Immunocytochemical localization of thrombomodulin in the aqueous humor passage of the rat eye.
This report describes the distribution and localization of thrombomodulin (TM) in the rat eye by light and electron microscopic immunocytochemistry. In addition to the endothelium of the entire vasculature, TM was found on the non-vascular structures lining the cavities of the posterior and anterior chambers and the limbus. TM was localized on the basal, lateral, and apical plasma membranes of the inner and outer ciliary epithelium, and the posterior iris epithelium in which there was no polarized expression of TM. In the anterior chamber, TM was localized on the luminal surface of the corneal endothelium, but was negative on the anterior border layer of the iris, which is composed of a discontinuous layer of fibroblasts and collagen fibers. Thus, TM was present at sites of cell-to-cell contact. TM was also present on the endothelia of the trabecular meshwork and the Schlemm's canal in the limbus. TM was localized not only on the luminal plasma membrane, but also on the cytoplasmic giant vacuoles in the endothelial cells of the Schlemm's canal. These findings extend the importance of anticoagulant mechanisms to the systems of secretion, circulation, and drainage of the aqueous humor.


Plasma membrane localization and function of TRPC1 is dependent on its interaction with beta-tubulin in retinal epithelium cells.
Mammalian homologues of the Drosophila canonical Transient Receptor Potential (TRPC) protein have been proposed to encode the store-operated Ca2+ influx (SOC) channel(s). This study examines the role of TRPC1 in the SOC mechanism of retinal cells. htrpc1 transcript was detected in bovine retinal and in human adult retinal pigment epithelial (ARPE) cells. Western blot analysis also confirmed the expression of TRPC1 protein in neuronal cells including retina and ARPE cells. To determine the role of TRPC1 protein in retinal cells, TRPC1 was recombinantly expressed in ARPE cells and changes in intracellular Ca2+ were analyzed. ARPE cells stably transfected with htrp1 cDNA displayed 2-fold higher Ca2+ influx with no significant increase in the basal influx. Consistent with this the overexpressed TRPC1 protein was localized in the plasma membrane region of ARPE cells. Interestingly, both bovine retinal tissues and ARPE cells showed that TRPC1 protein co-localizes and could be co-immunoprecipitated with beta-tubulin. Disruption of tubulin by colchicine significantly decreased both plasma membrane staining of the TRPC1 protein and Ca2+ influx in ARPE cells. These results suggest that TRPC1 channel protein is expressed in retinal cells, further, targeting/retention of the TRPC1 protein to the plasma membrane in retinal cells is mediated via its interaction with beta-tubulin.


When pain gets stuck: the evolution of pain chronification and treatment resistance.
It is well-recognized that, despite similar pain characteristics, some people with chronic pain recover, whereas others do not. In this review, we discuss possible contributions and interactions of biological, social, and psychological perturbations that underlie the evolution of treatment-resistant chronic pain. Behavior and brain are intimately implicated in the production and maintenance of perception. Our understandings of potential mechanisms that produce or exacerbate persistent pain remain relatively unclear. We provide an overview of these interactions and how differences in relative contribution of dimensions such as stress, age, genetics, environment, and immune responsivity may produce different risk profiles for disease development, pain severity, and chronicity. We propose the concept of "stickiness" as a soubriquet for capturing the multiple influences on the persistence of pain and pain behavior, and their stubborn resistance to therapeutic intervention. We then focus on the neurobiology of reward and aversion to address how alterations in synaptic complexity, neural networks, and systems (eg, opioidergic and dopaminergic) may contribute to pain stickiness. Finally, we propose an integration of the neurobiological with what is known about environmental and social demands on pain behavior and explore treatment approaches based on the nature of the individual's vulnerability to or protection from allostatic load.


The joint line convergence angle (JLCA) correlates with intra-articular arthritis.
Knees with unicompartmental varus osteoarthritis (OA) usually display a combination of tibiofemoral bony deformity and increased joint line convergence angle (JLCA). The JLCA is a product of intra-articular deformity and lateral soft tissue laxity. This study aims to define the correlation between the JLCA and progression of OA. A retrospective radiological analysis of 501 patients, who underwent either high tibial osteotomy (HTO) or unicompartmental knee arthroplasty (UKA), was performed. The preoperative OA grade was reported based on the Ahlbäck and the Kellgren-Lawrence (KL). The hip-knee-ankle angle (HKA), the medial proximal tibial angle (MPTA), the mechanical lateral distal femoral angle (mLDFA) and the joint line convergence angle (JLCA) were recorded. The primary outcome was the relationship between the JLCA values and the OA grade. The secondary outcomes were comparing the JLCA and other alignment parameter values between HTO and UKA groups. A total of 501 (59.3% females n = 297) cases were included, comprising 293 cases of HTO and 208 cases of UKA. Patients had a mean age of 57.63 ± 8.97 years, a mean BMI of 28.37 ± 7.39 kg/m2. Patients with Ahlbäck grade 2 represented 49.3% of all patients (n = 247) and patients with KL grade 3 represented 54.7% of all patients (n = 274). A high JLCA was observed in both groups. The reported mean JLCA in the UKA group was 3.69 ± 2.1°, and in the HTO group was 2.93 ± 1.82. There was a significant association between the increase in the JLCA and the progression of OA based on both the Ahlbäck and KL grades (both p values < 0.001). The mean JLCA in patients with Ahlbäck grades 1 and 4 was 1.48 ± 1.32°, and 7 ± 0.93°, respectively. The mean JLCA in patients with KL grades 1 and 4 was 1.77 ± 1.42°, and 4.89 ± 1.73°, respectively. The mean recorded preoperative HKA angle in the UKA group was 175.06 ± 3.08°, and in the HTO group was 173.26 ± 3.02°, whereas the mean MPTA was 88.63 ± 1.72° for the UKA group and 89.31 ± 2.29° for the HTO group. The JLCA progressively increases with osteoarthritis progression in patients with unicompartmental varus knee osteoarthritis. The JLCA can potentially be used as a grading parameter for osteoarthritis progression akin to Ahlbäck and Kellgren-Lawrence grading systems.


Evaluating wildlife as a potential source of Salmonella serotype Newport (JJPX01.0061) contamination for tomatoes on the eastern shore of Virginia.
Eastern Shore of Virginia red, round tomatoes contaminated with Salmonella serotype Newport pattern JJPX01.0061 have been a source of several multistate outbreaks within the last 10 years. No source of the contamination has yet been identified. The goal of this study was to evaluate wildlife as a potential source of contamination. Faecal samples from deer, turtles and birds were collected between November 2010 and July 2011 from seventeen locations on the Eastern Shore of Virginia. A total of 262 samples were tested for the presence of Salmonella using an enzyme-linked immunosorbent assay (ELISA). A total of 23 (8.8%) samples tested positive for Salmonella spp. and were further characterized by serotyping and pulsed-field gel electrophoresis (PFGE) subtyping. Overall, twelve serotypes were identified, including Salmonella serotype Javiana, another common serotype associated with tomato-related outbreaks. Only one avian sample collected in July 2011 was determined to be positive for S. Newport pattern 61. This sample was collected from the ground at a site where birds, mostly gulls, were congregating. Although many of the avian samples from this site were dry, the site yielded eleven positive Salmonella samples. This suggests that certain Salmonella serotypes may persist in the environment despite extreme conditions. The recovery of one Newport pattern 61 isolate alone does not yield much information regarding the environmental reservoirs of this pathogen, but when combined with other data including the recovery of several isolates of Javiana from birds, it suggests that birds might be a potential source of Salmonella contamination for tomatoes on the Eastern Shore.


Education on pain disciplines in physical therapy in Chile: In need of change.
Pain is a major public health concern associated with emotional disorders and physical disability and generates increased sick leave and healthcare expenditures. However, despite its social impact and the high pain-related costs, the training of healthcare professionals, such as physical therapists, in pain management is insufficient, leading to an inadequate therapeutic approach. This study aimed to determine the existence of a specific program on pain within the curricula of physical therapy careers in accredited universities in Chile. Out of 40 physical therapy careers, we analyzed 38 curricula. None of them had a specific discipline on pain management in their curricula. Although there is no concrete definition of the best modality for pain education in undergraduate students, it has been shown that following the International Association for The Study of Pain curricula improves students' knowledge and awareness of pain management.


Low background high efficiency radiocesium detection system based on positron emission tomography technology.
After the 2011 nuclear power plant accident at Fukushima, radiocesium contamination in food became a serious concern in Japan. However, low background and high efficiency radiocesium detectors are expensive and huge, including semiconductor germanium detectors. To solve this problem, we developed a radiocesium detector by employing positron emission tomography (PET) technology. Because (134)Cs emits two gamma photons (795 and 605 keV) within 5 ps, they can selectively be measured with coincidence. Such major environmental gamma photons as (40)K (1.46 MeV) are single photon emitters and a coincidence measurement reduces the detection limit of radiocesium detectors. We arranged eight sets of Bi4Ge3O12 (BGO) scintillation detectors in double rings (four for each ring) and measured the coincidence between these detectors using PET data acquisition system. A 50 × 50 × 30 mm BGO was optically coupled to a 2 in. square photomultiplier tube (PMT). By measuring the coincidence, we eliminated most single gamma photons from the energy distribution and only detected those from (134)Cs at an average efficiency of 12%. The minimum detectable concentration of the system for the 100 s acquisition time is less than half of the food monitor requirements in Japan (25 Bq/kg). These results show that the developed radiocesium detector based on PET technology is promising to detect low level radiocesium.


