Induction of dentin formation on canine amputated pulp by recombinant human bone morphogenetic proteins (BMP)-2 and -4.
Dental pulp cells have the potential to differentiate into odontoblasts. The molecular mechanisms underlying differentiation are not clear. Demineralized dentin matrix is osteoinductive and contains bone morphogenetic protein (BMP) activity. BMPs have been implicated in embryonic odontogenic differentiation and hence may play a role in the differentiation of adult pulp cells into odontoblasts during pulpal healing. This study examined the hypothesis that BMPs induce dentin formation on amputated canine pulp. Recombinant human BMP-2 and BMP-4 were capped with inactivated dentin matrix on amputated pulp. At two months, the amputated pulp was filled with tubular dentin in the lower part and osteodentin in the upper part. The amount of dentin formed was markedly diminished when dentin matrix alone was implanted. These findings imply that recombinant human BMP-2 and BMP-4 induce differentiation of adult pulp cells into odontoblasts. Thus, BMPs may have a role in dentistry as a bioactive pulp-capping agent to induce dentin formation.


Ebola virus as a sexually transmitted infection.
The ongoing Ebola virus epidemic in West Africa is a major global health challenge. The main mode of transmission is through contact with bodily fluids and skin of those infected or who have died. This review was undertaken to consider the evidence for transmission by contact with bodily fluids occurring through sexual activity. No cases in the previous 20 outbreaks or the current outbreak in West Africa have been shown to be sexually transmitted, although other types of viral haemorrhagic fever have had sexual transmission implicated. Ebola virus is found in sites and fluids associated with sexual activity but this occurs at different stages of the disease. Persistence in the convalescent period occurs in rectum, vagina and semen, with persistence in semen being longest of up to at least 101 days. Recommendations based on this data are that those recovering from Ebola virus disease should abstain from all sexual intercourse, or if this is not possible, use condoms, for 3 months after the onset of symptoms. There is theoretical plausibility for sexual transmission of Ebola virus but there has been no evidence of this occurring. Further research is needed to consider if sexual activity contributes to the epidemic in order to inform individuals with regard to avoiding acquisition or transmission by those recovering from Ebola virus disease.


New approaches to the use of pharmacokinetics in toxicology and drug development.
1. The use of pharmacokinetics in toxicology, clinical pharmacology and in the individualization of dosage has been critically examined. 2. In toxicity studies, doses are given to animals with the aim of achieving substantially higher plasma levels than the therapeutic level in man. However, small animals have faster metabolic rates, shorter life spans and drug clearance is many fold faster than in man, and this difference may not be compensated for by simply mg per kg dosing. Since toxicity still occurs at these lower levels, it begs the question whether small animals require such high doses to produce toxic effects. 3. A literature survey revealed that only 5 to 31% of the papers studied attempt to relate activity with plasma levels. Examples are given of how such relationships can be used, as with D-fenfluramine, where by investigating individual responses using drug plasma levels as a probe, a greater understanding of eating disorders may be obtained. Also, with tertatolol its prolonged pharmacological activity (greater than 24 h) can be explained mathematically despite a plasma half-life of only 3 h. 4. The advantages and disadvantages of population kinetics are discussed in relation to its use in individualizing dosage, particularly in disease, its appreciation by pharmaceutical companies and regulatory authorities and the information which has been obtained so far. 5. It is of interest that one of the youngest of drug development disciplines, pharmacokinetics, is now one of the most important.


[Evidences from J-EDIT for diabetes mellitus in the elderly].
The high prevalence of diabetic complications including physical and functional disabilities decrease QOL of elderly patients with diabetes mellitus and increase the social burden. In order to elucidate clinical evidences for the prevention of cardiovascular disease (CVD) and disabilities, we have performed a multi-center 6-year prospective randomized controlled trial (RCT) for diabetes mellitus in the elderly, the Japanese Elderly Diabetes Intervention Trial (J-EDIT). J-EDIT has demonstrated that "the lower the better" appears doubtful for HbA1c, but seems to be true for LDL- and non-HDL-cholesterol. Intake of vegetable- and fish-rich diet improves metabolic control and prognosis of the patients. Maintenance/increase of physical activity is important to prevent CVD, especially stroke. Other several evidences from J-EDIT will be demonstrated also in this article.


Diattenuation of brain tissue and its impact on 3D polarized light imaging.
3D-polarized light imaging (3D-PLI) reconstructs nerve fibers in histological brain sections by measuring their birefringence. This study investigates another effect caused by the optical anisotropy of brain tissue - diattenuation. Based on numerical and experimental studies and a complete analytical description of the optical system, the diattenuation was determined to be below 4 % in rat brain tissue. It was demonstrated that the diattenuation effect has negligible impact on the fiber orientations derived by 3D-PLI. The diattenuation signal, however, was found to highlight different anatomical structures that cannot be distinguished with current imaging techniques, which makes Diattenuation Imaging a promising extension to 3D-PLI.


γ-Glutamyl transpeptidase (GgtA) of Aspergillus nidulans is not necessary for bulk degradation of glutathione.
Aspergillus nidulans exhibited high γ-glutamyl transpeptidase (γGT) activity in both carbon-starved and carbon-limited cultures. Glucose repressed, but casein peptone increased γGT production. Null mutation of creA did not influence γGT formation, but the functional meaB was necessary for the γGT induction. Deletion of the AN10444 gene (ggtA) completely eliminated the γGT activity, and the mRNA levels of ggtA showed strong correlation with the observed γGT activities. While ggtA does not contain a canonical signal sequence, the γGT activity was detectable both in the fermentation broth and in the hyphae. Deletion of the ggtA gene did not prevent the depletion of glutathione observed in carbon-starved and carbon-limited cultures. Addition of casein peptone to carbon-starved cultures lowered the formation of reactive species (RS). Deletion of ggtA could hinder this decrease and resulted in elevated RS formation. This effect of γGT on redox homeostasis may explain the reduced cleistothecia formation of ΔggtA strains in surface cultures.


Metabolic Characterization of a Novel RORα Knockout Mouse Model without Ataxia.
The retinoic acid receptor-related receptor α (RORα) is a nuclear receptor that plays an important role in regulation of metabolism and the immune system. Genetic deletion of the receptor yields mice with significant cerebellar developmental issues associated with severe ataxia. Although many metabolic studies have been performed in these models, the impaired locomotor activity of these mice is known to affect their normal mobility and feeding behaviors. This creates some difficulty in interpretation of the role of RORα in models of metabolic disease where feeding and muscle function is a critical component of the pathophysiology. We generated a mouse with a floxed Rora allele that we crossed with a mouse line expressing Cre recombinase under the control of the EIIa promoter to obtain a full body deletion of Rora. This cross led to a partial deletion of the Rora locus likely due to mosaic expression of the EIIa-Cre transgene. These mice lack any signs of ataxia but display an improved metabolic profile relative to normal WT mice. The mice were resistant to diet- and age-induced metabolic syndrome and exhibited improved glucose tolerance and increased insulin sensitivity. Decreased RORα expression in the mice was also associated with reduced inflammation in models of metabolic syndrome. These data indicate that suppression of RORα activity improves metabolic function and reduces inflammation.


Obesity and thinness: insights from genetics.
Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.


[Use of beta-blockers in the acute phase of myocardial infarction].
Several experimental studies have demonstrated that the early administration of beta blockers in the setting of an acute myocardial infarction (in the first six hours) tended to diminish the area of myocardial necrosis. Numerous attempts to limit infarct size with beta blockers have occurred over the past ten years. Without a reliable and reproducible method to measure necrosed tissue, it has been difficult to evaluate the effectiveness of this therapy. Presently available studies have demonstrated, however, that beta blockers are well tolerated in the setting of an acute infarction as long as none of the usual contraindications are present. The majority (but not all) of these studies indicated improvement in parameters used to determine the amount of tissue necrosis and a tendency (not always significant due to the small numbers studied) to decrease morbidity and mortality during hospitalization. One study using metoprolol administered during the acute phase and continued during the first three months demonstrated a significant decrease in mortality. The results of this study are very demonstrative, nevertheless, once the acute necrotic phase is over, it is difficult to ascertain whether diminished tissue necrosis or the preventive effect of beta blockers is responsible for these findings until a recurrence or sudden death occurs.


Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study.
Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care. In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy. Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]). Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design. US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research. For the Italian and German translations of the abstract see Supplementary Materials section.


A common developmental program can produce diverse leaf shapes.
Eudicot leaves have astoundingly diverse shapes. The central problem addressed in this paper is the developmental origin of this diversity. To investigate this problem, we propose a computational model of leaf development that generalizes the largely conserved molecular program for the reference plants Arabidopsis thaliana, Cardamine hirsuta and Solanum lycopersicum. The model characterizes leaf development as a product of three interwoven processes: the patterning of serrations, lobes and/or leaflets on the leaf margin; the patterning of the vascular system; and the growth of the leaf blade spanning the main veins. The veins play a significant morphogenetic role as a local determinant of growth directions. We show that small variations of this model can produce diverse leaf shapes, from simple to lobed to compound. It is thus plausible that diverse shapes of eudicot leaves result from small variations of a common developmental program.


