GIS walking maps to promote physical activity in low-income public housing communities: a qualitative examination.
Walking is the most commonly reported leisure-time activity. Members of racial/ethnic minority groups and people of low socioeconomic status disproportionately live in urban environments that are perceived to be unsafe, thereby reducing opportunities for engaging in walking. We examined the use of walking maps for increasing physical activity (PA) among low-income residents of public housing sites in Boston, Massachusetts. PA facilities, local businesses, and destinations in a walkable half-mile radius of the housing community were identified and plotted on maps by using geographic information systems technology. Four focus groups (n = 24) were conducted to learn how the walking maps were used by the residents and to understand map features that promoted use. Maps were used by participants to increase their PA, and use of the maps increased participants' awareness of community resources. Maps changed participants' perception of distances and were discussed as a means of fostering a sense of community. Use of the maps also increased participants' awareness of neighborhood incivilities. Barriers to map use were difficulty in interpreting the maps and lack of access to the maps. Walking maps that display PA opportunities and resources may be useful in increasing walking among residents of public housing sites.


Corynebacterium endometrii sp. nov., isolated from the uterus of a cow with endometritis.
A Gram-stain-positive bacterial strain, designated LMM-1653T, was isolated from a uterus swab from a Holstein Frisian dairy cow in the frame of a clinical sampling trial. The isolated strain, which showed a rod to coccoid shape, was catalase-positive and oxidase-negative. Based on 16S rRNA gene sequence similarity, its closest relatives were Corynebacterium flavescens and Corynebacterium argatoratense (96.50 % similarity each), suggesting that this isolate represents a novel species. Strain LMM-1653T had a quinone system consisting mainly of menaquinones MK-8(H2) and MK-9(H2). The polar lipid profile showed presence of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol-mannoside as well as one unidentified glycolipid and one unidentified aminoglycolipid. Moderate to minor amounts of three unidentified glycolipids, β-gentiobiosyl diacylglycerol, one unidentified aminoglycolipid and three unidentified lipids without a functional group were also found. The cell wall contained meso-diaminopimelic acid and the strain also contained corynemycolic acids. The fatty acid profile was predominantly composed of straight-chain, saturated and mono-unsaturated fatty acids, dominated by C18 : 1ω9c and C16 : 0. Since this isolate differs from the nearest related established Corynebacterium species in its genetic and phenotypic traits, a novel species named Corynebacterium endometrii LMM-1653T (=LMG-31164T=CCM 8952T) of the genus Corynebacterium is proposed.


An exploratory study of health behaviors and the risks for triple H (hypertension, hyperlipidemia, and hyperglycemia) in young adults with disabilities between 20 and 39 years of age.
Metabolic syndrome is highly prevalent and has important implications for the health care sector. However, information on the implications of metabolic syndrome for people with disabilities is limited. The purpose of this study was to explore the relationship between health behaviors and the risk for triple H (hypertension, hyperlipidemia, and hyperglycemia) in young adults with disabilities. The present study analyzed the annual health examination charts of 705 young adults with disabilities between ages 20 and 39 in Taiwan. Results found that the prevalence of hyperglycemia, hyperlipidemia, and hypertension in adults with disabilities was 5%, 15% and 17.7%, respectively. These prevalence figures were higher than those for the general population of the same age group in Taiwan. Multivariate logistic regression analyses revealed that almost none of the health behaviors were significantly correlated with the occurrence of triple H disorders among young adults with disabilities. Only one factor, BMI, independently predicted the occurrence of triple H disorders. We suggest that future studies should scrutinize the effects of health behaviors on triple-H disorders in people with disabilities to initiate personalize health promotion programs for this group.


Implementation and Evaluation of a Smartphone Application for the Perioperative Care of Neurosurgery Patients at an Academic Medical Center: Implications for Patient Satisfaction, Surgery Cancelations, and Readmissions.
Smartphone applications (apps) in the health care arena are being increasingly developed with the aim of benefiting both patients and their physicians. The delivery of adequate instructions both before and after a procedure or surgery is of paramount importance in ensuring the best possible outcome for patients. To demonstrate that app-based instructions with built-in reminders may improve patient understanding and compliance and contribute to reducing the number of surgery cancellations and postoperative complications and readmissions. We prospectively accrued 56 patients undergoing routine neurosurgery procedures who subsequently downloaded the app. The median age was 54 (range 27-79). Patients were followed for successful registration and use of the app, compliance with reading instructions before and after surgery, and sending pain scores and/or wound images. The number of surgeries cancelled, postoperative complications, 30-d readmissions, and phone calls for surgery-related questions were examined. Fifty-four of the 56 patients successfully registered, downloaded, and used the app and read and complied with instructions both before and after surgery. There were no cancelled surgeries. There was 1 postoperative complication. There were no readmissions. Eight of the 54 patients (14.8%) called the office on a single occasion for a surgery related question. We demonstrate the utility of a smartphone application in the perioperative neurosurgical care setting with regard to patient compliance and satisfaction as well as surgery cancellations and readmissions. Further study of a larger number of patients with a control group is warranted.


Treatment plans optimization for contrast-enhanced synchrotron stereotactic radiotherapy.
Synchrotron stereotactic radiotherapy (SSRT) is a treatment that involves the targeting of high-Z elements into tumors followed by stereotactic irradiation with monochromatic x-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, as well as the secondary particles generated at a higher yield by the medium energy x-rays on the high-Z atoms (characteristic x-rays, photoelectrons, and Auger electrons), produces a localized dose enhancement in the tumor. Iodine-enhanced SSRT with systemic injections of iodinated contrast agents has been successfully developed in the past six years in the team, and is currently being transferred to clinical trials. The purpose of this work is to study the impact on the SSRT treatment of the contrast agent type, the beam quality, the irradiation geometry, and the beam weighting for defining an optimized SSRT treatment plan. Theoretical dosimetry was performed using the MCNPX particle transport code. The simulated geometry was an idealized phantom representing a human head. A virtual target was positioned in the central part of the phantom or off-centered by 4 cm. The authors investigated the dosimetric characteristics of SSRT for various contrast agents: Iodine, gadolinium, and gold; and for different beam qualities: Monochromatic x-ray beams from a synchrotron source (30-120 keV), polychromatic x-ray beams from an x-ray tube (80, 120, and 180 kVp), and a 6 MV x-ray beam from a linear accelerator. Three irradiation geometries were studied: One arc or three noncoplanar arcs dynamic arc therapy, and an irradiation with a finite number of beams. The resulting dose enhancements, beam profiles, and histograms dose volumes were compared for iodine-enhanced SSRT. An attempt to optimize the irradiation scheme by weighing the finite x-ray beams was performed. Finally, the optimization was studied on patient specific 3D CT data after contrast agent infusion. It was demonstrated in this study that an 80 keV beam energy was a good compromise for treating human brain tumors with iodine-enhanced SSRT, resulting in a still high dose enhancement factor (about 2) and a superior bone sparing in comparison with lower energy x-rays. This beam could easily be produced at the European Synchrotron Radiation Facility medical beamline. Moreover, there was a significant diminution of dose delivered to the bone when using monochromatic x-rays rather than polychromatic x-rays from a conventional tube. The data showed that iodine SSRT exhibits a superior sparing of brain healthy tissue in comparison to high energy treatment. The beam weighting optimization significantly improved the treatment plans for off-centered tumors, when compared to nonweighted irradiations. This study demonstrated the feasibility of realistic clinical plans for low energy monochromatic x-rays contrast-enhanced radiotherapy, suitable for the first clinical trials on brain metastasis with a homogeneous iodine uptake.


Chlamydia trachomatis type III secretion: evidence for a functional apparatus during early-cycle development.
The obligate intracellular bacterium Chlamydia trachomatis occupies a parasitophorous vacuole termed an inclusion. During its intracellular developmental cycle, C. trachomatis maintains this intracellular niche, presumably by expressing a type III secretion system, which deploys a set of host cell-interactive proteins including inclusion membrane-localized proteins termed Incs. Some Incs are expressed and secreted by 2 h (early cycle) after infection, whereas the expression of type III-specific genes is not detectable until 6-12 h (mid-cycle). To resolve this paradox, we investigated the presence of a type III apparatus on elementary bodies (EBs) that might function early in infection. We demonstrate the existence of the type III secretory apparatus by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and immunoblot analyses of purified EB extracts. Immunoblots using polyclonal antibodies specific for the core apparatus component CdsJ identified this protein in both EB and reticulate body (RB) extracts. Furthermore, CdsJ-specific signals were detected by immunoblot of whole infected-culture extracts and by indirect immunofluorescence of infected monolayers at times before the detection of cdsJ-specific message. Finally, expression of IncC, expressed by 2 h after infection during C. trachomatis infections, in Yersinia pseudotuberculosis resulted in its secretion via the Yersinia type III apparatus. Based on these data, we propose a model in which type III secretion pores are present on EBs and mediate secretion of early Incs and possible additional effectors. Mid-cycle expression of type III genes would then replenish secretion apparatus on vegetative RBs and serve as a source of secretion pores for subsequently formed EBs.


Photochemical activation of drugs for the treatment of therapy-resistant cancers.
Resistance to chemotherapy, molecular targeted therapy as well as radiation therapy is a major obstacle for cancer treatment. Cancer resistance may be exerted through multiple different mechanisms which may be orchestrated as observed in multidrug resistance (MDR). Cancer resistance may be intrinsic or acquired and often leaves patients without any treatment options. Strategies for alternative treatment modalities for resistant cancer are therefore highly warranted. Photochemical internalization (PCI) is a technology for cytosolic delivery of macromolecular therapeutics based on the principles of photodynamic therapy (PDT). The present report reviews the current knowledge of PCI of therapy-resistant cancers. In summary, PCI may be able to circumvent several of the major mechanisms associated with resistance towards chemotherapeutics including increased expression of drug efflux pumps, altered intracellular drug distribution and increased ROS scavenging. Current data also suggest PCI of targeted toxins as highly effective in cancers resistant to clinically available targeted therapy such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). PCI may therefore, in general, represent a future treatment option for cancers resistant to other therapies.


