Regulatory and T Effector Cells Have Overlapping Low to High Ranges in TCR Affinities for Self during Demyelinating Disease.
Having regulatory T cells (Tregs) with the same Ag specificity as the responding conventional T cells is thought to be important in maintaining peripheral tolerance. It has been demonstrated that during experimental autoimmune encephalomyelitis there are myelin oligodendrocyte glycoprotein (MOG)--specific Tregs that infiltrate into the CNS. However, the affinity of naturally occurring polyclonal Tregs for any self-antigen, let alone MOG, has not been analyzed in the periphery or at the site of autoimmune disease. Utilizing the highly sensitive micropipette adhesion frequency assay, which allows one to determine on a single-cell basis the affinity and frequency of polyclonal Ag-specific T cells directly ex vivo, we demonstrate that at peak disease MOG-specific Tregs were progressively enriched in the draining cervical lymph nodes and CNS as compared with spleen. These frequencies were greater than the frequencies measured by tetramer analysis, indicative of the large fraction of lower affinity T cells that comprise the MOG-specific conventional T cell (Tconv) and Treg response. Of interest, the self-reactive CD4(+) Tconvs and Tregs displayed overlapping affinities for MOG in the periphery, yet in the CNS, the site of neuroinflammation, Tconvs skew toward higher affinities. Most of the MOG-specific Tregs in the CNS possessed the methylation signature associated with thymic-derived Tregs. These findings indicate that thymic-derived Treg affinity range matches that of their Tconvs in the periphery and suggest a change in TCR affinity as a potential mechanism for autoimmune progression and escape from immune regulation.


Massive pulmonary embolism and thrombophilia.
A 32-year-old man presented overnight to the accident and emergency unit with mild breathlessness on exertion. He was found to be hypoxic on room air and his chest x-ray revealed areas of patchy lung consolidation. He was given intravenous antibiotics for presumed community-acquired pneumonia. Unfortunately his condition deteriorated and he remained significantly hypoxic despite high-flow oxygen with ECG evidence of right heart strain. Further questioning revealed a history of protein S deficiency and a strong family history of venous thromboembolic disease. An urgent CT pulmonary angiogram showed an evidence of massive pulmonary embolism and the patient was successfully thrombolysed.


Reproducible paired sources from concurrent EEG-fMRI data using BICAR.
We introduce BICAR, an algorithm for obtaining robust, reproducible pairs of temporal and spatial components at the individual subject level from concurrent electroencephalographic and functional magnetic resonance imaging data. BICAR assigns a task-independent measure of component quality, reproducibility, to each paired source. Under BICAR a reproducibility cutoff is derived that can be used to objectively discard spuriously paired EEG-fMRI components. BICAR is run on minimally processed data: fMRI images undergo the standard preprocessing steps (alignment, motion correction, etc.) and EEG data, after scanner artifact removal, are simply bandpass filtered. This minimal processing allows the secondary scoring of the same set of BICAR components for a variety of different endpoint analyses; in this manuscript we propose a general method for scoring components for task event synchronization (evoked response analysis), but scoring using many other criteria, for example frequency content, are possible. BICAR is applied to five subjects performing a visual search task, and among the most reproducible components we find biologically relevant paired sources involved in visual processing, motor planning, execution, and attention.


The etiology of symptoms in patients with recurrent carotid stenosis.
We performed 33 carotid endarterectomies in 29 patients for recurrent carotid stenosis. The interval between the initial and second operations ranged from six weeks to 11 years with a mean of 56 months. Three types of pathologic lesions were identified: (1) recurrent atherosclerosis (RA), (2) neointimal fibromuscular hyperplasia (NFH), and (3) lesions with elements of both RA and NFH (complex lesions). Histologic examination of early-recurring lesions (less than three years) revealed NFH in 17 patients and one complex lesion. Late-recurring lesions (three years or later) were due to atherosclerosis in eight vessels, NFH in four, and both RA and NFH in three. Focal neurologic symptoms occurred in 25 (76%) of 33 vessels, and an embolic source could be identified in 16 (64%) of 25 patients. Embolic events rather than reduced blood flow due to progressive stenosis are more frequent causes of symptoms in patients with recurrent carotid stenosis than was formerly believed.


Liver resections for hilar cholangiocarcinoma.
Hilar cholangiocarcinoma (HC) is a rare tumor which has to be distinguished by intrahepatic cholagiocarcinoma invading hepatic hilum because the former has better prognosis then the latter. Patients with HC are difficult to manage because many challenging issues remain in the treatment of this tumour regarding correct diagnosis and therapeutic strategy. HC is resectable in about 30% of cases, but operative risk is highly influenced by septic complications of preoperative biliary drainage and by the need of major liver resection associated with biliary resection. We report the results of 43 resected patients (28 M/15 F; mean age 60 years, range 33-78), accounting for 29% of 149 patients with HC. Symptomless jaundice was the most common clinical presentation (87%; 130 patients). Biliary stricture was classified according to the Bismuth-Corlette classification as type 1 in 3 patients (7%); type 2 in 12 patients (28%); type 3 in 28 patients (65%). Ten patients underwent preoperative right portal vein embolization. Main biliary confluence excision associated with major hepatectomy was performed in 40 patients (93%), with R0 resection rate by 77%. Postoperative mortality rate was 6.9% (3 patients). Morbidity rate was 52.5% (21 patients), being biliary fistula (38%) and liver failure (19%) the most frequent complications. Five-year overall and disease-free survival rate were 36.1% and 28.2, respectively. Surgical resection remains the only chance of cure for patients with HC. However, due to the complexity of surgery immediate results remain unsatisfactory with morbidity and mortality rates higher than those reported after liver resection for other malignancies. This is mainly related to septic complications, strictly linked to complications of preoperative biliary drainage. Selective biliary drainage, careful management of biliary drains, drainage of excluded ducts in case of cholangitis, bile culture guided antibiotic use and preoperative portal vein embolization are important factors to reduce the risk of cholangitis and of postoperative complications. Because of the significant perioperative risk, the demanding operative management and the rarity of this tumor, patients with HC should be referred to tertiary surgical centers.


A GPU-accelerated Monte Carlo dose calculation platform and its application toward validating an MRI-guided radiation therapy beam model.
The clinical commissioning of IMRT subject to a magnetic field is challenging. The purpose of this work is to develop a GPU-accelerated Monte Carlo dose calculation platform based on penelope and then use the platform to validate a vendor-provided MRIdian head model toward quality assurance of clinical IMRT treatment plans subject to a 0.35 T magnetic field. penelope was first translated from fortran to c++ and the result was confirmed to produce equivalent results to the original code. The c++ code was then adapted to cuda in a workflow optimized for GPU architecture. The original code was expanded to include voxelized transport with Woodcock tracking, faster electron/positron propagation in a magnetic field, and several features that make gpenelope highly user-friendly. Moreover, the vendor-provided MRIdian head model was incorporated into the code in an effort to apply gpenelope as both an accurate and rapid dose validation system. A set of experimental measurements were performed on the MRIdian system to examine the accuracy of both the head model and gpenelope. Ultimately, gpenelope was applied toward independent validation of patient doses calculated by MRIdian's kmc. An acceleration factor of 152 was achieved in comparison to the original single-thread fortran implementation with the original accuracy being preserved. For 16 treatment plans including stomach (4), lung (2), liver (3), adrenal gland (2), pancreas (2), spleen(1), mediastinum (1), and breast (1), the MRIdian dose calculation engine agrees with gpenelope with a mean gamma passing rate of 99.1% ± 0.6% (2%/2 mm). A Monte Carlo simulation platform was developed based on a GPU- accelerated version of penelope. This platform was used to validate that both the vendor-provided head model and fast Monte Carlo engine used by the MRIdian system are accurate in modeling radiation transport in a patient using 2%/2 mm gamma criteria. Future applications of this platform will include dose validation and accumulation, IMRT optimization, and dosimetry system modeling for next generation MR-IGRT systems.


Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer's disease.
The development of blood-based biomarkers for early diagnosis and treatment of Alzheimer's disease (AD) is desirable. In AD model mouse brain and neuronal cells, Abelson helper integration site-1 (AHI1) protein is reduced. AHI1 facilitates intracellular amyloid precursor protein (APP) translocation to inhibit amyloidogenic pathology of AD, and thus may be an AD biomarker. This study was conducted among 32 AD patients and 54 healthy control (HC) subjects. AHI1-related protein levels from initially collected serum samples in each group were screened using Western blotting. The protein concentrations of AHI1 and amyloid-β (Aβ), peptide(s) derived from APP, from all serum samples were analyzed using ELISA. In AD serum, AHI1 and a large truncated C-terminal APP fragment were significantly reduced. The average concentrations of serum AHI1 and Aβ in AD were significantly lower than those in HC. Notably, AHI1 concentration in HC serum was decreased in an age-dependent manner, while it was consistently low in AD serum and had no correlation with Aβ or mini-mental state examination score. The receiver operating characteristic analysis on all subjects demonstrated an area under curve (AUC) value of 0.7 for AHI1 on AD diagnosis, while the AUC increased to 0.82 on the subjects younger than 77 years old, suggesting a good diagnostic performance of serum AHI1 for AD especially at relatively young age. An early event of AHI1 reduction in the body of AD patients was observed. Serum AHI1 may be valuable for early diagnosis of AD.