Predisposing preventable factors in patients with bleeding due to warfarin usage: Evaluation of 114 patients.
Warfarin is one of the commonly used oral anticoagulant. The aim of our study is to evaluate the predisposing preventable factors among patients with bleeding due to warfarin usage. This study was performed on 114 cases who were admitted to emergency service for bleeding and whose ages range between 27 and 89 years. The mean time between the onset of the bleeding and admission to the hospital was 2.9 ± 3.4 days. The mean dose of warfarin being used at the time of admission was 31.2 ± 10.8 mg weekly. Only 37 cases were being controlled regularly. The mean number of the drugs being used other than warfarin was 4.8 ± 2.5 drugs. Forty-eight cases were using aspirin, 28 nonsteroidal anti-inflammatory drugs other than aspirin and 18 cases were using various antibiotics. Forty eight patients knew that they had to use this drug under the regular follow-up of a physician and 43 knew that during monitoring a laboratory test had to be done while using the drug named as warfarin. Only 39 patients knew that this drug may cause bleeding. It was also surprising that only 9 patients knew that there may be drug interaction and 1 knew that this drug may be affected from the dietary factors. As a result, it may be concluded that most of the patients admitting to the emergency service had a lack of basic knowledge about this drug, which might invite bleeding.


Disinfection performance of Fe(VI) in water and wastewater: a review.
Ferrate(VI) [FeVIO4(2-), Fe(VI)] has excellent disinfectant properties and can inactivate a wide variety of microorganisms at low Fe(VI) dosages. The final product of Fe(VI) is Fe(III), a non-toxic compound. The treatment by Fe(VI) does not give any chlorination by-products, which makes Fe(VI) an environmentally-friendly ion. The results demonstrate that Fe(VI) can inactivate Escherichia coli (E. coli) at lower dosages or shorter contact time than hypochlorite. Fe(VI) can also kill many chlorine resistant organisms, such as aerobic spore-formers and sulphite-reducing clostridia, and would be highly effective in treating emerging toxins in the aquatic environment. Fe(VI) can thus be used as an effective alternate disinfectant for the treatment of water and wastewater. Moreover, Fe(VI) is now becoming economically available in commercial quantities and can be used as a treatment chemical to meet the water demand of this century. This paper reviews the potential role of Fe(VI) as disinfectant in water and wastewater treatment processes.


Immobilized enzyme electrodes for glucose determination for the artificial pancreas.
Immobilized enzymes are useful in the development of techniques for analytical chemistry measurements, primarily because of the specificity of enzymes for given substrates. In the case of glucose an in vivo assay is needed for closed loop operation of an artificial pancreas insulin delivery system. Several enzymatic methods are available for in vitro determinations of glucose, but only two or three of these methods hold any promise of adaptation for in vivo use. The most promising enzymatic approaches include the use of immobilized glucose oxidase in conjunction with 1) an oxygen electrode to give an amperometric output or 2) a reference electrode to give a potentiometric output. The use of glucose oxidase or other D-glucose-specific enzymes in conjunction with sensitive thermistors to measure the heat of reaction may also be a feasible method. The two most promising approaches are described in terms of their feasibility for continuous measurement of blood glucose levels in vivo without the necessity of withdrawing body fluids for the assay.


ROOT NODULE SYMBIOSIS. I. ENDOPHYTE OF MYRICA CERIFERA L.
Silver, Warren S. (University of Florida, Gainesville). Root nodule symbiosis. I. Endophyte of Myrica cerifera. J. Bacteriol. 87:416-421. 1964.-Electron microscopy of 0.1-mu thick sections of root nodules, fixed with permanganate and embedded with methacrylate, showed that infected plant cells were filled with a mycelial endophyte. The endophyte was filamentous, 1 mu in diameter, septate, and had an enlarged, club-shaped terminus. Although structurally the endophyte strongly resembles an actinomycete, it was not isolated in pure culture on a variety of appropriate media.


[Characteristics of the mechanisms of psychological adaptation of patients with ischemic heart disease and hypertension].
A fixed orientation principle was used for the examination of 203 patients with coronary heart disease (CHD) and 123 patients with essential hypertension. Psychological adaptation mechanisms and variation therein were studied in relation to the form, severity, pattern and stage of the disease. The fixed orientation method is based on evoking illusory perception in a subject. Basic fixed orientation types are identified depending on the way one gets rid of the orientation. Variable-stable orientation mediating high motivation, dominance, impulsiveness and aggressiveness in prevalent in CHD irrespective of its form. In hypertensive patients, variable-labile orientation prevails that features impulsiveness, inconsistency, anxiety, psychasthesnia and depression. The occurrence of these parameters was unrelated to form, severity and stage of the disease. Premorbid nature of these features is postulated. The fixed orientation method is recommended as a highly informative way of identifying psychological adaptation mechanisms.


The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels.
This study investigated the relationship of children's autism symptoms with their toxic metal body burden and red blood cell (RBC) glutathione levels. In children ages 3-8 years, the severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and SAS. Toxic metal body burden was assessed by measuring urinary excretion of toxic metals, both before and after oral dimercaptosuccinic acid (DMSA). Multiple positive correlations were found between the severity of autism and the urinary excretion of toxic metals. Variations in the severity of autism measurements could be explained, in part, by regression analyses of urinary excretion of toxic metals before and after DMSA and the level of RBC glutathione (adjusted R(2) of 0.22-0.45, P < .005 in all cases). This study demonstrates a significant positive association between the severity of autism and the relative body burden of toxic metals.


Synchronous dynamic focusing for ultrasound imaging.
An approach to dynamic focusing of ultrasound linear array scanners is presented, leading to the unique capability of implementing a focus that continuously tracks the return signal along the penetration depth. An electronically variable lens is obtained by a heterodyning process, in which the phases of echo signals at the array elements are equalized by mixing with suitable reference oscillations. These are generated by control of a single voltage-controlled oscillator, whose frequency is properly varied in synchronism with the delay of signal from different depths. The technique has been experimentally demonstrated by modifying the focusing processor of a conventional echographic linear scanner. Superior performances have been obtained with respect to fixed-focus operation mode. The image quality results are comparable with those of multizone-focus operation mode, in which the focus is varied over more transmit/receive cycles at the expense of lower frame rate.


Expanding the ProteOn XPR36 biosensor into a 36-ligand array expedites protein interaction analysis.
Here we demonstrate methods to expand the throughput of the ProteOn XPR36 biosensor allowing for the simultaneous kinetic characterization of several multiplexed formats, such as 36 disparate antibodies targeting the same antigen, and facilitating detailed epitope binning and mapping studies. The kinetic rate constants determined by these methods correlated with those obtained on Biacore 2000 and the absolute parameter values obtained on the ProteOn's alginate-based GLC chip agreed closer with those from Biacore's flat C1 chip than Biacore's dextran-based CM4 chip. Pairwise epitope binning data from the ProteOn 36-ligand array format and those generated on an orthogonal array-based biosensor, the Octet QK384, gave similar results. In an epitope mapping study using biotinylated peptides, all three biosensor platforms were similar in their ability to identify antibodies that bound to linear epitopes. We apply alternative formats of the ProteOn array that enable a significantly higher number of assays to be conducted simultaneously than previously anticipated on this platform.


Reinitiation of cell wall growth after threonine starvation of Streptococcus faecalis.
Cultures of Streptococcus faecalis ATCC 9790 were starved of threonine for 10 hr and then allowed to reinitiate growth in a fresh complete medium. On regrowth, culture turbidity began to increase within 10 min, but the ability of cells to autolyze did not begin to increase until after 30 min. Ultrastructural studies of regrowth of the initially thick-walled cells showed, at about 30 min, centripetal linear extension of new thin cross wall. This was followed, at about 40 min, by a notching, splitting, and peeling apart of the base of the cross wall. After this, extension of new thin peripheral wall from the nascent cross wall appeared to push old thick wall toward the poles. After the first cell division, asymmetric cells with one initial generation thick-walled pole and one second generation thin-walled pole were seen. After two divisions, thick-walled hemispheres were still seen, suggesting conservation of old wall during this time. A small fraction of the initial cell population exhibited aberrations and difficulties in reinitiating linear wall extension and were useful in the establishment of a model for the reinitiation of linear wall extension.


A comprehensive review on facemask manufacturing, testing, and its environmental impacts.
The coronavirus pandemic (COVID-19) is currently the biggest threat to human lives due to its rapid transmission rate causing severe damage to human health and economy. The transmission of viral diseases can be minimized at its early stages with proper planning and preventive practices. The use of facemask has proved to be most effective measure to curb the spread of virus along with social distancing and good hygiene practices. This necessitates more research on facemask technology to increase its filtration efficiencies and proper disposal, which can be accelerated with knowledge of the current manufacturing process and recent research in this field. This review article provides an overview of the importance of facemask, fundamentals of nonwoven fabrics, and its manufacturing process. It also covers topics related to recent research reported for improved facemask efficiencies and testing methods to evaluate the performance of facemask. The plastic waste associated with the facemask and measures to minimize its effect are also briefly described. A systematic understanding is given in order to trigger future research in this field to ensure that we are well equipped for any future pandemic.


A ubiquitous healthcare system of 3D printing facilities for making dentures: Application of type-II fuzzy logic.
A ubiquitous healthcare (UH) system of multiple 3D printing facilities is established in this study for making dentures. The UH system receives orders from dental clinics, and then distributes the dentures to be printed among 3D printing facilities to save time. Compared with existing systems for similar purposes, the UH system has two novel features. The first is the consideration of the possibility of reprinting in formulating the plan to avoid replanning. The other is the cooperation with home delivery services that have gradually become popular during the COVID-19 pandemic to save transportation time. The new features are subject to considerable uncertainties. To account for the uncertainties, both printing time and transportation time are modelled using interval type-II trapezoidal fuzzy numbers. Subsequently, an interval type-II fuzzy mixed integer-linear programming (FMILP) model is formulated and optimized to plan the operations of the UH system. A case study has been conducted to illustrate the applicability of the proposed methodology. According to experimental results, the proposed methodology was able to shorten the order fulfillment time by up to 9%.


