Metabolic muscle damage and oxidative stress markers in an America's Cup yachting crew.
Activities of enzymes involved in muscle damage [creatine kinase (CK) and aspartate aminotransferase (AST)] and levels of malondialdehyde (MDA) as a marker of oxidative stress were monitored in the plasma of 27 members of an America's Cup yachting crew. The preventive benefits of allopurinol on muscle damage were also tested. In racing period A, the crew was divided into two groups according to their tasks on board. Blood samples from all 27 sailors were obtained before the start of a 5-day fleet race, after the last race, and after the ten match races. In period B, crew members were divided at random into two groups. One group (13 participants) received 300 mg/day of allopurinol 3 h before racing. The other ten members received placebo. Blood samples were collected just before and after the second round of the Louis Vuitton Cup. All participants showed increased CK and AST activities after the racing period A. The increase in CK activity was highest in sailors involved in strenuous physical work. At the end of period A, plasma MDA levels were higher in all participants as compared with non-participant athletes. In period B, a significant decrease in CK activity, but not in AST, appeared among participants receiving allopurinol. Plasma MDA decreased in sailors treated with allopurinol, but this reduction did not reach statistical significance. America's Cup is a sailing sport with high physical demands, as shown by the increase in muscle-damage markers. Treatment with allopurinol appeared to decrease the levels of muscle damage markers.


Class I heme peroxidases: characterization of soybean ascorbate peroxidase.
An efficient expression system [D. A. Dalton et al. Arch. Biochem. Biophys. 328, 1-8, 1996) for soybean nodule ascorbate peroxidase (APX) has, for the first time, been used to generate enzyme in large enough quantities for detailed biophysical analysis. The recombinant APX has been characterized by electronic absorption, EPR, NMR and circular dichroism spectroscopies, and by electrochemistry. Electronic, EPR, and NMR spectra are consistent with a high-spin ferric resting state for the enzyme at 298 K. Low-temperature EPR (7 K) and electronic absorption (77 K) experiments indicate formation of a low-spin heme derivative at these temperatures. The midpoint reduction potential for the Fe(III)/Fe(II) redox couple, determined by spectroelectrochemistry, is -159 +/- 2 mV vs SHE (pH 7.0, 25.0 degrees C, mu = 0.10 M). Circular dichroism spectra of pea and soybean APXs are very similar, indicating common structural features for the two enzymes. The melting temperature of soybean APX, as monitored by circular dichroism spectroscopy, is 49 degrees C. These results represent the first detailed spectroscopic and electrochemical analysis of soybean ascorbate peroxidase and are discussed in the broader context of other class I peroxidases.


Ecological and evolutionary factors in dental morphological diversification among modern human populations from southern South America.
The knowledge of processes involved in morphological variation requires the integrated analysis of evolutionary and ecological factors. Here, we investigate the factors responsible for dental variation among human populations from southern South America. The aim of this work is to test the correspondence of dental size and shape variation with geographical, molecular (i.e. mtDNA) and ecological (i.e. climate, diet and food preparation) variables employing comparative phylogenetic methods, which have not previously been extensively applied at a within-species level. The results of the Procrustes analysis show a significant association of shape variables with molecular distance and geography, whereas dental size is not associated with molecular or geographical distances among groups. Phylogenetic generalized least-squares analysis, which takes into account the evolutionary autocorrelation among populations, shows a significant relationship between dental size variation and diet, while temperature and pottery do not correspond with dental size or shape. Specifically, groups with diets rich in carbohydrates, as well as the maritime hunter-gatherers, have the smallest teeth. In summary, our results support ecological factors as the dominant factor on dental size diversification in this region, while evolutionary relationships account for variation in dental shape.


Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue.
We reported that resveratrol decreased DNA methyltransferase (DNMT) 1 and 3b expression in vitro and demethylates tumor suppressor RASSF-1a in women at increased breast cancer risk. We investigated the effects of resveratrol on DNMT and miRNA expression in normal and tumor mammary tissue in a rodent model of estrogen dependent mammary carcinoma. Eighty-nine female ACI rats received estradiol plus: low dose (lo) resveratrol, high dose (hi) resveratrol, 5-aza-2-deoxycytidine (Aza), a known inhibitor of DNMTs, or control (no additional treatment). After 21 wk of treatment, animals were sacrificed and mammary glands harvested. Matched tumor/normal tissues were available from 36 rats. DMNT3b (but not DNMT1) differed in tumor vs. normal tissue after lo (P = .04) and hi (P = .007) resveratrol and Aza treatment. With hi resveratrol, DNMT3b decreased in tumor but increased normal tissue. Hi resveratrol increased miR21, -129, -204, and -489 >twofold in tumor and decreased the same miRs in normal tissue 10-50% compared to control. There was an inverse association between DNMT3b and miR129, -204, and -489 in normal and/or tumor tissue. Treatment with resveratrol differentially influences tumor vs. normal tissue DNMT3b and miRNA expression. This mechanism of action of resveratrol to influence mammary carcinogenesis warrants further investigation.


Fully Automated Synthesis of Nitrogen-13-NH3 by SHIs HM-18 Cyclotron and Dedicated Module for Routine Clinical Studies: Our Institutional Experiences.
The production of nitrogen-13 (13N)-NH3 by ethanol method using automated synthesizer and accessing the production yield, quality control for clinical application. 13N, together with 18F, 15O, and 11C, is one of the positron emitters that can be produced on the multi-gigabecquerel scale in biomedical cyclotrons. (13N)-ammonia is frequently used for cardiac PET studies. It is widely applied for the evaluation of myocardial perfusion in the clinical assessment of cardiac disorders. Simple, fast, and reliable preparation methods have contributed to the routine application of this tracer. Although only two methods are available, a challenge remains to adopt a more efficient and consistent approach to its production. For clinical application, routine production of this tracer is mandatory in compliance with regulatory guidelines. Being at hospital radiopharmacy it is our responsibility to support the clinical service with uninterrupted production and supply of (13N)-NH3. The chemicals were used commercially available from Sigma Aldrich, India, Ltd., and Fisher Scientific, India, Ltd. (Mumbai, India), Sep-Pak CM cartridges (Waters India, Pvt., Ltd.,). Radio-thin layer chromatography was carried out using aluminum sheets precoated with silica gel 60 F254 (E. Merck, India). The protocol developed with MPS-100 synthesizer yield (13N)-NH395-97% (EOB) with a synthesis time of around 7 min. With the installation of HM-18 cyclotron at our hospital, center is capable to produce (13N)-NH3 of good yield and purity through the ethanol method, for mycocardial perfusion studies. Our protocol is simple, reproducible, and robust.


Causal relationship between hypoalbuminemia and acute kidney injury.
Our meta-analysis published in 2010 provided evidence that low levels of serum albumin (hypoalbuminemia) are a significant independent predictor of acute kidney injury (AKI) and death following AKI. Since then, a large volume of additional data from observational clinical studies has been published further evaluating the relationship between serum albumin and AKI occurrence. This is an updated review of the literature to re-evaluate the hypothesis that hypoalbuminemia is independently associated with increased AKI risk. Eligible studies published from September 2009 to December 2016 were sought in PubMed (MEDLINE) and forty-three were retained, the great majority being retrospective observational cohort studies. These included a total of about 68000 subjects across a diverse range of settings, predominantly cardiac surgery and acute coronary interventions, infectious diseases, transplant surgery, and cancer. Appraisal of this latest data set served to conclusively corroborate and confirm our earlier hypothesis that lower serum albumin is an independent predictor both of AKI and death after AKI, across a range of clinical scenarios. The body of evidence indicates that hypoalbuminemia may causally contribute to development of AKI. Furthermore, administration of human albumin solution has the potential to prevent AKI; a randomized, controlled study provides evidence that correcting hypoalbuminemia may be renal-protective. Therefore, measurement of serum albumin to diagnose hypoalbuminemia may help identify high-risk patients who may benefit from treatment with exogenous human albumin. Multi-center, prospective, randomized, interventional studies are warranted, along with basic research to define the mechanisms through which albumin affords nephroprotection.


Somatosensory comparison during haptic tracing.
Active sensing involves memory retrieval and updating as well as mechanisms that trigger corrections to the ongoing exploratory movement. The present study examined this process in a task where human subjects moved the index fingertip clockwise around the circumference of a virtual sphere created by a robotic device. The fingertip pressed into the sphere during the movement, and the subjects were to report slight differences in sphere size (or surface curvature), which occurred from trial to trial. During each 2- to 3-s trial, subjects gradually adjusted their speed and pressure according to the current surface curvature, achieving a consistent level of contact force in the last half of the exploration. The results demonstrate that subjects were gradually accumulating haptic information about curvature and, at the same time, gradually changing the motor commands for the movement. When subjects encountered an unexpected transition in curvature (from circular to flat), they reacted by abruptly decreasing contact force at a latency of about 50 ms. This short latency indicates that spinally mediated corrections are engaged during this task. The results support the hypothesis that during haptic exploration, the neural comparison between expected and actual somatosensory feedback takes places at multiple levels, including the spinal cord.


Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors.
Tumor environment can be critical for preventing the immunological destruction of antigenic tumors. We have observed a selective accumulation of CD4(+)CD25(+) T cells inside tumors. In a murine fibrosarcoma L(d)-expressing Ag104, these cells made up the majority of tumor-infiltrating lymphocytes at the late stage of tumor progression, and their depletion during the effector phase, rather than priming phase, successfully enhanced antitumor immunity. We show here that CD4(+)CD25(+) T cells suppressed the proliferation and interferon-gamma production of CD8(+) T cells in vivo at the local tumor site. Blockade of the effects of IL-10 and TGF-beta partially reversed the suppression imposed by the CD4(+) cells. Furthermore, local depletion of CD4(+) cells inside the tumor resulted in a change of cytokine milieu and led to the eradication of well-established highly aggressive tumors and the development of long-term antitumor memory. Therefore, CD4(+)CD25(+) T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.


