm(2) for prediction of protein and fat, respectively, and correlation coefficients (rVal) > 0.99. To improve the sensitivity, swabbing and concentration steps were used prior to IRMS analysis obtaining SECV of 0.04 and 0.01 μg/cm(2) for the prediction of protein and fat, respectively, and rVal > 0.99. The PLSR models accurately predicted the levels of protein and fat on autoclaved stainless steel coupons soiled with milk. A simple, reliable, and robust protocol based on IRMS and multivariate analysis was developed for multicomponent characterization of stainless steel surfaces that can contribute to more efficient cleaning verification with regard to contamination on surfaces of processing equipment. We report the application of Fourier transform infrared microspectroscopy (FTIR) for the validation of CIP cleaning efficiency that would provide a basis for better understanding of the mechanisms involved in the removal of physical soil and food residues from different types of equipment surfaces commonly utilized in the biotech, pharmaceutical, and food industries. Reliable calibration models were generated that showed the ability to predict the amounts of dairy soils on the surface of stainless steel coupons. Including a swabbing step of the coupons before infrared spectral acquisition provided improved sensitivity and reproducibility for multicomponent cleaning verification. Results from this research project would allow designing experiments to rapidly evaluate different materials and finishes, the effects of process variables, the influence of food components, and the development of reliable and robust cleaning validation protocols to ensure the safety and quality of the product.


Impairment of insulin action on peripheral glucose uptake and hepatic glucose production in tumor-bearing rats.
The present study was performed to determine the time-course for the development of peripheral and hepatic insulin resistance in rats as a result of an increasing tumor burden. Animals were inoculated with Yoshida ascites hepatoma, and studies were conducted during the early phase of tumor growth (day 4) at which time there was no change in food intake and at a later time point (day 8) when the tumor burden was increased and rats demonstrated anorexia. In vivo insulin action was accessed under euglycemic hyperinsulinemic conditions, in which insulin was infused at rates sufficient to produce arterial insulin levels that represent high physiological (3.5 ng/ml) or maximally stimulating values (180 ng/ml). On day 4, tumor-bearing (TB) rats were euglycemic, and whole body glucose turnover was elevated 32%. Insulin-mediated glucose uptake (IMGU) in TB rats was similar to control values at the low insulin infusion rate but reduced by 53% under maximally stimulating conditions. The insulin-induced suppression of glucose production was similar in TB and control animals at this time point. In contrast, on day 8, TB rats were hypoglycemic and glucose turnover was reduced 35%. The impairment in IMGU was more severe than seen earlier, with glucose uptake being reduced 39 and 61% at both levels of hyperinsulinemia. At this time point, the ability of insulin to inhibit glucose production was also impaired. These results indicate that the insulin resistance induced by the Yoshida hepatoma was manifested initially by a reduction in IMGU by peripheral tissues. As the tumor burden increased peripheral insulin resistance became more severe and an impairment in hepatic insulin action was observed.


Comparison Between Relative Efficacy of Erector Spinae Plane Block and Caudal Epidural Block for Postoperative Analgesia in Lumbar Fusion Surgery- A Prospective Randomized Controlled Study.
Prospective, randomized controlled double-blinded study. To compare the relative efficacy of ultrasound-guided ESPB and CEB for postoperative analgesia after a single-level lumbar fusion surgery and compared it with conventional multimodal analgesia. 81 patients requiring single-level lumbar fusion surgery were randomly allocated into 3 groups (ESPB group, CEB group, and the control group). Demographic and surgical data (blood loss, duration of surgery, perioperative total opioid consumption, muscle relaxants used) were assessed. Postoperatively, the surgical site pain, alertness scale, satisfaction score, time to mobilization, and complications were recorded. The total opioid consumption in the first 24 hours was significantly lower in both the block groups than in the control group (103.70 ± 13.34 vs 105 ± 16.01 vs 142.59 ± 40.91mcg; P < .001). The total muscle relaxant consumption was also significantly less in block groups compared to controls (50.93 ± 1.98 vs 52.04 ± 3.47 vs 55.00 ± 5.29 mg; P < .001). The intraoperative blood loss was significantly less in both the block group (327.78 ± 40.03 mL, 380.74 ± 77.80 mL) than the control group (498.89 ± 71.22 mL) (P < .001). Among the block groups, the immediate postoperative pain relief was better in the CEB group, however, the ESPB group had a longer duration of postoperative pain relief. Both ESPB and CEB produce adequate postoperative analgesia after lumbar fusion however the duration of action was significantly longer in the ESPB group with relatively shorter surgical time and lesser blood loss compared to the CEB group.