Exosomal derived miR-1246 from hydroquinone-transformed cells drives S phase accumulation arrest by targeting cyclin G2 in TK6 cells.
Hydroquinone (HQ), a major metabolite of benzene and known hematotoxic carcinogen. MicroRNA 1246 (miR-1246), an oncogene, regulates target genes in carcinogenesis including leukemia. This study investigates the impact of exosomal derived miR-1246 from HQ-transformed (HQ19) cells on cell-to-cell communication in recipient TK6 cells. RNA sequencing was used to identify differentially expressed exosomal miRNAs in HQ19 cells and its phosphate buffered solution control cells (PBS19), which were then confirmed using qRT-PCR. The impact of exosomal miR-1246 derived from HQ-transformed cells on cell cycle distribution was investigated in recipient TK6 cells. RNA sequencing analysis revealed that 34 exosomal miRNAs were upregulated and 158 miRNAs were downregulated in HQ19 cells compared with PBS19 cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses predicted that their targets are enriched in cancer development-related pathways, such as MAPK signaling, microRNAs in cancer, apoptosis, PI3K-Akt signaling, cell cycle, Ras signaling, and Chronic myeloid leukemia. Eleven miRNAs were confirmed to have differential expression through qRT-PCR, with 6 upregulated (miR-140-3p, miR-551b-3p, miR-7-5p, miR-1290, miR-92a-3p, and miR-1246) and 5 downregulated (miR-183-5p, miR-26a-5p, miR-30c-5p, miR-205-5p, and miR-99b-3p). Among these, miR-1246 exhibited the highest expression level. HQ exposure resulted in a concentration-dependent increase in miR-1246 levels and decrease Cyclin G2 (CCNG2) levels in TK6 cells. Similarly, exosomes from HQ19 exhibited similar effects as HQ exposure. Dual luciferase reporter gene assays indicated that miR-1246 could band to CCNG2. After HQ exposure, exosomal miR-1246 induced cell cycle arrest at the S phase, elevating the expression of genes like pRb, E2F1, and Cyclin D1 associated with S phase checkpoint. However, silencing miR-1246 caused G2/M-phase arrest. HQ-transformed cells' exosomal miR-1246 targets CCNG2, regulating TK6 cell cycle arrest, highlighting its potential as a biomarker for HQ-induced malignant transformation.


Replication of lactate dehydrogenase-elevating virus in macrophages. 1. Evidence for cytocidal replication.
Cultures of starch-elicited peritoneal mouse macrophages in medium containing macrophage growth factor (MGF) were infected with lactate dehydrogenase-elevating virus (LDV) and, after various times in culture, LDV production was monitored as a function of time by infectivity titrations in mice, by measuring [3H]uridine incorporation into LDV RNA and extracellular LDV, by autoradiographic analysis of the proportion of productively infected cells and by electron microscopy. Regardless of the age of the cultures when infected with LDV, only a small proportion of the macrophages (generally between 3 and 20% of the total) became productively infected after a primary infection; maximum virus RNA synthesis and virus production occurred during the first 24 h after infection and then decreased precipitously. Productively infected macrophages could be readily recognized in electron micrographs of 24-h infected macrophage cultures and in sections of spleens from 24-h infected mice by characteristic morphological alterations. These consisted of formation of clusters of double-membrane vesicles with a diameter of 100 to 300 mumol, budding of nucleocapsids into vesicles with single membranes and accumulation of mature virions in these vesicles. One to 4 days later, however, such cells were no longer found in infected cultures or spleens of infected mice and superinfection did not restimulate LDV replication. Cultures established with macrophages from 1-day LDV-infected mice also did not support LDV replication. We conclude that LDV replication in cultures or mice is limited to a single cycle in a subpopulation of macrophages and that infection leads to cell death and rapid phagocytosis of the dead cells by the resistant, uninfected macrophages.


[Ecoparasitoses and public health in Brazil: challenges for control].
Parasitic skin diseases such as scabies, pediculosis, tungiasis, and cutaneous larva migrans are hyperendemic in the numerous poor communities in Brazil and are commonly associated with considerable morbidity. However, programs to control ectoparasites are non-existent in the country's public health system. Due to neglect of these diseases by the population itself and health care professionals, the diseases' highly contagious characteristics, and lack of effective treatment and/or presence of animal reservoirs together with a complex life cycle, effective control of ectoparasites is an enormous public health challenge. This article discusses potential measures to control parasitic skin diseases in affected communities, based on mass treatment, health education, and (when applicable) eradication of animal reservoirs.


Clinical and Angiographic Results with the Multi-Linkª Coronary Stent System Ñ The West European Stent Trial (WEST).
BACKGROUND: The objectives for the West European Stent Trial (WEST) were to assess the safety and efficacy of the new ACS Multi-Linkª coronary stent system with regards to bleedings and vascular complications and incidence of major adverse cardiac events during 12 months follow-up. METHODS AND RESULTS: The balloon-expandable Multi-Link stent is made from a single hypotube and is composed of 316 L stainless steel. In an open, non-randomized, multicenter registry, 102 patients with angina pectoris to be treated with this stent were recruited from 7 European centers. Following stent implantation, patients were given heparin infusion and oral coumadin treatment was maintained for 3 months. Procedural success was achieved in 100 of the 102 patients (98%). One patient had subacute stent thrombosis and 6 patients had major bleeds during the hospital stay. All patients were alive at 12 months and 85% were free of angina pectoris. Nineteen patients (19%) reached a primary clinical endpoint; four patients underwent bypass surgery (two in connection with the stent procedure), four patients suffered an acute myocardial infarction and 11 had a repeat angioplasty of the target vessel. Quantitative angiography showed that the minimum lumen diameter had decreased from 2.66 +/- 0.34 mm after stent deployment to 2.02 +/- 0.58 mm at 6 months and the percent diameter stenosis had increased from 18 +/- 7% to 33 +/- 16%. The in-stent restenosis rate was 12% and appearance of a stenosis in the target vessel outside the stent occurred in an additional 5%. CONCLUSION: The WEST study has demonstrated a high degree of safety and efficacy of the Multi-Link stent with a low incidence of complications and clinical events during follow-up. The results compare favorably with data from other stents.


Invasive group A streptococcal infections in Sweden in 1994 and 1995: epidemiology and clinical spectrum.
A nationwide study of invasive group A streptococcal (GAS) infections in Sweden during 1994-1995 was carried out. All Swedish microbiological laboratories were asked to report isolates of GAS from normally sterile sites. During the study period they were also asked to send their isolates for T typing. Questionnaires were sent to the physicians in charge of each patient. The incidence, serotype, clinical presentation, symptoms and outcome were recorded. Clinical data were obtained for 468 of 556 patients with GAS bacteraemia. The lethality rate was 16%, but was much higher (37%) in the 113 patients who developed streptococcal toxic shock syndrome (STSS). Streptococci of serotype T1 dominated during the study period and were linked to the increase in invasive GAS infections. They also carried an increased risk of causing STSS. Invasive streptococcal disease with STSS most often has an unknown primary focus or is associated with soft tissue infections. Invasive streptococcal disease not associated with STSS most often has a skin infection as portal of entry or else an unknown focus.


Echocardiographic Molecular Imaging of the Effect of Anticytokine Therapy for Atherosclerosis.
Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1β (IL-1β) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1β therapy. In wild-type and atherosclerotic mice deficient for the low-density lipoprotein-receptor and Apobec-1, closed-chest myocardial infarction (MI) was performed to mimic high-risk clinical cohorts. Control animals had sham surgery. Post-MI animals were randomized to either no therapy or anti-IL-1β immunotherapy, which was continued weekly. At post-MI day 3 or 21, in vivo ultrasound molecular imaging of aortic VCAM-1, P-selectin, von Willebrand factor A1-domain, and platelet GPIbα in the thoracic aorta was performed. Aortic histology and NF-κB activity were assessed in atherosclerotic mice. In both atherosclerotic and wild-type mice, MI produced a several-fold increase (P < .05) in aortic molecular signals for P-selectin, VCAM-1, von Willebrand factor, and GPIbα. In atherosclerotic mice, signal remained elevated at day 21. Anti-IL-1β therapy completely abolished the post-MI increase in signal for all endothelial targets (P < .05 vs nontreated) at day 3 and 21. In atherosclerotic mice, MI triggered an increase in aortic plaque growth and macrophage content, a decrease in plaque collagen, and elevated aortic NF-κB (P < .05 for all changes). All of these remote plaque adverse changes were inhibited by anti-IL-1β therapy. Echocardiographic molecular imaging of the vascular endothelium can quantify the beneficial effects of therapies designed to suppress the proatherosclerotic arterial thromboinflammatory effects of alarmins such as IL-1β. This approach could potentially be used to evaluate the biologic variables that influence response in preclinical studies, and possibly to select patients most likely to benefit from therapy.


