Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study.
Five patients with documented recurrences of glioblastoma multiforme were given continuous infusions of methotrexate delivered intratumorally using implantable catheters and subcutaneous refillable pumps. A continuous infusion of methotrexate (1 mg/d) was begun with concomitant oral administration of folinic acid. The methotrexate dose was increased every 2 weeks to 3, 10, 30, and, ultimately, 75 mg/d in two patients. Samples of serum and ventricular cerebrospinal fluid (CSF) were obtained to determine the levels of methotrexate and total bioactive folates, and brain tissue was obtained from two patients for determination of methotrexate concentration. The patients survived from 7 to 49 weeks after the implantation of the infusion device. Neither the clinical examination nor sequential radiological studies gave clear evidence of reduction in tumor size. Pneumonia developed in one patient, and mild hepatitis and increased seizure frequency in another. Methotrexate was stable in the delivery system over 12 days, and ventricular CSF reached steady-state levels by 5 days. Steady-state ventricular CSF levels of methotrexate were higher than serum levels in some patients, while the reverse was true in others. Levels of total bioactive folates in the CSF did not increase above the normal range. Methotrexate concentrations were highest at the center of the tumor, but measurable amounts of methotrexate were detectable in all areas of the brain. At autopsy in four patients, variable liquefactive necrosis of the brain tumors was seen, and viable tumor was found at the periphery of the tumor bed. These preliminary results suggest that it is technically feasible to infuse methotrexate into brain tumor cavities, and show that little central nervous system or systemic toxicity was encountered in five patients. Better delineation of the safety and efficacy of this therapeutic approach will require further clinical trials.


Spool-shaped proximal pedal phalanges.
We have observed that "spool-shaped" proximal pedal phalanges sometimes are found in single or multiple toes, often affecting both feet. These changes may be present in normal as well as abnormal feet. The etiology is unknown. Such changes do not occur in the hands.


Influence of environmental exposures on patients with chronic obstructive pulmonary disease in Korea.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and results from environmental factors and genetic factors. Although cigarette smoking is a major risk factor, other environmental exposures can influence COPD. The purpose of this study is to investigate the clinical characteristics of COPD according to the history of environmental exposure. The study population comprised of 347 subjects with COPD who were recruited from the pulmonary clinics of 14 hospitals within the Korean Obstructive Lung Disease Study Group. We classified environmental exposures according to history of living near factory, and direct exposure history to firewood or briquette. According to living environmental exposures, we compared the frequency of respiratory symptoms, pulmonary function, quality of life, exercise capacity, and computed tomography phenotypes. Thirty-one subjects (8.9%) had history of living near factory, 271 (78.3%) had exposure history to briquette, and 184 (53.3%) had exposure history to firewood. Patients with history of living near a factory had a significantly longer duration of sputum, while patients with exposure to firewood tended to have lower forced expiratory volume in one second, and patients with exposure to briquette tended to have lower six minute walk distance. COPD subjects with the history of living near factory had more frequent respiratory symptoms such as sputum. Our data suggest that environmental exposure may influence clinical phenotype of COPD.


Stochastic model of receptor-mediated cytomechanics and dynamic morphology of leukocytes.
The proposed mathematical model investigates the simplified cytomechanics of cell shape change driven by stochastic stimulation from chemosensory receptors. The cytomechanical component of our model describes the dynamical distribution of F-actin and associated forces in an idealized cortical actin network around the cell periphery. The chemosensory component describes the distribution of chemotactic receptors in the cell membrane surrounding the cortex, where bound receptors give rise to an intracellular signal which modulates some property of the cortical network. As in our earlier models, an account is made for (1) the reactive, contractive properties of cortical actin, but here also for a stress induced by curvature of the cortex-membrane complex which carries an effective surface tension, and (2) statistical fluctuations in receptor binding, but generalized here to include statistical fluctuations in the spatial distribution of receptors, entirely determined by the additional prescription of membrane diffusion coefficients along with total receptor number, receptor binding rate constants and the local concentration field of chemotactic factor. We simplify the analysis by restricting the model to a prototype in which viscous stresses in the cortical network are negligible and the radial extension of the cell cortex is a prescribed function of the cortical actin concentration. We assume in particular that the assembly rate of cortical actin depends on the local density of bound receptors. These assumptions lead to a 4th-order parabolic differential equation on the unit circle coupled to a system of stochastic differential equations. We characterize via bifurcation analysis, stochastic simulations, and analytical correlation functions the spatial-temporal pattern of cell morphology under the influence of fluctuations in the bound receptor distribution for the case of a uniform concentration field of chemotactic factor. In addition to addressing the biological significance of our model, we remark on its relevance to the generic problem of the influence of correlated stochastic perturbations on spatial patterns in morphogenetic media.


Early results of the Ross procedure in simple and complex left heart disease.
The Ross procedure has been used increasingly to treat aortic valve disease in children and young adults. Benefits include the lack of anticoagulation after surgery and the potential growth and durability of the autograft. The purpose of this study was to review our institutional experience with the Ross procedure and to compare early outcome in simple aortic valve disease and complex left heart disease. Between January 1995 and October 1998, 66 patients (median age, 10.8 years; range, 6 days to 34.8 years) underwent the Ross procedure. The primary indication for surgery was isolated valvular disease in 41 patients: aortic stenosis (AS; n=3), aortic insufficiency (AI; n=11), and AS/AI (n=27). The remaining 25 patients had multiple levels of left ventricular outflow tract obstruction, 12 of whom had at least moderate AI. Additional left heart disease in the complex group included subaortic stenosis (n=20), arch obstruction (n=7), mitral valve disease (n=5), apical aortic conduit stenosis or insufficiency (n=3), and supravalvar AS (n=2). There were 123 prior interventions performed in 51 patients, including aortic valvotomy/valvuloplasty (n=56), coarctation repair (n=21), subaortic stenosis resection/Konno procedure (n=10), ventricular septal defect closure (n=8), apical aortic conduit placement (n=3), aortic valve replacement (n=3), and other (n=22). An isolated Ross procedure was performed in 41 patients, 10 of whom required concurrent aortic annulus enlargement procedure to accommodate the larger pulmonary autograft. In the remaining 25 patients, 49 concurrent procedures were performed, including the Konno procedure (n=17), aortic annulus enlargement (n=2), subaortic membrane resection (n=9), arch augmentation (n=5), mitral valvuloplasty (n=5), ventricular septal defect closure (n=4), apicoaortic conduit division (n=3), and other (n=4). One patient (1.5%) died 3 days after a Ross-Konno procedure, which included arch reconstruction, from presumed arrhythmia. There were no other early deaths. One patient required ECMO (extracorporeal membrane oxygenation) for 3 days after a ventricular tachycardia (VT)-related cardiac arrest. Transient complete heart block was seen in 4 patients; the duration was <5 days. No patient had left ventricular outflow tract obstruction on discharge echocardiography. Neo-AI was graded as none (n=5), trivial-mild (n=57), or moderate (n=3). All 3 patients with moderate neo-AI at discharge had abnormal pulmonary valves before surgery. Perioperative VT was noted in 18 patients (27.2%), 2 of whom were discharged on antiarrhythmic medication. The Ross procedure can be performed in isolation or in combination with other complex procedures with low mortality (1.5%) and acceptable short-term results, even in patients with complex left heart disease and multiple prior interventions. Postoperative VT is common. Anatomic abnormalities of the pulmonary valve preclude its use as an autograft.


Monitoring of CaSO(4) deposition behaviors on biofilm during nanofiltration via ultrasonic time-domain reflectometry (UTDR).
The ultrasonic time-domain reflectometry (UTDR) as a non-destructive real-time method was employed to monitor the CaSO(4) deposition behaviors on biofilm during nanofiltration (NF). Two parallel experiments were performed to compare the different behaviors of CaSO(4) deposition with and without biofilm on the membrane. Results showed that the flux decline during combined fouling was slower than that in case of CaSO(4) fouling alone. The Ca(2 + ) rejection obtained with biofilm was higher than that without. A larger acoustic differential signal obtained by UTDR in the combined fouling revealed a denser and thicker layer formed on the membrane surface. Furthermore, the amount of CaSO(4) deposition on the biofouled membrane was more than that on non-biofouled membrane as a result of microorganisms as crystal nucleus to induce CaSO(4) crystallization and deposition. SEM images indicate that the CaSO(4) crystals deposited in order on the non-biofouled membrane, whereas on the biofouled membrane they were embedded in the biofilm. The denser and thicker fouling layer formed with biofilm was impermeable, resulting in a high Ca(2 + ) rejection. The complexation of Ca with polysaccharide in biofilm would eliminate the cake-enhanced osmotic pressure effect leading to a slow flux decline. To sum up, the independent measurements corroborate the ultrasonic measurements.


[The SGO Health Research Promotion Program. XIII. Evaluation of the section 'Addiction Research'].
As a part of the SGO Health Research Promotion Programme a research programme on addiction research was realized. Aim of the programme was to strengthen and concentrate the Dutch research into addiction. Within the Amsterdam Institute for Addiction Research (AIAR), a structural collaboration between the Jellinek Treatment Centre for Addiction, the University of Amsterdam and the Academic Hospital of the University of Amsterdam, strategic research programmes were developed on the borderland of addiction and psychiatry, notably 'Clinical epidemiology addiction' and 'Developmental disorders, addiction and psychotraumas'. The institution of a co-ordinating platform of research groups conducting socio-epidemiological addiction research improved the co-ordination of research lines in this field.