High Exposure to Organophosphate Flame Retardants in Infants: Associations with Baby Products.
Infant products containing polyurethane foam are commonly treated with organophosphate flame retardants (PFRs), including tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and triphenyl phosphate (TPHP). Infants may have greater exposure due to greater contact with these products, yet little is known about levels of exposure or the factors contributing to higher exposure. We recruited children age 2-18 months from North Carolina to investigate PFR exposure (n = 43; recruited 2014-2015). Parents provided information on potential sources and modifiers of exposure, and reported whether they owned common infant products. We measured five PFR metabolites in urine samples collected from children. TDCIPP and TPHP metabolites (bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP)) were most commonly detected (>93% detect). Other metabolites were detected infrequently (<35% detect). Although we did not observe a clear age trend for infants, BDCIPP levels were substantially higher than those reported for adults (geometric mean = 7.3 ng/mL). The number of infant products owned was strongly associated with BDCIPP; children with >16 products had BDCIPP levels that were 6.8 times those with <13 (p = 0.02). Infants attending daycare centers also had higher BDCIPP levels (3.7 times those of others; p = 0.07), suggesting time spent in this microenvironment contributes to higher exposure. In contrast, DPHP levels were not related to products owned, time in different microenvironments, or behavior.


Synthesis and biological evaluation of novel diaziridinylquinone-acridine conjugates.
The synthesis and biological evaluation of a homologous series of conjugates (9-13) of 2,5-diaziridinylbenzoquinone (DZQ) and 9-carbonylacridine, a DNA intercalating moiety, via a polymethylene unit (n=2-6) are described. In addition, the non-acridine compound 14, analogous to compound 12, and the 5-methyl-DZQ derivatized conjugate 15, an analog of compound 10, were also prepared. Through a Comet assay, compounds 9-13 were shown to produce DNA interstrand cross-links at submicromolar concentrations, consistent with K562 leukemia cells accumulating in the G2/M stage in the cell cycle. The cytotoxicity of compounds 9-15 was examined using a MTT assay on several human cancer cell lines, including chronic myeloid leukemia K562, the non-small cell lung cancers H596 and H460, and colon carcinoma cells BE and HT29. H460 and HT29 are rich in DT-diaphorase (DTD), and H596 and BE cells have negligible amounts of functional DTD. Under continuous exposure of drugs, except to the non-aziridine compound 19b, the IC50 values of all other compounds were determined to be in the range of 0.3-11.3 nM. Compound 10, which has a propyl linker group, was subjected to in vivo studies. When BDF1 mice with established mouse mammary carcinoma were treated with compound 10 (2 mg/kg at day 1 and 5 mg/kg at day 7), a significant delay (9-10 days) in cancer growth was recorded when compared to untreated controls. Furthermore, administration of compound 10 to nu/nu BDF1 mice bearing human lung cancer H460 xenograft (1.5 mg/kg for 10 for five consecutive days from day 13 and 17) also showed a significant reduction in tumor growth compared to untreated controls. The half-life of compound 10 in the presence of five different peptidases (porcine esterase, carboxypeptidase A, B and Y, and pepsin) was determined to be between 30 and 60 h.


Integrated polarization beam splitter with relaxed fabrication tolerances.
Polarization handling is a key requirement for the next generation of photonic integrated circuits (PICs). Integrated polarization beam splitters (PBS) are central elements for polarization management, but their use in PICs is hindered by poor fabrication tolerances. In this work we present a fully passive, highly fabrication tolerant polarization beam splitter, based on an asymmetrical Mach-Zehnder interferometer (MZI) with a Si/SiO(2) Periodic Layer Structure (PLS) on top of one of its arms. By engineering the birefringence of the PLS we are able to design the MZI arms so that sensitivities to the most critical fabrication errors are greatly reduced. Our PBS design tolerates waveguide width variations of 400nm maintaining a polarization extinction ratio better than 13dB in the complete C-Band.


Comparative velocity investigations in cerebral arteries and aneurysms: 3D phase-contrast MR angiography, laser Doppler velocimetry and computational fluid dynamics.
In western populations, cerebral aneurysms develop in approximately 4% of humans and they involve the risk of rupture. Blood flow patterns are of interest for understanding the pathogenesis of the lesions and may eventually contribute to deciding on the most efficient treatment procedure for a specific patient. Velocity mapping with phase-contrast magnetic resonance angiography (PC-MRA) is a non-invasive method for performing in vivo measurements on blood velocity. Several hemodynamic properties can either be derived directly from these measurements or a flow field with all its parameters can be simulated on the basis of the measurements. For both approaches, the accuracy of the PC-MRA data and subsequent modeling must be validated. Therefore, a realistic transient flow field in a well-defined patient-specific silicone phantom was investigated. Velocity investigations with PC-MRA in a 3 Tesla MR scanner, laser Doppler velocimetry (LDV) and computational fluid dynamics (CFD) were performed in the same model under equal flow conditions and compared to each other. The results showed that PC-MRA was qualitatively similar to LDV and CFD, but showed notable quantitative differences, while LDV and CFD agreed well. The accuracy of velocity quantification by PC-MRA was best in straight artery regions with the measurement plane being perpendicular to the primary flow direction. The accuracy decreased in regions with disturbed flow and in cases where the measurement plane was not perpendicular to the primary flow. Due to these findings, it is appropriate to use PC-MRA as the inlet and outlet conditions for numerical simulations to calculate velocities and shear stresses in disturbed regions like aneurysms, rather than derive these values directly from the full PC-MRA measured velocity field.


Development of an American Indian Diabetes Education Cultural Supplement: A Qualitative Approach.
The purpose of this study was to culturally enhance a diabetes education program for Diné (Navajo) community members with Type 2 diabetes. Though the recommendation to culturally adapt health education curricula was meant to improve health education for American Indians and Alaskan Natives (AIANs), it has inadvertently created a "one size fits all" approach. This approach does not properly address the need for tribe-specific cultural health messaging, defined as incorporating cultural elements deemed relevant to the population. Tribe-specific health information and programming, such as integrating Diné worldviews and Indigenous knowledge among Diné people as described here, are essential to creating a culturally relevant and effective and meaningful approach to disease self-management. A conversation guide, based on the Hózhó Resilience Model-a Diné framework on healthy living, was used to engage key cultural experts in interviews about traditional stories and teachings regarding health and wellness. Three specific self-care behaviors relevant to Type 2 diabetes self-management were discussed: (1) healthy eating, (2) physical activity, and (3) healthy coping. Interviews were audio-recorded, transcribed and analyzed using a qualitative thematic analysis method. Diné healers and cultural experts informed the development of an educational tool called Diné Health. Key themes that emerged from the data included the importance of discipline, positivity and mindfulness in the context of Hózhó. Culturally safe and meaningful engagement with cultural leaders and the use of qualitative research methods can inform deep-level cultural adaptations essential to developing tribe-specific diabetes education programs. The approaches used here can guide the development, implementation, and testing of culturally-informed health education for AIAN populations.


Kit regulates HSC engraftment across the human-mouse species barrier.
In-depth analysis of the cellular and molecular mechanisms regulating human HSC function will require a surrogate host that supports robust maintenance of transplanted human HSCs in vivo, but the currently available options are problematic. Previously we showed that mutations in the Kit receptor enhance engraftment of transplanted HSCs in the mouse. To generate an improved model for human HSC transplantation and analysis, we developed immune-deficient mouse strains containing Kit mutations. We found that mutation of the Kit receptor enables robust, uniform, sustained, and serially transplantable engraftment of human HSCs in adult mice without a requirement for irradiation conditioning. Using this model, we also showed that differential KIT expression identifies two functionally distinct subpopulations of human HSCs. Thus, we have found that the capacity of this Kit mutation to open up stem cell niches across species barriers has significant potential and broad applicability in human HSC research.


Effectiveness of Dowels in Concrete Pavement.
Dowels are located in transverse joints of Jointed Plain Concrete Pavements (JPCP) and they are used to provide load transfer between individual slabs, reduce faulting and improve performance. Dowels and the concrete itself are under the highest stress in the vicinity of joints; thus, in terms of pavement design, the joints are the weakest points of the whole structure. This study dealt with the drawbacks of JPCP with dowels. The evaluation was based on direct measurements on real airport and motorway pavements and highlights insufficient efficiency of load transfer and its possible causes. The authors present a successful outcome with validation by using the finite element method where high tensile stress values of the surrounding concrete were found.


Resetting our priorities in environmental health: an example from the South-North partnership in Lake Chapala, Mexico.
Lake Chapala is a major source of water for crop irrigation and subsistence fishing for a population of 300,000 people in central Mexico. Economic activities have created increasing pollution and pressure on the whole watershed resources. Previous reports of mercury concentrations detected in fish caught in Lake Chapala have raised concerns about health risks to local families who rely on fish for both their livelihood and traditional diet. Our own data has indicated that 27% of women of childbearing age have elevated hair mercury levels, and multivariable analysis indicated that frequent consumption of carp (i.e., once a week or more) was associated with significantly higher hair mercury concentrations. In this paper we describe a range of environmental health research projects. Our main priorities are to build the necessary capacities to identify sources of water pollution, enhance early detection of environmental hazardous exposures, and deliver feasible health protection measures targeting children and pregnant women. Our projects are led by the Children's Environmental Health Specialty Unit nested in the University of Guadalajara, in collaboration with the Department of Environmental Health of Harvard School of Public Health and Department of Pediatrics of the New York School of Medicine. Our partnership focuses on translation of knowledge, building capacity, advocacy and accountability. Communication will be enhanced among women's advocacy coalitions and the Ministries of Environment and Health. We see this initiative as an important pilot program with potential to be strengthened and replicated regionally and internationally.