Social determinants of health in India: progress and inequities across states.
Despite the recognized importance of social determinants of health (SDH) in India, no compilation of the status of and inequities in SDH across India has been published. To address this gap, we assessed the levels and trends in major SDH in India from 1990 onwards and explored inequities by state, gender, caste, and urbanicity. Household- and individual-level SDH indicators were extracted from national household surveys conducted between 1990 and 2011 and means were computed across population subgroups and over time. The multidimensional poverty index (MPI), a composite measure of health, education, and standard of living, was calculated for all three rounds of the National Family Health Survey, adjusting the methodology to generate comparable findings from the three datasets. Data from government agencies were analyzed to assess voting patterns, political participation, and air and water pollution. Changes in the MPI demonstrate progress in each domain over time, but high rates persist in important areas: the majority of households in India use indoor biomass fuel and have unimproved sanitation, and over one-third of households with a child under the age of 3 years have undernourished children. There are large, but narrowing, gender gaps in education indicators, but no measurable change in women's participation in governance or the labor force. Less than 25% of workers have job security and fewer than 15% have any social security benefit. Alarming rates of air pollution are observed, with particulate matter concentrations persistently above the critical level at over 50% of monitoring stations. This assessment indicates that air pollution (indoor and outdoor), child undernutrition, unimproved sanitation, employment conditions, and gender inequality are priority areas for public policy related to SDH in India.


Nutraceuticals' Novel Formulations: The Good, the Bad, the Unknown and Patents Involved.
Traditional nutraceuticals and cosmeceuticals hold pragmatic nature with respect to their definitions, claims, purposes and marketing strategies. Their definitions are not well established worldwide. They also have different regulatory definitions and registration regulatory processes in different parts of the world. Global prevalence of nutraceuticals and cosmeceuticals is noticeably high with large market share with minimal regulation compared to traditional drugs. The global market is flooded with nutraceuticals and cosmeceuticals claiming to be of natural origin and sold with a therapeutic claim by major online retail stores such as Amazon and eBay. Apart from the traditional formulations, many manufacturers and researchers use novel formulation technologies in nutraceutical and cosmeceutical formulations for different reasons and objectives. Manufacturers tend to differentiate their products with novel formulations to increase market appeal and sales. On the other hand, researchers use novel strategies to enhance nutraceuticals and cosmeceuticals activity and safety. The objective of this review is to assess the current patents and research adopting novel formulation strategies in nutraceuticals and cosmeceuticals. Patents and research papers investigating nutraceutical and cosmeceutical novel formulations were surveyed for the past 15 years. Various nanosystems and advanced biotechnology systems have been introduced to improve the therapeutic efficacy, safety and market appeal of nutraceuticals and cosmeceuticals, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of nutraceuticals and cosmeceuticals current technologies, highlighting their pros, cons, misconceptions, regulatory definitions and market. This review also aims in separating the science from fiction in the nutraceuticals and cosmeceuticals development, research and marketing.


Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome.
A family is described in which 2 siblings born to healthy parents presented with abnormal facies, persistent diarrhoea, and early death. Exhaustive pathological and biochemical investigations failed to find a cause. The scalp hair of both babies had an abnormal amino-acid composition, and presented an appearance that was unique on scanning electron microscopical examination; this fact and the clinical picture probably represents a new syndrome.


Muscle and fat composition in patients with newly diagnosed multiple myeloma.
Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010-2019 who had an 18F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively (P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively (P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics.


A compositional based model for the tear film lipid layer.
The tear film lipid layer is formed from lipids secreted by meibomian glands of the eyelid. After initial analyses of these lipids we concluded that an understanding of the function of the various classes of lipids in a normal lipid layer could only be understood after detailed investigations of both polar and nonpolar lipids of the meibomian gland. Meibomian gland secretions were obtained from normals. Lipids were separated by thin layer chromatography and high pressure liquid chromatography, and analyzed by UV absorbance, gas chromatography and mass spectroscopy. Based on our analyses we concluded that the current understanding of lipid layer composition and function were inadequate or misleading. We therefore propose that the more polar lipids function as a structure (with surfactant characteristics) upon which the functional stability of the more nonpolar lipids are dependent. We further suggest that the interrelationships between lipid classes present, length of fatty acids and alcohols, their unsaturation, and hydroxylation are important for maintaining proper thixotropic characteristics of the lipid layer as well as optimal barrier properties. The tear film lipid layer is composed of 2 phases: (1) a thin polar phase adjacent to the aqueous-mucin phase and (2) a thick nonpolar phase associated with both the polar phase and the air interface. The structural characteristics of the polar phase and the barrier functions of the nonpolar phase are a direct result of specific compositional parameters.


Stabilization of the 53,000-dalton nonviral tumor antigen is not required for transformation by simian virus 40.
We have isolated a simian virus 40 deletion mutant, F8dl, that lacks the sequences from 0.168 to 0.424 map units. The deleted sequences represent about one-half of the coding region for large T antigen. We present evidence here that F8dl is able to transform mouse cells in a focus assay and that cell lines derived from these foci exhibit fully transformed phenotypes, have integrated mutant genomes, and express mutant-encoded proteins. This result implies that the region of the simian virus 40 genome between 0.168 and 0.424 map units is not essential for the maintenance of transformation. In addition, we have found that cells fully transformed by F8dl produce a 53,000-dalton nonviral tumor antigen (p53) that is as unstable as the p53 of untransformed cells. From this result we infer that transformation by simian virus 40 does not require the stabilization of p53.


Transport of potassium in the rabbit pars recta.
Unidirectional fluxes of 42K+ and 86Rb+ were measured in isolated perfused segments of proximal straight tubules and no differences were found between the two isotopes for the same flux determination. In the three segments examined (the early and late superficial proximal straight tubule and the juxtamedullary proximal straight tubule) there was apparent net active K+ secretion as demonstrated by differences in the unidirectional fluxes of 2.6, 3.2, and 4.8 pmol.min-1.mm-1, respectively. However, in contrast to the expectations for active K+ secretion, the bath-to-lumen fluxes were unaffected by 0.1 mM ouabain added to the bathing solution, and in the early superficial and juxtamedullary segments these fluxes were directly proportional to the K+ concentration of the bathing solution over a range of concentrations. Apparent K+ permeability coefficients were calculated from lumen-to-bath fluxes to be 0.14 +/- 0.02, 0.10 +/- 0.02, and 0.52 +/- 0.07 micrometers.s-1 in the early and late superficial and juxtamedullary segments, respectively. Based on these data and on a mathematical analysis, we have concluded that active K+ secretion of the magnitude measured would have little importance in determining the K+ load delivered to the descending limb of the loop of Henle. However, the higher passive permeability of the juxtamedullary segment would allow significant net K+ secretion if the outer medullary interstitium had even a moderately elevated K+ concentration.


Synchronization of two GaAs photoconductive semiconductor switches triggered by two laser diodes.
In this Letter, we show the synchronization of two 2-mm-gap gallium arsenide (GaAs) photoconductive semiconductor switches (PCSS), which are in parallel and triggered by two laser diodes (LDs) independently. The comparison of the synchronization is measured by varying the bias electric field and optical excitation energy, respectively. An optimum synchronization is achieved as low as 200.5 ps, while the GaAs PCSS are biased at 1.2 kV with optical excitation energy of 1.91 μJ. The simulations demonstrate the relationship between the synchronization, the carriers average drift velocity, and the number of carriers undergoing intervalley scattering.


Establishment and characterization of a goat synovial membrane cell line susceptible to small ruminant lentivirus infection.
Primary goat synovial membrane (GSM) cells are widely used to study small ruminant lentiviruses (SRLV), i.e. maedi visna virus (MVV) and caprine arthritis-encephalitis virus (CAEV), but their limited life-span of 15-20 passages in vitro is problematic. Here, we report that ectopic expression of the catalytic subunit of human telomerase (hTERT) was sufficient to immortalize primary GSM cells. Cultures of hTERT-transfected GSM cells have been passaged for 2 years without showing any phenotypic difference from the original primary GSM cells. The hTERT-transfected cells continued to grow beyond a population doubling number of 250, while no net telomere lengthening was observed for these cells. Moreover, the immortalized GSM cells were susceptible to infection by both CAEV and MVV and were able to propagate theses viruses. Such cell line provides a useful source of standard and robust cells for both research and veterinary purposes.


Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule.
Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical complications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also deposition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar "stop-and-go" motion of sickle cell red blood cells on tumor factor-α-activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein factor Has an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential contribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.


Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.
The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.


Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange clinic registry.
Few studies have assessed factors associated with severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D). Our objective was to determine frequency of and factors associated with the occurrence of SH and DKA in adults with T1D. We conducted a cross-sectional analysis from the T1D Exchange clinic registry at 70 U.S. endocrinology centers. Analysis included 7012 participants in the T1D Exchange clinic registry aged 26 to 93 years old with T1D for ≥2 years. Higher frequencies of SH and DKA were associated with lower socioeconomic status (P < .001). SH was strongly associated with diabetes duration (P < .001), with 18.6% of those with diabetes ≥40 years having an event in the past 12 months. SH frequency was lowest in those with hemoglobin A1c (HbA1c) levels of 7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), being higher in those with HbA1c levels <7.0% (<53 mmol/mol) or >7.5% (>58 mmol/mol). DKA frequency increased with higher HbA1c levels (P < .001), with 21.0% of those with HbA1c ≥10.0% (≥86 mmol/mol) having an event in the past 12 months. SH and DKA are more common in those with lower socioeconomic status. DKA, most common in those with HbA1c ≥10.0% (≥86 mmol/mol), should be largely preventable. In contrast, SH, most frequent with diabetes ≥40 years duration, cannot be abolished given the limitation of current therapies. To reduce SH in adults with longstanding diabetes, consideration should be given to modifying HbA1c goals, particularly in patients with very low HbA1c levels.


