Injuries and illnesses in the national basketball association: a 10-year perspective.
To present an overview of the medical conditions experienced by athletes competing in the National Basketball Association (NBA) from the 1988-1989 through the 1997-1998 seasons. Athletic trainers completed profiles that provided demographic information for each player. Injury reports indicated when and where the injury occurred, pathology, onset, activity, and the mechanism of injury. The amount of time lost, injured list status, hospitalization, and surgery were also reported. Reportable injuries were those that resulted in (1) physician referral, (2) a practice or game being missed, or (3) emergency care being rendered. A total of 1094 players appeared in the database 3843 times (mean, 3.3 +/- 2.6 seasons). Mean player demographics were age 26.7 (+/- 3.7) years, NBA playing experience 4.1 (+/- 3.7) years, height 200.8 (+/- 9.9) cm, and weight 100.2 (+/- 13.5) kg. Players averaged 52 (+/- 34.7) games and 1263.1 (+/- 1073.8) minutes played. The frequency of injury, time lost, and game exposures were tabulated, and game-related injury rates were then calculated. Ankle sprains were the most frequently occurring orthopaedic injury (942, 9.4%), followed by patellofemoral inflammation (803, 8.1%), lumbar strains (491, 5.0%), and knee sprains (258, 2.3%). The greatest number of days missed were related to patellofemoral inflammation (7569, 11.5%), knee sprains (5712, 8.6%), ankle sprains (5122, 7.7%), and lumbar strains (3365, 5.1%). Professional athletes in the NBA experience a rate of game-related injuries that is twice as high as their collegiate counterparts. Patellofemoral inflammation is a significant problem among NBA players.


[The role of high cut off membranes in renal replacement therapy of acute kidney injury in the course of sepsis - the current state of knowledge].
Sepsis as a systemic inflammatory reaction to infection is an important interdisciplinary clinical problem. Over the past 20 years, the number of patients who have contracted sepsis has doubled. The occurrence of acute kidney injury in the course of sepsis increases mortality twice, while chronic kidney disease develops in 50% of the patients who survived sepsis. The pathophysiology of acute kidney injury (AKI) development in the course of sepsis is not fully understood. Some researchers, to emphasize the distinctiveness of AKI in the course of sepsis, describe the changes that occur in the kidneys in its course as sepsis induced-AKI. In the last decade, the theory regarding the possibility of modulation of inflammatory pathways through extracorporeal blood purification methods (HCO - using high cut off membranes) from pro-inflammatory cytokines and attempts to restore homeostasis in this way has gained great recognition. The basis for the implementation of this type of treatment was the "maximum concentration" hypothesis, which assumes that, avoiding the onset of the early peak of circulating proinflammatory molecules is possible to prevent and modulate the clinical effects of an excessively expressed inflammatory reaction in the course of sepsis. This study is an attempt to analyze and summarize the current state of knowledge on the effectiveness of using HCO membranes in patients with sepsis who have developed AKI. For this purpose, the resources of MEDLAIN/Pubmed bases from 1965 to April 2018 have been analyzed, taking into account only the full versions of articles in English, using a combination of the following words: super high-flux, high cut-off, dialysis, renal replacement therapy, filtration, diafiltration, hemodialysis, hemofiltration, hemodiafiltration, sepsis, cytokine, inflammatory mediators, inflammation.


Spatiotemporal signal space separation method for rejecting nearby interference in MEG measurements.
Limitations of traditional magnetoencephalography (MEG) exclude some important patient groups from MEG examinations, such as epilepsy patients with a vagus nerve stimulator, patients with magnetic particles on the head or having magnetic dental materials that cause severe movement-related artefact signals. Conventional interference rejection methods are not able to remove the artefacts originating this close to the MEG sensor array. For example, the reference array method is unable to suppress interference generated by sources closer to the sensors than the reference array, about 20-40 cm. The spatiotemporal signal space separation method proposed in this paper recognizes and removes both external interference and the artefacts produced by these nearby sources, even on the scalp. First, the basic separation into brain-related and external interference signals is accomplished with signal space separation based on sensor geometry and Maxwell's equations only. After this, the artefacts from nearby sources are extracted by a simple statistical analysis in the time domain, and projected out. Practical examples with artificial current dipoles and interference sources as well as data from real patients demonstrate that the method removes the artefacts without altering the field patterns of the brain signals.


The Unani traditional medical system in India: a case study in health behaviour.
The study examines the practice of Unani traditional medicine in India. The case study is based on the Unani Clinic situated in Aligarh Town; patients, practitioner of Unani medicine, and para-medical staff were interviewed about their patterns of patients' health behaviour, of particular interest was the utilization of Unani medical facilities by people of different age groups and belonging to different socio-economic strata. Observations are made regarding effectiveness of the Unani medical system.


The pulse volume recorder as a measure of peripheral vascular status in people with diabetes mellitus.
Peripheral vascular disease is common in persons with diabetes. There is growing evidence that the vascular contribution to foot disease in diabetes is greater than has previously been realized. A cross-sectional study of vascular status in 205 subjects with type 1 and type 2 diabetes mellitus was carried out as part of a larger diabetes assessment study. Palpation of pedal pulses, color spectral waveforms, pulse volume recording, and Doppler ankle-brachial pressure index (ABPI) were recorded bilaterally in all subjects. These modalities were evaluated descriptively, and kappa statistics were used to evaluate agreement between ABPI and pulse volume recording. In addition, visual comparisons between the color spectral waveforms (study gold standard) and pulse volume recordings were also undertaken, and clinical usefulness of pulse volume recording was evaluated. Results of this study identified 15.6% (n = 32) subjects having one or more pedal pulses absent on either foot, 47% (n = 98) an abnormal ABPI (<0.9/>1.30), 7.8% (n = 16) an abnormal monophasic waveform, and 7.3% (n = 15) with an abnormal pulse volume recording. The level of agreement between ABPI and pedal pulse palpation was low at 52.2%, between ABPI and spectral waveforms was low at 58%, and between ABPI and pulse volume recording was also low at 45.3%. When the pulse volume recordings were compared with the color spectral waveforms, however, the level of agreement was high at 91.7%. Pulse volume recording agrees well with the color spectral waveforms. It can be used with all subjects including those with edema. It is simple, quick, and valuable in a community setting to determine the need for further investigations.


Characterization of aerosols produced by cell sorters and evaluation of containment.
Despite the recognition of potential aerosol hazards associated with cell sorting by the flow cytometry community, there has been no previous study that has thoroughly characterized the aerosols that can be produced by cell sorters. In this study, an aerodynamic particle sizer was used to determine the concentration and aerodynamic diameter (AD) of aerosols produced by a FACS Aria II cell sorter under various conditions. Aerosol containment and evacuation were also evaluated using this novel methodology. The results showed that high concentrations of aerosols in the range of 1-3 μm can be produced in fail mode and that with decreased sheath pressure, aerosol concentration decreased and AD increased. Although the engineering controls of the FACS Aria II for containment were effective, sort chamber evacuation of aerosols following a simulated nozzle obstruction was ineffective. However, simple modifications to the FACS Aria II are described that greatly improved sort chamber aerosol evacuation. The results of this study will facilitate the risk assessment of cell sorting potentially biohazardous samples by providing much needed data regarding aerosol production and containment.


Phospholipase A2-Induced Degradation and Release from Lipid-Containing Polymersomes.
Hybrid vesicles, comprising blends of amphiphilic block copolymers and phospholipids, have attracted significant attention recently because of their unique combination of chemical and physical properties. We report a method to make unilamellar hybrid vesicles with diameters of 100 nm by mixing polybutadiene-block-poly(ethylene oxide) and phosphocholine lipids using a combination of solvent inversion and sonication. We show that homogeneous hybrid vesicles are formed when one component is a minor fraction. At compositions with balanced mass fractions, separate populations of similarly sized pure liposomes and hybrid vesicles are indicated. We investigate the release kinetics of calcein encapsulated in the lumen as hybrid large and giant unilamellar vesicles (LUVs and GUVs) of different compositions are exposed to phospholipase A2 (PLA2). PLA2 hydrolyzes lipids, which leads to dissolution of lipid domains and provides a trigger for the release of calcein as pores are formed. We demonstrate that depending on the polymer mole fraction, block copolymers can either protect or boost the rate of lipid degradation and thereby the release rate from nanoscale hybrid vesicles. Strong indications of lipid phase separation into nanoscale domains in LUVs are observed. Most importantly, hybrid GUV with lipids in the fluid phase release calcein slowly as lipids in the liquid-disordered phase do not phase-separate, but they show the fastest release of all blends as LUVs. This indicates phase separation on the nanoscale in contrast to on the microscale, but it also indicates retained high mobility of lipids between the nanoscale domains, which is absent for lipids in the gel phase. Our results demonstrate several ways in which nanoscale hybrid vesicles can and should be optimized for PLA2-triggered release of water-soluble compounds.


Hunger makes apex predators do risky things.
In Focus: Blecha, K. A., Boone, R. B., & Alldredge, M. W. (2018). Hunger mediates apex predator's risk avoidance response in wildland-urban interface. Journal of Animal Ecology, 87, 609-622. https://doi.org/10.1111/1365-2656.12801 Puma (Puma concolor), an apex predator, can live at the edge of cities where pockets of low-density human dwellings form residential patches in the wildland-urban interface. Blecha, Boone, and Alldredge () tracked puma via global positioning system (GPS) telemetry collars to determine when and where they hunted and made kills. Well-fed puma (1-2 days between kills) strongly avoided residential patches despite these areas having higher mule deer (Odocoileus hemionus) densities and higher kill success for puma. However, the strong avoidance of residential patches completely disappeared as puma became hungrier (4-10 days since last kill) making it more likely that hungry individuals hunted in residential areas and ultimately increasing the likelihood of puma-human conflict.