Hierarchical genomic analysis of carried and invasive serogroup A Neisseria meningitidis during the 2011 epidemic in Chad.
Serogroup A Neisseria meningitidis (NmA) was the cause of the 2011 meningitis epidemics in Chad. This bacterium, often carried asymptomatically, is considered to be an "accidental pathogen"; however, the transition from carriage to disease phenotype remains poorly understood. This study examined the role genetic diversity might play in this transition by comparing genomes from geographically and temporally matched invasive and carried NmA isolates. All 23 NmA isolates belonged to the ST-5 clonal complex (cc5). Ribosomal MLST comparison with other publically available NmA:cc5 showed that isolates were closely related, although those from Chad formed two distinct branches and did not cluster with other NmA, based on their MLST profile, geographical and temporal location. Whole genome MLST (wgMLST) comparison identified 242 variable genes among all Chadian isolates and clustered them into three distinct phylogenetic groups (Clusters 1, 2, and 3): no systematic clustering by disease or carriage source was observed. There was a significant difference (p = 0.0070) between the mean age of the individuals from which isolates from Cluster 1 and Cluster 2 were obtained, irrespective of whether the person was a case or a carrier. Whole genome sequencing provided high-resolution characterization of the genetic diversity of these closely related NmA isolates. The invasive meningococcal isolates obtained during the epidemic were not homogeneous; rather, a variety of closely related but distinct clones were circulating in the human population with some clones preferentially colonizing specific age groups, reflecting a potential age-related niche adaptation. Systematic genetic differences were not identified between carriage and disease isolates consistent with invasive meningococcal disease being a multi-factorial event resulting from changes in host-pathogen interactions along with the bacterium.


Learning from our patients: one participant's impact on clinical trial research and informed consent.
This Perspective includes an essay on modifying phase I clinical trials, written by George Zimmer, who was a professor of English and a commentary on that essay. Professor Zimmer was a cancer patient who participated in the phase I clinical trial program at the University of Chicago. His ideas are eloquently expressed and have had a profound effect on our investigational research for anticancer agents. Although at times his suggestions may seem radical, Professor Zimmer urges us to reconsider the 50-year-old Nuremberg paradigm that participants in human research are ignorant and vulnerable and must be protected. Although we must protect patients who have life-threatening diseases from coercive inducements and misplaced hopes, we must also listen carefully and thoughtfully to our patients. This is particularly true when, as research participants in the face of sacrifice and the threat of a life-ending diagnosis, they have made the effort to express their concerns. With the effect of the acquired immunodeficiency syndrome movement on clinical studies and on drug research and development, a precedent has been set that allows patients to reshape their role as participants in research trials. On a personal level, the essay by Professor Zimmer has had a significant effect on our research methods and, indeed, the focus of our research efforts. Thus, it is with a sense of respect and honor that we share George Zimmer's thoughts and our comments about the influence he has had on our research practices.


The interval robotic transabdominal cerclage in a morbidly obese patient.
The most commonly used prophylactic treatment of cervical insufficiency is cerclage but it carries significant morbidity either through vaginal or abdominal approach. A robotic-assisted transabdominal cerclage (RoboTAC) placement as an interval procedure could offer advantages over the conventional laparoscopic approach especially in morbidly obese patients. We report the use of interval RoboTAC procedure in a morbidly obese patient and ultimately she delivered a healthy infant at 38 weeks 2 days nonetheless removal of the cerclage.


Detecting dissociations in single-case studies: Type I errors, statistical power and the classical versus strong distinction.
Dissociations observed in single-case studies play an important role in building and testing theory in neuropsychology; therefore the criteria used to identify their presence should be subjected to empirical scrutiny. Extending work on classical dissociations, Monte Carlo simulation is used to examine the Type I error rate for two methods of detecting strong dissociations. When a Type I error was defined as misclassifying a healthy control, error rates were low for both methods. When Type I errors were defined as misclassifying patients with strictly equivalent deficits on two tasks, error rates for strong dissociations were high for the "conventional" criteria and were very high when cases misclassified as exhibiting either form of dissociation (strong or classical) were combined (maximum = 55.1%). The power to detect strong and classical dissociations was generally low-to-moderate, but was moderate-to-high in most scenarios when power was defined as the ability to detect either form of dissociation. In most scenarios patients with strong dissociations were more likely to be classified as exhibiting classical dissociations. The results question the practical utility of the distinction between strong and classical dissociations regardless of the criteria employed to test for their presence.


Electrosmog and autoimmune disease.
Studies in mice have shown that environmental electromagnetic waves tend to suppress the murine immune system with a potency similar to NSAIDs, yet the nature of any Electrosmog effects upon humans remains controversial. Previously, we reported how the human Vitamin-D receptor (VDR) and its ligand, 1,25-dihydroxyvitamin-D (1,25-D), are associated with many chronic inflammatory and autoimmune diseases. We have shown how olmesartan, a drug marketed for mild hypertension, acts as a high-affinity partial agonist for the VDR, and that it seems to reverse disease activity resulting from VDR dysfunction. We here report that structural instability of the activated VDR becomes apparent when observing hydrogen bond behavior with molecular dynamics, revealing that the VDR pathway exhibits a susceptibility to Electrosmog. Further, we note that characteristic modes of instability lie in the microwave frequency range, which is currently populated by cellphone and WiFi communication signals, and that the susceptibility is ligand dependent. A case series of 64 patient-reported outcomes subsequent to use of a silver-threaded cap designed to protect the brain and brain stem from microwave Electrosmog resulted in 90 % reporting "definite" or "strong" changes in their disease symptoms. This is much higher than the 3-5 % rate reported for electromagnetic hypersensitivity in a healthy population and suggests that effective control of environmental Electrosmog immunomodulation may soon become necessary for successful therapy of autoimmune disease.


Coronavirus Disease 2019 Catheterization Laboratory Survey.
Background The coronavirus disease 2019 pandemic is expected to affect operations and lifestyles of interventional cardiologists around the world in unprecedented ways. Timely gathering of information on this topic can provide valuable insight and improve the handling of the ongoing and future pandemic outbreaks. Methods and Results A survey instrument developed by the authors was disseminated via e-mail, text messaging, WhatsApp, and social media to interventional cardiologists between April 6, 2020, and April 11, 2020. A total of 509 responses were collected from 18 countries, mainly from the United States (51%) and Italy (36%). Operators reported significant decline in coronary, structural heart, and endovascular procedure volumes. Personal protective equipment was available to 95% of respondents; however FIT-tested N95 or equivalent masks were available to only 70%, and 74% indicated absence of coronavirus disease 2019 pretesting. Most (83%) operators expressed concern when asked to perform cardiac catheterization on a suspected or confirmed coronavirus disease 2019 patient, primarily because of fear of viral transmission (88%). Although the survey demonstrated significant compliance with social distancing, high use of telemedicine (69%), and online education platforms (80%), there was concern over impending financial loss. Conclusions Our survey indicates significant reduction in invasive procedure volumes and concern for viral transmission. There is near universal adoption of personal protective equipment; however, coronavirus disease 2019 pretesting and access to FIT-tested N95 masks is suboptimal. Although there is concern over impending financial loss, substantial engagement in telemedicine and online education is reported.


Long non-coding RNA PVT1 is associated with tumor progression and predicts recurrence in hepatocellular carcinoma patients.
PVT1, which maps to chromosome 8q24, is a copy number amplification-associated long non-coding RNA. Overexpression of PVT1 is a powerful predictor of tumor progression and patient survival in a diverse range of cancer types. However, the association between PVT1 and hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to examine the expression pattern of PVT1, and its clinical significance in HCC. Between 2003 and 2012, reverse transcription-quantitative polymerase chain reaction was used to determine the expression levels of PVT1 in two independent cohorts: Cohort one, 58 HCC resection samples; and cohort 2, 214 HCC transplant samples. Additionally, the correlation between PVT1 expression levels and clinical parameters and outcomes was analyzed. The relative expression levels of PVT1 were significantly higher in cancerous tissues compared with the corresponding non-cancerous tissues (cohort one, P=0.0016; cohort two, P=0.0274). Furthermore, overexpression of PVT1 was associated with a higher serum α-fetoprotein expression level (P=0.011) and a higher recurrence rate (P=0.004). Kaplan-Meier analysis indicated that the patients with high PVT1 expression exhibited poor recurrence-free survival (P=0.021), and multivariate analysis demonstrated that high levels of PVT1 expression are an independent predictor for HCC recurrence (P=0.042; hazard ratio, 1.653). Thus, the high expression levels of PVT1 in HCC may serve as a novel biomarker for predicting tumor recurrence in HCC patients, and as a potential therapeutic target.


Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Cardiac, Endocrine, Metabolic, and Motoric Effects in a Randomized, Double-Blind, Placebo-Controlled Study.
To examine motoric, cardiovascular, endocrine, and metabolic effects of adjunctive ziprasidone in adults with major depressive disorder (MDD) and prior nonresponse to 8 weeks of open-label escitalopram. A multicenter, parallel, randomized, double-blind, placebo-controlled trial was conducted at 3 US academic medical centers from July 2008 to October 2013. Recruited were 139 outpatients with persistent DSM-IV MDD following an 8-week open-label trial of escitalopram. Subjects were then randomized to adjunctive ziprasidone (escitalopram + ziprasidone, n = 71) or placebo (escitalopram + placebo, n = 68) for 8 additional weeks. Cardiac and metabolic measures were obtained at each treatment visit. Barnes Akathisia Scale and Abnormal Involuntary Movement Scale (AIMS) scores were also obtained. Changes in outcome measures for each treatment group were compared by independent-samples t test. A trend toward significance (P = .06) in corrected QT interval (QTc) increase was observed for ziprasidone (mean [SD] = 8.8 [20.2] milliseconds) versus placebo (-0.02 [25.5] milliseconds). Ziprasidone-treated patients had a significantly greater increase in global akathisia scores (P = .01) and significant weight increase (mean [SD] = 3.5 [11.8] kg, or 7.7 [26.1] lb) compared to placebo (1.0 [6.4] kg, or 2.2 [14.1] lb) (P = .03). No significant changes in AIMS scores were observed for either treatment group. Adjunctive ziprasidone, added to escitalopram, led to a greater weight gain and greater but modest akathisia compared to placebo. The effect of ziprasidone on QTc showed a trend toward significance, and therefore caution should be used in the administration of ziprasidone. While ziprasidone augmentation in patients with MDD appears safe, precautions should be taken in practice, specifically regular monitoring of electrocardiogram, weight, extrapyramidal symptoms, and involuntary movements. ClinicalTrials.gov identifier: NCT00633399.


In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy.
The use of antisense 'splice-switching' oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2'O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R² 0.89) and 53 (R² 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of a target exon.


Epidemiology of Pseudomonas aeruginosa in a general hospital: a four-year study.
A retrospective study was done to determine the epidemiology of infection and/or colonization due to Pseudomonas aeruginosa in a Brazilian general hospital. In 1966, 1968, and 1969, there were only two instances where probable cross-contamination was shown; the remaining isolates were unrelated. In late 1971 the hospital experienced a marked increase in P. aeruginosa isolation. Contaminated dextrose solutions used in the infant feeding were the apparent cause of the problem which occurred in the premature and special care nurseries. A contaminated oxygen humidifying bottle was the source of a different outbreak in surgery. There was also evidence in four instances that cross-infection and/or contamination had occurred. Pyocin and serological typing revealed that many strains were involved and led to a clear understanding of the complex epidemiological relationships among all the strains.


Lack of cardioprotective efficacy of allopurinol in coronary artery surgery.
To examine the cardioprotective efficacy of allopurinol in patients undergoing elective coronary artery surgery. Prospective randomised trial. London teaching hospital. Twenty patients with at least moderately good left ventricular function undergoing elective coronary artery surgery and requiring at least two bypass grafts. Patients were randomised to receive allopurinol (1200 mg in two divided doses) or to act as controls. The primary determinant of the efficacy of myocardial protection was serial measurement (preoperatively and subsequently at one, six, 24, and 72 hours after the end of cardiopulmonary bypass) of cardiac troponin T (cTnT) a highly sensitive and specific marker of myocardial damage. Additional evidence was provided by serial measurement of the MB-isoenzyme of creatine kinase (CK-MB) and myoglobin, ECG changes, and clinical outcome. There was no significant difference in age, ejection fraction, number of grafts, bypass times, or cross clamp times between the two groups. In both groups there was a highly significant (p < 0.01) rise in cTnT, CK-MB, and myoglobin. Peak concentrations were reached between one (CK-MB and myoglobin) and six hours (cTnT) after the end of cardiopulmonary bypass. At 72 hours cTnT concentrations were six times higher than baseline concentrations whereas CK-MB and myoglobin were approximately double baseline concentrations. There was no significant difference in cTnT, CK-MB, or myoglobin between the allopurinol and control groups at any time. There was no diagnostic ECG evidence of perioperative infarction in any patient. Unlike previous reports this study did not show that allopurinol had a cardioprotective effect in patients with good left ventricular function undergoing elective coronary artery surgery.


The columnar and laminar organization of inhibitory connections to neocortical excitatory cells.
The cytoarchitectonic similarities of different neocortical regions have given rise to the idea of 'canonical' connectivity between excitatory neurons of different layers within a column. It is unclear whether similarly general organizational principles also exist for inhibitory neocortical circuits. Here we delineate and compare local inhibitory-to-excitatory wiring patterns in all principal layers of primary motor (M1), somatosensory (S1) and visual (V1) cortex, using genetically targeted photostimulation in a mouse knock-in line that conditionally expresses channelrhodopsin-2 in GABAergic neurons. Inhibitory inputs to excitatory neurons derived largely from the same cortical layer within a three-column diameter. However, subsets of pyramidal cells in layers 2/3 and 5B received extensive translaminar inhibition. These neurons were prominent in V1, where they might correspond to complex cells, less numerous in barrel cortex and absent in M1. Although inhibitory connection patterns were stereotypical, the abundance of individual motifs varied between regions and cells, potentially reflecting functional specializations.


TSS seq based core promoter architecture in blood feeding Tsetse fly (Glossina morsitans morsitans) vector of Trypanosomiasis.
Transcription initiation regulation is mediated by sequence-specific interactions between DNA-binding proteins (transcription factors) and cis-elements, where BRE, TATA, INR, DPE and MTE motifs constitute canonical core motifs for basal transcription initiation of genes. Accurate identification of transcription start site (TSS) and their corresponding promoter regions is critical for delineation of these motifs. To this end, the genome scale analysis of core promoter architecture in insects has been confined to Drosophila. The recently sequenced Tsetse fly genome provides a unique opportunity to analyze transcription initiation regulation machinery in blood-feeding insects. A computational method for identification of TSS in newly sequenced Tsetse fly genome was evaluated, using TSS seq tags sampled from two developmental stages namely; larvae and pupae. There were 3134 tag clusters among which 45.4% (1424) of the tag clusters mapped to first coding exons or their proximal predicted 5'UTR regions and 1.0% (31) tag clusters mapping to transposons, within a threshold of 100 tags per cluster. These 1393 non transposon-derived core promoters had propensity for AT nucleotides. The -1/+1 and 1/+1 positions in D. melanogaster, and G. m. morsitans had propensity for CA and AA dinucleotides respectively. The 1393 tag clusters comprised narrow promoters (5%), broad with peak promoters (23%) and broad without peak promoters (72%). Two-way motif co-occurrence analysis showed that the MTE-DPE pair is over-represented in broad core promoters. The frequently occurring triplet motifs in all promoter classes are the INR-MTE-DPE, TATA-MTE-DPE and TATA-INR-DPE. Promoters without the TATA motif had higher frequency of the MTE and INR motifs than those observed in Drosophila, where the DPE motif occur more frequently in promoters without TATA motif. Gene ontology terms associated with developmental processes were overrepresented in the narrow and broad with peak promoters. The study has identified different motif combinations associated with broad promoters in a blood-feeding insect. In the case of TATA-less core promoters, G.m. morsitans uses the MTE to compensate for the lack of a TATA motif. The increasing availability of TSS seq data allows for revision of existing gene annotation datasets with the potential of identifying new transcriptional units.


Do non-monetary incentives for pregnant women increase antenatal attendance among Ethiopian pastoralists?
In a pastoralist setting in Ethiopia, we assessed changes in attendance between the first and subsequent antenatal care (ANC) visits following the implementation of non-monetary incentives in a primary health care centre over a 3-year period from October 2009 to September 2012. Incentives included the provision of a bar of soap, a bucket, a mosquito net, sugar, cooking oil, a jerrycan and a delivery kit. The first ANC visits increased by 48% in the first year to 60% in the second. Subsequent visits did not show a similar pattern due to ruptures in incentive stocks. Incentives appear to increase ANC attendance; however, ruptures in stock should be avoided to sustain the effect.


Taking variation of evolutionary rates between sites into account in inferring phylogenies.
As methods of molecular phylogeny have become more explicit and more biologically realistic following the pioneering work of Thomas Jukes, they have had to relax their initial assumption that rates of evolution were equal at all sites. Distance matrix and likelihood methods of inferring phylogenies make this assumption; parsimony, when valid, is less limited by it. Nucleotide sequences, including RNA sequences, can show substantial rate variation; protein sequences show rates that vary much more widely. Assuming a prior distribution of rates such as a gamma distribution or lognormal distribution has deservedly been popular, but for likelihood methods it leads to computational difficulties. These can be resolved using hidden Markov model (HMM) methods which approximate the distribution by one with a modest number of discrete rates. Generalized Laguerre quadrature can be used to improve the selection of rates and their probabilities so as to more nearly approach the desired gamma distribution. A model based on population genetics is presented predicting how the rates of evolution might vary from locus to locus. Challenges for the future include allowing rates at a given site to vary along the tree, as in the "covarion" model, and allowing them to have correlations that reflect three-dimensional structure, rather than position in the coding sequence. Markov chain Monte Carlo likelihood methods may be the only practical way to carry out computations for these models.