Granular Cell Tumor of the Orbit: Review of the Literature and a Proposed Treatment Modality.
To document a unique case of granular cell tumor of the orbit, located lateral to and abutting the optic nerve, that benefited from treatment with proton beam irradiation, with a comprehensive review of the literature on granular cell tumor of the orbit. Clinicopathologic case report with detailed imaging features and histopathologic and immunohistochemical evaluation for cytoplasmic tumor biomarkers differentiating granular cell tumor (GCT) from it mimicking lesions with relevant literature citations. The authors reviewed 20 cases of orbital GCT from 2011 to 2020 in addition to 40 cases from 1948 to 2011 and included a summary of imaging and clinical features, outcomes, and recommended treatment modalities. A 32-year-old man with 1-year history of left retrobulbar pain and diplopia on lateral gaze, intermittent left eyelid swelling, and a tonic left pupil was found to have a fusiform intraconal mass extending toward the orbital apex and abutting the optic nerve. Histopathologic and immunohistochemical investigations collectively supplied data diagnostic of a GCT with an initial low proliferation rate. GCT is a soft tissue neoplasm that originates in the nervous system and can occur anywhere in the body. This enhancing tumor is isointense to gray matter on T1-weighted MRI, hypointense on T2. After an incisional biopsy, the patient's symptoms persisted, and follow-up imaging several months later revealed further growth of the mass. The impossibility of complete surgical removal prompted the decision to treat with proton beam radiation therapy, which resulted in substantial regression in the size of the residual tumor. Most frequently involving the inferior rectus muscle (42%), orbital GCT is usually benign with only 4 reported cases of malignant orbital GCT (7%). Wide surgical resection with complete removal is usually curative for benign orbital GCT, and proton beam radiation therapy can aid in tumor shrinkage. GCT should be considered in the differential diagnosis when encountering patients with mass lesions involving the extraocular muscles, peripheral nerves, or less frequently, the optic nerve or orbital apex. Immunohistochemical analysis of biopsied tissue is required for the definitive diagnosis of GCT. Consideration of adjuvant therapies such as proton beam radiation therapy may be appropriate in cases of incomplete surgical resection of benign GCT. Proton beam radiation therapy can be an excellent therapeutic option for symptomatic relief and residual tumor size reduction with an acceptable toxicity profile.


Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages.
Macrophages are important in the activation of innate immune responses and in a tissue-specific manner in the maintenance of organ homeostasis. Testicular macrophages (TM), which reside in the testicular interstitial space, comprise the largest leukocyte population in the testes and are assumed to play a relevant function in maintaining testicular immune privilege. Numerous studies have indicated that the interstitial fluid (IF) surrounding the TM has immunosuppressive properties, which may influence the phenotype of TM. However, the identity of the immunosuppressive molecules present in the IF is poorly characterized. We show that the rat testicular IF shifted GM-CSF-induced M1 toward the M2 macrophage phenotype. IF-polarized M2 macrophages mimic the properties of TM, such as increased expression of CD163, high secretion of IL-10, and low secretion of TNF-α. In addition, IF-polarized macrophages display immunoregulatory functions by inducing expansion of immunosuppressive regulatory T cells. We further found that corticosterone was the principal immunosuppressive molecule present in the IF and that the glucocorticoid receptor is needed for induction of the testis-specific phenotype of TM. In addition, TM locally produce small amounts of corticosterone, which suppresses the basal expression of inflammatory genes as a means to render TM refractory to inflammatory stimuli. Taken together, these results suggest that the corticosterone present in the testicular environment shapes the immunosuppressive function and phenotype of TM and that this steroid may play an important role in the establishment and sustenance of the immune privilege of the testis.


Use of the NMDA antagonist magnesium sulfate during monitored anesthesia care for shockwave lithotripsy.
To assess whether intravenous magnesium sulfate infusion affects analgesic requirements during monitored anesthesia care (MAC) for shockwave lithotripsy (SWL). Fifty patients in ASA class I or II undergoing SWL with MAC were randomized into two groups. Induction of MAC was produced by bolus doses of midazolam 0.03 mg/kg(-1) and fentanyl 0.5 microg/kg(-1) followed by intravenous infusion of midazolam 0.015 to 0.06 mg/kg(-1)/hr(-1) with fentanyl supplementation 0.2 microg/kg(-1). In addition, group I patients received magnesium sulfate 30 mg/kg(-1) intravenously as a bolus dose followed by a continuous infusion of 10 mg/kg(-1) /hr(-1) beginning 15 minutes before induction of sedation. The midazolam infusion rate and additional fentanyl doses were adjusted by verbal analog scale (VAS) measurements, observer assessment sedation score (OAA/S), and achieving a target bispectral index (BIS) in a range of 70 to 90. At the end of SWL, the total midazolam and total fentanyl consumptions were recorded, and the serum magnesium concentration was measured. Magnesium caused significant decreases in the total consumption of midazolam (P = 0.001) and fentanyl (P = 0.001). The VAS values at the 15th, 20th, and 25th minute in group I were significantly lower than in group II. In group I, hemodynamic and arterial oxygen parameters were better than in group II. A magnesium bolus and infusion can be utilized to reduce analgesic requirements under MAC during SWL.


Implementing a Standardized Transition Care Plan in Skilled Nursing Facilities.
Prior studies have not described strategies for implementing transitional care in skilled nursing facilities (SNFs). As part of the Connect-Home study, we pilot tested the Transition Plan of Care (TPOC) template, an implementation tool that SNF staff used to deliver transitional care. A retrospective chart review was used to describe the impact of the TPOC template on three implementation outcomes: reach to patients, staff adoption of the template, and staff fidelity to the intervention protocol for transition care planning. The template reached 100% of eligible patients (N = 68). Adoption was high, with documentation by four disciplines in 90.6% of patient records (N = 61). Fidelity to the intervention protocol was moderately high, with 73% of documentation that was concordant with the protocol. Our findings suggest an electronic medical record (EMR)-based implementation tool may increase the ability of staff to prepare older adults and their caregivers for self-care at home. Further research is needed to test the efficacy of the protocol on patient outcomes after transitions from SNF to home.


Asthma Severity and Control and Their Association With Perinatal Mental Illness.
Growing evidence suggests asthma increases perinatal mental illness risk, but few studies have explored the impact of asthma severity and control. Our objective was to explore the association between asthma severity and control and perinatal mental illness risk and the impact of asthma exacerbations during pregnancy on postpartum mental illness risk. This was a population-based retrospective cohort study of all women in Ontario, Canada, from 2005 to 2015 with a singleton live birth who used public drug insurance, excluding women with recent history of mental illness. We constructed modified Poisson regression models to assess the risk of perinatal mental illness, defined as a mood or anxiety, psychotic or substance use disorder, self-harm or other mental illness diagnosed from conception to 365 days postnatally. Models controlled for socio-demographic factors and medical history. There were 62,583 women in the cohort (46.7% between 15 - 24 years), of whom 22.7% had asthma (94.3% mild, 5.7% moderate/severe; 86.5% controlled and 13.5% uncontrolled). After adjustment, there was increased risk of perinatal mental illness with mild asthma (adjusted relative risk [RR]: 1.12; 95% confidence interval [CI], 1.09 to 1.16) and moderate/severe asthma (aRR: 1.16; 95% CI, 1.04 to 1.30) compared to no asthma. Controlled asthma (aRR: 1.11; 95% CI, 1.08 to 1.15) and uncontrolled asthma (aRR: 1.19; 95% CI, 1.11 to 1.27) were also associated with increased perinatal mental illness risk compared to no asthma. Women with worsened asthma during pregnancy had the highest risk of postpartum mental illness compared to no change in asthma status (by severity: aRR: 1.57; 95% CI, 1.36 to 1.80; by control: aRR: 1.37; 95% CI, 1.22 to 1.54). Asthma is associated with increased risk of perinatal mental illness, particularly in the presence of asthma exacerbations in pregnancy. The results support multidisciplinary collaborative care programmes throughout the perinatal period, especially among women with asthma exacerbations during pregnancy.


[Central action of melanostatin and the opiate system of the brain].
The effects of intraventricular administration of melanostatin (MIF--I, Pro--Ley--Gly--NH2) on the behaviour and electrical activity in neocortex, amygdala, hippocampus and hypothalamus involved an enhancement of electrical activity: MIF enhanced the 3--7/sec high--voltage activity of neocortex, amygdala, hippocampus and the 7--12/sec one of neocortex. Morphine facilitated the effects of MIF whereas preliminary administration of MIF blocked the effect of threshold doses of morphine. After lesion of the central nucleus of amygdala the responsiveness of ipsilateral neocortex disappeared whereas that of hippocampus preserved.


Methods for examining cancer symptom clusters over time.
In this article, we address statistical techniques appropriate for examining longitudinal changes in cancer symptom clusters. When the cluster structure is not pre-determined, researchers may examine symptom clusters either at each time point or use composite scores to examine the symptom clusters across time points. When the cluster structures are pre-determined, the statistical techniques depend on the research assumptions or purposes. Multilevel modeling, generalized estimating equations, latent growth curve modeling, and multivariate repeated-measure analysis of variance are good choices for exploring whole cluster changes over time. Alternately, confirmatory factor analysis and path analysis are appropriate techniques for examining changes in symptom relationships within clusters over time. Each technique is described, with examples and strengths and weaknesses.