N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies.
One of the most popular experimental paradigms for functional neuroimaging studies of working memory has been the n-back task, in which subjects are asked to monitor the identity or location of a series of verbal or nonverbal stimuli and to indicate when the currently presented stimulus is the same as the one presented n trials previously. We conducted a quantitative meta-analysis of 668 sets of activation coordinates in Talairach space reported in 24 primary studies of n-back task variants manipulating process (location vs. identity monitoring) and content (verbal or nonverbal) of working memory. We found the following cortical regions were activated robustly (voxelwise false discovery rate = 1%): lateral premotor cortex; dorsal cingulate and medial premotor cortex; dorsolateral and ventrolateral prefrontal cortex; frontal poles; and medial and lateral posterior parietal cortex. Subsidiary meta-analyses based on appropriate subsets of the primary data demonstrated broadly similar activation patterns for identity monitoring of verbal stimuli and both location and identity monitoring of nonverbal stimuli. There was also some evidence for distinct frontoparietal activation patterns in response to different task variants. The functional specializations of each of the major cortical components in the generic large-scale frontoparietal system are discussed. We conclude that quantitative meta-analysis can be a powerful tool for combining results of multiple primary studies reported in Talairach space. Here, it provides evidence both for broadly consistent activation of frontal and parietal cortical regions by various versions of the n-back working memory paradigm, and for process- and content-specific frontoparietal activation by working memory.


Education for patients with limb loss or absence: Aging, overuse concerns, and patient treatment knowledge gaps.
The goals of vascular composite allotransplantation (VCA) for hand are to maximize functional status and psychosocial wellbeing and to improve quality of life. Candidates are carefully vetted by transplant programs through an extensive evaluation process to exclude those patients with contraindications and to select those that are most likely to attain functional or quality of life benefit from transplant. Patient choice for any treatment, however, requires that candidates be able to understand the risks, benefits, and alternatives before choosing to proceed. This study aimed to understand patients' knowledge and perceptions about treatment options for hand loss, including hand transplant. This study will be used to inform a standardized education approach and develop conversation aids for use by clinicians and patients throughout the treatment decision process. Ten individuals who had experienced hand amputation or had congenital limb loss were interviewed to better understand previous and current decisions about treatment, experiences in adjusting to their treatment, and perceptions about hand VCA. From this qualitative interview data, four findings emerged: (1) knowledge and education around VCA as a treatment option; (2) adaptation of individuals with limb loss; (3) fear of risk associated with transplantation; (4) issues of aging and overuse injuries to existing limbs. Results suggests that there is opportunity for expanding education about all treatment options for patients with new loss, long-term loss, and congenital limb loss. Establishing a baseline of knowledge about all options-prosthetics, rehabilitative strategies, and VCA-can help patients evaluate their values and goals of treatment. Issues associated with aging, including overuse and injury, and adaptability over the life course should be included in considerations about treatment choices. Data indicate the need for routinely assessing patient preferences about treatment choice so patients can plan for their future as they adapt and age and as technology for treatments change. To assure that thorough information is provided for current and future decision-making, education about treatment choices and selection procedures for VCA should be standardized.


Genome Sequence, Proteome Profile, and Identification of a Multiprotein Reductive Dehalogenase Complex in Dehalogenimonas alkenigignens Strain BRE15M.
Bacteria of the genus Dehalogenimonas respire with vicinally halogenated alkanes via dihaloelimination. We aimed to describe involved proteins and their supermolecular organization. Metagenomic sequencing of a Dehalogenimonas-containing culture resulted in a 1.65 Mbp draft genome of Dehalogenimonas alkenigignens strain BRE15M. It contained 31 full-length reductive dehalogenase homologous genes (rdhA), but only eight had cognate rdhB gene coding for membrane-anchoring proteins. Shotgun proteomics of cells grown with 1,2-dichloropropane as an electron acceptor identified 1152 proteins representing more than 60% of the total proteome. Ten RdhA proteins were detected, including a DcpA ortholog, which was the strongest expressed RdhA. Blue native gel electrophoresis (BNE) demonstrating maximum activity was localized in a protein complex of 146-242 kDa. Protein mass spectrometry revealed the presence of DcpA, its membrane-anchoring protein DcpB, two hydrogen uptake hydrogenase subunits (HupL and HupS), an iron-sulfur protein (HupX), and subunits of a redox protein with a molybdopterin-binding motif (OmeA and OmeB) in the complex. BNE after protein solubilization with different detergent concentrations revealed no evidence for an interaction between the putative respiratory electron input module (HupLS) and the OmeA/OmeB/HupX module. All detected RdhAs comigrated with the organohalide respiration complex. Based on genomic and proteomic analysis, we propose quinone-independent respiration in Dehalogenimonas.


Select small nucleolar RNAs in blood components as novel biomarkers for improved identification of comorbid traumatic brain injury and post-traumatic stress disorder in veterans of the conflicts in Afghanistan and Iraq.
The present study was designed to validate the ability of our recently identified set of small noncoding RNA candidate mild traumatic brain injury (mTBI) biomarkers to diagnose mTBI in the presence or absence of post-traumatic stress disorder (PTSD) comorbidity. Using qPCR, we explored the regulation of the candidate biomarkers in peripheral blood mononuclear cells (PBMC) from 58 veterans. We confirmed that 4 small nucleolar RNAs (snoRNAs), ACA48, U35, U55, and U83A, are significantly down-regulated in PBMC from veterans with mTBI and PTSD compared to non-TBI, control subjects with PTSD only. We found that the snoRNA biomarkers are able to dissect subjects with comorbid mTBI and PTSD from PTSD subjects without mTBI with 100% sensitivity, 81% accuracy, and 72% specificity. No significant differential expression of snoRNA biomarkers was found in mTBI subjects without comorbid PTSD. However, we found significantly lower U55 contents in subjects with PTSD. We explored the regulation of ACA48 in rodent models of PTSD or blast-induced mTBI to gather proof-of-concept evidence that would connect the regulation of the biomarkers and the development of mTBI or PTSD. We found no change in the regulation of ACA48 in the mTBI rat model. We did, however, find significant down-regulation of ACA48 in the PTSD mouse model 24 hours following psychological trauma exposure. This may reflect a short-term response to trauma exposure, since we found no change in the regulation of ACA48 in veteran PTSD subjects 3.6 years post-deployment. Additional application of the 4 snoRNA biomarker to current diagnostic criteria may provide an objective biomarker pattern to help identify veterans with comorbid mTBI and PTSD. Our observations suggest that biological interactions between TBI and PTSD may contribute to the clinical features of veterans with comorbid mTBI and PTSD. Future investigations on mTBI mechanisms or TBI biomarkers should consider their interactions with PTSD.


[Method of gradient chromatography for the isolation of purified lipid fractions from nerve tissue in studies using radioactive carbon, C14].
A method is developed for separation of lipids from nervous tissue by thin-layer chromatography in silica gel. Cholesterol and "minor" lipids were removed from the start by the first chromatography in the system ether-benzol-ethanol-acetic acid. Phospholipids and galactolipids, which remained at the start, were separated by the repeated chromatography in the system chloroform-methanol-NH4OH. The purified fractions of cholesterol, cerebrosides, sulfatides and the total fraction of phospholipids were obtained from 100-150 mg of nervous tissue in amounts, sufficient for estimation of their specific radioactivity in experiments with 14C.


Inflammation and physical dysfunction: responses to moderate intensity exercise in chronic kidney disease.
People with chronic kidney disease (CKD) experience skeletal muscle wasting, reduced levels of physical function and performance, and chronic systemic inflammation. While it is known that a relationship exists between inflammation and muscle wasting, the association between inflammation and physical function or performance in CKD has not been well studied. Exercise has anti-inflammatory effects, but little is known regarding the effect of moderate intensity exercise. This study aimed to (i) compare systemic and intramuscular inflammation between CKD stage G3b-5 and non-CKD controls; (ii) establish whether a relationship exists between physical performance, exercise capacity and inflammation in CKD; (iii) determine changes in systemic and intramuscular inflammation following 12 weeks of exercise; and (iv) investigate whether improving inflammatory status via training contributes to improvements in physical performance and muscle mass. This is a secondary analysis of previously collected data. CKD patients stages G3b-5 (n = 84, n = 43 males) and non-CKD controls (n = 26, n = 17 males) underwent tests of physical performance, exercise capacity, muscle strength and muscle size. In addition, a subgroup of CKD participants underwent 12 weeks of exercise training, randomized to aerobic (AE, n = 21) or combined (CE, n = 20) training. Plasma and intramuscular inflammation and myostatin were measured at rest and following exercise. Tumour necrosis factor-α was negatively associated with lower $^{^{^{.}}}{\rm V}$O2Peak (P = 0.01), Rectus femoris-cross sectional area (P = 0.002) and incremental shuttle walk test performance (P < 0.001). Interleukin-6 was negatively associated with sit-to-stand 60 performances (P = 0.006) and hand grip strength (P = 0.001). Unaccustomed exercise created an intramuscular inflammatory response that was attenuated following 12 weeks of training. Exercise training did not reduce systemic inflammation, but AE training did significantly reduce mature myostatin levels (P = 0.02). Changes in inflammation were not associated with changes in physical performance. Systemic inflammation may contribute to reduced physical function in CKD. Twelve weeks of exercise training was unable to reduce the level of chronic systemic inflammation in these patients, but did reduce plasma myostatin concentrations. Further research is required to further investigate this.


Modern-day prostate cancer is not meaningfully associated with lower urinary tract symptoms: Analysis of a propensity score-matched cohort.
We sought to determine if prostate cancer (PCa) is associated with worse lower urinary tract symptoms (LUTS) than matched benign prostates, with attention to cancer characteristics, in a contemporary cohort. Using a single-institution database (January 1, 2009-June 30, 2013), men diagnosed with PCa on biopsy and controls with negative biopsies were matched 1:1 on age, prostate volume, and a propensity score predicting the probability of PCa diagnosis. International Prostate Symptom Score (IPSS) was compared between PCa cases and controls using paired statistics, stratifying on grade, cancer volume, stage, and D'Amico risk group. Sensitivity analyses were performed separately, repeating the match for high-grade, high-volume, and high-stage cancers only, and excluding users of benign prostatic hyperplasia medications. In our cohort of 1330 men (665 with PCa), there were 284 (42.7%) Gleason 6 cancers (Grade Group 1), 315 (47.4%) Gleason 7 cancers (Grade Group 2-3), and 66 (9.9%) Gleason 8-10 cancers (Grade Group 4-5). There was no difference in IPSS between PCa cases (median 6.5, interquartile range [IQR] 3-12) and benign controls (median 7, IQR 3-13; p=0.34). Subgroup analyses based on cancer grade, volume, or stage, showed no significant differences in IPSS between men with and without PCa, except among men with cT2b-cT4 PC (median 9, IQR 5-16) vs. matched benign counterparts (median 8, IQR 3-12; p=0.03). Sensitivity analyses supported these findings. Modern PCa does not appear to be associated with worse LUTS compared to benign prostates of the same size. Outlet obstruction is likely a late event in the natural history of PCa. This has implications for timely PCa detection, which should ideally be prior to the onset of LUTS.