Household surveillance of severe neonatal illness by community health workers in Mirzapur, Bangladesh: coverage and compliance with referral.
Effective and scalable community-based strategies are needed for identification and management of serious neonatal illness. As part of a community-based, cluster-randomized controlled trial of the impact of a package of maternal-neonatal health care, community health workers (CHWs) were trained to conduct household surveillance and to identify and refer sick newborns according to a clinical algorithm. Assessments of newborns by CHWs at home were linked to hospital-based assessments by physicians, and factors impacting referral, referral compliance and outcome were evaluated. Seventy-three per cent (7310/10,006) of live-born neonates enrolled in the study were assessed by CHWs at least once; 54% were assessed within 2 days of birth, but only 15% were attended at delivery. Among assessments for which referral was recommended, compliance was verified in 54% (495/919). Referrals recommended to young neonates 0-6 days old were 30% less likely to be complied with compared to older neonates. Compliance was positively associated with having very severe disease and selected clinical signs, including respiratory rate > or = 70/minute; weak, abnormal or absent cry; lethargic or less than normal movement; and feeding problem. Among 239 neonates who died, only 38% were assessed by a CHW before death. Despite rigorous programmatic effort, reaching neonates within the first 2 days after birth remained a challenge, and parental compliance with referral recommendation was limited, particularly among young neonates. To optimize potential impact, community postnatal surveillance must be coupled with skilled attendance at delivery, and/or a worker skilled in recognition of neonatal illness must be placed in close proximity to the community to allow for rapid case management to avert early deaths.


Cranial magnetic resonance imaging findings in kwashiorkor.
Protein energy malnutrition (PEM) is an important public health problem in the developing countries, although it is becoming uncommon in South West Nigeria. Cerebral changes have been associated with severe PEM. This study evaluated the neurological changes using Magnetic Resonance Imaging (MRI) in Ibadan south west Nigeria. The 5 children evaluated had a median age of 16 months and all the children had brain changes compatible with cerebral atrophy. In addition two of the children had periventricular white matter changes, while one these two had mega cisterna magna in addition. Though this study did not re-evaluate the brains of these children after nutritional rehabilitation, it is possible that changes are reversible as demonstrated in earlier studies.


Endoscopic therapy of colonic liver flexure mucocele.
Colorectal mucoceles usually arise in the appendix, and colonic disease is very rare. We report the first case of a mucocele of the colonic liver flexure that was treated successfully with endoscopy. A 36-year-old man was admitted to our hospital because of abdominal distension persisting for 3 days. Colonoscopic examination revealed a round polyp in the hepatic flexure, and we performed hot snare polypectomy with argon plasma coagulation. Histologically, the polypectomy specimen was confirmed to be a mucocele, with no neoplastic changes. Follow-up examinations at 6 and 12 months showed no evidence of recurrence.


Perception and Use of COVID Contact Tracing Mobile Applications in New York State (NYS).
The study explores the use of COVID-19 related apps for contact tracing deployed in New York State (NYS). The project seeks to understand potential differences in perception, adoption, or privacy concerns among racial and ethnic populations and across age groups. Using the Antecedent-Privacy Concerns-Outcomes (APCO) framework and the perceived usefulness construct, this study explores factors influencing the individual level adoption of these apps. Data collected from 120 Amazon Mechanical Turkers located in NYS was analyzed. The results indicate that race and gender are important factors to consider in expanding the Antecedent-Privacy Concerns-Outcomes (APCO) framework. Specifically, race impacted the perception of the seriousness of the pandemic, with Asians and Black being serious about the pandemic. Age played a role in privacy and security concerns. The youngest group of respondents, aged 18-24, did not have many privacy and security concerns about mobile apps. These results provided empirical results and evidence that can contribute to the expansion of the APCO model and help further the model's development.


Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies.
Formulation of proton pump inhibitors (PPIs) into oral solid dosage forms is challenging because the drug molecules are acid-labile. The aim of this study is to evaluate different formulation strategies (monolithic and multiparticulates) for three PPI drugs, that is, rabeprazole sodium, lansoprazole, and esomeprazole magnesium, using delayed release film coating applications. The core tablets of rabeprazole sodium were prepared using organic wet granulation method. Multiparticulates of lansoprazole and esomeprazole magnesium were prepared through drug layering of sugar spheres, using powder layering and suspension layering methods, respectively. Tablets and drug-layered multiparticulates were seal-coated, followed by delayed release film coating application, using Acryl-EZE(R), aqueous acrylic enteric system. Multiparticulates were then filled into capsules. The final dosage forms were evaluated for physical properties, as well as in vitro dissolution testing in both compendial acid phase, 0.1N HCl (pH 1.2), and intermediate pH, acetate buffer (pH 4.5), followed by phosphate buffer, pH 6.8. The stability of the delayed release dosage forms was evaluated upon storage in accelerated conditions [40 degrees C/75% relative humidity] for 3 months. All dosage forms demonstrated excellent enteric protection in the acid phase, followed by rapid release in their respective buffer media. Moreover, the delayed release dosage forms remained stable under accelerated stability conditions for 3 months. Results showed that Acryl-EZE enteric coating systems provide excellent performance in both media (0.1N HCl and acetate buffer pH 4.5) for monolithic and multiparticulate dosage forms.


The counterdiffusion of HCl and NH3: An experimental and modeling analysis of topochemistry, diffusion, reaction, and phase transitions.
Vapor-phase ammonia, NH3(g), and hydrochloric acid, HCl(g), undergo a series of complex reactions, including nucleation and growth, to form solid ammonium chloride, NH4Cl(s). The counterdiffusional experiment, whereby HCl(g) and NH3(g) diffuse from opposite ends of a tube and react to form spatiotemporally complex patterns, has a rich history of study. In this paper, we combine experimental data, molecular simulations, and analysis and simulations of a partial differential equation model to address the questions of where the first unobserved vapor product NH4Cl(g) and visually observable precipitate NH4Cl(s) form and how these positions depend on experimental parameters. These analyses yield a consistent picture which involves a moving reaction front as well as previously unobserved heterogeneous nucleation, wall nucleation, and homogeneous nucleation. The experiments combined with modeling allow for an estimate of the heterogeneous and homogeneous nucleation thresholds for the vapor-to-solid phase transition. The results, synthesized with the literature on this vapor-to-particle reaction, inform a discussion of the details of the reaction mechanism, including the role of water, which concludes the paper.


Development and validation of a patient-specific model to predict postoperative SIRS in older patients: A two-center study.
Postoperative systemic inflammatory response syndrome (SIRS) is common in surgical patients especially in older patients, and the geriatric population with SIRS is more susceptible to sepsis, MODS, and even death. We aimed to develop and validate a model for predicting postoperative SIRS in older patients. Patients aged ≥65 years who underwent general anesthesia in two centers of Third Affiliated Hospital of Sun Yat-sen University from January 2015 to September 2020 were included. The cohort was divided into training and validation cohorts. A simple nomogram was developed to predict the postoperative SIRS in the training cohort using two logistic regression models and the brute force algorithm. The discriminative performance of this model was determined by area under the receiver operating characteristics curve (AUC). The external validity of the nomogram was assessed in the validation cohort. A total of 5,904 patients spanning from January 2015 to December 2019 were enrolled in the training cohort and 1,105 patients from January 2020 to September 2020 comprised the temporal validation cohort, in which incidence rates of postoperative SIRS were 24.6 and 20.2%, respectively. Six feature variables were identified as valuable predictors to construct the nomogram, with high AUCs (0.800 [0.787, 0.813] and 0.822 [0.790, 0.854]) and relatively balanced sensitivity (0.718 and 0.739) as well as specificity (0.718 and 0.729) in both training and validation cohorts. An online risk calculator was established for clinical application. We developed a patient-specific model that may assist in predicting postoperative SIRS among the aged patients.


[Part II: Recognising facial expressions].
In this second part, we address particularly the question of the neural mechanisms and structures involved in the recognition of facial emotional expressions that are crucial in social cognition. Emotion recognition in others can be critically impaired in some neurodegenerative and neurovascular diseases. That dysfunction sometimes correlated to disabling behavioural disorders and interpersonal communication impairment must be further understood. The results of a series of scalp and intracranial event related potential recordings, as well as recent advances in the literature, are reported. ERPs to facial emotional expressions were thus recorded in multiple subcortical and cortical areas in drug refractory epileptical patients implanted with depth electrodes. The roles of amygdala, insula and prefrontal cortex located at crossroads between perceptive analysis and emotional conceptual knowledge are particularly underlined. Altogether, these studies demonstrate that facial expressions are widely processed in space and time, some structures reacting very early and automatically, others providing a sustained reaction depending on the attention.


[Contribution of MRI to the topography of oculomotor disorders in multiple sclerosis].
Magnetic resonance imaging (MRI) was performed in 20 patients with multiple sclerosis and abnormal electro-oculographic examination. All but 2 patients showed MRI abnormalities in the infratentorial region: hypersignal on T2-weighted sequences and/or images of atrophy. Usually, each patient had multiple abnormalities, which could prevent anatomico-oculographic correlations. With oculomotor disorders of cerebellar origin, correlations between clinical findings and MRI images were satisfactory, but with disorders due to brainstem lesions correlations were not so good, as shown by the results in 9 patients with internuclear ophthalmoplegia.