Assessing the Continuation of Glucagon-Like Peptide-1 Receptor Agonists When Weight and HBA1C Are Not Reduced.
Background: Glucagon-like peptide-1 agonists (GLP-1) reportedly lower HbA1c and promote weight reduction and improve cardiovascular outcomes. The primary objective of this study was to evaluate the use of GLP-1 agents in patients and changes in HbA1c, weight loss, blood pressure, and lipoid profiles. Methods: Patient information was extracted from a regional Veteran Affairs data mart. Patients were included if they had prescriptions for at least 90 days of a GLP-1 between April 1, 2005, and December 1, 2016, and HbA1Cs and weights at both baseline and within first 15 months of therapy. Blood pressure and lipids were also measured. Pearson's correlation and multiple regression analysis were used. Results: Three hundred twenty-two patients met inclusion criteria. Average HbA1c decreased by 0.81% and weight by 4.4 kg. At 1 year, 160 patients had both weight and HbA1c measured, and of those, 92 (58%) patients had HbA1c reduction of at least 0.5% and 94 (59%) patients had <-2 kg change in weight. Fifty-seven (36%) patients met both of those outcomes. Veterans who met both weight and HbA1c outcomes were slightly, but significantly, older than those who did not meet both. No correlation was found between weight and HbA1c change at each quarter (P > 0.05); however, weight change was correlated with systolic blood pressure change (P = 0.03). Multiple regression for meeting weight and HbA1c target outcomes, and changes at quarters 1-3, all correlated to success at 1 year (P < 0.05). Conclusions: Weight change was independent of HbA1c changes in patients receiving GLP-1s for diabetes control. Weight loss was associated with decreases in systolic BP.


Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.
The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.


Professional socialisation and professional fit: Theoretical approaches to address student learning and teaching in speech-language pathology.
Purpose: The sociocultural and historical context and membership of the speech-language pathology (SLP) profession underpins our norms of practice and our discourses. This context also informs and defines the ways that we practice today, including who we legitimise to enter our profession and why. In this paper, we used theory as a tool to critically explore how this socioculturally constituted knowledge and practice influences how students experience learning in SLP practice placements.Method: We used the theory of Legitimate Peripheral Participation (1991) as a conceptual framework to interpret qualitative data from two separate programs of research that had explored the phenomena of student learning in SLP practice placements.Result: The analysis cast light on how our understanding and expectations of SLP students' learning and competency development in placements is recursive and strongly legitimised in our profession. Students adjust to accommodate the professional knowledges, practices and expectations they encounter in their placements. This facilitates the perpetuation of practices proffered by the majority culture.Conclusion: The use of theory allowed us to explore the phenomena of student learning in placements in a new light, which unmasked new understandings of the longstanding challenge to increase diversity in the SLP community.


Closed-loop control of artificial pancreatic Beta -cell in type 1 diabetes mellitus using model predictive iterative learning control.
A novel combination of iterative learning control (ILC) and model predictive control (MPC), referred to here as model predictive iterative learning control (MPILC), is proposed for glycemic control in type 1 diabetes mellitus. MPILC exploits two key factors: frequent glucose readings made possible by continuous glucose monitoring technology; and the repetitive nature of glucose-meal-insulin dynamics with a 24-h cycle. The proposed algorithm can learn from an individual's lifestyle, allowing the control performance to be improved from day to day. After less than 10 days, the blood glucose concentrations can be kept within a range of 90-170 mg/dL. Generally, control performance under MPILC is better than that under MPC. The proposed methodology is robust to random variations in meal timings within +/-60 min or meal amounts within +/-75% of the nominal value, which validates MPILC's superior robustness compared to run-to-run control. Moreover, to further improve the algorithm's robustness, an automatic scheme for setpoint update that ensures safe convergence is proposed. Furthermore, the proposed method does not require user intervention; hence, the algorithm should be of particular interest for glycemic control in children and adolescents.


Outcomes of inflammatory bowel disease in patients with eosinophil-predominant colonic inflammation.
Inflammatory bowel disease (IBD) is characterised by acute intestinal mucosal inflammation with chronic inflammatory features. Various degrees of mucosal eosinophilia are present along with the typical acute (neutrophil-predominant) inflammation. The effect of intestinal eosinophils on IBD outcomes remains unclear. This is a retrospective study. Archived intestinal mucosal biopsy specimens of treatment-naïve IBD patients were examined by two pathologists. The number of eosinophils per high-power field was counted, and the mucosal inflammation was classified according to the eosinophilic inflammatory patterns. Clinical outcomes during the follow-up period were recorded. 142 treatment-naïve IBD patients were included. Mean age was 39 years. 83% of patients had ulcerative colitis, and median follow-up was 3 years. 41% of patients had disease flare(s) and 24% required hospitalisation. Eosinophil count was not associated with risk of disease flare or hospitalisation. Patients with neutrophil-predominant inflammation (>70% neutrophils) had greater risk of disease flare(s): 27(55%) versus 24(36%) and 7(28%) in patients with mixed and eosinophil-predominant inflammation, respectively (p=0.04). Overall, patients with neutrophil-predominant inflammation were more likely to have a disease flare; HR: 2.49, 95% CI (1.0 to 5.6). Hospitalisation rate was higher in patients with neutrophil-predominant inflammation: 17(35%) compared to 17(19%) in patients with eosinophil-rich inflammation (p=0.04). Kaplan-Meier analysis showed higher flare-free survival in patients with eosinophil-predominant inflammation compared to mixed and neutrophil-predominant inflammation. IBD patients with eosinophil-predominant inflammation phenotype might have reduced risk of disease flares and hospitalisation. Larger prospective studies to assess IBD outcomes in this subpopulation are warranted.


Use of an Automatic Methane Potential Test System for evaluating the biomethane potential of sugarcane bagasse after different treatments.
A multi-channel analyzer was used to evaluate biogas potential of sugarcane bagasse (SCB). The Automatic Methane Potential Test System contained fifteen parallel reactors and the same number of gas flow meters attached to the acquisition system. The set of reactors - gas flow meters gave reproducible results during anaerobic digestion of chemically defined carbon source and the units were used to evaluate the biomethane potential of SCB after different pretreatments, such as treatment with water, acid, acid followed by enzymatic treatment and acid followed by treatment with inactive enzymes. Combined pretreatment with 2% sulphuric acid and enzymatic hydrolysis (3.5% enzymes) resulted in conversion of 79% to monomeric sugars present in SCB. SCB treated with acid followed by enzymatic hydrolysis achieved the methane yield of 200 NL per kg VS(added). Enzymatic saccharification of acid pretreated SCB resulted in increase of methane yield by 16±5% compared to that from acid treated SCB.


Epidemiological causality.
Epidemiological methods, which combine population thinking and group comparisons, can primarily identify causes of disease in populations. There is therefore a tension between our intuitive notion of a cause, which we want to be deterministic and invariant at the individual level, and the epidemiological notion of causes, which are invariant only at the population level. Epidemiologists have given heretofore a pragmatic solution to this tension. Causal inference in epidemiology consists in checking the logical coherence of a causality statement and determining whether what has been found grossly contradicts what we think we already know: how strong is the association? Is there a dose-response relationship? Does the cause precede the effect? Is the effect biologically plausible? Etc. This approach to causal inference can be traced back to the English philosophers David Hume and John Stuart Mill. On the other hand, the mode of establishing causality, devised by Jakob Henle and Robert Koch, which has been fruitful in bacteriology, requires that in every instance the effect invariably follows the cause (e.g., inoculation of Koch bacillus and tuberculosis). This is incompatible with epidemiological causality which has to deal with probabilistic effects (e.g., smoking and lung cancer), and is therefore invariant only for the population.


(Oligo-)Thiophene Functionalized Tetraazaperopyrenes: Donor-Acceptor Dyes and Ambipolar Organic Semiconductors.
Tetraazaperopyrenes (TAPPs) have been functionalized with thiophene and terthiophene units of different architecture resulting in a variety of organic donor-acceptor (D-A) compounds. The influence of the connection of the thiophenes to the TAPP core on their structural, photophysical and electrochemical properties has been studied in detail by a combination of X-ray crystallography, UV-vis and fluorescence spectroscopy as well as cyclic voltammetry, which allowed the establishment of structure-property relationships. The HOMO-LUMO gap is significantly decreased upon substitution of the TAPP core with electron-donating thiophene units, the extent of which is strongly influenced by the orientation of the thiophene units. The latter also crucially directs the molecular packing in the solid. Linkage at the α-position allows both inter- and intramolecular N···S interaction, whereas linkage in the β-position prevents intramolecular N···S interaction, resulting in a less pronounced conjugation of the TAPP core and the thiophene units. The new TAPP derivatives were processed as semiconductors in organic thin-film transistors (TFTs) that show ambipolar behavior. The insight into band gap and structure engineering may open up new possibilities to tailor the electronic properties of TAPP-based materials for certain desired applications.


Transcriptional inactivation of c-myc and the transferrin receptor in dibutyryl cyclic AMP-treated HL-60 cells.
Treatment of HL-60 cells with dibutyryl cyclic AMP induced rapid transcriptional inactivation of c-myc and the transferrin receptor. Transcriptional inactivation was followed by loss of c-myc and transferrin receptor mRNA and protein. Treated cells completed one round of proliferation, followed by growth arrest, G1 synchronization, and monocytic differentiation. These data suggest that cyclic AMP-mediated control of growth and differentiation may be achieved, at least in part, by transcriptional regulation of certain growth-associated proto-oncogenes and growth factor receptor genes.