Patient, Provider, and Clinic Characteristics Associated with Opioid and Non-Opioid Pain Prescriptions for Patients Receiving Low Back Imaging in Primary Care.
To describe characteristics of patients, providers, and clinics associated with opioid or non-opioid pain medication prescribing patterns for patients who received lower spine imaging in primary care clinics. In these secondary analyses of the Lumbar Imaging with Reporting of Epidemiology (LIRE) study, a randomized controlled trial conducted in 4 health systems in the United States, we evaluated characteristics associated with receipt of pain medication prescriptions. The outcomes were receipt of prescriptions for opioid or, separately, non-opioid pain medications within 90 days after imaging. Among patients who received opioid or non-opioid prescriptions, we evaluated receipt of multiple prescriptions in the year following imaging. Mixed models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Compared with whites, patients identified as Asian (OR, 0.53; 95% CI, 0.51-0.56), Native Hawaiian/Pacific Islander (OR, 0.73; 95% CI, 0.64-0.83), multiracial (OR, 0.84; 95% CI, 0.71-0.98) or Black (OR, 0.92; 95% CI, 0.89-0.96) had significantly reduced odds for receiving prescriptions for opioids within 90 days. Patients identified as Native American/Alaska Native had greater odds for receiving prescriptions for non-opioid pain medications within 90 days (OR, 1.12; 95% CI, 1.01-1.24). Receipt of pain prescriptions 120 days before imaging was strongly predictive of subsequent receipt of pain prescriptions across all categories. After adjusting for factors that could affect prescribing, the strongest differences observed in pain-medication prescribing were across racial categories and for patients with previous pain prescriptions. Further research is needed to understand these differences and to optimize prescribing.


Climate change relaxes the time constraints for late-born offspring in a long-distance migrant.
Animals in seasonal environments need to fit their annual-cycle stages, such as moult and migration, in a tight schedule. Climate change affects the phenology of organisms and causes advancements in timing of these annual-cycle stages but not necessarily at the same rates. For migratory birds, this can lead to more severe or more relaxed time constraints in the time from fledging to migration, depending on the relative shifts of the different stages. We tested how a shift in hatch date, which has advanced due to climate change, impacts the organization of the birds' whole annual cycle. We experimentally advanced and delayed the hatch date of pied flycatcher chicks in the field and then measured the timing of their annual-cycle stages in a controlled laboratory environment. Hatch date affected the timing of moult and pre-migratory fattening, but not migration. Early-born birds hence had a longer time to fatten up than late-born ones; the latter reduced their interval between onset of fattening and migration to be able to migrate at the same time as the early-born birds. This difference in time constraints for early- and late-born individuals may explain why early-born offspring have a higher probability to recruit as a breeding bird. Climate change-associated advancements of avian egg-lay dates, which in turn advances hatch dates, can thus reduce the negative fitness consequences of reproducing late, thereby reducing the selection for early egg-laying migratory birds.


Perfusion settings and additives in liver normothermic machine perfusion with red blood cells as oxygen carrier. A systematic review of human and porcine perfusion protocols.
Liver machine perfusion (MP) at normothermic temperature (NMP) is a promising way to preserve and evaluate extended criteria donor livers. Currently, no consensus exists in methodology and perfusion protocols. Here, the authors performed a systematic literature search to identify human and porcine studies reporting on liver NMP with red blood cells. A qualitative synthesis was performed concerning technical aspects of MP, fluid composition, gas supply, and liver positioning. Thirty-seven publications including 11 human and 26 porcine studies were considered for qualitative synthesis. Control mode, pressure, flow, perfusate additives, and targeted blood gas parameters varied across human as well as porcine studies. For future analyses, it is advisable to report flow adjusted to liver weight and exact pressure parameters including mean, systolic, and diastolic pressure. Parenteral nutrition and insulin addition was common. Parenteral nutrition included amino acids and/or glucose without lipids. Taurocholic acid derivatives were used as bile flow promoters. However, short-term human NMP without taurocholic acid derivatives seems to be possible. This finding is relevant due to the lack of clinical grade bile salts. Near physiological oxygen tension in the perfusate is doable by adjusting gas flows, while blood gas parameters regulation needs more detailed description.


Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin.
Studies on the molecular biology of lipoprotein lipase (LPL) deficiency have been facilitated by the availability of LPL gene probes and the recent characterization of gene mutations underlying human LPL deficiency. Typically, missense mutations have predominated and show a preferential localization to exons 4 and 5. This distribution supports earlier studies attributing functional significance to residues encoded by these exons. We now report a further missense mutation within exon 5 of the LPL gene in three unrelated patients. Amplification of individual exons by the polymerase chain reaction and direct sequencing revealed a T----C transition at codon 194 of the LPL cDNA which results in a substitution of threonine for isoleucine at this residue. The catalytic abnormality induced by this mutation was confirmed through in vitro mutagenesis studies in COS-1 cells. Transfection with a LPL cDNA containing the codon 194 transition resulted in the synthesis and secretion of a catalytically defective protein. The Thr194 substitution was associated with two different DNA haplotypes, consistent with a multicentric origin for this mutation.


[11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment.
Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI. The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years. During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other. The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.


Mitochondrial DNA marker (D-loop) reveals high genetic diversity but low population structure in the pale bent-wing bat (Miniopterus pallidus) in Iran.
This study investigates the population genetic structure of Miniopterus pallidus using the D-loop region of mitochondrial DNA (331 bp) from 13 localities in Iran. We found a high number of haplotypes (N = 43) and high nucleotide diversity (π = 0.02). The average K2P genetic distance was high within (2.59%) and between (2.54%) the Iranian populations of M. pallidus and analysis of molecular variance revealed that most genetic variability was related to differences within populations. The positive and significant association between pairwise genetic and environmental distances (r = 0.443, p = .01) after accounting for the effect of geographical distances suggests that substantial influence of the climatic factors among different sites have shaped the genetic variation in this species. Neutrality tests showed historical demographic events when applying Fu's Fs, but Tajima's statistic was nonsignificant, indicating a deviation from the theoretical model of expansion. The hypothesis of sudden-expansion was not rejected by analyses of mismatch distribution as the Raggedness and SSD were insignificant (p(r)= .39 and p(SSD) = .38). Similarly, BSP results approximately revealed a major historical expansion around 81,000 years ago and a recent population decline around 13,000 years ago. Phylogenetic trees illustrated that all Iranian M. pallidus populations, as well as those from eastern Turkey and Azerbaijan, form a monophyletic clade, whereas the samples from western Turkey, Georgia and Greece belong to M. schreibersii clade. The haplotype network was consistent with these findings for M. pallidus populations in Iran and showed a high level of reticulation.


Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus.
The importance of effective immune responses in recovery from acute hepadnaviral hepatitis has been demonstrated. However, there is no conclusive delineation of virological and immunological events occurring in the liver immediately after hepadnavirus invasion and during the preacute phase of infection. These very early events might be of primary importance in determining the recovery or progression to chronic hepatitis and the intrinsic hepadnaviral propensity to persist. In this study, applying the woodchuck model of acute hepatitis B, the hepatic kinetics of hepadnavirus replication and activation of genes encoding cytokines, cytotoxicity effectors, and immune cell markers were quantified in sequential liver biopsies collected from 1 h postinoculation onward by sensitive real-time cDNA amplification assays. The results revealed that hepadnavirus replication is established in the liver as early as 1 hour after infection. In 3 to 6 h, significantly augmented intrahepatic transcription of gamma interferon and interleukin-12 were evident, suggesting activation of antigen-presenting cells. In 48 to 72 h, NK and NKT cells were activated and virus replication was transiently but significantly reduced, implying that this early innate response is at least partially successful in limiting virus propagation. Nonetheless, T cells were activated 4 to 5 weeks later when hepatitis became histologically evident. Collectively, our data demonstrate that virus replication is initiated and the innate response activated in the liver soon after exposure to a liver-pathogenic dose of hepadnavirus. Nevertheless, this response is unable to prompt a timely adaptive T-cell response, in contrast to infections caused by other viral pathogens.


Mechanism of HIV reverse transcriptase: enzyme-primer interaction as revealed through studies of a dNTP analogue, 3'-azido-dTTP.
Primer and dNTP recognition by purified HIV reverse transcriptase have been investigated. Earlier kinetic studies suggested that the reaction pathway for DNA synthesis is ordered, with template-primer and free enzyme combining to form the first complex in the reaction sequence [Majumdar et al. (1988) J. Biol. Chem. 263, 15657-15665], and through use of a particularly high affinity template-primer analogue [r(I)n.Sd(C)28], rate values for formation of the first complex were calculated [Majumdar et al. (1989) Biochemistry 28, 1340-1346]. We now report rate values for first complex formation in the usual model replication system with poly[r(A)].oligo [d(T)] as template-primer. We find that 3'-azido-dTTP (AZTTP) is a linear competitive inhibitor of DNA synthesis against the substrate dNTP (dTTP) in the poly[r(A)].oligo[d(T)] replication system. This suggests that 3'-azido-dTTP and dTTP combine with the same form of the enzyme in the reaction scheme, i.e., the enzyme-primer complex. This is not trivial, since a second analogue, 3'-amino-dTTP, also is an inhibitor against dTTP, but the mechanism in this case is linear noncompetitive. Because the inhibition by 3'-azido-dTTP is linear competitive, the KD for physical binding to the enzyme is assumed to be the same as the Ki for inhibition (20 nM). Substrate kinetic studies of DNA synthesis using 3'-azido-dTTP as substrate revealed that the Michaelis constant is 3 microM. Therefore, the Km for this substrate analogue is 100-fold higher than the KD for binding of the analogue to the enzyme-primer complex.(ABSTRACT TRUNCATED AT 250 WORDS)