Korean immigrants don't buy health insurance: The influences of culture on self-employed Korean immigrants focusing on structure and functions of social networks.
Culture has been pinpointed as a culprit of disparities in health insurance coverage between Korean immigrants and other ethnic groups. This study explored specific mechanisms by which culture influences a decision to buy health insurance among self-employed Korean immigrants living in ethnic enclaves by focusing on the structure and functions of social networks. Between March and June 2015, we recruited 24 Korean immigrant adults (aged 18 or older) who identified as self-employed and being uninsured for substantial periods before 2014 in Southern California. Interviews were conducted in Korean, and Korean transcripts were translated into English by two bilingual interpreters. Using constant comparative analysis, we explored why participants didn't purchase health insurance after migrating to the United States and how their social networks influenced their decisions whether to purchase health insurance. Results indicate Korean immigrants sought health information from dense and homogeneous social networks whose members are mostly Korean immigrants embedded in similar social contexts. Social learning was frequently observed when people sought health care while uninsured. However, respondents often noted social ties do not provide helpful information about benefits, costs, and ways to use health insurance. "Koreans don't buy health insurance" was a dominant social norm reported by most respondents. Findings indicate that social learning and normative influence occur inside social networks and these mechanisms seemingly prevent purchasing of health insurance. In addition to the individual mandate in the Patient Protection and Affordable Care Act, more targeted approaches that consider the structure and functions of social networks could improve the public health of Korean immigrants.


Engineering Complexity in Bacterial Regulatory Circuits for Biotechnological Applications.
Engineering microbial systems allows the generation of new technologies having significant impact in the biotechnological industry and on human health. In the past few years, several synthetic biology approaches have been implemented in bacteria to allow precise engineering of novel regulatory circuits for several applications. The advent of high-throughput technologies and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based DNA editing techniques have been pivotal in this process. Yet, despite the tremendous advances experienced recently, there are still a number of bottlenecks that need to be overcome in order to generate high-performance redesigned living machines, and the use of novel computer-aided approaches would be essential for this task. In this perspective, we discuss some of the main advances in the field of microbial engineering and the new technologies and approaches that should allow the construction of on demand synthetic microbial factories through the redesign of regulatory complexity.


Surgical treatment for pulmonary tuberculosis: is video-assisted thoracic surgery "better" than thoracotomy?
To compare video-assisted thoracoscopic surgery (VATS) lobectomy and conventional open lobectomy in patients with pulmonary tuberculosis (TB) who require surgery. Forty patients with pulmonary TB who required lobectomy were randomized to receive either VATS or open lobectomy. Patient demographic, pulmonary function, operative, and postoperative data were compared between the groups. There were 20 patients who received VATS lobectomy (median age 31.5 years, range 19-67 years) and 20 that received open lobectomy (median age 33.5 years, range 16-60 years). The two groups were similar with respect to gender, age and pulmonary function (all, P>0.05). Lobectomy was completed by VATS in 19 of 20 patients (95%), and by thoracoscope-assisted mini-incision lobectomy in 1 patient. The median intraoperative blood loss was 345 mL (range, 100-800 mL), and the median duration of pleural cavity closed drainage was 5 days (range, 3-7 days). All open lobectomies were completed successfully, and the median intraoperative blood loss was 445 mL (range, 150-950 mL) and the median duration of pleural cavity closed drainage was 5 days (range, 3-9 days). No statistically significant differences were found between the groups with respect to operation completion rates, type of lung resection, intraoperative blood loss, closed pleural drainage duration and volume of postoperative chest drainage. The operation time, number of postoperative complications, postoperative pain index at 24 hours after surgery and postoperative hospital stay were all significantly less in the VATS group. With a median follow-up duration of 14 months (range, 8-18 months) no positive sputum examination results were found in either group. VATS lobectomy is an effective and minimally invasive method for treating patients with pulmonary TB.


Variable costs of ICU patients: a multicenter prospective study.
To analyze the costs of treating critically ill patients. Multicenter, observational, prospective, cohort, bottom-up study on variable costs in 51 ICUs. A total of 1,034 patients aged over 14 years who either spent less than 48 h in the ICU or had multiple trauma, major abdominal surgery, ischemic stroke, chronic obstructive pulmonary disease, cardiac failure, isolated head injury, acute lung injury/adult respiratory distress syndrome (ALI/ARDS), nontraumatic intracranial hemorrhage or coronary surgery. Data recorded for each patient: length of ICU stay, and cost in euros of all diagnostic and therapeutic procedures, drugs and equipment used, and consultations by physicians from other units. To express cost-efficiency we calculated for each diagnostic group the cost per surviving patient (expenditure for all patients/number of surviving patients) and money loss per patient (expenditure for patients who died/total number of patients). Median costs for a multiple trauma patient were euro 4076 and for coronary surgery patient euro 380. The variability is largely due to different lengths of ICU stay. Cost per surviving patient was higher for ALI/ARDS, nontraumatic intracranial hemorrhage, multiple trauma, and emergency abdominal surgery. Money loss per patient was higher for ALI/ARDS and lower for multiple trauma. Planned coronary and major abdominal surgery and short-stay patients were treated most cost-efficiently. Cost of treatment in an ICU varies widely for different types of patients. Strategies are needed to contain the major determinants of high costs and low cost-efficiency.


Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.


Chrysophanol increases osteoblast differentiation via AMPK/Smad1/5/9 phosphorylation in vitro and in vivo.
Chrysophanol (Chrysophanic acid; CA) is a natural anthraquinone found in Senna tora and rhubarb that has various characteristic features, including the ability to suppress adipogenesis. However, its effects on osteoblast differentiation have not been investigated. Herein, this study aimed to demonstrate the mechanism by which CA induces the osteoblast differentiation. CA increased the expression of osteogenic genes. The staining levels Alkaline phosphatase (ALP) and Alizarin Red S (ARS) were increased by chrysophanol. CA induced osteoblast differentiation through AMP-activated protein kinase (AMPK)/Small mothers against decapentaplegic (Smad1/5/9) activation in MC3T3-E1 cells. In addition, compound C, AMPK inhibitor (Comp. C)-induced cells suppressed osteogenic genes expression and AMPK/Smad1/5/9 activation. Interestingly, AMPK in the CA-induced AMPK/Smad1/5/9 signalling pathway was an upstream regulator of Smad1/5/9. In order to further dissect in bone development, we used a zebrafish model to investigate the effect of CA on bone development. These results suggest that CA stimulated bone development via AMPK/Smad1/5/9. Overall, our results demonstrate that CA promotes osteoblast differentiation via AMPK/Smad1/5/9 expression in vitro and in vivo.


Accurate band gaps and dielectric properties from one-electron theories (abstract only).
For semiconductor modeling, a major shortcoming of density functional theory is that the predicted band gaps are usually significantly too small. It is generally argued that this shortcoming is related to the fact that density functional theory is a ground state theory, and as a result, one is not allowed to associate the one-electron energies with the energies of quasi-particles. Although this fundamental objection is certainly correct, the modeling of the positioning of donor and acceptor levels in semiconductors faces serious limitations with present density functionals. Several solutions to this problem have been suggested. A particular attractive and fairly simple one is the inclusion of a small fraction of the non-local exchange in the Hamiltonian (hybrid functionals). This approach leads to sensible band gaps for most semiconductors, but fails for ionic solids. A more reliable approach is via many-electron Green's function techniques, which have made tremendous advances in recent years. Here GW calculations in various flavors are presented for small gap and large gap systems, comprising typical semiconductors (Si, SiC, GaAs, GaN, ZnO, ZnS, CdS and AlP), small gap semiconductors (PbS, PbSe, PbTe), insulators (C, BN, MgO, LiF) and noble gas solids (Ar, Ne). The general finding is that single-shot G(0)W(0) calculations based on wavefunctions obtained from conventional density functional theory yield too small band gaps, whereas G(0)W(0) calculations following hybrid functional calculations tend to overestimate the band gaps by roughly the same amount. This is at first sight astonishing, since the hybrid functionals yield very good band gaps themselves. The contradiction is resolved by showing that the inclusion of the attractive electron-hole interactions (excitonic effects) is required to obtain good static and dynamic dielectric functions using hybrid functionals. The corrections are usually incorporated in GW calculations using 'vertex corrections', and in fact inclusion of these vertex corrections rectifies the predicted band gaps. Finally, in order to remove the dependence on the initial wavefunctions, self-consistent GW calculations are presented, again including an approximate treatment of vertex corrections. The results are in excellent agreement with experiment, with a few per cent deviation for all materials considered. We conclude that predictive band gap engineering is now possible with the theoretical description approaching experimental accuracy.


Stable and reproducible porcine model of acute lung injury induced by oleic acid.
Previous studies on acute lung injury induced with oleic acid did not attempt to limit the influence of secondary changes on pulmonary circulation, and cardiopulmonary variable data were only collected and processed intermittently. Our study was designed to continuously monitor the following variables in five swine: systemic and pulmonary pressure; mixed venous oxygen saturation (SVO2) and arterial oxygen saturation (SaO2); minute oxygen consumption and CO2 production before, during, and for 4 hr after the infusion of oleic acid. A personal computer was programmed to produce 20-sec updates of deadspace ratio (VD/VT), venous admixture (Qsp/Qt), pulmonary (PVR) and systemic vascular resistance (SVR), and cardiac output (Qt) from these data. During the oleic acid infusion, there were increases in PVR, SVR, heart rate (HR), mean pulmonary arterial pressure (MPAP), Qsp/Qt, and VD/VT, and a decrease in Qt, SaO2, and SVO2. Thirty minutes after the oleic acid infusion, there was a further increase in HR, Qsp/Qt, and VD/VT, while MPAP, PVR, and SVR gradually decreased to pre-oleic acid infusion levels. No further decrease in SaO2, SVO2, and Qt was observed during that time. After the 30-min period, there was no further change in the cardiopulmonary variables. Our method of continuous monitoring was able to demonstrate in swine both the dynamic changes during, and stability after, the oleic acid infusion.