Dissipation and Residues of Pyrethrins in Leaf Lettuce under Greenhouse and Open Field Conditions.
Pyrethrins are nowadays widely used for prevention and control of insects in leaf lettuce. However, there is a concern about the pesticide residue in leaf lettuce. A reliable analytical method for determination of pyrethrins (pyrethrin-and П, cinerin І and П, and jasmolin І and П) in leaf lettuce was developed by using gas chromatography-mass spectrometry (GC-MS). Recoveries of pyrethrins in leaf lettuce at three spiking levels were 99.4-104.0% with relative standard deviations of 0.9-3.1% (n = 5). Evaluation of dissipation and final residues of pyrethrins in leaf lettuce were determined at six different locations, including the open field, as well as under greenhouse conditions. The initial concentration of pyrethrins in greenhouse (0.57 mg/kg) was higher than in open field (0.25 mg/kg) and the half-life for pyrethrins disappearance in field lettuce (0.7 days) was less than that greenhouse lettuce (1.1 days). Factors such as rainfall, solar radiation, wind speed, and crop growth rate are likely to have caused these results. The final residue in leaf lettuce was far below the maximum residue limits (MRLs) (1 mg/kg established by the European Union (EU), Australia, Korea, Japan).


Effects of boron nitride nanotube content on waterborne polyurethane-acrylate composite coating materials.
Waterborne polyurethane-acrylate (WPUA) is a promising eco-friendly material for adhesives and coatings such as paints and inks on substrates including fibers, leather, paper, rubber, and wood. Recently, WPUA and its composites have been studied to overcome severe problems such as poor water resistance, mechanical properties, chemical resistance, and thermal stability. In this study, composite films consisting of WPUA and rod-type boron nitride nanotubes (BNNTs), which have excellent intrinsic properties including high mechanical strength and chemical stability, were investigated. Specifically, BNNT/WPUA composite films were synthesized by mixing aqueous solutions of BNNT and WPUA via facile mechanical agitation without any organic solvents or additives, and the optimal content of BNNTs was determined. For the 2.5 wt% BNNT/WPUA composite, the BNNTs were found to be well distributed in the WPUA matrix and this material showed the overall best performance in terms of water resistance, thermal conductivity, and corrosion resistance. Owing to these advantageous properties and their environmentally friendly nature, BNNT/WPUA composite coating materials are expected to be applicable in a wide variety of industries.


Quality assurance in changing times: proposals for reform and research in the clinical laboratory field.
The U.S. Department of Health and Human Services recently commissioned a comprehensive analysis of the effectiveness and appropriateness of federal clinical regulations. The analysis found that many federal regulations are technically obsolescent and many may be operationally unnecessary as a result of changing laboratory technology and changed federal reimbursement policies. Among changes recommended by the HHS-funded analysis are: the regulatory classification system based upon physical location of laboratories is no longer appropriate and should be replaced with a classification system reflecting laboratory functions; a single, uniform set of federal regulations should be developed that covers all civilian laboratories receiving federal reimbursement or operating in interstate commerce; a revised federal regulatory system should emphasize measures of performance such as personnel and inspection requirements; and clinical laboratory regulations should be based upon objective data to the maximum extent possible.


Mutations in the conserved glycine and serine of the MutS ABC signature motif affect nucleotide exchange, kinetics of sliding clamp release of mismatch and mismatch repair.
The MutS protein controls genomic stability by coordinating recognition and repair of DNA mismatches with ATP utilization. The nature of this coordination is unclear. This study demonstrates the importance of a highly conserved flexible loop found in Escherichia coli MutS (residues 658-670) in DNA mismatch repair. This loop is speculated to be analogous to the ABC signature motif of drug transporters based on its proximity to the ATP catalytic site in crystal structures. Our studies show that amino acid residues G666 and S668 control MutS functions subsequent to mismatch recognition by MutS, i.e., nucleotide-mediated exchange and ATP-dependent dissociation from mismatch. G666V mutation affects mismatch-provoked ADP-ATP exchange and results in slower dissociation kinetics of MutS from the mismatch while S668A mutation affects stable clamp formation and dissociation kinetics but does not affect nucleotide exchange. Both mutants harbor defects in ATP hydrolysis and cause a significant mutator phenotype in vivo. The mutator effect of S668A is indistinguishable from that of a MutS-deficient background and is similar to that seen with G658A. Neither mutations affect protein stability or cause a dominant mutator effect. Together with our studies on G658, D661 and F670 [1], this study implicates the signature motif as a primary regulator of MutS function and suggests concerted action of the individual amino acid residues within this motif in mediating communication between the Walker and mismatch recognition domains.


Extracorporeal shock wave lithotripsy today.
Even 32 years after its first introduction shockwave lithotripsy (SWL) remains a matter of discussion and controversy. Since the first SWL in 1980, millions of treatments have been performed worldwide. To this day SWL remains the least invasive of all stone treatments and is considered the treatment modality of first choice for the majority of urinary stones. Despite the massive scale on which SWL is performed in a wide range of indications, complication rate has always remained very low and usually limited to minor side effects and complications. The introduction of affordable multifunctional lithotripters has made SWL available to more and more departments of urology worldwide. Still many centers are disappointed with the treatment results and concerned about the adverse tissue effects. In this SWL proves to be the victim of its uninvasiveness and its apparent ease of practice. Urologists need proper skill and experience; however, to adequately administer shockwaves in order to improve outcome. This aspect is too often minimized and neglected. Apart from this the power of shockwaves often is underestimated by operators of shockwave machines. Basic knowledge of the physics of shockwaves could further reduce the already minimal adverse tissue effects. Good training and coaching in the administration of shockwaves would no doubt lead to a renaissance of SWL with better treatment results and minimal adverse tissue effects.


Pancreatic Paraganglioma: A Case Report.
Background: Paraganglionic neoplasms that originate in the adrenal medullas are referred to as pheochromocytomas, but if they arise from other paraganglia scattered throughout the body, they are referred to as paragangliomas. Pancreatic paragangliomas are an extremely rare entity as only 20 cases have been reported in the literature. They tend to be nonfunctional and typically occur in the fourth to fifth decade of life without a gender predilection. We describe in this study a case of a pancreatic paraganglioma and its CT appearance. Case Presentation: A 62-year-old woman undergoing presurgical evaluation for an olfactory groove meningioma resection was incidentally found to have a pancreatic mass. Multiple fine needle aspirations of the mass through endoscopic ultrasound yielded only atypical epithelial cells. The mass demonstrated avid enhancement on serial CTs with mild interval growth over a period of 5 years. No lymphadenopathy was ever found. The patient's complete blood count, complete metabolic panel, and plasma carcinoembryonic antigen levels were all within normal limits. Urine catecholamine metabolite levels were never checked as the patient demonstrated no symptoms of catecholamine excess. The patient underwent a laparoscopic distal pancreatectomy and splenectomy, and the mass was eventually diagnosed as a pancreatic paraganglioma through pathology. While the patient tolerated the surgery well, she did require a biliary sphincterotomy and placement of a pancreatic duct stent postoperatively for treatment of a pancreatic duct leak, which completely resolved. She showed no evidence of disease recurrence on multiple subsequent CTs and continues to do well. Conclusion: Pancreatic paragangliomas are usually incidentally discovered and typically demonstrate avid homogenous enhancement on contrast-enhanced CT or MR. Aggressive surgical resection is necessary to maximize the chances of disease-free survival. Pancreatic paragangliomas are similar histologically, whether benign or malignant, to paragangliomas that occur anywhere else in the body, with ∼70% in the abdomen and 30% in the chest.


Proteome-wide identification of ubiquitin interactions using UbIA-MS.
Ubiquitin-binding proteins play an important role in eukaryotes by translating differently linked polyubiquitin chains into proper cellular responses. Current knowledge about ubiquitin-binding proteins and ubiquitin linkage-selective interactions is mostly based on case-by-case studies. We have recently reported a method called ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), which enables comprehensive identification of ubiquitin interactors for all ubiquitin linkages from crude cell lysates. One major strength of UbIA-MS is the fact that ubiquitin interactors are enriched from crude cell lysates, in which proteins are present at endogenous levels, contain biologically relevant post-translational modifications (PTMs) and are assembled in native protein complexes. In addition, UbIA-MS uses chemically synthesized nonhydrolyzable diubiquitin, which mimics native diubiquitin and is inert to cleavage by endogenous deubiquitinases (DUBs). Here, we present a detailed protocol for UbIA-MS that proceeds in five stages: (i) chemical synthesis of ubiquitin precursors and click chemistry for the generation of biotinylated nonhydrolyzable diubiquitin baits, (ii) in vitro affinity purification of ubiquitin interactors, (iii) on-bead interactor digestion, (iv) liquid chromatography (LC)-MS/MS analysis and (v) data analysis to identify differentially enriched proteins. The computational analysis tools are freely available as an open-source R software package, including a graphical interface. Typically, UbIA-MS allows the identification of dozens to hundreds of ubiquitin interactors from any type of cell lysate, and can be used to study cell type or stimulus-dependent ubiquitin interactions. The nonhydrolyzable diubiquitin synthesis can be completed in 3 weeks, followed by ubiquitin interactor enrichment and identification, which can be completed within another 2 weeks.


