Early intervention for spinal cord injury with human induced pluripotent stem cells oligodendrocyte progenitors.
Induced pluripotent stem (iPS) cells are at the forefront of research in regenerative medicine and are envisaged as a source for personalized tissue repair and cell replacement therapy. Here, we demonstrate for the first time that oligodendrocyte progenitors (OPs) can be derived from iPS cells generated using either an episomal, non-integrating plasmid approach or standard integrating retroviruses that survive and differentiate into mature oligodendrocytes after early transplantation into the injured spinal cord. The efficiency of OP differentiation in all 3 lines tested ranged from 40% to 60% of total cells, comparable to those derived from human embryonic stem cells. iPS cell lines derived using episomal vectors or retroviruses generated a similar number of early neural progenitors and glial progenitors while the episomal plasmid-derived iPS line generated more OPs expressing late markers O1 and RIP. Moreover, we discovered that iPS-derived OPs (iPS-OPs) engrafted 24 hours following a moderate contusive spinal cord injury (SCI) in rats survived for approximately two months and that more than 70% of the transplanted cells differentiated into mature oligodendrocytes that expressed myelin associated proteins. Transplanted OPs resulted in a significant increase in the number of myelinated axons in animals that received a transplantation 24 h after injury. In addition, nearly a 5-fold reduction in cavity size and reduced glial scarring was seen in iPS-treated groups compared to the control group, which was injected with heat-killed iPS-OPs. Although further investigation is needed to understand the mechanisms involved, these results provide evidence that patient-specific, iPS-derived OPs can survive for three months and improve behavioral assessment (BBB) after acute transplantation into SCI. This is significant as determining the time in which stem cells are injected after SCI may influence their survival and differentiation capacity.


A Social Approach to Rule Dynamics Using an Agent-Based Model.
A well-trod debate at the nexus of cognitive science and linguistics, the so-called past tense debate, has examined how rules and exceptions are individually acquired (McClelland & Patterson, ; Pinker & Ullman, ). However, this debate focuses primarily on individual mechanisms in learning, saying little about how rules and exceptions function from a sociolinguistic perspective. To remedy this, we use agent-based models to examine how rules and exceptions function across populations. We expand on earlier work by considering how repeated interaction and cultural transmission across speakers affects the dynamics of rules and exceptions in language, measuring linguistic outcomes within a social system rather than focusing individual learning outcomes. We consider how population turnover and growth effect linguistic rule dynamics in large and small populations, showing that this method has considerable potential particularly in probing the mechanisms underlying the linguistic niche hypothesis (Lupyan & Dale, ).


Detection of bilateral breast cancer at biennial screening mammography in the Netherlands: a population-based study.
To determine the incidence of bilateral breast cancer at biennial screening mammography and to assess the sensitivity of screening in the detection of bilateral breast cancer. All women gave written informed consent, and the requirement to obtain review board approval was waived. The authors included all 302,196 screening mammograms obtained in 80,466 women aged 50-75 years in a southern breast screening region of the Netherlands between May 1998 and July 2008. During 2-year follow-up, the authors collected clinical data, breast imaging reports, biopsy results, and breast surgery reports from all patients with screening-detected and interval cancers. Two screening radiologists reviewed the screening and clinical mammograms of all bilateral screening-detected and interval cancers for mammographic abnormalities. The radiologists were initially blinded to each other's referral opinion, and discrepant assessments were followed by consensus reading. Of all women with screening-detected cancer (n = 1555) or interval cancer (n = 585), 52 (2.4%) had bilateral breast cancer. The sensitivity of screening mammography in the detection of bilateral breast cancer was 19% (10 of 52 women; 95% confidence interval: 8.5%, 29.9%). At blinded review, 18 of the 53 tumors not detected at screening (34%) were considered to be missed, 11 (21%) showed nonspecific minimal signs, and 24 (45%) had been mammographically occult at screening. Five women referred for further analysis experienced a 6-17-month delay in the diagnosis of the second breast cancer; in four of those women, the delay resulted from an incorrect Breast Imaging Reporting and Data System classification at clinical mammography. The sensitivity of screening mammography in the detection of bilateral breast cancer is disappointingly low. Both screening radiologists and clinical radiologists should pay vigorous attention to the contralateral breast to detect bilateral malignancies without diagnostic delay.


Nucleosomes in pancreatic cancer patients during radiochemotherapy.
Nucleosomes appear spontaneously in elevated concentrations in the serum of patients with malignant diseases as well as during chemo- and radiotherapy. We analyzed whether their kinetics show typical characteristics during radiochemotherapy and enable an early estimation of therapy efficacy. We used the Cell Death Detection Elisa plus (Roche Diagnostics) and investigated the course of nucleosomes in the serum of 32 patients with a local stage of pancreatic cancer who were treated with radiochemotherapy for several weeks. Ten of them received postsurgical therapy, 21 received primary therapy and 1 received therapy for local relapse. Blood was taken before the beginning of therapy, daily during the first week, once weekly during the following weeks and at the end of radiochemotherapy. The response to therapy was defined according to the kinetics of CA 19-9: a decrease of CA 19-9 > or =50% after radiochemotherapy was considered as 'remission'; an increase of > or =100% (which was confirmed by two following values) was defined as 'progression'. Patients with 'stable disease' ranged intermediately. Most of the examined patients showed a decrease of the concentration of nucleosomes within 6 h after the first dose of radiation. Afterwards, nucleosome levels increased rapidly, reaching their maximum during the following days. Patients receiving postsurgery, primary or relapse therapies did not show significant differences in nucleosome values during the time of treatment. Single nucleosome values, measured at 6, 24 and 48 h after the application of therapy, could not discriminate significantly between patients with no progression and those with progression of disease. However, the area under the curve of the first 3 days, which integrated all variables of the initial therapeutic phase, showed a significant correlation with the progression-free interval (p=0.008). Our results indicate that the area under the curve of nucleosomes during the initial phase of radiochemotherapy could be valuable for the early prediction of the progression-free interval.


Mesoporous layer-by-layer ordered nanohybrids of layered double hydroxide and layered metal oxide: highly active visible light photocatalysts with improved chemical stability.
Mesoporous layer-by-layer ordered nanohybrids highly active for visible light-induced O(2) generation are synthesized by self-assembly between oppositely charged 2D nanosheets of Zn-Cr-layered double hydroxide (Zn-Cr-LDH) and layered titanium oxide. The layer-by-layer ordering of two kinds of 2D nanosheets is evidenced by powder X-ray diffraction and cross-sectional high resolution-transmission electron microscopy. Upon the interstratification process, the original in-plane atomic arrangements and electronic structures of the component nanosheets remain intact. The obtained heterolayered nanohybrids show a strong absorption of visible light and a remarkably depressed photoluminescence signal, indicating an effective electronic coupling between the two component nanosheets. The self-assembly between 2D inorganic nanosheets leads to the formation of highly porous stacking structure, whose porosity is controllable by changing the ratio of layered titanate/Zn-Cr-LDH. The resultant heterolayered nanohybrids are fairly active for visible light-induced O(2) generation with a rate of ∼1.18 mmol h(-1) g(-1), which is higher than the O(2) production rate (∼0.67 mmol h(-1) g(-1)) by the pristine Zn-Cr-LDH material, that is, one of the most effective visible light photocatalysts for O(2) production, under the same experimental condition. This result highlights an excellent functionality of the Zn-Cr-LDH-layered titanate nanohybrids as efficient visible light active photocatalysts. Of prime interest is that the chemical stability of the Zn-Cr-LDH is significantly improved upon the hybridization, a result of the protection of the LDH lattice by highly stable titanate layer. The present findings clearly demonstrate that the layer-by-layer-ordered assembly between inorganic 2D nanosheets is quite effective not only in improving the photocatalytic activity of the component semiconductors but also in synthesizing novel porous LDH-based hybrid materials with improved chemical stability.


A review of mastery learning: The roseman model as an illustrative case.
An educational method gaining acceptance in health profession's training is mastery learning. Mastery learning requires learners to demonstrate essential knowledge and skills measured against rigorously set standards without regard to time. The key elements of mastery learning include focus on a single subject, short curricular blocks, setting specific objectives, using frequent feedback, deliberative practice, and demonstrating mastery before moving onto the next subject. Roseman University of the Health Sciences College of Pharmacy (COP) developed and delivered an accelerated mastery learning curriculum designed to develop knowledge and skills through active learning. The COP uses a mastery model for its PharmD program. The didactic curriculum is divided into 2-week assessment blocks focusing on a single subject. Students must demonstrate mastery, defined as ≥90% on an assessment, to pass a block. Students failing a block assessment receive feedback and a second opportunity to pass. Students failing their repeat assessment continue onto the next block, but require summer remediation before moving onto the next year. National pass rates for the US pharmacy board examination ranged between 92.6% and 96.9% during the 2010-2015 period, while the COP scores ranged from 93.0% to 99.0% and fell below national pass rates on only one occasion. The attrition rate was 6.5%, below the national rate of 10.8%. Students reported an overall satisfaction with their education of 3.82 (Likert scale 1-5) and 4.04 for the block system. Overall, the Roseman University mastery model is successful. Students report high levels of satisfaction and outcomes on examinations and attrition compares favorably to national averages.