Functional interaction between DNA-PKcs and telomerase in telomere length maintenance.
DNA-PKcs is the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex that functions in the non-homologous end-joining of double-strand breaks, and it has been shown previously to have a role in telomere capping. In particular, DNA-PKcs deficiency leads to chromosome fusions involving telomeres produced by leading-strand synthesis. Here, by generating mice doubly deficient in DNA-PKcs and telomerase (Terc(-/-)/DNA-PKcs(-/-)), we demonstrate that DNA-PKcs also has a fundamental role in telomere length maintenance. In particular, Terc(-/-)/DNA-PKcs(-/-) mice displayed an accelerated rate of telomere shortening when compared with Terc(-/-) controls, suggesting a functional interaction between both activities in maintaining telomere length. In addition, we also provide direct demonstration that DNA-PKcs is essential for both end-to-end fusions and apoptosis triggered by critically short telomeres. Our data predict that, in telomerase-deficient cells, i.e. human somatic cells, DNA-PKcs abrogation may lead to a faster rate of telomere degradation and cell cycle arrest in the absence of increased apoptosis and/or fusion of telomere-exhausted chromosomes. These results suggest a critical role of DNA-PKcs in both cancer and aging.


A pediatric case of pheochromocytoma without apparent hypertension associated with von Hippel-Lindau disease.
Pheochromocytomas are catecholamine-secreting tumors. These tumors are rare in children, and they may be associated with hereditary syndromes such as von Hippel-Lindau (VHL) disease. Most pediatric patients with pheochromocytoma present with sustained hypertension, while 10% to 69% of adult patients are asymptomatic. Herein, we present the case of a 12-yr-old Japanese girl with pheochromocytoma due to a germline mutation in the VHL (Arg161Gln). The only complaint was loss of weight. Pyrexia, anemia, and increases in C-reactive protein (CRP) and ferritin were observed. Abdominal ultrasonography revealed a right adrenal gland tumor. Fractionated catecholamines and metanephrines in plasma and 24-h collected urine revealed elevated levels of norepinephrine and normetanephrine. Although hypertension and tachycardia were inapparent by an ordinary physical examination, paroxysmal mild hypertension and tachycardia were identified by a thorough examination after walking and abdominal compression. Paroxysmal hypertension and tachycardia were profound during operation. In conclusion, pheochromocytoma can be a consideration in the differential diagnosis of weight loss. Hypertension and tachycardia can be inapparent and paroxysmal in pediatric patients as well as in adults; thus, thorough assessment should be repeated.


The need to change: Is there a critical role of midlife adaptation in mental health later in life?
Although late-life depression (LLD) is a serious health problem and more common than dementia in people over 60, it is underdiagnosed and undertreated. The cognitive-emotional etiology of LLD is particularly poorly understood. This is in contrast to the now extensive literature from psychology and cognitive neuroscience on the characteristics of emotionally healthy aging. This research consistently shows a change in emotional processing in older adults that is modulated by prefrontal regulation. Lifespan theories explain this change in terms of neurocognitive adaptation to limited opportunities and resources that typically occur in the second half of life. Epidemiological data on an increase in well-being after a low point around age 50 suggest that the majority of people seem quite capable of making this adaptation, even though empirical evidence for a causal modulation of this so called 'paradox of aging' and for the role of the midlife dip is still lacking. Intriguingly, LLD is associated with deficits in emotional, cognitive, and prefrontal functions similar to those shown to be crucial for healthy adaptation. Suspected causes of these deficits, such as white matter lesions or affective instability, become apparent as early as midlife when internal and external changes as well as daily challenges set in. Based on these findings, we propose that some individuals who develop depression at older ages may not have been able to successfully implement self-regulatory adaptation at midlife. Here, we review the current evidence and theories on successful aging, the neurobiology of LLD, and well-being across the lifespan. Drawing on recent advances in lifespan theories, emotion regulation research, and cognitive neuroscience, we propose a model of successful versus unsuccessful adaptation that emphasizes the increasing need for implicit habitual control and resource-based regulatory choice during midlife.


Novel Antigen Targets for Immunotherapy of Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) was the first malignancy for which immunotherapy, in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT), was integrated into the standard of care. Allo-HSCT however is an imperfect therapy associated with significant morbidity and mortality while offering only incomplete prevention of AML clinical relapse. These limitations have motivated the search for AML-related antigens that might be used as more specific and effective targets of immunotherapy. While historically such investigations have focused on protein targets expressed uniquely in AML or at significantly higher levels than in normal tissues, this article will review recent discoveries which have identified a novel selection of potential antigen targets for AML immunotherapy, such as non-protein targets including lipids and carbohydrates, neo-antigens created from genetic somatic mutations or altered splicing and post-translational modification of protein targets, together with innovative ways to target overexpressed protein targets presented by cell surface peptide-MHC complexes. These novel antigens represent promising candidates for further development as targets of AML immunotherapy.


Particle-particle particle-mesh method for dipolar interactions: on error estimates and efficiency of schemes with analytical differentiation and mesh interlacing.
The interlaced and non-interlaced versions of the dipolar particle-particle particle-mesh (P(3)M) method implemented using the analytic differentiation scheme (AD-P(3)M) are presented together with their respective error estimates for the calculation of the forces, torques, and energies. Expressions for the optimized lattice Green functions, and for the Madelung self-forces, self-torques and self-energies are given. The applicability of the theoretical error estimates are thoroughly tested and confirmed in several numerical examples. Our results show that the accuracy of the calculations can be improved substantially when the approximate (mesh computed) Madelung self-interactions are subtracted. Furthermore, we show that the interlaced dipolar AD-P(3)M method delivers a significantly higher accuracy (which corresponds approximately to using a twice finer mesh) than the conventional method, allowing thereby to reduce the mesh size with respect to the non-interlaced version for a given accuracy. In addition, we present similar expressions for the dipolar ik-differentiation interlaced scheme, and we perform a comparison with the AD interlaced scheme. Rough tests for the relative speed of the dipolar P(3)M method using ik-differentiation and the interlaced/non-interlaced AD schemes show that when FFT computing time is the bottleneck, usually when working at high precisions, the interlaced AD-scheme can be several times faster than the other two schemes. For calculations with a low accuracy requirement, the interlaced version can perform worse than the ik and the non-interlaced AD schemes.


The BATTLE to personalize lung cancer prevention through reverse migration.
Agents can enter clinical development for cancer prevention either initially or after previous development for a different indication, such as arthritis, with both approaches consuming many years of development before an agent is fully evaluated for cancer prevention. We propose the following, third approach: reverse migration, that is, importing agents, targets, and study designs to personalize interventions and concepts developed in advanced cancer to the setting of cancer prevention. Importing these "ready-made" features from therapy will allow reverse migration to streamline preventive agent development. We recently reported the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial of personalized lung cancer therapy and now propose the reverse migration development of personalized lung cancer prevention based on the BATTLE model.


In Vivo Dual-Modality Fluorescence and Magnetic Resonance Imaging-Guided Lymph Node Mapping with Good Biocompatibility Manganese Oxide Nanoparticles.
Multifunctional manganese oxide nanoparticles (NPs) with impressive enhanced T₁ contrast ability show great promise in biomedical diagnosis. Herein, we developed a dual-modality imaging agent system based on polyethylene glycol (PEG)-coated manganese oxide NPs conjugated with organic dye (Cy7.5), which functions as a fluorescence imaging (FI) agent as well as a magnetic resonance imaging (MRI) imaging agent. The formed Mn₃O₄@PEG-Cy7.5 NPs with the size of ~10 nm exhibit good colloidal stability in different physiological media. Serial FI and MRI studies that non-invasively assessed the bio-distribution pattern and the feasibility for in vivo dual-modality imaging-guided lymph node mapping have been investigated. In addition, histological and biochemical analyses exhibited low toxicity even at a dose of 20 mg/kg in vivo. Since Mn₃O₄@PEG-Cy7.5 NPs exhibited desirable properties as imaging agents and good biocompatibility, this work offers a robust, safe, and accurate diagnostic platform based on manganese oxide NPs for tumor metastasis diagnosis.


Specific sensitization of Lyt-1+2- T cells to spleen cells modified by the drug D-penicillamine or a stereoisomer.
A mouse model for assessing the sensitization of T cells to the drug D-penicillamine (D-Pen) has been established. Mice were primed with D-Pen in vivo and the secondary response of specific T cells was measured in a proliferative assay in vitro. Priming was achieved by injecting either free D-Pen or, more effectively, D-Pen in complete Freund's adjuvant at the base of the tail. After 7 to 9 days, the draining lymph node cells (responder cells) were restimulated in vitro with syngeneic spleen cells that had been preincubated with D-Pen for 20 to 22 hr and washed (D-Pen-SC). The thiol (-SH) group of D-Pen was required for generating effective stimulator cells; other thiol compounds, however, or heavy metals (Hg, Au) were unable to generate cross-reacting stimulators on incubation with spleen cells. Although D-Pen-SC proved to be good stimulator cells, thymocytes and mouse erythrocytes, after having been preincubated with D-Pen, completely failed to stimulate. The proliferating responder cells were Lyt-1+2- T cells that were highly specific for D-Pen-SC and were even capable of distinguishing between the two stereoisomers D-Pen and L-Pen. The splenic T cells of recipient mice were effectively primed by injecting D-Pen-SC, but not free D-Pen, via the i.v. route. These findings indicate that D-Pen can act as a hapten for specific T cells when presented on the surface of appropriate stimulator cells. Conceivably, if D-Pen were able to generate effective stimulator cells in vivo, this could lead to T cell reactions comparable to those in the graft-vs-host reaction (GVHR). We discuss the possibility that the GVH-like adverse immunologic side-effects of D-Pen in patients may have a GVHR-like pathogenesis.


[Computer-assisted drug information].
Experience with a university hospital based drug information service (DIS) is reported. A total of 501 drug related questions were analyzed during two prospective evaluation periods of 13 and 14 months' duration respectively. Information was requested by physicians and pharmacists chiefly on practical aspects of drug treatment in individual patients (77%), such as drug choice, dosage adaptation, side effects and interactions. Inquiries on drug safety in pregnancy and lactation (8.8%), and questions on pharmaceutical properties (14.2%), including pharmacokinetics, were also frequent. Our experience indicates that a problem-oriented, comprehensive DIS necessitates close cooperation between physicians trained in clinical pharmacology and pharmacists within the same team. The use of electronic media greatly facilitates the collection of drug related information, data retrieval and storage. Drug information services can contribute to improved quality and safety of drug therapy.