Sarm1 knockout protects against early but not late axonal degeneration in experimental allergic encephalomyelitis.
Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. To test the hypothesis that loss of SARM1 will reduce axonal degeneration in immune-mediated CNS inflammatory disorders, the course and pathology of EAE was compared in Sarm1 knockout mice and wild type littermates. The clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal yellow fluorescent protein (YFP) showed significantly less axonal degeneration in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. At 21 days post-induction, however, difference in axonal degeneration was not significant. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury, and were similar with respect to axonal density in the lumbar cords. There was no significant change in peripheral immune activation or CNS inflammatory cell infiltration associated with EAE in Sarm1 knockout mice. In conclusion, Sarm1 deletion delayed axonal degeneration early in the course of CNS inflammation, but did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.


[Age-related aspects of intensive therapy of acute poisoning of chemical etiology].
Assay of the clinical course of poisoning with acetic acid, dichloroethane, carbophos, chlorophos, phenobarbital and sodium etaminal in 2538 patients made it possible to define, with the use of the probit analysis, the 25, 50, 75 and 95% concentration thresholds of the lethality in acute poisonings with acetic acid, carbophos and dichloroethane. It was established that under exposure to the toxic substances undergoing different chemical changes in the body, the increase of the lethality risk varied in different age groups. The differences in the structure of outcomes in patients of different age groups formed the basis for making up a classification of the toxicity of the chemical compounds. The differences revealed require a differential approach to the determination of the scope of intensive care of poisonings in terms of the age-associated features.


Cerebral venous thrombosis due to high-altitude polycythemia. Case report.
A case of cerebral venous thrombosis due to polycythemia secondary to adaptation to a high altitude is reported. A 27-year-old previously healthy man developed severe neurological symptoms after climbing 8511 m. Computerized tomography and cerebral angiography suggested hemorrhagic infarction or intratumoral hemorrhage, and a craniotomy was performed. Pathological examination confirmed the diagnosis of hemorrhagic infarction secondary to cortical venous thrombosis. The etiology and incidence of cerebral venous thrombosis secondary to polycythemia are discussed.


[Xenoplasty of the dura mater by means of formalinized grafts].
The possibility of using as plastic material animal (neat cattle, pig) dura mater stored in 0.5% formaldehyde solution was studied. The structure of the dura mater tissue is maintained for a 3-year storage period, and it therefore can be used during this period. The results of experiments (on 30 dogs) and clinical observations (63 patients) show that dura mater grafts used to repair a defect ensure airtightness of the subdural space and separate the brain from the overlying tissues, thus preventing the development of an adhesive-cicatricial process. On resorption, the graft is replaced by an organ-typical regenerated material performing the function of the lost dura mater.


Hydrazine-air fuel cells. Hydrazine-air fuel cells emerge from the laboratory.
A fuel cell is an electrochemical device that continues to generate electrical power as long as reactants are supplied and products are removed at properly controlled rates. An assembly of cells is required within which the conversion of chemical to electrical energy occurs; also required is a set of auxiliary components to supply the reactants and remove the products (including waste heat) under controlled steady-state conditions. In addition to the desired energy-conversion reactions, there are deleterious side reactions that can impair fuel economy. From knowledge of these factors influencing the possible reactions, and guided by principles of elementary chemical thermodynamics, the electrochemist can select optimum conditions for cell performance. It is then the job of the engineer to design auxiliary components and controlling devices to provide the electrochemical cells with the best possible approach to these optimum conditions.


[Classification of chronic graft-versus-host disease].
The NIH classification intends to standardize the diagnostic criteria for chronic CVHD and to establish prognosis groups that will help to identify patient risk and thus decide on the most appropriate treatment. This study assesses the predictive value of this classification and analyzes new prognostic factors in a series of 820 patients receiving allogeneic grafts at three sites: Hospital Universitario de Salamanca, Hospital de la Santa Creu i Sant Pau, in Barcelona, and Karolinska Institutet, in Stockholm. In the univariate analysis, the classification limited/extensive, the NIH class, and the type of onset have a significant influence on overall survival and transplant-related mortality. Additionally, the overlap syndrome is associated with a shorter survival in the multivariate analysis, only the NIH class-with on HR of 2.89 (95% Cl: 1.75-4.76; p < 0.007) for mild and moderate versus severe disease-has a significant influence on survival. Excluding the NIH class, the type of onset is Identified as an independent factor for survival. Therefore, the NIH class and the type of onset are confirmed as the most significant variables. This is important in order to identify patients with a higher risk of death after transplantation, and shorter survival. On the other hand, it is a very laborious classification; for this reason it is necessary to establish the degree of involvement of lungs, skin, digestive tract, and liver, and to identify the number of organs, because these factors significantly affect survival.


Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes.
Complement factor H (fH) is a member of a family of proteins involved in the regulation of complement activation (RCA). These proteins share a common structural motif, the Short Consensus Repeat (SCR), which is structurally conserved among related genes and between phylogenetically divergent species. fH is composed of 20 such SCRs and a variety of biological functions have been localised to specific SCR domains. The majority of individual SCRs identified are encoded by single exons, and processes such as gene conversion, duplication and exon shuffling have been implicated in the evolution and genomic radiation of SCR-encoding genes. We have analysed two GenBank sequence entries relating to two overlapping PAC clones sequenced at the Sanger Centre which contain the entire human fH gene and two adjacent fH-related (fHR) genes, fHR-1 and fHR-3. Here, we report the detailed analysis of the assembled 221 kb of contiguous, ungapped genomic sequence from human chromosome 1q32, in part employing the RUMMAGE-DP automated annotation tool. Genomic duplications involving fH and fHR exons were identified and Alu/L1 repeat dating established that the duplications occurred after the separation of rodent and primate lineages. The analysis indicates that retrotransposition as well as single and multiple exon duplication events are likely to have been involved in SCR radiation and RCA gene evolution, facilitated by conservation of splice-phasing and the single-exon, single-SCR nature of the encoded domains.


Stable alkali metal ion intercalation compounds as optimized metal oxide nanowire cathodes for lithium batteries.
Intercalation of ions in electrode materials has been explored to improve the rate capability in lithium batteries and supercapacitors, due to the enhanced diffusion of Li(+) or electrolyte cations. Here, we describe a synergistic effect between crystal structure and intercalated ion by experimental characterization and ab initio calculations, based on more than 20 nanomaterials: five typical cathode materials together with their alkali metal ion intercalation compounds A-M-O (A = Li, Na, K, Rb; M = V, Mo, Co, Mn, Fe-P). Our focus on nanowires is motivated by general enhancements afforded by nanoscale structures that better sustain lattice distortions associated with charge/discharge cycles. We show that preintercalation of alkali metal ions in V-O and Mo-O yields substantial improvement in the Li ion charge/discharge cycling and rate, compared to A-Co-O, A-Mn-O, and A-Fe-P-O. Diffraction and modeling studies reveal that preintercalation with K and Rb ions yields a more stable interlayer expansion, which prevents destructive collapse of layers and allow Li ions to diffuse more freely. This study demonstrates that appropriate alkali metal ion intercalation in admissible structure can overcome the limitation of cyclability as well as rate capability of cathode materials, besides, the preintercalation strategy provides an effective method to enlarge diffusion channel at the technical level, and more generally, it suggests that the optimized design of stable intercalation compounds could lead to substantial improvements for applications in energy storage.


The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients.
Based on the antibody profiles of inflammatory myositis patients, we investigated the type 1 IFN (T1-IFN) signature in serum and DM skin to determine the relationship between T1-IFN and vasculopathy in anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive DM patients. We examined 47 patients with new-onset inflammatory myositis. We divided them into three groups: the anti-MDA5 antibody-positive patients (MDA5 group, n = 16), the anti-aminoacyl-tRNA synthetase antibody-positive patients (aminoacyl-tRNA synthetase group, n = 12), and the double-negative patients (n = 19). Serum T1-IFN signatures were revealed by a functional reporter assay, and we evaluated the T1-IFN signatures of skin based on Mx1 expression by immunohistochemistry. The numbers of patients with classical DM, clinically amyopathic DM and interstitial lung disease were 1, 15 and 13 in the MDA5 group, 2, 3 and 11 in the aminoacyl-tRNA synthetase group, and 10, 1 and 4 in the double-negative group, respectively. The signs of vasculopathies (i.e. palmer papules, skin ulcers and mononeuritis multiplex) were identified only in the MDA5 patients. Most of the MDA5 group showed the highest serum T1-IFN signatures among the three groups. In the histological analysis of DM skin, perivascular inflammations were significant in the MDA5 group. The MDA5 group's Mx1 expression was significantly strong, distributed in blood vessels and interstitial fibroblasts, and had spread to deep dermis. Anti-MDA5 antibody-positive DM patients showed high T1-IFN signatures in serum and affected skin. The high T1-IFN signatures of the MDA5 antibody-positive DM patients in serum and deep vasculatures suggested that T1-IFN may have important roles in the vasculopathy of these patients.


Intrinsic brain activity in altered states of consciousness: how conscious is the default mode of brain function?
Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain-behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto-cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level-dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark.