Longitudinal proxy measurements in multiple sclerosis: patient-proxy agreement on the impact of MS on daily life over a period of two years.
The use of self-report measurements in clinical settings is increasing. However, in patients with limitations that interfere with reliable self-assessment such as cognitive impairment or mood disturbances, as may be the case in multiple sclerosis (MS), data collection might be problematic. In these situations, information obtained from proxy respondents (e.g. partners) may replace self-ratings. The aim of this study was to examine the value of proxy ratings at separate points in time and to assess patient-proxy agreement on possible changes in disease impact of MS. Fifty-six MS patients and their partners completed the Multiple Sclerosis Impact Scale (MSIS-29) at baseline and follow-up, two years later. Patient-proxy agreement was assessed at both time points by calculating intraclass correlation coefficients (ICCs), exact and global agreement and the mean directional differences between groups. Agreement of change over time was assessed by calculating ICCs between change scores. In parallel, global ratings of both patients and proxy respondents of the extent to which the patient had improved or deteriorated over the past two years were collected to validate possible changes on the MSIS-29. At both time points, agreement on the physical scale was higher than agreement on the psychological scale (ICCs at baseline were 0.81 for the physical scale and 0.72 for the psychological scale; at follow-up, the ICC values were 0.86 and 0.65 respectively). At follow-up, statistically significant mean differences between patients and proxies were noted for the physical scale (-4.8 +/- 12.7, p = 0.006) and the psychological scale (-8.9 +/- 18.8, p = 0.001). Agreement between change scores on the MSIS-29 was fair (ICC < 0.60). Our analyses suggest that the validity of measuring changes over time might be better for proxy respondents compared to patients. Proxy respondents could act as a reliable source of information in cross-sectional studies. Moreover, results suggested that agreement on change over time might be better for proxy respondents compared to patients. Although this remarkable finding should be interpreted cautiously because of several limitations of the study, it does plead for further investigation of this important topic.


Nonadiabatic dynamics of electron transfer in solution: explicit and implicit solvent treatments that include multiple relaxation time scales.
The development of efficient theoretical methods for describing electron transfer (ET) reactions in condensed phases is important for a variety of chemical and biological applications. Previously, dynamical dielectric continuum theory was used to derive Langevin equations for a single collective solvent coordinate describing ET in a polar solvent. In this theory, the parameters are directly related to the physical properties of the system and can be determined from experimental data or explicit molecular dynamics simulations. Herein, we combine these Langevin equations with surface hopping nonadiabatic dynamics methods to calculate the rate constants for thermal ET reactions in polar solvents for a wide range of electronic couplings and reaction free energies. Comparison of explicit and implicit solvent calculations illustrates that the mapping from explicit to implicit solvent models is valid even for solvents exhibiting complex relaxation behavior with multiple relaxation time scales and a short-time inertial response. The rate constants calculated for implicit solvent models with a single solvent relaxation time scale corresponding to water, acetonitrile, and methanol agree well with analytical theories in the Golden rule and solvent-controlled regimes, as well as in the intermediate regime. The implicit solvent models with two relaxation time scales are in qualitative agreement with the analytical theories but quantitatively overestimate the rate constants compared to these theories. Analysis of these simulations elucidates the importance of multiple relaxation time scales and the inertial component of the solvent response, as well as potential shortcomings of the analytical theories based on single time scale solvent relaxation models. This implicit solvent approach will enable the simulation of a wide range of ET reactions via the stochastic dynamics of a single collective solvent coordinate with parameters that are relevant to experimentally accessible systems.


Design and implementation of haptic virtual environments for the training of the visually impaired.
This paper presents a haptic virtual reality (VR) tool developed for the training of the visually impaired. The proposed approach focuses on the development of a highly interactive and extensible haptic VR training system (the ENORASI VR training system) that allows visually impaired, to study and interact with various virtual objects in specially designed virtual environments, while allowing designers to produce and customize these configurations. Based on the system prototype and the use of the CyberGrasp haptic device, a number of custom applications have been developed. An efficient collision detection algorithm is also introduced, by extending the proximity query package (PQP) algorithm to handle five points of contact (a case studied with the use of CyberGrasp). Two test categories were identified and corresponding tests were developed for each category. The training scenarios include: object recognition and manipulation and cane simulation, used for performing realistic navigation tasks. Twenty-six blind persons conducted the tests and the evaluation results have shown the degree of acceptance of the technology and the feasibility of the proposed approach.


Alterations in amino acid clearance during ischemia predict hepatocellular ATP changes.
Although decreases in hepatic adenosine triphosphate (ATP) levels during ischemia are thought to reflect loss of hepatic energy reserves and decreased viability, such changes have not been correlated with a clinically relevant index of hepatic function or viability. Ability to clear amino acids from plasma has been shown to correlate with function of the allograft in hepatic transplantation and survival after portal decompression in patients with hepatic cirrhosis. The effects of 60 minutes of warm ischemia in two groups of mongrel dogs were studied to assess the relationship between loss of ATP and amino acid clearance. One group (shunted) had portal decompression during the ischemic period and the other (portal stasis) did not. There was a significant correlation between loss of ATP and amino acid clearance after ischemia. Although the effects of ischemia on the liver were similar in both groups, the portal stasis group demonstrated significantly elevated SGOT levels during reperfusion that were related to impaired net adenine monophosphate synthesis and suggestive of ongoing injury. These data support the contention that loss of ATP during ischemia is associated with reduced functional capacity. In addition, they suggest that portal stasis produces toxic products that can impede hepatic recovery from ischemia.


Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.


Enhancement of frequency domain indices of heart rate variability by cholinergic stimulation with pyridostigmine bromide.
Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor. The aim of this study was to determine the effect of orally administration of single dose sustained-released tablet of pyridostigmine bromide (PBSR) on the frequency domain indices of heart rate variability (HRV). Thirty-two healthy young men were participated in this study. They were divided into 2 groups; the pyridostigmine group (n = 22) and the placebo group (n = 10). Electrocardiogram (ECG) was recorded at 10, 30, 60, 90, 120, 150, 180, 210, 240, 300 and 420 min after PBSR administration. At each time, simultaneously, a blood sample was prepared and PB plasma concentration was measured by high-performance liquid chromatography (HPLC) method. Statistical analysis showed that in different indices of HRV, there is a significant increase in low frequency (LF) band at 300 min, but no difference in high frequency band (HF). It also showed significant decreases in normalized high frequency band (Hfnu), normalized low frequency band (Lfnu) and LF/HF ratio at 120, 240 and 300 min after PBSR administration. Maximum plasma concentration of PB was 150 min after the administration. In conclusion, administration of a single dose PBSR can enhance the frequency domains indices of HRV and improvesympathovagal balance.


Carbohydrate and protein contents of grain dusts in relation to dust morphology.
Grain dusts contain a variety of materials which are potentially hazardous to the health of workers in the grain industry. Because the characterization of grain dusts is incomplete, we are defining the botanical, chemical, and microbial contents of several grain dusts collected from grain elevators in the Duluth-Superior regions of the U.S. Here, we report certain of the carbohydrate and protein contents of dusts in relation to dust morphology. Examination of the gross morphologies of the dusts revealed that, except for corn, each dust contained either husk or pericarp (seed coat in the case of flax) fragments in addition to respirable particles. When viewed with the light microscope, the fragments appeared as elongated, pointed structures. The possibility that certain of the fragments within corn, settled, and spring wheat were derived from cell walls was suggested by the detection of pentoses following colorimetric assay of neutralized 2 N trifluoroacetic acid hydrolyzates of these dusts. The presence of pentoses together with the occurrence of proteins within water washings of grain dusts suggests that glycoproteins may be present within the dusts. With scanning electron microscopy, each dust was found to consist of a distinct assortment of particles in addition to respirable particles. Small husk fragments and "trichome-like" objects were common to all but corn dust.


Prophage induction and inactivation by UV light.
Analysis of the induction curves for UV light-irradiated Haemophilus influenzae lysogens and the distribution of pyrimidine dimers in a repair-deficient lysogen suggests that one dimer per prophage-size segment of the host bacterial chromosome is necessary as a preinduction event. The close correlations obtained prompted a renewed consideration of the possibility that direct prophage induction occurs when one dimer is stabilized within the prophage genome. The host excision-repair system apparently functions to reduce the probability of "stabilizing" within the prophage those dimers that are necessary for induction and inactivation. The presence of the inducible defective prophage in strain Rd depresses the inducibility of prophage HP1c1.