Structural and biochemical effects of essential fatty acid deficiency on peripheral nerve.
The effect of postweaning essential fatty acid (EFA) deficiency on the peripheral nerve was studied in groups of rats. At 325 days, the characteristic biochemical changes of EFA deficiency were present in isolated peripheral myelin, although to a lesser degree than reported in non-neural tissues. There was no significant difference between control and deficient groups in number or size distributions of myelinated fibers (MFs) in muscle and sensory nerves, in the incidence of teased fiber abnormalities, in rates of axonal transport of dopamine-beta-hydroxylase and acetylcholinesterase, or in conduction velocity and compound action potentials of peripheral nerve in vivo or in vitro. Four weeks after a standard sciatic crush injury, the median MF diameter in regenerated peroneal nerves was significantly smaller in EFA-deficient rats than in control rats, but this difference was no longer significant at 18 weeks. At 18 weeks, EFA-deficient and control regenerated nerves showed similar myelin periodicity and relationship of axonal area to number of myelin lamellae. We conclude that acquired EFA deficiency in the rat leads to biochemically abnormal peripheral myelin, but that this state is unaccompanied by clinical, physiological, or morphological evidence of neuropathy.


Over-production of the D1:2 protein makes Synechococcus cells more tolerant to photoinhibition of photosystem II.
Over-expression of the psbAIII gene encoding for the D1 protein (form II; D1:2) of the photosystem II reaction centre in the Synechococcus sp. PCC 7942 was studied using a tac promoter and the lacIQ system. Over-expression was induced with 40 microgram/ml IPTG in the growth medium for either 6 or 12 h at growth irradiance (50 mumol photons m-2 s-1). This treatment doubled the amount of psbAII/III mRNA and the D1:2 protein in membranes but decreased the amount of psbAI messages and the D1:1 protein. The total amount of both heterodimeric reaction centre proteins, D1 and D2, remained constant under growth light conditions, indicating that the number of PSII centres in the membranes was not affected, only the form of the D1 protein was changed from D1:1 to D1:2 in most centres. When the cells were photoinhibited either at 500 or 1000 mumol photons m-2 s-1, in the presence or absence of the protein synthesis inhibitor lincomycin, the D1:2 protein remained at a higher level in cells in which over-expression had been induced by IPTG. These cells were also less prone to photoinhibition of PSII. It is suggested that the tolerance of cells to photoinhibition increases when most PSII reaction centres contain the D1:2 protein at the beginning of high irradiance. This tolerance is further strengthened by maintaining psbAIII gene over-expression during the photoinhibitory treatment.


The quantum magnetism of individual manganese-12-acetate molecular magnets anchored at surfaces.
The high intrinsic spin and long spin relaxation time of manganese-12-acetate (Mn(12)) makes it an archetypical single molecular magnet. While these characteristics have been measured on bulk samples, questions remain whether the magnetic properties replicate themselves in surface supported isolated molecules, a prerequisite for any application. Here we demonstrate that electrospray ion beam deposition facilitates grafting of intact Mn(12) molecules on metal as well as ultrathin insulating surfaces enabling submolecular resolution imaging by scanning tunneling microscopy. Using scanning tunneling spectroscopy we detect spin excitations from the magnetic ground state of the molecule at an ultrathin boron nitride decoupling layer. Our results are supported by density functional theory based calculations and establish that individual Mn(12) molecules retain their intrinsic spin on a well chosen solid support.


Insulin resistance for glucose metabolism in disused soleus muscle of mice.
Our hypothesis was that insulin resistance for carbohydrate metabolism develops after a single day of muscular disuse. The immobilization of the mouse hindlimb for 24 h was used to produce muscular disuse (group c). As food intake was voluntarily decreased during the immobilization, two additional groups were used: group A was untreated and ate ad libitum, whereas group B was anesthetized with group C and was fed amounts of food similar to those eaten by group C. Because groups B and C differed only by limb immobilization, group B was used as the reference group. When insulin was present in the incubation media, the rates of 2-deoxyglucose uptake and glycogen synthesis were always significantly decreased in soleus muscles from group C (anesthetized, ate less, immobilized) as compared to group B (anesthetized, pair-fed food that group C ate). Significant interaction between the factors of insulin and muscular disuse for the rates of 2-deoxyglucose uptake and glycogen synthesis support the concept that disuse of skeletal muscle attenuates insulin action. These observations are a direct demonstration of a decrease in insulin responsiveness in skeletal muscle as the result of a single day of muscular inactivity. Because plasma insulin concentrations were significantly lower in groups B and C than in the untreated group, it seems likely that the development of insulin resistance in disused skeletal muscle is independent of plasma insulin levels.


Seizure preconditioning and epileptic tolerance: models and mechanisms.
One or more brief seizures can serve to activate endogenous protective programmes which render brain regions temporarily less susceptible to damage following an otherwise harmful episode of status epilepticus (a prolonged seizure). Epileptic tolerance has been demonstrated using a variety of seizure preconditioning paradigms, including electroconvulsive shocks and low doses of excitotoxins such as kainic acid. The cell and molecular mechanisms underlying the protection are not fully understood but proposed mediators include the transcription factor NfκB, altered ion channel expression, upregulation of growth factors and other protective genes, and suppression of pro-apoptotic Bcl-2 family proteins. Application of microarrays to profile the transcriptome of seizure-preconditioning and tolerance has provided further insights, including roles for chromatin remodeling and evidence that preconditioning generates an anti-excitotoxicity phenotype by reprogramming the transcriptional response to status epilepticus. This review summarizes the various animal models of epileptic tolerance, reviews the key effector(s) and the utility of this experimental paradigm for identifying novel targets for neuroprotection and anti-epileptogenesis.


Behavioral response of Anopheles darlingi to DDT-sprayed house walls in Amazonia.
The behavioral response of Anopheles darlingi females to spraying of house walls with DDT was studied along the Ituxi River in Amazonas, Brazil, using a house sprayed with 2 g DDT per square meter of wall surface and an untreated house serving as a control. It was found that hardly any An. darlingi females entered, exited, or took blood meals inside the treated house after it was sprayed with DDT, and that specimens marked and released inside the house tended to depart immediately. This behavior appears to constitute true repellency rather than contact irritability. Since the typical house in the vicinity of the study site had only two walls, the persistence of malaria in the local area was probably due to home construction practices.


Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients.
Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.


Neurological update: dizziness.
The diagnosis and management of vertigo remains a challenge for clinicians, including general neurology. In recent years there have been advances in the understanding of established vestibular syndromes, and the development of treatments for existing vestibular diagnoses. In this 'update' I will review how our understanding of previously "unexplained" dizziness in the elderly is changing, explore novel insights into the pathophysiology of vestibular migraine, and its relationship to the newly coined term 'persistent postural perceptual dizziness', and finally discuss how a simple bedside oculomotor assessment may help identify vestibular presentations of stroke.


Efficacy and safety of water-exchange enteroscopy compared to carbon dioxide insufflation during enteroscopy.
carbon dioxide (CO2) insufflation during enteroscopy reduces procedure time and subsequent symptoms and increases the insertion depth compared with room air. In colonoscopy, the water-exchange (WE) technique is associated with less pain compared with CO2 insufflation. The WE technique is not well studied in enteroscopy. The aim of this study was to compare the efficacy and safety of enteroscopy with WE and CO2. a prospective, comparative and observational study was performed of double balloon enteroscopies (DBE) that were randomized in two groups. The first group used WE while the second group used CO2 insufflation. The data collected was evaluated via univariate analysis and multiple logistic regression (variables with p ≤ 0.10 according to the univariate analysis). forty-six DBE were included; 23 in each arm. The median age of cases was 63.5 years and 37% were female. There were no statistical differences between the groups with regard to the access route, findings, therapy and complications. Four patients (20%) in the CO2 group had adverse events (abdominal distension and pain) and one in the WE group (nausea), which was not statistically significant. The median insertion depth was greater in the CO2 group; 260 cm vs 160 cm (p = 0.048). Multiple logistic regression showed a statistically significant difference in the insertion depth using CO2 insufflation (OR 1.009, 1.001-1.017; p = 0.034). DBE with a CO2 insufflation technique and WE are safe with a greater insertion depth with CO2.


Optical imaging of hemoglobin oxygen saturation using a small number of spectral images for endoscopic application.
Tissue hypoxia is associated with tumor and inflammatory diseases, and detection of hypoxia is potentially useful for their detailed diagnosis. An endoscope system that can optically observe hemoglobin oxygen saturation (StO2) would enable minimally invasive, real-time detection of lesion hypoxia in vivo. Currently, point measurement of tissue StO2 via endoscopy is possible using the commercial fiber-optic oximeter T-Stat, which is based on visible light spectroscopy at many wavelengths. For clinical use, however, imaging of StO2 is desirable to assess the distribution of tissue oxygenation around a lesion. Here, we describe our StO2 imaging technique based on a small number of wavelength ranges in the visible range. By assuming a homogeneous tissue, we demonstrated that tissue StO2 can be obtained independently from the scattering property and blood concentration of tissue using four spectral bands. We developed a prototype endoscope system and used it to observe tissue-simulating phantoms. The StO2 (%) values obtained using our technique agreed with those from the T-Stat within 10%. We also showed that tissue StO2 can be derived using three spectral band if the scattering property is fixed at preliminarily measured values.


[Kinetics of the reaction between scorpion toxin and the sodium channels of nodes of Ranvier].
The kinetics of the scorpion Buthus eupeus venom toxin binding to sodium channels at holding potential -120 mV and subsequent dissociation of the toxin-channel complex with the membrane potential shifts to -60 divided by +120 mV were studied under voltage clamp conditions in the Ranvier node membrane. The dissociation rate is shown to increase exponentially when shifting the membrane potential towards more positive values, with an e-fold increase for each 32.3 mV. The results are consistent with the suggestion that the dissociation of the toxin-channel complex is due to a difference in electric energy between normal and toxin-modified inactivated sodium channels.