CD80 expression and infiltrating regulatory T cells in idiopathic nephrotic syndrome of childhood.
CD80 (also known as B7-1) is a co-stimulatory molecule that is expressed in biopsies and also excreted in urine in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). CD80 is inhibited by the cytotoxic T-lymphocyte-associated-antigen 4 (CTLA4), which is mainly expressed on regulatory T cells (Tregs). Ineffective circulating Treg response is involved in the pathogenesis of nephrotic syndrome. In this study, we evaluated CD80 expression and infiltrating Tregs in children with MCD and FSGS. Evaluation of CD80 expression and semi-quantitative evaluation of Tregs (FOXP3-positive CD4 T cells) were carried out in 31 kidney biopsies (12 MCD, 19 FSGS) with immunofluorescence and immunohistochemistry staining. All MCD sections were stained negative; whereas six out of 19 FSGS sections (all from steroid-resistant (SR) patients), including one from a Wilms' tumor 1 (WT1) mutation-positive FSGS patient, stained positive for anti-CD80 goat antibody, and negative for anti-CD80 rabbit antibody. FSGS biopsy specimens had significantly higher FOXP3-positive cells/mm2 compared with MCD and control samples (P < 0.001). Biopsy samples from SR-FSGS patients (n = 12) with positive CD80 staining (n = 6) had significantly less Tregs (FOXP3-positive CD4 T cells) compared with CD80 (-) biopsies (n = 6; P = 0.004). CD80 expression was not detected in the majority of the archival biopsy sections and the results were not consistent across the different antibodies. In the SR-FSGS sections, however, CD80-positive biopsies had decreased FOXP3-positive CD4 T cells, suggesting that a decreased anti-inflammatory milieu may be the cause of increased CD80 expression.


Early feeding leads to molecular maturation of the gut mucosal immune system in suckling piglets.
Diet-microbiota-host interactions are increasingly studied to comprehend their implications in host metabolism and overall health. Keeping in mind the importance of early life programming in shaping intestinal mucosal development, the pre-weaning period can be utilised to understand these interactions in suckling piglets. The objective of this study was to investigate the consequences of early life feeding on the time-resolved mucosal transcriptional program as well as mucosal morphology. A customised fibrous feed was provided to piglets (early-fed or EF group; 7 litters) from five days of age until weaning (29 days of age) in addition to sow's milk, whereas control piglets (CON; 6 litters) suckled mother's milk only. Rectal swabs, intestinal content, and mucosal tissues (jejunum, colon) were obtained pre- and post-weaning for microbiota analysis (16S amplicon sequencing) and host transcriptome analysis (RNA sequencing). Early feeding accelerated both microbiota colonisation as well as host transcriptome, towards a more "mature state", with a more pronounced response in colon compared to jejunum. Early feeding elicited the largest impact on the colon transcriptome just before weaning (compared to post-weaning time-points), exemplified by the modulation of genes involved in cholesterol and energy metabolism and immune response. The transcriptional impact of early feeding persisted during the first days post-weaning and was highlighted by a stronger mucosal response to the weaning stress, via pronounced activation of barrier repair reactions, which is a combination of immune activation, epithelial migration and "wound-repair" like processes, compared to the CON piglets. Our study demonstrates the potential of early life nutrition in neonatal piglets as a means to support their intestinal development during the suckling period, and to improve adaptation during the weaning transition.


Deep insights into biodegradability mechanism and growth cycle adaptability of polylactic acid/hyperbranched cellulose nanocrystal composite mulch.
The widespread use of petroleum-based plastic mulch in agriculture has accelerated white and microplastic pollution while posing a severe agroecological challenge due to its difficulty in decomposing in the natural environment. However, endowing mulch film with degradability and growth cycle adaptation remains elusive due to the inherent non-degradability of petroleum-based plastics severely hindering its applications. This work reports polylactic acids hyperbranched composite mulch (PCP) and measured biodegradation behavior under burial soil, seawater, and ultraviolet (UV) aging to understand the biodegradation kinetics and to increase their sustainability in the agriculture field. Due to high interfacial interactions between polymer and nanofiler, the resultant PCP mulch significantly enhances crystallization ability, hydrophilicity, and mechanical properties. PCP mulch can be scalable-manufactured to exhibit modulated degradation performance under varying degradation conditions and periods while concurrently enhancing crop growth (wheat). Thus, such mulch with excellent performance can reduce labor costs and the environmental impact of waste mulch disposal to replace traditional mulch for sustainable agricultural production.


Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aβ42) mediated neurodegeneration.
Alzheimer's disease (AD, OMIM: 104300), a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42) aggregates that trigger neuronal cell death by unknown mechanism(s). We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb) as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.


Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells.
Little is known about the enzyme(s) required for the endoproteolytic processing of mammalian Ras proteins. We identified a mouse gene (designated Rce1) that shares sequence homology with a yeast gene (RCE1) implicated in the proteolytic processing of Ras2p. To define the role of Rce1 in mammalian Ras processing, we generated and analyzed Rce1-deficient mice. Rce1 deficiency was lethal late in embryonic development (after embryonic day 15.5). Multiple lines of evidence revealed that Rce1-deficient embryos and cells lacked the ability to endoproteolytically process Ras proteins. First, Ras proteins from Rce1-deficient cells migrated more slowly on SDS-polyacrylamide gels than Ras proteins from wild-type embryos and fibroblasts. Second, metabolic labeling of Rce1-deficient cells revealed that the Ras proteins were not carboxymethylated. Finally, membranes from Rce1-deficient fibroblasts lacked the capacity to proteolytically process farnesylated Ha-Ras, N-Ras, and Ki-Ras or geranylgeranylated Ki-Ras. The processing of two other prenylated proteins, the farnesylated Ggamma1 subunit of transducin and geranylgeranylated Rap1B, was also blocked. The absence of endoproteolytic processing and carboxymethylation caused Ras proteins to be mislocalized within cells. These studies indicate that Rce1 is responsible for the endoproteolytic processing of the Ras proteins in mammals and suggest a broad role for this gene in processing other prenylated CAAX proteins.


Nef can enhance the infectivity of receptor-pseudotyped human immunodeficiency virus type 1 particles.
Nef is an accessory protein of human immunodeficiency virus type 1 (HIV-1) that enhances the infectivity of progeny virions when expressed in virus-producing cells. The requirement for Nef for optimal infectivity is, at least in part, determined by the envelope (Env) glycoprotein, because it can be eliminated by pseudotyping HIV-1 particles with pH-dependent Env proteins. To investigate the role of Env in the function of Nef, we have examined the effect of Nef on the infectivity of Env-deficient HIV-1 particles pseudotyped with viral receptors for cells expressing cognate Env proteins. We found that Nef significantly enhances the infectivity of CD4-chemokine receptor pseudotypes for cells expressing HIV-1 Env. Nef also increased the infectivity of HIV-1 particles pseudotyped with Tva, the receptor for subgroup A Rous sarcoma virus (RSV-A), even though Nef had no effect if the pH-dependent Env protein of RSV-A was used for pseudotyping. However, Nef does not always enhance viral infectivity if the normal orientation of the Env-receptor interaction is reversed, because the entry of Env-deficient HIV-1 into cells expressing the vesicular stomatitis virus G protein was unaffected by Nef. Together, our results demonstrate that the presence of a viral Env protein during virus production is not required for the ability of Nef to increase viral infectivity. Furthermore, since the infectivity of Tva pseudotypes was blocked by inhibitors of endosomal acidification, we conclude that low-pH-dependent entry does not always bypass the requirement for Nef.


Potential for phosphonoacetate utilization by marine bacteria in temperate coastal waters.
Phosphonates are organic compounds that contain a C-P bond and are a poorly characterized component of the marine phosphorus cycle. They may represent a potential source of bioavailable phosphorus, particularly in oligotrophic conditions. This study has investigated the distribution of the phnA gene which encodes phosphonoacetate hydrolase, the enzyme that mineralizes phosphonoacetate. Using newly designed degenerate primers targeting the phnA gene we analysed the potential for phosphonoacetate utilization in DNA and cDNA libraries constructed from a phytoplankton bloom in the Western English Channel during July 2006. Total RNA was isolated and reverse transcribed and phosphonoacetate hydrolase (phnA) transcripts were PCR amplified from the cDNA with the degenerate primers, cloned and sequenced. Phylogenetic analysis demonstrated considerable diversity with 14 sequence types yielding five unique phnA protein groups. We also identified 28 phnA homologues in a 454-pyrosequencing metagenomic and metatranscriptomic study from a coastal marine mesocosm, indicating that > 3% of marine bacteria in this study contained phnA. phnA homologues were also present in a metagenomic fosmid library from this experiment. Finally, cultures of four isolates of potential coral pathogens belonging to the Vibrionaceae contained the phnA gene. In the laboratory, these isolates were able to grow with phosphonoacetate as sole P and C source. The fact that the capacity to utilize phosphonoacetate was evident in each of the three coastal environments suggests the potential for widespread utilization of this bioavailable P source.