Regulation of extrasynaptic 5-HT by serotonin reuptake transporter function in 5-HT-absorbing neurons underscores adaptation behavior in Caenorhabditis elegans.
Serotonin [5-hydroxytryptamine (5-HT)]-absorbing neurons use serotonin reuptake transporter (SERT) to uptake 5-HT from extracellular space but do not synthesize it. While 5-HT-absorbing neurons have been identified in diverse organisms from Caenorhabditis elegans to humans, their function has not been elucidated. Here, we show that SERT in 5-HT-absorbing neurons controls behavioral response to food deprivation in C. elegans. The AIM and RIH interneurons uptake 5-HT released from chemosensory neurons and secretory neurons. Genetic analyses suggest that 5-HT secreted by both synaptic vesicles and dense core vesicles diffuse readily to the extrasynaptic space adjacent to the AIM and RIH neurons. Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT. Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of selective serotonin reuptake inhibitors in humans.


Recent advances in hydrogen research as a therapeutic medical gas.
Recent basic and clinical research has revealed that hydrogen is an important physiological regulatory factor with antioxidant, anti-inflammatory and anti-apoptotic protective effects on cells and organs. Therapeutic hydrogen has been applied by different delivery methods including straightforward inhalation, drinking hydrogen dissolved in water and injection with hydrogen-saturated saline. This review summarizes currently available data regarding the protective role of hydrogen, provides an outline of recent advances in research on the use of hydrogen as a therapeutic medical gas in diverse models of disease and discusses the feasibility of hydrogen as a therapeutic strategy. It is not an overstatement to say that hydrogen's impact on therapeutic and preventive medicine could be enormous in the future.


An actin network is present in the cytoplasm throughout the cell cycle of carrot cells and associates with the dividing nucleus.
We have studied the F-actin network in cycling suspension culture cells of carrot (Daucus carota L.) using rhodaminyl lysine phallotoxin (RLP). In addition to conventional fixation with formaldehyde, we have used two different nonfixation methods before adding RLP: extracting cells in a stabilizing buffer; inducing transient pores in the plasma membrane with pulses of direct current (electroporation). These alternative methods for introducing RLP revealed additional features of the actin network not seen in aldehyde-fixed cells. The three-dimensional organization of this network in nonflattened cells was demonstrated by projecting stereopairs derived from through-focal series of computer-enhanced images. F-actin is present in interphase cells in four interconnected configurations: a meshwork surrounding the nucleus; thick cables in transvacuolar strands and deep in the cytoplasm; a finer network of bundles within the cortical cytoplasm; even finer filaments that run in ordered transverse array around the cell periphery. The actin network is organized differently during division but it does not disappear as do the cortical microtubules. RLP stains a central filamentous cortical band as the chromatin begins to condense (preprophase); it stains the mitotic spindle (as recently shown by Seagull et al. [Seagull, R. W., M. Falconer, and C. A. Weerdenburg, 1987, J. Cell Biol., 104:995-1004] for aldehyde fixed suspension cells) and the cytokinetic apparatus (as shown by Clayton, L., and C. W. Lloyd, 1985, Exp. Cell Res., 156:231-238). However, it is now shown that an additional network of F-actin persists in the cytoplasm throughout division associating in turn with the preprophase band, the mitotic spindle, and the cytokinetic phragmoplast.


Education, income and disability in African Americans.
To determine whether the association between SES and disability vary by age in African Americans. Logistic regression models were conducted to estimate the association between SES and disability by age group in 395 African Americans participating in the Carolina African American Twin Study of Aging. Disability was defined as difficulty in performing at least one of seven basic activities of daily living. Education and family income were used as measures of SES. Age was categorized as individuals aged < 49 years and aged > or = 50 years. After adjusting for demographic and health-related characteristics among older adults, a higher odds of disability was associated with no post-secondary education (OR = 3.09, 95% CI: 1.24-7.71), and with low-income (OR = 2.74, 95% CI: 1.17-6.43) compared to more educated or affluent people, respectively. No association between SES and disability was observed in young adults. When considering the combined effect of no post-secondary education and low-income on disability, older adults with no post-secondary education had a greater odds of being disabled (OR = 2.63, 95% CI: 1.03-6.73) relative to those with a post-secondary education controlling for covariates. The findings demonstrate the advantage of disentangling the confounding of race and SES as an initial step to understanding the relationship among age, SES and disability in African Americans.


Microbial manipulation as primary therapy for Crohn's disease.
While antimicrobials are clinically effective in preventing post-operative recurrence, the role for antibiotics in primary therapy for Crohn's disease (CD) remains unclear. The recent multicenter phase 2 trial by Prantera et al received wide attention because it demonstrated an increase in the week 12 remission rate in patients with moderately active CD treated with rifaximin and renewed interest in microbial manipulation as primary therapy for CD. In this commentary, we discuss aspects of durability, immune cell polarization, and safety of microbial manipulation as primary therapy for CD.


MAPK, CREB and zif268 are all required for the consolidation of recognition memory.
There has been nearly a century of interest in the idea that encoding and storage of information in the brain requires changes in the efficacy of synaptic connections between neurons that are activated during learning. Recent research into the molecular mechanisms of long-term potentiation (LTP) has brought about new knowledge that has provided valuable insights into the neural mechanisms of memory storage. The evidence indicates that rapid activation of the genetic machinery can be a key mechanism underlying the enduring modification of neural networks required for the stability of memories. In recent years, a wealth of experimental data has highlighted the importance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling in the regulation of gene transcription in neurons. Here, we briefly review experiments that have shown MAPK/ERK, cAMP response element-binding protein (CREB) and the immediate early gene (IEG) zif268 are essential components of a signalling cascade required for the expression of late phase LTP and of certain forms of long-term memory. We also present experiments in which we have assessed the role of these three molecules in recognition memory. We show that pharmacological blockade of MAPK/ERK phosphorylation, functional inactivation of CREB in an inducible transgenic mouse and inactivation of zif268 in a mutant mouse result in a similar deficit in long-term recognition memory. In the continuing debate about the role of LTP mechanisms in memory, these findings provide an important complement to the suggestion that synaptic changes brought about by LTP and memory consolidation and storage share, at least in part, common underlying molecular mechanisms.


Association of Cerebrospinal Fluid Neurofilament Light Protein With Risk of Mild Cognitive Impairment Among Individuals Without Cognitive Impairment.
Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Risk of MCI. At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.


Human onchocerciasis in Nigeria: isotypic responses and antigen recognition in individuals with defined cutaneous pathology.
Antigen (Ag)-specific isotype responses to Onchocerca volvulus Ag (OvAg) were assessed by enzyme-linked immunosorbent assay and immunoblot in 123 residents of a mesoendemic area in northern Nigeria and 16 Nigerians from a nonendemic area. Individuals from an endemic area were divided into six groups on the basis of cutaneous onchocercal pathology: acute papular onchodermatitis (APOD), chronic papular onchodermatitis (CPOD), lichenified onchodermatitis (LOD), atrophy (ATR), depigmentation (DPM) and normal skin, high microfilarial load (NSHMF). Immunoglobulin (Ig)G1-4 levels were all significantly associated with residence in an endemic area after controlling for age and sex (all P values = 0.0001). Both IgG1 and IgG3 were significantly associated with onchocercal clinical category after controlling for age, sex, and microfilarial load (P = 0.0031 and 0.0035, respectively). The IgG1 and IgG3 responses were both highest in LOD and lowest in NSHMF and ATR, respectively. A significant inverse association was found between IgG1 levels and microfilarial load after controlling for age, sex, and clinical category (P = 0.0061). On immunoblotting, 20 (44.4%) of 45 individual onchocerciasis sera contained IgG4 antibodies against a band of 29-31 kD, which was not recognized by pooled sera from individuals with other filarial infections. There was heterogeneity of antigen recognition within each of the onchocercal clinical groups, which together with the small numbers examined by immunoblotting, limits interpretation. Nevertheless, some differences in patterns of antigen recognition were found between the onchocercal groups. The LOD group demonstrated prominent immunoreactivity in IgG1 and IgG3 while a general paucity of low molecular weight reactivity was seen with NSHMF in IgG1-3 subclasses, but there was no specific banding pattern that differentiated NSHMF from those with pathology. Comparison of microfilariae-positive (mf+) and mf- individuals with onchocercal skin disease revealed significantly higher levels of all IgG subclasses and higher overall scores on semiquantitative assessment of immunoblots for IgG1, IgG2, and IgG4 for mf+ individuals. Differing isotypic responses may play a role in the pathogenesis of the clinical spectrum of cutaneous onchocerciasis.