Disability from depression: the public health challenge to primary care.
Epidemiologists have identified that depression will soon be the leading cause of disability throughout the world. To inform public health campaigns to reduce this problem, this paper summarizes current scientific knowledge about optimizing the potential of primary care settings to reduce disability by providing effective treatment for depression. To meet this challenge, primary care practices need to be re-engineered: 1) to conduct systematic screening programs to identify depressed patients, 2) to provide depressed patients initial evidence-based treatment, and 3) to monitor treatment adherence and symptom response in treated patients over 2 years. While additional research is needed in developing countries, preliminary evidence indicates that primary care practices re-engineered to improve depression management can make a substantial contribution to reducing depression-associated disability.


Aggregation-fragmentation processes and decaying three-wave turbulence.
We use a formal correspondence between the isotropic three-wave kinetic equation and the rate equations for a nonlinear fragmentation-aggregation process to study the wave frequency power spectrum of decaying three-wave turbulence in the infinite capacity regime. We show that the transient spectral exponent is lambda+1 , where lambda is the degree of homogeneity of the wave interaction kernel and derive a formula for the decay amplitude. When lambda=0 the transient exponent coincides with the thermodynamic equilibrium exponent leading to logarithmic corrections to scaling which we calculate explicitly for the case of constant interaction kernel.


The effect of water on the physicochemical properties of an ethylene glycol and choline chloride mixture containing Cu2+ ions: electrochemical results and dynamic molecular simulation approach.
The effect of water on the physicochemical properties of an ethylene glycol and choline chloride mixture containing Cu2+ ions was investigated by electrochemical techniques and molecular dynamics simulation. The experiments and computational calculations were carried out by increasing the water content from 0 up to 10% (v/v). The cyclic voltammetry and chronopotentiometry techniques showed that the diffusion coefficient of Cu2+ ions increased and that the peak potentials for both the Cu2+/Cu+ and Cu+/Cu redox couples shifted towards more positive potentials with the increase in the water content in the solution. The molecular dynamics simulation indicated that the water molecules replaced the ethylene glycol molecules that were coordinated with Cu2+ ions, while the interactions between Cu2+ and Cl- ions were not influenced by the presence of water.


The incidence of cervical cancer and duration of oral contraceptive use.
In a prospective study carried out on a cohort of 17,942 women belonging to the Kaiser Foundation Health Plan and living in suburban communities of the San Francisco Bay Area, a positive association was found between the incidence of cervical carcinoma and total duration of oral contraceptive use. The association was established while controlling for the effects of age, education, and selected infections. The association persists when incident cases of dysplasia are added to those of carcinoma. A further study, in which covariates relating to sexual behavior will also be taken into account, is in progress.


Discovery and verification of Q-markers for promoting blood circulation and removing stasis of raw and wine-steamed Vaccaria segetalis based on pharmacological evaluation combined with chemometrics.
Dried and mature seeds of Vaccaria segetalis (Neck.) Garcke ex Asch. (VS) are known for their therapeutic effects, as they stimulate blood circulation, promote menstruation and diuresis and eliminate gonorrhoea. However, due to its hard shell, the dissolution of its active ingredients is often improved by steaming and frying in clinical applications. Among the processed products, wine-steamed Vaccaria segetalis (WVS) is one of the commonly used ones. Numerous historical records have shown that wine steaming can enhance the efficacy of drugs to promote blood circulation and remove blood stasis. However, the differences in the efficacy of VS and WVS in promoting blood circulation and removing blood stasis have not been thoroughly studied, and the possible reasons for these differences have not been reported. The objective of this study was to identify quality markers (Q-markers) that could differentiate the efficacy of promoting blood circulation and removing blood stasis of VS and WVS, which could serve as a basis for the rational application of VS and WVS in clinical settings. A pharmacodynamic comparison between the water extracts of VS and WVS was carried out based on a mouse acute blood stasis model (ABS) and thrombus zebrafish model. The potential bioactive substances of WVS were screened by investigating the correlation between common peaks identified for 10 batches of WVS by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and their rate of thrombosis inhibition in zebrafish. Furthermore, multivariate statistical analysis of chemical components between VS and WVS was conducted to speculate the Q-markers combined with the results of the bioactive components. Based on the efficacy verification of Q-markers, the content of Q-markers in 10 batches of WVS was evaluated. The results of efficacy comparison assays demonstrated that the efficacy of WVS was more prominent than VS at the same dose. Five components were screened as effective components of WVS for promoting blood circulation and removing blood stasis by correlation analysis. Furthermore, a total of 24 common ingredients were identified in VS and WVS extracts, and 9 of them showed increased dissolution rate after wine steaming, including 4 active ingredients, Hypaphorine, Vaccarin, Saponarin, and Isovitexin-2″-O-arabinoside, which were screened out by correlation analysis. The monomer test suggested that these 4 components could activate blood circulation and remove blood stasis in a dose-dependent manner. Consequently, Hypaphorine, Vaccarin, Saponarin, and Isovitexin-2″-O-arabinoside were selected as Q-markers to distinguish between VS and WVS. The content determination showed that the total contents of 4 Q-markers of WVS from 10 batches with different origins ranged from 0.478% to 0.716%. This study compared the efficacy of VS and WVS in promoting blood circulation and resolving stasis and revealed Q-markers that reflected the difference in efficacy between them for the first time, which laid the foundation for establishing quality standards for WVS.


Differences in SARS-CoV-2 Clinical Manifestations and Disease Severity in Children and Adolescents by Infecting Variant.
Since the COVID-19 pandemic began, different SARS-CoV-2 variants have been identified and associated with higher transmissibility than the ancestral nonvariant strain. During January 1, 2021-January 15, 2022, we assessed differences in clinical and viral parameters in a convenience sample of COVID-19 outpatients and inpatients 0-21 years of age in Columbus, Ohio, USA, according to the infecting variant, identified using a mutation-specific reverse transcription PCR assay. Of the 676 patients in the study, 17.75% were infected with nonvariant strains, 18.49% with the Alpha variant, 41.72% with Delta, and 16.42% with Omicron. Rates of SARS-COV-2/viral co-infections were 15.66%-29.41% and were comparable across infecting variants. Inpatients with acute Delta and Omicron infections had lower SARS-CoV-2 cycle threshold values and more frequent fever and respiratory symptoms than those with nonvariant strain infections. In addition, SARS-COV-2/viral co-infections and the presence of underlying conditions were independently associated with worse clinical outcomes, irrespective of the infecting variant.


Light filaments with higher-order Kerr effect.
The influence mechanism of higher-order Kerr effect on the propagation of laser beam is investigated by a modified model, which indicates that a collapsing wave will transform into a universe blowup profile. The analysis of higher-order terms of the nonlinear refractive index shows that the filamentation process can be induced by Kerr self-focusing without the occurrence of the ionization effect. The determining role of the combination of self-focusing and spontaneous defocusing and the energy reservoir in formation of lengthy filament is confirmed visually.


Adult age differences in the effects of goals on self-regulated sentence processing.
The authors examined age differences in adults' allocation of effort when reading text for either high levels of recall accuracy or high levels of efficiency. Participants read a series of sentences, making judgments of learning before recall. Older adults showed less sensitivity than the young to the accuracy goal in both reading time allocation and memory performance. Memory accuracy and differential allocation of effort to unlearned items were age equivalent, so age differences in goal adherence were not attributable to metacognitive factors. However, comparison with data from a control reading task without monitoring showed that learning gains among older adults across trial were reduced relative to those of the young by memory monitoring, suggesting that monitoring may be resource consuming for older learners. Age differences in the responsiveness to (information-acquisition) goals could be accounted for, in part, by independent contributions from working memory and memory self-efficacy. Our data suggest that both processing capacity ("what you have") and beliefs ("knowing you can do it") can contribute to individual differences in engaging resources ("what you do") to effectively learn novel content from text.


Oxcarbazepine and spasticity: further observations.
The previously described anti-spastic effect of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine was found accidentally in 2 patients undergoing a double-blind comparative study for evaluation of antiepileptic effect. In this study oxcarbazepine was given orally in doses of 300-2700 mg daily to one patient with transverse myelitis and to two patients with multiple sclerosis, all of whom had clinically disabling spasticity in the form of difficulty in walking, lower limb rigidity, spastic contractions of the lower limbs and ankle clonus. Anti-spastic effect was observed at doses between 600-1200 mg daily and consisted in a substantial decrease in the above symptoms of spasticity. The anti-spastic effect appears at a dose immediately below that which produces nausea, dizziness and somnolence.


Caffeic acid loading wound dressing: physicochemical and biological characterization.
Caffeic acid has been described as active against bacteria commonly isolated from wound infections. However, its low stability and poor solubility reduce caffeic acid applicability as a pharmaceutical product. These parameters can be enhanced by complexation with cyclodextrin. The main goal of the present work was to incorporate caffeic acid on cyclodextrin-based hydrogels capable of controlled delivery, in order to be used as antibacterial wound dressing. Cyclodextrin-based hydrogels were prepared by direct crosslinking of β-cyclodextrin or hydroxypropyl-β-cyclodextrin with 1,4-butanediol diglycidyl ether in the presence of hydroxypropyl methylcellulose. The hydrogels obtained combine good physicochemical properties (viscoelasticity, superabsorbency and high ability to retain and deliver caffeic acid) with the preservation of caffeic acid' antibacterial activity and effect on fibroblasts, with gel-β-cyclodextrin the most suited. The hydrogels obtained could be useful as caffeic acid delivery-system devices for the treatment of wound infections.