Swelling and mechanical properties of hydrogels composed of binary blends of inter-linked pH-responsive microgel particles.
We show that a new type of hydrogel can be prepared by covalently inter-linking binary blends of microgel (MG) particles and that the swelling ratio and modulus of the gels can be predicted from their composition. In previous work we established that physical gels of glycidyl methacrylate (GMA) functionalised poly(methyl methacrylate-co-methacrylic acid-co-ethyleneglycol dimethacrylate) microgel particles (GMA-MG) could be covalently inter-linked to give hydrogels, termed doubly crosslinked microgels, DX MGs. We build on this concept here by investigating the properties of DX MGs containing binary blends of GMA-MG particles and glycidyl oligo(ether ester) acrylate-functionalised microgel particles (GOE-MG). These new hydrogels were assembled by inter-linking nanoscale MG building blocks in the absence of small molecule monomers or crosslinkers. The volume fraction of GMA-MG particles used to prepare the GOE-GMA DX MGs was systematically varied. Rheology data showed that inclusion of GMA-MG and GOE-MG within the GOE-GMA DX MGs increased the modulus and yield strain, respectively, compared to the values measured for the respective physical gels. The data for the covalent GOE-GMA DX MG gels showed that the ductility increased with increasing GOE-MG content. GOE provided covalent inter-linking of the MG particles and also acted as a lubricant between particles due to its low Tg. By demonstrating compositionally determined swelling and mechanical properties for DX MG gels prepared using binary blends of MG particles, this study introduces a new, widely applicable, hydrogel construction assembly concept that is not available for conventional hydrogels.


Changes in serum triiodothyronine, thyroxine, and thyrotropin during treatment with thyroxine in severe primary hypothyroidism.
Studies were performed on 40 patients with severe primary hypothyroidism, during treatment with varying doses of T4. Therapy was initiated with 50 mug/day and was continued for at least 2 months. Subsequent repeated increases of 25 mug/day were continued for at least 2 months until the serum TSH level was less than 10 muU/ml. Measurements of serum T4 and T3, RT3U, and serum TSH were carried out at monthly intervals. TRH tests were performed after TSH levels of less than 10 muU/ml had been attained and the dose of T4 had been maintained for at least 2 months. In most of the samples obtained during treatment with various doses of T4 (50-175 mug/day), serum T4 concentrations were within the normal range, even when patients were receiving only 50 mug/day of T4; however, approximately 60% of the samples had subnormal T3 concentrations. Fifty per cent of the samples had elevated TSH concentrations despite normal T4 levels, while only 7% of the samples with normal T3, as well as T4, levels had slightly elevated TSH concentrations. Similar relationships were observed between serum TSH and free T4 indices and free T3 indices. Among patients with serum TSH levels of less than 10 muU/ml, none showed subnormal T4 concentrations, while subnormal T3 concentrations were found in some of them. Hyper-response to TRH was noted in patients with subnormal T3 levels, and normal responses were observed in patients with normal T3 and T4 concentrations. These data indicate that, during the treatment of hypothyroidism with T4, 1) normal basal TSH correlates better with normal serum T4 and T3 than with normal T4 alone, 2) the response of TSH to TRH is supranormal in patients with subnormal T3 levels, in spite of normal basal TSH and T4, and 3) the calculated maintenance dose of T4, which is associated with a normal TRH response, is 2.08 mug/day/kg of body weight.


Short screening tools for cancer-related distress: a review and diagnostic validity meta-analysis.
Clinicians are increasingly seeking efficient methods to identify distress in cancer settings, using short screening tools with fewer than 14 items that take less than 5 minutes to complete. This article examines the value of these tools for identifying cancer-related distress, defined by semi-structured interview. An updated search, appraisal, and meta-analysis, with adjustments made for heterogeneity and underlying prevalence variations, identified 45 potentially useful short and ultra-short tools, although most were intended to help diagnose depression, with few targeted at distress (or anxiety). Very few studies attempted robust validation in cancer settings. When studies were limited to those tested against distress defined by semi-structured interview, only 6 methods had been validated, namely the Hospital Anxiety and Depression Scale (HADS; 13 studies, 14 items), the Distress Thermometer (DT; 4 studies, 1 item), a single verbal question (4 studies, 1 item), the Psychological Distress Inventory (PDI; 1 study, 13 items), combined DT and an impact thermometer (1 study, 2 items), and combined 2 verbal questions (1 study, 2 items). Comparing these 6 approaches side-by-side suggests that for screening, all tools have approximately the same accuracy. Therefore, choice of a short screening tool for distress can be based on acceptability or cost-effectiveness. Here, best evidence supports use of the DT or single verbal question. Remarkably, the overall accuracy of these single-item approaches seems comparable to that of the 14-item HADS (total score), whereas their efficiency is superior. For case-finding, data are sparse but no method seems to be entirely satisfactory. Current evidence suggests that the optimal short methods for identifying distress are 2 verbal questions or PDI. Of these approaches, the 2 verbal questions has superior efficiency. All short methods may be augmented by repeated application, an assessment of unmet needs (problem list), and clarification regarding the need for professional help. No screening tool should be seen as an alternative to careful clinical assessment and management. Despite much interest in the development of short and ultra-short tools, data on validation and implementation are currently incomplete. Nevertheless, short methods seem to be at least as successful as the HADS, although substantially more efficient and hence more acceptable, and therefore may be a suitable initial method of assessment in busy clinical settings.


CT for evaluation of myocardial cell therapy in heart failure: a comparison with CMR imaging.
The aim of this study was to use multidetector computed tomography (MDCT) to assess therapeutic effects of myocardial regenerative cell therapies. Cell transplantation is being widely investigated as a potential therapy in heart failure. Noninvasive imaging techniques are frequently used to investigate therapeutic effects of cell therapies in the preclinical and clinical settings. Previous studies have shown that cardiac MDCT can accurately quantify myocardial scar tissue and determine left ventricular (LV) volumes and ejection fraction (LVEF). Twenty-two minipigs were randomized to intramyocardial injection of phosphate-buffered saline (placebo, n = 9) or 200 million mesenchymal stem cells (MSC, n = 13) 12 weeks after myocardial infarction (MI). Cardiac magnetic resonance and MDCT acquisitions were performed before randomization (12 weeks after MI induction) and at the study endpoint 24 weeks after MI induction. None of the animals received medication to control the intrinsic heart rate during first-pass acquisitions for assessment of LV volumes and LVEF. Delayed-enhancement MDCT imaging was performed 10 min after contrast delivery. Two blinded observers analyzed MDCT acquisitions. MDCT demonstrated that MSC therapy resulted in a reduction of infarct size from 14.3 ± 1.2% to 10.3 ± 1.5% of LV mass (p = 0.005), whereas infarct size increased in nontreated animals (from 13.8 ± 1.3% to 16.5 ± 1.5%; p = 0.02) (placebo vs. MSC; p = 0.003). Both observers had excellent agreement for infarct size (r = 0.96; p < 0.001). LVEF increased from 32.6 ± 2.2% to 36.9 ± 2.7% in MSC-treated animals (p = 0.03) and decreased in placebo animals (from 33.3 ± 1.4% to 29.1 ± 1.5%; p = 0.01; at week 24: placebo vs. MSC; p = 0.02). Infarct size, end-diastolic LV volume, and LVEF assessed by MDCT compared favorably with those assessed by cardiac magnetic resonance acquisitions (r = 0.70, r = 0.82, and r = 0.902, respectively; p < 0.001). This study demonstrated that cardiac MDCT can be used to evaluate infarct size, LV volumes, and LVEF after intramyocardial-delivered MSC therapy. These findings support the use of cardiac MDCT in preclinical and clinical studies for novel myocardial therapies.


Subclinical hyperthyroidism impacts left ventricular deformation: 2D and 3D echocardiographic study.
We sought to investigate left ventricular (LV) function and mechanics assessed by three-dimensional echocardiography (3DE) and speckle tracking in patients with subclinical hyperthyroidism (SCH). We included 35 untreated women with SCH and 35 healthy control women matched by age. All participants underwent laboratory analyses which included thyroid hormone levels, and complete 2DE and 3DE examination. 2DE LV longitudinal and circumferential strain was significantly decreased in the SCH subjects. 2DE LV systolic and early diastolic strain rates in longitudinal and circumferential directions were reduced, whereas late diastolic strain rates were increased in SCH individuals. 3DE LV end-diastolic volume and cardiac output were significantly elevated in the SCH patients. 3DE LV deformation in all three directions, as well as 3DE area strain, were significantly lower in the SCH group. Serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels correlated with 2DE LV mass index, 2DE longitudinal strain, and 3DE LV area strain in the whole study population. LV deformation evaluated by 3DE and speckle tracking imaging are significantly impaired in SCH subjects. TSH and FT4 levels correlate with 2DE and 3DE LV structure and mechanics.


Hydrogen Sulfide in Renal Physiology and Disease.
Hydrogen sulfide (H2S) has only recently gained recognition for its physiological effects. It is synthesized widely in the mammalian tissues and regulates several biologic processes ranging from development, angiogenesis, neurotransmission to protein synthesis. Recent Advances: The aim of this review is to critically evaluate the evidence for a role for H2S in kidney function and disease. H2S regulates fundamental kidney physiologic processes such as glomerular filtration and sodium reabsorption. In kidney disease states H2S appears to play a complex role in a context-dependent manner. In some disease states such as ischemia-reperfusion and diabetic kidney disease it can serve as an agent that ameliorates kidney injury. In other diseases such as cis-platinum-induced kidney disease it may mediate kidney injury although more investigation is needed. Recent studies have revealed that the actions of nitric oxide and H2S may be integrated in kidney cells. Further studies are needed to understand the full impact of H2S on kidney physiology. As it is endowed with the properties of regulating blood flow, oxidative stress, and inflammation, H2S should be investigated for its role in inflammatory and toxic diseases of the kidney. Such in-depth exploration may identify specific kidney diseases in which H2S may constitute a unique target for therapeutic intervention. Antioxid. Redox Signal. 25, 720-731.