Oscillatory shear stress mediates directional reorganization of actin cytoskeleton and alters differentiation propensity of mesenchymal stem cells.
Shear stress stimuli differentially regulate cellular functions based on the pattern, magnitude as well as duration of the flow. Shear stress can modify intracellular kinase activities and cytoskeleton reorganization to result in changes of cell behavior. Mesenchymal stem cells (MSCs) are mechano-sensitive cells, but little is known about the effects of oscillatory shear stress (OS). In this study, we demonstrate that OS of 0.5 ± 4 dyn/cm(2) induces directional reorganization of F-actin to mediate the fate choice of MSCs through the regulation of β-catenin. We also found that intercellular junction molecules are the predominant mechanosensors of OS in MSCs to deliver the signals that result in directional rearrangement of F-actin, as well as the increase of phosphorylated β-catenin (pβ-catenin) after 30 minutes of OS stimulation. Depolymerization of F-actin and increase in pβ-catenin also lead to the upregulation of Wnt inhibitory factors sclerostin and dickkopf-1. Inhibition of β-catenin/Wnt signaling pathway is accompanied by the upregulation of sex determining region Y-box2 and NANOG to control self-renewal. In conclusion, the reorganization of actin cytoskeleton and increase in β-catenin phosphorylation triggered by OS regulate the expression of pluripotency genes via the β-catenin/Wnt signaling pathway to differentially direct fate choices of MSCs at different time points. Results from this study have provided new information regarding how MSCs respond to mechanical cues from their microenvironment in a time-dependent fashion, and such biophysical stimuli could be administered to guide the fate and differentiation of stem cells in addition to conventional biochemical approaches.


Effects of molgramostim, filgrastim and lenograstim in the treatment of myelokathexis.
Myelokathexis is a very rare form of chronic hereditary neutropenia resulting from impaired neutrophil releasing mechanism in the bone marrow. The recombinant human granulocyte-macrophage (molgramostim) and granulocyte (filgrastim, lenograstim) colony stimulating factors release the mature granulocytes from the bone marrow. We describe a 43-year-old woman suffering from myelokathexis, with the absolute neutrophil count ranging between 0.03 and 1.35 x 10(9)/L. In the period before the introduction of cytokines, the patient had more than 80 major infectious episodes. Since 1991, infections in this patient have been treated with cytokines, given in conjunction with antibiotics. Initially, she received molgramostim in a daily dose of 5 microg/kg subcutaneously, which stimulated the release of granulocytes from her bone marrow, thereby allowing successful treatment of infection. After the development of hypersensitivity, molgramostim was substituted with filgrastim. Finally, lenograstim was given a trial. With all three cytokines, the patient's neutrophil count always attained normal values already 4 hours after subcutaneous application of the drug in a dose of 5 microg/kg, the highest neutrophil levels were measured at 24 hours post-injection, and the neutrophil count was again close to the baseline value 72 hours after the treatment. A slight neutropenia was present 48 hours after the application of filgrastim. We believe that all three cytokines are equally effective in increasing the neutrophil count in venous blood of patients with myelokathexis.


Imaging of the Pediatric Knee.
The knee joint is commonly injured in the young athlete. This article discusses the common injury patterns around the knee that are unique to this patient population. Pediatric patients have relative weak points at their physes and apophyses that result in different forces on ligaments and bones during injury compared with adults. Common pathologic findings seen on imaging include patellar and patellar tendon injury, physeal fractures, osteochondral abnormality, ligament tears, and meniscal injury. Imaging studies are also performed to evaluate pediatric patients after surgical knee injury repair, and radiologists should be familiar with certain pediatric-specific knee repair techniques and their imaging appearances. A thorough knowledge of normal and pathologic imaging findings of the pediatric knee allows the radiologist to make important diagnostic and management contributions.


Do older men benefit from curative therapy of localized prostate cancer?
Prior decision-analytic models are based on outdated or suboptimal efficacy, patient preference, and comorbidity data. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) associated with available treatments for localized prostate cancer in men aged >/= 65 years, adjusting for Gleason score, patient preferences, and comorbidity. We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP), external beam radiotherapy (EBRT), and watchful waiting (WW). Rates of treatment complications and pretreatment incontinence and impotence were derived from published studies. We estimated treatment efficacy using three data sources: cancer registry cohort data, pooled case series, and modern radiotherapy studies. Utilities were obtained from 141 prostate cancer patients and from published studies. For men with well-differentiated tumors and few comorbidities, potentially curative therapy (RP or EBRT) prolonged LE up to age 75 years but did not improve QALE at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to age 75 years. For poorly differentiated disease, potentially curative therapy resulted in LE and QALE gains up to age 80 years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When cohort and pooled case series data were used, RP was preferred over EBRT in all groups but was comparable to modern radiotherapy. Potentially curative therapy results in significantly improved LE and QALE for older men with few comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to treatment in this group.


Axis I anxiety and mental health disorders among stuttering adolescents.
The purpose of this study was to evaluate anxiety and psychological functioning among adolescents seeking speech therapy for stuttering using a structured, diagnostic interview and psychological questionnaires. This study also sought to determine whether any differences in psychological status were evident between younger and older adolescents. Participants were 37 stuttering adolescents seeking stuttering treatment. We administered the Computerized Voice Version of the Diagnostic Interview Schedule for Children, and five psychometric tests. Participants were classified into younger (12-14 years; n=20) and older adolescents (15-17 years; n=17). Thirty-eight percent of participants attained at least one diagnosis of a mental disorder, according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; APA, 2000), with the majority of these diagnoses involving anxiety. This figure is double current estimates for general adolescent populations, and is consistent with our finding of moderate and moderate-severe quality of life impairment. Although many of the scores on psychological measures fell within the normal range, older adolescents (15-17 years) reported significantly higher anxiety, depression, reactions to stuttering, and emotional/behavioral problems, than younger adolescents (12-14 years). There was scant evidence that self-reported stuttering severity is correlated with mental health issues. There are good reasons to believe these results are conservative because many participants gave socially desirable responses about their mental health status. These results reveal a need for large-scale, statistically powerful assessments of anxiety and other mental disorders among stuttering adolescents with reference to control populations. The reader will be able to: (a) explain the clinical importance of assessing for mental health with stuttering adolescents, (b) state the superior method for adolescent mental health assessment and (c) state a major issue with determining the genuineness of stuttering adolescent responses to psychological assessment.


Cercarial Behavior Determines Risk of Predation.
The potential for local biodiversity to affect transmission success of parasites has been shown to be particularly important in trematodes, where non-host organisms can feed on and 'dilute' free-living infective stages (cercariae). Earlier studies have analyzed the effects of various predators on transmission stages of single trematode species, but not how cercariae of different species react to predation pressure. Here, we tested whether cercariae with different host-searching movement patterns show varying susceptibility to predation by non-host species with different feeding habits. For this study, we performed a set of predation experiments with 6 species of trematode cercariae (Coitocaecum parvum, Maritrema poulini, Apatemon sp., Telogaster opisthorchis, Plagiorchioid sp. I, and Aporocotylid sp. II) that represent 2 groups of host-searching behavior, free-swimming vs. bottom-dwelling, and 2 predators ( Sphaerium sp., Physa acuta) with distinct feeding modes, a filter feeder and a grazer. Our results show that cercarial susceptibility to predation is highly dependent on the interspecific interaction between dispersal behavior of cercariae and feeding behavior of non-host organisms: Filter feeders only diluted free-swimming cercarial stages, not bottom-dwelling ones; grazers on the other hand, had no effect on free-swimming cercariae but reduced bottom-dwelling cercariae in 1 trematode species. Our findings give further support to the hypothesis that the transmission dynamics of trematodes do not simply depend on local biodiversity but rather on the species-specific interactions between parasite transmission stages and free-living organisms in the ecosystem. This has important implications for disease dynamics in ecological communities (e.g., the parasites' infection success), and for ecosystem energetics, as cercariae constitute important food items.


The N-methyl D-aspartate receptor glycine site and D-serine metabolism: an evolutionary perspective.
The N-methyl D-aspartate (NMDA) type of glutamate receptor requires two distinct agonists to operate. Glycine is assumed to be the endogenous ligand for the NMDA receptor glycine site, but this notion has been challenged by the discovery of high levels of endogenous d-serine in the mammalian forebrain. I have outlined an evolutionary framework for the appearance of a glycine site in animals and the metabolic events leading to high levels of D-serine in brain. Sequence alignments of the glycine-binding regions, along with the scant experimental data available, suggest that the properties of invertebrate NMDA receptor glycine sites are probably different from those in vertebrates. The synthesis of D-serine in brain is due to a pyridoxal-5'-phosphate (B(6))-requiring serine racemase in glia. Although it remains unknown when serine racemase first evolved, data concerning the evolution of B(6) enzymes, along with the known occurrences of serine racemases in animals, point to D-serine synthesis arising around the divergence time of arthropods. D-Serine catabolism occurs via the ancient peroxisomal enzyme d-amino acid oxidase (DAO), whose ontogenetic expression in the hindbrain of mammals is delayed until the postnatal period and absent from the forebrain. The phylogeny of D-serine metabolism has relevance to our understanding of brain ontogeny, schizophrenia and neurotransmitter dynamics.


