[Significance of indices of potential selection for residents of the USSR].
Crow's indices of the opportunity for selection and their components connected with differential mortality (Im) and differential fertility (If) were estimated for populations of Soviet Union republics and for a number of USSR ethnic groups on the basis of demographic statistics. More than 10-fold decrease in the Im value was revealed in the total population of the USSR during 1926-1987. At present, the Im values in republics vary from 0.020 to 0.094 for urban population and from 0.030 to 0.121 in rural population, the ratio of perinatal mortality in the whole structure of prereproductive mortality being higher in the republics with lower values of the Im. The range of the If values for different peoples (0.148-0.643) is wider than for the populations of the republics (0.326-0.578). Interethnic differences contribute 47% of the variance in fertility. The structure of Crow's indices is given for urban and rural populations of the republics. Genetic implications of the data presented are discussed with respect to possible manifestation of the effects of inter-group selection.


Hydrodynamics and collective behavior of the tethered bacterium Thiovulum majus.
The ecology and dynamics of many microbial systems, particularly in mats and soils, are shaped by how bacteria respond to evolving nutrient gradients and microenvironments. Here we show how the response of the sulfur-oxidizing bacterium Thiovulum majus to changing oxygen gradients causes cells to organize into large-scale fronts. To study this phenomenon, we develop a technique to isolate and enrich these bacteria from the environment. Using this enrichment culture, we observe the formation and dynamics of T. majus fronts in oxygen gradients. We show that these dynamics can be understood as occurring in two steps. First, chemotactic cells moving up the oxygen gradient form a front that propagates with constant velocity. We then show, through observation and mathematical analysis, that this front becomes unstable to changes in cell density. Random perturbations in cell density create oxygen gradients. The response of cells magnifies these gradients and leads to the formation of millimeter-scale fluid flows that actively pull oxygenated water through the front. We argue that this flow results from a nonlinear instability excited by stochastic fluctuations in the density of cells. Finally, we show that the dynamics by which these modes interact can be understood from the chemotactic response of cells. These results provide a mathematically tractable example of how collective phenomena in ecological systems can arise from the individual response of cells to a shared resource.


Detecting human CD34+ and CD34- hematopoietic stem and progenitor cells using a Sysmex automated hematology analyzer.
In clinical medicine, particularly in the newly developing stem cell therapies required to support the practice of regenerative medicine, the measurement of both CD34+ and CD34- hematopoietic stem cells (HSC)/hematopoietic progenitor cells (HPC) is important in obtaining more accurate information about the total HSC/HPC content in various stem/progenitor cell sources. We report the results of an investigation into methods of detecting CD34+ and CD34- HSC/HPC using the immature information (IMI) channel incorporated into the Sysmex XE-2100 and SE-9000 automated hematology analyzers. In this study, CD34+ and CD34- HSC/HPC were separated by immunologic methods and quantified by flow cytometry (FACScan) and IMI channel analysis. In addition, CD34-/CD133+ HSC were prepared by a sequential antibody-based positive selection strategy. These cells appeared in the same area as CD34+ cells in the IMI channel of the automated hematology analyzer. These findings confirmed that an automated hematology analyzer can be used to measure both CD34+ and CD34- HSC. These results may explain the difference in HSC/HPC counts sometimes observed between the automated hematology analyzer and flow cytometric methods for CD34+ measurement. The results of this study demonstrated the potential of automated cell counting methods for measuring HSC content in cellular products for both research and clinical applications.


Geographic predictors of primary multidrug-resistant tuberculosis cases in an endemic area of Lima, Peru.
Peru reports among the highest multidrug-resistant tuberculosis (MDR-TB) rates in the Americas, with a growing proportion in previously untreated tuberculosis (TB) cases. The identification of clusters of primary MDR-TB compared with drug-susceptible TB (DS-TB) could help prioritize interventions. To examine the clustering of primary MDR-TB case residences and their proximity to high-risk locations in San Juan de Lurigancho District, Lima, Peru. Enrolled primary MDR-TB and primary DS-TB cases were interviewed and their primary residence was recorded using handheld Global Positioning System devices. Kuldorff's spatial scan statistic was used for cluster detection (SaTScan(TM), v. 9.1.1). Identified clusters were visualized in Quantum Geographic Information Systems software (v1.8.0). The following cluster centers were tested: a health centre with the highest TB and MDR-TB rates (Clinic X), a hospital and two prisons. Using regression analyses, we examined predictors of primary MDR-TB cases. A statistically significant cluster of primary MDR-TB cases was identified within a 2.29 km radius around Clinic X. Proximity to Clinic X remained a significant predictor of primary MDR-TB in adjusted regression analyses. We identified a hotspot of primary MDR-TB cases around Clinic X in a TB-endemic area. Causes of this clustering require investigation; targeted interventions for this high-risk area should be considered.


The Roles of Sclerostin in Immune System and the Applications of Aptamers in Immune-Related Research.
Wnt signaling is one of the fundamental pathways that play a major role in almost every aspect of biological systems. In addition to the well-known influence of Wnt signaling on bone formation, its essential role in the immune system also attracted increasing attention. Sclerostin, a confirmed Wnt antagonist, is also proven to modulate the development and differentiation of normal immune cells, particularly B cells. Aptamers, single-stranded (ss) oligonucleotides, are capable of specifically binding to a variety of target molecules by virtue of their unique three-dimensional structures. With in-depth study of those functional nucleic acids, they have been gradually applied to diagnostic and therapeutic area in immune diseases due to their various advantages over antibodies. In this review, we focus on several issues including the roles of Wnt signaling and Wnt antagonist sclerostin in the immune system. For the sake of understanding, current examples of aptamers applications for the immune diseases are also discussed. At the end of this review, we propose our ideas for the future research directions.


Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative.
The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind.


AMP-activated protein kinase regulates the expression of human telomerase reverse transcriptase.
The expression of hTERT in tumor cells contributes to oncogenic transformation by promoting immortalization. For this reason, hTERT is one of the major targets for cancer therapy, and an efficient method to downregulate hTERT expression is required for treatment of hTERT-positive cancer. In this report, we demonstrated that inhibition of AMP-activated protein kinase (AMPK) downregulates the expression of hTERT. We screened cell signaling pathways in AMPK α1 knockout cells and found that AMPKα1 is required for activity of the hTERT promoter. AMPKα1 knockout cells showed decreased expression of hTERT mRNA and protein. We also demonstrated that compound C, a reversible AMPK inhibitor, suppressed the expression of hTERT. However, AMPK activators, including AICAR and metformin, did not increase the level of hTERT protein. Finally, we showed that tumor cells stably expressing hTERT are resistant to compound C treatment. These results indicate that AMPK activity is required for tumor progression.


Do drug interaction alerts between a chemotherapy order-entry system and an electronic medical record affect clinician behavior?
We developed an enhancement to a chemotherapy order-entry system that alerted prescribers to potential drug interactions between patients' usual outpatient medications and those prescribed for onsite cancer treatment. This report summarizes the interactions and analyzes the impact of alerts on clinician behavior. We studied electronic orders created from November 2010 to December 2011 by oncology clinicians at two comprehensive cancer centers who shared a chemotherapy order-entry system and an ambulatory electronic medical record. The enhancement generated an alert if a new chemotherapy system order for an antineoplastic agent or supportive care medication interacted with an existing medication in the ambulatory record, and tracked prescribers' responses. New chemotherapy system orders triggered 29,592 drug interaction alerts. New orders for antineoplastic agents accounted for 495 (32.6%) of 1518 high- and medium-severity alerts. Interactions with antibiotics accounted for the majority of these alerts. New chemotherapy system orders for antiemetics triggered 352 (23.2%) alerts and more than two-thirds were attributed to interactions with analgesic opioids. High- and medium-severity alerts changed prescriber behavior in 224 (14.8%) occurrences, including potentially fatal interactions between meperidine and monoamine oxidase inhibitors. Clinicians who overrode alerts indicated that they would monitor the patient (54.6%), the patient already tolerated the combination (24.5%), and they would adjust the dose (15.1%). Cancer patients are at risk of serious interactions between medications ordered for cancer care and those provided for general medical care. Organizations and order-entry applications should develop countermeasures to identify and prevent potentially serious drug interactions.


[Neurologic manifestations in Ollier's disease].
The authors describe a case of Ollier's syndrome which developed in a 31-year-old female patient. The patient manifested hypertrophy of osseous and soft tissues, deformity of the dorsum sellae and of the walls of the cavernous sinus and siphon of the internal carotid artery. In the clinical picture of the disease, one could see symptoms of the impairment of pairs III and VI of the craniocerebral nerves, pains due to the irritation of the first branch of nerve V.


Prevalence and treatment costs of infant caries in Northern California.
To determine the prevalence of infant caries in low-socioeconomic-status children and to analyze the costs of their treatment, we retrospectively evaluated 357 children, ages eight months to seven years, who were treated during 1992 at a university-associated medical center in Northern California. Infant caries was diagnosed by several different standards, and prevalence varied according to the diagnostic criteria employed: 27 percent by the presence of any labiolingual lesion on the maxillary incisors; 32 percent by the presence of at least two carious maxillary incisors; 27 percent by the presence of at least three carious maxillary incisors; and 36 percent by a dmft > or = 5. Prevalence was higher among boys than girls (37 percent versus 27 percent), and highest in the group ages 3-4 years (43 percent). The cost of dental treatment increased with deft and ranged from $408 for deft 2-5 to $1725 for deft 16-20. Many patients failed to comply with recommended treatment for reasons of cost. Our results showed that (1) the prevalence of infant caries varies depending upon the clinical criteria used for diagnosis; (2) the cost of rehabilitating primary dentition increases in proportion to the number of teeth involved; and (3) low-income patients avoid treatment of infant caries for a variety of reasons related to the cost involved.


Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1.
Retinal degenerative diseases result in retinal pigment epithelial (RPE) and photoreceptor cell loss. These cells are continuously exposed to the environment (light) and to potentially pro-oxidative conditions, as the retina's oxygen consumption is very high. There is also a high flux of docosahexaenoic acid (DHA), a PUFA that moves through the blood stream toward photoreceptors and between them and RPE cells. Photoreceptor outer segment shedding and phagocytosis intermittently renews photoreceptor membranes. DHA is converted through 15-lipoxygenase-1 into neuroprotectin D1 (NPD1), a potent mediator that evokes counteracting cell-protective, anti-inflammatory, pro-survival repair signaling, including the induction of anti-apoptotic proteins and inhibition of pro-apoptotic proteins. Thus, NPD1 triggers activation of signaling pathway/s that modulate/s pro-apoptotic signals, promoting cell survival. This review provides an overview of DHA in photoreceptors and describes the ability of RPE cells to synthesize NPD1 from DHA. It also describes the role of neurotrophins as agonists of NPD1 synthesis and how photoreceptor phagocytosis induces refractoriness to oxidative stress in RPE cells, with concomitant NPD1 synthesis.


Assessment of major carcinogenic tobacco-specific N-nitrosamines in Thai cigarettes.
This report presents new findings on the content of cancer-causing tobacco-specific N-nitrosamines (TSNA) in mainstream smoke of nine brands of commercially produced Thai cigarettes, representing about 85% of market share in Thailand. Also tested were two major and popular brands of U.S. cigarettes sold in Thailand, representing about 10% of market share. The cigarettes included filter and nonfilter cigarettes with high, moderate, and low tar and nicotine yields. The observed range for N-nitrosonornicotine (NNN) was from 28 to 730 ng/cigarette and for 4-(methylnitrosamino)-1-(3-pyridyl-1-butanone (NNK) from 16 to 369 ng/cigarette. The relatively highest TSNA values were obtained in filter and nonfilter cigarettes with high tar (22.3-28.1 mg/cigarette) and high nicotine (1.78-2.42 mg/cigarette) deliveries. The results demonstrated that there is a correlation between TSNA and tar and nicotine deliveries in mainstream smoke. The TSNA deliveries, along with the tar and nicotine levels in mainstream smoke depended on the tobacco composition. According to these results, the tar levels alone, while significant, are not a sufficient measure for the biological activity and the carcinogenic potential of cigarettes in Thailand. Consumption of tobacco products nearly quadrupled over the last three decades (1966-1995) in Thailand. Lung cancer is the leading malignancy for men and a common malignancy for women in Thailand. This report provides information that may prove helpful in evaluating the TSNA-carcinogens burden on smokers. Our goal is to offer the scientific basis for voluntary and/or government-regulated reduction of the smoke yields of TSNA in tobacco products in Thailand and in other countries.


Clinical factors associated with malignancy and HIV status in patients with ocular surface squamous neoplasia at Kilimanjaro Christian Medical Centre, Tanzania.
To describe the clinical characteristics of ocular surface squamous neoplasia (OSSN) in a sub-Saharan referral hospital setting according to histopathological diagnosis and HIV status. All patients were enrolled who presented consecutively to the Kilimanjaro Christian Medical College eye department with lesions suspected to be OSSN from September 2005 to May 2007 and from February 2008 to September 2008. Clinical characteristics were documented on a standardised form, excision biopsies were performed and histopathological diagnosis was obtained on all cases. Data were analysed to look for associations among various factors. 150 patients were enrolled. Histopathological study showed OSSN in 88% of cases. Of these, 128 (85.6%) were under the age of 50 years and 60% were HIV positive. The median CD4 cell count was 71 cells/μl among HIV-positive cases. Independent of size, the lesions of patients who were HIV positive were more likely to be higher grade malignancy than those who were HIV negative. In a sub-Saharan setting, OSSN occurs in persons who are younger than in industrialised countries and is often associated with HIV positivity. CD4 cell counts indicate that a majority of HIV-positive patients with OSSN are significantly immunosuppressed at presentation. Higher grade malignancy in this group could indicate a more aggressive course.


Long-term ACE inhibition doubles lifespan of hypertensive rats.
We compared the outcome of lifelong treatment with the ACE inhibitor ramipril in young prehypertensive stroke-prone spontaneously hypertensive rats (SHR-SP) and age-matched normotensive Wistar-Kyoto (WKY) rats. Ramipril was given in an antihypertensive and subantihypertensive dose. In addition to the primary end point, lifespan, surrogate parameters such as cardiac left ventricular hypertrophy, cardiac function and metabolism, and endothelial function were studied. One-month-old SHR-SP and WKY rats, 135 of each, were randomized into 3 groups. Each group was treated via drinking water with an antihypertensive high dose of ramipril (HRA, 1 mg x kg(-1) x d(-1)), a nonantihypertensive low dose of ramipril (LRA, 10 microg x kg(-1) x d(-1)), or placebo. Body weight and blood pressure were determined every 3 months. Molecular, biochemical, and functional data were assessed in SHR-SP and WKY rats after 15 and 30 months, respectively. These were the times when approximately 80% of the corresponding placebo group had died. Early-onset long-term ACE inhibition with HRA doubled lifespan to 30 months in SHR-SP, which was identical to the lifespan of placebo-treated normotensive WKY rats. LRA treatment prolonged lifespan from 15 to 18 months. In SHR-SP, left ventricular hypertrophy was completely prevented by HRA but not by LRA treatment. Cardiac function and metabolism as well as endothelial function were significantly improved by both doses of ramipril. Carotid expression of endothelial NO synthase was moderately enhanced, whereas cardiac ACE expression and activity were decreased to values of placebo-treated WKY rats. Lifelong ACE inhibition doubles lifespan in SHR-SP, matching that of normotensive WKY rats. This effect correlated with preservation of endothelial function, cardiac function/size, and metabolism. Thus, these data predict a beneficial outcome on survival in high-risk patients with hypertension and associated cardiovascular diseases by ACE inhibition.


Streptococcus anginosus pyogenic liver abscess following a screening colonoscopy.
A previously healthy 58-year-old man presented with a septic thrombosis of the right hepatic vein and a pyogenic liver abscess (PLA) one week after undergoing a screening colonoscopy. Blood cultures and a radiological drainage specimen were both positive for Streptococcus anginosus. Evolution was favourable after six weeks of antibiotherapy. To the authors' knowledge, the present report is the first to describe a PLA following a screening colonoscopy with no intervention. The authors hypothesize that silent microperforations during colonoscopy contributed to the infection. Although 20% to 40% of reported PLA cases are cryptogenic in the literature, it may be because of failure to recognize and report a precipitating factor such as colonoscopy. As more cases similar to the present case are reported, the number of cryptogenic cases may decrease.


Win/win partnerships between Geneva health-related institutions and caregivers of people with dementia: a descriptive cross-sectional study.
In the context of an ageing population and an increase in the appearance of chronic diseases, the commitment of caregivers makes it possible for people confronted with disease to remain at home. Over time, they need support to overcome their difficulties. They also show a need for recognition for their participation in the economic maintenance of the health system. To promote this support, so-called "win/win" partnerships are envisaged. Research is needed to identify the building blocks of an innovative intervention. A cross-sectional descriptive study was carried out with health institutions in the canton of Geneva to identify the proportion of institutions with a positive opinion on partnership with caregivers. It has also identified potential partnerships with caregivers of people facing dementia and possible compensation in exchange for the provision of their skills. Descriptive statistics are presented according to their frequencies and relative percentages (categorical variables), as well as by their mean, standard deviation and median (continuous variables). Logistic regression models were used to assess the factors associated with a favorable opinion towards win/win partnerships. The proportion of executives of health-related institutions with a positive opinion of partnership with caregivers is high: 74.7% (95% CI: 64.8-83.1%). Several types of potential partnerships have been identified between health institutions and caregivers. Areas in which certain activities have been identified as being able to be carried out by caregivers include governance, care, provision of services, accompaniment and support, training and research. Types of compensation for caregivers have also been highlighted. This study shows that some areas activities of health facilities in the canton of Geneva could be the subject of win-win partnerships with caregivers of people with dementia. Positive view of health executives on partnership with caregivers is encouraging. In the future, innovative projects can emerge to meet the needs of each party.


[Diagnosis and treatment of simultaneous injuries of the thorax and abdomen].
Results of examinations and treatment of 167 patients with simultaneous injuries of the thorax and abdomen are presented. It is demonstrated that x-ray and ultrasonic examinations help make choice on right surgical policy. All the patients were divided into two groups. Study group (137 patients) was treated according to proposed curative algorithm. The rest 30 patients were included into control group. Volume of intra-surgical hemorrhage and time of surgery were greater in the control group compared with the study group. Proposed algorithm permitted to reduce number of postoperative complications from 46.7 to 21.2%, and lethality -- from 13.3 to 4.1%.