Isolation and characterisation of an extracellular alkaline protease of Aspergillus fumigatus.
Aspergillus fumigatus secreted an inducible alkaline protease (AlPase) when cultivated in the presence of collagen (200 micrograms/ml) as sole nitrogen and carbon source. Proteolytic activity was maximum at pH 9.0 with azocollagen as substrate. The enzyme, which was the major protein found in the supernate of a liquid culture, was purified by ammonium sulphate precipitation and gel filtration. The Mr was determined to be 33 Kda by gel filtration and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The isoelectric point was estimated to be pH 8.2. Divalent cations strongly inhibited enzyme activity, whereas non-ionic detergents and reducing agents had no effect. A. fumigatus AlPase was totally inhibited by phenylmethanesulphonyl fluoride, antipain, chymostatin and alpha-2-macroglobulin. A. fumigatus AlPase is closely related to the A. oryzae AlPase, a serine protease of the subtilisin family, as attested by the antigen pattern seen by immunoblotting. The high collagenic activity and the ability of A. fumigatus AlPase to digest elastin could play a role in the invasion of the tissues by the fungus.


Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents.
Numerous questions surround the nature of reward processing in the developing adolescent brain, particularly in regard to polysubstance use. We therefore sought to examine incentive-elicited brain activation in the context of three common substances of abuse (cannabis, tobacco, and alcohol). Due to the role of the nucleus accumbens (NAcc) in incentive processing, we compared activation in this region during anticipation of reward and loss using a monetary incentive delay (MID) task. Adolescents (ages 14-18; 66% male) were matched on age, gender, and frequency of use of any common substances within six distinct groups: cannabis-only (n=14), tobacco-only (n=34), alcohol-only (n=12), cannabis+tobacco (n=17), cannabis+tobacco+alcohol (n=17), and non-using controls (n=38). All groups showed comparable behavioral performance on the MID task. The tobacco-only group showed decreased bilateral nucleus accumbens (NAcc) activation during reward anticipation as compared to the alcohol-only group, the control group, and both polysubstance groups. Interestingly, no differences emerged between the cannabis-only group and any of the other groups. Results from this study suggest that youth who tend toward single-substance tobacco use may possess behavioral and/or neurobiological characteristics that differentiate them from both their substance-using and non-substance-using peers.


Australian Community and Health Professionals Perceptions of Equine-Assisted Psychotherapy.
Mental health conditions are increasingly prevalent in the Australian population, and despite the large evidence-based support for contemporary treatments, there are barriers which inhibit their efficacy. Thus, there is a perceived need for therapists to consider other therapeutic options which have potential to enhance treatment outcomes. There is increasing acceptance for complementary and alternative medicines (CAM) among general practitioners and clients/general community. Specifically, more than 70% of Australians utilize CAM. Equine-assisted psychotherapy (EAP) is an underutilized, culturally sensitive, complementary therapy, which has the potential to mitigate barriers of conventional therapy. The present study aimed to determine the level of knowledge about and general acceptance of EAP as a treatment for general psychopathology symptomology within community members and health professionals. The current sample included 144 community members and 55 health professionals, all with Australian citizenship. Data analysis comprised the independent t-test and two hierarchical multiple regressions. Results indicated that community members are significantly more accepting of EAP as a treatment compared to health professionals. Of the predictors tested, higher social support and openness within community members were significant predictors of accepting perceptions, and rural location was the only significant predictor for health professional's accepting perceptions of EAP. This is one of the first studies to investigate perceptions of EAP outside the EAP field and through comparison between community members and health professionals. The current study identifies the need for future research to further investigate perceptions of EAP among Australian health professionals.


Disparities in survival after female breast cancer diagnosis: a population-based study.
Despite advances in treatment and increased screening, female breast cancer survival is affected by race, ethnicity, and socioeconomic status (SES). The purpose of this study was to substantiate disparities in breast cancer mortality in a large and unique dataset containing 7 distinct racial groups, 31 comorbidities, demographic and clinical/pathological patient characteristics, and neighborhood poverty information. Florida Cancer Data System registry (1996-2007) linked with the Agency for Health Care Administration and U.S. Census tract (n = 127,754) explored median survival and 1-, 3-, and 5-year survival rates by the Kaplan-Meier method. Log-rank tests compared survival curves by race/ethnicity/SES. Cox proportional hazards regression models were used to obtain unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals. Native Americans had the lowest median survival (7.4 years) and Asians had the highest (12.6 years). For the univariate analysis, worse survival was seen for blacks (HR = 1.44; p < 0.001) and better survival for Asians (HR = 0.71; p < 0.001), Asian Indians or Pakistanis (HR = 0.65; p = 0.013), and Hispanics (HR = 0.92; p < 0.001). Multivariate analysis demonstrated sustained survival detriment for blacks (HR = 1.28; p < 0.001) and improved survival for Hispanics (HR = 0.90; p = 0.001). For SES, there was an incremental improvement in survival for each higher SES category in all analyses (p < 0.001). Utilizing a large enriched state cancer registry controlling for multiple demographic, clinical, and comorbidities, we fully explored survival disparities in female breast cancer and found certain aspects of race, ethnicity, and SES to remain significantly associated with breast cancer survival. More research is needed to uncover the source of these ongoing disparities.


Beluga whale and bottlenose dolphin ACE2 proteins allow cell entry mediated by spike protein from three variants of SARS-CoV-2.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses infect numerous non-human species. Spillover of SARS-CoV-2 into novel animal reservoirs may present a danger to host individuals of these species, particularly worrisome in populations already endangered or threatened by extinction. In addition, emergence in new reservoirs could pose spillback threats to humans, especially in the form of virus variants that further mutate when infecting other animal hosts. Previous work suggests beluga whales (Delphinapterus leucas) and bottlenose dolphins (Tursiops truncatus) may be at risk owing to their formation of social groups, contact with humans, exposure to contaminated wastewater, and structure of their angiotensin-converting enzyme 2 (ACE2) proteins, which SARS-CoV-2 uses as a cellular receptor. We examined marine-mammal susceptibility to virus infection by challenging 293T cells expressing beluga or dolphin ACE2 with pseudovirions bearing the SARS-CoV-2 spike protein. Beluga and dolphin ACE2 were sufficient to allow cell entry by an early pandemic isolate (Wuhan-Hu-1) and two evolved variants (Delta B.1.617.2 and Omicron BA.1 strains). We conclude that SARS-CoV-2 poses a potential threat to marine mammal reservoirs that should be considered in surveillance efforts.


Downstaging therapy followed by liver transplantation for hepatocellular carcinoma beyond Milan criteria.
Orthotopic liver transplantation is a curative treatment for hepatocellular carcinoma within Milan criteria, but these criteria preclude many patients from transplant candidacy. Recent studies have demonstrated that downstaging therapy can reduce tumor burden to meet conventional criteria. The present study reports a single-center experience with tumor downstaging and its effects on post-orthotopic liver transplantation outcomes. All patients with hepatocellular carcinoma who were evaluated by our multidisciplinary liver services team from 2012 to 2016 were identified (N = 214). Orthotopic liver transplantation candidates presenting outside of Milan criteria at initial radiographic diagnosis and/or an initial alpha-fetoprotein >400 ng/mL were categorized as at high risk for tumor recurrence and post-transplant mortality. Of the 214 patients newly diagnosed with hepatocellular carcinoma, 73 (34.1%) eventually underwent orthotopic liver transplantation. The majority of patients who did not undergo orthotopic liver transplantation were deceased or lost to follow-up (47.5%), with 14 of 141 (9.9%) currently listed for transplantation. Among transplanted patients, 21 of 73 (28.8%) were considered high-risk candidates. All 21 patients were downstaged to within Milan criteria with an alpha-fetoprotein <400 ng/mL before orthotopic liver transplantation, through locoregional therapies. Recurrence of hepatocellular carcinoma was higher but acceptable between downstaged high-risk and traditional candidates (9.5% vs 1.9%; P > .05) at a median follow-up period of 17 months. Downstaged high-risk candidates had a similar overall survival compared with those transplanted within Milan criteria (log-rank P > .05). In highly selected cases, patients with hepatocellular carcinoma outside of traditional criteria for orthotopic liver transplantation may undergo downstaging therapy in a multidisciplinary fashion with excellent post-transplant outcomes. These data support an aggressive downstaging approach for selected patients who would otherwise be deemed ineligible for transplantation.


Native or Proteolytically Activated NanI Sialidase Enhances the Binding and Cytotoxic Activity of Clostridium perfringens Enterotoxin and Beta Toxin.
Many Clostridium perfringens strains produce NanI as their major sialidase. Previous studies showed that NanI could potentiate C. perfringens epsilon toxin cytotoxicity by enhancing the binding of this toxin to host cells. The present study first determined that NanI exerts similar cytotoxicity-enhancing effects on C. perfringens enterotoxin and beta toxin, which are also important toxins for C. perfringens diseases (enteritis and enterotoxemia) originating in the gastrointestinal (GI) tract. Building upon previous work demonstrating that purified trypsin can activate NanI activity, this study next determined that purified chymotrypsin or mouse intestinal fluids can also activate NanI activity. Amino acid sequencing then showed that this effect involves the N-terminal processing of the NanI protein. Recombinant NanI (rNanI) species corresponding to major chymotrypsin- or small intestinal fluid-generated NanI fragments possessed more sialidase activity than did full-length rNanI, further supporting the proteolytic activation of NanI activity. rNanI species corresponding to proteolysis products also promoted the cytotoxic activity and binding of enterotoxin and beta toxin more strongly than did full-length rNanI. Since enterotoxin and beta toxin are produced in the intestines during human and animal disease, these findings suggest that intestinal proteases may enhance NanI activity, which in turn could further potentiate the activity of intestinally active toxins during disease. Coupling these new results with previous findings demonstrating that NanI is important for the adherence of C. perfringens to enterocyte-like cells, NanI sialidase is now emerging as a potential auxiliary virulence factor for C. perfringens enteritis and enterotoxemia.