PBTK model for assessment of operator exposure to haloxyfop using human biomonitoring and toxicokinetic data.
Physiologically-based toxicokinetic (PBTK) models are mathematical representations of chemical absorption, distribution, metabolism and excretion (ADME) in animals. Each parameter in a PBTK model describes a physiological, physicochemical or biochemical process that affects ADME. Distributions can be assigned to the model parameters to describe population variability and uncertainty. In this study to assess potential crop sprayer operator exposure to the herbicide haloxyfop, a permeability-limited PBTK model was constructed with parameter uncertainty and variability, and calibrated using Bayesian analysis via Markov chain Monte Carlo methods. A hierarchical statistical model was developed to reconstruct operator exposure using available measurement data: experimentally determined octanol/water partition coefficient, mouse and human toxicokinetic data as well as human biomonitoring data from seven operators who participated in a field study. A chemical risk assessment was performed by comparing the estimated systemic exposure to the acceptable operator exposure level (AOEL). The analysis suggested that in one of the seven operators, the model estimates systemic exposure to haloxyfop of 49.04 ± 10.19 SD μg/kg bw in relation to an AOEL of 5.0 μg/kg bw/day. This does not represent a safety concern as this predicted exposure is well within the 100-fold uncertainty factor applied to the No Observed Adverse Effect Level (NOAEL) in animals. In addition, given the availability of human toxicokinetic data, the 10x uncertainty factor for interspecies differences in ADME could be reduced (EFSA, 2006). Thus the AOEL could potentially be raised tenfold from 5.0 to 50.0 μg/kg bw/day.


EPIQ Review.
A checklist that promotes compliance with aseptic technique during line insertion is a component of many care bundles aimed at reducing nosocomial infections among intensive care unit patients. To determine whether the use of bundled interventions that include a checklist during central-line insertions reduces catheter-related bloodstream infections in intensive care unit patients. A literature review was performed using methodology adapted from the American Heart Association's International Liaison Committee on Resuscitation. Seventeen cohort studies were included. Thirteen studies were supportive of the intervention, while four were neutral. Infection rates ranged from 1.6 to 10.8 per 1000 central-line days in control groups, and from 0.0 to 3.8 per 1000 central-line days in the intervention groups. There is fair evidence to recommend the use of care bundles that include a checklist during central-line insertion in intensive care unit patients to reduce the incidence of catheter-related bloodstream infections.


Polyatomic anion assistance in the assembly of [2]pseudorotaxanes.
We describe the use of polyatomic anions for the quantitative assembly of ion-paired complexes displaying pseudorotaxane topology. Our approach exploits the unique ion-pair recognition properties exhibited by noncovalent neutral receptors assembled through hydrogen-bonding interactions between a bis-calix[4]pyrrole macrocycle and linear bis-amidepyridyl-N-oxides. The complexation of bidentate polyatomic anions that are complementary in size and shape to the receptor's cavity, in which six NH hydrogen-bond donors converge, induces the exclusive formation of four particle-threaded assemblies.


[Clinicopathophysiological aspects of utilization of local physiotherapy device mavit in combined treatment of patients with chronic prostatitis and symptomatic prostatic adenoma].
Clinical efficacy of combined treatment with application of MAVIT device was studied in 45 patients with chronic prostatitis. By the results of examination the patients were divided into two groups: group 1 consisted of 25 patients with the diagnosis of prostatic adenoma of stage I-II complicated with chronic prostatitis; group 2 - of 20 patients with chronic prostatitis. Biotissue effect of MAVIT on prostatic blood circulation was studied in 10 patients of group 2 who were examined with transrectal ultrasound (color Doppler mapping) before and after the physiotherapeutic session. The ultrasound examination assessed linear peak blood flow velocity, index of peripheral vascular resistance, intensity of organic vascular net. The treatment results were followed up in both groups for 3-12 months. Positive changes were registered: reduction or disappearance of dysuria, subjective improvement of urination, alleviation of genital pain. Thus, combined conservative treatment of chronic prostatitis in patients with symptomatic prostatic adenoma has a pathogenetic significance and provides adequate preparation for surgery. MAVIT device can be recommended for treatment of chronic prostatitis including patients with prostatic adenoma.


Leptin, body composition, and indices of malnutrition in patients on dialysis.
A cross-sectional study was performed in a group of dialysis patients and control subjects to identify the determinants of serum levels of leptin, the protein product of the obese (ob) gene. Twenty-eight patients on dialysis (19 patients on hemodialysis [HD] and nine patients on peritoneal dialysis [PD]) and 41 healthy control subjects were studied. For each subject, blood was drawn for measurement of serum leptin levels and body composition was analyzed by dual-energy x-ray absorptiometry. Regression analyses were performed to determine the predictors of leptin levels, the independent contribution of HD and PD, and the relationship between leptin levels and markers of malnutrition and protein intake in the patients on dialysis. As expected, percentage of body fat was strongly correlated with leptin levels in the group as a whole and in each subgroup when analyzed separately. However, the slope of the relationship was significantly greater for dialysis patients than for control subjects (P < 0.05). Multivariate regression analysis showed that patients on HD and PD had higher leptin levels than control subjects even after adjustment for age, gender, and percentage of body fat. Univariate analyses were performed to assess the relationship between leptin levels and markers of nutritional status such as albumin, blood urea nitrogen, protein catabolic rate (PCR), transferrin, cholesterol, and lean body mass per height. There was a significant negative correlation between leptin levels and serum albumin (r = -0.598, P < 0.001) and between leptin and PCR (r = -0.433, P < 0.05) in the patients on dialysis. It is concluded that leptin levels adjusted for percentage of body fat are increased in dialysis patients compared with control subjects, particularly in those on PD. In addition, increased leptin levels are associated with low serum albumin levels and PCR in dialysis patients.


Association between implantable cardioverter-defibrillator therapy and different lead positions in patients with cardiac resynchronization therapy.
To evaluate the impact of different right and left ventricular lead positions (RV-LP and LV-LP) on the risk of therapy for ventricular tachycardia/ventricular fibrillation in patients with a cardiac resynchronization therapy device (CRT-D). We performed a large nationwide cohort study on patients in Denmark receiving a CRT-D device from 2008 to 2012 from the Danish Pacemaker and implantable cardioverter defibrillator (ICD) registry. Lead positions were registered during the implantation and categorized as anterior/lateral/posterior and basal/mid-ventricular/apical for the LV-LP, and as apical/non-apical for the RV-LP. Appropriate and inappropriate therapies were registered during follow-up via remote monitoring or at device interrogations. Time to event was summarized with Kaplan-Meier plots, and competed risk regression analysis was used to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Following variables were included in the analysis: gender, age, heart failure aetiology, New York heart association class, left ventricular ejection fraction, QRS duration, indication (secondary or primary prophylactic), RV-LP, LV-LP, and antiarrhythmic therapy. We included 1643 patients [mean age 68 (±10) years, 1343 (83%) men]. After a mean of 2.0 years, 322 (20%) patients received appropriate and 66 (4%) patients received inappropriate therapy. The aHR for appropriate therapy with a non-apical RV-LP was 0.70 95% CI (0.55-0.87, P = 0.002) as compared with an apical. We observed no significant association between appropriate therapy and LV-LP in left anterior oblique or right anterior oblique views or inappropriate therapy between any lead positions. An apical RV-LP is associated with an increased risk of appropriate therapy for ventricular tachyarrhythmia in patients with a CRT-D device.


Enhanced interleukin-2 gene transfer immunotherapy of breast cancer by coexpression of B7-1 and B7-2.
The capability of B7-1 to augment the antitumor activity of some cytokines has been shown primarily for such cytokines as interleukin-12 (IL-12), IL-7, and to a lesser extent IL-2. In this study, we investigate the ability of B7-1 and B7-2 to augment the antitumor activity of IL-2. Considering the affinity of both molecules for CD28 (T cell receptor for B7-1 and B7-2), we postulated that their potential to augment IL-2 antitumor activity would be similar. Two murine transgenic adenocarcinoma models were chosen to investigate the activity of adenoviral vectors constructed to express either B7-1 and IL-2 or B7-2 and IL-2. Before administering the vector intratumorally to tumor-bearing mice, we determined the expression of B7-1, B7-2, MHC I, and MHC II on these tumor cells and demonstrated positive expression of only MHC I. Intratumoral injection of the vector expressing B7-1 and IL-2 resulted in complete regression of all tumors treated. In contrast, the vector expressing B7-2 and IL-2 was significantly less effective at regressing PyMT tumors, whereas both double recombinant vectors demonstrated similar levels of complete regression in the Neu (NDL 8142) model. Regressed mice were all protected for rechallenge in both models and demonstrated antigen-specific cytotoxic T lymphocytes (CTL) in the PyMT model. These findings indicate that the combination of IL-2 with B7-1 or B7-2 significantly enhances the antitumor activity of IL-2.


Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F.
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are known to play a critical role in a variety of fundamental processes, including wound healing, angiogenesis, and development of multiple organ systems. Mutations in the FGFR gene family have been linked to a series of syndromes (the craniosynostosis syndromes) whose primary phenotype involves aberrant development of the craniofacial skeleton. Craniosynostosis syndrome-linked FGFR mutations have been shown to be gain of function in terms of receptor activation and have been presumed to result in increased levels of FGF/FGFR signaling. Unfortunately, studies attempting to link expression of mutant FGFRs with changes in cellular phenotype have yielded conflicting results. In an effort to better understand the biochemical consequences of these mutations on receptor function, here we have investigated the effect of the FGFR2C278F mutation of Crouzon craniosynostosis syndrome on receptor trafficking, ubiquitination, degradation, and signaling. We find that FGFR2C278F exhibits diminished glycosylation, increased degradation, and limited cellular sublocalization in the osteoblastic cell line, MC3T3E1(C4). Additionally, we show that trafficking and autoactivation of wild type FGFR2 is glycosylation-dependent. Both FGFR2C278F and unglycosylated wild type FGFR2 signal through phospholipase Cgamma in a ligand-independent manner as well as exhibit dramatically increased binding to the adaptor protein, Frs2. These findings suggest that autoactive FGFR2 can signal from intracellular compartments. Based upon our results, we propose that the functional signaling of craniosynostosis mutant, autoactive receptors is limited in some cell types by protective cellular responses, such as increased trafficking to lysosomes and proteasomes for degradation.