TEARS: a longitudinal investigation of the prevalence, psychological associations and trajectory of poststroke emotionalism.
There are few longitudinal studies of poststroke emotionalism (PSE) and our understanding of the psychological associations of PSE is limited, constraining assessment of existing interventions and the development of new therapies. This study aimed to assess the prevalence and course of PSE over the first year poststroke, and its psychological associations. Consenting stroke survivors who were physically and cognitively able to participate were assessed within 2 weeks, 6 and 12 months of stroke to determine PSE point prevalence using a diagnostic, semistructured PSE interview (Testing Emotionalism After Recent Stroke-Diagnostic Interview). At the same assessments, neuropsychological and disability status were determined using Hospital Anxiety and Depression Scale, Abbreviated Mental Test, National Institute of Health Stroke Scale, Barthel Index and Euro-Qol. Two hundred and seventy seven stroke survivors were recruited between 1 October 2015 and 30 September 2018. Diagnostic data were available at baseline for 228 of 277 cohort participants. Point prevalence for PSE was 27.2% at 2 weeks; estimated prevalence at 6 months adjusted for baseline was 19.9% and at 12 months 22.3%. PSE was associated with symptoms of anxiety and event-related distress. PSE affects at least one in five stroke patients acutely following their stroke, and continues to affect one in eight longer term. PSE is associated with anxiety and event-related distress but is not simply a manifestation of mood disorder over time. Such psychological correlates may have implications for longer term social rehabilitation.


Relationship of "dose" of intracranial hypertension to outcome in severe traumatic brain injury.
It has recently been suggested that the degree of intracranial pressure (ICP) above the treatment goal can be estimated by the area under the curve (AUC) of ICP versus time in patients with severe traumatic brain injury (TBI). The objective of this study was to determine whether the calculated "ICP dose"-the ICP AUC-is related to mortality rate, outcome, and Marshall CT classification. Of 135 patients (age range 1-82 years) with severe TBI treated during a 5-year period at the authors' institution, 113 patients underwent ICP monitoring (84%). Ninety-three patients with a monitoring time>24 hours were included for analysis of ICP AUC calculated using the trapezoidal method. Computed tomography scans were assessed according to the Marshall TBI classification. Patients with Glasgow Outcome Scale scores at 6 months and >3 years were separated into 2 groups based on outcome. Sixty patients (65%) had ICP values>20 mm Hg, and 12 (13%) developed severe intracranial hypertension and died secondary to herniation. A multiple regression analysis adjusting for Glasgow Coma Scale score, age, pupillary abnormalities and Injury Severity Scale score demonstrated that the ICP AUC was a significant predictor of poor outcome at 6 months (p=0.034) and of death (p=0.035). However, it did not predict long-term outcome (p=0.157). The ICP AUC was significantly higher in patients with Marshall head injury Categories 3 and 4 (24 patients) than in those with Category 2 (23 patients, p=0.025) and Category 5 (46 patients, p=0.021) TBIs using the worst CT scan obtained. The authors found a significant relationship between the dose of ICP, the worst Marshall CT score, and patient outcome, suggesting that the AUC method may be useful in refining and improving the treatment of ICP in patients with TBI.


[Seminal vesiculoscopy in the treatment of refractory hemospermia and ejaculatory duct obstruction].
To summarize the experience in the diagnosis and treatment of refractory hematospermia and ejaculatory duct obstruction by seminal vesiculoscopy. We retrospectively analyzed the clinical data about 42 cases of refractory hematospermia and 6 cases of ejaculatory duct obstruction with azoospermia. We investigated the diagnosis, treatment, and prognosis of the diseases. All the patients underwent pelvic MRI and seminal vesiculoscopy. MRI for the 42 refractory hematospermia patients showed that 21 (50.0%) had cystic dilatation in the uni- or bilateral seminal vesicles, 25 (59.5%) had abnormal internal signal intensity in the uni- or bilateral seminal vesicles, 12 (28.6%) had both the problems above, and 4 (9.52%) had no obvious abnormality in the seminal vesicle area. The bilateral seminal vesicles were <1 cm in width in 3 of the 6 cases of ejaculatory duct obstruction, and obviously enlarged in the other 3, but without abnormal internal signals. No recurrence was found during the 3-36 months follow-up. The history and physical examination play important roles in the diagnosis of refractory hemospermia, and MRI is more valuable than TRUS in the diagnosis of seminal vesicle diseases. Seminal vesiculoscopy is an effective option for the management of persistent hematospermia and ejaculatory duct obstruction.


Fluid dynamic instabilities: theory and application to pattern forming in complex media.
In this review article, we exemplify the use of stability analysis tools to rationalize pattern formation in complex media. Specifically, we focus on fluid flows, and show how the destabilization of their interface sets the blueprint of the patterns they eventually form. We review the potential use and limitations of the theoretical methods at the end, in terms of their applications to practical settings, e.g. as guidelines to design and fabricate structures while harnessing instabilities.This article is part of the themed issue 'Patterning through instabilities in complex media: theory and applications'.