[Evolution of the weight-height and weight-age relationship in children 3-6 years of age receiving preschool care in Sorocaba (SP), Brazil].
The nutritional status of Brazilians has improved over the last three decades. Still, little is known about the role played by nutritional assistance programs that public institutions and philanthropic organizations provide for low-income preschool children, who face greater nutritional risk. Therefore, we carried out a quasi-experimental study to evaluate the nutritional impact of the municipal preschool nutritional assistance program in the city of Sorocaba, São Paulo, Brazil. Over the course of a year, we performed quarterly measurements of weight and height on 444 children, whose ages ranged from 3 months to 6 years. In this population, 164 children were assisted by the preschool nutritional program (intervention group), and 280 children were not (nonintervention group). The children in the nonintervention group were identified by a special census for that purpose; they did not attend the preschool but lived nearby. After obtaining informed consent and carrying out a pretest, professionals and university students interviewed the mothers of the participating children, following standard techniques and conditions. Anthropometric measurements were done by teams of two interviewers, one of whom was a permanent member of the team, using equipment calibrated by the appropriate regional technical organization. The correspondence between the first measurement and subsequent measurements was evaluated by stratifying the population into three groups by z scores for weight-for-age and for weight-for-height, using U.S. National Center for Health Statistics reference curves. The z score groupings were established at the beginning of the study for three different age groups: younger than 24 months, 24-36 months, and older than 36 months. The two study groups (intervention and nonintervention) were similar sociodemographically, with the following exceptions: maternal employment (more of the mothers of children in the intervention group had jobs outside the home); age (children in the intervention group were significantly older); nutritional status (it was worse in the intervention group); and prevalence of hospital admittance (it was higher in the intervention group). After just the first three months of the study, 32% of the children in the intervention group had moved to a higher nutritional stratum, whereas only 13% of children in the nonintervention group had shown improved nutritional status. The difference in favor of the intervention group increased with the length of the intervention and was higher among older children. These results show that the preschool nutritional assistance program helped to improve the assisted children's nutritional status.


Astrocytic control of synaptic NMDA receptors.
Astrocytes express a wide range of G-protein coupled receptors that trigger release of intracellular Ca2+, including P2Y, bradykinin and protease activated receptors (PARs). By using the highly sensitive sniffer-patch technique, we demonstrate that the activation of P2Y receptors, bradykinin receptors and protease activated receptors all stimulate glutamate release from cultured or acutely dissociated astrocytes. Of these receptors, we have utilized PAR1 as a model system because of favourable pharmacological and molecular tools, its prominent expression in astrocytes and its high relevance to neuropathological processes. Astrocytic PAR1-mediated glutamate release in vitro is Ca2+ dependent and activates NMDA receptors on adjacent neurones in culture. Activation of astrocytic PAR1 in hippocampal slices induces an APV-sensitive inward current in CA1 neurones and causes APV-sensitive neuronal depolarization in CA1 neurones, consistent with release of glutamate from astrocytes. PAR1 activation enhances the NMDA receptor-mediated component of synaptic miniature EPSCs, evoked EPSCs and evoked EPSPs in a Mg2+-dependent manner, which may reflect spine head depolarization and consequent reduction of NMDA receptor Mg2+ block during subsequent synaptic currents. The release of glutamate from astrocytes following PAR1 activation may also lead to glutamate occupancy of some perisynaptic NMDA receptors, which pass current following relief of tonic Mg2+ block during synaptic depolarization. These results suggest that astrocytic G-protein coupled receptors that increase intracellular Ca2+ can tune synaptic NMDA receptor responses.


Coexistent Acanthamoeba keratitis and herpetic keratitis.
To describe a series of patients with proved herpes simplex virus keratitis (herpetic keratitis) who also had documented Acanthamoeba keratitis. Herpetic keratitis was documented with viral cultures, immunologic stains, or histopathologic examination for multinucleated giant cells in the corneal epithelium. Acanthamoeba organisms were identified using confocal microscopy and epithelial biopsy with hematoxylin-eosin staining. Biopsy of the stroma and epithelium was used to identify Acanthamoeba organisms in 1 case. Cultures for herpes simplex virus were positive in 6 of the 9 cases. Immunologic stains were positive in an additional 2 cases, and in 1 case multinucleated giant cells were present in the epithelium consistent with the diagnosis of herpes simplex virus keratitis. Tandem scanning confocal microscopic findings were positive for Acanthamoeba in 8 of the 9 cases, and all of them demonstrated Acanthamoeba organisms in epithelial scrape biopsy specimens. In 1 case, which was not evaluated with confocal microscopy, Acanthamoeba was detected using a stromal and epithelial biopsy. Two of the 9 patients had a history of contact lens use. Acanthamoeba keratitis may be present as a secondary or opportunistic infection in patients with herpetic keratitis.


Identification of a point mutation in the ace1 gene of Therioaphis trifolli maculata and detection of insecticide resistance by a diagnostic PCR-RFLP assay.
Aphids are important agricultural pests worldwide. Their control is largely based on chemical insecticides. One species that shows important invasive abilities and host-plant-related differences is Therioaphis trifolii (Monell) (Hemiptera: Aphididae). T. trifolii maculata, also known as spotted alfalfa aphid (SAA), can be very injurious to alfalfa crops in certain regions, such as in Saudi Arabia for effective control it is essential to diagnose and monitor the resistance mechanisms in the SAA populations. In the present study, we analysed acetylcholinesterase (ace) target site insensitivity mechanisms. A 650 bp length DNA containing the putative acetylcholinesterase (ace1) precursor was obtained and compared with other Hemipteran species. The sequences of many individual aphids collected from alfalfa crops in Saudi Arabia were analysed for the presence of resistance mutations: no resistance mutations were found at the resistance mutation loci 302; however, the presence of a serine-phenylalanine substitution (S431F) was identified in one individual. The S431F substitution, has been shown to confer significant levels of both organophosphate and carbamate resistance in other aphid species, and is now found for the first time in T. trifolii. We subsequently developed a simple polymerase chain reaction-restriction fragment length polymorphism assays for the S431F mutation, using a TaqI restriction site destroyed by the S431F mutation. The novel diagnostic assay may support the implementation of Insecticide Resistance Management strategies, for the control of SAA in alfalfa crops in the Kingdom of Saudi Arabia, and other countries worldwide.


For Which Side the Bell Tolls: The Laterality of Approach-Avoidance Associative Networks.
The two hemispheres of the brain appear to play different roles in emotion and/or motivation. A great deal of previous research has examined the valence hypothesis (left hemisphere = positive; right = negative), but an increasing body of work has supported the motivational hypothesis (left hemisphere = approach; right = avoidance) as an alternative. The present investigation (N = 117) sought to provide novel support for the latter perspective. Left versus right hemispheres were briefly activated by neutral lateralized auditory primes. Subsequently, participants categorized approach versus avoidance words as quickly and accurately as possible. Performance in the task revealed that approach-related thoughts were more accessible following left-hemispheric activation, whereas avoidance-related thoughts were more accessible following right-hemispheric activation. The present results are the first to examine such lateralized differences in accessible motivational thoughts, which may underlie more "downstream" manifestations of approach and avoidance motivation such as judgments, decision making, and behavior.


Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C- Cells.
Monocytes are circulating, short-lived mononuclear phagocytes, which in mice and man comprise two main subpopulations. Murine Ly6C+ monocytes display developmental plasticity and are recruited to complement tissue-resident macrophages and dendritic cells on demand. Murine vascular Ly6C- monocytes patrol the endothelium, act as scavengers, and support vessel wall repair. Here we characterized population and single cell transcriptomes, as well as enhancer and promoter landscapes of the murine monocyte compartment. Single cell RNA-seq and transplantation experiments confirmed homeostatic default differentiation of Ly6C+ into Ly6C- monocytes. The main two subsets were homogeneous, but linked by a more heterogeneous differentiation intermediate. We show that monocyte differentiation occurred through de novo enhancer establishment and activation of pre-established (poised) enhancers. Generation of Ly6C- monocytes involved induction of the transcription factor C/EBPβ and C/EBPβ-deficient mice lacked Ly6C- monocytes. Mechanistically, C/EBPβ bound the Nr4a1 promoter and controlled expression of this established monocyte survival factor.


Results of the national pilot screening program for venous disease by the American Venous Forum.
This report describes the pilot of a free comprehensive national screening program for venous disease. The screening process consisted of a venous thromboembolism (VTE) risk assessment, abbreviated duplex examination for venous obstruction and reflux, inspection for signs of chronic venous insufficiency (CVI), and an exit interview. Physicians coordinating the screenings were members of the American Venous Forum. Seventeen institutions screened 476 people (mean, 28 per site; range, 6 to 71). Mean age was 60 years (range, 40 to 91 years), with 78% women and 68% with a body mass index of > or =25. If placed in a situation conducive for VTE, 22 participants (5%) were low risk, 87 (18%) were moderate risk, 186 (39%) were high risk, and 179 (38%) were at very high risk. In 26 people (6%), one or more segments had venous obstruction, and 190 (40%) had one or more segments of venous reflux in the lower extremities. Varicose veins were present in 32%, edema without skin changes in 11%, skin changes attributable to venous disease in 8%, and healed or active venous stasis ulcer in 1.3% (CEAP classification 2, 3, 4, 5, and 6, respectively). Increasing age and increasing deep venous thrombosis risk score significantly correlated with increasing clinical classification, r = 0.09, P = .04, and r = 0.16, P = .0004, respectively. Those participants with reflux in one or more segments were significantly more likely to have a higher clinical classification compared with those with no reflux (P = .0001). The first comprehensive national screening for venous disease was performed. Participants were informed of their risk for VTE if placed in a situation conducive to VTE, screened for evidence of obstruction, reflux, and CVI, and empowered to share their results with their primary care provider.


Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans.
Body composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity. A retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided. Three hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CI = 15.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CI = 14.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74). DLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.