Incidence and seasonality of respiratory syncytial virus hospitalisations in young children in Denmark, 2010 to 2015.
For future decisions on respiratory syncytial virus (RSV)-vaccination strategies and implementation into national immunisation-programmes, we used national registry data (hospitalisation, microbiology and vital statistics) to determine the age-specific incidence and direct medical costs of annual RSV-associated admissions in children < 5 years-old for the period of 2010-2015. We identified ca 2,500 RSV-associated hospitalisations annually amounting to total direct medical-costs of ca EUR 4.1 million per year. The incidence of RSV-associated hospitalisations peaked in infants 1-2 months of age followed by infants 2-3 months of age, and infants < 1 month of age, respectively. Infant boys were at higher risk of severe RSV infection as compared to infant girls: male-to-female ratio peaked with 1.4 at four months of age and gradually levelled out with increasing age to 1.0 at 4 years of age. Five RSV-associated deaths were identified. Our findings demonstrate that in a western country as Denmark, RSV constitutes a considerable burden on childhood health. Furthermore, the best approach to reduce the high incidence of RSV-associated hospitalisations in young infants < 3 months of age may be maternal vaccination due to general challenges in achieving sufficient and protective immune responses in young infants.


How to build and rebuild a lens.
Evolution has used many different strategies to build eyes and lenses. However, the genetic regulation involved seems to be quite conserved. Likewise, the regeneration of eye structures is remarkable, especially in salamanders. This review outlines the basic mechanisms of lens regeneration and its induction and the possibility of creating lenses by transdifferentiation of the pigment epithelial cells, by stem cells or by bioengineering.


[Immunohistochemical studies of the histogenesis of dermatofibrosarcoma protuberans].
Paraffin-embedded tissue sections taken from 16 patients with dermatofibrosarcoma protuberans were stained by means of the peroxidase-antiperoxidase technique using antibodies against S 100 protein, NSE, Leu 7, lysozyme, alpha-1 antitrypsin, alpha-1 antichymotrypsin, cytokeratin, desmin, vimentin, and factor VIII. Most of the tumor cells showed positive reactions to vimentin. Only 1-3% of the cells within the tumor area answered to the histiocytic markers lysozyme, alpha-1 antitrypsin, and alpha-1 antichymotrypsin. The remaining antibodies investigated did not react with the tumor cells. Our results support a fibroblastic, and contradict a neural or histiocytic, histogenesis of dermatofibrosarcoma protuberans.


Medium to long-term clinical outcome following stentless aortic valve replacement: comparison between allograft and xenograft valves.
The xenograft stentless valve was designed to emulate the haemodynamic performance of the allograft. Early outcomes using either surgical option (stentless xenograft valve or allograft) have been similar. However, follow-up outcomes remain to be compared. Between 1st January 1991 and 1st January 2001, 415 patients underwent aortic valve replacement. Two hundred and seventeen patients received an allograft and in 198 patients a Toronto stentless porcine valve (TSPV) was implanted. Mean time to follow-up was 6.3+/-4.4 years. Ten years freedom from structural valve deterioration (SVD) (TSPV 86+/-5%, allograft 82+/-5%, P=0.49) and freedom from reoperation (RE) (TSPV 80+/-4% vs. allograft 85+/-4%, P=0.61) were not significantly different. The TSPV was associated with significantly worse actuarial survival than the homograft (TSPV 40+/-4% vs. homograft 55+/-4%, P=0.02). However, after adjustment for other variables using a multivariate model, TSPV use was not an independent predictor of impaired late survival (LS) (P=0.44). Kaplan-Meier analysis in a subgroup of patients aged 45-65 years comparing LS, RE and SVD between xenografts and allografts identified similar results. The porcine stentless valve may be associated with similar clinical performance to the allograft over the medium to long-term.


Biologic function and clinical potential of telomerase and associated proteins in cardiovascular tissue repair and regeneration.
Telomeres comprise long tracts of double-stranded TTAGGG repeats that extend for 9-15 kb in humans. Telomere length is maintained by telomerase, a specialized ribonucleoprotein that prevents the natural ends of linear chromosomes from undergoing inappropriate repair, which could otherwise lead to deleterious chromosomal fusions. During the development of cardiovascular tissues, telomerase activity is strong but diminishes with age in adult hearts. Dysfunction of telomerase is associated with the impairment of tissue repair or regeneration in several pathologic conditions, including heart failure and infarction. Under both physiologic and pathophysiologic conditions, telomerase interacts with promyogenic nuclear transcription factors (e.g. myocardin, serum response factor) to augment the potency of cardiovascular cells during growth, survival, and differentiation. We review recent findings on the biologic function of telomerase and its potential for clinical application in cardiovascular development and repair. Understanding the roles of telomerase and its associated proteins in the functional regulation of cardiovascular cells and their progenitors may lead to new strategies for cardiovascular tissue repair and regeneration.


HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis.
In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF.


[Are glomerular hyperfiltration and hyperperfusion involved in the development and progression of nephropathies?].
In the present paper the significance of non-immunological factors in the development and progression of nephropathies according to the hypothesis of Brenner et al. especially hemodynamic changes in the glomerula with glomerular hyperperfusion and/or hyperfiltration is discussed and therapeutic conclusions are made. The normalized glomerular pressure conditions (converting-enzyme inhibitors), a normalization of hyperglycemia in diabetics, a retention in the use of protein-rich diet and platelet-aggregation inhibitors, respectively, play a special part in the treatment of chronic nephropathies.


Diabetes Mellitus and Its Association to the Occurrence of Medication-Related Osteonecrosis of the Jaw.
To date there is no consensus on the role of diabetes in the development of medication-related osteonecrosis of the jaws (MR-ONJ). Therefore, this study aimed to investigate the prevalence of diabetes and pathological glucose metabolism in patients with MR-ONJ compared to the general population. All maxillofacial surgery inpatients in one year at our department were investigated regarding diagnosis, anamnesis, medication, and blood glucose readings. 1374 records were analyzed. 35 patients with MR-ONJ were identified. Diabetics accounted for 14.3%. No significant difference in the prevalence of known diabetes was found, except for pathological glucose metabolism in patients with MR-ONJ (p < 0.001). Diabetes does not necessarily promote the onset of MR-ONJ. Therefore, diabetes should not be considered as a standalone risk factor. On the contrary, hyperglycemia as a possible indicator for poorly managed or yet undetected diabetes is associated with MR-ONJ.


Chronic obstructive pulmonary disease: on an exponential curve of progress.
The last 50 years have witnessed major progress in our understanding of the underlying nature of chronic obstructive pulmonary disease (COPD) and approaches to care. During the last 10 years, however, there has been an explosive expansion of knowledge related to this disorder. Large-scale epidemiologic studies show that COPD is the fourth leading cause of death in the United States and will be the fifth leading health burden worldwide by the year 2020. We have also learned that COPD is an inflammatory disorder of small airways, which presents new opportunities for therapy involving interfering with the early components of the inflammatory cascade. Unfortunately, most clinicians fail to perform spirometric screening of at-risk individuals, so most patients first present with COPD during a sudden exacerbation of the disease. Worldwide interest is emerging in promoting earlier diagnosis and finding new pharmacologic interventions to halt the progression of airway and parenchymal damage. In this review, evidence is presented that we are on the upward limb of an exponential curve of progress in managing COPD, which will produce major advances in our ability to recognize and treat this disorder in its earliest stages.


Characterization of freeze-fractured epithelial plasma membranes on nanometer scale with ToF-SIMS.
Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to characterize the freeze-fracturing process of human epithelial PANC-1 and UROtsa cells. For this purpose, phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and phosphatidylserine standard samples were investigated to find specific signals with both high specificity and signal intensity. The results were used to investigate single cells of subconfluent cell layers prepared with a special silicon wafer sandwich preparation technique. This freeze-fracturing technique strips cell membranes off the cells, isolating them on opposing silicon wafer substrates. Criteria were found for defining regions with stripped off cell membranes and, on the opposing wafer, complementary regions with the remaining cells. Measured ethanolamine/choline and serine/choline ratios in these regions clearly showed that in the freeze-fracturing process, the lipid bilayer of the plasma membrane is split along its central zone. Accordingly, only the outer lipid monolayer is stripped off the cell, while the inner lipid monolayer remains attached to the cell on the opposing wafer, thus allowing detailed analysis of a single lipid monolayer. Furthermore, it could be shown that using different washing procedures did not influence the transmembrane lipid distribution. Under optimized preparation conditions, it became feasible to detect lipids with a lateral resolution of approximately 100 nm. The data indicate that ToF-SIMS would be a very useful technique to study with very high lateral resolution changes in lipid composition caused, for example, by lipid storage diseases or pharmaceuticals that interfere with the lipid metabolism.


Demographic and clinical characterization of human visceral leishmaniasis in the State of Pernambuco, Brazil between 2006 and 2015.
Human visceral leishmaniasis (HVL) primarily occurs in regions that present socioeconomic, health, and environmental vulnerability. In Pernambuco, Brazil, this neglected zoonosis has expanded in magnitude as well as geographically, and efforts to manage HVL have been insufficient to contain its spread. The objective of this study was to describe the epidemiological profile of human illness due to HVL during 2006 to 2015 in Pernambuco State. This study was conducted using secondary data collected from the Health Information System. During the study period, Pernambuco accounted for 2.4% of HVL cases in Brazil, with 49.6% of these concentrated in the macroregions of São Francisco Valley and Araripe. The percentage of municipalities that reported cases at the beginning of the study period increased from 21.1% (n = 39) to 43.8% (n = 81) by the end of the period. Cases were found predominantly among males, brown-skinned individuals, children aged 1-4 years, and individuals with incomplete 1st to 4th grade education. Coinfection with HIV was present in 5.6% of cases. Incidence was 9.7 cases per 100,000 inhabitants, and lethality was 12.3%. HVL has shown worrying expansion and evolution, in addition to high lethality, in Pernambuco. The only study of its kind in the past decade, it was evident from this study that despite efforts to contain this disease, HVL in Pernambuco exhibits patterns similar to those described in previous studies. Based on our results, we suggest reassessing the current prevention and control measures in the state.