The effect of functional electrical stimulation on the physiological cost of gait in people with multiple sclerosis.
Functional electrical stimulation (FES) is used clinically in the management of drop foot in people suffering from neurological conditions. The aim of the study was to investigate the effects of FES, in terms of speed and physiological cost of gait, in people with multiple sclerosis (pwMS). Twelve pwMS and 12 healthy matched controls walked at their own preferred walking speed (PWS) for 5 min around a 10 m elliptical course. Subjects with MS completed the protocol with and without using their FES. In addition, control subjects completed the protocol twice more walking at the same PWS of the pwMS to which they were matched. Wearing FES lead to a significant improvement in walking speed (0.49 ms(-1) and 0.43 ms(-1) with and without their FES respectively; P<0.001) and a significant reduction in the physiological cost of gait (0.41 mL min(-1) kg(-1) m(-1) and 0.46 mL min(-1) kg(-1) m(-1) with and without FES respectively; P=0.017) in pwMS. The speed of walking, oxygen uptake, and physiological cost were significantly different between pwMS and controls both at preferred and matched speeds. Although pwMS exhibit a higher physiological cost of walking, FES offers an orthotic benefit to pwMS and should be considered as a possible treatment option.


Quantum-chemical and electrochemical investigation of the electrochemical windows of halogenated carborate anions.
The range of electrochemical stability of a series of weakly coordinating halogenated (Hal=F, Cl, Br, I) 1-carba-closo-dodecaborate anions, [1-R-CB(11)X(5)Y(6)](-) (R=H, Me; X=H, Hal, Me; Y=Hal), has been established by using quantum chemical calculations and electrochemical methods. The structures of the neutral and dianionic radicals, as well as the anions, have been optimized by using DFT calculations at the PBE0/def2-TZVPP level. The calculated structures are in good agreement with existing experimental data and with previous calculations. Their gas-phase ionization energies and electron affinities were calculated based on their optimized structures and were compared with experimental (cyclic and square-wave) voltammetry data. Electrochemical oxidation was performed in MeCN at room temperature and in liquid sulfur dioxide at lower temperatures. All of the anions show a very high resistance to the onset of oxidation (2.15-2.85 V versus Fc(0/+)), with only a minor dependence of the oxidation potential on the different halogen substituents. In contrast, the reduction potentials in MeCN are strongly substituent dependent (-1.93 to -3.32 V versus Fc(0/+)). The calculated ionization energies and electron affinities correlate well with the experimental redox potentials, which provide important verification of the thermodynamic validity of the mostly irreversible redox processes that are observed for this series. The large electrochemical windows that are afforded by these anions indicate their suitability for electrochemical applications, for example, as supporting electrolytes.


Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells.
MicroRNAs (miRNAs) regulate cell proliferation and differentiation by silencing gene expression at the post-transcriptional level; moreover, by binding to the complementary sequences within mRNAs in cancer cells, these small non-coding RNA molecules can function as tumor suppressors or oncogenes. Recently, the dysregulation of miRNA expression has been found to be associated with increased tumorigenicity and poor prognosis in several cancer types, including osteosarcoma (OS). To identify potential oncogenic factors in OS, we analyzed changes in the expression profile of miRNAs and its downstream mRNAs in five OS cell lines and human mesenchymal stem cells (hMSCs) by a microarray-based approach. The expression of an miRNA-let‑7a was significantly downregulated and E2F2 was significantly upregulated in all tested OS cells compared with hMSCs. When let-7a was transfected into OS cell lines, the expression of E2F2 in the cells was greatly suppressed, suggesting that E2F2 is a target of miRNA-let-7a in OS cells. The transfection of let-7a further inhibited cell cycle progression and proliferation of OS cells. In addition, let-7a overexpression in OS cells significantly suppressed the tumor growth in vivo. The present study demonstrates the novel mechanism that regulates E2F2 expression via miRNA-let-7a in OS cells. Because E2F2 is pivotal in promoting cell growth through the regulation of several genes, our results might facilitate the development of new therapeutic targets for the treatment of OS.


Indices of social risk among first attenders of an emergency mental health service in post-conflict East Timor: an exploratory investigation.
Little is known about the profile of patients treated in mental health services in low-income, post-conflict countries, especially in the post-emergency phase. We postulated that patients attending the first community mental health service in East Timor would be characterized not only by mental disturbance but by high levels of social vulnerability. Drawing on existing methods and on consultations with East Timorese mental health staff, five social indicators were identified: dangerousness; inability to undertake life-sustaining self-care; bizarre behaviour; incapacitating distress; and social unmanageability. Adequate levels of interrater reliability (65-91%) were achieved in identifying these indicators from case notes. Forty-eight randomly selected case notes were analyzed to ascertain the prevalence of social risk factors as well as the referral source and broad diagnostic groupings. Major referral sources were the family, humanitarian agencies and the police. Twenty-nine percent met criteria for dangerousness; 42% for inability to undertake self-care; 58% for bizarre behaviour; 75% for distress; and 19% for unmanageability. Ninety-eight percent fulfilled at least one social indicator, with the modal score being 2. Although the approach to documentation and analysis was preliminary, the data suggest that a focus on social risk indicators may assist in determining those mentally disturbed persons in need of priority care in resource-poor post-conflict countries.