[Joint position error in patients with headache : Systematic review of the literature and experimental data for patients with chronic migraine].
Chronic migraine (CM) is a primary headache type associated with a severe reduction in the quality of life. The association of sensorimotor dysfunction in the neck, measured with the joint position error test (JPE), and CM is largely unknown, even though up to 60% of migraine patients report neck pain accompanying the migraine. This manuscript reports a systematic review of the literature on JPE in patients with headache as well as data on an observational study. To determine the JPE of migraine patients, 37 subjects with CM were tested and compared with a control group (CG; n = 22). In an additional analysis, CM patients were divided into two subgroups based on the medical treatment approach. The measurements were taken in the three movement dimensions with five repetitions in each direction using a laser pointer fixed to the head. The mean JPE in the sagittal plane was 3.7° (SD ± 1.4°) and 3.1° (SD ± 1.1°) for CM (n = 37) and CG, respectively. In the transverse plane it was measured as 3.7° (SD ± 1.5°) for CM and 3.2° (SD ± 1°) for the CG, while it was 3.6° (SD ± 1.2°; CM) and 3.3° (SD ± 1.1°; CG) in the frontal plane. The between group difference was not significant for all movement planes. When groups according to the treatment regimen, both groups showed similar migraine and neck pain features but the JPE was significantly larger in the CM + BTh group compared to the CM without BTh group and the CG. In the sagittal plane, the JPE was 4.21° (SD ± 1.8°) for the CM + BTh compared to 2.99° (SD ± 1.2°) in CM without BTh and 3.21° (SD ± 1.2°) in the CG (p = 0.0053). The difference between CM + BTh and CM without BTh was 1.52° (p = 0.016) after propensity score matching in the sagittal plane. Only patients in the CM + BTh group showed a statistically increased JPE. The influence of neck pain does not explain the between group difference. A possible factor is the degree of chronification. This study indicates that the JPE might discriminate a subgroup of migraine patients.


[Metabolic evolution of hypertonic dehydration treated with fluidotherapy: revision of 40 infants (author's transl)].
Authors study the metabolic evolution of osmolarity, natraemia, chloremia, kaliemia and uremia of 40 infants with hypertonic dehydration. They divide the serie into two groups in accordance with initial value of natraemia: more or less than 170 mEq./l. The slow average decreases by hour of osmolarity, natraemia and chloremia were evaluated, and that justifies good evolution of hypertonic dehydration and minimal neurological repercussion found. Renal function in this metabolic condition is discussed. The usefulness of the fluidotherapic technique employed is demonstrated.


Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease.
The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)-specific CD4(+) and CD8(+) T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8(+) cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA(-)CD27(+)CCR7(-) CTLs, although classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4(+) T-cell response preceded CMV-specific CD8(+) T-cell responses, in symptomatic individuals the CMV-specific effector-memory CD4(+) T-cell response was delayed and only detectable after antiviral therapy. The appearance of disease symptoms in these patients suggests that functional CD8(+) T-cell and antibody responses are insufficient to control viral replication and that formation of effector-memory CD4(+) T cells is necessary for recovery of infection.


Appearance of spatiotemporal noise and its effect on transport of electron pairs in a superconducting junction device.
Transport of electron pairs in a superconducting junction device with spatiotemporal noise is investigated. It is shown that, in a superconducting junction device, spatiotemporal noise can appear and induce a nonzero current due to the symmetry breaking induced by the correlation of the spatiotemporal noise with the phase difference. We found that there is a negative current for the electron pairs, exhibiting a well with increasing thermal noise strength. Our results can provide a theoretical foundation for the further investigation of superconducting junctions.


Increased formation of carcinogenic PAH metabolites in fish promoted by nitrite.
Nitrite (NO(2)(-)), a highly reactive chemical species, accumulates in coastal waters as a result of pollution with nitrogenous waste and/or an imbalance in the bacterial processes of nitrification and denitrification. The present study probed the impact of nitrite (NO(2)(-)) on the metabolism of polycyclic aromatic hydrocarbons (PAHs) in fish. In a laboratory experiment, exposure of euryhaline fish, Oreochromis mossambicus to industrial effluents containing PAHs in the presence of NO(2)(-) enhanced the cytochrome P450-dependent biotransformation activity determined as 7-ethoxyresorufin-O-deethylase (EROD), by nearly 36% compared to the value observed in the absence of NO(2)(-) (50.2 +/- 6.74 pmol resorufin min(-1) g(-1) liver). Fixed wavelength fluorescence measurements in bile revealed maximum enhancement to have occurred in the metabolites of benzo[a]pyrene, a carcinogenic PAH. Lasting, sublethal physiological deterioration was apparent in fish exposed simultaneously to an oil refinery effluent and NO(2)(-), from the unremittingly decreasing liver somatic index, even after the withdrawal of the contaminants.


[Neuroendocrine carcinoma of the skin. Morphology and differential diagnosis based on 2 clinical cases].
Two cases of neuroendocrine carcinomas of the skin were examined by light microscopic and electron microscopic methods. In both patients the disease showed an unusual course characterized by the occurrence of numerous and wide-spread skin nodules. Light microscopically, we found a uniform tumor tissue with trabecular, nest- or cord-like arrangement of cancer cells. At electron microscopic investigation, neurosecretory granules (dense-cored vesicles) were detected. These organelles had a diameter between 90 and 220 nm. Furthermore, small bundles of intermediate filaments and a well-developed Golgi system as well as numerous vesicular structures were recognized. Specialized cell junctions were lacking, tumor cell complexes were often enveloped by a basal lamina-like structure. The light microscopic and electron microscopic observations are in accordance with other reports. The relationship of neuroendocrine skin carcinomas to Merkel cells is discussed. However, we suggest an origin of these carcinomas from multipotent epithelial stem cells. The multicentric development in our cases, the tumor localization, and recent electron microscopic findings in basal cell carcinomas lend the basis for speculations on relations between neuroendocrine carcinomas and basal cell carcinomas of the skin. Lastly, the morphologic differential diagnosis of neuroendocrine carcinomas is presented. Special attention is called to the distinction from melanomas, lymphomas and other neuroendocrine tumors. In spite of the fact that neuroendocrine carcinomas of the skin are well defined and considered to be a clinico-pathologic entity there are some open questions concerning the tumor biology and histogenesis.


Progressive tension sutures in the prevention of postabdominoplasty seroma: a prospective, randomized, double-blind clinical trial.
The purpose of this study was to evaluate the seroma reduction capabilities of progressive tension sutures and compare them with the conventional use of drains. Sixty female patients were randomized into four groups: group 1 (control, no drains, and no progressive tension sutures), group 2 (progressive tension sutures alone), group 3 (drains alone), and group 4 (progressive tension sutures and drains). All patients underwent a classic abdominoplasty and drains were left for 7 days in the corresponding groups. Clinical and ultrasound assessments were performed 2 weeks after the operation by blinded evaluators. Punctures, volumes, nonseroma complications, and aesthetic outcome were also measured. Surgical time was 50 minutes longer in groups 2 and 4. Drain outputs were higher in group 3 than in group 4. The clinical and ultrasound seroma frequency was 35 percent and 90 percent respectively, without significant differences among the groups. The control group was interrupted at 10 patients because of considerably larger seromas and an increased amount of punctures needed for treatment. No differences were found in the other groups. There were no differences with respect to complication rates and aesthetic outcome after follow-up. Progressive tension sutures increase surgical time, reduce drain outputs, and have the same clinical and ultrasound seroma frequency as the use of drains alone. The combination of both methods simultaneously does not add any advantages. However, complications and interventions increase if at least one of them is not used. The mechanism of action of progressive tension sutures could be the compartmentalization of the fluid collection under the flap facilitating absorption.


The Influence of Cellulose-Type Formulants on Anti-Candida Activity of the Tyrocidines.
Candida species are highly adaptable to environmental changes with their phenotypic flexibility allowing for the evasion of most host defence mechanisms. Moreover, increasing resistance of human pathogenic Candida strains has been reported against all four classes of available antifungal drugs, which highlights the need for combinational therapies. Tyrocidines are cyclic antimicrobial peptides that have shown synergistic activity with antifungal drugs such as caspofungin and amphotericin B. However, these cyclodecapeptides have haemolytic activity and cytotoxicity, but they have been used for decades in the clinic for topical applications. The tyrocidines tend to form higher-order structures in aqueous solutions and excessive aggregation can result in variable or diminished activity. Previous studies have shown that the tyrocidines prefer ordered association to celluloses. Therefore, a formulation with soluble cellulose was used to control the oligomer stability and size, thereby increasing the activity against Candida spp. Of the formulants tested, it was found that commercial hydroxy-propyl-methyl cellulose, E10M, yielded the best results with increased stability, increased anti-Candida activity, and improved selectivity. This formulation holds promise in topical applications against Candida spp. infections.


[Non-classical cellular and molecular deficits in cancer development].
A wide number of genetic and epigenetic changes are required to drive normal cells towards malignancy. These changes participate in oncogenic intracellular pathways that allow tumor cells proliferation and dissemination. Hanahan and Weinberg' in their seminal paper "The hallmarks of cancer" described the classic cell hallmarks acquired in cancer development and progression: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replication potential, sustained angiogenesis, tissue invasion and metastasis. This review covers other recently described biological characteristics associated with the emergence of cancer. Some of the main non-classical hallmarks of cancer that are broadly accepted include: genetic instability, evasion of cell senescence, epigenetic alterations of cancer related-genes, RNA interference alterations in the expression of cancer related-genes, changes in glucose and glutamine metabolism, participation of cancer stem cells in cellular proliferation, stromal cell participation in the tumor's micro-environment, and changes in antigenic presentation and immunosuppression due to cytokines in the tumor's micro-environment. The identification of molecular biomarkers of classical and non classical tumor processes in a specific tumor will allow a better understanding of its pathophysiology. It will also permit the design of ad-hoc therapeutic strategies.