Supramolecular ordering of DNA in the cholesteric liquid crystalline phase: an ultrastructural study.
Aqueous solutions of 146-base pair DNA fragments form a cholesteric liquid crystalline phase in the range of about 160-290 mg/ml. We present a structural analysis of this phase by comparing the data obtained from polarizing and electron microscopy. This phase shows multiple aspects or "textures" which are presented and interpreted. They mainly depend on the orientation of the structure relative to the observation plane and on the nature, distribution, and amount of defects present in the phase. These defects are then analyzed with the two methods, and the molecular orientations can be defined precisely in their core. The biological interest of such structural analyses is discussed in relation with the understanding of chromatin structure and function.


Making sense of it all: Ethical reflections on the conditions surrounding the first genome-edited babies.
In November 2018 the birth of the first genome-edited human beings was announced by Chinese scientist, He Jiankui. The ensuing ethical controversy, institutional investigations and legal proceedings led to the revision of standards, rules and procedures at many levels. Arguably, however, these developments have not fundamentally changed the conditions or the culture that nourished He Jiankui's vaulting ambition in the first place and enabled it to find expression. In this paper we explore the clinical, regulatory and societal circumstances of the 'gene-edited baby' case, the political, cultural and economic conditions that created a radical and dangerous climate for biotechnology innovation, and the responsibilities of the international research community, many of whose members were apprised of Dr He's intentions. The aim is not to heap anathemas on the heads of implicated individuals but to draw attention to the need for different communities (researchers, authorities and domestic publics) to play a part actively in the governance of biomedical innovation and for research to be bridled by human values.


Climate Shapes the Geographic Distribution and Introgressive Spread of Color Ornamentation in Common Wall Lizards.
AbstractClimate can exert an effect on the strength of sexual selection, but empirical evidence is limited. Here, we tested whether climate predicts the geographic distribution and introgressive spread of sexually selected male color ornamentation across 114 populations of the common wall lizard, Podarcis muralis. Coloration was highly structured across the landscape and did not reflect genetic differentiation. Instead, color ornamentation was consistently exaggerated in hot and dry environments, suggesting that climate-driven selection maintains geographic variation in spite of gene flow. Introgression of color ornamentation into a distantly related lineage appears to be ongoing and was particularly pronounced in warm climates with wet winters and dry summers. Combined, these results suggest that sexual ornamentation is consistently favored in climates that allow a prolonged reproductive season and high and reliable opportunities for lizard activity. This pattern corroborates theoretical predictions that such climatic conditions reduce the temporal clustering of receptive females and increase male-male competition, resulting in strong sexual selection. In summary, we provide compelling evidence for the importance of climate for the evolution of color ornamentation, and we demonstrate that geographic variation in the strength of sexual selection influences introgression of this phenotype.


MHC isoform composition and Ca(2+)- or Sr(2+)-activation properties of rat skeletal muscle fibers.
Chemically skinned single fibers from adult rat skeletal muscles were used to test the hypothesis that, in mammalian muscle fibers, myosin heavy chain (MHC) isoform expression and Ca(2+)- or Sr(2+)-activation characteristics are only partly correlated. The fibers were first activated in Ca(2+)- or Sr(2+)-buffered solutions under near-physiological conditions, and then their MHC isoform composition was determined electrophoretically. Fibers expressing only the MHC I isoform could be appropriately identified on the basis of either the Ca(2+)- or Sr(2+)-activation characteristics or the MHC isoform composition. Fibers expressing one or a combination of fast MHC isoforms displayed no significant differences in their Ca(2+)- or Sr(2+)-activation properties; therefore, their MHC isoform composition could not be predicted from their Ca(2+)- or Sr(2+)-activation characteristics. A large proportion of fibers expressing both fast- and slow-twitch MHC isoforms displayed Ca(2+)- or Sr(2+)-activation properties that were not consistent with their MHC isoform composition; thus both fiber-typing methods were needed to fully characterize such fibers. These data show that, in rat skeletal muscles, the extent of correlation between MHC isoform expression and Ca(2+)- or Sr(2+)-activation characteristics is fiber-type dependent.


Outcomes of endovascular occlusion and stenting in the treatment of carotid blowout.
Carotid blowout is a life threatening complication of invasive head and neck cancers and their treatments. This is commonly treated with endovascular embolization and carotid stenting. Using the Nationwide Inpatient Sample, we report the immediate clinical results of patients receiving embolization and/or stenting for treatment of carotid blowout associated with head and neck cancer. Using the Nationwide Inpatient Sample from the period 2003-2011, we defined carotid blowout patients as those with head and neck malignancies receiving carotid stenting and/or endovascular embolization without open surgery. Outcomes studied included mortality, acute ischemic stroke, hemiplegia/paresis, and other post-operative neurologic complications. Outcomes for the endovascular embolization and carotid stenting group were compared. A total of 1218 patients underwent endovascular treatment for carotid blowout. Of these, 1080 patients (88.6%) underwent embolization procedures and 138 patients (11.4%) underwent carotid stenting. The mortality rate of endovascular embolization patients was similar to that of carotid stenting patients (8.0%, 95% confidence interval (CI) = 6.5%-9.7% versus 10.2%, 95% CI=6.0%-16.4%, p = 0.36). Stroke rate was similar between embolization patients and stenting patients (2.3%, 95% CI=1.6%-3.4% vs. 3.4%, 95% CI=1.3%-8.4%, p = 0.43). Hemiplegia rates were significantly higher rate in stenting patients compared with endovascular occlusion patients (3.8%, 95% CI=1.3%-8.4% vs. 1.4%, 95% CI=1.4%-2.4%, p = 0.05). The rate of post-operative neurologic complications was higher in stenting patients compared with embolization patients (6.5%, 95% CI=3.3%-12.1% vs. 1.4%, 95% CI=0.9%-2.4%, p < 0.0001). Given the natural history of carotid blowout, carotid stenting and endovascular embolization are acceptable means of treating this disease. Endovascular embolization remains the most common treatment among patients with head and neck cancers with lower overall rates of post-operative neurologic complications, including hemiplegia/paresis and stroke.


The inhibition of steroid hormones determines the fate of IPC-366 tumor cells, highlighting the crucial role of androgen production in tumor processes.
Inflammatory mammary cancer (IMC) is a disease that affects female dogs. It is characterized by poor treatment options and no efficient targets. However, anti-androgenic and anti-estrogenic therapies could be effective because IMC has a great endocrine influence, affecting tumor progression. IPC-366 is a triple negative IMC cell line that has been postulated as a useful model to study this disease. Therefore, the aim of this study was to inhibit steroid hormones production at different points of the steroid pathway in order to determine its effect in cell viability and migration in vitro and tumor growth in vivo. For this purpose, Dutasteride (anti-5αReductase), Anastrozole (anti-aromatase) and ASP9521 (anti-17βHSD) and their combinations have been used. Results revealed that this cell line is positive to estrogen receptor β (ERβ) and androgen receptor (AR) and endocrine therapies reduce cell viability. Our results enforced the hypothesis that estrogens promote cell viability and migration in vitro due to the function of E1SO4 as an estrogen reservoir for E2 production that promotes the IMC cells proliferation. Also, an increase in androgen secretion was associated with a reduction in cell viability. Finally, in vivo assays showed large tumor reduction. Hormone assays determined that high estrogen levels and the reduction of androgen levels promote tumor growth in Balb/SCID IMC mice. In conclusion, estrogen levels reduction may be associated with a good prognosis. Also, activation of AR by increasing androgen production could result in effective therapy for IMC because their anti-proliferative effect.


Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use.
Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood. Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume). Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%; P<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second; P<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%; P<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second; P=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median [interquartile range] 3 [0, 174] mL3 versus 0 [0, 69] mL3; P=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16-1.03 SD units]; P=0.008). Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.


Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Prior studies reveal that bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) is mostly in the osteopaenic range and is associated with lifetime glucocorticoid dose. The forearm, a measure of cortical bone density, has not been evaluated. We aimed to evaluate BMD at various sites, including the forearm, and the factors associated with low BMD in CAH patients. Eighty CAH adults (47 classic, 33 nonclassic) underwent dual-energy-x-ray absorptiometry and laboratory and clinical evaluation. BMD Z-scores at the AP spine, total hip, femoral neck, forearm and whole body were examined in relation to phenotype, body mass index, current glucocorticoid dose, average 5-year glucocorticoid dose, vitamin D, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHEAS). Reduced BMD (T-score <-1 at hip, spine, or forearm) was present in 52% and was more common in classic than nonclassic patients (P = 0·005), with the greatest difference observed at the forearm (P = 0·01). Patients with classic compared to nonclassic CAH, had higher 17-hydroxyprogesterone (P = 0·005), lower DHEAS (P = 0·0002) and higher non-traumatic fracture rate (P = 0·0005). In a multivariate analysis after adjusting for age, gender, height standard deviation, phenotype and cumulative glucocorticoid exposure, higher DHEAS was independently associated with higher BMD at the spine, radius and whole body. Classic CAH patients have lower BMD than nonclassic patients, with the most affected area being the forearm. This first study of forearm BMD in CAH patients suggests that low DHEAS may be associated with weak cortical bone independent of glucocorticoid exposure.


Congenital disease SNPs target lineage specific structural elements in protein kinases.
The catalytic domain of protein kinases harbors a large number of disease-causing single nucleotide polymorphisms (SNPs) and common or neutral SNPs that are not known or hypothesized to be associated with any disease. Distinguishing these two types of polymorphisms is critical in accurately predicting the causative role of SNPs in both candidate gene and genome-wide association studies. In this study, we have analyzed the structural location of common and disease-associated SNPs in the catalytic domain of protein kinases and find that, although common SNPs are randomly distributed within the catalytic core, known disease SNPs consistently map to regulatory and substrate binding regions. In particular, a buried side-chain network that anchors the flexible activation loop to the catalytic core is frequently mutated in disease patients. This network was recently shown to be absent in distantly related eukaryotic-like kinases, which lack an exaggerated activation loop and, presumably, are not regulated by phosphorylation.