MRI findings of radiation-associated angiosarcoma of the breast (RAS).
To describe the magnetic resonance imaging (MRI) characteristics of radiation-associated breast angiosarcomas (RAS). In this Institutional Review board (IRB)-approved retrospective study, 57 women were diagnosed with pathologically confirmed RAS during the study period (January 1999 to May 2013). Seventeen women underwent pretreatment breast MRI (prior to surgical resection or chemotherapy), of which 16 studies were available for review. Imaging features, including all available mammograms, ultrasounds, and breast MRIs, of these patients were evaluated by two radiologists independently and correlated with clinical management and outcomes. The median age of patients at original breast cancer diagnosis was 69.3 years (range 42-84 years), with average time from initial radiation therapy to diagnosis of RAS of 7.3 years (range 5.1-9.5 years). Nine women had mammograms (9/16, 56%) and six had breast ultrasound (US) (6/16, 38%) prior to MRI, which demonstrated nonsuspicious findings in 5/9 mammograms and 3/6 ultrasounds. Four patients had distinct intraparenchymal masses on mammogram and MRI. MRI findings included diffuse T2 high signal skin thickening (16/16, 100%). Nearly half (7/16, 44%) of patients had T2 low signal intensity lesions; all lesions rapidly enhanced on postcontrast T1 -weighted imaging. All women underwent surgical resection, with 8/16 (50%) receiving neoadjuvant chemotherapy. Four women died during the study period. Clinical, mammographic, and sonographic findings of RAS are nonspecific and may be occult on conventional breast imaging; MRI findings of RAS include rapidly enhancing dermal and intraparenchymal lesions, some of which are low signal on T2 weighted imaging.


Berberine induces dendritic cell apoptosis and has therapeutic potential for rheumatoid arthritis.
To investigate the effects of berberine on dendritic cell (DC) apoptosis and its potential as a therapeutic agent in rheumatoid arthritis (RA). Bone marrow (BM)-derived myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) were generated by culturing BM cells with granulocyte-macrophage colony-stimulating factor/interleukin-4 or flt3L, respectively. Splenic DCs, T cells, and B cells were purified using a magnetic-activated cell sorting system. In vitro apoptosis was assessed by annexin V/propidium iodide or Hoechst 33258 staining. The in vivo effects of berberine were examined in mice with collagen-induced arthritis (CIA). Immune responses against type II collagen (CII) were determined by assaying serum antibody levels, lymphocyte proliferation, and cytokine production. The proportions of DCs and apoptosis of different immune cell subsets in spleens and lymph nodes were analyzed by flow cytometry and immunohistochemistry after subset-specific surface marker labeling and TUNEL staining. Exposure of MDCs to berberine during BM cell differentiation reduced cell recovery by inducing apoptosis. Sensitivity to berberine-induced apoptosis was acquired starting on day 3 of DC differentiation, and mature DCs were more sensitive to berberine than immature DCs. Murine peritoneal macrophages, RAW 264.7 cells, and Jurkat cells were insensitive to berberine-induced apoptosis. Splenic DCs were more sensitive to berberine than T and B cells. Susceptibility of PDCs to berberine-induced apoptosis was similar to that of MDCs. In mice with CIA, berberine treatment ameliorated arthritis, suppressed CII-specific immune responses, and selectively increased the incidence of apoptosis in DCs within spleens and lymph nodes. These findings show that berberine selectively induces apoptosis in DCs. Berberine may thus represent a novel therapeutic agent for RA.


Induction of rat hepatic and intestinal alkaline phosphatase activity produced by bile from bile duct-ligated animals.
Bile duct ligation caused a threefold elevation of not only hepatic but also intestinal alkaline phosphatase. The increase was transient in intestinal mucosa and peaked at 12 h. Hepatic phosphatase levels reached a plateau by 36 h. Intraperitoneal injection of bile from ligated animals into normal rats produced qualitatively similar results. Studies were performed to further characterize the induction of phosphatase activity in both tissues. The addition of bile from ligated animals to organ explants of liver and intestine produced a two- and threefold rise in activity, respectively. Therefore, neural and hormonal factors are not essential in producing this induction. The increased activity produced in vitro in both tissues was due to heat-stable and dialyzable factor(s) and was blocked by inhibitors of protein synthesis. In the intestine activity occurred over the entire brush border as demonstrated by electron microscopic histochemistry. In the liver, increased activity was noted over the entire plasma membrane and was not localized to the canalicular membrane. Tunicamycin treatment of liver and intestinal explants markedly suppressed the induced phosphatase activity. Simultaneous treatment with protease inhibitors restored some of the phosphatase activity. These findings suggest that glycosylation of the alkaline phosphatase might provide at least partial protection from proteolysis.


Genetic basis for virulence differences of various Cryptosporidium parvum carcinogenic isolates.
Cryptosporidium parvum is known to cause life-threatening diarrhea in immunocompromised hosts and was also reported to be capable of inducing digestive adenocarcinoma in a rodent model. Interestingly, three carcinogenic isolates of C. parvum, called DID, TUM1 and CHR, obtained from fecal samples of naturally infected animals or humans, showed higher virulence than the commercially available C. parvum IOWA isolate in our animal model in terms of clinical manifestations, mortality rate and time of onset of neoplastic lesions. In order to discover the potential genetic basis of the differential virulence observed between C. parvum isolates and to contribute to the understanding of Cryptosporidium virulence, entire genomes of the isolates DID, TUM1 and CHR were sequenced then compared to the C. parvum IOWA reference genome. 125 common SNVs corresponding to 90 CDSs were found in the C. parvum genome that could explain this differential virulence. In particular variants in several membrane and secreted proteins were identified. Besides the genes already known to be involved in parasite virulence, this study identified potential new virulence factors whose functional characterization can be achieved through CRISPR/Cas9 technology applied to this parasite.


Facial deformities and their treatment.
Even minor facial deformities impose a burden on the personality: the face is vital for its identification of the individual. Defects in facial form cannot be concealed. The origins of most deformities lie in the bony skeleton. They may be either congenital or acquired. In the congenital deformities, form, size and function are disturbed during the course of development, whereas in the acquired deformities parts of the face are lost by surgery or trauma. Occlusion is always affected in deformities of the central and lower thirds of the face. Conversely, massive disturbances of occlusion have repercussions on facial form. Congenital deformities should be corrected early if function is also disturbed, but additional correction is often necessary after growth is complete. If only the proportions of the bony skeleton of the face are affected, the deformity is corrected after the termination of growth. Reconstruction of normal occlusion is essential in the correction of facial deformities. Tissue missing as a result of surgery or trauma is replaced by grafts. Disturbances of development caused by local disease (neoplasia or osteomyelitis) affecting the face constitute an intermediate form of deformity. These defects should receive only functional correction during growth, final reconstruction not being undertaken until it is complete.


Charged amino acids (R83, E567, D617, E625, R669, and K678) of CusA are required for metal ion transport in the Cus efflux system.
Gram-negative bacteria expel various toxic chemicals via tripartite efflux pumps belonging to the resistance-nodulation-cell division superfamily. These pumps span both the inner and outer membranes of the cell. The three components of these tripartite systems are an inner-membrane, substrate-binding transporter (or pump); a periplasmic membrane fusion protein (or adaptor); and an outer-membrane-anchored channel. These three efflux proteins interact in the periplasmic space to form the three-part complexes. We previously presented the crystal structures of both the inner-membrane transporter CusA and membrane fusion protein CusB of the CusCBA tripartite efflux system from Escherichia coli. We also described the co-crystal structure of the CusBA adaptor-transporter, revealing that the trimeric CusA efflux pump assembles with six CusB protein molecules to form the complex CusB(6)-CusA(3). We here report three different conformers of the crystal structures of CusBA-Cu(I), suggesting a mechanism on how Cu(I) binding initiates a sequence of conformational transitions in the transport cycle. Genetic analysis and transport assays indicate that charged residues, in addition to the methionine pairs and clusters, are essential for extruding metal ions out of the cell.


Dynamic quantum clustering: a method for visual exploration of structures in data.
A given set of data points in some feature space may be associated with a Schrödinger equation whose potential is determined by the data. This is known to lead to good clustering solutions. Here we extend this approach into a full-fledged dynamical scheme using a time-dependent Schrödinger equation. Moreover, we approximate this Hamiltonian formalism by a truncated calculation within a set of Gaussian wave functions (coherent states) centered around the original points. This allows for analytic evaluation of the time evolution of all such states opening up the possibility of exploration of relationships among data points through observation of varying dynamical distances among points and convergence of points into clusters. This formalism may be further supplemented by preprocessing such as dimensional reduction through singular-value decomposition or feature filtering.