Properties of the prosthetic groups of rabbit liver aldehyde oxidase: a comparison of molybdenum hydroxylase enzymes.
Rabbit liver aldehyde oxidase (AO), like milk xanthine oxidase (XO) and chicken liver xanthine dehydrogenase (XDH), possesses the following prosthetic groups: FAD, a functional Mo center, and two spectroscopically distinct iron-sulfur centers, one with gav less than 2.0 (termed Fe/S I) and the other with gav greater than 2.0 (termed Fe/S II) in the reduced enzyme. EPR spectra for the Mov species were found to be nearly identical in AO and XO for a number of enzyme complexes, and the midpoint reduction potentials for functional MoVI/MoV (-359 mV) and MoV/MoVI (-351 mV) were nearly the same in all three enzymes (50 mM phosphate, pH 7.8). A strong magnetic interaction between MoV and reduced Fe/S I, previously detected in XO and XDH, was also found in AO. No MoV-Fe/S II interaction could be detected in AO (nor in XO). In contrast, the order of reduction of Fe/S I and Fe/S II, as measured from their midpoint potentials, is reversed in AO (Em = -207 and -310 mV, respectively) as compared to XO (Em = -280 and -245 mV, respectively) in phosphate buffer at pH 7.8. The oxidized-reduced extinction coefficients at 450 and 550 nm for the two centers are also apparently reversed in AO and XO. Although magnetic interaction between FAD and one or both reduced Fe/S centers has been detected in both AO and XO, no magnetic interaction between the two reduced Fe/S centers themselves was found in AO (although such interaction has been seen in XO). The average FAD reduction potential is substantially more positive in AO (Em for FAD/FADH., -258 mV; FADH./FADH2, -212 mV at pH 7.8) than in XO or XDH. It can be concluded that although the properties and immediate environment of the functional Mo center are conserved in the three Mo hydroxylase enzymes, and all three enzymes possess the same set of prosthetic groups, the properties of the groups which transfer electrons from the Mo to the ultimate electron acceptor can vary substantially in AO, XO, and XDH.


Massachusetts Justice Community Opioid Innovation Network (MassJCOIN).
A major driver of the U.S. opioid crisis is limited access to effective medications for opioid use disorder (MOUD) that reduce overdose risks. Traditionally, jails and prisons in the U.S. have not initiated or maintained MOUD for incarcerated individuals with OUD prior to their return to the community, which places them at high risk for fatal overdose. A 2018 law (Chapter 208) made Massachusetts (MA) the first state to mandate that five county jails deliver all FDA-approved MOUDs (naltrexone [NTX], buprenorphine [BUP], and methadone). Chapter 208 established a 4-year pilot program to expand access to all FDA-approved forms of MOUD at five jails, with two more MA jails voluntarily joining this initiative. The law stipulates that MOUD be continued for individuals receiving it prior to detention and be initiated prior to release among sentenced individuals where appropriate. The jails must also facilitate continuation of MOUD in the community on release. The Massachusetts Justice Community Opioid Innovation Network (MassJCOIN) partnered with these seven diverse jails, the MA Department of Public Health, and community treatment providers to conduct a Type 1 hybrid effectiveness-implementation study of Chapter 208. We will: (1) Perform a longitudinal treatment outcome study among incarcerated individuals with OUD who receive NTX, BUP, methadone, or no MOUD in jail to examine postrelease MOUD initiation, engagement, and retention, as well as fatal and nonfatal opioid overdose and recidivism; (2) Conduct an implementation study to understand systemic and contextual factors that facilitate and impede delivery of MOUDs in jail and community care coordination, and strategies that optimize MOUD delivery in jail and for coordinating care with community partners; (3) Calculate the cost to the correctional system of implementing MOUD in jail, and conduct an economic evaluation from state policy-maker and societal perspectives to compare the value of MOUD prior to release from jail to no MOUD among matched controls. MassJCOIN made significant progress during its first six months until the COVID-19 pandemic began in March 2020. Participating jail sites restricted access for nonessential personnel, established other COVID-19 mitigation policies, and modified MOUD programming. MassJCOIN adapted research activities to this new reality in an effort to document and account for the impacts of COVID-19 in relation to each aim. The goal remains to produce findings with direct implications for policy and practice for OUD in criminal justice settings.


Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence.
We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four-way, crossover, single-dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.