Mucinous nonneoplastic cyst of the pancreas: apomucin phenotype distinguishes this entity from intraductal papillary mucinous neoplasm.
Mucinous nonneoplastic cyst of the pancreas is a newly described and rare cystic lesion with unknown histogenesis. It is defined as a cystic lesion lined with mucinous epithelium, supported by hypocellular stroma and not communicating with the pancreatic ducts. It is very challenging to differentiate this lesion from other cystic mucinous neoplasms of the pancreas such as branch-duct intraductal papillary mucinous neoplasm by morphology. In this study, a total of 436 pancreatic specimens resected between 2002 and 2007 in our institution were reviewed. Fifteen (3.4%, 15/436) mucinous nonneoplastic cysts were identified. They included 3 males and 12 females, with a median age of 60 years. Forty-six percent of cases (7/15) occurred in pancreatic head, 27% (4/15) in neck, 7% (1/15) in body, and 20% (3/15) in tail. The size of lesions ranged from 0.5 to 3.5 cm in greatest dimension. In most cases (12/15, 80%), mucinous nonneoplastic cyst was associated or adjacent to acinar-ductal mucinous metaplasia. These morphologic data indicate that mucinous nonneoplastic cyst is not really a rare disease and may originate from acinar-duct mucinous metaplasia histogenestically. Furthermore, apomucin immunostains of mucinous nonneoplastic cyst showed MUC1 expressed in 27% (4/15) cases, MUC5AC in 67% (10/15 cases), and MUC2 was were negative in all cases, whereas intraductal papillary mucinous neoplasm (n = 17; 5 main duct type, 12 branch-duct type) showed focal and weak MUC1 positivity in 18% (3/17) cases, MUC2 positivity in 71% (12/17) cases, and all intraductal papillary mucinous neoplasm (17/17) were MUC5AC positive. The clonality assay with the HUMARA gene revealed that the mucinous nonneoplastic cysts were of polyclonal origin. For the first time, using HUMARA assay, we demonstrate the nonneoplastic nature of these cysts and further characterize morphologic and immunophenotypic properties that allow differentiation from intraductal papillary mucinous neooplasm.


Ruptured abdominal aortic aneurysm.
Between 1974 and 1984, 174 patients with ruptured abdominal aneurysms have been treated by three vascular surgeons. The 11-year period showed a dramatic increase in the number of patients presenting with ruptured aneurysms. The overall operative survival, including patients who died before a graft could be inserted, was 67 per cent with improvement from 60 per cent in the first half of the period to 69 per cent in the second. The overall survival rate for the 162 who had a completed graft was 72 per cent. Reference to data from the Lothian area surgical audit showed that there has been a transfer of responsibility from general to vascular surgeons with an increase in the proportion of patients treated by operation. Concentration of care within a single specialized unit appears to have had a favourable effect on survival.


The role of corticosteroid therapy in children with pneumococcal meningitis.
The records of 97 infants and children with pneumococcal meningitis treated in Dallas, Tex, from 1984 to 1990 were reviewed to determine whether corticosteroid therapy improved disease outcome as has been demonstrated in patients with Haemophilus meningitis. Forty-one patients received corticosteroid therapy, 39 of whom were given dexamethasone in the conventional 4-day regimen. There were no significant differences in the demographic and clinical characteristics of steroid- and non-steroid-treated patients. In addition, there were no significant differences between treatment groups with regard to presence of seizures, subdural effusions, hydrocephalus, and positive cerebrospinal fluid cultures 24 hours after the start of treatment. When steroid therapy was given before or concurrently with antibiotic therapy, none of 30 steroid-treated vs 16 of 52 non-steroid-treated patients developed evidence of neurologic or cardiovascular instability after the first parenteral antibiotic dose was given. Among 86 survivors examined, significantly fewer steroid-treated patients had an adverse neurologic long-term outcome, including hearing impairment, compared with non-steroid-treated patients (four of 35 vs 14 of 43). This was also true for those patients with overwhelming meningeal infection. We believe that corticosteroid therapy is also beneficial in infants and children with pneumococcal meningitis.


[Regional redistributions of the blood in high and low small intestine obstruction].
In the experimental model of high and low obstruction of the small intestine during 24 hours the authors observed considerable shifts in electrolytic blood content. Total amount of circulating blood, compared with control (laparotomy), was not changed. These data allowed a new consideration of the entity of the pathological syndrome in intestinal obstruction.


Latitudinal variation for two enzyme loci and an inversion polymorphism in Drosophila melanogaster from Central and South America.
Many organisms show latitudinal variation for various genetically determined traits. Such clines may involve neutral variation and originate from historical events or their maintenance may be explained by selection. For Drosophila melanogaster, latitudinal variation for allozymes, inversions, and quantitative traits has been found on several continents. We sampled D. melanogaster populations in Panama and along a transect of 40 latitudinal degrees on the west coast of South America. Negative correlations with latitude were found for AdhS and alpha GpdhF allele frequencies and for the frequency of the cosmopolitan inversion In(2L)t in AdhS alpha GpdhF chromosomes. A positive correlation existed between wing length and latitude. Significant correlations were found between these traits and climatic variables like temperature and rainfall. The observed clines show considerable resemblance to those found on other continents. Gametic disequilibrium between AdhS and alpha GpdhF occurred predominantly at higher latitudes and was caused by the presence of In(2L)t. The reasons for the clinal distributions are discussed and it is argued that selection is the most likely explanation. However, the exact nature of the selective force and the interactions of allozymes with each other and with In(2L)t are complex and not fully understood. In tropical regions In(2L)t-containing genotypes have higher fitness than ST/ST and Adh and alpha Gpdh hitchhike with the inversion, but there is also evidence for balancing selection at the Adh locus.


Comparison between different referral strategies for acute ischemic stroke patients in a hub-spoke emergency stroke network: a real-world experience in south-east Lazio.
To describe different referral strategies for acute ischemic stroke (AIS) patients in a Hub-Spoke emergency stroke network with their incidence, time metrics and related outcomes. Referral paradigms were defined as follows: primary transfer to the comprehensive stroke center (CSC) from a remote region, called mothership (MS); secondary transfer to the CSC from a primary stroke center where intravenous thrombolysis was available, called drip and ship (DS); secondary transfer to the CSC from a community hospital where no reperfusion therapy was available, called ship and drip (SD); primary transfer to the CSC from its catchment area, called direct CSC (dCSC). Among 517 anterior circulation AIS patients treated with mechanical thrombectomy between 2015 and 2020, 16.6% of them were SD, in addition to the well-known referral paradigms of MS (21.8%) and DS (18.1%). This rate grew to 30% when only patients whose place of onset was outside the CSC catchment area were considered. In the SD group, onset to CSC and onset to groin were significantly longer (178±80 min vs. 102±60 min, p<0.001, and 277±77 min vs. 211±61 min, p<0.001, respectively), and the risk of any intracranial hemorrhage (ICH) was significantly higher (OR: 2.514; 95%CI: 1.18-5.35, p=0.017) compared to MS. In this hub-spoke stroke network, a high proportion of SD paradigm was found, which was associated with longer times to treatment and higher rates of any ICH. A closer cooperation between hospital stroke physicians, national health system staff, and paramedics is warranted to identify the most appropriate referral strategy for each patient.


Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis.
Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies.


Photosensitized UVA-Induced Cross-Linking between Human DNA Repair and Replication Proteins and DNA Revealed by Proteomic Analysis.
Long wavelength ultraviolet radiation (UVA, 320-400 nm) interacts with chromophores present in human cells to induce reactive oxygen species (ROS) that damage both DNA and proteins. ROS levels are amplified, and the damaging effects of UVA are exacerbated if the cells are irradiated in the presence of UVA photosensitizers such as 6-thioguanine (6-TG), a strong UVA chromophore that is extensively incorporated into the DNA of dividing cells, or the fluoroquinolone antibiotic ciprofloxacin. Both DNA-embedded 6-TG and ciprofloxacin combine synergistically with UVA to generate high levels of ROS. Importantly, the extensive protein damage induced by these photosensitizer+UVA combinations inhibits DNA repair. DNA is maintained in intimate contact with the proteins that effect its replication, transcription, and repair, and DNA-protein cross-links (DPCs) are a recognized reaction product of ROS. Cross-linking of DNA metabolizing proteins would compromise these processes by introducing physical blocks and by depleting active proteins. We describe a sensitive and statistically rigorous method to analyze DPCs in cultured human cells. Application of this proteomics-based analysis to cells treated with 6-TG+UVA and ciprofloxacin+UVA identified proteins involved in DNA repair, replication, and gene expression among those most vulnerable to cross-linking under oxidative conditions.