An active Mitochondrial Complex II Present in Mature Seeds Contains an Embryo-Specific Iron-Sulfur Subunit Regulated by ABA and bZIP53 and Is Involved in Germination and Seedling Establishment.
Complex II (succinate dehydrogenase) is an essential mitochondrial enzyme involved in both the tricarboxylic acid cycle and the respiratory chain. In Arabidopsis thaliana, its iron-sulfur subunit (SDH2) is encoded by three genes, one of them (SDH2.3) being specifically expressed during seed maturation in the embryo. Here we show that seed SDH2.3 expression is regulated by abscisic acid (ABA) and we define the promoter region (-114 to +49) possessing all the cis-elements necessary and sufficient for high expression in seeds. This region includes between -114 and -32 three ABRE (ABA-responsive) elements and one RY-enhancer like element, and we demonstrate that these elements, although necessary, are not sufficient for seed expression, our results supporting a role for the region encoding the 5' untranslated region (+1 to +49). The SDH2.3 promoter is activated in leaf protoplasts by heterodimers between the basic leucine zipper transcription factors bZIP53 (group S1) and bZIP10 (group C) acting through the ABRE elements, and by the B3 domain transcription factor ABA insensitive 3 (ABI3). The in vivo role of bZIP53 is further supported by decreased SDH2.3 expression in a knockdown bzip53 mutant. By using the protein synthesis inhibitor cycloheximide and sdh2 mutants we have been able to conclusively show that complex II is already present in mature embryos before imbibition, and contains mainly SDH2.3 as iron-sulfur subunit. This complex plays a role during seed germination sensu-stricto since we have previously shown that seeds lacking SDH2.3 show retarded germination and now we demonstrate that low concentrations of thenoyltrifluoroacetone, a complex II inhibitor, also delay germination. Furthermore, complex II inhibitors completely block hypocotyl elongation in the dark and seedling establishment in the light, highlighting an essential role of complex II in the acquisition of photosynthetic competence and the transition from heterotrophy to autotrophy.


Sudden switchover between the polyamorphic phase separation and the glass-to-liquid transition in glassy LiCl aqueous solutions.
Lithium chloride aqueous solutions (LiClaq solutions) below 10 mol.% are vitrified by cooling from room temperature to 77 K at 0.3 GPa. We examine the solvent state of the glassy sample and its transformation by heating at 1 atm using low-temperature differential scanning calorimetry and Raman spectroscopy. This experimental study suggests strongly that the solvent state of the glassy LiClaq solution closely relates to the state of high-density amorphous ice. Moreover, we reconfirm that the separation into the low-density amorphous ice and the glassy highly concentrated LiClaq solution occurs in the glassy dilute LiClaq solution at ∼130 K, not the glass-to-liquid transition which is commonly observed in the glassy LiClaq solution above ∼10 mol.%. In order to interpret the sudden switchover between the glass-to-liquid transition and the phase separation at ∼10 mol.%, we propose a state diagram of LiClaq solution which connects with a polyamorphic state diagram of pure water and discuss a possibility that the electric field induces a polyamorphic transition of water.


Evaluating the stage of change model to a cervical cancer screening intervention among Ohio Appalachian women.
Cervical cancer incidence and mortality rates are disproportionally high among women living in Appalachia Ohio. This study used the Transtheoretical Model to examine screening barriers before and after a lay health advisor (LHA) intervention (2005-2009) to increase cervical cancer screening rates. Ohio Appalachian women (n = 90) who were in need of a Pap test, based on risk-appropriate guidelines, were randomized to a 10-month LHA intervention and received two in-person visits, two phone calls, and four mailed postcards targeted to the participant's stage of change. Findings revealed that 63% had forward stage movement 10 months after the intervention. The most frequently reported screening barriers were time constraints, forgetting to make an appointment, and cost. Women who reported the following barriers-doctor not recommending the test; being unable to afford the test; and being embarrassed, nervous, or afraid of getting a Pap test-were less likely to be in the action stage. Understanding the stages of change related to Pap testing and reported barriers among this underserved population may help inform researchers and clinicians of this population's readiness for change and how to set realistic intervention goals.


Cloning adult animals - what is the genetic age of the clones?
The rapid progress in cloning research along with its many ramifications will soon have a significant beneficial impact on basic research, agriculture, and biomedicine. However, for the nuclear transfer technology to reach its fullest potential, it is important to understand whether the cloning procedure can reverse cellular aging and generate clones with normal genetic and physiological age, similar to those produced from natural reproduction. Telomere shortening is believed to correlate with cellular aging both in vitro and in vivo. Telomere lengths in cells of cloned individuals thus may reflect their genetic age. However, controversies have developed over whether the eroded telomere in somatic cells used for nuclear transfer can be restored during the cloning process.


High-Speed Intrinsic Dissolution Rate in One Minute Using the Single-Particle Intrinsic Dissolution Rate Method.
Intrinsic dissolution rate (IDR) has traditionally been determined from a constant surface area of a substance. Here we present an optofluidic single-particle intrinsic dissolution rate (SIDR) method, by means of which real-time determination of IDR from continuously changing effective surface areas of dissolving individual microparticles, is possible. The changing surface area of the individual microparticles is characterized through continuous random orientation 3D particle morphology characterization during the dissolution process. Using noninvasive optical monitoring and nonspecific image analysis, we determined IDRs of a diverse set of substances from individual pure-substance microparticles (14-747 μg) with an average relative standard deviation of 9.4%. A linear fit between SIDR and literature equilibrium solubility values (R(2) = 0.999) was achieved and kinetic solubility equivalent SIDRs were obtained, for all substances, in as little as 1 min. Such miniaturized methods could become valuable tools in drug discovery, by providing resource sparing higher quality data acquisition means to replace current high-throughput solubility methods.


Giant fusiform aneurysm presenting as fatal basilar artery occlusion.
Fusiform aneurysms are often asymptomatic, and therefore their actual incidence is unknown. Ischemic stroke has been linked to dislodgment of small thrombi formed inside the aneurysm but is uncommon. This article describes two patients with rapidly fatal infarction in the entire pons, both cerebellar hemispheres, thalamus, and occipital lobes, findings consistent with occlusion of the vertebrobasilar artery complex. In both patients, autopsies revealed a giant fusiform aneurysm of the basilar artery.


Persistent hyperinsulinemic neonatal hypoglycemia caused by focal nesidioblastosis. Preoperative diagnosis by pancreatic venous sampling.
A female infant with persistent hyperinsulinemic hypoglycemia is described. Persistent euglycemia could not be achieved by diazoxide, somatostatin and frequent, low protein feeds. Preoperative localization of focal insulin hypersecretion by percutaneous pancreatic venous sampling allowed excision of only a small pancreatic portion which was followed by normalization of blood glucose levels.


Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms.
Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two-way interaction trauma history × MAOA genotype. There was a significant three-way interaction trauma history × MAOA genotype × depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation.


Detecting mutation pattern of drug-resistant Mycobacterium tuberculosis isolates in Himachal Pradesh using GenoType(®) MTBDRplus assay.
Tuberculosis (TB) is a major public health problem in India and a principal cause of death in adults, especially among the economically productive age group. India accounts for one-fifth of the global burden of TB. It is estimated that about 40% of Indian population is infected with TB bacillus. The GenoType® MTBDRplus molecular method allows rapid diagnosis of the clinical samples and detection of the most common mutations in the genes associated with rifampicin (R) and isoniazid (H) resistance. To study the drug resistance and mutational patterns in multidrug-resistant (MDR) suspects clinical strains using GenoType® MTBDRplus assay. A total of 770 sputum samples of the MDR-TB suspects were included in this study, which were received at Intermediate Reference Laboratory, Government TB Sanatorium, Dharampur, Solan, Himachal Pradesh from the Designated Microscopy Centres of Himachal Pradesh for the culture and susceptibility testing. All the 521 Mycobacterium tuberculosis complex (MTBC) strains were subjected to GenoType® MTBDRplus (HAIN Lifescience) assay to detect molecular resistance pattern to first line anti-tubercular drugs (isoniazid and rifampicin). Of 770 samples, 556 (72.20%) were from male and 214 (27.80%) were from female. Among the 521 MTBC strains, 19.76% were found to be MDR and mono-resistance to isoniazid and rifampicin was detected in 8.63% and 6.14% strains respectively. About 74.81%, 76.35% and 5.40% strains harboured known mutation in rpoB, katG and inhA genes respectively. In rpoB gene, the most common mutation is associated with S531 L region. The GenoType® MTBDRplus assay is a rapid test for the detection of the most common mutations in MDR-TB strains. In our study, unknown rpoB gene mutations were found in 25.18% strains that may further be detected by gene sequencing.


Mental health in the Dutch population and in general practice: 1987-2001.
In the last 15 years, both the demand for and supply of specialised mental health care increased considerably in the Netherlands. Increased demand may reflect a change in psychological morbidity, but may also be a consequence of increased supply. Specialised health care in the Netherlands is accessible only through referral by a GP, and so it is important to consider the role of primary care in the diagnosis of mental health problems. The aim of this study is to achieve a better understanding of the development of mental health status in the Dutch population and the consequent help-seeking behaviour in primary care. Using two comparable morbidity studies carried out in the Dutch population and in primary care, we compared data from 1987 and 2001 to assess the following: possible differences in mental health between 1987 and 2001; possible differences in prevalence of mental disorder as diagnosed by GPs in 1987 and 2001; possible differences in the sociodemographic determinants of mental health and mental disorder in primary care between 1987 and 2001. Our results show an increase in mental and social problems in the population between 1987 and 2001. However, GPs diagnosed fewer patients as having a mental disorder in 2001 than they did in 1987. The risk of mental disorders or social problems in several sociodemographic groups remained largely the same, as did the chance of receiving a psychological or social diagnosis. We conclude that, while mental disorder in the population is increasing, the role of primary care has changed. Although GPs diagnose a lower percentage of mental problems as such, they refer an increasingly larger proportion of these to secondary care.