Secretion of surfactant by rat alveolar type II cells: morphometric analysis and three-dimensional reconstruction.
Secretion of surfactant by alveolar type II cells occurs by exocytosis and is stimulated by several mechanical and hormonal mechanisms, including beta-agonists. We examined the morphological correlates of this process by electron microscopy and by three dimensional reconstructions of rat lung alveolar epithelial type II cells before and after isoproterenol stimulation. Male rats were given a dose of isoproterenol 2 hours prior to anesthesia. The lungs were fixed by intratracheal instillation and lung tissue was processed by methods designed to enhance the retention of saturated phospholipids. The type II cells were evaluated by transmission and scanning electron microscopy and morphometry of the type II cells was performed. Three dimensional reconstruction of secretory events at the alveolar air border was also done. We observed a dose dependent increase in elliptical cell-surface pores averaging 0.2 X 0.4 micron in size on the alveolar luminal side of type II cells. Most often these pores were surrounded by an elevated area lacking microvilli and overlying an area of granular cytoplasm. The pores observed were about half the average diameter of the lamellar bodies and a deformation of that spherical secretory organelle was seen frequently. We conclude these cell-surface pores represent the structures through which surfactant is released by type II cells. During the secretion of lamellar bodies, deformation may be imposed at the restriction of the surface pores. This deformation could be important in the transformation of the lamellar material from an intracellular storage site to its active role on the alveolar surface.


Genetic polymorphism in ERCC5 and breast cancer risk.
ERCC5 plays crucial role in excision repair DNA damage induced by UV in NER pathway. Single neuleotide polymorphism in ERCC5 were responsible for different cancers. Therefore, current study evaluated the relationship between ERCC5 (rs1047768 T>C) polymorphism and the risk of breast cancer in Pakistani population. The rs1047768 polymorphism was screened among 175 females including one hundred breast cancer cases and age matched seventy-five healthy controls. Genotyping was performed with Tetra amplification-refractory mutation system (ARMS) PCR and products were observed through electrophoresis. Multivariate logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (95% CI) investigating relationship between genotypes, clinical parameters and risk of breast cancer. Statistical analysis exhibited significant relationship between the TC genotype (OR=7.2, 95% CI=1.5-34.3) and increased breast cancer risk. Moreover, family history (OR=6.25; 95% CI= 2.61-15.00) and late menopause (OR=2.41; 95% CI=1.20-4.83) were found to be breast cancer associated risk factors. In conclusion, ERCC5 (rs1047768 T>C) polymorphism may contribute towards increased risk of breast cancer in Pakistani population.


Effects of dietary threonine supplementation on intestinal barrier function and gut microbiota of laying hens.
The effects of supplemental dietary threonine (Thr) on laying performance, expression of intestinal mucin 2 (MUC2) and secretory IgA (sIgA), and intestinal microbiota of laying hens fed a low CP diet were investigated. A total of 240 Lohmann Brown laying hens, 28 wk of age, was allocated to 3 dietary treatments, each of which included 5 replicates of 16 hens. Hens were fed a control diet (16% CP), a low CP diet (14% CP), or a low CP diet supplemented with 0.3% L-Thr for 12 weeks. Chemical analyses of the diets for Thr are 0.49, 0.45, and 0.69%, respectively. Lowering dietary CP impaired egg production and egg mass of laying hens. Dietary Thr supplementation to the low CP diet increased (P < 0.05) egg production and egg mass. In addition, ileal sIgA contents and MUC2 and sIgA mRNA expression were increased (P < 0.05) by dietary Thr addition. Dietary CP reduction reduced (P < 0.05) intestinal bacterial diversity, whereas dietary Thr supplementation to the low CP diet recovered the bacteria diversity and significantly increased the abundance of potential beneficial bacteria. In conclusion, dietary Thr supplementation to a low CP diet could affect intestinal health and hence productivity via regulating intestinal mucin and sIgA expression, and microbial population of laying hens.


Does end-tidal carbon dioxide monitoring detect respiratory events prior to current sedation monitoring practices?
The value of ventilation monitoring with end-tidal carbon dioxide (ETCO2) to anticipate acute respiratory events during emergency department (ED) procedural sedation and analgesia (PSA) is unclear. The authors sought to determine if ETCO2 monitoring would reveal findings indicating an acute respiratory event earlier than indicated by current monitoring practices. The study included a prospective convenience sample of ED patients undergoing PSA. Clinicians performed ED PSA procedures with generally accepted patient monitoring, including oxygen saturation (SpO2), and clinical ventilation assessment. A study investigator recorded ETCO2 levels and respiratory events during each PSA procedure, with clinical providers blinded to ETCO(2) levels. Acute respiratory events were defined as SpO2 < or =92%, increases in the amount of supplemental oxygen provided, use of bag-valve mask or oral/nasal airway for ventilatory assistance, repositioning or airway alignment maneuvers, and use of physical or verbal means to stimulate patients with depressed ventilation or apnea, and reversal agent administration. Enrollment was stopped after independent review of 20 acute respiratory events in 60 patient sedation encounters (33%). Abnormal ETCO2 findings were documented in 36 patients (60%). Seventeen patients (85%) with acute respiratory events demonstrated ETCO2 findings indicative of hypoventilation or apnea during PSA. Abnormal ETCO2 findings were documented before changes in SpO2 or clinically observed hypoventilation in 14 patients (70%) with acute respiratory events. Abnormal ETCO2 findings were observed with many acute respiratory events. A majority of patients with acute respiratory events had ETCO2 abnormalities that occurred before oxygen desaturation or observed hypoventilation.


Renal failure and posterior reversible encephalopathy syndrome in patients with thrombotic thrombocytopenic purpura.
Little is known of the nature of the neurologic manifestations in thrombotic thrombocytopenic purpura (TTP). We have recently reported posterior reversible encephalopathy syndrome (PRES) as the predominant brain abnormality in patients with TTP. Posterior reversible encephalopathy syndrome has been associated with a variety of medications and pathologic states including increased arterial blood pressure and renal failure. The factors that predispose patients with TTP to PRES are not known. To ascertain whether the presence and degree of hypertension and typical laboratory abnormalities seen in hospitalized patients with TTP are predictors of PRES. Design, Setting, and Patients We performed a retrospective analysis of brain imaging in 46 hospitalized patients with acute TTP seen at St Mary's and Rochester Methodist hospitals in Rochester, Minnesota, from January 1997 to June 2007. Head computed tomographic scans and brain magnetic resonance images were evaluated independently by 2 investigators. We then performed statistical analysis to determine whether the presence of PRES was associated with the presence of hypertension or abnormal laboratory data, including renal function. Forty-seven incidences of patients having TTP and neuroimaging were evaluated over a 10-year period. Thirty-three patients (70%) had brain magnetic resonance imaging performed. Of the patients who had acute abnormalities on brain magnetic resonance imaging, 13 (48%) were found to have PRES. Degree of hypertension was not associated with PRES on brain magnetic resonance imaging (P = .55). There was no association between hematocrit or platelet nadir, maximum blood urea nitrogen, D dimer, fibrinogen, lactate dehydrogenase, or total bilirubin levels and occurrence of PRES. The only variable highly associated with PRES on neuroimaging was the glomerular filtration rate (P = .02). The occurrence of PRES in patients with acute TTP is associated with worse renal function.


Coal cleaning residues and Fe-minerals implications.
In the present investigation, a study was undertaken to understand the origin of Fe-minerals presents in Brazilian coal mining and to understand the environmental implication and the chemical heterogeneity in the study area. Coal cleaning residue samples rich in clays, quartz, sulphides, carbonates, sulphates, etc. were sampled from Lauro Muller, Urussanga, Treviso, Siderópolis, and Criciúma cities in the Santa Catarina State and a total of 19 samples were collected and Mössbauer, XRD, SEM/EDX, and TEM analyses were conducted on the samples. The major Fe-minerals identified are represented by the major minerals chlorite, hematite, illite, and pyrite, while the minor minerals include, ankerite, chalcopyrite, goethite, hematite, jarosite, maghemite, magnetie, marcasite, melanterite, natrojarosite, oligonite, pyrrhotite, rozenite, schwertmannite, siderite, and sideronatrile. Pyrite is relatively abundant in some cases, making up to around 10% of the mineral matter in several samples. The sulphates minerals such as jarosite and others, probably represent oxidation products of pyrite, developed during exposure or storage.


Role of transcriptional and posttranscriptional regulation in expression of histone genes in Saccharomyces cerevisiae.
We analyzed the role of posttranscriptional mechanisms in the regulation of histone gene expression in Saccharomyces cerevisiae. The rapid drop in histone RNA levels associated with the inhibition of ongoing DNA replication was postulated to be due to posttranscriptional degradation of histone transcripts. However, in analyzing the sequences required for this response, we showed that the coupling of histone RNA levels to DNA replication was due mostly, if not entirely, to transcriptional regulatory mechanisms. Furthermore, deletions which removed the negative, cell cycle control sequences from the histone promoter also uncoupled histone transcription from DNA replication. We propose that the arrest of DNA synthesis prematurely activates the regulatory pathway used in the normal cell cycle to repress transcription. Although posttranscriptional regulation did not appear to play a significant role in coupling histone RNA levels to DNA replication, it did affect the levels of histone RNA in the cell cycle. Posttranscriptional regulation could apparently restore much of the periodicity of histone RNA accumulation in cells which constitutively transcribed the histone genes. Unlike transcriptional regulation, periodic posttranscriptional regulation appears to operate on a clock which is independent of events in the mitotic DNA cycle. Posttranscriptional recognition of histone RNA must require either sequences in the 3' end of the RNA or an intact three-dimensional structure since H2A- and H2B-lacZ fusion transcripts, containing only 5' histone sequences, were insensitive to posttranscriptional controls.