Type III-Dependent Translocation of HrpB2 by a Nonpathogenic hpaABC Mutant of the Plant-Pathogenic Bacterium Xanthomonas campestris pv. vesicatoria.
The plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria employs a type III secretion (T3S) system to translocate effector proteins into plant cells. The T3S apparatus spans both bacterial membranes and is associated with an extracellular pilus and a channel-like translocon in the host plasma membrane. T3S is controlled by the switch protein HpaC, which suppresses secretion and translocation of the predicted inner rod protein HrpB2 and promotes secretion of translocon and effector proteins. We previously reported that HrpB2 interacts with HpaC and the cytoplasmic domain of the inner membrane protein HrcU (C. Lorenz, S. Schulz, T. Wolsch, O. Rossier, U. Bonas, and D. Büttner, PLoS Pathog 4:e1000094, 2008, http://dx.doi.org/10.1371/journal.ppat.1000094). However, the molecular mechanisms underlying the control of HrpB2 secretion are not yet understood. Here, we located a T3S and translocation signal in the N-terminal 40 amino acids of HrpB2. The results of complementation experiments with HrpB2 deletion derivatives revealed that the T3S signal of HrpB2 is essential for protein function. Furthermore, interaction studies showed that the N-terminal region of HrpB2 interacts with the cytoplasmic domain of HrcU, suggesting that the T3S signal of HrpB2 contributes to substrate docking. Translocation of HrpB2 is suppressed not only by HpaC but also by the T3S chaperone HpaB and its secreted regulator, HpaA. Deletion of hpaA, hpaB, and hpaC leads to a loss of pathogenicity but allows the translocation of fusion proteins between the HrpB2 T3S signal and effector proteins into leaves of host and non-host plants. The T3S system of the plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria is essential for pathogenicity and delivers effector proteins into plant cells. T3S depends on HrpB2, which is a component of the predicted periplasmic inner rod structure of the secretion apparatus. HrpB2 is secreted during the early stages of the secretion process and interacts with the cytoplasmic domain of the inner membrane protein HrcU. Here, we localized the secretion and translocation signal of HrpB2 in the N-terminal 40 amino acids and show that this region is sufficient for the interaction with the cytoplasmic domain of HrcU. Our results suggest that the T3S signal of HrpB2 is required for the docking of HrpB2 to the secretion apparatus. Furthermore, we provide experimental evidence that the N-terminal region of HrpB2 is sufficient to target effector proteins for translocation in a nonpathogenic X. campestris pv. vesicatoria strain.


[Optimization of base editing in Corynebacterium glutamicum].
In recent years, CRISPR/Cas9-mediated base editing has been developed to a powerful genome editing tool, providing advantages such as without introducing double-stranded DNA break, a donor template and relying on host homologous recombination repair pathway, and has been widely applied in animals, plants, yeast and bacteria. In previous study, our group developed a multiplex automated base editing method (MACBETH) in the important industrial model strain Corynebacterium glutamicum. In this study, to further optimize the method and improve the base editing efficiency in C. glutamicum, we first constructed a green fluorescent protein (GFP) reporter-based detection system. The point mutation in the inactivated GFP protein can be edited to restore the GFP fluorescence. By combining with flow cytometry analysis, the base-editing efficiency can be quickly calculated. Then, the base editor with the target gRNA was constructed, and the editing efficiency with the initial editing condition was (13.11±0.21)%. Based on this result, the editing conditions were optimized and the result indicated that the best medium is CGXII, the best initial OD₆₀₀ of induction is 0.05, the best induction time is 20 h, and the best IPTG concentration is 0.01 mmol/L. After optimization, the editing efficiency was improved to (30.35±0.75)%, which was 1.3-fold of that in initial condition. Finally, endogenous genomic loci of C. glutamicum were selected to assess if the optimized condition can improve genome editing in other loci. Editing efficiency of different loci in optimized condition were improved to 1.7-2.5 fold of that in original condition, indicating the effectiveness and versatility of the optimized condition. Our research will promote the better application of base editing technology in C. glutamicum.


Effect of lung volume on the oesophageal diaphragm EMG assessed by magnetic phrenic nerve stimulation.
Previous studies have shown conflicting results on the effect of lung volume on the diaphragm compound muscle action potential (CMAP). Consequently, the ability to quantify the oesophageal diaphragm electromyography (EMG) has been questioned. If lung volume changes have little effect on the diaphragm CMAP the accurate measurement of voluntary EMG, as an index of respiratory drive, may be possible. Furthermore, the measurement of CMAP could provide useful clinical information when evaluating patients with neuromuscular disease. To reassess the effect of lung volume on the oesophageal diaphragm CMAP, six normal subjects were studied using an oesophageal catheter incorporating seven electrodes (number one being proximal and seven distal) that were 1 cm in length and 1 cm apart. Electrode number three was positioned at the centre of the electrically active region of the diaphragm (EARdi) at functional residual capacity (FRC). The diaphragm CMAP elicited by bilateral magnetic stimulation of the phrenic nerves was simultaneously recorded from four electrode pairs. Pair one was created from electrodes one and three, pair two from electrodes two and four, pair three from electrodes three and five, and pair four from electrodes five and seven. Phrenic nerve stimulation was at residual volume (RV), FRC, FRC+1.0 L, FRC+2.0 L, and total lung capacity (TLC). The CMAP recorded from pair one was least influenced by changes in lung volume and the amplitude was 2.41+/-0.39 (mean+/-SD), 2.60+/-0.27, 2.64+/-0.29, and 2.71+/-0.45 mV at RV, FRC, FRC+1.0 L and FRC+2.0 L, respectively. At TLC the CMAP was more variable. The CMAP amplitude recorded from pair two increased with increasing lung volume and at FRC+2.0 L was 3.7 times larger than that at FRC. Pair four usually recorded substantially smaller CMAPs at all lung volumes. This study shows that the diaphragm compound muscle action potential recorded from an oesophageal electrode just above the diaphragm is relatively stable over the lung volume range residual volume to functional residual capacity+2.0 L.


Topical Treatments in Acne Vulgaris: Guidance for the Busy Dermatologist.
Acne is a very common skin disease; frequently seen in adolescents and often persisting or occurring into adulthood. Topical therapy is very effective in mild to moderate disease, and is used as maintenance therapy. Fixed combination products have been studied in moderately severe disease. Combinations of benzoyl peroxide and either clindamycin or adapalene appear very effective. When utilizing a topical retinoid alone or in combination, it is essential to incorporate an appropriate skin care regimen to minimize local irritation. In the absence of direct comparative clinical trials, this review provides timely guidance for clinicians on the use of these agents, and their benefits in special populations.


Crowding-induced structural alterations of random-loop chromosome model.
We investigate structural alterations of random-loop polymers due to changes in the crowding condition, as a model to study environmental effects on the structure of chromosome subcompartments. The polymer structure is changed in a nonmonotonic fashion with an increasing density of crowders: condensed at small volume fractions; decondensed at high crowding volume fractions. The nonmonotonic behavior is a manifestation of the nontrivial distance dependence of the depletion interactions. We also show that crowding-induced structural alterations affect the access of binding proteins to the surface of polymer segments and are distinguished from structural changes due to the increased number of specific polymer loops.


Carotid endarterectomy among Medicare beneficiaries: a statewide evaluation of appropriateness and outcome.
We sought to examine the appropriateness and the surgical outcomes of carotid endarterectomy (CE) in unselected community hospitals to identify opportunities for improvement. We performed a retrospective review of all CEs performed on Medicare beneficiaries in Georgia in 1993 (n = 1945). Conclusions regarding appropriateness were based on current guidelines as interpreted by a physician reviewer and were supported by the aggregate results of structured, blinded overreading by clinicians with relevant expertise. Adverse outcomes were confirmed and rated as to severity by a physician. Outcomes were correlated with demography, vascular anatomic findings, comorbidity, surgical techniques, and hospital characteristics. The majority of the patients (51%) were asymptomatic at presentation. CEs were performed appropriately in 96.1% of the cases in accordance with current guidelines. There was no significant difference in the rate of appropriateness between the symptomatic (96%) and the asymptomatic patients (96.4%). Survival without stroke or myocardial infarction (MI) was 94.3%. The 30-day mortality was 1.9%; moderate to severe strokes occurred in 1.8%, stroke-related death in 0.7%, MI in 1.1%, and MI-related death in 0.5%. Those hospitals performing <10 CEs in the observed year had a statistically significant higher morbidity and mortality as well as an increase in less severe complications such as hematomas, wound dehiscence, wound infection, and pneumonia than did hospitals with higher volume of CEs.. Older patients and women had statistically significantly higher morbidity and mortality. Patients with a Charlson Severity Index score of > or =1 had a risk for adverse outcomes 3.4 times higher than patients with a score of 0 after adjustment for age and sex. The great majority of CEs performed in Georgia on Medicare patients were appropriate, according to current guidelines. Slightly more than half of the patients were asymptomatic as defined in the Asymptomatic Carotid Atherosclerosis Study. In hospitals performing <CEs in the index year, we noted higher morbidity and mortality, as well as an increase in less severe complications. This relationship between the volume of surgery and outcome was confirmed in the analysis of the 30-day mortality for all Medicare cases (n = 10,569) performed in Georgia from 1991 to 1995. This was the most important opportunity for improvement identified in this study. In view of the increased use of CE, it is important to continue to monitor the patterns of practice for this procedure to improve outcomes.