Alcohol and breast cancer: the mechanisms explained.
Breast cancer is a leading cause of death amongst women, several studies have shown significant association between alcohol consumption and breast cancer. The aim of this overview is to highlight some of the mechanisms by which alcohol consumption could increase the risk of developing breast cancer. Using online Medline search engine, article containing details about mechanisms which explain the link between alcohol and breast cancer were examined. A number of mechanisms were found by which alcohol could increase the risk of breast cancer, alcohol's interaction and effect on oestrogen secretion; number of oestrogen receptors; the generation of acetaldehyde and hydroxyl free radicals; cells migration and metastasis; secretion of IGF1 and interaction with HRT and folate metabolism. In conclusion, it is essential for clinicians to understand these mechanisms and inform patients of the link between alcohol and breast cancer. Breast cancer; Alcohol; Mechanisms.


Contextual equipoise: a novel concept to inform ethical implications for implementation research in low-income and middle-income countries.
The call for universal health coverage requires the urgent implementation and scale-up of interventions that are known to be effective, in resource-poor settings. Achieving this objective requires high-quality implementation research (IR) that evaluates the complex phenomenon of the influence of context on the ability to effectively deliver evidence-based practice. Nevertheless, IR for global health is failing to apply a robust, theoretically driven approach, leading to ethical concerns associated with research that is not methodologically sound.Inappropriate methods are often used in IR to address and report on context. This may result in a lack in understanding of how to effectively adapt the intervention to the new setting and a lack of clarity in conceptualising whether there is sufficient evidence to generalise findings from previous IR to a new setting, or if a randomised controlled trial (RCT) is needed. Some of the ethical issues arising from this shortcoming include poor-quality research that may needlessly expose vulnerable participants to research that has not been adapted to suit local needs and priorities, and the inappropriate use of RCTs that denies participants in the control arm access to treatment that is effective within the local context.To address these concerns, we propose a complementary approach to clinical equipoise for IR, known as contextual equipoise We discuss challenges in the evaluation of context and also with assessing the certainty of evidence to justify an RCT. Finally, we describe methods that can be applied to improve the evaluation and reporting of context and to help understand if contextual equipoise can be justified or if significant adaptations are required. We hope our analysis offers helpful insight to better understand and ensure that the ethical principle of beneficence is upheld in the real-world contexts of IR in low-resource settings.


Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker.
Detection of asbestos-associated diseases like asbestosis or mesothelioma is still challenging. We sought to improve the diagnosis of benign asbestos-associated disease (BAAD) by detection of the protein cysteine-rich angiogenic inducer 61 (Cyr61) in human plasma. Plasma Cyr61 was quantified using an enzyme-linked immunosorbent assay. Plasma samples from males diagnosed with BAAD, but without a malignant disease (n = 101), and malignant mesothelioma (n = 21; 15 males, 6 females), as well as nonasbestos-exposed healthy control participants (n = 150; 58 males, 92 females) were analyzed. Clinical sensitivity and specificity of Cyr61 were determined by receiver operating characteristic analysis. The median plasma Cyr61 concentration for healthy control participants was 0.27 ng/mL. Cytoplasmic Cyr61 in peripheral blood mononuclear cells from healthy control participants was evenly distributed, as detected by immunofluorescent staining. The increase in plasma Cyr61 concentrations in the BAAD study group was statistically significant compared to the healthy control participants (P < 0.0001). For the detection of BAAD vs male healthy control participants, clinical sensitivity was 88% and clinical specificity 95% with an area under the curve of 0.924 at maximal Youden Index. For a predefined clinical specificity of 100%, the clinical sensitivity was 76%. For male mesothelioma patients vs male healthy control participants, the clinical sensitivity at maximal Youden Index was 95% with a clinical specificity of 100% (area under the curve, 0.997) and for a predefined clinical specificity of 100%, the clinical sensitivity was 93%. In our study, plasma Cyr61 protein concentrations showed to be a new biomarker for asbestos-associated diseases like BAAD and mesothelioma in men, which deserves further investigation in large-scale cohort studies.


Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.
Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.


Imaging vibrating vocal folds with a high speed 1050 nm swept source OCT and ODT.
Vocal fold vibration is vital in voice production and the correct pitch of speech. We have developed a high speed functional optical coherence tomography (OCT) system with a center wavelength of 1050 nm and an imaging speed of 100,000 A-lines per second. We imaged the vibration of an ex-vivo swine vocal fold. At an imaging speed of 100 frames per second, we demonstrated high quality vocal fold images during vibration. Functional information, such as vibration frequency and vibration amplitude, was obtained by analyzing the tissue surface during vibration. The axial direction velocity distribution in the cross-sectional images of the vibrating vocal folds was obtained with the Doppler OCT. The quantitative transverse direction velocity distribution in the cross-sectional images was obtained with the Doppler variance images.


Reduced unloaded sarcomere shortening velocity and a shift to a slower myosin isoform in acute murine coxsackievirus myocarditis.
We developed a mouse myocardial preparation to study cellular dysfunction in acute coxsackievirus myocarditis. Thin right ventricular papillary muscles from normal mice (n = 8) were compared with muscles from mice 7 days after coxsackievirus infection (n = 7). Sarcomere shortening was studied with laser diffraction (HeNe, lambda = 623.8 nm). A servomotor was used to shorten a muscle until slack early in isometric contraction. Unloaded sarcomere shortening velocity (Vo) was measured at the start of zero force at slack length. Vo was independent of the extent of slack release and was the same as that estimated with an isotonic force-sarcomere shortening velocity relation. Resting muscle stiffness was calculated from shortening perturbations in resting muscles. The histology of some papillary muscles (normal, n = 4; infected, n = 3) was studied. There was no ventricular hypertrophy. Resting sarcomere length (SL) in infected preparations (2.11 +/- 0.07 micron) (mean +/- 1 SD) was the same as in normal preparations (2.11 +/- 0.08 micron). In isometric twitches in normal and infected muscles, total peak force (4.31 +/- 1.07 and 3.77 +/- 1.86 g/mm2, respectively) resting force (0.81 +/- 0.37 and 0.81 +/- 0.35 g/mm2, respectively), and time to peak force (129.5 +/- 20.3 and 125.2 +/- 13.0 milliseconds, respectively) were not significantly different. Vo was 4.14 +/- 0.84 micron/s in normal muscles at an SL of 2.08 +/- 0.09 micron and 1.70 +/- 0.33 micron/s in infected muscles at an SL of 2.06 +/- 0.08 micron. Resting stiffness was the same for normal and infected muscles. There was inflammation but no fibrosis or necrosis. Thus, Vo was depressed early in acute viral myocarditis without hypertrophy, myocyte necrosis, fibrosis, or altered resting stiffness. Pyrophosphate gel electrophoresis showed a shift from predominantly fast to slow myosin isoforms. Apparently, there is remodeling of the contractile apparatus early in acute coxsackievirus myocarditis that is caused either by the direct effects of the virus or the immune response.


Simulation of human gait with body weight support: benchmarking models and unloading strategies.
Gait training with partial body weight support (BWS) has become an established rehabilitation technique. Besides passive unloading mechanisms such as springs or counterweights, also active systems that allow rendering constant or modulated vertical forces have been proposed. However, only pilot studies have been conducted to compare different unloading or modulation strategies, and conducting experimental studies is costly and time-consuming. Simulation models that predict the influence of unloading force on human walking may help select the most promising candidates for further evaluation. However, the reliability of simulation results depends on the chosen gait model. The purpose of this paper is two-fold: First, using human experimental data, we evaluate the accuracy of some of the most prevalent walking models in replicating human walking under the influence of Constant-Force BWS: The Simplest Walking model (SW), the Spring-Loaded Inverted Pendulum model (SLIP) and the Muscle-Reflex (MR) gait model. Second, three realizations of BWS, based on Constant-Force (CF), Counterweight (CW) and Tuned-Spring (TS) approaches, are compared to each other in terms of their influence on gait parameters. We conducted simulations in Matlab/Simulink to model the behaviour of each gait model under all three BWS conditions. Nine simulations were undertaken in total and gait parameter response was analysed in each case. Root mean square error (mrmse) w.r.t human data was used to compare the accuracy of gait models. The metrics of interest were spatiotemporal parameters and the vertical ground reaction forces. To scrutinize the BWS strategies, loss of dynamic similarity was calculated in terms of root mean square difference in gait dynamics (Δgd) with respect to the reference gait under zero unloading. The gait dynamics were characterized by a dimensionless number Modela-w. SLIP model showed the lowest mrmse for 6 out of 8 gait parameters and for 1 other, the mrmse value were comparable to the MR model; SW model had the highest mrmse. Out of three BWS strategies, Tuned-Spring strategies led to the lowest Δgd values. The results of this work demonstrate the usefulness of gait models for BWS simulation and suggest the SLIP model to be more suitable for BWS simulations than the Simplest Walker and the Muscle-reflex models. Further, the Tuned-Spring approach appears to cause less distortions to the gait pattern than the more established Counterweight and Constant-Force approaches and merits experimental verification.