Caregivers, young people with complex needs, and multiple service providers: a study of triangulated relationships.
Five patterns of service provider-caregiver-adolescent interaction are discussed using qualitative interviews and file review data from 44 youth with complex needs who were clients of more than one psychosocial service (child welfare, mental health, addictions, juvenile justice, and special education). Findings show that young people and their families become triangulated with service providers, either engaging with, or resisting, interventions. For young people with complex needs involved with multiple service providers, both positive and negative patterns of interaction contribute to the complexity of caregiver-child interactions. According to young people themselves, the most functional of these patterns, empowerment, was experienced as protective when it helped them to meet their personal needs and enhance communication. In contrast, four problematic patterns produced triangulations described as conflictual or unsupportive. The implications of these patterns for family therapy are discussed with an emphasis on the therapist as both clinician and advocate for better services from multiple providers.


The dilated cardiomyopathies: experimental aspects.
Dilated cardiomyopathy is characterized by the primacy of systolic dysfunction. Experimental animal models have contributed greatly to our current knowledge and promise to continue to expand our understanding, especially as methods of cellular and molecular biology are increasingly applied. Although specific etiologies dominate in some forms of dilated cardiomyopathy, the cause is generally multifactorial--that is, the full expression results from the interplay of a number of etiologic and enhancing factors. Recognition of these factors paves the way for therapy as well as primary and secondary prevention. This article has focused chiefly on experimental models of dilated cardiomyopathy associated with congestive heart failure and on interventions producing or aggravating heart failure. Many factors associated with the production or aggravation of experimental myocardial necroses have not been considered here. Even so, this overview reaffirms the concept that dilated cardiomyopathies are pluricausal. In Table 3, the major processes identifies as pathogenetic in experimental dilated cardiomyopathy are listed. Table 4 presents a list of major categories of enhancing factors. The evidence offered in this article indicates that in most models many pathogenetic mechanisms and enhancing factors may be operative, and this is also believed to be the case in human dilated cardiomyopathy Recognition of the multifactorial etiologies of the dilated cardiomyopathies is an important first step in therapeutic and preventive interventions. Experimental work in human dilated cardiomyopathy has not been included in this article, but some recent studies provide challenging insights.


Benefits of Integrating an Explicit Self-Efficacy Intervention With Calculation Strategy Training for Low-Performing Elementary Students.
This study examined the malleability of math self-efficacy (SE) among children with poor calculation fluency via an intervention that targeted four sources of SE (mastery experiences, vicarious experiences, social persuasions, and emotional and physiological states). The effect of pure strategy training was contrasted with an intervention that integrated strategy training and explicit SE support. Moreover, the changes in SE source experiences and their relation with math SE, as well as the relation between math-SE profiles and calculation fluency development, were examined. In a quasi-experimental design, 60 Finnish children with calculation fluency problems in Grades 2 to 4 participated in strategy training (N = 38) or in an intervention that integrated SE support with strategy training (N = 32) for 12 weeks. The results showed that the explicit SE intervention integrated with strategy training enhanced math SE among children with poor calculation fluency and low SE (effect size, r = 0.61). Changes in mastery experiences and social persuasions were positively associated with changes in math SE among children who received the explicit SE intervention. An initially high math-SE profile and a profile indicating an increase from low to high math SE were related to growth in calculation fluency that approached the children's average age level during the interventions. In conclusion, an integrated approach that combined skill training and SE intervention was especially beneficial for children with poor calculation fluency and low math SE.


Injection Moulding into 3D-Printed Plastic Inserts Produced Using the Multi Jet Fusion Method.
Most injection-moulded plastics are injection moulded into moulds made from conventional materials such as steel or aluminium. The production costs of the mould are considerable. 3D printing from plastic can be used for injection moulds to save these costs. This article deals with injection moulding into a 3D-printed plastic mould. The injection insert was produced on a HP Multi Jet Fusion 4200 3D printer. The other part of the mould was made of aluminium. A custom injection mould was designed for the research. One insert was made from plastic, and one from aluminium. Both moulds were injected under the same injection conditions. A comparison of injection moulding into the plastic and aluminium inserts is made in this article. The difference when injection moulding into the plastic insert is explained using the different technological conditions. The part injected into the plastic insert was also different from the part injected into the aluminium insert. The difference is explained in this article. This article also looks at the interface between the injection-moulded part and the plastic insert using an electron microscope. The images taken clarify the differences between injection moulding into a plastic insert and an aluminium insert and the differences of the injection-moulded part from the plastic insert.


A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma.
The hypereosinophilic syndromes (HESs) are a heterogeneous group of diseases characterized by peripheral blood eosinophilia with end-organ damage and varying in severity from nonspecific symptoms to life-threatening. Treatment objectives are a safe reduction of blood and tissue eosinophil levels and prevention of eosinophil-mediated tissue damage. Current treatment of patients with HESs, who lack the FIP-1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion gene, is mainly systemic corticosteroid therapy. Eosinophil development from hematopoietic progenitor cells is regulated by IL-5, which influences maturation, differentiation, mobilization, activation, and survival. Consequently, inhibiting IL-5 is a logical therapeutic objective for patients with HESs or selected patients with asthma. Mepolizumab is a fully humanized anti-IL-5 monoclonal IgG(1) antibody that binds to free IL-5 with high affinity and specificity to prevent IL-5 from associating with the IL-5 receptor complex alpha-chain on the surface of eosinophils. In clinical trials with patients with HESs, mepolizumab reduced blood eosinophil counts and the maintenance corticosteroid dose and had no major safety concerns. Mepolizumab reduced airway and blood eosinophils and prevented asthma exacerbations. Thus, mepolizumab may be effective for long-term treatment of patients with selected eosinophilic disorders.


Local Decision Making for Implementing Social Distancing in Response to Outbreaks.
Social distancing is the practice of restricting contact among persons to prevent the spread of infection. This study sought to (1) identify key features of preparedness and the primary concerns of local public health officials in deciding to implement social distancing measures and (2) determine whether any particular factor could explain the widespread variation among health departments in responses to past outbreaks. We conducted an online survey of health departments in the United States in 2015 to understand factors influencing health departments' decision making when choosing whether to implement social distancing measures. We paired survey results with data on area population demographic characteristics and analyzed them with a focus on broad trends. Of 600 health departments contacted, 150 (25%) responded. Of these 150 health departments, 63 (42%) indicated that they had implemented social distancing in the past 10 years. Only 10 (7%) health departments had a line-item budget for isolation or quarantine. The most common concern about social distancing was public health impact (n = 62, 41%). Concerns about law, politics, finances, vulnerable populations, and sociocultural issues were each identified by 7% to 10% of health departments. We were unable to clearly predict which factors would influence these decisions. Variations in the decision to implement social distancing are likely the result of differences in organizational authority and resources and in the primary concerns about implementing social distancing. Research and current social distancing guidelines for health departments should address these factors.


Effect of thiol-binding reagents on the metabolism of Chromatium D.
Thiosulfate, intracellular sulfur, and acetate utilization by Chromatium D were inhibited by iodoacetamide, N-ethylmaleimide (NEM), p-hydroxymercuribenzoate (CMB), and HgCl(2). Pyruvate, sulfide, and sulfite utilization were insensitive to iodoacetamide, and were less sensitive to NEM, CMB, and HgCl(2) than thiosulfate, intracellular sulfur, and acetate utilization. The effect of the thiol-binding reagents on cell viability was dependent upon the method of exposure; cells exposed to the thiol-binding reagents in the presence of thiosulfate were protected from the killing action of these agents, but not from their inhibitory effect. Although the inhibitory effects of the thiol-binding reagents could, in some cases, be attributed to their effect on viability, they were inhibitory under conditions where viability was unaffected. The most straightforward results were obtained with iodoacetamide, which revealed a sharp separation in sensitivities between the systems tested but had no effect on cell viability. The results are consistent with the hypothesis that thiols are involved in thiosulfate, intracellular sulfur, and acetate utilization.


Exponentially Accelerated Approach to Stationarity in Markovian Open Quantum Systems through the Mpemba Effect.
Ergodicity breaking and slow relaxation are intriguing aspects of nonequilibrium dynamics both in classical and quantum settings. These phenomena are typically associated with phase transitions, e.g., the emergence of metastable regimes near a first-order transition or scaling dynamics in the vicinity of critical points. Despite being of fundamental interest the associated divergent timescales are a hindrance when trying to explore steady-state properties. Here we show that the relaxation dynamics of Markovian open quantum systems can be accelerated exponentially by devising an optimal unitary transformation that is applied to the quantum system immediately before the actual dynamics. This initial "rotation" is engineered in such a way that the state of the quantum system no longer excites the slowest decaying dynamical mode. We illustrate our idea-which is inspired by the so-called Mpemba effect, i.e., water freezing faster when initially heated up-by showing how to achieve an exponential speeding-up in the convergence to stationarity in Dicke models, and how to avoid metastable regimes in an all-to-all interacting spin system.