[Model investigations of the impedance effectiveness conerning bacterial relevant to food hygiene].
The impedance technique mostly meets today's requirements of microbiological rapid methods. At relatively high prime cost for the equipment the advantages are marked by low personnel and material costs as well as swiftness combined with highly flexible usage. The method is applicable for both quantitative and qualitative examinations but can fail occasionally in total count determination, especially if the sample material contains heterogeneous microbes. In model investigations with 53 strains of 17 different genera Enterobacteriaceae strains, Aeromonads and Enterococcus strains proved to be highly impedance effective. Lactobacillus strains and Pseudomonads as well as Staphylococcus aureus strains showed a low impedance effectiveness. Several strains, for example of the genera Micrococcus, Acinetobacter and Brochothrix, did not show any changes of the medium impedance under the chosen conditions. Criterion for characterization of impedance effectiveness was the impedance detection time starting with identical initial counts (10(3) cfu/ml). Impedance effectiveness of microbes was determined at highly varying degree by the parameters of generation time, lag-phase duration and relative activity. This can lead either to wrong negative (underestimations) or wrong positive (overestimations) results of bacterial count.


High-dose liposomal amphotericin B in the therapy of systemic candidiasis in neonates.
High-dose (5-7 mg/kg/day) liposomal amphotericin B was evaluated prospectively during the period 1995-2001 in 41 episodes of systemic candidiasis occurring in 37 neonates (36 of the 37 were premature infants with very low birth weights). Median age at the onset of systemic candidiasis was 17 days. Candida spp. were isolated from blood in all patients and from urine, skin abscesses and peritoneal fluid in 6, 5 and 1 neonates, respectively. Candidiasis was due to Candida parapsilosis in 17 cases, Candida albicans in 15 cases, Candida tropicalis in 5 cases, Candida guilliermondii in 2 cases, Candida glabrata in 2 cases and an unidentified Candida sp. in 1 case. Twenty-eight, five and eight infants received 7, 6-6.5 and 5 mg/kg/day, respectively. Median duration of therapy was 18 days; median cumulative dose was 94 mg/kg. Fungal eradication was achieved in 39 of 41 (95%) episodes; median duration of therapy until fungal eradication was 8.7+/-4.5 days. Fungal eradication was achieved after 10.9+/-4.8 days in patients who had received previous antifungal therapy compared to 8.2+/-4.3 days in those treated with liposomal amphotericin B as first-line therapy. One patient died due to systemic candidiasis on day 12 of therapy. High-dose liposomal amphotericin B was effective and safe in the treatment of neonatal candidiasis. Fungal eradication was more rapid in patients treated early with high doses and in patients who received high-dose liposomal amphotericin B as first-line therapy.


Prospective, multi-center study of the effectiveness of orthodontic/orthognathic surgery care in the United Kingdom.
The aim of this study was to evaluate the effectiveness of orthodontic/orthognathic surgical care provided in the North West region of England. It was an observational, prospective cohort study at 13 maxillofacial clinics in the United Kingdom. The 131 patients comprised 47 males (35.9%) and 84 females (64.1%), with an average age of 22.6 years. They received orthodontic/orthognathic treatment according to the normal protocols of the operators. They were then followed until all orthodontic treatment was completed. Final skeletal pattern, final peer assessment rating score, number of attendances, and duration of treatment were recorded. At the end of the 5-year study, 94 patients had completed treatment, and 71 had complete data. Data analysis showed that, overall, the treatments provided were effective in terms of skeletal and dental occlusal outcomes; the final mean peer assessment rating score was 10.58. However, treatment duration was longer than commonly expected, with a mean length of 32.8 months (SD,11.3). The outcome of treatment was influenced by only pretreatment skeletal discrepancy. This prospective investigation showed that orthodontic/orthognathic surgical care was effective. The outcome of treatment was influenced only by the severity of the pretreatment skeletal discrepancy.


Use of time differences in normal hearing--cortical processing of promontorial stimuli.
To test the hypothesis that ability to discriminate small duration differences is positively correlated with activity in the right temporal lobe, we used positron emission tomography in six normally hearing subjects, stimulated via the promontory in a procedure that mimics the auditory nerve stimulation with a cochlear implant. Stimulus consisted of electrical bursts, and tasks included gap detection and temporal difference limen (TDL). TDL is a measure of discriminatory processing of sound duration in cochlear implant candidates, demonstrated to predict outcome. Good speech perception after cochlear implantation is associated with activity in right temporal areas. Although perceived variably by the subjects, the stimulus itself activated bilateral secondary somatosensory cortex, suggesting differential stimulation of multiple sensory modalities. Only TDL raised blood flow in both posterior middle temporal gyri (MTG) and the right prefrontal cortex. As the right posterior MTG is known to be active during duration discrimination of different modalities and in the perception of words containing manipulated phonemes, we conclude that recruitment of this part of the right hemisphere is important to the comprehension of speech containing mostly temporal cues. The study shows that stimulus-induced activation reflects the goal of the task rather than the nature of the stimulus.


Scion on a stock producing siRNAs of potato spindle tuber viroid (PSTVd) attenuates accumulation of the viroid.
Plants can attenuate the replication of plant viruses and viroids by RNA silencing induced by virus and viroid infection. In higher plants, silencing signals such as small interfering RNAs (siRNAs) produced by RNA silencing can be transported systemically through phloem, so it is anticipated that antiviral siRNA signals produced in a stock would have the potential to attenuate propagation of viruses or viroids in the scion. To test whether this is indeed the case, we prepared transgenic tobacco (Nicotiana benthamiana) expressing a hairpin RNA (hpRNA) of Potato spindle tuber viroid (PSTVd) in companion cells by using a strong companion cell-specific promoter. A grafting experiment of the wild type tobacco scion on the top of the transgenic tobacco stock revealed that accumulation of PSTVd challenge-inoculated into the scion was apparently attenuated compared to the control grafted plants. These results indicate that genetically modified rootstock expressing viroid-specific siRNAs can attenuate viroid accumulation in a non-genetically modified scion grafted on the stock.


Developmental aspects of the intracerebral microvasculature and perivascular spaces: insights into brain response to late-life diseases.
The development of the microvasculature of the human cerebral cortex offers insight into the response of the cerebral cortex to later-life brain injury. We describe the 3 basic and distinct components of the developmental anatomy of the cerebral cortical microvascular system. The first compartment is meningeal and, therefore, extracerebral. In addition to the major venous sinuses, arachnoidal arteries, and veins, the pial anastomotic capillary plexus that covers the surface of the developing and adult cerebral cortex represents the source of thepenetrating vessels that become the second component, the intracerebral extrinsic microvascular compartment. During embryogenesis, sprouting vascular elements from pial capillaries pierce the brain's external glial limiting membrane and penetrate the cortex. These vessels, which eventually differentiate into arterioles and venules, are separated from the cortical tissue by the extravascular Virchow-Robin compartment (V-RC) formed between the internal vascular and the external glial basal laminae. The V-RC remains open to the meningeal interstitial spaces and outside the blood-brain barrier (BBB) and acts asa prelymphatic drainage system for removal of substances that cannot be transported into the blood or catabolized intracellularly. The third element is the dense intracerebralintrinsic microvascular compartment. Intracerebral capillary vessels sprout from the perforating vessels, penetrate through the Virchow-Robin glial membrane, and enter the neuropil. Intracerebral capillaries lack smooth muscle and a V-RC and consist only of endothelial cells separated from the intracerebral space by a basal lamina. Their role as the physiological BBB is the exchange of oxygen, glucose, and small molecules. This developmental perspective highlights 3 principles: (a) the V-RC is intimately related to the cortical penetrating arterioles and venules and represents an inefficient protolymphatic system that lacks the anatomic and physiological constituents found in lymphatic beds elsewhere in the body; (b)the anatomic contiguity of the V-RC and the penetrating vascular compartment (arterioles and venules) implies that the pathology in 1 compartment could lead to dysfunction in the others; and (c) the anatomic localization of the immunologic BBB at the level of the penetrating venules might impose constraints on immunologically mediated transport involving the V-RC.


A phase II trial of paclitaxel and cisplatin in patients with locally advanced metastatic esophageal cancer: a preliminary report.
We demonstrated in an earlier trial that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has substantial antineoplastic activity, with acceptable toxicity, in patients with advanced metastatic esophageal cancer. Preclinical and clinical data from studies in other tumors indicate substantial additive or even synergistic activity for paclitaxel/cisplatin combination chemotherapy. We encountered substantial toxicity with a cisplatin/paclitaxel/5-fluorouracil combination. To maximize paclitaxel dose, we initiated a phase II trial using cisplatin and paclitaxel alone. This report summarizes preliminary data from that trial. Paclitaxel 200 mg/m2 is given as a continuous, 24-hour infusion on day 1. On day 2, cisplatin 75 mg/m2 is given. Courses are repeated every 21 days. Dose adjustments are based on myelosuppression, neurotoxicity, and (for cisplatin) renal or auditory toxicity. All patients receive recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary end point of the study is tumor regression. Secondary end points include duration of response and toxicity. Two groups of patients are being studied. Those with advanced metastatic disease receive chemotherapy alone as palliative treatment. The second group has locoregional disease that is potentially resectable. These patients receive combined-modality therapy involving induction paclitaxel/cisplatin chemotherapy followed by surgery. To date, 37 evaluable patients have been treated. Twenty had advanced metastatic disease and 17 were treated before planned surgery. Twenty-seven patients had adenocarcinoma and 10 had epidermoid carcinoma. Major objective responses were seen in 49% of all patients, with similar response rates for patients with metastatic and locoregional disease. The median duration of response for patients with metastases is 4+ months. Among 14 patients treated before surgery, one experienced a complete pathologic response, and the neoplasms of 43% were downstaged. Primary toxicity was neutropenia, which was tolerable. Surgical morbidity or mortality did not increase. Cisplatin plus paclitaxel is an active combination in the treatment of patients with advanced or locoregional esophageal cancer. Further studies with this combination both in metastatic and locally advanced disease are indicated.


Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia.
A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.


Is enough oxygen too much?
Human cells require O2 for their energy supply, and critical illness can threaten the efficient delivery of O2 in accordance with tissue metabolic needs. In the accompanying article, Martin and colleagues point out that hypoxia is a normal and well-tolerated stress during embryonic development. A better understanding of how fetal cells survive these conditions and how adult cells adapt to high altitude exposure may provide insight into how these mechanisms might be engaged in the treatment of hypoxemic patients. They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O2 levels we should consider the broader effects of hypoxia on tissue repair in critical illness.


The development of knee osteoarthritis and serum carotenoid levels among community-dwelling people in Japan.
Carotenoids are plant pigments found in many vegetables, functioning as antioxidants scavenging singlet molecular oxygen and peroxyl radicals. No longitudinal study exists on the relationship between carotenoids and knee osteoarthritis (KOA) development. We aimed to determine the incidence of KOA development for 10 years in community-dwelling people in Japan and assess its association with serum carotenoids. Data of 440 participants (174 men, 266 women) with health-screening records for at least 10 years were analysed. We defined KOA development as advancing from K/L grade 0/1 at the initial check-up to grade ≥2 in a unilateral knee during a 10-year follow-up period. Serum carotenoid levels were measured using high-performance liquid chromatography. We used the Cox hazard model for multivariate analysis and investigated each carotenoid's impact on KOA development. KOA developed in 33.4% of patients; the annual KOA development rate was significantly higher among women than among men (p < .01; 3.4% vs. 1.6%). Among the carotenoids measured, only retinol was associated with KOA development in women using multivariable analysis. KOA development was not associated with any carotenoids in men. The annual rate of KOA development was higher in women, and retinol was associated with KOA development in women.


Life events, psychopathology, and suicidal behavior in Chinese adolescents.
Little is known about risk factors of suicidal behavior among Chinese adolescents. This study examined the associations between negative life events, psychopathology, and suicidal behavior in rural adolescents of China. A total of 1362 adolescent students in a rural prefecture of China completed a self-administered questionnaire concerning suicidal behavior, psychopathology, life events, and demographics. Data analyses were conducted using multivariate logistic regression modeling. Females were more likely to report suicidal ideation than males (22.0% vs. 17.5%). While the rate of suicide attempt was slightly higher in younger males (12-15 years) than in females (4.7% vs. 3.1%), the rate was higher in older females (16-18 years) than in males (12.7% vs. 9.5%). Suicide attempters reported more negative life events during the past year than suicidal ideators and non-suicidal adolescents. Academic stress and family conflicts were the major stress domains of adolescents at risk for suicidal behavior. A significant dose-response relationship was observed between the number of life events and suicidal behavior. Negative life events were also associated with increased risk for internalizing and externalizing problems. Both internalizing and externalizing problems were significantly associated with elevated risk for suicidal behavior after negative life events were controlled. This is a cross-sectional study. Longitudinal study is warranted to examine the roles of life stress in adolescent suicidal behavior. Adolescents who experienced more negative life events are at increased risk for suicidal behavior. Both internalizing and externalizing problems mediate the effect of life events on adolescent suicidal behavior.


The Role of Sequential BMP Signaling in Directing Human Embryonic Stem Cells to Bipotential Gonadal Cells.
Human gonads arise as a pair of epithelial ridges on the surface of intermediate mesoderm (IM)-derived mesonephros. Toxic environmental factors and mutations in various genes are known to disturb normal gonadal development, but because of a lack of suitable in vitro models, detailed studies characterizing the molecular basis of the observed defects have not been performed. To establish an in vitro method for studying differentiation of bipotential gonadal progenitors by using human embryonic stem cells (hESCs) and to investigate the role of bone morphogenetic protein (BMP) in gonadal differentiation. We tested 17 protocols using activin A, CHIR-99021, and varying durations of BMP-7 and the BMP inhibitor dorsomorphin. Activation of activin A, WNT, and BMP pathways was optimized to induce differentiation. Academic research laboratory. Cell differentiation, gene expression, and flow cytometry. The two most efficient protocols consistently upregulated IM markers LHX1, PAX2, and OSR1 at days 2 to 4 and bipotential gonadal markers EMX2, GATA4, WT1, and LHX9 at day 8 of culture. The outcome depended on the combination of the duration, concentration, and type of BMP activation and the length of WNT signaling. Adjusting any of the parameters substantially affected the requirements for other parameters. We have established a reproducible protocol for directed differentiation of hESCs into bipotential gonadal cells. The protocol can be used to model early gonadal development in humans and allows further differentiation to mature gonadal somatic cells.


Accounting for Patient Preferences Regarding Life-Sustaining Treatment in Evaluations of Medical Effectiveness and Quality.
The importance of understanding patient preferences for life-sustaining treatment is well described for individual clinical decisions; however, its role in evaluations of healthcare outcomes and quality has received little attention. Decisions to limit life-sustaining therapies are strongly associated with high risks for death in ways that are unaccounted for by routine measures of illness severity. However, this essential information is generally unavailable to researchers, with the potential for spurious inferences. This may lead to "confounding by unmeasured patient preferences" (a type of confounding by indication) and has implications for assessments of treatment effectiveness and healthcare quality, especially in acute and critical care settings in which risk for death and adverse events are high. Through a collection of case studies, we explore the effect of unmeasured patient resuscitation preferences on issues critical for researchers and research consumers to understand. We then propose strategies to more consistently elicit, record, and harmonize documentation of patient preferences that can be used to attenuate confounding by unmeasured patient preferences and provide novel opportunities to improve the patient centeredness of medical care for serious illness.


Blood inflammatory and endothelial markers in women with von Willebrand disease.
VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls. The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI. Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle. Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia-common complication of VWF deficiency. The latter statement requires confirmation in larger studies.


[Genetic ecology of rice allelopathy on receiver plant].
In this study, 5 parental rice lines with different allelopathic potential were employed in partial diallel cross (4 x 5) to get 10 groups of F1 seeds. After testing the inhibitory effects of 5 parents and 10 F1s under different environment at different leaf stage on the shoot length of receiver plant lettuce(Lactuca sativa L.), dynamic genetics of rice allelopathy and its genotype x environment effects were analyzed by using additive-dominant developmental genetic models. The results showed that additive and dominant effect genes expressed alternatively during 3-leaf stage to 8-leaf stage in rice seedling. As additive effect genes were pronounced at 7-leaf stage, dominant effect genes appeared to play the most important role at 3-leaf stage and 6-leaf stage but the two effect genes were equally important at 5-leaf stage and 8-leaf stage. Heritabilities analysis indicated that the general heritability in the narrow sense(HN2) was significant at 5-, 7- and 8-leaf stage, and decreased with increasing leaf stage. Rice allelopathy was significantly affected by genotype x environment (GE) interaction, suggesting that the environment of allelopathic rice development must be controlled for practical use.


In-Vivo and Ex-Vivo Tissue Analysis through Hyperspectral Imaging Techniques: Revealing the Invisible Features of Cancer.
In contrast to conventional optical imaging modalities, hyperspectral imaging (HSI) is able to capture much more information from a certain scene, both within and beyond the visual spectral range (from 400 to 700 nm). This imaging modality is based on the principle that each material provides different responses to light reflection, absorption, and scattering across the electromagnetic spectrum. Due to these properties, it is possible to differentiate and identify the different materials/substances presented in a certain scene by their spectral signature. Over the last two decades, HSI has demonstrated potential to become a powerful tool to study and identify several diseases in the medical field, being a non-contact, non-ionizing, and a label-free imaging modality. In this review, the use of HSI as an imaging tool for the analysis and detection of cancer is presented. The basic concepts related to this technology are detailed. The most relevant, state-of-the-art studies that can be found in the literature using HSI for cancer analysis are presented and summarized, both in-vivo and ex-vivo. Lastly, we discuss the current limitations of this technology in the field of cancer detection, together with some insights into possible future steps in the improvement of this technology.


[Effects of vibration and noise on the reproductive function in experimental animals].
Experimental animal studies of the reproduction function were performed under prolonged vibration and noise conditions. For 4 months and 5 days male white rats were exposed to 4-hour noise and vibration effect in a noise-protected chamber. The correlated vibration velocity index was 5.07.10(-2) m/s. The permanent wide range noise level reached 92 dBA. It was established that: in a long-term experiment, vibration and noise affected the reproduction function in male white rats; in a combined vibration and noise action, marked changes in the reproduction function were revealed, and in the noise exposition alone, the function changes were not so vivid.


Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake.
Fructose induces metabolic syndrome in rats; but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake. Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid, and markers of inflammation were assessed. Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with up-regulation of fructose-dependent transporter Glut5 and fructokinase. Fatty liver and low-grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro. Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver, and type 2 diabetes mellitus in male breeder rats; and the effects are independent of excess energy intake.