Emergence of evolutionarily stable communities through eco-evolutionary tunnelling.
Ecological and evolutionary dynamics of communities are inexorably intertwined. The ecological state determines the fate of newly arising mutants, and mutations that increase in frequency can reshape the ecological dynamics. Evolutionary game theory and its extensions within adaptive dynamics have been the mathematical frameworks for understanding this interplay, leading to notions such as evolutionarily stable states (ESS) in which no mutations are favoured, and evolutionary branching points near which the population diversifies. A central assumption behind these theoretical treatments has been that mutations are rare so that the ecological dynamics has time to equilibrate after every mutation. A fundamental question is whether qualitatively new phenomena can arise when mutations are frequent. Here, we describe an adaptive diversification process that robustly leads to complex ESS, despite the fact that such communities are unreachable through a step-by-step evolutionary process. Rather, the system as a whole tunnels between collective states over a short timescale. The tunnelling rate is a sharply increasing function of the rate at which mutations arise in the population. This makes the emergence of ESS communities virtually impossible in small populations, but generic in large ones. Moreover, communities emerging through this process can spatially spread as single replication units that outcompete other communities. Overall, this work provides a qualitatively new mechanism for adaptive diversification and shows that complex structures can generically evolve even when no step-by-step evolutionary path exists.


Contemporary Management of Struvite Stones Using Combined Endourologic and Medical Treatment: Predictors of Unfavorable Clinical Outcome.
Struvite stones have been associated with significant morbidity and mortality, yet there has not been a report on the medical management of struvite stones in almost 20 years. We report on the contemporary outcomes of the surgical and medical management of struvite stones in a contemporary series. A retrospective review of patients who were treated with percutaneous nephrolithotomy (PCNL) for struvite stones at Duke University Medical Center between January 2005 and September 2012 identified a total of 75 patients. Of these, 43 patients had adequate follow-up and were included in this analysis. Stone activity, defined as either stone recurrence or stone-related events, and predictors of activity were evaluated after combined surgical and medical treatment. The study included 43 patients with either pure (35%) or mixed (65%) struvite stones with a median age of 55±15 years (range 21-89 years). The stone-free rate after PCNL was 42%. Stone recurrence occurred in 23% of patients. Postoperatively, 30% of patients had a stone-related event, while 60% of residual stones remained stable with no growth after a median follow-up of 22 months (range 6-67 mos). Kidney function remained stable during follow-up. Independent predictors of stone activity included the presence of residual stones >0.4 cm(2), preoperative large stone burden (>10 cm(2)), and the presence of medical comorbidities (P<0.05). Struvite stones can be managed safely with PCNL followed by medical therapy. The majority of patients with residual fragments demonstrated no evidence of stone growth on medical therapy. With careful follow-up and medical management, kidney function can be maintained and stone morbidity can be minimized. Initial large stone burden, residual stones after surgery, and associated medical comorbidities may have deleterious effect on stone recurrence or residual stone-related events.


Effect of diabetes mellitus on the presentation and triage of patients with acute chest pain without known coronary artery disease.
Patients with diabetes and acute chest pain may be admitted to hospitals more frequently than patients without diabetes because physicians suspect atypical presentations for ischemic heart disease. This study aimed to determine whether the presentation of acute myocardial infarction and risk for major cardiac complications differs among patients without known coronary artery disease who do or do not have diabetes. Data from an emergency department of an urban teaching hospital on the medical histories, physical examinations, and electrocardiograms of 2,694 subjects with acute chest pain and without known coronary artery disease were prospectively recorded. Diabetes was present in 301 (11%) patients. Compared with patients without diabetes, patients with diabetes were more likely to be < or = 60 years old (51% versus 20%) and to have a history of hypertension (70% versus 35%) or high blood cholesterol (35% versus 19%). A discharge diagnosis of acute myocardial infarction was made in 25 diabetic (8%) and in 148 nondiabetic (6%; P = 0.16) patients. A major cardiac complication occurred in two patients with diabetes (0.7%) and in 20 patients without diabetes (0.8%; P = 1.0). Patients with and without diabetes who had atypical chest pain complaints had similar rates of myocardial infarction (3% and 4%, respectively; P = 0.6). Patients with diabetes were more likely to be hospitalized (67% versus 47%; P = 0.001) both before and after adjusting for clinical and electrocardiographic data. For patients with acute chest pain without a prior history of coronary artery disease, diabetes was not associated with a higher rate of acute myocardial infarction or complications. However, diabetes was associated with a higher rate of hospitalization in this population, suggesting that physicians have a lower threshold for admission to the hospital of patients with diabetes.


Nematic liquid crystals of bifunctional patchy spheres.
Anisotropic interactions can bring about the formation, through self-assembly, of semi-flexible chains, which in turn can give rise to nematic phases for suitable temperatures and concentrations. A minimalist model constituted of hard cylinders decorated with attractive sites has been already extensively studied numerically. Simulation data shows that a theoretical approach recently proposed is able to properly capture the physical properties of these self-assembly-driven liquid crystals. Here, we investigated a simpler model constituted of bifunctional Kern-Frenkel hard spheres which does not possess steric anisotropy but which can undergo a istropic-nematic transition as a result of their self-assembly into semi-flexible chains. For this model we compare an accurate numerical estimate of isotropic-nematic phase boundaries with theoretical predictions. The theoretical treatment, originally proposed for cylinder-like particles, has been greatly simplified and its predictions are in good agreement with numerical results. Finally, we also assess a crucial, and not obvious, hypothesis used in the theory, i.e. the ability of the Onsager trial function to properly model particle orientation in the presence of aggregation, that has not been properly checked yet.


The Function and Modification of Human Defensin 5.
The antibacterial and antiviral functions of human defensin 5 lay the foundation for its role as a core host protective component. In addition, HD5 also has the function of inhibiting tumor proliferation and immune regulation. However, everything has two sides; cytotoxic and proinflammatory properties may exist, while HD5 performs physiological functions. Accordingly, the modification and engineering of HD5 are particularly important. Therefore, this review summarizes the role of HD5 in various aspects of host defense, as well as modification of HD5 to ameliorate the biological activity, with a view to promoting the clinical use of HD5.


Luminescent carbon nanodots: emergent nanolights.
Similar to its popular older cousins the fullerene, the carbon nanotube, and graphene, the latest form of nanocarbon, the carbon nanodot, is inspiring intensive research efforts in its own right. These surface-passivated carbonaceous quantum dots, so-called C-dots, combine several favorable attributes of traditional semiconductor-based quantum dots (namely, size- and wavelength-dependent luminescence emission, resistance to photobleaching, ease of bioconjugation) without incurring the burden of intrinsic toxicity or elemental scarcity and without the need for stringent, intricate, tedious, costly, or inefficient preparation steps. C-dots can be produced inexpensively and on a large scale (frequently using a one-step pathway and potentially from biomass waste-derived sources) by many approaches, ranging from simple candle burning to in situ dehydration reactions to laser ablation methods. In this Review, we summarize recent advances in the synthesis and characterization of C-dots. We also speculate on their future and discuss potential developments for their use in energy conversion/storage, bioimaging, drug delivery, sensors, diagnostics, and composites.


Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system.
The oral protease inhibitor nirmatrelvir is of key importance for prevention of severe coronavirus disease 2019 (COVID-19). To facilitate resistance monitoring, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir in cell culture. Resistant variants harbored combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetics revealed that E166V and L50F + E166V conferred high resistance in infectious culture, replicon, and Mpro systems. While L50F, E166V, and L50F + E166V decreased replication and Mpro activity, L50F and L50F + E166V variants had high fitness in the infectious system. Naturally occurring L50F compensated for fitness cost of E166V and promoted viral escape. Molecular dynamics simulations revealed that E166V and L50F + E166V weakened nirmatrelvir-Mpro binding. Polymerase inhibitor remdesivir and monoclonal antibody bebtelovimab retained activity against nirmatrelvir-resistant variants, and combination with nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatments with efficacy against SARS-CoV-2 and emerging sarbecoviruses.


Increased Risk of Colorectal Cancer in Individuals With a History of Serrated Polyps.
Serrated polyp (SPs) are precursors to 20% to 30% of cases of colorectal tumors, but patients' long-term risk after removal of SPs is poorly understood. We investigated the risk of colorectal cancer (CRC) in individuals with a history of SPs. We performed a retrospective cohort study of Kaiser Permanente Northern California members who underwent colonoscopy from 2006 through 2016. Study participants were categorized based on the size and location of SPs. We used Cox proportional hazards modeling to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association of CRC diagnosed more than 1 year after colonoscopy, with polyp type vs no polyp after adjustment for year of colonoscopy, age, sex, race/ethnicity, and smoking history. The study included 233,393 individuals, of whom 445 developed incident CRC. At 10 years, the cumulative incidence rates of CRC for individuals with no polyp, proximal small SPs, proximal large SPs, and distal SPs were 4.7 (95% CI, 4.0-5.6), 14.8 (95% CI, 9.0-24.3), 30.2 (95% CI, 13.2-68.4), and 5.9 (95% CI, 3.6-9.5) per 1000 persons, respectively. In patients with SPs, risk of CRC was not increased until 3 years or more after the first colonoscopy (HR for small proximal SPs 2.6; 95% CI, 1.7-3.9 and HR for large proximal SPs 8.0; 95% CI, 3.6-16.1). The presence of synchronous adenomas increased the risk for CRC (HR for proximal SPs with synchronous adenomas 4.0; 95% CI, 3.0-5.5 and HR for distal SPs with synchronous adenomas 2.4; 95% CI, 1.7-3.4). In a retrospective analysis of a large cohort of individuals examined by colonoscopy, we found that risk of incident CRC increased in individuals with proximal SPs (large SPs in particular) 3 years or more after the colonoscopy. These findings support guidelines that recommend surveillance colonoscopy for individuals with SPs.