Myeloperoxidase is associated with insulin resistance and inflammation in overweight subjects with first-degree relatives with type 2 diabetes mellitus.
Family history of type 2 diabetes mellitus (T2DM) is one of risk factors for that in future a subject can develop diabetes. Insulin resistance (IR) is important in the pathogenesis of T2DM. There is evidence that oxidative stress plays an important role in the etiology and/or progression of diabetes. Myeloperoxidase (MPO) participates in developing of inflammation. The objective was to investigate if MPO is associated with IR and inflammation in individuals with first-degree relatives of T2DM. Cross-sectional study in 84 overweight individuals with family history of T2DM divided in two groups according to IR, group with IR (homeostasis model assessment [HOMA] ≥2.5; n=43) and control group (CG; HOMA <2.5; n=41). Complete clinical history and a venous blood sample were collected for measuring glucose and lipids profile, insulin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), MPO, glutathione reductase (GRd), glutathione peroxidase, and superoxide dismutase. MPO, TNF-α, and IL-6 were higher in patients with IR than in CG (MPO: 308.35 [190.85 to 445.42] vs. 177.35 [104.50 to 279.85], P=0.0001; TNF-α: 13.46 [10.58 to 18.88] vs. 9.39 [7.53 to 11.25], P=0.0001; IL-6: 32.93 [24.93 to 38.27] vs. 15.60 [12.93 to 26.27]; P=0.0001, respectively). MPO was associated with IR (rho de Spearman=0.362, P=0.001). In the analysis of lineal regression, MPO predicts IR (β, 0.263; t, 2.520; P=0.014). In the univariate analysis, MPO had an odds ratio of 9.880 for risk of IR (95% confidence interval, 2.647 to 36.879). MPO had relation with IR and inflammation parameters in overweight subjects with first-degree relatives of T2DM. We need studies on a casual relationship and molecular mechanisms among the increased serum MPO levels, inflammation markers, and IR.


Modified-release capsules containing sodium riboflavin 5'-phosphate.
The focus of this work was to produce delayed-release capsules containing riboflavin (vitamin B2, as API) layered pellets. Riboflavin therapy is indicated in patients with a riboflavin deficiency, which usually occurs in conjunction with malabsorption, alcoholism or a protein-calorie deficiency and rarely as the sole vitamin deficiency. Riboflavin is readily absorbed from the upper gastrointestinal tract by a specific transport mechanism. The dissolution rate of coated capsules was controlled through the coating of the capsules and the thickness of the coating layer. The core pellets (Cellet 300) were loaded with a 10% aqueous solution of sodium riboflavin 5'-phosphate by a layering technique in a coating pan. Hard capsules were filled with riboflavin layered pellets and coated with Eudragit NE polymer with different coating layer thicknesses. The dissolution was tested in gastric and intestinal fluids with the half-change method. The dissolution profiles were analyzed with the use of different mathematical models and an attempt was made to predict the optimum coating film thickness that ensures the required degree and rate of dissolution. A new solid dosage form was developed which can enhance the bioavailability of riboflavin. RRSBW distribution and the Chapman-Richards growth function were used to fit the dissolution profiles. Statistical analysis indicated that the best products were described by the Chapman-Richards equation. The results were utilized to create a theoretical model suitable for prediction of the optimum film thickness that ensures the required release of riboflavin.


The influence of maternal and paternal factors on time to pregnancy--a Dutch population-based birth-cohort study: the GECKO Drenthe study.
Both maternal and paternal factors have been suggested to influence a couple's fecundity. To investigate this, we examined the role of several maternal and paternal lifestyle and socio-demographic factors as determinants of time to pregnancy (TTP) in a Dutch birth-cohort. Groningen Expert Center for Kids with Obesity (GECKO) Drenthe is a population-based birth-cohort study of children born between April 2006 and April 2007 in Drenthe, a province of The Netherlands. Both partners received extensive questionnaires during pregnancy. Univariable and multivariable Cox regression analyses were used to determine the impact of the investigated factors on TTP. A total of 4778 children were born, and the parents of 2997 children (63%) gave their consent to participate. After excluding unintended pregnancies and pregnancies as a result of fertility treatment, the data of 1924 couples were available for analysis. Hazards ratios and 95% confidence intervals of factors influencing TTP in multivariable Cox regression analysis were: maternal age 1.23 (0.98-1.54) for age <25 years, 1.17 (1.03-1.32) for age 25-30 years and 0.72 (0.61-0.85) for age >35 years (reference category: 30-35 years); paternal age: 1.31 (0.94-1.82) for age <25 years, 1.11 (0.97-1.28) for age 25-30 years and 0.91 (0.80-1.04 for age >35 years (reference category: 30-35 years); nulliparity: 0.76 (0.68-0.85) versus multiparity; menstrual cycle length: 1.12 (0.95-1.30) for 3 weeks, 0.72 (0.62-0.83) for 4-6 weeks, 0.68 (0.40-1.16) for >6 weeks and 0.66 (0.54-0.81) for irregular cycle (reference category: 4 weeks); prior contraceptive use: 0.78 (0.67-0.91) for no contraception, 1.68 (1.45-1.95) for condom use, 1.08 (0.89-1.33) for condom use combined with oral contraception, 1.40 (1.16-1.70) for intrauterine device and 0.50 (0.25-1.01) for contraceptive injection (reference category: oral contraception); and maternal educational level 0.75 (0.62-0.92) for low education level and 0.81 (0.73-0.90) for medium educational level (reference category: high educational level). This population-based birth-cohort study performed in fertile couples who had conceived revealed neither maternal nor paternal modifiable lifestyle factors were significantly associated with TTP after adjustment for confounding by socio-demographic factors. In contrast, several non-modifiable maternal socio-demographic factors are significant predictors of a couple's fecundity.


Evaluation of Clinical Efficacy and Safety of a Novel Cyclosporin A Nanoemulsion in the Treatment of Dry Eye Syndrome.
Topical administration of the anti-inflammatory agent cyclosporin A (CsA) is recommended for long-term management of dry eye syndrome (DES), yet standard ophthalmic CsA preparations have been reported to be unstable. In this trial, the efficacy and safety of Clacier™ (based on a phase 3 study developed by Huons Co. Ltd.), a novel 0.05% CsA nanoemulsion formulation, are compared with those of the conventional Restasis® emulsion. Patients with moderate-to-severe DES were randomly assigned to receive topical 0.05% CsA in the form of Clacier or Restasis, to be administered twice daily for 12 weeks. The primary efficacy outcome was the change from baseline in corneal fluorescein staining scores at week 12; changes at weeks 4 and 8 were secondary endpoints. Additional endpoints included score changes from baseline in nonanesthetic Schirmer's test I, tear breakup time, ocular surface disease index, and conjunctival staining. At week 12, corneal staining scores were improved in patients treated with Clacier and Restasis, with no significant difference between treatments (P = 0.41). Temporal conjunctival surface damage was significantly more ameliorated with Clacier treatment than with Restasis treatment (P = 0.034). Notably, tear film stability was improved more rapidly in Clacier patients at week 4 (P = 0.005) than in Restasis patients (P = 0.36). Improvements in tear production were comparable with both Clacier and Restasis treatments. Clacier did not increase the risk of adverse events as compared with Restasis. Treatment with Clacier alleviated clinical signs and symptoms of DES comparably to the commercially available Restasis, resulting in improved quality of life for patients. Clacier is an effective and safe therapeutic agent for DES.


Identification of potentially avoidable hospitalizations in patients with GI cancer.
To identify and characterize potentially avoidable hospitalizations in patients with GI malignancies. We compiled a retrospective series of sequential hospital admissions in patients with GI cancer. Patients were admitted to an inpatient medical oncology or palliative care service between December 2011 and July 2012. Practicing oncology clinicians used a consensus-driven medical record review process to categorize each hospitalization as "potentially avoidable" or "not avoidable." Patient demographic and clinical data were abstracted, and quantitative and qualitative analyses were performed to identify patient characteristics and outcomes associated with potentially avoidable hospitalizations. We evaluated 201 hospitalizations in 154 unique patients. The median age was 62 years, and colorectal cancer was the most common diagnosis (32%). The majority of hospitalized patients had metastatic cancer (81%). In all, 53% of hospitalizations were attributable to cancer symptoms, and 28% were attributable to complications of cancer treatment. Medical oncologists identified 39 hospitalizations (19%) as potentially avoidable. Hospitalizations were more likely to be categorized as potentially avoidable for patients with the following characteristics: age ≥ 70 years (odds ratio [OR], 2.63; 95% CI, 1.15 to 6.02), receipt of an oncologist's advice to consider hospice (OR, 6.09; 95% CI, 2.54 to 14.58), or receipt of three or more lines of chemotherapy (OR, 2.68; 95% CI, 1.01 to 7.08). Ninety-day mortality was higher after avoidable hospitalizations compared with hospitalizations that were not avoidable (OR, 6.4; 95% CI, 1.8 to 22.3). Potentially avoidable hospitalizations are common in patients with advanced GI cancer. The majority of potentially avoidable hospitalizations occurred in patients with advanced treatment-refractory cancers near the end of life.


Software-programmable continuous-flow multi-purpose lab-on-a-chip.
Current lab-on-a-chip (LoC) devices are assay-specific and are custom-built for each single experiment. Performing an experiment requires scientists or engineers to go through the time-consuming process of designing, fabricating, and testing a chip before conducting the actual experiment. This prolonged cycle can take months to complete, increasing effort and cost and reducing productivity. Similarly, minor modifications to an assay protocol re-incur the overheads of the design cycle. In this paper, we develop a multi-purpose, software-programmableLab-on-a-Chip (SPLoC), where the user simply writes or downloads a program for each experiment. We describe the components necessary to realize the SPLoC, which include a high-level programming language, an abstract instruction set, a runtime and control system, and a microfluidic device. We describe two key features of our high-level language compiler, and describe a novel variable-volume variable-ratio mixer. Finally, we demonstrate our SPLoC on four diverse, real-world assays.


[Effect of mycotoxin T-2 on bioluminescence intensity of bacteria].
The acute and chronic toxicity of T-2 was studied by bioluminescent method with the use of two strains of luminous bacteria--P. phosphorum Sq3 u V. fischeri F1 as biological objects. It was shown that in acute experiments after 10 min incubation of bacteria in the presence of T-2 the bioluminescence inhibition on the 50% level was observed at the toxin concentration equal to 12 mg/mL. In chronic experiments such a level of bioluminescence inhibition was registered after 16 hours incubation at the toxin concentration of 18 mg/mL. T-2 toxicity was also investigated in the presence of different serum albumin concentrations. It decreases with the increase of albumin concentration at the short term of incubation (5 min) of the mixture to be analyzed. In case of the longer term of incubation (up to 30 min) of this mixture T-2 toxicity was restored. Probably, it is a result of destruction of protein-toxin complex, which is, evidently, reversible and may be characterized by some index. It is necessary to emphasize that the sensitivity of T-2 analysis increases under the decrease of pH value up to lower bacterial physiological level, i.e. to 5-5.5. The revealed abilities of T-2 toxin effect on the intensity of bacterial bioluminescence may be used under the development of instrumental analytical approach on the basis of biosensor technology for testing this toxin in the environment. Taking into account the analysis simplicity and rapidity, such analytical device may have a perspective for wide practical application.


Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2.
Nitric oxide (NO) is well established as a neurotransmitter in the central and peripheral nervous systems. More recently, another gas, carbon monoxide (CO) has also been implicated in neurotransmission. In the nervous system CO is formed by a subtype of heme oxygenase (HO) designated HO2. HO2 is localized to discrete neuronal populations in the brain resembling localizations of soluble guanylyl cyclase, which is activated by CO. CO may also function in the peripheral autonomic nervous system, in conjunction with NO. The majority of ganglia in the myenteric plexus possess both HO2 and neuronal NO synthase (NOS). Defects in myenteric plexus neurotransmission occur both in mice with targeted deletion of genes for HO2 and neuronal NOS. HO2 also occurs in other autonomic ganglia including the petrosal, superior cervical and nodose ganglia. Neuronal NOS is localized to neurons regulating male reproductive behavior, such as penile erection, and NOS inhibitors prevent erection. Because of the other parallels between NO and CO, we speculated that CO may play a role in male reproductive behavior. In the present study we describe HO2 localization in neuronal structures regulating copulatory reflexes. Reflex activity of the bulbospongiosus muscle, which mediates ejaculation and ejaculatory behavior, is markedly diminished in mice with targeted deletion of the gene for HO2 (HO2-).


[Tissue typing of blood lymphocytes in normal Chinese and diseases (author's transl)].
The histocompatibility antigens were determined in 170 normal Chinese by a modified micro-lymphocytotoxicity test of Terasaki using 26 typing sera obtained from Behring Laboratories and Stanford University, and the data were compared with those obtained from 36 systemic lupus erythematosus, 30 rheumatoid arthritis, 17 ankylosing spondylitis as well as 45 leprosy patients. In normal individuals HLA-A2,A11 and A9 were dominant in locus A, the frequency were 42.35%, 41.76% and 32.35% respectively. HLA-Bw17, B13 and B5 were dominant in locus B, the frequency were 55.29%, 19.41% and 14.70% respectively. In systemic lupus erythematosus, the frequency of B8, Bw38 and A3 were slightly higher than normal (relative risk > 2); the frequency of Bw21 and B7 were little lower (risk of Bw21 < 0.5, frequency of B7 > 5% in normals but none in patients). In rheumatoid arthritis, the frequency of A28 and A10 (Aw25+26) were slightly lower than normal (risk < 0.5). In ankylosing spondylitis, the frequency of B27 was extremely high (risk = 44.92), Aw24 was also rather high (risk > 2); the frequency of B5, Bw35 and A10 (Aw25+26) was low (risk < 0.5), Bw15 and Bw21 > 5% in normals but none in patients. In leprosy, the frequency of B18 was relatively high (risk > 2); A3, Aw30+31+32, B27 and Bw35 were somewhat low (risk < 0.5). Because of the small sample size, however, the differences were not significant by Chi square analysis except the high frequency of B27 in ankylosing spondylitis (corrected P < 0.001).


Gastrointestinal Manifestations of Chagas Disease: A Systematic Review with Meta-Analysis.
The aims of this study were to estimate the prevalence of gastrointestinal manifestations among individuals with positive serology for Chagas disease (ChD) and to describe the clinical gastrointestinal manifestations of the disease. A systematic review with meta-analysis was conducted based on the criteria and recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The PubMed, Scopus, Virtual Health Library, Web of Science, and Embase databases were used to search for evidence. Two reviewers independently selected eligible articles and extracted data. RStudio® software was used for the meta-analysis. For subgroup analysis, the studies were divided according to the origin of the individuals included: 1) individuals from health units were included in the health care service prevalence analysis, and 2) individuals from the general population were included in the population prevalence analysis. A total of 2,570 articles were identified, but after removal of duplicates and application of inclusion criteria, 24 articles were included and 21 were part of the meta-analysis. Most of the studies were conducted in Brazil. Radiological diagnosis was the most frequent method used to identify the gastrointestinal clinical form. The combined effect of meta-analysis studies showed a prevalence of gastrointestinal manifestations in individuals with ChD of 12% (95% CI, 8.0-17.0%). In subgroup analysis, the prevalence for studies involving health care services was 16% (95% CI, 11.0-23.0%), while the prevalence for population-based studies was 9% (95% CI, 5.0-15.0%). Megaesophagus and megacolon were the main forms of ChD presentation in the gastrointestinal form. The prevalence of gastrointestinal manifestations of ChD was 12%. Knowing the prevalence of ChD in its gastrointestinal form is an important step in planning health actions for these patients.


Subcellular distribution of the major immediate early proteins of human cytomegalovirus changes during infection.
The 72K immediate early (IE) 1 protein of human cytomegalovirus and the 68K protein, also encoded by the IE1 gene, were detected by immunoelectron microscopy using monoclonal antibodies specific for the 68K or 72K proteins. Early after infection, both proteins were localized to the nucleus, but with different localization patterns. Late after infection, both of the proteins decreased markedly in the nucleus, in which nucleocapsids appeared. Simultaneously, the 68K protein became diffusely distributed in the cytoplasm and the plasma membrane, whereas the 72K protein was distributed in the nuclear envelope and the plasma membrane. Both proteins were also observed in the coating membrane of the extracellular dense bodies.


A comparative study of enflurane and halothane using systolic time intervals.
The effects of enflurane and halothane anesthesia on systolic time intervals were studied in 12 healthy patients. Cardiovascular measurements were made at equipotent levels of anesthesia: enflurane 1.23% end-tidal and halothane 0.65% end-tidal. These agents were studied first with 50% N2O and then without N2O. Systolic, diastolic, and mean arterial blood pressure were decreased more by enflurane than by halothane (p less than 0.05). However, halothane caused significantly more myocardial depression than enflurane, as indicated by a larger preejection period (PEP) and preejection period/left ventricular ejection time (PEP/LVET) and a smaller 1/PEP2 and ejection fraction. When N2O was discontinued, both agents increased PEP and PEP/LVET and decreased 1/PEP2 and the ejection fraction.


Measurement of QALYS and the welfare implications of survivor consumption and leisure forgone.
In previous work (Health Econ. 2004; 13: 417-427; Health Econ. 2006; 15: 319-322) has suggested that survivor consumption costs should be included in cost-utility analyses only if the corresponding utility gains are also included. Here, it is further argued that the welfare implications of survivor consumption are already known because unlike new medical treatments or interventions whose complex and uncertain outcomes and third-party purchasing make the welfare implications unclear, survivor consumption must have passed a private market welfare test. That is, the gains must have exceeded the costs in order for the survivor consumption to be purchased; therefore, survivor consumption is welfare increasing. The same would apply for survivor leisure forgone. Implications for cost-benefit analysis are clear, but are less so for cost-utility analysis. Moreover, as it is currently practiced, cost-utility analysis does not evaluate welfare because quality-adjusted life years (QALYs) do not meet all the criteria for representing utility. Therefore, rather than using QALYs to analyze welfare, cost-QALY analysis should be differentiated from cost-utility analysis. The former should continue to employ existing QALYs as a measure of health-focused effectiveness, but the latter should develop a new broader measure that meets the criteria for representing utility, and either this new measure or cost-benefit analysis should be used to evaluate welfare.


Site-specific relaxation and recombination by the Tn3 resolvase: recognition of the DNA path between oriented res sites.
We studied the dynamics of site-specific recombination by the resolvase encoded by the Escherichia coli transposon Tn3. The pure enzyme recombined supercoiled plasmids containing two directly repeated recombination sites, called res sites. Resolvase is the first strictly site-specific topoisomerase. It relaxed only plasmids containing directly repeated res sites; substrates with zero, one or two inverted sites were inert. Even when the proximity of res sites was ensured by catenation of plasmids with a single site, neither relaxation nor recombination occurred. The two circular products of recombination were catenanes interlinked only once. These properties of resolvase require that the path of the DNA between res sites be clearly defined and that strand exchange occur with a unique geometry. A model in which one subunit of a dimeric resolvase is bound at one res site, while the other searches along adjacent DNA until it encounters the second site, would account for the ability of resolvase to distinguish intramolecular from intermolecular sites, to sense the relative orientation of sites and to produce singly interlinked catenanes. Because resolvase is a type 1 topoisomerase, we infer that it makes the required duplex bDNA breaks of recombination one strand at a time.


Novel Surgical Treatment Strategies for Unstable Lumbar Osteodiscitis: A 3-Patient Case Series.
Lumbar osteomyelitis frequently affects patients with medical comorbidities and poor preoperative health. Surgery is indicated when medical management fails or patients present with spinal instability or neural compromise. Successful arthrodesis can be difficult and sometimes requires alternative surgical techniques. To report 3 novel methods, each illustrated by a case, for achieving arthrodesis for lumbar osteomyelitis. A retrospective review was performed of 3 cases of surgical treatment of lumbar osteomyelitis. Novel aspects of the surgical techniques are reported, as are perioperative clinical details and imaging results. In the first patient, a vascularized iliac crest graft on a quadratus lumborum pedicle was rotated into the posterolateral fusion bed of the affected level. In the second, an anterior approach with debridement of affected lumbar levels was followed by rotation of a vascularized iliac crest graft on an iliacus muscle pedicle into the anterior lumbar defect. In the third, a structural, nonvascularized iliac crest graft was harvested via a lateral approach to provide better surgical access, and an autologous tricortical bone graft was obtained for placement in the debridement defect. Follow-up imaging suggested successful early incorporation of all the grafts in the fusion beds. Patients with multiple risk factors for pseudarthrosis and recurrent infection often require alternative surgical strategies to augment fusion. These 3 novel methods for lumbar debridement, fixation, and fusion using vascularized or nonvascularized autograft accommodate posterior, anterior, and lateral surgical approaches. Further experience with these techniques is required to compare outcomes with those of traditional techniques.