Related Factors of Suicidal Ideation among North Korean Refugee Youth in South Korea.
This study investigated the factors associated with suicidal ideation among 174 North Korean refugees (aged 13⁻27 years) residing in South Korea. Specifically, we compared sociodemographic, familial, social, and psychological characteristics between participants with and without suicidal ideation. Twenty-nine refugees (16.7%) had exhibited suicidal ideation in the past 12 months. These refugees had significantly lower levels of familial cohesion (U = 1459.0; p < 0.001), self-esteem (U = 1032.0; p < 0.001), and resilience (U = 1190.0; p < 0.001), as well as higher levels of expressional suppression (U = 1202.5; p < 0.001) and post-traumatic stress disorder symptoms (U = 1303.0; p = 0.001), (with Cohen's d > 0.5), compared to those without suicidal ideation. A multiple logistic regression analysis showed that the level of emotional suppression and familial cohesion were significantly associated with suicidal ideation, after controlling for the other variables. Familial and individual interventions, particularly those focused on encouraging emotional expression and familial cohesion, will be useful for North Korean refugee youth, who have a high risk of suicide.


Captopril in congestive heart failure resistant to other vasodilators.
In an attempt to study the possible mechanism(s) by which captopril controls resistant heart failure, sequential haemodynamic studies (radioisotope technique) and humoral measurements (plasma renin activity, plasma aldosterone and plasma catecholamines) were obtained in 11 such patients. The studies were made at the time patients became unresponsive to other vasodilators (hydralazine or prazosin); the vasodilator drug was then discontinued and five days later, the 'no-vasodilator' studies were obtained. Captopril therapy was then started. Optimum daily maintenance dose of captopril varied from 75 to 200 mg in different patients. Studies were again repeated after a period of time equal to the duration of the previous vasodilator therapy. Digitalis and diuretic doses were kept constant throughout. Captopril improved effort tolerance in ten patients. Haemodynamically, mean blood pressure and peripheral resistance were lower than during vasodilator therapy (85 +/- 3.1 v. 92 +/- 3.3 mmHg and 47 +/- 4.4 v. 59 +/- 4.4 U.M2, respectively; p less than 0.05 for both). Cardiac index was higher during captopril treatment (1.95 +/- 0.15 v. 1.63 +/- 0.10 l/m2, p less than 0.01) and pulmonary mean transit was normalized by captopril (14.6 +/- 1.7 v. 18.4 +/- 1.3 s, p less than 0.05). Humoral indices revealed a significant (p less than 0.05) reduction in plasma aldosterone during captopril therapy (25.9 +/- 5.6 ng/dl during captopril, v. 62 +/- 22 ng/dl with no vasodilators and 50.9 +/- 6.1 ng/dl with other vasodilators). Moreover, there was a decrease in circulating plasma catecholamines during captopril treatment, but differences between the three treatment periods were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)


Dichotomy in the tissue origin of schistosome acquired class I and class II major histocompatibility complex antigens.
Schistosoma mansoni schistosomula recovered from the lungs of mice have previously been shown to express host-derived class I and class II major histocompatibility complex (MHC) antigens. To investigate the tissue origin of parasite-acquired MHC products, lung-stage schistosomula were obtained from a series of parent leads to F1 and F1 leads to parent bone marrow chimeras and the parasites typed by immunofluorescence for the presence of haplotype-specific K region and I region MHC determinants. The results of these experiments indicated that, despite their intravascular residence in the host, schistosomula derive all of their class I antigen from a nonhemapoietic tissue source. In contrast, the class II antigens expressed on the surface of schistosomula were found to originate from bone marrow-derived donor cells. These results support the hypothesis that MHC product acquisition by schistosomes involves selective and specific interactions with host tissue and, in the case of class I antigens, suggest that the endothelium may be a major site of host molecule uptake for the parasite.


Dialysis Requirement and Long-Term Major Adverse Cardiovascular Events in Patients with Chronic Kidney Disease and Superimposed Acute Kidney Injury.
Chronic kidney disease (CKD) patients who experience superimposed acute kidney injury (AKI) have been shown to be at higher risk of long-term sequelae of AKI when compared to those who do not experience AKI. It remains unclear whether the need for temporary dialysis intervention following superimposed AKI in patients with CKD has any effect on the long-term major adverse cardiovascular events (MACE). This study examines the relationship between temporary dialysis therapy following AKI and long-term major cardiovascular events in patients with background CKD. The study population consists of adults who developed AKI while on admission at the University of Virginia Medical Center between January 1, 2002 and December 31, 2012, and who had preadmission estimated glomerular filtration rate (eGFR) between 20 and 60 mL/min/1.73 m2 and survived beyond 30 days of AKI. Demographic and baseline clinical variables were used to generate propensity score. Survivors who had temporary dialysis were matched to those managed conservatively according to the propensity score in a ratio of 1:3. Overall, 6,634 (n = 381 and 6,253 in the temporary dialysis-requiring AKI and non-dialysis AKI groups respectively) met entry criteria for the full cohort. Of these, 381 (5.7%) received temporary dialysis. There were 3,147 (47.4% of all patients) MACE events during the study period. The crude incidence for MACE after 30 days of AKI was similar in both dialyzed and non-dialyzed patients. After the propensity score matching, the adjusted hazard ratio for MACE in dialyzed versus non dialyzed patients was 1.162 (95% CI 0.978-1.381). Treatment of AKI with temporary dialysis in hospitalized patients with baseline eGFR between 20 and 60 mL/min/1.73 m2 was not associated with an increased risk for subsequent admission for MACE. If confirmed by prospective studies, clinicians may not need to worry that the dialysis procedure may contribute to additional risk for long-term MACE in CKD patients with superimposed AKI.


Estimation of Starch and Sugar Intake in a Japanese Population Based on a Newly Developed Food Composition Database.
Due to a lack of a food composition database on starch and sugars, we developed a comprehensive database on starch and seven types of sugars in commonly consumed foods (n = 2222) in Japan. Dietary record data of 368 toddlers (aged 18⁻35 months), 376 preschool children (aged 3⁻6 years), 915 schoolchildren (aged 8⁻14 years) and 392 adults (aged 20⁻69 years) were used. The mean starch intake ranged from 55.6 g/day (female toddlers) to 206.0 g/day (male schoolchildren). Irrespective of age and sex, >50% of starch was provided by rice and grains. The mean total sugar intake ranged from 46.1 g/day (female toddlers) to 68.7 g/day (male schoolchildren). In all age and sex groups, the major contributors of total sugar included sucrose (mean: 18.2⁻34.0 g/day), glucose (7.8⁻13.1 g/day), lactose (5.3⁻13.1 g/day) and fructose (7.6⁻11.1 g/day). The top food sources were dairy products (toddlers) and confectionaries (other age groups) for total sugar, confectionaries for sucrose, fruits (toddlers) and vegetables (other age groups) for glucose, dairy products for lactose and fruits (toddlers and preschool children) and vegetables (schoolchildren and adults) for fructose. In conclusion, this study clarified the starch and sugar intake in Japan and provides a foundation for future research.


Charge separation in a ruthenium-quencher conjugate bound to DNA.
A novel tris heteroleptic dipyridophenazine complex of ruthenium(II), [{Ru(phen)(dppz)(bpy'-his)}{Ru(NH3)5}]5+, containing a covalently tethered ruthenium pentammine quencher coordinated through a bridging histidine has been synthesized and characterized spectroscopically and biochemically in a DNA environment and in organic solvent. Steady-state and time-resolved luminescence measurements indicate that the tethered Ru complex is quenched relative to the parent complexes [Ru(phen)(dppz)(bpy')]2+ and [Ru(phen)(dppz)(bpy'-his)]2+ in DNA and acetonitrile, consistent with intramolecular photoinduced electron transfer. Intercalated into guanine-containing DNA, [{Ru(phen)(dppz)(bpy'-his)}{Ru(NH3)5}]5+, upon excitation and intramolecular quenching, is capable of injecting charge into the duplex based upon the EPR detection of guanine radicals. DNA-mediated charge transport is also indicated using a kinetically fast cyclopropylamine-substituted base as an electron hole trap. Guanine damage is not observed, however, in measurements using the guanine radical as the kinetically slower hole trap, indicating that back electron-transfer reactions are competitive with guanine oxidation. Moreover, transient absorption measurements reveal a novel photophysical reaction pathway for [{Ru(phen)(dppz)(bpy'-his)}{Ru(NH3)5}]5+ in the presence of DNA that is competitive with the intramolecular flash-quench process. These results illustrate the remarkably rich redox chemistry that can occur within a bimolecular ruthenium complex intercalated in duplex DNA.


Arthritis due to Mycobacterium xenopi: a retrospective study of 7 cases in France.
Mycobacterium xenopi is a nontuberculous mycobacterium responsible for opportunistic and nosocomial infections, chiefly of the lung; few cases of bone and joint infection have been reported. From July 1989 through May 1993, an outbreak of 58 cases of nosocomial discitis due to M. xenopi infection following percutaneous nucleotomy occurred in a French hospital. Peripheral M. xenopi arthritis seems exceedingly rare. We conducted a study to assess the epidemiological and clinical patterns of M. xenopi arthritis. We retrospectively reviewed cases of M. xenopi arthritis reported from May 1993 through October 2004. We identified 7 cases, all of which occurred after invasive surgical procedures were performed on the affected joint, suggesting a nosocomial pattern of infection. Two patients may have been contaminated at the hospital where the M. xenopi discitis outbreak occurred. No source was identified in the other 5 patients. Despite the probable nosocomial nature of the infections, the diagnosis was delayed (mean time until diagnosis, 50 months). Repeated collection of deep tissue specimens for bacteriological analysis seemed crucial to the diagnosis. The treatment relied on combination antimicrobial therapy and surgery. Among 11 cases of M. xenopi osteoarticular infection reported in the literature from 1975 to 2005, (arthritis in 9 cases and osteitis in 2), none were nosocomial. A high index of suspicion should be maintained to ensure the diagnosis of M. xenopi arthritis before chronic monoarthritis and before the development of irreversible joint damage.