Nitrogen washout and mortality.
We studied the association between different tests of pulmonary function and subsequent mortality. Subjects were drawn from an epidemiology study of chronic obstructive pulmonary disease. Between 1971 and 1976, 2,539 nonpatient adults had tests of forced expiration, diffusing capacity, and single-breath nitrogen washout. By 1981, 115 of those subjects had died, including 3 from known lung disease. In assessing the relationship between lung function and mortality, the following tests of pulmonary function were examined: forced expiratory volume in one second as a percentage of forced vital capacity, forced expiratory volume divided by height cubed, slope of phase III from the single-breath nitrogen test, closing capacity, diffusing capacity for CO, and the ratio of maximal flow at 75% to that at 25% vital capacity. When adjustments for age and smoking were made, slope of phase III was strongly associated with mortality, even more so than tests of forced expiration. There are two possible explanations for this striking relationship between these observed abnormalities of lung function and subsequent overall mortality (which is largely from nonpulmonary disease): the lungs may serve to protect other systems of the body and therefore poor pulmonary function may contribute to a number of diseases leading to death, or lung function may merely reflect existing disorders in other systems of the body, and the observed association between mortality and pulmonary function is a byproduct of nonpulmonary diseases.


Hospital stay for healthy term newborns.
The hospital stay of the mother and her healthy term newborn infant should be long enough to allow identification of early problems and to ensure that the family is able and prepared to care for the infant at home. The length of stay should also accommodate the unique characteristics of each mother-infant dyad, including the health of the mother, the health and stability of the infant, the ability and confidence of the mother to care for her infant, the adequacy of support systems at home, and access to appropriate follow-up care. Input from the mother and her obstetrician should be considered before a decision to discharge a newborn is made, and all efforts should be made to keep mothers and infants together to promote simultaneous discharge.


Mental Health and Wellbeing of Retired Elite and Amateur Rugby Players and Non-contact Athletes and Associations with Sports-Related Concussion: The UK Rugby Health Project.
Concerns have intensified over the health and wellbeing of rugby union and league players, and, in particular, about the longer-term effects of concussion. The purpose of this study was to investigate whether there were differences in mental health, sleep and alcohol use between retired elite and amateur rugby code players and non-contact athletes, and to explore associations with sports-related concussion. 189 retired elite (ER, n = 83) and amateur (AR, n = 106) rugby code players (rugby union n = 145; rugby league n = 44) and 65 former non-contact athletes (NC) were recruited to the UK Rugby Health Project between 2016 and 2018. Details on sports participation and concussion history were obtained by questionnaire, which also included questions on mental health, anger, sleep, mood, alcohol use, social connections and retirement from injury. Data were compared between sports groups (ER, AR and NC), between exposure of three or more or five or more concussions and for years in sport. ER reported more concussions than AR (5.9 ± 6.3 vs. 3.7 ± 6.3, p = 0.022) and NC (0.4 ± 1.0, p < 0.001). ER had a higher overall negative mental health score (indicating poor mental health) than AR (10.4 ± 6.3 vs. 7.4 ± 6.5, d = 0.47, p = 0.003) and NC (7.1 ± 4.8, d = 0.57, p = 0.006) and a lower overall positive score (indicating good mental health) than NC (8.9 ± 4.1 vs. 10.7 ± 3.4, d = 0.46, p = 0.021). Negative scores were highest and positive scores lowest in those reporting three or more concussions (d = 0.36, p = 0.008; d = 0.28, p = 0.040, respectively) or five or more concussions (d = 0.56, p < 0.001; d = 0.325, p = 0.035, respectively). Reported symptoms for sleep disruption were more prevalent in ER than NC, and in former athletes with three or more concussions (d = 0.41-0.605, p < 0.05). There were no significant differences in alcohol score (p = 0.733). Global anger score and covert anger expression was higher in former athletes with five or more concussions (d = 0.32, p = 0.035; d = 0.37, p = 0.016). AR reported greater attachment to friends than NC (d = 0.46, p = 0.033) and 20% of ER reported that they would not turn to anyone if they had a problem or felt upset about anything. There was a significantly higher prevalence of adverse mental health and sleep disruption in ER and in former athletes who reported a higher number of concussions. Anger and irritability were more prevalent in former athletes with a history of five or more concussions. Strategies are needed to address mental health and sleep disturbance in elite rugby code athletes, who are also less likely to seek help should they need it. Further research is needed to elucidate causation, and the neurobiological connection between concussion, sub-concussions and longer-term psychological health and wellbeing.


Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte.
The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumours), is mainly because of the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non-tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to-epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. In particular, we will focus on hepatocyte and describe the pivotal role in the control of EMT/MET dynamics exerted by a tissue-specific molecular mini-circuitry. Recent evidence, indeed, highlighted as two transcriptional factors, the master gene of EMT Snail, and the master gene of hepatocyte differentiation HNF4α, exhorting a direct reciprocal repression, act as pivotal elements in determining opposite cellular outcomes. The different balances between these two master regulators, further integrated by specific microRNAs, in fact, were found responsible for the EMT/METs dynamics as well as for the preservation of both hepatocyte and stem/precursor cells identity and differentiation. Overall, these findings impact the maintenance of stem cells and differentiated cells both in in vivo EMT/MET physio-pathological processes as well as in culture.


Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin's lymphoma: a meta-analysis.
The prevalence and prognostic significance of Epstein-Barr virus (EBV) infection in classical Hodgkin's lymphomas (cHLs) remain elusive. To examine the epidemiological and prognostic differences between EBV-positive and -negative cHLs, we conducted a meta-analysis of 119 published studies including 13,045 cases. We pooled the results of relevant published studies identified using the PubMed and Embase. The effect sizes of outcome parameters were calculated by prevalence, odds ratio (OR), or hazard ratio using a random-effects model. The pooled prevalence of EBV infection in cHL was 47.9%, which was significantly higher in Africa and Central and South America than other regions. EBV-positive cHL showed higher incidence in children than in adults (69.7 vs. 41.1%). EBV-positive cHL was significantly related to male (OR = 1.8, 95% CI: 1.510-2.038; p <0.001), mixed cellularity subtype (OR = 3.8, 95% CI: 3.243-4.451; p <0.001), and advanced clinical stages (OR = 1.2, 95% CI: 1.072-1.369; p = 0.002). However, the presence of EBV in cHL was not associated with overall or event-free survival. The prevalence of EBV differs according to age, sex, region, histologic subtype, and clinical stage of cHL. However, the presence of EBV has little effects on cHL patient's survival.


Role of cytokines and nitric oxide in the induction of tuberculostatic macrophage functions.
The aim of this study was to determine phenotypic differences when BCG invades macrophages. Bacilli prepared from the same BCG primary seed, but produced in different culture media, were analysed with respect to the ability to stimulate macrophages and the susceptibility to treatment with cytokines and nitric oxide (NO). Tumour necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) were assayed by enzyme-linked immunosorbent assay (ELISA), whereas NO levels were detected by Griess colorimetric reactions in the culture supernatant of macrophages incubated with IFN-gamma, TNF or NO and subsequently exposed to either BCG-I or BCG-S. We found that BCG-I and BCG-S bacilli showed different ability to simulate peritoneal macrophages. Similar levels of IL-6 were detected in stimulated macrophages with lysate from two BCG samples. The highest levels of TNF and IFN-gamma were observed in macrophages treated with BCG-S and BCG-I, respectively. The highest levels of NO were observed in cultures stimulated for 48 h with BCG-S. We also found a different susceptibility of the bacilli to exogenous treatment with IFN-gamma and TNF which were capable of killing 60 and 70% of both bacilli, whereas NO was capable of killing about 98 and 47% of BCG-I and BCG-S, respectively. The amount of bacilli proportionally decreased with IFN-gamma and TNF, suggesting a cytokine-related cytotoxic effect. Moreover, NO also decreased the viable number of bacilli. Interestingly, NO levels of peritoneal macrophages were significantly increased after cytokine treatment. This indicates that the treatment of macrophages with cytokines markedly reduced bacilli number and presented effects on NO production. The results obtained here emphasize the importance of adequate stimulation for guaranteeing efficient killing of bacilli. In this particular case, the IFN-gamma and TNF were involved in the activation of macrophage bactericidal activity.


Depiction of Physiological Homeostasis by Self-Coupled System and Its Significance.
The negative feedback system (NFS) was regarded as the basic unit of regulation of physiological homeostasis for more than 70 years. However, NFS-based depiction possesses some limitations. The self-coupled system (SCS), a non-stop system in which the output of the current moment becomes the input of the next moment, can also be utilized to depict homeostasis. In SCS-based depiction, all of the related regulatory mechanisms of a homeostasis are regarded as an entity. Then, homeostatic dynamics can be expressed by simple mathematical language. A new disease group was revealed and some useful inferences were obtained through mathematical deduction. They were supported by published studies. SCS-based depiction of homeostasis should be a requisite supplement to medical knowledge systems based on NFS.


Interactions of hairpin oligo-2'-O-methylribonucleotides containing methylphosphonate linkages with HIV TAR RNA.
Methylphosphonate-modified oligo-2'-O-methylribonucleotides 15-20 nucleotides (nt) in length were prepared whose sequences are complementary to the 5' and 3' sides of the upper hairpin of HIV trans-acting response element (TAR) RNA. These anti-TAR oligonucleotides (ODNs) form stable hairpins whose melting temperatures (Tm) range from 55 degrees C to 80 degrees C. Despite their rather high thermal stabilities, the hairpin oligo-2'-O-methylribonucleotides formed very stable complexes with TAR RNA, with dissociation constants in the nanomolar concentration range at 37 degrees C. The affinities of the hairpin oligomers for TAR RNA were influenced by the positions of the methylphosphonate linkages. The binding affinity was reduced approximately 17-fold by the presence of two methylphosphonate linkages in the TAR loop complementary region (TLCR) of the oligomer, whereas methylphosphonate linkages outside this region increased binding affinity approximately 3-fold. The configurations of the methylphosphonate linkages in the TLCR also affected binding affinity, with the RpRp isomer showing significantly higher binding than the SpSp isomer. In addition to serving as probes of the interactions between the oligomer and TAR RNA, the presence of the methylphosphonate linkages in combination with the hairpin structure increases the resistance of these oligomers to degradation by exonucleases found in mammalian serum. The combination of high binding affinity and nuclease resistance of the hairpin ODNs containing methylphosphonate linkages suggests their potential utility as antisense compounds.