Perturbation in Long-Range Contacts Modulates the Kinetics of Amyloid Formation in α-Synuclein Familial Mutants.
The characteristic cross-β-sheet-rich amyloid fibril formation by intrinsically disordered α-synuclein proteins is one of the pathological hallmarks of Parkinson's disease. Although unstructured in solution, the presence of autoinhibitory long-range contacts in monomeric form prevents protein aggregation. Out of the various factors that affect the rate of amyloid formation, familial mutations play an important role in α-synuclein aggregation. Even though these mutations are believed to form an aggregation-prone intermediate by perturbing these contacts, the correlation between perturbation and rate of fibril formation is not very straightforward. A combination of solution and solid-state NMR in conjunction with other biophysical methods has been used to identify the underlying mechanism behind the anomaly in the rate of aggregation for the novel mutants H50Q (fast aggregating) and G51D (slow aggregating). Perturbation of long-range contacts at the mutation sites and C-termini in all of the six familial mutants of α-synuclein during the diseased condition (acidic pH) was observed. These contacts get rearranged at physiological pH resulting in the shielding of mutation sites. Additional contacts at the mutation site in a slow aggregating mutant could be the reason for slower aggregation. Indeed, these contacts provide more rigidity to the monomeric G51D. Nonetheless, these mutations did not alter the overall secondary structure. The differential pattern of the long-range contacts at the monomeric level resulted in the perturbation of the fibrillar-core region, which was evident in the solid-state NMR spectra. Our results provide valuable insights in understanding the effect of long-range contacts on the aggregation of α-synuclein and its mutants.


Towards machine to brain interfaces: sensory stimulation enhances sensorimotor dynamic functional connectivity in upper limb amputees.
Recent development of sensory stimulation techniques demonstrates the ability to elicit touch-like phantom sensations in upper limb amputees. The cortical processing of this phantom sensation and the corresponding influences on sensorimotor functional connectivity have not been studied. We hypothesize that sensory stimulation has a profound impact on the sensorimotor cortical functional interactions, which will be uncovered by dynamic functional connectivity (dFC) analysis of amputees' electroencephalogram (EEG) recordings. We investigated dFC between cortical areas associated with somatosensory, motor, visual, and multisensory processing functions using EEG signals. We applied dFC to the EEG of two amputees performing hand movements with and without sensory stimulation and compared the results with those from three able-bodied subjects. We quantified the changes due to sensory stimulation using dFC metrics, namely temporal distance, number of connection paths, temporal global and local efficiencies, and clustering coefficient. We show a significant effect of sensory stimulation on functional connectivity in the amputee brains, with notable facilitation on multisensory processing among the cortical systems involved in sensorimotor processing. The dFC metrics reveal that sensory stimulation enhances the speed of information transfer (shown by decreases in temporal distance) and the number of connection paths between the brain systems involved in sensorimotor processing, including primary somatosensory and motor, and higher order processing regions. This is the first work to reveal dynamic communication between somatosensory, motor, and higher order processing regions in the cortex of amputees in response to sensory stimulation. We believe that our work provides crucial insights into the cortical impact of sensory stimulation in amputees, which may lead to the design of personalized brain-informed sensory feedback paradigms. This in turn may lead to building novel Machine to Brain Interfaces involving sensory feedback and the resultant enhanced motor performance.


Evidence for low-voltage-activated (LVA) calcium currents in the dendrites of tiger salamander retinal ganglion cells.
We have evaluated the spatial distribution of low-voltage-activated calcium currents in ganglion cells of the tiger salamander retina. Whole-cell recordings were obtained from ganglion cells in a retinal slice preparation and from acutely dissociated ganglion cells that were identified through retrograde dye injection. In single dissociated cells, we estimated the magnitude (pA) and current density (pA/pF) of LVA currents in ganglion cells, both with and without dendritic processes. Ganglion cells that retained a portion of their dendritic arbor had larger LVA calcium currents and higher LVA current densities than those which lacked processes. When cell capacitance measurements were used to derive the surface area of the soma and dendritic processes, we concluded that a higher LVA current density was present in the dendrites; we estimate that, on average, the current density in the dendrites is approximately five times that of the soma. The presence of a significant density of LVA calcium channels in the dendrites of ganglion cells suggests that they could be involved in a number of cellular functions, including dendritic integration of synaptic currents, impulse generation, and homeostatic functions related to changes in the intradendritic calcium concentration.


All different, all equal: Evidence of a heterogeneous Neolithic population at the Bom Santo Cave necropolis (Portugal).
The objective of this paper was to contribute to the discussion regarding the socio-political organization of south-western Iberian Middle Neolithic populations. To that end, the preservation and distribution of human remains and the dispersion of grave goods within two rooms of the Bom Santo Cave (Rooms A and B) were investigated and combined with genetic and isotopic data previously published. Grave goods distribution and skeletal analyses highlighted an important diversity in terms of funerary practices thus corroborating data from ancient DNA and Sr/O isotopic analyses that suggested a great genetic and geographic diversity. Grave goods presented an uneven spatial distribution and were made of raw materials from different sources and using different pottery manufacturing styles albeit typologically homogeneous. The preservation and distribution of human remains suggested that Room A was mainly used for secondary depositions while Room B was used for both primary and secondary depositions. No link between the two rooms was found since remains from the same individuals were apparently exclusive of one room or another. The results suggest that this society presented substantial inner genetic, social and geographical heterogeneity. Most probably, this was due to the presence of distinct but coeval groups in the cave that shared a larger-scale social identity (as in "segmentary societies") or, less likely, to the presence of one single, but internally heterogeneous society (as in fully sedentary societies) that assimilated foreigners.


The relative importance of social versus commercial sources in youth access to tobacco, alcohol, and other drugs.
Youth substance use began to increase in 1992 following a decade-long decline, leading to increased interest in controlling access to tobacco, alcohol, and other drugs. The anonymous and voluntary Minnesota Student Survey was administered to 133,794 public school students in grades 6, 9, and 12. Questions addressed current frequency of use of tobacco, alcohol, and other drugs and how students obtained these substances. Data were analyzed to determine the relationship between grade level, gender, race/ethnicity, use frequency, and access to substances through social and commercial sources. (Tobacco analyses were limited to students under age 18 years.) Social sources (especially friends) predominate across all age groups and substances. Students are much more likely to obtain tobacco than alcohol from commercial sources but few rely exclusively on commercial sources for either. Females and infrequent users are more likely to depend on social sources exclusively while males and frequent users are more likely to use commercial sources. Because substances are easily accessible through social sources, prevention policies directed at retail outlets may not have the desired effect on reducing teen smoking and drinking. Greater attention to reducing access to all substances from social sources is needed.


Method for non-optical quantification of in situ local soft tissue biomechanics.
Soft tissues exhibit significant biomechanical changes as they grow, adapt, and remodel under a variety of normal and pathogenic stimuli. Biomechanical measurement of intact soft tissues is challenging because of its large strain and nonlinear behavior. Tissue distention through applied vacuum pressure is an attractive method for acquiring local biomechanical information minimally invasive and non-destructive, but the current requirement for optical strain measurement limits its use. In this study, we implemented a novel flexible micro-electrode array placed within a cylindrical probe tip. We hypothesized that upon tissue distention, contact with each electrode would result in a precipitous voltage drop (from the resistive connection formed between input and output electrodes) across the array. Hence, tissue distention (strain) can be derived directly from the electrode array geometry. In pilot studies, we compared the electrode array measurements directly against optical deformation measurements in-situ of agar tissue phantoms and freshly isolated porcine tissue. Our results demonstrate that the probe derived stress-strain profiles and modulus measurements were statistically indistinguishable from optical measurement. We further show that electrode geometry can be scaled down to 50μm in size (length and width) and spaced 50μm apart without impairing measurement accuracy. These results establish a promising new method for minimally invasive local soft tissue biomechanical measurement, which may be useful for applications such as disease diagnosis and health monitoring.


Anionic versus neutral Pt(II) complexes: The relevance of the charge for human serum albumin binding.
The focus of this work is pointing out the different behavior of two structurally related Pt(II) complexes, the anionic cyclometalated NBu4[(Bzq)Pt(Thio)], 1 and the neutral [(Phen)Pt(Thio)], 2, (Bzq = benzo[h]quinoline, Phen = 1,10-phenantroline, Thio = 1,2-benzenedithiolate), on the interaction with human serum albumin (HSA), a key drug-delivery protein in the bloodstream. Being very limited the number of anionic Pt(II) complexes reported to date, this is a pioneering example of report on a protein-ligand interaction involving a negatively charged platinum compound. The study was carried out by using fluorescence spectroscopy, differential scanning calorimetry and molecular docking simulations. The results revealed a strong binding affinity between the anionic compound and the protein, whereas a weak/moderate binding interaction was highlighted for the neutral one. Comparative studies with site specific ligands (warfarin and ibuprofen), allowed us to identify the protein binding sites of the two compounds. The work aims to shed light on the relevance of the charge in designing new drugs with a favorable binding affinity for HSA, which strongly contributes to influence their pharmacological and toxicological profile.


N-nitrosodimethylamine-Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users.
Background Since July 2018, numerous lots of valsartan have been found to be contaminated with N-nitrosodimethylamine (NDMA). We aimed to assess the association between exposure to valsartan products contaminated with NDMA and the risk of cancer. Methods and Results This study was based on data from the Système National des Données de Santé, which is a national database that includes all French residents' health-related expenses. The target population was consumers of valsartan between January 1, 2013 and December 31, 2017, aged between 40 and 80 years old. The association of exposure to contaminated valsartan with the occurrence of any malignancy and cancer by location was evaluated by fitting Cox proportional hazards models weighted by the inverse probability of treatment. A total of 1.4 million subjects without any history of cancer were included. A total of 986 126 and 670 388 patients were exposed to NDMA-contaminated and uncontaminated valsartan, respectively. The use of the NDMA-contaminated valsartan did not increase the overall risk of cancer (adjusted hazard ratio [aHR], 0.99 [95% CI, 0.98-1.0]). However, exposed patients had a higher risk of liver cancer (aHR, 1.12 [95% CI, 1.04-1.22]) and melanoma (aHR, 1.10 [95% CI, 1.03-1.18]). We estimated a mean of 3.7 and 5.8 extra cases per year per 100 000 person-years of liver cancer and melanoma, respectively. Conclusions Our study was the largest to date to examine cancer risks associated with exposure to NDMA-contaminated valsartan. Our findings suggest a slight increased risk of liver cancer and melanoma in patients exposed to NDMA in regularly taken medications.