Reduction in mitral regurgitation during therapy guided by measured filling pressures in the ESCAPE trial.
Dynamic mitral regurgitation (MR) contributes to decompensation in chronic dilated heart failure. Reduction of MR was the primary physiological end point in the ESCAPE trial, which compared acute therapy guided by jugular venous pressure, edema, and weight (CLIN) with therapy guided additionally by pulmonary artery catheters (PAC) toward pulmonary wedge pressure <or=15 and right atrial pressure <or=8 mm Hg. Patients were randomized to PAC or CLIN during hospitalization with chronic heart failure and mean left ventricular ejection fraction 20%, and at least 1 symptom and 1 sign of congestion. MR and mitral flow patterns, measured blinded to therapy and timepoint, were available at baseline and discharge in 133 patients, and at 3 months in 104 patients. Changes in MR and related transmitral flow patterns were compared between PAC and CLIN patients. Jugular venous pressure, edema, and weights decreased similarly during therapy in the hospital for both groups. In PAC but not in CLIN patients, MR jet area, MR/left atrial area ratio, and E velocity were each significantly reduced and deceleration time increased by discharge. By 3 months, patients had clinical evidence of increased jugular venous pressure, edema, and weight since discharge, reaching significance in the PAC arm, and the change in MR was no longer different between the 2 groups, although the change in E velocity remained greater in PAC patients. During hospitalization, therapy guided by PAC to reduce left-sided pressures improved MR and related filling patterns more than therapy guided clinically by evidence of systemic venous congestion. This early reduction did not translate into improved outcomes out of the hospital, where volume status reverted toward baseline.


Synergism between a foldase and an unfoldase: reciprocal dependence between the thioredoxin-like activity of DnaJ and the polypeptide-unfolding activity of DnaK.
The role of bacterial Hsp40, DnaJ, is to co-chaperone the binding of misfolded or alternatively folded proteins to bacterial Hsp70, DnaK, which is an ATP-fuelled unfolding chaperone. In addition to its DnaK targeting activity, DnaJ has a weak thiol-reductase activity. In between the substrate-binding domain and the J-domain anchor to DnaK, DnaJ has a unique domain with four conserved CXXC motives that bind two Zn(2+) and partly contribute to polypeptide binding. Here, we deleted in DnaJ this Zn-binding domain, which is characteristic to type I but not of type II or III J-proteins. This caused a loss of the thiol-reductase activity and strongly reduced the ability of DnaJ to mediate the ATP- and DnaK-dependent unfolding/refolding of mildly oxidized misfolded polypeptides, an inhibition that was alleviated in the presence of thioredoxin or DTT. We suggest that in addition to their general ability to target misfolded polypeptide substrates to the Hsp70/Hsp110 chaperone machinery, Type I J-proteins carry an ancillary protein dithiol-isomerase function that can synergize the unfolding action of the chaperone, in the particular case of substrates that are further stabilized by non-native disulfide bonds. Whereas the unfoldase can remain ineffective without the transient untying of disulfide bonds by the foldase, the foldase can remain ineffective without the transient ATP-fuelled unfolding of wrong local structures by the unfoldase.


Cloning and functional characterization of the UDP-glucosyltransferase UgtB1 involved in sophorolipid production by Candida bombicola and creation of a glucolipid-producing yeast strain.
Sophorolipids produced by the non-pathogenic yeast Candida bombicola ATCC 22214 are glycolipid biosurfactants applied commercially as biodegradable and eco-friendly detergents. Their low cell toxicity, excellent wetting capability and antimicrobial activity attract the attention of high-value markets, such as the cosmetic and pharmaceutical industries. Although sophorolipid production yields have been increased by the optimization of fermentation parameters and feed sources, the biosynthetic pathway and genetic mechanism behind sophorolipid production still remains unclear. Here we identify a UDP-glucosyltransferase gene, UGTB1, with a key function in this economically important pathway. The protein shows sequence and structural homology to several bacterial glycosyltransferases involved in macrolide antibiotic synthesis. Deletion of UGTB1 in C. bombicola did not affect cell growth and resulted in a yeast producing glucolipids, thereby opening the route for in vivo production of these glycolipid intermediates. Activity assays on cell lysates confirmed that the identified gene is responsible for the second glucosylation step during sophorolipid production and illustrated that sophorolipid production in C. bombicola involves the stepwise action of two independent glucosyltransferases. The complete UGTB1 sequence data have been submitted to the GenBank database (http://www.ncbi.nlm.nih.gov) under Accession No. HM440974.


Evaluation Indexes of Military Hospitals From the Experts' Perspective: A Qualitative Study.
Given the importance of evaluation in an organization and considering the objectives and missions of military hospitals, we aimed to extract some indexes (in addition to common evaluation indexes) for use in evaluating military hospitals. This was an applied-type qualitative study. The participants were 15 health experts who were first chosen by a purposeful sampling, which was then continued by theoretical sampling. The data obtained were analyzed by using MAXQDA11 software and the content analysis method. After 290 obtained codes were analyzed, 17 indexes in 6 domains were extracted, including capacity development for crisis periods, equipment and facilities, training and research, passive defense, treatment, and services, from which 8 indexes were related to capacity development for crisis periods and equipment and facilities (4 indexes each), 3 indexes were related to services, and 6 indexes were related to training and research, passive defense, and treatment (2 indexes each). The results of the present research, as a supplement to current evaluation methods such as accreditation, can be used for the comprehensive evaluation of military hospitals.


Physician decision making and variation in hospital admission rates for suspected acute cardiac ischemia. A tale of two towns.
The authors tested the "uncertainty hypothesis," which holds that variations in rates of hospitalization or surgeries across small geographic areas reflect differences in physicians' decision making when confronting uncertainty. A small-areas variation analysis of suspected acute cardiac ischemia (ACI) admissions in northern Michigan was performed, and two demographically nearly identical towns differing by a factor of 3 in ACI admission rates were selected. Medical records of all patients evaluated in the emergency departments of these hospitals for suspected ACI in 1988 were abstracted retrospectively. Probabilities of ACI were objectively estimated using the Acute Cardiac Ischemia Time-Insensitive Predictive Instrument. Logistic regression of admission on patient characteristics, other illnesses, probability of ACI, and community revealed no difference in admission decisions between the two hospitals (odds ratio for community = 0.766, 95% confidence interval, 0.542-1.08, n = 787, P > .1). Nearly twice as many patients with ACI presented to the emergency department of the high-admitting hospital as to the low-admitting hospital. The authors conclude that, at least for ACI, population-based area discharge rates do not necessarily reflect case-based decision rates. Drawing inferences regarding physician decision making from discharge or claims datasets may lead to error.


Exploring allosteric hits of the NS2B-NS3 protease of DENV2 by structure-guided screening.
Despite the rising number of cases and increasing global disease burden, there is no definitive therapy against dengue to date, which necessitates the urgent discovery of inhibitors against the virus. The NS2B-NS3 serine protease of the dengue virus (DENV) catalyses polyprotein cleavage and is a potential target for drug discovery. The protease possesses a potentially druggable allosteric site, and the binding of inhibitors to this site locks the protease in an inactive conformation. The allosteric site is a potential druggable target for drug discovery against flaviviruses. This study aimed to identify serotype-specific hits against the allosteric site in the NS2B-NS3 protease of DENV serotype 2 (DENV2) from the Enamine, Selleck, and ChemDiv antiviral libraries. The prepared libraries were screened using a redocking and rescoring-based strategy with Glide SP and Glide XP, and the hitlist was initially screened by comparing their docking scores with that of reported allosteric inhibitors, myricetin and curcumin. The hitlist was subsequently screened by comparing the molecular mechanics with generalised Born and surface area solvation (MM-GBSA) energy with that of the standards. Ten hits were finally selected by virtual screening, and the stability of the hit-receptor complexes was determined with 100 ns molecular dynamics (MD) simulations in an explicit solvent. Trajectory visualisation and analyses of the RMSD and RMSF values revealed that three hits, including two catechins, remained stably bound to the allosteric binding site throughout the production run. Hit-receptor interaction analyses revealed that the hits formed highly stable interactions with Glu 88, Trp 89, Leu 149, Ile 165, and Asn 167, and MM-GBSA energy analysis revealed that the three hits had high binding affinity to the allosteric site. The findings obtained herein can aid in identifying novel serotype-specific inhibitors of DENV protease in future.


Dynamic Assessment of Construction Materials in Urban Building Stocks: A Critical Review.
There is a lack of understanding on the different types of dynamics of building stocks, in real life and in models. Moreover, there is now a particular interest in the embodied impacts of construction materials, since with the increasing efficiency of buildings operation, embodied impacts gain more importance in the overall building life cycle. This critical review wants to advance the understanding of the type of dynamics, methods, and tools used. The well-known IPAT equation is adapted for building stocks and three dynamics are defined: spatial, evolutionary temporal, and spatial-cohort dynamic. A framework is defined that can help researchers choose a method, tool, and dynamics of input parameters depending on their research goal, case study, and data. Moreover, generally valid conclusions are drawn, including MFA is useful to model spatially dynamic material flows; GIS is needed to include spatial dynamics. Retrofit, compared to construction and demolition, is understudied and usually analyzed through top-down methods. Material intensity and emission intensity are rarely modeled in a dynamic way. Overall, scholars seem to perform increasingly data intensive and complex studies tailored to a specific case study. However, there are big differences in the quality depending on the dynamic of input parameters.


PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation.
PR-39 inhibits proteasome-mediated I kappa B alpha degradation and might protect against ischemia-reperfusion injury. We studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which lacks the ability to prevent I kappa B alpha degradation, in a rat heart ischemia-reperfusion model. After 30 min of ischemia and 24 h of reperfusion, cardiac function, infarct size, neutrophil infiltration, and myeloperoxidase activity were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion reduced infarct size by 65% and 57%, respectively, which improved blood pressure, left ventricular systolic pressure, and relaxation and contractility (+/-dP/dt) compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of I kappa B alpha degradation and subsequent inhibition of nuclear factor-kappa B-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.