Resistive thrust production can be as crucial as added mass mechanisms for inertial undulatory swimmers.
In this Rapid Communication, we address a crucial point regarding the description of moderate to high Reynolds numbers aquatic swimmers. For decades, swimming animals have been classified in two different families of propulsive mechanisms based on the Reynolds number: the resistive swimmers, using local friction to produce the necessary thrust force for locomotion at low Reynolds number, and the reactive swimmers, lying in the high Reynolds range, and using added mass acceleration (described by perfect fluid theory). However, inertial swimmers are also systems that dissipate energy, due to their finite size, therefore involving strong resistive contributions, even for high Reynolds numbers. Using a complete model for the hydrodynamic forces, involving both reactive and resistive contributions, we revisit here the physical mechanisms responsible for the thrust production of such swimmers. We show, for instance, that the resistive part of the force balance is as crucial as added mass effects in the modeling of the thrust force, especially for elongated species. The conclusions brought by this work may have significant contributions to the understanding of complex swimming mechanisms, especially for the future design of artificial swimmers.


Changing smokeless tobacco products new tobacco-delivery systems.
Smokeless or noncombusted oral tobacco use as a substitute for cigarette smoking has been gaining greater interest and attention by the public health community and the tobacco industry. In order for the product to appeal to smokers, tobacco companies have been manufacturing new noncombusted oral tobacco (i.e., moist snuff) that is lower in moisture content and nitrosamine levels, packaged in small sachets and "spitless." While the primary motives of the major tobacco companies are to maintain or increase tobacco use, some members of the public health community perceive the use of noncombusted oral tobacco products as a harm reduction tool. Because cigarette smoking is associated with greater toxicant exposure compared to noncombusted oral tobacco, reduced mortality and morbidity are hypothesized to ensue, if cigarette smokers switched completely to these products. However, variability exists in levels of nicotine and toxicants and potential health consequences from use within and across countries. Therefore, promulgating noncombusted oral tobacco products as a safer alternative to smoking or as a substitute for smoking may engender more rather than less harm. To date, limited research is available on the effects of marketing noncombusted oral tobacco products to smokers, to support the use of these products as a harm reduction tool, and to determine the effects of varying levels of tobacco toxicants including nicotine on health. The need exists for manufacturing standards to lower toxicant levels of all noncombusted oral tobacco products, for the formulation of appropriate tobacco-product regulations and for the development of a strategic plan by the public health community to address this controversial topic.


Increased serum concentrations of growth factor receptors and Neu in workers previously exposed to asbestos.
Epidermal growth factor receptor (EGFR) and oncogene Neu belong to a family of growth factor receptors which may play a part in carcinogenesis. Although increased serum concentrations of Neu and EGFR have been shown in several patients with asbestosis who later developed cancer, serum concentrations have not been studied in workers exposed in the past to asbestos but without asbestos related diseases. Serum concentrations of secreted growth factor receptors were studied in 300 workers exposed in the past to asbestos and the results were compared with those of 70 controls. In the controls 4.3% (3/70) had EGFR values > 912 units/ml, compared with 39% (117/299) of the exposed group (p < 0.001). The difference in high values was even more pronounced for Neu with 4.3% of controls having Neu values > 2580 fmol/ml compared with 72% (216/299) of the exposed workers (p < 0.001). Pleural plaques predicted lower serum concentrations of EGFR but not lower Neu concentrations, and this finding remained significant after adjustment for age, exposure time, smoking, and time from initial exposure. Enhanced secretion of EGFR and Neu was found in a large cohort of retired asbestos workers with a wide range of exposure and latency periods. They did not have asbestosis or cancer and their EGFR values were higher in those without plaques. Further studies are needed to confirm our results, to determine the source of the secreted growth factor receptors, and to study their possible value as risk factors in the development of cancer.


Epidemiological investigation of an acute case of Chagas disease in an area of active transmission in Peruvian Amazon region.
The study objective was to investigate an acute case of Chagas disease in the San Pedro de Shishita community, Pebas District, in the Peruvian Amazon basin, a non-endemic area. Both parents of the index case (acute case) were thoroughly interviewed, a seroepidemiological survey was carried out in the community, parasitological exams were carried out only in relatives of the index case, and triatomine bugs were searched for inside houses, peridomiciliary, and in wild environments. Seroprevalence for IgG anti-T. cruzi antibodies was 1/104 (0.96%), using an ELISA test and an indirect immunofluorescence assay. Panstrongylus geniculatus and Rhodnius pictipes adults were found. The index case is autochthonous from San Pedro de Shishita, but the source of transmission is unknown.


Association between angiotensin converting enzyme gene polymorphism and coronary artery disease in individuals of the South-Eastern Anatolian population.
The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene has been proposed as a genetic marker of the risk of coronary artery disease (CAD). In this study we aimed to determine the relevance of ACE gene polymorphism for coronary artery disease in the South-Eastern Anatolian population. Angiotensin converting enzyme genotypes were determined in 133 CAD patients who underwent coronary angiography. Severity of CAD was subgrouped according to the number of stenotic vessels on coronary angiography. The control group was selected from 154 healthy volunteers. Angiotensin converting enzyme genotypes were determined by agarose gel sizing after polymerase chain reaction (PCR) amplification. Frequency of ACE DD genotype did not differ between patients with CAD and control subjects. However the ACE II genotype in CAD group was significantly less frequent than in control group (p=0.02). The relative risks were 0.9 (95% CI=0.56-1.43) for the DD genotypes, and 2.2 (95% CI=1.09 - 4.11) for the II genotype. In the 2-vessel CAD subgroups, the II genotypes were significantly different from control group. Our study did not confirm the possibility that the ACE DD genotypes may be associated with predisposition to CAD in this certain population but there is a relationship between the least frequencies of the II genotype and CAD. The II genotype seems to be an independent protective factor for CAD in the South-Eastern Anatolian population.


The 57 mm thermal clearance probe: a non-invasive tool for measuring subcutaneous blood flow.
1. The segmented thermal clearance probe is a non-invasive instrument which measures heat thermal clearance, a variable directly proportional to superficial blood flow, with a depth sensitivity theoretically proportional to the sensor diameter. We compared an 18 mm sensor and a recently developed 57 mm sensor with the reference technique of xenon washout. 2. The theoretical depth sensitivity of the sensors was assessed using Perspex spacers. Ninety-five per cent of sensitivity had been lost at the respective depths of 3.5 mm and 7.1 mm for the 18 mm and 57 mm sensors. 3. A comparison was made between heat thermal clearance reading and 133Xe decay curves using the two probes for 15 min after injection of 133Xe at 2 mm and 6 mm depths in the anterior thigh in 41 subjects. The 57 mm sensor showed similar correlation with xenon washout at 2 mm injection depth (r = 0.89) and 6 mm injection depth (r = 0.86), whereas the 18 mm sensor showed greater correlation at 2 mm (r = 0.92) than at 6 mm (r = 0.62). 4. The 57 mm sensor was compared with xenon washout at 6 mm in eight insulin-treated diabetic subjects. The relationship was similar to that in non-diabetic subjects (r = 0.79), with no significant difference in slope or intercept. 5. It is concluded that the 57 mm thermal clearance probe may be used to study blood flow at the depth of insulin injection (6 mm) in diabetic and non-diabetic subjects.


Genetically closely related but phenotypically divergent Trichoderma species cause green mold disease in oyster mushroom farms worldwide.
The worldwide commercial production of the oyster mushroom Pleurotus ostreatus is currently threatened by massive attacks of green mold disease. Using an integrated approach to species recognition comprising analyses of morphological and physiological characters and application of the genealogical concordance of multiple phylogenetic markers (internal transcribed spacer 1 [ITS1] and ITS2 sequences; partial sequences of tef1 and chi18-5), we determined that the causal agents of this disease were two genetically closely related, but phenotypically strongly different, species of Trichoderma, which have been recently described as Trichoderma pleurotum and Trichoderma pleuroticola. They belong to the Harzianum clade of Hypocrea/Trichoderma which also includes Trichoderma aggressivum, the causative agent of green mold disease of Agaricus. Both species have been found on cultivated Pleurotus and its substratum in Europe, Iran, and South Korea, but T. pleuroticola has also been isolated from soil and wood in Canada, the United States, Europe, Iran, and New Zealand. T. pleuroticola displays pachybasium-like morphological characteristics typical of its neighbors in the Harzianum clade, whereas T. pleurotum is characterized by a gliocladium-like conidiophore morphology which is uncharacteristic of the Harzianum clade. Phenotype MicroArrays revealed the generally impaired growth of T. pleurotum on numerous carbon sources readily assimilated by T. pleuroticola and T. aggressivum. In contrast, the Phenotype MicroArray profile of T. pleuroticola is very similar to that of T. aggressivum, which is suggestive of a close genetic relationship. In vitro confrontation reactions with Agaricus bisporus revealed that the antagonistic potential of the two new species against this mushroom is perhaps equal to T. aggressivum. The P. ostreatus confrontation assays showed that T. pleuroticola has the highest affinity to overgrow mushroom mycelium among the green mold species. We conclude that the evolutionary pathway of T. pleuroticola could be in parallel to other saprotrophic and mycoparasitic species from the Harzianum clade and that this species poses the highest infection risk for mushroom farms, whereas T. pleurotum could be specialized for an ecological niche connected to components of Pleurotus substrata in cultivation. A DNA BarCode for identification of these species based on ITS1 and ITS2 sequences has been provided and integrated in the main database for Hypocrea/Trichoderma (www.ISTH.info).