"It can save your life, that's all I know," barriers and facilitators for engagement in take-home naloxone for people receiving opioid substitution treatment in regional Australia: An explorative study.
Engagement in take-home naloxone (THN) programs by people receiving opioid substitution treatment (OST) in Australia is low despite methadone being a significant contributor to opioid overdose deaths. Our aim was to explore barriers and facilitators for OST patients to engage in THN. We used a descriptive qualitative design with thematic analysis to gain insight into naloxone uptake by people engaged in an OST program in regional Australia. Eleven participants were interviewed; eight had previously engaged with THN. Barriers to THN included limited knowledge and understanding, lack of information, and not personally experiencing an overdose. Facilitators included having a traumatic experience of overdose, knowledge and understanding of THN and overdose, empowerment in carrying naloxone, and expanding THN programs. Support for the expansion of THN programs is desired among participants, and widespread peer distribution is understood to be the key to success. This study found that prior traumatic experience of overdose facilitates acceptance of THN, and being offered THN was the most important factor in engagement. Less clear is how to engage people who lack a traumatic overdose experience.


Recurrent ischemia after thrombolysis: importance of associated clinical findings. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA [tissue-plasminogen activator] for Occluded Coronary Arteries.
We sought to assess the incidence and clinical relevance of examination data to recurrent ischemia within an international randomized trial. Ischemic symptoms commonly recur after thrombolysis for acute myocardial infarction. Patients (n = 40,848) were prospectively evaluated for recurrent angina and transient electrocardiographic (ECG) or hemodynamic changes. Five groups were developed: Group 1, patients with no signs or symptoms of recurrent ischemia; Group 2, patients with angina only; Group 3, patients with angina and ST segment changes; Group 4, patients with angina and hemodynamic abnormalities; and Group 5, patients with angina, ST segment changes and hemodynamic abnormalities. Baseline clinical and outcome variables were compared among the five groups. Group 1 comprised 32,717 patients, and Groups 2 to 5 comprised 20% of patients (4,488 in Group 2; 3,021 in Group 3; 337 in Group 4; and 285 in Group 5). Patients with recurrent ischemia were more often female, had more cardiovascular risk factors and less often received intravenous heparin. Significantly more extensive and more severe coronary disease, antianginal treatment, angioplasty and coronary bypass surgery were observed as a function of ischemic severity. The 30-day reinfarction rate was 1.6% in Group 1, 6.5% in Group 2, 21.7% in Group 3, 13.1% in Group 4 and 36.5% in Group 5 (p < 0.0001); in contrast, the 30-day mortality rate was significantly lower (p < 0.0001) in Groups 1, 2 and 3 (6.6%, 5.4% and 7.7%, respectively) than in Groups 4 and 5 (21.8% and 29.1%). Postinfarction angina greatly increases the risk of reinfarction, especially when accompanied by transient ECG changes. However, mortality is markedly increased only in the presence of concomitant hemodynamic abnormalities.


Comparison of T2 and FLAIR imaging for target delineation in high grade gliomas.
FLAIR and T2 weighted MRIs are used based on institutional preference to delineate high grade gliomas and surrounding edema for radiation treatment planning. Although these sequences have inherent physical differences there is limited data on the clinical and dosimetric impact of using either or both sequences. 40 patients with high grade gliomas consecutively treated between 2002 and 2008 of which 32 had pretreatment MRIs with T1, T2 and FLAIR available for review were selected for this study. These MRIs were fused with the treatment planning CT. Normal structures, clinical tumor volume (CTV) and planning tumor volume (PTV) were then defined on the T2 and FLAIR sequences. A Venn diagram analysis was performed for each pair of tumor volumes as well as a fractional component analysis to assess the contribution of each sequence to the union volume. For each patient the tumor volumes were compared in terms of total volume in cubic centimeters as well as anatomic location using a discordance index. The overlap of the tumor volumes with critical structures was calculated as a measure of predicted toxicity. For patients with MRI documented failures, the tumor volumes obtained using the different sequences were compared with the recurrent gross tumor volume (rGTV). The FLAIR CTVs and PTVs were significantly larger than the T2 CTVs and PTVs (p < 0.0001 and p = 0.0001 respectively). Based on the discordance index, the abnormality identified using the different sequences also differed in location. Fractional component analysis showed that the intersection of the tumor volumes as defined on both T2 and FLAIR defined the majority of the union volume contributing 63.6% to the CTV union and 82.1% to the PTV union. T2 alone uniquely identified 12.9% and 5.2% of the CTV and PTV unions respectively while FLAIR alone uniquely identified 25.7% and 12% of the CTV and PTV unions respectively. There was no difference in predicted toxicity to normal structures using T2 or FLAIR. At the time of analysis, 26 failures had occurred of which 19 patients had MRIs documenting the recurrence. The rGTV correlated best with the FLAIR CTV but the percentage overlap was not significantly different from that with T2. There was no statistical difference in the percentage overlap with the rGTV and the PTVs generated using either T2 or FLAIR. Although both T2 and FLAIR MRI sequences are used to define high grade glial neoplasm and surrounding edema, our results show that the volumes generated using these techniques are different and not interchangeable. These differences have bearing on the use of intensity modulated radiation therapy (IMRT) and highly conformal treatment as well as on future clinical trials where the bias of using one technique over the other may influence the study outcome.


Differences between computer-aided diagnosis of breast masses and that of calcifications.
To compare the performance of a computer-aided diagnosis (CAD) system for diagnosis of previously detected lesions, based on radiologist-extracted findings on masses and calcifications. A feed-forward, back-propagation artificial neural network (BP-ANN) was trained in a round-robin (leave-one-out) manner to predict biopsy outcome from mammographic findings (according to the Breast Imaging Reporting and Data System) and patient age. The BP-ANN was trained by using a large (>1,000 cases) heterogeneous data set containing masses and microcalcifications. The performances of the BP-ANN on masses and microcalcifications were compared with use of receiver operating characteristic analysis and a z test for uncorrelated samples. The BP-ANN performed significantly better on masses than microcalcifications in terms of both the area under the receiver operating characteristic curve and the partial receiver operating characteristic area index. A similar difference in performance was observed with a second model (linear discriminant analysis) and also with a second data set from a similar institution. Masses and calcifications should be considered separately when evaluating CAD systems for breast cancer diagnosis.


Microglial response to amyloid plaques in APPsw transgenic mice.
Microglial activation is central to the inflammatory response in Alzheimer's Disease (AD). A recently described mouse line, Tg(HuAPP695.K670N/M671L)2576, expressing human amyloid precursor protein with a familial AD gene mutation, age-related amyloid deposits, and memory deficits, was found to develop a significant microglial response using Griffonia simplicifolia lectin or phosphotyrosine probe to identify microglia Both Griffonia simplicifolia lectin and phosphotyrosine staining showed increased numbers of intensely labeled, often enlarged microglia clustered in and around plaques, consistent with microglial activation related to beta-amyloid formation. Using quantitative image analysis of coronal phosphotyrosine-immunostained sections, transgene-positive 10- to 16-month-old, hemizygous, hybrid Tg2576 (APPsw) animals showed significantly increased microglial density and size in plaque-forming areas of hippocampus and frontal, entorhinal, and occipital cortex. Quantitative analysis of microglia as a function of distance from the center of plaques (double labeled for A beta peptide and microglia) revealed highly significant, two- to fivefold elevations in microglial number and area within plaques compared with neighboring regions. Tg2576 beta-amyloid-plaque-forming mice should be a useful system for assessing the consequences of the microglial-mediated inflammatory response to beta-amyloid and developing anti-inflammatory therapeutic strategies for Alzheimer's disease. These results provide the first quantitative link between beta-amyloid plaque formation and microglial activation in an animal model with neuritic plaques and memory deficits.


Mechanism of abnormal septal motion in patients with right ventricular volume overload: a cross-sectional echocardiographic study.
To evaluate the mechanism of paradoxical septal motion in patients with right ventricular volume overload (RVVO), short axis cross-sectional, echocardiographic studies of the left ventricle (LV) and interventricular septum (IVS) were performed in 19 patients with paradoxical septal motion due to RVVO and in 20 normal subjects. Short axis study in normal subjects revealed the left ventricle to be a relatively circular structure during both diastole and systole. In patients with RVVO a change in LC diastolic shape was observed. This change in shape varied from a slight flattening of the LV and IVS during diastole to total reversal of the normal direction of septal curvature such that the IVS became concave toward the RV and convex toward the LV. During systole the LV and IVS returned to their normal relatively circular configuration. This change in LV shape from diastole to systole resulted in net motion of the IVS toward the right ventricle (paradoxically). This study therefore suggests that paradoxical septal motion in patients with right ventricular volume overload is a result of a change in the diastolic shape of the left ventricle.