Identification of a new genogroup of aquareovirus by RNA-RNA hybridization.
The relative mobilities of the 11 dsRNA genomic segments of 22 aquareovirus isolates from fish and shellfish obtained from different geographical areas of the world were compared by PAGE. Using reciprocal RNA-RNA dot blot hybridization, a new sixth genetic group of aquareovirus (genogroup F) was identified. Genogroup A was represented by eight and genogroup B by 12 isolates. The remaining two isolates represented the new sixth genogroup (genogroup F). The genetic relationship of these aquareoviruses with mammalian rotavirus group A (SA 11) was also examined by reciprocal RNA-RNA blot hybridization but none was found under any of the stringency conditions used.


The Systems Research Organizing Model: a conceptual perspective for facilities design.
The purpose of this article is to (1) demonstrate the utility of the Systems Research Organizing Model (SROM) for evidence-based design; (2) explicate the SROM; and (3) demonstrate how the SROM can advance the science of healthcare design. Grounded in systems science and adapted from the Quality Health Outcomes Model, the SROM was originally designed to assist in the organization of nursing systems research. It is useful for research in other fields as well because it serves as a potential framework for new investigations, allows delineation of key factors in previous research studies, and allows for the synthesis of a body of research knowledge. By means of the latter function, it helps identify knowledge that is ready to be translated to the practice environment. MODEL DESIGN: The SROM is a fully justified model with four core constructs: client, context, action focus, and outcomes. Feedback loops in the model reflect the interrelatedness of the core constructs and recognize the complex nature of the healthcare environment. The SROM may be useful for organizing research studies of interest to healthcare design scientists and practitioners. This framework has promise for organizing studies, identifying gaps in current research studies, and synthesizing multiple studies for application to practice.


Evaluation of long-term efficacy of interferon alpha-2b and ribavirin in combination in naive patients with chronic hepatitis C: an Italian multicenter experience. Ribavirin-Interferon in Chronic Hepatitis Italian Group Investigators.
A combination of interferon alpha and ribavirin has been suggested to reach a higher rate of sustained virological response in patients with chronic hepatitis C than monotherapy. In this study we assessed the long-term efficacy of this combination therapy in the treatment of selected Italian naive chronic hepatitis C patients compared to interferon alpha monotherapy. We enrolled 428 naive patients who were randomly assigned to receive either recombinant interferon alpha-2b and ribavirin for 24 weeks or interferon alpha-2b alone for 48 weeks. The primary end-point of the study was the rate of sustained virological response. Serum HCV RNA levels were determined before treatment; during treatment at weeks 12 and 24 in the patients receiving the combination therapy; at weeks 12, 24, 36 and 48 in the patients receiving monotherapy; and after therapy at weeks 12, 24 and 48 in the patients in both study groups. Sustained virological response was observed in 43% of the patients treated with combination therapy and in 14% of the patients treated with monotherapy. Logistic regression analysis showed that sustained response was associated with the combination therapy, with HCV genotype other than 1b, with an HCV viral load of 3x10(6) copies/ml or less, with an inflammation score of 7 or less, and with an estimated duration of disease of 10 years or less. A 24-week treatment course with interferon alpha-2b and ribavirin offers a greater chance of sustained virological response compared to treatment with interferon alpha-2b alone for 48 weeks, and may be indicated as initial therapy in such patients.


Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms.
Tacrolimus, an immunosuppressant used after organ transplantation, has a narrow therapeutic range and its pharmacokinetic variability complicates its daily dose assessment. P-glycoprotein (P-gp), encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) and the cytochrome (CYP) 3A4 and 3A5 enzymes appears to play a role in the tacrolimus metabolism. In the present study, two different renal transplant recipient groups were used to examine the influence of ABCB1 and CYP3A polymorphisms on the daily tacrolimus dose and several pharmacokinetic parameters. In total 63 Caucasian renal transplant recipients divided into 26 early [median (range) of the days since transplantation - 16 (3-74)] and 37 late [median (range) of the days since transplantation - 1465 (453-4128)] post-transplant recipients were genotyped for ABCB1 and CYP3A polymorphisms. The pharmacokinetic parameters of tacrolimus were determined for all renal transplant recipients and correlated with their corresponding genotypes. A significant difference in allele frequencies of the CYP3A4*1B (P = 0.028) and CYP3A5*1 (P = 0.022) alleles was observed between the early and late post-transplant recipient groups. Significantly higher dose-normalized trough levels (dnC(0)), dose-normalized area under the curve (dnAUC(0-12)), and dose-normalized maximum concentration (dnC(max)) were observed for carriers of the CYP3A5*3 variant allele in both renal transplant patient groups. Except for the daily tacrolimus dose (P = 0.025) no significant differences were observed for carriers of the CYP3A4*1B variant allele. Neither the individual ABCB1 polymorphisms nor the ABCB1 haplotypes were associated with any pharmacokinetic parameter. We noticed that patients carrying a CYP3A5*1 allele require a twofold higher tacrolimus dose compared with homozygous carriers of the CYP3A5*3 variant allele to maintain the target dnAUC(0-12). Therefore, genotyping for the CYP3A5*3 variant allele can contribute to a better and more individualized immunosuppressive therapy in transplant patients.


Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial.
To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Randomized, double-blind, placebo-controlled trial. Six tertiary care medical centers in the US. One hundred one mechanically ventilated medical and surgical intensive care unit patients. Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.


Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing.
Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ± 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.


Rickettsia felis identified in two fatal cases of acute meningoencephalitis.
Rickettsia felis has recently emerged worldwide as a cause of human illness. Typically causing mild, undifferentiated fever, it has been implicated in several cases of non-fatal neurological disease in Mexico and Sweden. Its distribution and pathogenicity in Southeast Asia is poorly understood. We retroactively tested cerebrospinal fluid (CSF) or sera from 64 adult patients admitted to hospital in North Sulawesi, Indonesia with acute neurological disease. Rickettsia felis DNA was identified in the CSF of two fatal cases of meningoencephalitis using multi-locus sequence typing semi-nested PCR followed by Sanger sequencing. DNA from both cases had 100% sequence homologies to the R. felis reference strain URRWXCal2 for the 17-kDa and ompB genes, and 99.91% to gltA. The identification of R. felis in the CSF of two fatal cases of meningoencephalitis in Indonesia suggests the distribution and pathogenicity of this emerging vector-borne bacteria might be greater than generally recognized. Typically Rickettsia are susceptible to the tetracyclines and greater knowledge of R. felis endemicity in Indonesia should lead to better management of some acute neurological cases.


Risk compensation is not associated with male circumcision in Kisumu, Kenya: a multi-faceted assessment of men enrolled in a randomized controlled trial.
Three randomized controlled trials (RCTs) have confirmed that male circumcision (MC) significantly reduces acquisition of HIV-1 infection among men. The objective of this study was to perform a comprehensive, prospective evaluation of risk compensation, comparing circumcised versus uncircumcised controls in a sample of RCT participants. Between March 2004 and September 2005, we systematically recruited men enrolled in a RCT of MC in Kenya. Detailed sexual histories were taken using a modified Timeline Followback approach at baseline, 6, and 12 months. Participants provided permission to obtain circumcision status and laboratory results from the RCT. We evaluated circumcised and uncircumcised men's sexual behavior using an 18-item risk propensity score and acquisition of incident infections of gonorrhea, chlamydia, and trichomoniasis. Of 1780 eligible RCT participants, 1319 enrolled (response rate = 74%). At the baseline RCT visit, men who enrolled in the sub-study reported the same sexual behaviors as men who did not. We found a significant reduction in sexual risk behavior among both circumcised and uncircumcised men from baseline to 6 (p<0.01) and 12 (p = 0.05) months post-enrollment. Longitudinal analyses indicated no statistically significant differences between sexual risk propensity scores or in incident infections of gonorrhea, chlamydia, and trichomoniasis between circumcised and uncircumcised men. These results are based on the most comprehensive analysis of risk compensation yet done. In the context of a RCT, circumcision did not result in increased HIV risk behavior. Continued monitoring and evaluation of risk compensation associated with circumcision is needed as evidence supporting its' efficacy is disseminated and MC is widely promoted for HIV prevention.