Caged RNA: photo-control of a ribozyme reaction.
We report here the first photo-chemical control of a ribozyme reaction by the site-specific modification of the 2'-hydroxyl nucleophile in the hammerhead system with a caging functionality. Rapid laser photolysis of the O-(2-nitrobenzyl) caging group initiates an efficient and accurate hammerhead-catalyzed cleavage of substrate RNA under native conditions. RNAs in which reactive functionalities or recognition elements are caged in this manner will be useful tools to probe RNA reactivity and dynamics.


Seeing diabetes: visual detection of glucose based on the intrinsic peroxidase-like activity of MoS2 nanosheets.
Molybdenum disulfide (MoS2) has attracted increasing research interest recently due to its unique physical, optical and electrical properties, correlated with its 2D ultrathin atomic-layered structure. Until now, however, great efforts have focused on its applications such as lithium ion batteries, transistors, and hydrogen evolution reactions. Herein, for the first time, MoS2 nanosheets are discovered to possess an intrinsic peroxidase-like activity and can catalytically oxidize 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to produce a color reaction. The catalytic activity follows the typical Michaelis-Menten kinetics and is dependent on temperature, pH, H2O2 concentration, and reaction time. Based on this finding, a highly sensitive and selective colorimetric method for H2O2 and glucose detection is developed and applied to detect glucose in serum samples. Moreover, a simple, inexpensive, instrument-free and portable test kit for the visual detection of glucose in normal and diabetic serum samples is constructed by utilizing agarose hydrogel as a visual detection platform.


Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.
Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.


One fly-one genome: chromosome-scale genome assembly of a single outbred Drosophila melanogaster.
A high quality genome assembly is a vital first step for the study of an organism. Recent advances in technology have made the creation of high quality chromosome scale assemblies feasible and low cost. However, the amount of input DNA needed for an assembly project can be a limiting factor for small organisms or precious samples. Here we demonstrate the feasibility of creating a chromosome scale assembly using a hybrid method for a low input sample, a single outbred Drosophila melanogaster. Our approach combines an Illumina shotgun library, Oxford nanopore long reads, and chromosome conformation capture for long range scaffolding. This single fly genome assembly has a N50 of 26 Mb, a length that encompasses entire chromosome arms, contains 95% of expected single copy orthologs, and a nearly complete assembly of this individual's Wolbachia endosymbiont. The methods described here enable the accurate and complete assembly of genomes from small, field collected organisms as well as precious clinical samples.


Cardiac Magnetic Resonance Left Ventricular Filling Pressure Is Associated with NT-proBNP in Patients with New Onset Heart Failure.
Background and Objectives: Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping and estimating left ventricular (LV) filling pressure (LVFP). The N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is released from cardiac myocytes in response to mechanical load and wall stress. This study sought to investigate if CMR-derived LVFP is associated with the serum levels of NT-proBNP and, in addition, if it provides any incremental prognostic value in heart failure (HF). Materials and Methods: This study recruited 380 patients diagnosed with HF who underwent same-day CMR and clinical assessment between February 2018 and January 2020. CMR-derived LVFP was calculated, as previously, from long- and short-axis cines. During CMR assessment, serum NT-proBNP was measured. The pathological cut-offs were defined as follows: NT-proBNP ≥ 125 pg/mL and CMR LVFP > 15 mmHg. The incidence of HF hospitalisation was treated as a clinical outcome. Results: In total, 305 patients had NT-proBNP ≥ 125 pg/mL. Patients with raised NT-proBNP were older (54 ± 14 vs. 64 ± 11 years, p < 0.0001). Patients with raised NT-proBNP had higher LV volumes and mass. In addition, CMR LVFP was higher in patients with raised NT-proBNP (13.2 ± 2.6 vs. 15.4 ± 3.2 mmHg, p < 0.0001). The serum levels of NT-proBNP were associated with CMR-derived LVFP (R = 0.42, p < 0.0001). In logistic regression analysis, this association between NT-proBNP and CMR LVFP was independent of all other CMR variables, including LV ejection fraction, LV mass, and left atrial volume (coefficient = 2.02, p = 0.002). CMR LVFP demonstrated an independent association with the incidence of HF hospitalisation above NT-proBNP (hazard ratio 2.7, 95% confidence interval 1.2 to 6, p = 0.01). Conclusions: A CMR-modelled LVFP is independently associated with serum NT-proBNP levels. Importantly, it provides an incremental prognostic value over and above serum NT-proBNP levels.


L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.
Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.


Serum IL10, IL12 and circulating CD4+CD25high T regulatory cells in relation to long-term clinical outcome in head and neck squamous cell carcinoma patients.
IL10, but not IL12 or T regulatory cells in the circulation of newly presenting, pre-treatment head and neck squamous cell carcinoma (HNSCC) patients, has been shown previously to be related to survival over a mean follow-up period of 15 months. Here, we followed the same patients for a longer period to determine whether these associations change. Pre- and post-treatment serum IL10/IL12 and circulating T regs were measured using ELISA and flow cytometry respectively and were correlated with survival after a 33 month average follow-up in a cohort of newly presenting HNSCC patients (n=107), with cancers of the hypopharynx (n=16), larynx (n=36), oral cavity (n=21), oropharynx (n=25), sinonasal (n=4) or unknown origin (n=5). Although the mean survival time of patients with detectable levels of IL10 pre-treatment was lower (40.6 months) than that of those without detectable levels of IL10 (45.6 months), the difference was no longer significant, in contrast to earlier follow-up data. In conclusion, although serum levels of IL10 may be a prognostic indicator for HNSCC patients over the short-term, they become less significant as follow-up time increases.


Dual-modal MRI contrast agent with aggregation-induced emission characteristic for liver specific imaging with long circulation lifetime.
We herein report a novel dual-modal MRI contrast agent, TPE-2Gd, for both magnetic and fluorescence imaging. TPE-2Gd consists of a hydrophobic tetraphenylethene (TPE) fluorophore and two hydrophilic gadolinium (Gd) diethylenetriaminepentaacetic acid moieties. As an amphiphilic molecule, TPE-2Gd aggregates into micelles at a high concentration in aqueous medium. These aggregates are highly emissive, showing an aggregation-induced emission (AIE) characteristic. TPE-2Gd is used as a fluorescent agent for cell imaging, which demonstrates negligible cytotoxicity and excellent photostability owing to its AIE property. As a magnetic resonance imaging (MRI) contrast agent, TPE-2Gd exhibits similar longitudinal relaxivity in water (R1,TPE-2Gd = 3.36 ± 0.10 s(-1) per mM of Gd(3+)) as those commercial agents (e.g., Magnevist, R1,magnevist = 3.70 ± 0.02 s(-1) per mM of Gd(3+)). Compared with Magnevist, the circulation lifetime of TPE-2Gd nanoaggregates in living rats is extended from 10 min to 1 h. With relatively high specificity to the liver, the MR imaging could remain hyperintense in liver even after 150 min post injection. These TPE-2Gd nanoparticles can be excreted gradually via renal filtration due to the disassembly of the nanoparticles into small molecules during circulation. TPE-2Gd could thus potentially be used as a liver specific MRI contrast agent for clinical diagnosis.


Water (H2O and D2O) molar absorptivity in the 1000-4000 cm-1 range and quantitative infrared spectroscopy of aqueous solutions.
Water (H2O and D2O) molar absorptivity was measured by Fourier transform infrared transmission spectroscopy in the 1000-4000 cm-1 range at 25 degrees C. A series of assembled cells with path lengths from 1.2 to 120.5 microns was used for these measurements. The optimal path length (the path length of aqueous solution at which the IR spectrum of solute, corrected for water absorbance, has the highest signal-to-noise ratio) was calculated for all water absorbance bands. The results presented here show that the optimal path length does not depend on solute properties and is inversely proportional to the solvent (water) molar absorptivity. The maximal signal-to-noise ratio for measurements of IR spectra of aqueous solution in the 1650 cm-1 spectral region, of primary interest in biological applications, can be obtained at an optimal cell path lengths of 3-4 microns (H2O) and 40-60 microns (D2O). As an example, the signal-to-noise ratio was calculated as a function of the cell path length for the amide I (H2O) and amide I' (D2O) bands of an aqueous lysozyme solution. The molar absorptivities of water bands are several orders of magnitude weaker than those of the strongest bands of biological macromolecules in the same spectral regions. High net water absorbance in aqueous solutions is due simply to the very high molar concentration of water. A method is proposed for the quantitative measuring of the path length of the cell which exploits the molar absorptivity of the strongest water bands (stretching vibrations) or of bands which do not overlap with solute absorbance. A path length in the range from approximately 0.01 micron to approximately 1.0 mm can be determined with high precision using this technique for a samples of known concentration. Problems involved in the proper correction of strong water absorbance in IR spectra of aqueous solutions of biomolecules are discussed, including multiple reflections within the cell, the effects of pH, temperature, and perturbation of water spectral properties by polar solutes, as well as the selection of optimal spectral regions in which one may obtain the most precise absorbance corrections.