Melanoma antigen-encoding gene family member A1-6 and hTERT in the detection of circulating tumor cells following CD45- depletion and RNA extraction.
A total of 76 blood samples from patients without malignant disease and 107 blood samples from patients with malignant disease were investigated for the presence of circulating tumor cells (CTCs). To detect CTCs, hematopoietic cells were removed from the blood samples and different RNA extraction methods were used to amplify the melanoma antigen-encoding gene family member A1-family member A6 (MAGE A1-6) and the human telomerase reverse transcriptase (hTERT) gene as potential CTC markers. Comparison between four methods for extracting RNA from the blood was performed. The samples were enriched by cluster of differentiation 45 (CD45) antibody capturing, and the reverse transcription-quantitative polymerase chain reaction was used to amplify the MAGE A1-6 and hTERT genes. MAGE A1-6 and hTERT gene expression levels were also evaluated in 14 cancer cell lines, and the MAGE A1-6 and hTERT expression levels were 85.7 and 100%, respectively. The RNeasy method demonstrated the most sensitivity in the SNU1 cells mixed with blood, although the differences between methods was non-significant. The positive expression levels of MAGE A1-6 and hTERT was 11.8% in the control group and 58.9% in those with malignant disease. In the 70 patients with colorectal cancer, positive expression levels of MAGE A1-6 or hTERT were significantly higher in stages T3 and T4 compared with in stages T1 and T2. The CTC detection method involving CD45 antibody capture, RNA extraction and MAGE A1-6 and hTERT reverse transcription resulted in good rates of sensitivity and specificity. Thus, the present study concluded that MAGE A1-6 and hTERT genes may be potential and practical markers for CTCs in a clinical setting.


The future of cassava in the era of biotechnology in Southern Africa.
Cassava (Manihot esculenta) is a major staple food and the world's fourth source of calories. Biotechnological contributions to enhancing this crop, its advances, and present issues must be assessed regularly. Functional genomics, genomic-assisted breeding, molecular tools, and genome editing technologies, among other biotechnological approaches, have helped improve the potential of economically important crops like cassava by addressing some of its significant constraints, such as nutrient deficiency, toxicity, poor starch quality, disease susceptibility, low yield capacity, and postharvest deterioration. However, the development, improvement, and subsequent acceptance of the improved cultivars have been challenging and have required holistic approaches to solving them. This article provides an update of trends and gaps in cassava biotechnology, reviewing the relevant strategies used to improve cassava crops and highlighting the potential risk and acceptability of improved cultivars in Southern Africa.


Correct Diabetes Diagnosis and Treatment Allows Sailor to Remain on Active Duty.
Diabetes is a growing epidemic worldwide and among our active duty population, posing a significant threat to maintaining military health and operational readiness. Latent autoimmune diabetes in adults (LADA) is a growing clinical phenotype of diabetes, with overlap between traditional type 1 diabetes mellitus and type 2 diabetes mellitus. In this case, a 27-year-old active duty male presented with polydipsia, polyuria, polyphagia, and recent weight loss. He was diagnosed with LADA, placed on a period of limited duty status and started on insulin. Eight months after diagnosis, he was transitioned from insulin to a glucagon-like peptide-1 receptor agonist in an effort to be returned to full duty status and worldwide deployable. Over 3 years after initial diagnosis, he has achieved partial clinical remission. He remains on active duty, serving on a medically limited platform with a single medication (a glucagon-like peptide-1 receptor agonist) and high compliance with a gluten-free, low-carbohydrate diet and regular exercise. One should consider the diagnosis of LADA and its unique management, especially in the younger active duty population. Not only is making the correct diagnosis regarding the type of diabetes critical in regard to prognosis and optimal medical management, but it can affect the ability of military members to remain on active duty.


Events shape long-term memory for story information.
We segment what we read into meaningful events, each separated by a discrete boundary. How does event segmentation during encoding relate to the structure of story information in long-term memory? To evaluate this question, participants read stories of fictional historical events and then engaged in a post-reading verb arrangement task. In this task, participants saw verbs from each of the events placed randomly on a computer screen, and then they arranged the verbs into groups onscreen based on their understanding of the story. Participants who successfully comprehended the story placed verbs from the same event closer to each other than verbs from different events, even after controlling for orthographic, text-based, semantic, and situational overlap between verbs. Thus, how people structure story information into separate events during online comprehension is associated with how that information is stored in memory. Specifically, story information within an event is bound together in memory more so than information between events.


Differential oxidative modulation of voltage-dependent K+ currents in rat hippocampal neurons.
Oxidative stress is enhanced by [Ca2+]i-dependent stimulation of phospholipases and mitochondria and has been implicated in immune defense, ischemia, and excitotoxicity. Using whole cell recording from hippocampal neurons, we show that arachidonic acid (AA) and hydrogen peroxide (H2O2) both reduce the transient K+ current I(A) by -54 and -68%, respectively, and shift steady-state inactivation by -10 and -15 mV, respectively. While AA was effective at an extracellular concentration of 1 microM and an intracellular concentration of 1 pM, extracellular H2O2 was equally effective only at a concentration >800 microM (0.0027%). In contrast to AA, H2O2 decreased the slope of activation and increased the slope of inactivation of I(A) and reduced the sustained delayed rectifier current I(K(V)) by 22% and shifted its activation by -9 mV. Intracellular application of the antioxidant glutathione (GSH, 2-5 mM) blocked all effects of AA and the reduction of I(A) by H2O2. In contrast, intracellular GSH enhanced reduction of I(K(V)) by H2O2. Decrease of the slope of activation and increase of the slope of inactivation of I(A) by hydrogen peroxide was blocked and reversed to a decrease, respectively, by intracellular application of GSH. Intracellular GSH did not prevent H2O2 to shift inactivation and activation of I(A) and activation of I(K(V)) to more negative potentials. We conclude, that AA and H2O2 modulate voltage-activated K currents differentially by oxidation of GSH accessible intracellular and GSH inaccessible extracellular K+-channel domains, thereby presumably affecting neuronal information processing and oxidative damage.


An inquiry into protein structure and genetic disease: introducing undergraduates to bioinformatics in a large introductory course.
This inquiry-based lab is designed around genetic diseases with a focus on protein structure and function. To allow students to work on their own investigatory projects, 10 projects on 10 different proteins were developed. Students are grouped in sections of 20 and work in pairs on each of the projects. To begin their investigation, students are given a cDNA sequence that translates into a human protein with a single mutation. Each case results in a genetic disease that has been studied and recorded in the Online Mendelian Inheritance in Man (OMIM) database. Students use bioinformatics tools to investigate their proteins and form a hypothesis for the effect of the mutation on protein function. They are also asked to predict the impact of the mutation on human physiology and present their findings in the form of an oral report. Over five laboratory sessions, students use tools on the National Center for Biotechnology Information (NCBI) Web site (BLAST, LocusLink, OMIM, GenBank, and PubMed) as well as ExPasy, Protein Data Bank, ClustalW, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the structure-viewing program DeepView. Assessment results showed that students gained an understanding of the Web-based databases and tools and enjoyed the investigatory nature of the lab.


Simultaneous removal of H2S and NH3 in biofilter inoculated with Acidithiobacillus thiooxidans TAS.
H2S and NH3 gases are toxic, corrosive and malodorous air pollutants. Although there are numerous well-established physicochemical techniques presently available for the treatment of these gases, the growing demand for a more economical and improved process has prompted investigations into biological alternatives. In biological treatment methods, H2S is oxidized to SO4(2-) by sulfur-oxidizing bacteria, and then NH3 is removed by chemical neutralization with SO4(2-) to (NH4)2SO4. Since the accumulated (NH4)2SO4 can inhibit microbial activity, it is important to utilize an effective sulfur-oxidizing bacterium that has tolerance to high concentrations of (NH4)2SO4 for the simultaneous removal of H2S and NH3. In this study, a sulfur-oxidizing bacterium with tolerance to high concentrations of (NH4)2SO4 was isolated from activated sludge and identified as Acidithiobacillus thiooxidans TAS. A. thiooxidans TAS could display its sulfur-oxidizing activity in a medium supplemented with 60 g.l(-1) (NH4)2SO4, even though its growth and sulfur-oxidizing activity were completely inhibited in 80 g.l(-1) (NH4)2SO4. When H2S alone was supplied to a ceramic biofilter inoculated with A. thiooxidans TAS, an almost 100% H2S removal efficiency was maintained until the inlet H2S concentration was increased up to 900 microl.l(-1) and the space velocity up to 500 h(-1), at which the amount of H2S eliminated was 810 g-S.m(-3).h(-1). However, when NH3 (50-500 microl.l(-1)) was simultaneously supplied to the biofilter with H2S, the maximum amount of H2S eliminated decreased to 650 g-S.m(-3).h(-1). The inhibition of H2S removal by low NH3 concentrations (50-200 microl.l(-1)) was similar to that by high NH3 concentrations (300-500 microl.l(-1)). The critical inlet H2S load that resulted in over 99% removal was determined as 400 g-S.m(-3).h(-1) in the presence of NH3.