Luminescence studies of individual quantum dot photocatalysts.
Using far-field optical microscopy we report the first measurements of photoluminescence from single nanoparticle photocatalysts. Fluence-dependent luminescence is investigated from metal-semiconductor heterojunction quantum dot catalysts exposed to a variety of environments, ranging from gaseous argon to liquid water containing a selection of hole scavengers. The catalysts each exhibit characteristic nonlinear fluence dependence. From these structurally and environmentally sensitive trends, we disentangle the separate rate-determining steps in each particle across the very wide range of time scales, which follow the initial light absorption process. This information will significantly benefit the design of effective artificial photocatalytic systems for renewable direct solar-to-fuel energy conversion.


Spinal pain made worse by recumbency: a clue to spinal cord tumors.
In the absence of physical findings, pain in the low back, cervical or thoracic spine, or the extremities presents a diagnostic problem. On occasion the pain is present or made worse only when the patient lies down. We have attended four patients with underlying extradural tumors of the spinal canal. A 75-year-old woman with chronic back pain was treated for multiple myeloma with intravenous dexamethasone and 400 rads of x-ray irradiation to the lumbar spine and experienced marked pain relief in 24 hours. A 76-year-old woman with neck pain had complete pain relief after a vascular, calcified meningioma was removed surgically from under the 2nd and 3rd cervical nerve roots. A 38-year-old male with constant pain in the lumbar area and right leg and foot experienced marked relief from pain after a neurolemmoma of the cauda equina was surgically removed. A 57-year-old woman with knee pain became pain free 24 hours after radiation therapy to an enlarged nodular cauda equina. These four cases illustrate a diagnostic clue rarely mentioned in the literature.


Anti-Candida activity of existing antibiotics and their derivatives when used alone or in combination with antifungals.
Fungal infections are a growing challenge in immunocompromised patients, especially candidiasis. The prolonged use of traditional antifungals to treat Candida infection has caused the emergence of drug resistance, especially fluconazole. Therefore, new therapeutic strategies for Candida infection are warranted. Recently, attention has been paid to the anti-Candida activity of antibiotics and their derivatives. Studies revealed that a series of antibiotics/derivatives displayed potential anti-Candida activity and some of them could significantly increase the susceptibility of antifungals. Interestingly, the derivatives of aminoglycosides were even more active than fluconazole/itraconazole/posaconazole. This article reviews the anti-Candida activities and mechanisms of antibiotics/derivatives used alone or in combination with antifungals. This review will helpfully provide novel insights for overcoming Candida resistance and discovering new antifungals.


YccW is the m5C methyltransferase specific for 23S rRNA nucleotide 1962.
Methylation at the 5-position of cytosine [m(5)C (5-methylcytidine)] occurs at three RNA nucleotides in Escherichia coli. All these modifications are at highly conserved nucleotides in the rRNAs, and each is catalyzed by its own m(5)C methyltransferase enzyme. Two of the enzymes, RsmB and RsmF, are already known and methylate 16S rRNA at nucleotides C967 and C1407, respectively. Here, we report the identity of the third E. coli m(5)C methyltransferase. Analysis of rRNAs by matrix-assisted laser desorption/ionization mass spectrometry showed that inactivation of the yccW gene leads to loss of m(5)C methylation at nucleotide 1962 in E. coli 23S rRNA. This methylation is restored by complementing the knockout strain with a plasmid-encoded copy of the yccW gene. Purified recombinant YccW protein retains its specificity for C1962 in vitro and methylates naked 23S rRNA isolated from the yccW knockout strain. However, YccW does not methylate assembled 50S subunits, and this is somewhat surprising as the published crystal structures show nucleotide C1962 to be fully accessible at the subunit interface. YccW-directed methylation at nucleotide C1962 is conserved in bacteria, and loss of this methylation in E. coli marginally reduces its growth rate. YccW had previously eluded identification because it displays only limited sequence similarity to the m(5)C methyltransferases RsmB and RsmF and is in fact more similar to known m(5)U (5-methyluridine) RNA methyltransferases. In keeping with the previously proposed nomenclature system for bacterial rRNA methyltransferases, yccW is now designated as the rRNA large subunit methyltransferase gene rlmI.


Genetic modification of milk proteins.
It is now possible to change the protein composition of milk by direct manipulation of the germline. At present it is feasible only to add new milk-protein genes to dairy animals. If embryonic stem cells become available then it will also be possible to remove or replace endogenous genes. Various modifications made to milk proteins by using these germline-manipulation techniques are described. These are expected to enhance the processing, nutritional, and biomedical properties of milk.