Regional variations in action potential alternans in isolated murine Scn5a (+/-) hearts during dynamic pacing.
clinical observations suggest that alternans in action potential (AP) characteristics presages breakdown of normal ordered cardiac electrical activity culminating in ventricular arrhythmogenesis. We compared such temporal nonuniformities in monophasic action potential (MAP) waveforms in left (LV) and right ventricular (RV) epicardia and endocardia of Langendorff-perfused murine wild-type (WT), and Scn5a(+/-) hearts modelling Brugada syndrome (BrS) for the first time. a dynamic pacing protocol imposed successively incremented steady pacing rates between 5.5 and 33 Hz. A signal analysis algorithm detected sequences of >10 beats showing alternans. Results were compared before and following the introduction of flecainide (10 microm) and quinidine (5 microm) known to exert pro- and anti-arrhythmic effects in BrS. sustained and transient amplitude and duration alternans were both frequently followed by ventricular ectopic beats and ventricular tachycardia or fibrillation. Diastolic intervals (DIs) that coincided with onsets of transient (tr) or sustained (ss) alternans in MAP duration (DI*) and amplitude (DI') were determined. Kruskal-Wallis tests followed by Bonferroni-corrected Mann-Whitney U-tests were applied to these DI results sorted by recording site, pharmacological conditions or experimental populations. WT hearts showed no significant heterogeneities in any DI. Untreated Scn5a (+/-) hearts showed earlier onsets of transient but not sustained duration alternans in LV endocardium compared with RV endocardium or LV epicardium. Flecainide administration caused earlier onsets of both transient and sustained duration alternans selectively in the RV epicardium in the Scn5a (+/-) hearts. these findings in a genetic model thus implicate RV epicardial changes in the arrhythmogenicity produced by flecainide challenge in previously asymptomatic clinical BrS.


Development of a SNP genotyping panel for genetic monitoring of the laboratory mouse.
We have developed a genotyping system for detecting genetic contamination in the laboratory mouse based on assaying single-nucleotide polymorphism (SNP) markers positioned on all autosomes and the X chromosome. This system provides a fast, reliable, and cost-effective way for genetic monitoring, while maintaining a very high degree of confidence. We describe the allelic distribution of 235 SNPs in 48 mouse strains, thereby creating a database of polymorphisms useful for genotyping purposes. The SNP markers used in this study were chosen from publicly available SNP databases. Four genotyping methods were evaluated, and dynamic two-tube allele-specific PCR assays were developed for each marker and tested on a set of 48 inbred mouse strains. The minimal number of assays sufficient to distinguish groups consisting of different numbers of mouse strains was estimated, and a panel of 28 SNPs sufficient to distinguish virtually all of the inbred strains tested was selected. Amplifluor SNP detection assays were developed for these markers and tested on an extended list of 96 strains. This panel was used as a genetic quality control approach to monitor the genotypes of nearly 300 inbred, wild-derived, congenic, consomic, and recombinant inbred strains maintained at The Jackson Laboratory. We have concluded that this marker panel is sufficient for genetic contamination monitoring in colonies containing a large number of genetically diverse mouse strains and that reduced versions of the panel could be implemented in facilities housing a lower number of strains.


[Instability of immunoglobulin expression during differentiation induction in the human lymphoblastoid cell line RPMI-6410t].
The induction of immunoglobulin heavy chain classes switch from IgM to IgG was demonstrated in vitro in cells of RPMI-6410t line. The IgG+-sublines, formed as a result of the switch are characterized by instability of IgG synthesis. After removal of the inductor from the growth environment, IgG+ cells gradually reduce the level of secreted IgG. Such a transition to the functional rest state is likely to be connected with the convertible Ig-gene activity suppression in IgG+ cells, since after their activation by LPS IgG-secretion is partly or completely restored. The IgG+-sublines obtained may serve a convenient model for investigating the Ig-gene expression regulation in differentiated human B-cells.


Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.


Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes.
Fosmidomycin, a potent inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), has antibacterial and antimalaria activity. Due to its poor pharmacokinetics, more lipophilic DXR inhibitors are needed. However, the hydrophobic binding site(s) in DXR remains elusive. Here, pyridine/quinoline containing phosphonates are identified to be DXR inhibitors with IC(50) values as low as 840 nM. We also report three DXR:inhibitor structures, revealing a novel binding mode. The indole group of Trp211 is found to move ~4.6 Å to open up a mainly hydrophobic pocket, where the pyridine/quinoline rings of the inhibitors are located and have strong π-π stacking/charge-transfer interactions with the indole. Docking studies demonstrate our structures could be used to predict the binding modes of other lipophilic DXR inhibitors. Overall, this work shows an important role of Trp211 in inhibitor recognition and provides a structural basis for future drug design and development.


Biclustering-based association rule mining approach for predicting cancer-associated protein interactions.
Protein-protein interactions (PPIs) have been widely used to understand different biological processes and cellular functions associated with several diseases like cancer. Although some cancer-related protein interaction databases are available, lack of experimental data and conflicting PPI data among different available databases have slowed down the cancer research. Therefore, in this study, the authors have focused on various proteins that are directly related to different types of cancer disease. They have prepared a PPI database between cancer-associated proteins with the rest of the human proteins. They have also incorporated the annotation type and direction of each interaction. Subsequently, a biclustering-based association rule mining algorithm is applied to predict new interactions with type and direction. This study shows the prediction power of association rule mining algorithm over the traditional classifier model without choosing a negative data set. The time complexity of the biclustering-based association rule mining is also analysed and compared to traditional association rule mining. The authors are able to discover 38 new PPIs which are not present in the cancer database. The biological relevance of these newly predicted interactions is analysed by published literature. Recognition of such interactions may accelerate a way of developing new drugs to prevent different cancer-related diseases.


A Systematic Review of Sexual Assaults in Nursing Homes.
The dramatic growth in the older adults (65 years+) has created an equivalent increase in the number of nursing home (NH) residents. NH residents often lack physical and cognitive abilities, making them particularly vulnerable to assault. Although sexual assault is among one of the most shocking types of assault, it is also the least acknowledged, detected, and reported type of assault against NH residents. This systematic review examines victim/perpetrator sociodemographic and relationship characteristics as well as the forensic characteristics of sexual assaults occurring in NH. A 7 database systematic search of studies published between January 1, 1949 and October 26, 2015 was conducted that examined sexual assaults in NH. Articles reporting on sexual assault in NH and other institutional settings were eligible. Community-dwelling populations and studies not describing sexual assault or physical aspects of sexual assault were excluded. Sexual assault was not restricted to a single definition, study method, or country. Fifteen studies met inclusion criteria. Sexual assault was the least reported type of assault in NH. Victims of sexual assault were likely to be females with cognitive or physical impairments. Perpetrators were likely to be male residents, although staff members were also substantiated. Forensic characteristics and investigative data were limited. Study limitation included inconsistencies between study purposes and small sample sizes. This review highlights a gap in knowledge regarding sexual assaults in NH and demonstrates a need for better staff training in detecting, examining, and managing sexual assaults in NH.


Poor vitamin D status was associated with increased appendicular fat deposition in US Adults: Data from 2011-2018 National Health and Nutrition Examination Survey.
The aim of the study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and regional body fat deposition in 2011-2018 National Health and Nutrition Examination Survey participants aged 18 to 59 years. We hypothesized that serum 25(OH)D concentrations were negatively associated with total, appendicular, and truncal fat deposition. Serum 25(OH)D concentration was categorized into sufficient (≥75.0 nM), insufficient (50.0-74.9 nM), and deficient (<50.0 nM) groups. Fat mass (FM) was measured by dual-energy X-ray absorptiometry, and FM index (FMI) was calculated by dividing FM (kg) with height2 (m2). Multivariant linear regression and Granger causal analysis were performed to assess the causal relationship between vitamin D status and regional FMIs. Overall serum 25(OH)D concentrations were negatively associated with total (β = -0.029, standard error [SE] = 0.002), trunk (β = -0.015, SE = 0.001), arms (β = -0.004, SE = 3.09 × 10-4), and legs (β = -0.010, SE = 0.001) FMIs in all participants (P < .001, respectively); however, after stratified by vitamin D status and BMI, the negative associations were only observed in individuals with vitamin D deficiency and obesity. The causal analysis indicated that serum 25(OH)D concentrations may causally reduce the arms (F = 4.917, probability [P] = 0.007), legs (F = 5.783, P = 0.003), and total (F = 3.202, P = 0.041) FMIs except for trunk FMI but not vice versa. In conclusion, poor vitamin D status was associated with increased total and appendicular body fat deposition in US adults, particularly in participants with obesity.


Identifying the Optimal Number of Neoadjuvant Chemotherapy Cycles in Patients with Muscle Invasive Bladder Cancer.
We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer. In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated. pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57, p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p=0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p=0.08). Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.


Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine.
This study utilized drug discrimination procedures to assess the functional consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin depletion, and to determine whether concomitant injections of fluoxetine averted these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)-MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant procedure. After dose generalization tests were completed, training was suspended, and subjects were administered saline injections twice daily for four days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline, to ascertain that discriminative stimulus control was maintained in the absence of training over a two-week period. All subjects received two additional weeks of training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline (SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections, S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA generalization tests, and rose from 2.78% to 22.14% during SAL generalization tests. This disruption did not occur, however, in rats administered the combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated rats. Postmortem neurochemical assays indicated that 5-HT levels were significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL, compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5-HIAA levels were significantly lower in the prefrontal cortices of both (+/-)-MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control. These results support previous findings that fluoxetine protects against (+/-)-MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug discrimination is a sensitive assay in which to examine behavioral correlates of (+/-)-MDMA-induced serotonergic deficits, and the protection against these deficits by fluoxetine.


Synthesis of Diaryl Hydroxyl Dicarboxylic Acids from Amino Acids.
Herein we report a unique method for preparing diaryl hydroxyl dicarboxylic acids in a diastereospecific manner. The three-component reaction occurs between amino acid, aromatic aldehyde, and primary alcohol in alkaline solutions under microwave-assisted conditions. The dicarboxylic acids are isolated as sodium salts in high yields (up to 77%) by direct precipitation from the reaction solution. The experimental results suggest that the diastereospecificity originates from a [3,3]-sigmatropic rearrangement followed by a sodium-assisted hydride transfer. As further shown, the previously unreported dicarboxylic acids are easily turned into corresponding δ-lactones.


Activating factor for the iron protein of nitrogenase from Rhodospirillum rubrum.
As isolated from Rhodospirillum rubrum, the iron protein of nitrogenase has little or no activity. It can be activated by incubating it with a trypsin-sensitive, oxygen-labile component (activating factor) plus adenosine triphosphate and a divalent metal ion. After activation, the iron protein retains its nitrogenase activity when the activating factor is removed.


Immune Conversion of Tumor Microenvironment by Oncolytic Viruses: The Protoparvovirus H-1PV Case Study.
Cancer cells utilize multiple mechanisms to evade and suppress anticancer immune responses creating a "cold" immunosuppressive tumor microenvironment. Oncolytic virotherapy is emerging as a promising approach to revert tumor immunosuppression and enhance the efficacy of other forms of immunotherapy. Growing evidence indicates that oncolytic viruses (OVs) act in a multimodal fashion, inducing immunogenic cell death and thereby eliciting robust anticancer immune responses. In this review, we summarize information about OV-mediated immune conversion of the tumor microenvironment. As a case study we focus on the rodent protoparvovirus H-1PV and its dual role as an oncolytic and immune modulatory agent. Potential strategies to improve H-1PV anticancer efficacy are also discussed.


Innovative digital technology adapted in nursing education between Eastern and Western countries: a mini-review.
Advanced digital technologies have overcome the limitation of on-site teaching, especially after the COVID-19 epidemic. Various newly-developed digital technologies, such as e-learning, virtual reality, serious games, and podcasts, have gained renewed interest and come into the spotlight. Podcasts are becoming increasingly popular in nursing education as they provide a convenient and cost-effective way for students to access educational content. This mini-review article provides an overview of the development of podcasts in nursing education in Eastern and Western countries. It explores potential future trends in the use of this technology. The literature review demonstrates that nursing education in Western countries has already integrated podcasts into curriculum design, using the podcast to convey nursing education knowledge and skills and to improve students' learning outcomes. However, few articles address nursing education in Eastern countries. The benefits of integrating podcasts into nursing education appear far greater than the limitations. In the future, the application of podcasts can serve not only as a supplement to instructional methodologies but also as a tool for clinical practicing students in nursing education. In addition, with the aging population increasing in both Eastern and Western countries, podcasts have the potential to serve as an effective delivery modality for health education in the future, particularly for the older adult, whose eyesight declines with age, and those populations with visual impairments.


Prevalence of advanced renal failure in Northern Ireland.
To determine the prevalence of advanced chronic renal failure in Northern Ireland as part of an assessment by the Renal Association of the level of service provision for treatment of such patients. Prospective notification of patients reaching a defined level of advanced chronic renal failure (serum creatinine concentration greater than or equal to 500 mumol/l or blood urea concentration greater than or equal to 25 mmol/l) within one year and follow up for at least three, and, at most, four years after notification. Northern Ireland. 122 Patients with a serum creatinine or blood urea concentration higher than the defined level newly detected from 1 March 1985 to 28 February 1986. Survival after notification. 77 Patients of all ages/million population/year had advanced chronic renal failure compared with 67/million/year between the ages of 5 and 80 found in an earlier study of the same population. 62% Of the patients were older than 50 years. Seventeen (14%) of the patients either required dialysis or died within one month of notification, 51 (42%) survived for at least three months, and 23 (19%) for one year or longer. Three patients, all of whom were attending a renal clinic, survived for periods of 43, 45, and 46 months respectively without renal replacement treatment. The increased number of new patients disclosed in this survey compared with the earlier survey is mainly owing to an increased number of older patients. Such patients often have disabilities other than renal failure, are less likely to be capable of self treatment, may develop complications more often and require more frequent hospital admissions, and may not be suitable for transplantation and consequently have considerable resource implications for the NHS.


Total parenteral nutrition in the critically ill patient: a meta-analysis.
Nutritional support has become a standard of care for hospitalized patients, but whether total parenteral nutrition (TPN) affects morbidity and mortality is unclear. To examine the relationship between TPN and complication and mortality rates in critically ill patients. Computerized search of published research on MEDLINE from 1980 to 1998, personal files, and review of relevant reference lists. We reviewed 210 titles, abstracts, and papers. Primary studies were included if they were randomized clinical trials of critically ill or surgical patients that evaluated the effect of TPN (compared with standard care) on complication and mortality rates. We excluded studies comparing TPN with enteral nutrition. Relevant data were abstracted on the methodology and outcomes of primary studies. Data were abstracted in duplicate, independently. There were 26 randomized trials of 2211 patients comparing the use of TPN with standard care (usual oral diet plus intravenous dextrose) in surgical and critically ill patients. When the results of these trials were aggregated, TPN had no effect on mortality (risk ratio [RR], 1.03; 95% confidence interval [CI], 0.81-1.31). Patients who received TPN tended to have a lower complication rate, but this result was not statistically significant (RR, 0.84; 95% CI, 0.64-1.09). We examined several a priori hypotheses and found that studies including only malnourished patients were associated with lower complication rates but no difference in mortality when compared with studies of nonmalnourished patients. Studies published since 1989 and studies with a higher methods score showed no treatment effect, while studies published in 1988 or before and studies with a lower methods score demonstrated a significant treatment effect. Complication rates were lower in studies that did not use lipids; however, there was no difference in mortality rates between studies that did not use lipids and those studies that did. Studies limited to critically ill patients demonstrated a significant increase in complication and mortality rates compared with studies of surgical patients. Total parenteral nutrition does not influence the overall mortality rate of surgical or critically ill patients. It may reduce the complication rate, especially in malnourished patients, but study results are influenced by patient population, use of lipids, methodological quality, and year of publication.


Adaptors in toll-like receptor signaling and their potential as therapeutic targets.
To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group. Other TIR domain-containing proteins have also been shown to regulate these signaling pathways, including ST2 and SIGIRR, as well as several bacterial and viral TIR domain-containing proteins that modulate these pathways as virulence factors. TLR pathways and the adaptor proteins are associated with a number of diseases, including infection, sepsis, inflammatory, allergic and autoimmune diseases and cancer. We review our current understanding of the structure and function of adaptor proteins and their regulatory proteins, their association with disease and their potential as therapeutic targets in human disease.


Motorized 2-3 wheelers death rates over a decade: a global study.
Motorized 2-3-wheelers-related death is high due to the exposed body of the driver/passenger and the high speed. The United Nation (UN) Decade of Action for road safety aimed to reduce road traffic deaths by 50% by the year 2020. We aimed to study the factors affecting the death rates of motorized 2-3 wheelers injured victims and whether the reduction in the death rates has met the UN target. Data were retrieved from the WHO Global Status Reports on Road Safety published over 2009 to 2018 which covered the years of 2007 to 2016. Studied variables included motorized 2-3 wheelers death rates, percentage of helmet-wearing rate, helmet law enforcement, speed law enforcement, gross national income per capita, vehicles/person ratio, and motorized 2-3 wheelers/person ratio. A mixed linear model was used to define factors affecting the change of motorized 2-3 wheelers death rates over time. The global mean motorized 2-3 wheelers death rates increased from 2.37/100,000 population to 3.23/100,000 population over the studied decade (a relative ratio of 1.36) which was not statistically significant. Factors that affected mortality included GNI (p = 0.025), motorized 2-3 wheelers per person ratio (p < 0.0001), percentage of helmet wearing rate (p = 0.046), and the interaction between vehicle/person ratio and motorized 2-3 wheelers/person ratio (p = 0.016). There was a significant increase in the death rates over time in the low-income countries (a relative ratio of 2.52, p = 0.019, Friedman test), and middle-income countries (a relative ratio of 1.46, p < 0.0001, Friedman test), compared with a significant decrease in the high-income countries (a relative ratio of 0.72, p < 0.0001, Friedman test). Global mortality of motorized 2-3 wheelers has increased by a relative ratio of 1.36 over a recent decade. The UN target of reducing death was not met. The increase was related to the increase in motorized 2-3 wheelers per person ratio and economic inequity which has to be addressed globally. The economic global gap significantly impacts the mortality rates of motorized 2-3 wheelers.