Statistical mechanics of the glass transition in one-component liquids with an anisotropic potential.
We study a recently introduced model of one-component glass-forming liquids whose constituents interact with an anisotropic potential. This system is interesting per se and as a model of liquids such as glycerol (interacting via hydrogen bonds) which are excellent glass formers. We work out the statistical mechanics of this system, encoding the liquid and glass disorder using appropriate quasiparticles (36 of them). The theory provides a full explanation of the glass transition phenomenology, including the identification of a diverging length scale and a relation between the structural changes and the diverging relaxation times.


Progesterone responses to human chorionic gonadotropin in dairy cattle supplemented with beta-carotene.
Twenty Holstein cows were assigned to one of four groups according to milk production and beta-carotene supplementation to evaluate effects of supplementation and milk production on reproductive performance and response of corpus luteum to human chorionic gonadotropin indicated by release of progesterone and secretion of luteinizing hormone in blood plasma. Cows were divided into groups of high and low production and divided further into beta-carotene supplemented and unsupplemented groups. Blood samples were taken 10 days postestrus at 10-min intervals from 1 h prior to injection of 5000 IU human chorionic gonadotropin until 5 h postinjection. Mean days to first detected estrus were 33, 37, 34, and 36 in supplemented, unsupplemented, high-production, and low-production cows. Treatment with beta-carotene and milk production did not affect days to first breeding (63, 67, 62, and 67), or services per conception (3.2, 5.1, 4.6, and 3.7). However, days open were reduced by supplementation (116 versus 186), but milk production had no effect (173 versus 129). Regressions of progesterone on sampling time within treatment and within milk production were significant. Regression of luteinizing hormone on time within production group was also significant. Neither beta-carotene nor milk production affected most reproductive measures, but differences were subtle in corpus luteum response to human chorionic gonadotropin, which may alter endocrine function.


Realization of Translational Symmetry in Trapped Cold Ion Rings.
We crystallize up to 15 ^{40}Ca^{+} ions in a ring with a microfabricated silicon surface Paul trap. Delocalization of the Doppler laser-cooled ions shows that the translational symmetry of the ion ring is preserved at millikelvin temperatures. By characterizing the collective motion of the ion crystals, we identify homogeneous electric fields as the dominant symmetry-breaking mechanism at this energy scale. With increasing ion numbers, such detrimental effects are reduced. We predict that, with only a ten-ion ring, uncompensated homogeneous fields will not break the translational symmetry of the rotational ground state. This experiment opens a door towards studying quantum many-body physics with translational symmetry at the single-particle level.


Factors That Affect Tissue-Engineered Skeletal Muscle Function and Physiology.
Tissue-engineered skeletal muscle has the promise to be a tool for studying physiology, screening muscle-active drugs, and clinical replacement of damaged muscle. To maximize the potential benefits of engineered muscle, it is important to understand the factors required for tissue formation and how these affect muscle function. In this review, we evaluate how biomaterials, cell source, media components, and bioreactor interventions impact muscle function and phenotype.


Purification of human factor VIII:C and its characterization by Western blotting using monoclonal antibodies.
Human factor VIII:C has been purified over 300 000-fold from cryoprecipitate by polyelectrolyte purification followed by affinity chromatography on Sepharose linked to antibody to factor VIIIR:Ag (monoclonal or polyclonal) and Sepharose linked to monoclonal antibody to factor VIII:C. The purified material has been analyzed by polyacrylamide gel electrophoresis (PAGE) and Western blotting using monoclonal antibodies. PAGE shows predominant bands at 360K (unreduced), 210K, and 90K and an 80K/79K doublet; Western blotting showed all the monoclonal antibodies used bound the 360K form. In a small-scale purification, plasma from blood taken directly into thrombin inhibitor Kabi S-2581 was applied directly to the monoclonal anti-factor VIII:C column. Western blot analysis of this material showed the 360K band on reduction. The purified factor VIII:C could be activated 13-fold by human thrombin. Gel analysis of the activated material showed intensification followed by fading of the band at 90K and generation of bands at 70K/69K, 55K, and 40K. Western blotting shows that the 70K/69K doublet derives from the 80K/79K moiety and the 40K peptide derives from the 90K and is presumed to contain the active site. From these studies an epitope map of the factor VIII:C molecule has been constructed.


Crystallization and preliminary X-ray crystallographic analysis of the GluR0 ligand-binding core from Nostoc punctiforme.
GluR0 from Nostoc punctiforme (NpGluR0) is a bacterial homologue of the ionotropic glutamate receptor. The ligand-binding core of NpGluR0 was crystallized at 294 K using the hanging-drop vapour-diffusion method. The L-glutamate-complexed crystal belongs to space group C222(1), with unit-cell parameters a = 78.0, b = 145.1, c = 132.1 A. The crystals contain three subunits in the asymmetric unit, with a VM value of 2.49 A3 Da(-1). The diffraction limit of the L-glutamate complex data set was 2.1 A using synchrotron X-ray radiation at beamline BL-4A of the Pohang Accelerator Laboratory (Pohang, Korea).


Prediction of survival for advanced cancer patients by recursive partitioning analysis: role of Karnofsky performance status, quality of life, and symptom distress.
We performed an exploratory recursive partitioning analysis (RPA) in 429 metastatic cancer patients who had completed a Functional Assessment of Cancer Therapy-General (FACT-G) and a Memorial Symptom Assessment Scale-Short Form (MSAS-SF) to define survival prognostic groups. The Cox model analysis also was performed. Both RPA and Cox models included Karnofsky performance status (KPS), age, FACT-G subscales, and MSAS-SF subscales as survival predictors. Of 429 patients, 348 patients (81.1%) had expired at time of analysis. The median age was 67 years (27-89), with median length of survival of 147 days. The RPA identified four distinct survival groups (p < .0001) with three variables: KPS, physical well-being, and physical symptom distress. The most significant split was KPS of 50%, followed by physical well-being score of 25 and physical symptom distress score of 0.6. The median survival time was 29 days for patients with KPS < 50%; 146 days for patients with KPS > or = 50% and physical well-being < 25; 292 days for patients with KPS > 50%, physical well-being > or = 25, and physical symptom distress score > 0.6; and 610 days for patients with KPS > or = 50%, physical well-being > or = 25, and physical symptom distress score < or = 0.6. The Cox model found, in addition to KPS (p < .0001) and physical well-being (p = .08), different predictors: psychological symptom distress (p = .0007), global distress index (p = .02), and age (p < .0001). We concluded that the KPS, quality of life, and symptom distress scores can be combined to define prognostic groups. Such models may be helpful for clinical decision making.


Chromosomal aberration and single cell gel electrophoresis (Comet) assay in the longitudinal risk assessment of occupational exposure to pesticides.
In recent years the use of pesticides in agriculture has been increasing steadily. At present there are more than 1000 chemicals classified as pesticides. Therefore, the widespread use of pesticides and their potential genetic hazard suggests that evaluation of their genotoxicity should be extended using the newer assays now available. In the present study chromosomal aberration analysis and the alkaline single cell gel electrophoresis (Comet) assay were used to evaluate the extent of DNA damage and DNA repair in peripheral blood lymphocytes of subjects employed in pesticide production. In order to determine possible primary genotoxic effects in workers blood samples were taken after an 8 month long period of exposure to a complex mixture of pesticides. To detect the possible occurrence of DNA repair in lymphocytes of the same subjects the second blood sample was taken after an 8 month long period of absence from the pesticide exposure zone. Regardless of the period of sampling, in the exposed group statistically significantly increased numbers of aberrant cells, chromatid and chromosome breaks, acentric fragments and dicentric chromosomes compared with the controls were found. After the workers had spent 8 months out of the pesticide exposure zone the number of aberrant cells and all types of chromatid and chromosome aberrations decreased significantly compared with sampling after the high exposure period, but it still remained significantly higher in comparison with the control group. After the period of high exposure to a mixture of pesticides statistically significantly increased levels of DNA damage in the Comet assay in terms of tail length and tail moment were found. After the workers were removed from production for 8 months both Comet assay end-points decreased significantly compared with the first sampling point, but they remained increased compared with the control.


Comparison of visual--vestibular interaction in insulin-dependent and non-insulin-dependent diabetes mellitus.
We compared various measures of visual-vestibular interaction in subjects with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM), as well as non-diabetic controls. Subjects with IDDM exhibited significantly greater postural sway than controls on those conditions in the Clinical Test of Sensory Interaction and Balance (CTSIB) which require greater reliance on the vestibular system (p < 0.005). The IDDM group also exhibited significantly worse gaze-holding in darkness and a significantly higher mean slow phase eye velocity (SPV) of optokinetic nystagmus (OKN; p<0.05 for both comparisons). However, there were no significant differences in latency to circularvection (CV). The NIDDM group showed a significant increase in postural sway across all 12 conditions compared with the controls, as well as a significant decrease in gaze-holding in darkness (p < 0.05 and p < 0.0005, respectively). However, they showed no significant difference in OKN SPV and a significant decrease in latency to CV for anticlockwise trials only (p < 0.05). These results suggest that IDDM and NIDDM are both associated with specific but different changes in visual-vestibular interaction.