Evolution of the recombination signal sequences in the Ig heavy-chain variable region locus of mammals.
The Ig and T cell receptor (TCR) loci have an exceptionally dynamic evolutionary history, but the mechanisms responsible remain a subject of speculation. Ig and TCR genes are unique in vertebrates in that they are assembled from V, D, and J segments by site-specific recombination in developing lymphocytes. Here we examine the extent to which the V(D)J recombination in germline cells may have been responsible for remodeling Ig and TCR loci in mammals by asking whether gene segments have evolved as a unit, or whether, instead, recombination signal sequences (RSSs) and coding sequences have different phylogenies. Four distinct types of RSS have been defined in the human Ig heavy-chain variable region (Vh) locus, namely H1, H2, H3, and H5, and no other RSS type has been detected in other mammalian species. There is a well-supported discrepancy between the evolutionary history of the RSSs as compared with the Vh coding sequences: the RSS type H2 of one Vh gene segment has clearly become replaced by a RSS type H3 during mammalian evolution, between 115 and 65 million years ago. Two general models might explain the RSS swap: the first involves an unequal crossing over, and the second implicates germline activation of V(D)J recombination. The Vh-H2/RSS-H3 recombination product has likely been selected during the evolution of mammals because it provides better V(D)J recombination efficiency.


Telerehabilitation for people with low vision.
Low vision affects over 300 million people worldwide and can compromise both activities of daily living and quality of life. Rehabilitative training and vision assistive equipment (VAE) may help, but some visually impaired people have limited resources to attend in-person visits at rehabilitation clinics to receive training to learn to use VAE. These people may be able to overcome barriers to care through remote, Internet-based consultation (i.e. telerehabilitation). To compare the effects of telerehabilitation with face-to-face (e.g. in-office or inpatient) vision rehabilitation services for improving vision-related quality of life and near reading ability in people with visual function loss due to any ocular condition. Secondary objectives were to evaluate compliance with scheduled rehabilitation sessions, abandonment rates for VAE devices, and patient satisfaction ratings. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 6); Ovid MEDLINE; Embase.com; PubMed; ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any language restriction or study design filter in the electronic searches; however, we restricted the searches from 1980 onwards because the Internet was not introduced to the public until 1982. We last searched the electronic databases on 24 June 2019. We planned to include randomized controlled trials (RCTs) or controlled clinical trials (CCTs) in which participants diagnosed with low vision were undergoing low vision rehabilitation using an Internet, web-based technology compared with an approach involving in-person consultations. Two review authors independently screened titles and abstracts and then full-text articles against the eligibility criteria. We planned to have two review authors independently abstract data from the included studies. Any discrepancies were resolved by discussion. We identified two ongoing studies, but did not find any completed RCTs and CCTs that met the inclusion criteria for this review. We did not conduct a quantitative analysis. We discussed review articles on telemedicine for facilitating communication with elderly individuals or for providing remote ophthalmological care. We did not find any evidence from RCTs or CCTs on the efficacy of using telerehabilitation for remote delivery of rehabilitation services to individuals with low vision. Given the disease burden and the growing interest in telemedicine, the two ongoing studies, when completed, may provide evidence in understanding the potential for telerehabilitation as a platform for providing services to people with low vision.


Superradiant cascade in a seeded free-electron laser.
We report measurements demonstrating the concept of the free-electron laser (FEL) superradiant cascade. Radiation (λ(rad) = 200 nm) at the second harmonic of a short, intense seed laser pulse (λ(seed) = 400 nm) was generated by the cascaded FEL scheme at the transition between the modulator and radiator undulator sections. The superradiance of the ultrashort pulse is confirmed by detailed measurements of the resulting spectral structure, the intensity level of the produced harmonics, and the trend of the energy growth along the undulator. These results are compared to numerical particle simulations using the FEL code GENESIS 1.3 and show a satisfactory agreement.


Patient navigation and the quality of breast cancer care: an analysis of the breast cancer care quality indicators.
Patient navigation programs are initiated to help guide patients through barriers in a complex cancer care system. We sought to analyze the impact of our patient navigator program on the adherence to specific Breast Cancer Care Quality Indicators (BCCQI). A retrospective cohort of patients with stage I-III breast cancer seen the calendar year prior to the initiation of the patient navigation program were compared with patients treated in the ensuing two calendar years. Quality indicators deemed appropriate for analysis were those associated with overcoming barriers to treatment and those associated with providing health education and improving patient decision-making. A total of 134 consecutive patients between January 1, 2006 and December 31, 2006 and 234 consecutive patients between January 1, 2008 and December 31, 2009 were evaluated for compliance with the BCCQI. There was no significant difference in the mean age or race/ethnic distribution of the study population. In all ten BCCQI evaluated, there was improvement in the percentage of patients in compliance from pre and post implementation of a patient navigator program (range 2.5-27.0 %). Overall, compliance with BCCQI improved from 74.1 to 95.5 % (p < 0.0001). Indicators associated with informed decision-making and patient preference achieved statistical significance, while only completion axillary node dissection in sentinel node-positive biopsies in the process of treatment achieved statistical significance. The implementation of a patient navigator program improved breast cancer care as measured by BCCQI. The impact on disease-free and overall survival remains to be determined.


The Effect of Exogenous Spermidine Concentration on Polyamine Metabolism and Salt Tolerance in Zoysiagrass (Zoysia japonica Steud) Subjected to Short-Term Salinity Stress.
Salt stress, particularly short-term salt stress, is among the most serious abiotic factors limiting plant survival and growth in China. It has been established that exogenous spermidine (Spd) stimulates plant tolerance to salt stress. The present study utilized two zoysiagrass cultivars commonly grown in China that exhibit either sensitive (cv. Z081) or tolerant (cv. Z057) adaptation capacity to salt stress. The two cultivars were subjected to 200 mM salt stress and treated with different exogenous Spd concentrations for 8 days. Polyamine [diamine putrescine (Put), tetraamine spermine (Spm), and Spd], H2O2 and malondialdehyde (MDA) contents and polyamine metabolic (ADC, ODC, SAMDC, PAO, and DAO) and antioxidant (superoxide dismutase, catalase, and peroxidase) enzyme activities were measured. The results showed that salt stress induced increases in Spd and Spm contents and ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and diamine oxidase (DAO) activities in both cultivars. Exogenous Spd application did not alter polyamine contents via regulation of polyamine-degrading enzymes, and an increase in polyamine biosynthetic enzyme levels was observed during the experiment. Increasing the concentration of exogenous Spd resulted in a tendency of the Spd and Spm contents and ODC, SAMDC, DAO, and antioxidant enzyme activities to first increase and then decrease in both cultivars. H2O2 and MDA levels significantly decreased in both cultivars treated with Spd. Additionally, in both cultivars, positive correlations between polyamine biosynthetic enzymes (ADC, SAMDC), DAO, and antioxidant enzymes (SOD, POD, CAT), but negative correlations with H2O2 and MDA levels, and the Spd + Spm content were observed with an increase in the concentration of exogenous Spd.


A parcellation scheme for human left lateral parietal cortex.
The parietal lobe has long been viewed as a collection of architectonic and functional subdivisions. Though much parietal research has focused on mechanisms of visuospatial attention and control-related processes, more recent functional neuroimaging studies of memory retrieval have reported greater activity in left lateral parietal cortex (LLPC) when items are correctly identified as previously studied ("old") versus unstudied ("new"). These studies have suggested functional divisions within LLPC that may provide distinct contributions toward recognition memory judgments. Here, we define regions within LLPC by developing a parcellation scheme that integrates data from resting-state functional connectivity MRI and functional MRI. This combined approach results in a 6-fold parcellation of LLPC based on the presence (or absence) of memory-retrieval-related activity, dissociations in the profile of task-evoked time courses, and membership in large-scale brain networks. This parcellation should serve as a roadmap for future investigations aimed at understanding LLPC function.


Escherichia marmotae sp. nov., isolated from faeces of Marmota himalayana.
The taxonomic position of a group of seven closely related lactose-negative enterobacterial strains, which were isolated from fresh faecal samples of Marmota himalayana collected from the Qinghai-Tibetan plateau, China, was determined by using a polyphasic approach. Cells were Gram-reaction-negative, non-sporulating, non-motile, short rods (0.5-1 × 1-2.5 μm). By 16S rRNA gene sequences, the representative strain, HT073016(T), showed highest similarity values with Escherichia fergusonii ATCC 35469(T) at 99.3%, Escherichia coli ATCC 11775(T) at 99.2%, Escherichia albertii LMG 20976(T) at 98.9%, Escherichia hermannii CIP 103176(T) at 98.4%, and Escherichia vulneris ATCC 33821(T) at 97.7%. Phylogenetic analysis based on the 16S rRNA gene sequences showed that the seven strains formed a monophyletic group with five other species of the genus Escherichia. Digital DNA-DNA hybridization studies between strain HT073016(T) and five other species of the genus Escherichia showed that it shared less than 70% DNA-DNA relatedness with all known species of the genus Escherichia, supporting the novel species status of the strain. The DNA G+C content of strain HT073016(T) was 53.8 mol%. On the basis of phenotypic and phylogenetic characteristics, strain HT073016(T) and the six other HT073016(T)-like strains were clearly distinct from the type strains of other recognized species of the genus Escherichia and represent a novel species of the genus Escherichia, for which the name Escherichia marmotae sp. nov. is proposed, with HT073016(T) ( = CGMCC 1.12862(T) = DSM 28771(T)) as the type strain.