Hydrogen production by water dissociation in surface-modified BaCo(x)Fe(y)Zr(1-x-y)O(3-delta) hollow-fiber membrane reactor with improved oxygen permeation.
A porous perovskite BaCo(x)Fe(y)Zr(0.9-x-y)Pd(0.1)O(3-delta) (BCFZ-Pd) coating was deposited onto the outer surface of a BaCo(x)Fe(y)Zr(1-x-y)O(3-delta) (BCFZ) perovskite hollow-fiber membrane. The surface morphology of the modified BCFZ fiber was characterized by scanning electron microscopy (SEM), indicating the formation of a BCFZ-Pd porous layer on the outer surface of a dense BCFZ hollow-fiber membrane. The oxygen permeation flux of the BCFZ membrane with a BCFZ-Pd porous layer increased 3.5 times more than that of the blank BCFZ membrane when feeding reactive CH(4) onto the permeation side of the membrane. The blank BCFZ membrane and surface-modified BCFZ membrane were used as reactors to shift the equilibrium of thermal water dissociation for hydrogen production because they allow the selective removal of the produced oxygen from the water dissociation system. It was found that the hydrogen production rate increased from 0.7 to 2.1 mL H(2) min(-1) cm(-2) at 950 degrees C after depositing a BCFZ-Pd porous layer onto the BCFZ membrane.


Modelling the dynamics of the yeast pheromone pathway.
We present a mathematical model of the dynamics of the pheromone pathways in haploid yeast cells of mating type MATa after stimulation with pheromone alpha-factor. The model consists of a set of differential equations and describes the dynamics of signal transduction from the receptor via several steps, including a G protein and a scaffold MAP kinase cascade, up to changes in the gene expression after pheromone stimulation in terms of biochemical changes (complex formations, phosphorylations, etc.). The parameters entering the models have been taken from the literature or adapted to observed time courses or behaviour. Using this model we can follow the time course of the various complex formation processes and of the phosphorylation states of the proteins involved. Furthermore, we can explain the phenotype of more than a dozen well-characterized mutants and also the graded response of yeast cells to varying concentrations of the stimulating pheromone.


Mechanical characteristics and energy evolution of rock with circular hole defects.
In this paper, the uniaxial compression damage characteristics of specimens are analyzed containing holes using PFC2D. In addition, the crack propagation, stress distribution and energy development characteristics of the specimens were systematically discussed. The findings indicate that the strength parameters of various specimens drop initially and then increase with increasing center point connecting angle, in comparison to intact rock. The most significant reduction in strength parameters is observed at a center point connecting angle of 45°. The stress concentration around the holes occurs prior to crack initiation and vanishes upon specimen failure. The number of cracks in the specimens is small and the propagation length is short before touching the peak value, while the cracks expand rapidly in a short period of time after the stress touches the peak value, and the crack development rules in the two stages are quite different. With increasing center point connecting angle, the pre-peak energy and total energy drop first and then increase. After touching the peak value, the specimen is dominated by energy release and the ability to absorb energy is weakened. In the case of center point connecting angle of 45°, the specimen has the largest energy difference coefficient and the worst ability to resist damage. The damage behavior can be composed of no damage, initial damage and accelerated damage take into account the damage change rules of the specimens.


Basic residues within the ebolavirus VP35 protein are required for its viral polymerase cofactor function.
The ebolavirus (EBOV) VP35 protein binds to double-stranded RNA (dsRNA), inhibits host alpha/beta interferon (IFN-α/β) production, and is an essential component of the viral polymerase complex. Structural studies of the VP35 C-terminal IFN inhibitory domain (IID) identified specific structural features, including a central basic patch and a hydrophobic pocket, that are important for dsRNA binding and IFN inhibition. Several other conserved basic residues bordering the central basic patch and a separate cluster of basic residues, called the first basic patch, were also identified. Functional analysis of alanine substitution mutants indicates that basic residues outside the central basic patch are not required for dsRNA binding or for IFN inhibition. However, minigenome assays, which assess viral RNA polymerase complex function, identified these other basic residues to be critical for viral RNA synthesis. Of these, a subset located within the first basic patch is important for VP35-nucleoprotein (NP) interaction, as evidenced by the inability of alanine substitution mutants to coimmunoprecipitate with NP. Therefore, first basic patch residues are likely critical for replication complex formation through interactions with NP. Coimmunoprecipitation studies further demonstrate that the VP35 IID is sufficient to interact with NP and that dsRNA can modulate VP35 IID interactions with NP. Other basic residue mutations that disrupt the VP35 polymerase cofactor function do not affect interaction with NP or with the amino terminus of the viral polymerase. Collectively, these results highlight the importance of conserved basic residues from the EBOV VP35 C-terminal IID and validate the VP35 IID as a potential therapeutic target.


Nucleolin is a protein kinase C-zeta substrate. Connection between cell surface signaling and nucleus in PC12 cells.
We have previously shown that protein kinase C (PKC)-zeta is activated and required for nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma PC12 cells (Wooten, M. W., Zhou, G., Seibenhener, M. L., and Coleman, E. S. (1994) Cell Growth & Diff. 5, 395-403; Coleman, E. S., and Wooten, M. W. (1994) J. Mol. Neurosci. 5, 39-57). Here we report the characterization and identification of a 106-kDa nuclear protein as a specific substrate of PKC-zeta. NGF treatment of PC12 cells resulted in translocation of PKC-zeta and coincident phosphorylation of a protein that was localized within the nucleoplasm of nuclei isolated from PC12 cells. Addition of PKC-zeta pseudosubstrate peptide in vitro or myristoylated peptide in vivo diminished phosphorylation of pp106 in a dose-dependent fashion. Likewise, addition of purified PKC-zeta, but neither PKC-alpha nor delta, to nuclear extracts resulted in an incremental increase in the phosphorylation of pp106. Expression of dominant-negative PKC-zeta inhibited NGF-induced phosphorylation of pp106, by comparison overexpression of PKC-zeta enhanced basal phosphorylation without a noticeable effect upon NGF-induced effects. Amino acid sequence analysis of four peptides derived from purified pp106 revealed that this protein was homologous to nucleolin. Using an in vitro reconstitution system, purified nucleolin was likewise shown to be phosphorylated by purified PKC-zeta. The staining intensity of both enzyme and substrate in the nucleus increased upon treatment with NGF. In vivo labeling with 32Pi and stimulation of PC12 cells with NGF followed by immunoprecipitation with anti-nucleolin antibody corroborated the in vitro approach documenting enhanced phosphorylation of nucleolin by NGF treatment. Taken together, the findings presented herein document that nucleolin is a target of PKC-zeta that serves to relay NGF signals from cell surface to nucleus in PC12 cells.


The acute sensory neuronopathy syndrome: a distinct clinical entity.
Four to twelve days following initial antibiotic treatment for a febrile illness, three adults suddenly experienced numbness and pain over the face and entire body. Each had received a penicillin or a semisynthetic derivative, and two patients also received other antibiotics. Signs appeared rapidly and included profound sensory ataxia, areflexia, and widespread sensory loss, primarily of large fiber modalities (proprioceptive sensibility). Slowed or absent sensory conduction was found. There was no weakness, and electrical study of muscle and motor nerve conduction was normal in all. The cerebrospinal fluid was acellular, and protein levels were elevated to 126 and 175 mg/dl in two cases and were normal in the other. Presently, all have a severe, static, residual sensory deficit. During follow-up of five years, no evidence of neoplastic disease or immunological disorder has appeared. Because of the rapid onset, widespread and pure sensory involvement, and poor recovery, the lesion is most likely confined to the dorsal root and gasserian ganglia (sensory neuronopathy). This pattern resembles that of the experimental lesions induced by doxorubicin and pyridoxine. It appears likely that either the previously administered antibiotics or the illness for which they were administered were of pathogenetic importance. We designate this previously unrecognized disorder the acute sensory neuronopathy syndrome and suggest that it represents a distinct, readily identifiable clinical entity.


DCLK1 and its oncogenic functions: A promising therapeutic target for cancers.
Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and β-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.


Solid-phase synthesis of molecularly imprinted nanoparticles for protein recognition.
A solid-phase synthesis approach to prepare molecularly imprinted polymer nanoparticles (MIP-NPs) specific for trypsin is described. The protein is immobilized on a solid support upon which thermoresponsive MIP-NPs are synthesized. The MIP-NPs are released by a simple temperature change, resulting in synthetic antibody mimics exhibiting high specificity and selectivity for trypsin.


Severe intracranial atherosclerotic disease presenting as symptomatic isolated convexity subarachnoid haemorrhage.
Isolated convexity cortical subarachnoid haemorrhage (cSAH) is a rare form of non-traumatic subarachnoid haemorrhage localised to one or few cortical sulci of the brain without involving the adjacent brain parenchyma or spreading to sylvian fissure, interhemispheric fissure, basal cisterns and ventricles. cSAH has multiple aetiologies described in medical literature. Intracranial high-grade stenosis is rarely presented as cSAH, especially in young adult patients. Patients presenting with cSAH warrant appropriate diagnostic work up to identify and treat the underlying aetiology.