Nutritional evaluation of new reduced oligosaccharide soybean meal in poultry.
The nutritional values of a novel reduced-oligosaccharide soybean meal (SBM-RO) and conventional SBM (SBM-CV) were evaluated and compared in 4 experiments. The first experiment was a TMEn assay with conventional roosters. The second experiment was a precision-fed cecectomized rooster assay that was conducted to determine TMEn and amino acid (AA) digestibility. The third experiment was a standardized ileal AA digestibility assay, in which broiler chicks were fed semi-purified diets containing 20% protein (from only the test ingredient) for 17 to 21 d of age and ileal digesta were collected on d 21. The fourth experiment was a growth performance trial (7 to 20 d of age) where broiler chicks were fed corn-SBM diets (adequate in all AA) containing 38.84% SBM-RO or SBM-CV. The protein content (100% DM basis) of the SBM-CV and SBM-RO was 51.9 and 54.8%, respectively. The gross energy of the 2 SBM was similar. The TMEn values in both conventional roosters and cecectomized roosters were significantly higher (P < 0.05) for SBM-RO than for SBM-CV (difference was approximately 200 kcal/kg of DM). Amino acid digestibility in cecectomized roosters was not different between SBM-CV and SBM-RO, with the exception of Trp, Ala, Asp, and Cys (SBM-RO > SBM-CV, P < 0.05). No significant differences between the SBM were found for AA digestibility in the standardized ileal AA digestibility assay. In the growth performance trial (experiment 4), the corn-SBM diet containing SBM-RO yielded significantly higher feed efficiency than the diet containing SBM-CV (P < 0.001). The results indicated that the SBM-RO contains higher ME than the SBM-CV and that digestibility of AA in SBM-RO is similar to SBM-CV.


Does Carotid Intima-media Thickness have Relationship with Polycystic Ovary Syndrome?
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with cardiovascular disease (CVD) risk factors and metabolic disturbances and a genetically heterogeneous disease. Intima-media thickness (IMT) is an indicator of atherosclerosis. This study aimed to determine the relation between IMT and PCOS in women. This cross-sectional study was performed on 44 PCOS patients and 44 healthy women. Data collection included lipid profiles, blood pressure, waist circumference, body mass index (BMI), and common and internal IMT of carotid artery which were measured in studied subjects. IMT was measured by a radiologist using a linear 12 MHz ultrasound probe (LOGIC S6, GE) in carotid setting. IMT of common carotid artery (56.8 ± 7.6 in cases versus 49.8 ± 7.3 in controls), internal carotid artery (56.9 ± 6.03 in cases versus 49.6 ± 6.9 in controls), and both common and internal carotid artery (56.6 ± 6.7 in cases versus 49.7 ± 6.9 in controls) were significantly higher in PCOS patients than healthy women (P < 0.001). In summary, results demonstrated that carotid artery thickness as a risk for premature atherosclerosis in patients with PCOS is higher than healthy subjects. And hence care and monitoring of PCOS women with these risk factors sounds to be important and necessary.


Ethical challenges in mental health research among internally displaced people: ethical theory and research implementation.
Millions of people undergo displacement in the world. Internally displaced people (IDP) are especially vulnerable as they are not protected by special legislation in contrast to other migrants. Research conducted among IDPs must be correspondingly sensitive in dealing with ethical issues that may arise. Muslim IDPs in Puttalam district in the North-Western province of Sri Lanka were initially displaced from Northern Sri Lanka due to the conflict in 1991. In the backdrop of a study exploring the prevalence of common mental disorders among the IDPs, researchers encountered various ethical challenges. These included inter-related issues of autonomy, non-maleficence, beneficence, confidentiality and informed consent, and how these were tailored in a culture-specific way to a population that has increased vulnerability. This paper analyses how these ethical issues were perceived, detected and managed by the researchers, and the role of ethics review committees in mental health research concerning IDPs. The relevance of guidelines and methodologies in the context of an atypical study population and the benefit versus risk potential of research for IDPs are also discussed. The limitations that were encountered while dealing with ethical challenges during the study are discussed. The concept of post-research ethical conduct audit is suggested to be considered as a potential step to minimize the exploitation of vulnerable populations such as IDPs in mental health research.


Updates in the management of polycythemia vera and essential thrombocythemia.
Polycythemia vera (PV) and essential thrombocythemia (ET) are both classic, relatively indolent, chronic Philadelphia-chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) characterized by elevated blood counts, thrombotic as well as hemorrhagic tendencies, a variety of symptoms, cumulative risks of progression to myelofibrosis and transformation to acute myeloid leukemia over time, and long survival. Molecularly, PV is more homogenous, being driven by JAK2 mutations in virtually all cases, while ET can be JAK2-, CALR-, or MPL-mutated, as well as 'triple negative'. Recent targeted next-generation sequencing efforts have identified other, nondriver gene mutations, some with prognostic relevance. Prevention of thrombotic and hemorrhagic complications continues to be the major focus of management, although symptoms are increasingly being recognized as a relatively unmet need, particularly in ET. Thrombotic risk stratification in PV is still based on age and history of thrombosis, while in ET, the additional contribution of JAK2 V617F to thrombotic risk is now well established. The associations of leukocytosis with clotting risk (in both conditions) and mortality (in PV) have drawn increased attention with the availability of ruxolitinib as a second-line treatment in PV. Similarly, there is a renewed interest in interferons with the emergence of ropeginterferon alfa-2b as a potential new frontline treatment option in PV. Drug development is more difficult in ET, the most indolent of the classic Ph- MPNs, but ruxolitinib is being studied. Triggering apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (and synergism with interferon) is a new, promising therapeutic strategy.


Pathogenicity of entomopathogenic fungi Beauveria bassiana and Metarhizium anisopliae to Ixodidae tick species Dermacentor variabilis, Rhipicephalus sanguineus, and Ixodes scapularis.
Nymphal and adult ticks from three different tick species, Dermacentor variabilis Say, Ixodes scapularis Say, and Rhipicephalus sanguineus Latrielle, were treated with conidia and blastospores of the entomopathogenic fungi Beauveria bassiana (Bals.) Vuill. and Metarhizium anisopliae Metschnikoff. Dose-response experiments indicated that a critical concentration of fungal spores is required for infection and mortality. Over a 28-d time course, fungal suspensions of either B. bassiana or M. anisopliae at 10(8) conidia/ml resulted in 50-70% mortality in adult I. scapularis and R. sanguineus, but <20% mortality in D. variabilis ticks. R. sanguineus nymphs were highly susceptible to both entomopathogenic fungi, displaying >60% mortality within 14 d postinfection and >90% mortality within 21-28 d postinfection. D. variabilis nymphs also were more susceptible than their corresponding adults, displaying mortalities ranging from 20 to 40% 28 d postinfection. I. scapularis nymphs, however, seemed to be slightly less susceptible than adults (45% mortality, 28 d postinfection). The addition of nutrients to fungal cell suspensions did not have any noticeable effects on mortality toward any of the tick species tested. Significant mortality against D. variabilis adults (approximately 65%) was noted only when B. bassiana fungal cells with growth media carryover were used as the inoculum against the ticks. Entomopathogenic fungi such as B. bassiana and M. anisopliae may have the potential for controlling populations of I. scapularis and R. sanguineus, and under certain conditions D. variabilis. Our results indicate that inoculum conditions can greatly affect successful virulence and subsequent mortality.


Waterpipe and cigarette epigenome analysis reveals markers implicated in addiction and smoking type inference.
Waterpipe smoking is frequent in the Middle East and Africa with emerging prevalence worldwide. The epigenome acts as a molecular sensor to exposures and a crucial driver in several diseases. With the widespread use of waterpipe smoking, it is timely to investigate its epigenomic markers and their role in addiction, as a central player in disease prevention and therapeutic strategies. DNA methylome-wide profiling was performed on an exposure-rich population from the Middle East, constituting of 216 blood samples split equally between never, cigarette-only and waterpipe-only smokers. Waterpipe smokers showed predominantly distinct epigenetic markers from cigarette smokers, even though both smoking forms are tobacco-based. Moreover, each smoking form could be accurately (∼90 %) inferred from the DNA methylome using machine learning. Top markers showed dose-response relationship with extent of smoking and were validated using independent technologies and additional samples (total N = 284). Smoking markers were enriched in regulatory regions and several biological pathways, primarily addiction. The epigenetically altered genes were not associated with genetic etiology of tobacco use, and the methylation levels of addiction genes, in particular, were more likely to reverse after smoking cessation. In contrast, other epigenetic markers continued to feature smoking exposure after cessation, which may explain long-term health effects observed in former smokers. This study reports, for the first time, blood epigenome-wide markers of waterpipe smokers and reveals new markers of cigarette smoking, with implications in mechanisms of addiction and the capacity to discriminate between different smoking types. These markers may offer actionable targets to reverse the epigenetic memory of addiction and can guide future prevention strategies for tobacco smoking as the most preventable cause of illnesses worldwide.


The sleep apnea syndrome.
Four patients with sleep apnea syndrome were seen at the Vancouver General Hospital within the last three years and are discussed in this paper. The history of recognition of the syndrome, the types of apnea, and method of evaluation using polysomnographic techniques are reviewed, and methods of treatment are outlined.