Cardiac effect of thyrotoxicosis in acromegaly.
Cardiac structure and function are affected both by acromegaly and hyperthyroidism. Whereas the former is mainly characterized by ventricular hypertrophy as well as diastolic and systolic impairment, the latter frequently leads to increased heart rate and enhancement of contractility and cardiac output. To further investigate this issue, we designed this two-arm study. In the first cross-sectional study, we compared echocardiography and radionuclide angiography results obtained in eight hyperthyroid acromegalic patients, eight hyperthyroid nonacromegalic patients, and eight healthy subjects. All acromegalic patients were receiving treatment for acromegaly at the onset of hyperthyroidism. In the second longitudinal study, performed in the group of acromegalic patients, we compared the cardiovascular results obtained during hyperthyroidism with the retrospective data obtained at the initial diagnosis of acromegaly and after 1-yr treatment for this disease and those prospective data obtained during the remission of hyperthyroidism. In the cross-sectional study, hyperthyroid acromegalic patients showed an increase in the left ventricular (LV) mass index (LVMi) compared to healthy and hyperthyroid controls (P < 0.05), with evidence of LVMi hypertrophy in five of them (62.5%). A significant correlation was found between LVMi and GH levels (r = 0.785; P < 0.05). The LV ejection fraction (LVEF) at rest was higher in the control hyperthyroid population than in healthy controls (P < 0.05), whereas the LVEF response to exercise was reduced in acromegalic patients (P < 0.05 vs. healthy controls). In acromegalics, the exercise-induced change in LVEF was significantly reduced compared to that in healthy controls (P < 0.001), but not to that in hyperthyroid controls (P < 0.07), being abnormal (<5% increase vs. baseline values) in six patients. Four of these six patients (66%) had elevated GH and insulin-like growth factor I levels during the treatment of acromegaly. An inverse correlation between GH and LVEF at rest (r = -0.896;P < 0.05) and at peak exercise (r = -0.950; P < 0.001) was recorded. The peak filling rate was reduced in hyperthyroid acromegalic patients compared to those in both control populations (P < 0.05). In the longitudinal study, acromegalic patients showed an increased LVMi during hyperthyroidism compared to that observed after successful treatment of acromegaly (P < 0.05); resting LVEF was increased compared to both basal (P < 0.001) and posttreatment values (P < 0.05). However, the exercise-induced change in LVEF was reduced (P < 0.05 vs. previous follow-up values). Remission of hyperthyroidism led to significant reduction of LVMi (P < 0.05) and resting LVEF (P < 0.05) and an increase in exercise-induced LVEF (P < 0.05). In light of these findings, hyperthyroidism produces a detrimental effect on the cardiovascular system of acromegalic patients, particularly in those with uncontrolled disease. Thus, control of GH and insulin-like growth factor I should be a major objective, as cardiovascular risk persists in patients with ineffective hormonal suppression, and constant endocrine and cardiovascular surveillance remain crucial steps in patient follow-up.


Risk factors in the onset of neck/shoulder pain in a prospective study of workers in industrial and service companies.
To quantify the relative contribution of work related physical factors, psychosocial workplace factors, and individual factors and aspects of somatisation to the onset of neck/shoulder pain. Four year prospective cohort study of workers from industrial and service companies in Denmark. Participants were 3123 workers, previously enrolled in a cross sectional study, where objective measurement of physical workplace factors was used. Eligible participants were followed on three subsequent occasions with approximately one year intervals. Outcomes of interest were: new onset of neck/shoulder pain (symptom cases); and neck/shoulder pain with pressure tenderness in the muscles of the neck/shoulder region (clinical cases). During follow up, 636 (14.1%) participants reported neck/shoulder pain of new onset; among these, 82 (1.7%) also had clinical signs of substantial muscle tenderness. High shoulder repetition was related to being a future symptom case, and a future clinical case. Repetition was strongly intercorrelated with other physical measures. High job demands were associated with future status as a symptom case, and as a clinical case. A high level of distress predicted subsequent neck/shoulder pain, and neck/shoulder pain with pressure tenderness. High levels of distress, and physical and psychosocial workplace factors are predictors of onset of pain in the neck and/or shoulders, particularly pain with pressure tenderness in the muscles.


Impact of acquisition protocols and processing streams on tissue segmentation of T1 weighted MR images.
The segmentation of T1-weighted images into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) is a fundamental processing step in neuroimaging, the results of which affect many other structural imaging analyses. Variability in the segmentation process can decrease the power of a study to detect anatomical differences, and minimizing such variability can lead to more robust results. This paper outlines a straightforward strategy that can be used (1) to select more optimal data acquisition and processing protocols and (2) to quantify the impact of such optimization. Using this approach with multiple scans of a single subject, we found that the choice of a segmentation algorithm had the largest impact on variability, while the choice of a pulse sequence had the second largest impact. The data indicate that the classification of GM is the most variable, and that the optimal protocol may differ across tissue types. Therefore, the intended use of segmentation data should play a role in optimization. Examples are provided to demonstrate that the minimization of variability is not sufficient for optimization; the overall accuracy of the approach must also be considered. Simple volumetric computations are included to illustrate the potential gain of optimization; these results show that volume estimates from optimal pathways were on average three times less variable than estimates from suboptimal pathways. Therefore, the simple strategy illustrated here can be applied to many studies to optimize tissue segmentation, which should lead to a net increase in the power of structural neuroimaging studies.


Effect of chronic kidney disease on the expression of thiamin and folic acid transporters.
Chronic kidney disease (CKD) is associated with significant cardiovascular, neurological and metabolic complications. Thiamin and folate are essential for growth, development and normal cellular function, and their uptake is mediated by regulated transport systems. While plasma folate and thiamin levels are generally normal in patients with CKD, they commonly exhibit features resembling vitamin deficiency states. Earlier studies have documented impaired intestinal absorption of several B vitamins in experimental CKD. In this study, we explored the effect of CKD on expression of folate and thiamin transporters in the key organs and tissues. Sprague-Dawley rats were randomized to undergo 5/6 nephrectomy or sham operation and observed for 12 weeks. Plasma folate and thiamin concentrations and gene expression of folate (RFC, PCFT) and thiamin transporters (THTR-1 and THTR-2) were determined in the liver, brain, heart and intestinal tissues using real-time PCR. Hepatic protein abundance of these transporters was determined using western blot analysis. Plasma folate and thiamin levels were similar between the CKD and the control groups. However, expressions of both folate (RFC and PCFT) and thiamin (THTR-1, THTR-2) transporters were markedly reduced in the small intestine, heart, liver and brain of the CKD animals. Liver protein abundance of folate and thiamin transporters was significantly reduced in the CKD animals when compared with the sham-operated controls. Furthermore, we found a significant reduction in mitochondrial folate and thiamin transporters in the CKD animals. CKD results in marked down-regulation in the expression of folate and thiamin transporters in the intestine, heart, liver and brain. These events can lead to reduced intestinal absorption and impaired cellular homeostasis of these essential micronutrients despite their normal plasma levels.


Functional interconnections of HY1 with MYC2 and HY5 in Arabidopsis seedling development.
Arabidopsis seedling development is controlled by many regulatory genes involved in multiple signaling pathways. The functional relationships of these genes working in multiple signaling cascades have started to be unraveled. Arabidopsis HY1/HO1 is a rate-limiting enzyme involved in biosynthesis of phytochrome chromophore. HY5 (a bZIP protein) promotes photomorphogenesis, however ZBF1/MYC2 (a bHLH protein) works as a negative regulator of photomorphogenic growth and light regulated gene expression. Further, MYC2 and HY1 have been shown to play important roles in jasmonic acid (JA) signaling pathways. Here, we show the genetic interactions of HY1 with two key transcription factor genes of light signaling, HY5 and MYC2, in Arabidopsis seedling development. Our studies reveal that although HY1 acts in an additive manner with HY5, it is epistatic to MYC2 in light-mediated seedling growth and gene expression. This study further demonstrates that HY1 additively or synergistically functions with HY5, however it works upstream to MYC2 in JA signaling pathways. Taken together, this study demonstrates the functional interrelations of HY1, MYC2 and HY5 in light and JA signaling pathways.