Response to intervention as a vehicle for distinguishing between children with and without reading disabilities: Evidence for the role of kindergarten and first-grade interventions.
Children at risk for early reading difficulties were identified on entry into kindergarten, and half of these children received small-group intervention two to three times a week during their kindergarten year. The other half received whatever remedial assistance was offered by their home schools. These children were again assessed at the beginning of first grade, and those who continued to have difficulties in reading received either one-to-one daily tutoring offered by project teachers from the beginning to the end of first grade or whatever remedial assistance was offered by their home schools over the same time period. All target children were periodically assessed through the end of third grade. Results suggest that either kindergarten intervention alone or kindergarten intervention combined with first-grade intervention are both useful vehicles for preventing early and long-term reading difficulties in most at-risk children.


[Part of Chlamydia pneumoniae in atherosclerosis and exacerbation of chronic obstructive pulmonary disease and asthma].
Chlamydia pneumoniae infection has been often associated with several chronic diseases including asthma and chronic obstructive pulmonary diseases (COPD). The spectrum of Chlamydia pneumoniae infection has been expanded to the association with coronary heart disease (CHD). In Morocco, the implication of Chlamydia pneumoniae infection in these pathologies is unknown. The aim of our study was to determine the relationship between infection with Chlamydia pneumoniae and respiratory pathology and atherosclerosis. The patients were from two departments (department of respiratory disease and of cardiology), and presented exacerbation of COPD and asthma or atherosclerosis. The mean age was 45 years a with a 1.7 sex ratio for the first population and 61 years with a 1.4 sex ratio for the second population. Serological diagnosis of Chlamydia pneumoniae infection has been determined by microimmunofluorescence (MIF). All samples were tested for anti-Chlamydia pneumoniae IgG, IgA and IgM. In the first group, we found 42 % positive for IgG, 11 % for IgA, and no case for IgM. In the second group the presence of anti-Chlamydia pneumoniae IgG was observed in 67.5 % cases, IgA in 16.5 % cases and IgM in 2 % cases, 14 % of patients had negative serology for IgA, IgG, and IgM. Our results are in accord to those reported by other studies. According to these results, it seems that a certain degree of association exists between Chlamydia pneumoniae infection and exacerbation of COPD, asthma and atherosclerosis which should be of importance on a therapeutic point of view.


Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features.
Prior studies revealed that the leukemic B cells of patients with chronic lymphocytic leukemia (CLL) express a restricted Ig heavy chain variable region gene (VH gene) repertoire. However, this restriction needs to be re-evaluated in light of findings that the repertoire of Ig VH genes used by primary B cells of normal adults is actually more restricted than originally assumed. Because of this, we critically examined the Ig VH1 and VH7 genes expressed by leukemia cells of a random panel of patients with B cell CLL (n = 117). Forty-one (35%) had leukemia cells with functional VH1 gene rearrangements. Of these, the large majority expressed Ig VH1-69 (n = 26; 63%). The remaining leukemia cell samples expressed VH1-2 (n = 4; 10%), VH1-3 (n = 2; 5%), VH1-8 (n = 2; 5%), VH1-18 (n = 1; 2%), VH1-45 (n = 1; 2%), and VH1-46 (n = 5; 12%). Only 1 of the 117 examined (<1%) used Ig VH genes of the VH7 subgroup. We found that certain alleles of the IgVH1-69 locus are favored in CLL. Also, leukemia B cells that express VH1-69 have a distinctive use distribution of D and JH gene segments compared with that of VH1-expressing CLL B cells that do not use VH1-69 or non-neoplastic B cells that express VH1-69. Finally, the average length of the heavy chain third complementarity-determining regions (CDR3) of VH1-69-expressing leukemia cells is significantly longer than that of normal adult B cells that also express Ig encoded by VH1-69 genes. Collectively, this study indicates that the Ig expressed in CLL have distinctive molecular features that are not representative of the Ig expressed by primary B cells of normal adults.


Population divergence and gene flow in an endangered and highly mobile seabird.
Seabirds are highly vagile and can disperse up to thousands of kilometers, making it difficult to identify the factors that promote isolation between populations. The endemic Hawaiian petrel (Pterodroma sandwichensis) is one such species. Today it is endangered, and known to breed only on the islands of Hawaii, Maui, Lanai and Kauai. Historical records indicate that a large population formerly bred on Molokai as well, but this population has recently been extirpated. Given the great dispersal potential of these petrels, it remains unclear if populations are genetically distinct and which factors may contribute to isolation between them. We sampled petrels from across their range, including individuals from the presumably extirpated Molokai population. We sequenced 524 bp of mitochondrial DNA, 741 bp from three nuclear introns, and genotyped 18 microsatellite loci in order to examine the patterns of divergence in this species and to investigate the potential underlying mechanisms. Both mitochondrial and nuclear data sets indicated significant genetic differentiation among all modern populations, but no differentiation was found between historic samples from Molokai and modern birds from Lanai. Population-specific nonbreeding distribution and strong natal philopatry may reduce gene flow between populations. However, the lack of population structure between extirpated Molokai birds and modern birds on Lanai indicates that there was substantial gene flow between these populations and that petrels may be able to overcome barriers to dispersal prior to complete extirpation. Hawaiian petrel populations could be considered distinct management units, however, the dwindling population on Hawaii may require translocation to prevent extirpation in the near future.


Short-term effectiveness of simple advice as a withdrawal strategy in simple and complicated medication overuse headache.
The aim of this study was to compare the effectiveness of intensive advice (to withdraw the overused medication/s) as a withdrawal strategy in patients with simple and complicated medication overuse headache (MOH). One hundred consecutive MOH patients were included in the study. Exclusion criteria were co-existent severe medical or psychiatric illnesses, treatment with migraine prophylactic drugs within the past 3 months, and overuse of opioids and/or barbiturate-containing agents. MOH was defined as complicated in patients fulfilling at least one of the following criteria: (i) a diagnosis of co-existent, significant, and complicating medical illnesses; (ii) a current diagnosis of mood disorder, anxiety disorder, eating disorder, or substance addiction disorder; (iii) a relapse after previous detoxification treatment; (iv) psycho-social and environmental problems; and (v) daily use of multiple doses of symptomatic medication/s. Withdrawal therapy was considered successful if, after 2 months, the patient had had reverted to an intake of NSAIDs lower than 15 days/month or to an intake of other symptomatic medication/s lower than 10 days/month. Fifty-one patients had simple MOH and 49 patients had complicated MOH. Eleven patients failed to attend follow-up visits (simple MOH=3, complicated MOH=8, P>0.05). Of all the patients included in the study, we were able to detoxify 79% (92.1% of the patients with simple MOH and 65.3% of those with complicated MOH, P<0.01). Simple advice is highly effective in simple MOH and effective in most complicated MOH patients and should be regarded as the first step in a step-care approach to MOH management.


All-silica fiber Bessel-like beam generator and its applications in longitudinal optical trapping and transport of multiple dielectric particles.
A Bessel-like beam was generated in a novel all-fiber integrated structure. A concentric ring intensity pattern was achieved by the multimode interference along the coreless silica fiber, which was then focused by the integrated micro-lens to result in a Bessel-like beam. The average beam diameter of 7.5 μm maintained over 500 μm axial length for a continuous wave Yb-doped fiber laser input oscillating at the wavelength of 1.08 μm. The generated beam was successfully applied to two-dimension optical trapping and longitudinal transport of multiple dielectric particles confirming its unique non-diffracting and self-reconstructing nature. Physical principle of operation, fabrication, and experimental results are discussed.


Psychological and functional profiles in select subjects with low back pain.
Some researchers have found a correlation of poor treatment outcomes in patients with low back pain and abnormal psychological profiles, whereas others have failed to confirm this correlation. A critical feature of this debate has been whether abnormal psychological profiles seen in patients with back pain are the result of the ongoing back pain or whether pre-existing psychological features predispose to a poor clinical outcome. To determine the relationship of psychometric testing scores to the presence and duration of back pain of differing causes. This was a prospective observational study of the psychological profiles of groups of patients with low back pain and controls. Subjects having a variety of painful back conditions (n=310) were compared with a control group of subjects without low back complaints who had undergone cervical spine surgery (n=73). Psychometric testing (Modified Zung and Modified Somatic Pain Questionnaire) was performed along with pain scores (visual analog scale [VAS]), a standardized Low Back Pain Questionnaire, and the Oswestry Low Back Pain Disability Questionnaire in the evaluation of back pain and control subjects. The subjects with painful back conditions included patients with presumed discogenic pain undergoing discography (n=95); patients with symptomatic isthmic spondylolisthesis coming to fusion (n=61); patients with chronic vertebral osteomyelitis before diagnosis and treatment (n=39). There was also a nonpatient group of soldiers with chronic low back pain not seeking medical care (n=115). The control subjects without low back pain consisted of a group who had undergone cervical spine surgery (n=73). Psychometric testing was performed and compared in the evaluation of subjects having these different painful back conditions. Analysis was done comparing pain scores, function scores, and psychological testing scores between the symptomatic and asymptomatic groups. The VAS maximum in last week score for the entire group was 7.1, and scores were not significantly different in all low back pain groups. The Oswestry scores were poorest in the discography group compared to spondylolisthesis and osteomyelitis. Functional scores were similar in the soldiers with low back pain and controls without low back pain. Both Depression and Somatic Pain scores were most abnormal in the discogenic low back pain group. Only 21% of this group had normal scores, compared with 71% of the spondylolisthesis group, 79% of osteomyelitis group, and 88% of the group with chronic low back pain not seeking treatment (p<.001 in all groups). The asymptomatic control group had 85% normal scores. Despite similar pain levels and pain duration, patients with the discographic diagnosis of discogenic back pain have poorer functional scores and very abnormal psychological scores compared with other subjects with chronic low back pain resulting from spondylolisthesis requiring surgery or chronic pyogenic osteomyelitis. Chronic moderately severe mechanical low back pain in healthy subjects was not associated with abnormal psychological scores or functional disability.