Phorbol ester inhibits arginine vasopressin activation of phospholipase C and promotes contraction of, and prostaglandin production by, cultured mesangial cells.
We have previously shown that arginine vasopressin (AVP) causes a rapid (5-10 min) contractile response in cultured mesangial cells plated onto slippery substrata such as poly(hydroxyethyl methacrylate)-coated dishes. This contraction is associated with an increase in the levels of inositol trisphosphate (InsP3), diacylglycerol and prostaglandin E2 (PGE2). We now report that agents which are known to activate protein kinase C, i.e. phorbol 12-myristate 13-acetate (PMA) and oleolylacetylglycerol (OAG), also contract mesangial cells; however, the contractile response is slow to develop (15-30 min). The inactive phorbol ester, 4 alpha -phorbol 12,13-didecanoate, did not elicit contraction. PMA and OAG did not increase InsP3 release in mesangial cells. However, pretreatment of mesangial cells with PMA inhibited the formation of InsP3. This inhibition could not be explained by a reduction in AVP binding since PMA treatment did not influence the number or affinity of [3H]AVP binding sites in intact cells. PMA alone stimulated PGE2 production in mesangial cells to a degree similar to AVP. Contrary to what was seen with InsP3, pretreatment of cells with PMA before AVP had an additive effect on arachidonic acid release and PGE2 production. Thus, there is an apparent dissociation of phospholipase C activity from that of phospholipase A2.


Long-term management of severe ocular surface injury due to methamphetamine production accidents.
The aim of this study was to report the clinical features and management of patients with ocular surface damage during methamphetamine production accidents. This is a retrospective noncomparative interventional case series of 5 patients with methamphetamine production-related ocular injuries referred to the Cincinnati Eye Institute between 1999 and 2014. Four of 5 cases were white young men with severe bilateral ocular injury and extremely poor vision. All except 1 eye (9 of 10) were diagnosed with total or near-total ocular surface failure. Limbal stem cell transplantation was performed in 8 of 10 eyes. Keratolimbal allograft was followed by penetrating keratoplasty in 7 of 10 eyes. Ocular surface stability was achieved in 7 of 10 eyes after keratolimabl allograft. Postoperative visual acuity was better than 20/200 in 4 of 10 of eyes. Keratolimbal graft rejection occurred in 3 of 10 eyes; the rate of rejection of penetrating keratoplasty was also 3 out of 10 eyes. Methamphetamine-related accidents can lead to severe bilateral ocular injuries. Although stem cell transplantation procedure success is guarded in most of these patients because of severe conjunctival inflammation and accompanying ocular comorbidities, as well as personality issues, compliant patients can achieve good visual function with ocular surface transplantation and subsequent keratoplasty.


[Splenectomy in the treatment of severe generalized myasthenia gravis (first experience)].
The authors discuss the results of splenectomy carried out on 20 patients with generalized myasthenia in whom previous complex treatment including thymectomy, corticosteroid and azathioprine therapy, repeated courses of plasmapheresis during medication with anticholinesterase agents, did not cause any essential improvement. Different values of homeostasis and immunological status were studied before and in different periods after splenectomy. The condition improved in 65% of patients, which was confirmed by the results of myography; the doses of corticosteroids and anticholinesterase agents were reduced. Bearing in mind the severe condition of patients selected for splenectomy, it is recommended to treat them only in medical centers possessing sufficient experience in treatment of myasthenia. The indications and contraindications for splenectomy in complex treatment of myasthenia must be specified further.


Preoperative taxane-based chemotherapy and celecoxib for carcinoma of the esophagus and gastroesophageal junction: results of a phase 2 trial.
The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.


Predictive value of clinical features and CT radiomics in the efficacy of hip preservation surgery with fibula allograft.
Despite being an effective treatment for osteonecrosis of the femoral head (ONFH), hip preservation surgery with fibula allograft (HPS&FA) still experiences numerous failures. Developing a prediction model based on clinical and radiomics predictors holds promise for addressing this issue. This study included 112 ONFH patients who underwent HPS&FA and were randomly divided into training and validation cohorts. Clinical data were collected, and clinically significant predictors were identified using univariate and multivariate analyses to develop a clinical prediction model (CPM). Simultaneously, the least absolute shrinkage and selection operator method was employed to select optimal radiomics features from preoperative hip computed tomography images, forming a radiomics prediction model (RPM). Furthermore, to enhance prediction accuracy, a clinical-radiomics prediction model (CRPM) was constructed by integrating all predictors. The predictive performance of the models was evaluated using receiver operating characteristic curve (ROC), area under the curve (AUC), DeLong test, calibration curve, and decision curve analysis. Age, Japanese Investigation Committee classification, postoperative use of glucocorticoids or alcohol, and non-weightbearing time were identified as clinical predictors. The AUC of the ROC curve for the CPM was 0.847 in the training cohort and 0.762 in the validation cohort. After incorporating radiomics features, the CRPM showed improved AUC values of 0.875 in the training cohort and 0.918 in the validation cohort. Decision curves demonstrated that the CRPM yielded greater medical benefit across most risk thresholds. The CRPM serves as an efficient prediction model for assessing HPS&FA efficacy and holds potential as a personalized perioperative intervention tool to enhance HPS&FA success rates.


Health promotion and tobacco control: student nurses' perspectives.
This article reports findings about student nurses' understanding of the nursing role in health promotion related to tobacco issues. These findings were derived from the data of a larger project, examining smoking practices of baccalaureate nursing students in Manitoba, Canada. The study was conducted with second-year, third-year, and fourth-year university nursing students studying at several sites throughout the province (N = 272). From the data analysis of the interviews, class forums, and open-ended survey questions, five themes emerged (i.e., who they are-who they are becoming, central beliefs and attitudes, learning the facts, practice world-limited options, role conflict). Students expressed considerable uncertainty and conflict concerning individual autonomy around decisions about tobacco use. This resulted in confusion about themselves as role models and their use of health promotion interventions.


Role of androgens in mediating renal injury in aging SHR.
Men have an increased risk of cardiovascular and renal diseases and develop greater renal injury despite similar levels of blood pressure when compared with women. The mechanisms responsible for this predisposition are unknown. Using the spontaneously hypertensive rat (SHR), we have found that androgens play an important role in the development of hypertension in young male SHR. However, the role that androgens play in age-related renal injury and dysfunction in SHR is unknown. Our hypothesis was that despite reductions in serum testosterone with age, androgens mediate renal injury and dysfunction in male SHR. Male SHR were castrated at 8 months of age, studied at 18 months of age, and compared with age-matched, intact males and young intact males (4 months). Serum testosterone was reduced by 30% in aging males compared with young SHR. With castration, blood pressure (mean arterial pressure [MAP]) was decreased by >20 mm Hg compared with old males, glomerular filtration rate (GFR) was increased by >35%, and renal vascular resistance (RVR) was reduced by >40%. MAP, GFR, and RVR in castrated, old males were similar to values in young males. With castration, glomerular sclerosis was reversed and proteinuria was also decreased by >80% when compared with old intact males. In addition, in castrated old males, plasma renin activity was decreased by 30% compared with old males and by 60% compared with young rats. The data support the hypothesis that despite a reduction in testosterone with age, androgens play an important role in age-related renal injury and dysfunction in SHR.


Lung volume reduction therapies for advanced emphysema: an update.
Observational and randomized studies provide convincing evidence that lung volume reduction surgery (LVRS) improves symptoms, lung function, exercise tolerance, and life span in well-defined subsets of patients with emphysema. Yet, in the face of an estimated 3 million patients with emphysema in the United States, < 15 LVRS operations are performed monthly under the aegis of Medicare, in part because of misleading reporting in lay and medical publications suggesting that the operation is associated with prohibitive risks and offers minimal benefits. Thus, a treatment with proven potential for palliating and prolonging life may be underutilized. In an attempt to lower risks and cost, several bronchoscopic strategies (bronchoscopic emphysema treatment [BET]) to reduce lung volume have been introduced. The following three methods have been tested in some depth: (1) unidirectional valves that allow exit but bar entry of gas to collapse targeted hyperinflated portions of the lung and reduce overall volume; (2) biologic lung volume reduction (BioLVR) that involves intrabronchial administration of a biocompatible complex to collapse, inflame, scar, and shrink the targeted emphysematous lung; and (3) airway bypass tract (ABT) or creation of stented nonanatomic pathways between hyperinflated pulmonary parenchyma and bronchial tree to decompress and reduce the volume of oversized lung. The results of pilot and randomized pivotal clinical trials suggest that the bronchoscopic strategies are associated with lower mortality and morbidity but are also less efficient than LVRS. Most bronchoscopic approaches improve quality-of-life measures without supportive physiologic or exercise tolerance benefits. Although there is promise of limited therapeutic influence, the available information is not sufficient to recommend use of bronchoscopic strategies for treating emphysema.


Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis.
Detailed knowledge of how mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disturb the trafficking or function of the CFTR protein and the use of high-throughput drug screens have allowed novel therapeutic strategies for cystic fibrosis (CF). The main goal of treatment is slowly but surely shifting from symptomatic management to targeting the underlying CFTR defect to halt disease progression and even to prevent occurrence of CF complications. CFTR potentiators for patients with class III mutations, mutation R117H (and in United States also for patients with specific residual function mutations) and the combination of a CFTR modulator plus a potentiator for patients homozygous for F508del, are the two classes of modulators that are in use in the clinic. Approval of these therapeutics has progressively expanded to include both younger patients and a wider range of CFTR mutations. For a significant proportion of patients with CF, current treatment is however still insufficient or unavailable.This review provides an overview of the clinical trial results and the real-life efficacy data of approved CFTR modulators. In addition, we discuss the entire pipeline of CFTR modulators: novel potentiators and correctors, amplifiers, stabilizers, and read-through agents. Furthermore, we discuss other strategies to improve CFTR function like nonsense-mediated decay inhibitors, modified transfer ribonucleic acids, antisense oligonucleotides, and genetic therapies.CFTR modulators are already changing the face of CF and the pipeline of new therapies continues to be exciting.


Physiological and Transcriptional Responses of Candida parapsilosis to Exogenous Tyrosol.
Tyrosol plays a key role in fungal morphogenesis and biofilm development. Also, it has a remarkable antifungal effect at supraphysiological concentrations. However, the background of the antifungal effect remains unknown, especially in the case of non-albicans Candida species such as Candida parapsilosis We examined the effect of tyrosol on growth, adhesion, redox homeostasis, virulence, as well as fluconazole susceptibility. To gain further insights into the physiological consequences of tyrosol treatment, we also determined genome-wide gene expression changes using transcriptome sequencing (RNA-Seq). A concentration of 15 mM tyrosol caused significant growth inhibition within 2 h of the addition of tyrosol, while the adhesion of yeast cells was not affected. Tyrosol increased the production of reactive oxygen species remarkably, as revealed by a dichlorofluorescein test, and it was associated with elevated superoxide dismutase, glutathione peroxidase, and catalase activities. The interaction between fluconazole and tyrosol was antagonistic. Tyrosol exposure resulted in 261 and 181 differentially expressed genes with at least a 1.5-fold increase or decrease in expression, respectively, which were selected for further study. Genes involved in ribosome biogenesis showed downregulation, while genes related to the oxidative stress response and ethanol fermentation were upregulated. In addition, tyrosol treatment upregulated the expression of efflux pump genes, including MDR1 and CDR1, and downregulated the expression of the FAD2 and FAD3 virulence genes involved in desaturated fatty acid formation. Our data demonstrate that exogenous tyrosol significantly affects the physiology and gene expression of C. parapsilosis, which could contribute to the development of treatments targeting quorum sensing in the future.IMPORTANCECandida-secreted quorum-sensing molecules (i.e., farnesol and tyrosol) are key regulators in fungal physiology, which induce phenotypic adaptations, including morphological changes, altered biofilm formation, and synchronized expression of virulence factors. Moreover, they have a remarkable antifungal activity at supraphysiological concentrations. Limited data are available concerning the tyrosol-induced molecular and physiological effects on non-albicans Candida species such as C. parapsilosis In addition, the background of the previously observed antifungal effect caused by tyrosol remains unknown. This study reveals that tyrosol exposure enhanced the oxidative stress response and the expression of efflux pump genes, while it inhibited growth and ribosome biogenesis as well as several virulence-related genes. Metabolism was changed toward glycolysis and ethanol fermentation. Furthermore, the initial adherence was not influenced significantly in the presence of tyrosol. Our results provide several potential explanations for the previously observed antifungal effect.


[Treatment of reno-ureteral lithiasis with ESWL in obese patients. Apropos of 150 patients].
Obesity is considered a significant risk factor for diseases such as hypertension, diabetes, coronary artery disease, and metabolic diseases, increasing considerably the risk for surgery. We have treated with ESWL a significant number of patients with the aim of avoiding operations which could be long and have associated complications due to the patient's condition. From April 2000 to May 2002 we treated 150 obese patients with kidney and/or ureteral stones using a Nova Ultima lithotripter. 94% of the patients were treated with a neuroleptoanalgesic drug, and 6% of the cases required narcotic-neuroleptoanalgesia. 85% of the cases were admitted for 24 hours, and 15% were outpatient. 94 males and 56 females who weighted more than 90 kg (91-141 kg) and more than 80 kg (80-127 kg) respectively were treated. Mean age was 41 years (range 20-72). 134 stones were located in the kidney, 27 in the pelvis and 16 in the ureter (25 patients presented bilateral lithiasis and 2 one ureteral stone and one homolateral kidney stone). Mean stone size was 12 mm. Stone track down was easy in 64% of the cases and difficult in 36%, mainly ureteral and pelvic stones. All patients received 3,000 shock waves at 21-22 KV and high energy with an average time per session of 35 minutes. Ultrasound tracking was preferred in 80% of the patients. Results at three months were: 72% stone-free, 9% < 4 mm, 14% > = 4 mm, and 5% failures. Best results were obtained in pelvic and lumbar ureter stones (88%). Mean retreatment was 1.6, with one additional session in 34 patients, two sessions in 8, and three sessions in 5. In the treatment of urolithiasis in obese patients, lithotriptor machine characteristics and operator experience are very important. The knowledge and the application of stone tracking systems allow the urologist to obtain a higher percentage of stone free patients. These techniques are important in these patients because positioning is key to obtain a good result. The indication of ESWL in obese patients is a good choice but selection criteria should be respected. The percentage of stone free patients at three months has been satisfactory and complications are similar to those published by other authors.


Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: A single-center experience.
Gastric neuroendocrine tumors (G-NETs) are rare tumors, but their incidence is gradually increasing. Despite the existence of many classification systems, determining prognosis and planning treatment in patients with G-NETs remains a clinical challenge. In this study, the prognostic value of the World Health Organization (WHO) 2017 grading system and the effect of surgery on survival in low grade neuroendocrine tumors were investigated. G-NETs who were diagnosed between January 2000 and May 2017 were included in the study. Patients' demographic characteristics, treatment details, and survival data were obtained from medical charts. Pathological samples were re-classified according to the WHO 2017 grading system. Of the total 94 evaluated patients, 50 (53.2%) were classified with G1 NETs, 37(39.4%) with G2 NETs, 4(4.2%) with well-differentiated G3 NETs, and the remaining 3 patients with poorly differentiated G3 neuroendocrine carcinoma (NEC). The median follow-up time was 83.2 months. There was a statistically significant difference in 5-year progression free survival (PFS) between G1 tumors (100%) and G2 tumors (76%) (p<0.001). However, there was no statistically significant deference in 5-year overall survival rate (OS) for G1 (97%) and G2 (82%) tumors (p=0.141). When G2 and G1 NETs were compared according to their surgical approach, radical surgery was more frequently performed in patients with G2 tumors (p<0.001). However, radical surgery did not improve PFS in G1 and G2 NETs. The WHO 2017 NET classification system may have low prognostic value for determining the prognosis of patients with G1 and G2 tumors. Radical surgery for G1 and G2 NETs did not improve PFS in our study.


Diversification of a protein kinase cascade: IME-2 is involved in nonself recognition and programmed cell death in Neurospora crassa.
Kinase cascades and the modification of proteins by phosphorylation are major mechanisms for cell signaling and communication, and evolution of these signaling pathways can contribute to new developmental or environmental response pathways. The Saccharomyces cerevisiae kinase Ime2 has been well characterized for its role in meiosis. However, recent studies have revealed alternative functions for Ime2 in both S. cerevisiae and other fungi. In the filamentous fungus Neurospora crassa, the IME2 homolog (ime-2) is not required for meiosis. Here we determine that ime-2 interacts genetically with a transcription factor vib-1 during nonself recognition and programmed cell death (PCD). Mutations in vib-1 (Δvib-1) suppress PCD due to nonself recognition events; however, a Δvib-1 Δime-2 mutant restored wild-type levels of cell death. A role for ime-2 in the post-translational processing and localization of a mitochondrial matrix protein was identified, which may implicate mitochondria in N. crassa nonself recognition and PCD. Further, Δvib-1 strains do not produce extracellular proteases, but protease secretion reverted to near wild-type levels in a Δvib-1 Δime-2 strain. Mass spectrometry analysis revealed that the VIB-1 protein is phosphorylated at several sites, including a site that matches the IME-2 consensus. The genetic and biochemical data for ime-2 and vib-1 indicate that IME-2 is a negative regulator of VIB-1 and suggest parallel negative regulation by IME-2 of a cell death pathway in N. crassa that functions in concert with the VIB-1 cell death pathway. Thus, IME2 kinase function has evolved following the divergence of S. cerevisiae and N. crassa and provides insight into the evolution of kinases and their regulatory targets.


Whole isolated neocortical and hippocampal preparations and their use in imaging studies.
This study shows that two whole isolated preparations from the young mouse, the neocortical 'slab' and the hippocampal formation, are useful for imaging studies requiring both global monitoring using light transmittance (LT) imaging and high resolution cellular monitoring using 2-photon laser scanning microscopy (2PLSM). These preparations share advantages with brain slices such as maintaining intrinsic neuronal properties and avoiding cardiac or respiratory movement. Important additional advantages include the maintenance of all local input and output pathways, the absence of surfaces injured by slicing and the preservation of three-dimensional tissue structure. Using evoked extracellular field recording, we demonstrate long-term (hours) viability of both whole preparations. We then show that propagating cortical events such as anoxic depolarization (AD) and spreading depression (SD) can be imaged in both preparations, yielding results comparable to those in brain slices but retaining the tissue's three-dimensional structure. Using transgenic mice expressing green fluorescent protein (GFP) in pyramidal and granule cell neurons, 2PLSM confirms that these preparations are free of the surface damage observed in sliced brain tissue. Moreover the neurons undergo swelling with accompanying dendritic beading following AD induced by simulated ischemia, similar to cortical damage described in vivo.