A Materials Science Perspective of Midstream Challenges in the Utilization of Heavy Crude Oil.
An increasing global population and a sharply upward trajectory of per capita energy consumption continue to drive the demand for fossil fuels, which remain integral to energy grids and the global transportation infrastructure. The oil and gas industry is increasingly reliant on unconventional deposits such as heavy crude oil and bitumen for reasons of accessibility, scale, and geopolitics. Unconventional deposits such as the Canadian Oil Sands in Northern Alberta contain more than one-third of the world's viscous oil reserves and are vital linchpins to meet the energy needs of rapidly industrializing populations. Heavy oil is typically recovered from subsurface deposits using thermal recovery approaches such as steam-assisted gravity drainage (SAGD). In this perspective article, we discuss several aspects of materials science challenges in the utilization of heavy crude oil with an emphasis on the needs of the Canadian Oil Sands. In particular, we discuss surface modification and materials' design approaches essential to operations under extreme environments of high temperatures and pressures and the presence of corrosive species. The demanding conditions for materials and surfaces are directly traceable to the high viscosity, low surface tension, and substantial sulfur content of heavy crude oil, which necessitates extensive energy-intensive thermal processes, warrants dilution/emulsification to ease the flow of rheologically challenging fluids, and engenders the need to protect corrodible components. Geopolitical reasons have further led to a considerable geographic separation between extraction sites and advanced refineries capable of processing heavy oils to a diverse slate of products, thus necessitating a massive midstream infrastructure for transportation of these rheologically challenging fluids. Innovations in fluid handling, bitumen processing, and midstream transportation are critical to the economic viability of heavy oil. Here, we discuss foundational principles, recent technological advancements, and unmet needs emphasizing candidate solutions for thermal insulation, membrane-assisted separations, corrosion protection, and midstream bitumen transportation. This perspective seeks to highlight illustrative materials' technology developments spanning the range from nanocomposite coatings and cement sheaths for thermal insulation to the utilization of orthogonal wettability to engender separation of water-oil emulsions stabilized by endogenous surfactants extracted during SAGD, size-exclusion membranes for fractionation of bitumen, omniphobic coatings for drag reduction in pipelines and to ease oil handling in containers, solid prills obtained from partial bitumen solidification to enable solid-state transport with reduced risk of damage from spills, and nanocomposite coatings incorporating multiple modes of corrosion inhibition. Future outlooks for onsite partial upgradation are also described, which could potentially bypass the use of refineries for some fractions, enable access to a broader cross-section of refineries, and enable a new distributed chemical manufacturing paradigm.


Protein folding dynamics in the cell.
Protein folding is a remarkably fast unimolecular reaction, spanning microseconds to hours at room temperature. Thus, free energy differences and activation barriers on the free energy landscape of proteins are rather small. This opens up the possibility of living cells modulating their protein's landscapes, providing cells another way to control the function of their proteomes after transcriptional control, translational control, and post-translational modification. In this Feature Article, we discuss advances in physicochemical studies of protein stability and folding inside living cells. We focus in particular on our studies using fast relaxation imaging (FREI). Although the effect of the cell on protein free energy landscapes is only a few kT, the strong cooperativity of many folding and binding processes allows small modulation of the energy and entropy to produce a large population modulation. Lastly, we discuss some biomolecular processes that are particularly likely to be affected by in-cell modulation of the proteome, and thus of interest for quantitative physical chemistry studies.


[Dynamics of main characteristics of activities of forensic biological departments of forensic medical bureaus of the Russian Federation for the period from 1980 till 2008].
Voluminous materials characterizing activities of forensic biological units of forensic medical bureaus of the Russian Federation for the period from 1980 till 2008 have been collected, summarized, and systematized. The study is the first attempt to analyse the entire scope of work performed by forensic biologists during a large period of time and to estimate the proportion of its constituent components. It revealed long-term dynamics (increase and decrease) of the number of forensic biological studies.


Initial and delayed stress phase imaging in a single-injection double-acquisition SPECT. The potential value of early 99mTc-MIBI redistribution in assessment of myocardial perfusion reversibility in patients with coronary artery disease.
Some studies reported that 99mTc-MIBI may redistribute in ischaemic myocardium and this phenomenon may have potential role for better assessment of viability by delayed 99mTc-MIBI imaging. Some studies also suggested that infusion of low dose dobutamine during delayed imaging may enhance the value of 99mTc-MIBI imaging for evaluation of viability. The aim of this study is to determine whether the observed changes of perfusion defects on delayed images are caused by early radiotracer redistribution or as a result of reversal partial volume effect secondary to inotropic stimulation. 89 patients with angiographically proven coronary artery disease (CAD) were enrolled in this randomized clinical trial study. In all cases, gated-SPECT images were obtained 60 minutes after stress with dipyridamole injection. Subsequently the patients were randomly allocated in two groups and the second imaging was performed at 120th minute during low dose dobutamine (dobutamine group; 45 cases) or placebo infusion (placebo group; 44 cases). Difference between summed stress score of the first (SSS1) and second (SSS2) stress images (DeltaSSS) was considered as a marker of reversibility in single-injection double-acquisition (SIDA) protocol. Also summed difference score (SDS) was recorded as a marker of reversibility in standard stress/rest, double-injection double-acquisition (DIDA) protocol. DeltaSSS of the two studied groups were compared. Also the correlation and agreement between DeltaSSS and SDS were analyzed. A significant difference was found between SSS1 (median 15, range 0-48) and SSS2 (median 11, range 0-42) in total patients (p < 0.0001). A significant correlation was noted between DeltaSSS and SDS in dobutamine group (r = 0.58, p = 0.002) as well as in placebo group (r = 0.57, p < 0.0001). Considering DIDA protocol as a standard reference method, the influence of dobutamine infusion was not shown to be significantly different from the placebo effect on the magnitude of fixed or reversible perfusion defects in SIDA protocol. The changes in the magnitude of the perfusion defects may occur in the first hours of 99mTc-MIBI injection in the stress phase imaging. These changes correlate well and are in agreement with perfusion improvement on the rest images. This phenomenon may be independent of improvement in myocardial function, in more delayed imaging or following inotropic augmentation, and thus is likely due to 99mTc-MIBI redistribution. This may open new technical and clinical aspects and potentials for 99mTc-MIBI imaging.


Sciatic nerve excursion during a modified passive straight leg raise test in asymptomatic participants and participants with spinally referred leg pain.
Minimal data exists on in-vivo sciatic nerve motion during straight leg raise (SLR), particularly in symptomatic participants. Such data could help clinicians to better understand nerve mechanic changes following nerve dysfunction. Cross-sectional, controlled laboratory study. To investigate whether individuals with spinally referred leg pain have different nerve excursion patterns compared to healthy participants. The sciatic nerve was scanned using ultrasound imaging in the posterior thigh in asymptomatic participants, and individuals with spinally referred leg pain sub-grouped into somatic pain, radicular pain or radiculopathy. Nerve excursion was measured in transverse and longitudinal planes during a side-lying modified SLR. The ultrasound data was analysed off-line using cross correlation software. Longitudinal plane data was collected from 16 asymptomatic and 60 symptomatic participants and transverse plane data from 16 asymptomatic and 56 symptomatic participants. There was no significant difference in longitudinal nerve excursion between the 4 groups. The direction of transverse plane motion altered between groups. These varied movements may be related to protective muscle activation between the groups, although this is speculative at present. Longitudinal sciatic nerve excursion at the posterior thigh during a modified SLR is not different between asymptomatic participants and those with spinally referred leg pain. Transverse plane movement appears to be more varied. This may suggest that in individuals with nerve root pain, there is no restriction in nerve excursion. However, as it was not possible to measure excursion at the nerve root, more research is needed to confirm these findings.


The role of the CSF-1 receptor gene (C-fms) in cell transformation.
The macrophage colony stimulating factor, CSF-1 (M-CSF) exerts its pleiotropic effects on hematopoietic cells of the mononuclear phagocyte series by binding to a single class of high affinity receptors encoded by the c-fms proto-oncogene. Binding of CSF-1 to its receptor activates an intrinsic tyrosine kinase activity, resulting in autophosphorylation of the receptor on tyrosine, rapid receptor down modulation, and phosphorylation of as yet unidentified physiologic substrates that initiate a mitogenic response. Transduction of a human CSF-1 receptor cDNA into mouse fibroblasts enables them to proliferate in response to human recombinant CSF-1, suggesting that the receptor gene contains all the information necessary to elicit a mitogenic response, even in cells which do not normally respond to the growth factor. The v-fms oncogene product has undergone genetic alterations which constitutively activate the receptor kinase in the absence of CSF 1. Insertion of the v-fms gene into macrophage or immature myeloid cell lines abrogates their dependence on hematopoietic growth factors and renders them tumorigenic in nude mice. Reconstitution of lethally irradiated mice with bone marrow stem cells containing the v-fms oncogene also induces clonal proliferation and, ultimately, frank malignancies of multiple hematopoietic lineages. Thus, constitutive activation of the CSF-1 receptor gene, either by mutation or gene rearrangement, might be expected to contribute to leukemia.


Microsurgical clipping of true posterior communicating artery aneurysms.
"True" posterior communicating artery (PCOM) aneurysms are rare variants in which the aneurysm arises solely from the PCOM rather than the junction of the internal carotid artery and the PCOM. It is critical to note that for true PCOM aneurysms, the neck arises distal to the origin of the PCOM and therefore lies in what is traditionally an intra-operative blind spot. The PCOM must be followed posteriorly to visualise the aneurysm neck for microsurgical clipping. A thorough pre-operative understanding of this unique anatomy is essential in minimising morbidity associated with microsurgical clipping of this aneurysm configuration.


ECHO Care: Providing Multidisciplinary Specialty Expertise to Support the Care of Complex Patients.
Programs for high-need, high-cost (HNHC) patients can improve care and reduce costs. However, it may be challenging to implement these programs in rural and underserved areas, in part due to limited access to specialty consultation. Evaluate the feasibility of using the Extension for Community Health Outcomes (ECHO) model to provide specialist input to outpatient intensivist teams (OITs) dedicated to caring for HNHC patients. Weekly group videoconferencing sessions that connect multidisciplinary specialists with OITs. Six OITs across New Mexico, typically consisting of a nurse practitioner or physician assistant, a registered nurse, a counselor or social worker, and at least one community health worker. OITs and specialists participated in weekly teleECHO sessions focused on providing the OITs with case-based mentoring and support. OITs and specialists discussed 427 highly complex patient cases, many of which had social or behavioral health components to address. In 70% of presented cases, the teams changed their care plan for the patient, and 87% reported that they applied what they learned in hearing case presentations to other HNHC patients. Pairing the ECHO model with intensive outpatient care is a feasible strategy to support OITs to provide high-quality care for HNHC patients.