Is the regulation of insulin signaling multi-organismal?
The sustained health of an individual animal depends on the composition and activities of its resident microbiota. A major challenge is to identify the processes by which the microbiota and animal interact, recognizing that this research should lead ultimately to novel strategies to promote human health. Drosophila is emerging as a tractable model system to investigate these interactions. New evidence reveals that the gut microbiota promotes insulin signaling in Drosophila, leading to increased growth and development rates. Different gut bacteria and mechanisms [corrected] were implicated: acetic acid produced by Acetobacter pomorum and the promotion of amino acid nutrition by Lactobacillus plantarum. [corrected]. These findings raise the possibility that multiple bacterial effectors may interact with signaling networks to shape animal health.


Effects of sonication and ultraviolet-C treatment as a hurdle concept on quality attributes of Chokanan mango (Mangifera indica L.) juice.
The growing demand for fresh-like food products has encouraged the development of hurdle technology of non-thermal processing. In this study, freshly squeezed Chokanan mango juice was treated by paired combinations of sonication (for 15 and 30 min at 25 ℃, 40 kHz frequency) and UV-C treatment (for 15 and 30 min at 25 ℃). Selected physicochemical properties, antioxidant activities, microbial inactivation and other quality parameters of combined treated juice were compared to conventional thermal treatment (at 90 ℃ for 60 s). After thermal and combined treatment, no significant changes occurred in physicochemical properties. A significant increase in extractability of carotenoids (15%), polyphenols (37%), flavonoids (35%) and enhancement in antioxidant capacity was observed after combined treatment. Thermal and combined treatment exhibited significant reduction in microbial load. Results obtained support the use of sonication and UV-C in a hurdle technology to improve the quality of Chokanan mango juice along with safety standards.


A systematic review of cognitive interventions to improve functional ability in people who have cognitive impairment following stroke.
Cognitive impairment is a frequent consequence of stroke and can impact the ability of people who have had a stroke to perform everyday activities. There are a number of intervention strategies that various health professionals may use when working with people who have cognitive impairment post stroke. The purpose of this systematic review was to determine whether interventions for people with cognitive impairment after a stroke improve their functional performance of basic and/or instrumental activities of daily living (ADL). Searches were performed in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, PsycINFO, PsycBITE, OTseeker, and Dissertation Abstracts. Studies were eligible for inclusion if they were a randomised controlled trial or quasi-randomised controlled trial that evaluated an intervention that focused on providing cognitive retraining to adults with clinically defined stroke and confirmed cognitive impairment and measured functional ability, either basic or instrumental ADL, as either a primary or secondary outcome measure. Four studies, involving a total of 376 participants, were included in this review. There was no statistically significant difference between groups on basic ADL performance in any of the four studies or on instrumental ADL in the one study that measured this. There were not an adequate number of high quality trials to be able to make recommendations that support or refute the use of specific cognitive retraining interventions to improve functional outcomes following a stroke. More research is required before conclusions can be made about the effect of cognitive interventions on functional outcomes post stroke.


Transcriptional regulation of rat liver protein disulphide-isomerase gene by insulin and in diabetes.
The mRNA encoding for rat protein disulphide-isomerase (PDI) increases 3-fold in the liver of diabetic rats and is accompanied by similar changes at the protein level. Long treatment (for 3 days) of diabetic rats with insulin reverses this effect of diabetes both at the mRNA and protein levels. The higher expression of rat PDI mRNA in diabetes is due to an increase in the transcriptional rate of the gene, and insulin treatment of diabetic animals produces within 30 min a decrease in the level of transcription of PDI gene, as judged by nuclear run-on transcription experiments performed in vivo. These results clearly show a role for insulin in the regulation of transcription of the gene encoding this multifunctional protein in rat liver.


Effects of iron intake on iron stores in elderly men and women: longitudinal and cross-sectional results.
For middle aged and elderly subjects there is a concern that increased iron intake, especially heme iron associated with consumption of red meat, leads to increased iron stores resulting in disturbed glucose homeostasis and risk for cardiovascular disease and certain types of cancer. The aim of this study was to investigate the influence of heme, non-heme and iron supplementation on iron stores in healthy elderly men and women. We conducted a 10 year longitudinal study (48 men and 77 women) and a one year cross-sectional study (165 men and 226 women) in healthy elderly men and women enrolled in the New Mexico Aging Process Study. Iron stores were estimated by serum ferritin concentrations and iron intake was determined by three-day food records in the longitudinal study and by a food frequency questionnaire in the cross-sectional study. We found no association between heme iron intake and iron stores in either the longitudinal or cross sectional study. In the cross-sectional study we found in women, but not in men, that age and supplemental iron intake were significantly and positively associated with increased iron stores. Iron stores in elderly men are thought to reach steady state levels where iron absorption is adjusted to a level just sufficient to cover basal iron losses. In elderly women, we speculate that not enough time has elapsed for postmenopausal women to reach steady state levels of iron stores resulting in increases in iron absorption with age. Another factor is that use of hormone replacement therapy could further delay some women in reaching steady state iron levels due to continued menstrual blood losses.