Avoidance response, house response, and wind responses of the sporangiophore of Phycomyces.
Avoidance response: An object placed 1 mm from the growing zone of a Phycomyces sporangiophore elicits a tropic response away from the object. The dependence of this response on the size of the object and its distance from the specimen is described, as well as measurements which exclude electric fields, electromagnetic radiation, temperature, and humidity as avoidance-mediating signals. This response is independent of the composition and surface properties of the object and of ambient light. House Response: A house of 0.5- to 10-cm diameter put over a sporangiophore elicits a transient growth response. Avoidance responses inside closed houses are slightly smaller than those in the open. Wind responses: A transverse wind elicits a tropic response into the wind, increasing with wind speed. A longitudinal wind, up or down, elicits a transient negative growth response to a step-up in wind speed, and vice versa. It is proposed that all of the effects listed involve wind sensing. This proposal is supported by measurements of aerodynamic effects of barriers and houses on random winds. The wind sensing is discussed in terms of the hypothesis that a gas is emitted by the growing zone (not water or any normal constituent of air), the concentration of which is modified by the winds and monitored by a chemical sensor. This model puts severe constraints on the physical properties of the gas.


Associations among Neighborhood Socioeconomic Deprivation, Physical Activity Facilities, and Physical Activity in Youth during the Transition from Childhood to Adolescence.
This study aims to examine the longitudinal association of neighborhood socioeconomic deprivation (SED) with physical activity in youth during the transition from elementary to middle school, and to determine if access to physical activity facilities moderates this relationship. Data were obtained from the Transitions and Activity Changes in Kids (TRACK) study, which was a multilevel, longitudinal study designed to identify the factors that influence changes in physical activity as youth transition from elementary to middle school. The analytic sample for the current study included 660 youth with complete data in grades 5 (baseline) and 7 (follow-up). A repeated measures multilevel framework was employed to examine the relationship between SED and physical activity over time and the potential moderating role of elements of the built environment. Decreases in physical activity varied by the degree of neighborhood SED with youth residing in the most deprived neighborhoods experiencing the greatest declines in physical activity. Access to supportive physical activity facilities did not moderate this relationship. Future research studies are needed to better understand how neighborhood SED influences youth physical activity over time.


Heme Binding to HupZ with a C-Terminal Tag from Group A Streptococcus.
HupZ is an expected heme degrading enzyme in the heme acquisition and utilization pathway in Group A Streptococcus. The isolated HupZ protein containing a C-terminal V5-His6 tag exhibits a weak heme degradation activity. Here, we revisited and characterized the HupZ-V5-His6 protein via biochemical, mutagenesis, protein quaternary structure, UV-vis, EPR, and resonance Raman spectroscopies. The results show that the ferric heme-protein complex did not display an expected ferric EPR signal and that heme binding to HupZ triggered the formation of higher oligomeric states. We found that heme binding to HupZ was an O2-dependent process. The single histidine residue in the HupZ sequence, His111, did not bind to the ferric heme, nor was it involved with the weak heme-degradation activity. Our results do not favor the heme oxygenase assignment because of the slow binding of heme and the newly discovered association of the weak heme degradation activity with the His6-tag. Altogether, the data suggest that the protein binds heme by its His6-tag, resulting in a heme-induced higher-order oligomeric structure and heme stacking. This work emphasizes the importance of considering exogenous tags when interpreting experimental observations during the study of heme utilization proteins.


A mechanism for surface attachment in spores of a plant pathogenic fungus.
Rice blast disease is caused by a fungus that attacks all above-ground parts of the rice plant. In a study of the means by which the fungus attaches to the hydrophobic rice leaf surface, it was found that spores(conidia) of the rice blast fungus Magnaporthe grisea have a mechanism for immediate and persistent attachment to various surfaces, including Teflon. This attachment occurs at the spore apex and is blocked by the addition of the lectin concanavalin A. Microscopy of hydrated conidia shows that a spore tip mucilage that binds concanavalin A is expelled specifically from the conidial apex before germ tube emergence. Ultrastructural analysis of dry conidia shows a large periplasmic deposit, presumably spore tip mucilage, at the apex. The results indicate a novel mechanism for the attachment of phytopathogenic fungal spores to a plant surface.


Using Topic Modeling to Develop Multi-level Descriptions of Naturalistic Driving Data from Drivers with and without Sleep Apnea.
One challenge in using naturalistic driving data is producing a holistic analysis of these highly variable datasets. Typical analyses focus on isolated events, such as large g-force accelerations indicating a possible near-crash. Examining isolated events is ill-suited for identifying patterns in continuous activities such as maintaining vehicle control. We present an alternative approach that converts driving data into a text representation and uses topic modeling to identify patterns across the dataset. This approach enables the discovery of non-linear patterns, reduces the dimensionality of the data, and captures subtle variations in driver behavior. In this study topic models are used to concisely described patterns in trips from drivers with and without untreated obstructive sleep apnea (OSA). The analysis included 5000 trips (50 trips from 100 drivers; 66 drivers with OSA; 34 comparison drivers). Trips were treated as documents, and speed and acceleration data from the trips were converted to "driving words." The identified patterns, called topics, were determined based on regularities in the co-occurrence of the driving words within the trips. This representation was used in random forest models to predict the driver condition (i.e., OSA or comparison) for each trip. Models with 10, 15 and 20 topics had better accuracy in predicting the driver condition, with a maximum AUC of 0.73 for a model with 20 topics. Trips from drivers with OSA were more likely to be defined by topics for smaller lateral accelerations at low speeds. The results demonstrate topic modeling as a useful tool for extracting meaningful information from naturalistic driving datasets.


A novel technique of concurrent esophagoscopy and transgastrostomy gastroscopy to dilate a completely obstructed distal esophageal stricture in a child following fundoplication.
We report a successful dilation of a completely obstructed distal esophageal stricture in a 4-year-old boy with combined immune deficiency syndrome, at 2 and half years after fundoplication and gastrostomy tube insertion. Barium studies and esophagoscopy had revealed complete obstruction of the lower esophagus. Transgastrostomy gastroscopy demonstrated a pinhole lumen through the fundoplication wrap; a guide wire was passed into the esophagus; and the stricture was dilated with Savary dilators. We presumed that the stricture was secondary to chronic esophagitis. The stricture was identified and successfully dilated using a novel technique of concurrent esophagoscopy and transgastrostomy gastroscopy.


The influence of learning history on anterograde interference.
Classically interpreted as a competition between opposite memories (A vs B), anterograde interference (AI) also emerges in the absence of competing memories (A vs A), suggesting that mechanisms other than those involved in memory competition contribute to AI. To investigate this, we tested the hypothesis that extending motor practice would enhance a first memory, but come at the cost of reduced learning capabilities when subsequently exposed to a second learning session of the same task. Based on converging biological evidence, AI was expected to depend upon the degree of extended practice of the initial exposure. During a first Session, four conditions were carried out where participants (n = 24) adapted to a gradually introduced -20° visual deviation while the extent of the initial exposure was manipulated by varying the duration or type of the performance asymptote. Specifically, the performance asymptote at -20° was either Short (40 trials), Moderate (160 trials), Long (320 trials), or absent due to continuously changing perturbations around the mean of -20° (Jagged; 160 trials). After a 2-min interval, participants re-adapted to the same (-20°) visual deviation, which was meant to probe the effect of extended practice in the first Session on the learning capabilities of a second identical memory (A vs A). The results first confirmed that the duration of exposure in the first Session enhanced immediate aftereffects in the Moderate, Long, and Jagged conditions as compared to the Short condition, suggesting that extended practice enhanced retention of the first memory. When comparing the second Session to the first one, results revealed a different pattern of re-adaptation depending on the duration of initial exposure: in the Short condition, there was evidence for facilitated re-adaptation and similar aftereffects. However, in the Moderate, Long and Jagged conditions, re-adaptation was similar and aftereffects were impaired, suggestive of AI. This suggests that extended practice initially enhances memory formation, but comes at the cost of reduced subsequent learning capabilities. One possibility is that AI occurs because extended practice induces the emergence of network-specific homeostatic constraints, which limit subsequent neuroplastic and learning capabilities in the same neural network.


Circulating autoantibodies to the 200,000-dalton protein of neurofilaments in the serum of healthy individuals.
There is substantial evidence that human serum contains antibodies to many autoantigens. For example, all healthy people have autoantibodies (immunoglobulin M) to some undefined brain antigens. In this study immunoblots and immunohistochemical staining were used to detect antibodies to neural tissues in serum samples from 200 healthy people and 200 patients with various neurological diseases. Ninety-nine percent of the 400 subjects had serum immunoglobulin M and 95 percent had immunoglobulin G that bound to a 200-kilodalton protein in homogenates of neural tissues. In most cases there were no antibodies to anything else in the homogenates. The 200-kilodalton protein was the heaviest of the neurofilament triplet proteins. These observations do not support a role for antibodies to the 200-kilodalton protein of neurofilaments in the pathogenesis of neurological diseases.