A simple and traceless solid phase method simplifies the assembly of large peptides and the access to challenging proteins.
Chemical protein synthesis gives access to well-defined native or modified proteins that are useful for studying protein structure and function. The majority of proteins synthesized up to now have been produced using native chemical ligation (NCL) in solution. Although there are significant advantages to assembling large peptides or proteins by solid phase ligation, reports of such approaches are rare. We report a novel solid phase method for protein synthesis which relies on the chemistry of the acetoacetyl group and ketoxime ligation for the attachment of the peptide to the solid support, and on a tandem transoximation/rearrangement process for the detachment of the target protein. Importantly, we show that the combination of solid phase and solution ligation techniques facilitates the production of a challenging and biologically active protein made of 180 amino acids. We show also that the solid phase method enables the purification of complex peptide segments through a chemoselective solid phase capture/release approach.


The office management of ejaculatory disorders.
Premature ejaculation (PE), delayed ejaculation (DE), anejaculation (AE) and retrograde ejaculation (RE) are four main ejaculatory disorders (EjDs) observed in clinical practice. Despite their high prevalence, EjDs remain underdiagnosed and undertreated. Primary care physicians should incorporate the discussion of sexual health topics into routine visits to facilitate EjD diagnosis and treatment. Because the causes of EjDs are multifactorial, the management of EjDs is etiology-specific and may require a holistic approach. Dapoxetine, a selective serotonin reuptake inhibitor, is the only drug approved for on-demand treatment of lifelong and acquired PE. In clinical practice, scheduled follow-up visits, risk factor treatment, appropriate dose escalation, adequate sexual attempts, patient education, and partner involvement are critical factors responsible for optimal overall management of PE and dapoxetine treatment outcomes.


Apoptosis of human peripheral blood mononuclear cells by wild-type measles virus infection is induced by interaction of hemagglutinin protein and cellular receptor, SLAM via caspase-dependent pathway.
Although MV infection causes lymphopenia and degradation of cell-mediated immunity, the mechanisms are poorly known. MV interacts with cellular receptors which mediate virus binding and uptake and are on the surface of PBMC. In this study, apoptosis of MV-infected PBMC in vitro was analyzed. Both PBMC treated with UV-inactivated viruses and those infected with live MV underwent apoptosis. Apoptosis of wild-type MV-infected PBMC was blocked by anti-SLAM and anti-MV hemagglutinin antibodies, respectively. Furthermore, addition of soluble MV hemagglutinin recombinant protein induced apoptosis in PBMC. These data suggest that induction of apoptosis in MV-infected PBMC is triggered by interaction between hemagglutinin protein of MV and receptor, without other viral components. To further determine the mechanisms of apoptosis, caspase activity was analyzed by Western blotting. Wild-type virus Yonekawa strain-induced apoptosis was blocked by pretreatment with pan-caspase inhibitor (Z-VAD-fmk). Intriguingly, the laboratory-adapted Nagahata strain-induced apoptosis was not blocked by Z-VAD-fmk, indicating that there may be different apoptosis pathways which depend on the viral receptors, SLAM and CD46. Both extrinsic and intrinsic apoptotic pathways, including activation of caspase-3, -8 and -9, are involved in Yonekawa strain-induced apoptosis. Taken together, the findings of this study could open up a new avenue for understanding the molecular mechanisms of MV-induced PBMC apoptosis and immunosuppression.


Evaluation of synthetic vascular grafts in a mouse carotid grafting model.
Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance.


Gene conversion events contribute to the polymorphic variation of the surrogate light chain gene lambda 5/14.1.
Normally occurring and experimentally induced models of immunodeficiency indicate that B cell development and antibody production are influenced by genetic factors. It is highly likely that polymorphic variants in genes that encode receptors for growth and differentiation factors, signal transduction molecules, and components of the B cell and pre-B-cell receptor complex contribute to this genetic control. We have identified a surprisingly large number of polymorphic variants in lambda5/14.1. Together with VpreB, lambda5/14.1 forms the surrogate light chain in the pre-B-cell receptor complex. Thirteen variant alleles of lambda5/14.1 were found in 134 unrelated individuals. Nine of these variants result in changes in the amino acid sequence of this small protein. The majority of the single base pair substitutions in lambda5/14.1 could be attributed to gene conversion events in which donor sequences from the lambda5 pseudogenes, 16.1, 16.2, and Glambda1, replace the wild-type sequence in the lambda5/14.1 functional gene. These findings indicate that gene conversion events play a major role in generating diversity that could affect stability or expression of the pre-B-cell receptor complex.


Prescribing--a case for prolonged treatment.
In an earlier study it was shown that general practitioners changed some of their prescribing habits when they were given detailed analyses of their prescriptions every six months for two years and provided with opportunities to discuss the information with participating colleagues. A follow-up study of the same doctors two years later revealed that most of the effects of the intervention had disappeared, though the increase in generic prescribing persisted. It is concluded that a more sustained intervention is needed to bring about more lasting change.


Nucleotide sequence analysis of cellular flanking regions of intracisternal A-particle gene 81.
The cellular nucleotide sequences flanking the mouse intracisternal A-particle gene 81 were determined. The results indicated that they were made of many small oligonucleotide repeats both direct and indirect in orientation. These two different kinds of repeating sequences were often found to be overlap. The overall base composition of this region is relatively A + T rich. The most important feature of the sequences determined was that it consists of several repeated dinucleotide tracts containing a (CA)16 repeating cluster in the 5' end flanking region of one strand and another repeating dinucleotide cluster, (GT)16, in the 3' end flanking region of the same strand of this gene. In addition, the existence of two clusters of 9 continuous 5-bp repeat units, GCTTT, was found in the 3' end flanking region. The possible roles of such repeating sequence were discussed.


Cytochrome c oxidase assembly in primates is sensitive to small evolutionary variations in amino acid sequence.
Respiring mitochondria require many interactions between nuclear and mitochondrial genomes. Although mitochondrial DNA (mtDNA) from the gorilla and the chimpanzee are able to restore oxidative phosphorylation in a human cell, mtDNAs from more distant primate species are functionally incompatible with human nuclear genes. Using microcell-mediated chromosome and mitochondria transfer, we introduced and maintained a functional orangutan mtDNA in a human nuclear background. However, partial oxidative phosphorylation function was restored only in the presence of most orangutan chromosomes, suggesting that human oxidative phosphorylation-related nuclear-coded genes are not able to replace many orangutan ones. The respiratory capacity of these hybrids was decreased by 65%-80%, and cytochrome c oxidase (COX) activity was decreased by 85%-95%. The function of other respiratory complexes was not significantly altered. The translation of mtDNA-coded COX subunits was normal, but their steady-state levels were approximately 10% of normal ones. Nuclear-coded COX subunits were loosely associated with mitochondrial membranes, a characteristic of COX assembly-defective mutants. Our results suggest that many human nuclear-coded genes not only cannot replace the orangutan counterparts, but also exert a specific interference at the level of COX assembly. This cellular model underscores the precision of COX assembly in mammals and sheds light on the nature of nuclear-mtDNA coevolutionary constraints.


[State of human bronchopulmonary apparatus under hypobaric hypoxia and its adaptation to that condition].
The influence of hypobaric hypoxia (HH) on the bronchial tree smooth muscle state at 208 men was investigated. It was shown, that HH relaxes smooth muscle of bronchus, eliminating the phenomena of bronchismus, is activities mucocilsary clearance. The increase of the forced speed of an exhalation for 1 sec in one month after ending a course (2.5 + 0.25 l/sec against 2.1 + 0.13 l/sec) was marked. In 6 months after ending a course of HH the forced speed of an exhalation for the first second continues to grow and is statistically authentically above initial (2.6 + 0.15 l/sec). The increase of an Teffno index was marked which in 6 months of treatment comes nearer to 100% (97.5 + 6.1 against 79 + 2.6%).


Management of the axilla in early breast cancer: is it time to change tack?
The standard surgical treatment of the axilla in patients with early breast cancer is about to undergo a radical change. Although axillary dissection is an excellent procedure for both staging and local control, particularly in the clinically positive axilla, it has considerable morbidity and may understage a significant proportion of patients, because it will usually miss micrometastases that can occur in approximately 10% of 'node negative' patients. An increasing number of patients whose tumours are either non-invasive (ductal carcinoma in situ; DCIS), micro-invasive, tubular cancers or low-grade T1a tumours without lymphovascular invasion may be spared axillary surgery because the risk of axillary disease is 0-3%. Many studies, both prospective trials and large retrospective series, show that axillary radiotherapy alone provides similar local control rates to axillary dissection in patients with clinically negative axillas. Primary treatment of the axilla with radiotherapy alone, however, does not allow appropriate staging. Sentinel lymph node biopsy is being increasingly used in patients with breast cancer to provide this information. When a sentinel node is identified it is equal to or better than axillary dissection for staging the axilla and, if the node is positive, it will help select patients who should then proceed to further axillary surgery or axillary radiotherapy. Although sentinel lymph node biopsy is being rapidly adopted in many centres worldwide, the results of randomized controlled trials are needed before it can be recommended as the standard of care.


Participation patterns of children with acquired brain injury.
To describe the participation patterns of children and youth with Acquired Brain Injury (ABI) and to compare these patterns with typically-developing peers. One hundred and thirty-five children with ABI completed the Children Assessment of Participation and Enjoyment (CAPE) to measure their participation diversity and intensity in outside-of-school activities (i.e. recreational, physical, social, self-improvement and skill-based activities). Results were compared to 354 typically-developing peers. ANOVA analyses were performed while controlling for age and gender. Similar to typically-developing children, individuals with ABI proportionally participated mostly in social and recreational activities and were less likely to engage in skill-based activities. However, level of intensity and diversity within each activity type was different between the two groups. Children with ABI participated in fewer activities and were less frequently involved in all the CAPE's activity types except for intensity in social activities. These differences, characterized by small-to-medium effect sizes, were not dependent on the child's age and gender. Participation of children with ABI is restricted in comparison to their typically-developing peers even in a sample where minor injury is predominant. Future studies might address additional factors that potentially affect participation, e.g. child's preferences and family function.