Molecular pathomechanism of distal myopathy with rimmed vacuoles.
Distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM) are now known to be the same disease and are caused by mutations in tile GNE gene that encodes a bifunctional protein with two enzymatic activities: UDP-GlcNAc2-epimerase (GNE) and ManNAc kinase (MNK). GNE catalyzes the rate-limiting step in the sialic acid biosynthesis and MNK catalyzes the next step. So far, we have found homozygous or compound heterozygous mutations in 55 unrelated Japanese DMRV patients. Among them, c.1714G>C (p.V572L) mutation is the most common, accounting for 57% of the mutant alleles. The same mutation was recently identified also in Korean DMRV patients, raising the possibility of the presence of a common founder. We have also found that cardiac involvement is not very rare and is found in 18% of patients, albeit degree of severity widely varies; in some patients, it can result in sudden death. The length of time when patients become non ambulatory is diverse. The severity of clinical symptoms also varies widely, as evidenced by the presence of an asymptomatic homozygote harboring of p.D176V, the second most common mutation among Japanese patients. Patients' fibroblasts and myotubes are hyposialylated and this hyposialylation can be recovered by adding GNE metabolite, ManNAc, or sialic acid per se, NeuAc. Accordingly, the sialylation status in the skeletal muscle tissue is also greatly altered especially in fibers with rimmed vacuoles, suggesting the tight association between hyposialylation and the formation of rimmed vacuoles. However, we still do not know why hyposialylation leads to the formation of rimmed vacuoles. To further elucidate the pathomechanism and to develop a therapy of DMRV, we need to produce mouse model mouse for this disease.


Quadruple intercalated G-6 stack: a possible motif in the fold-back structure of the Drosophila centromeric dodeca-satellite?
The purine-rich strand d(GTACGGGACCGA)(n) of the Drosophila centromeric dodeca-satellite sequence is highly conserved and was found to form stable fold-back structures in which the homopurine 5'-GGGA-3' sequence was determined to play a crucial role. Here, we report the stable formation of the d(GGGA)(2) motif in the stem of a DNA hairpin closed by a single-residue d(ACC) loop. Similar to the zipper-like d(GGA)(2) motif observed in the human centromeric (TGGAA)(n) sequence, the central four guanosine bases in the d(GGGA)(2) motif do not pair, but interdigitate to form an elongated zipper-like quadruple-intercalated G-6 stack bracketed by sheared G.A base-pairs. Comparison between the current d(GGGA)(2) structure and the published crystal d(GAAA)(2) structure implies that the alignment of the unpaired purine bases plays an important role in determining the minor groove width of the purine-rich d(GPuPuA)(2) motif. Similarity between the zipper-like motifs possibly present in the Drosophila centromeric dodeca-satellite sequence and in the human centromeric (TGGAA)(n) sequence led us to propose that these special zipper-like motifs may constitute common cores in organizing eukaryotic centromeres.


Arteriography in the evaluation of pancreatic pseudocysts.
A policy of limiting preoperative diagnostic imaging of pancreatic pseudocysts to barium studies, sonography, or computed tomography will result in failure to detect frequently associated lesions which may only be appreciated by arteriography and which radically alter both the prognosis and surgical approach. These associated lesions include: (1) pseudoaneurysms, probably the most common cause of major gastrointestinal hemorrhage in pseudocyst patients; (2) pancreatic carcinoma, a possible etiologic factor leading to formation of the pseudocyst; (3) benign or malignant cystadenomas which mimic pseudocysts clinically but can be usually identified arteriographically by prominant neovascularity; and (4) splenic vein obstruction which can produce extrahepatic portal hypertension and necessitate splenectomy. In our experience, these complicating lesions are relatively common. Their preoperative detection is desirable and is best accomplished by arteriography. For this reason, arteriography should be routinely performed in patients suspected of pancreatic pseudocyst.


The role of ADAM-like decysin 1 in non-eosinophilic chronic rhinosinusitis with nasal polyps.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is classified into two subtypes: eosinophilic (ECRSwNP) and non-eosinophilic (NECRSwNP). Although the inflammatory patterns of ECRSwNP have been elucidated, NECRSwNP is poorly understood. The metalloproteinase ADAM-like decysin 1 (ADAMDEC1) has been reported to play a role in the early stages of the inflammatory response. We investigated the role of ADAMDEC1 in the pathogenesis of CRSwNP. We compared ADAMDEC1 expression in nasal polyp tissue from CRS patients using immunohistochemistry and RT-qPCR. Macrophages were cultured and ADAMDEC1 expression was determined at baseline and after exposure to lipopolysaccharide (LPS). ADAMDEC1 was virtually undetectable in tissues from control patients but was highly expressed in the NECRSwNP group compared with the ECRSwNP group. In nasal polyp tissues, ADAMDEC1 was expressed by CD68-positive cells, with a positive correlation between ADAMDEC1-positive and CD68-positive cells, and also between ADAMDEC1 and CD68 mRNA levels. Furthermore, stimulation of monocyte-derived macrophages with LPS induced ADAMDEC1 expression. This study demonstrates that ADAMDEC1 is involved in the pathogenesis of NECRSwNP, and also bacterial endotoxin signalling in macrophages; however, the underlying mechanism remains to be elucidated.


Restoration of auditory evoked responses by human ES-cell-derived otic progenitors.
Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.


Translation, Cultural Adaptation, Validation, and Reliability of Persian-Revised Heart Failure Compliance Questionnaire.
Compliance with health-related behaviors is a dilemma among heart failure (HF) patients. The present study aimed to assess the validity and reliability of a Persian translation of the revised heart failure compliance questionnaire (RHFCQ) in Iranian HF sufferers. This methodological study was performed on outpatient HF individuals referred to a heart clinic in Isfahan, Iran. The forward-backward translation method was used for translation. Twenty subjects were invited to express their opinions on the provided items concerning simplicity and understandability. Twelve experts were invited to rate the items regarding the content validity index (CVI). Cronbach's α was used to evaluate internal consistency. The patients were asked to complete the questionnaire for the second time after 2 weeks to investigate test-retest reliability using the intraclass correlation coefficient (ICC). There were no obvious difficulties during the translation and assessment of the simplicity and comprehensiveness of the questionnaire items. The CVI of the items ranged from 0.833 to 1.000. Totally, 150 patients (age: 64.60±15.00 y, males: 58.0%) filled in the questionnaire twice with no missing data. The highest and lowest compliance rates were attributed to alcohol and exercise domains, respectively (83.00±7.70% and 45.55±12.00%, respectively). Cronbach's α was 0.629. After the omission of 3 items related to smoking and alcohol cessation, Cronbach's α rose to 0.655. The ICC showed an acceptable value of 0.576 (95% CI, 0.462 to 0.673). The modified Persian RHFCQ is a simple and meaningful tool with acceptable moderate reliability and good validity for assessing compliance in Iranian HF patients.


IgG subclass deficiency in patients with Down's syndrome and aberrant hepatitis B vaccine response.
Seventeen adult patients with Down's syndrome (DS) and 19 adult healthy references were vaccinated with a hepatitis B vaccine in order to study the IgG subclass response. An enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies specific for IgG subclasses was employed. In spite of normal levels of total IgG1 and normal or even high levels of IgG3 in the DS patients, a significantly lower IgG1 response to the vaccine was observed in trisomic patients than in the references.


Estrogen-regulated expression of P450arom genes in the brain and ovaries of adult female Indian climbing perch, Anabas testudineus.
Cytochrome P450arom (CYP19), a product of cyp19a1 gene, catalyzes the conversion of androgens to estrogens and is essential for regulation of reproductive function in vertebrates. In the present study, we isolated partial cDNA encoding the ovarian (cyp19a1a) and brain (cyp19a1b) P450arom genes from adult female perch, Anabas testudineus and investigated their regulation by estrogen in vivo. Results demonstrated that cyp19a1a and cyp19a1b predominate in ovary and brain respectively, with quantity of both attuned to reproductive cycle. To elucidate estrogen-regulated expression of cyp19a1b in brain and cyp19a1a in ovary, dose- and time-dependent studies were conducted with estrogen in vitellogenic-stage fish in the presence or absence of specific aromatase inhibitor fadrozole. Results demonstrated that treatment of fish with 17β-estradiol (E2; 1.0 μM)) for 6 days caused significant upregulation of cyp19a1b transcripts, aromatase B protein, and aromatase activity in brain in a dose- and time-dependent manner. Ovarian cyp19a1a mRNA, aromatase protein, and aromatase activity, however, was less responsive to E2 than brain. Treatment of fish with an aromatase inhibitor fadrozole for 6 days attenuated both brain and ovarian cyp19a1 mRNAs expression and stimulatory effects of E2 was also significantly reduced. These results indicate that expression of cyp19a1b in brain and cyp19a1a in ovary of adult female A. testudineus was closely associated to plasma E2 levels and seasonal reproductive cycle. Results further show apparent differential regulation of cyp19a1a and cyp19a1b expression by E2/fadrozole manipulation.


Characteristics of pheochromocytoma in a 4- to 20-year-old population.
Hypertension in children and adolescents has become a major health problem recently recognized, and in a significant number of patients it is due to an endocrine tumor. The aim of this study was to establish the characteristics of pheochromocytoma in a population of 58 patients between 4 and 20 years of age studied at our Center. They represented a 23% of the total population of 255 pheochromocytoma patients studied. In the younger group (under 20 years of age), there was a marked predominance of severe sustained hypertension (93%), only 7% presented paroxysmal hypertension and none of them was normotensive. The youngsters studied showed a higher incidence of bilateral adrenal pheochromocytoma (34%) and extra-adrenal pheochromocytoma (22%). Malignancy was found in 12% of these patients. In addition, the incidence of familial pheochromocytoma was elevated in these patients (39%). Surprisingly, in contrast with the adult population where the most frequent familial pheochromocytomas were multiple endocrine neoplasia (MEN) type 2A (15%), the younger population showed a higher predominance of von Hippel-Lindau (VHL) (28%) and lower incidence of MEN 2A, MEN 2B, neurofibromatosis (NF), and succinate dehydrogenase subunit B (SDHB). In the VHL group, only two patients belonging to one family, showed the R167W mutation, while the others showed novel mutations in conserved amino acids. It may be speculated that the high incidence of VHL in youngsters may account for the biochemical and clinical features they usually present.