Enterococcus faecium genome dynamics during long-term asymptomatic patient gut colonization.
Enterococcus faecium is a gut commensal of humans and animals. In addition, it has recently emerged as an important nosocomial pathogen through the acquisition of genetic elements that confer resistance to antibiotics and virulence. We performed a whole-genome sequencing-based study on 96 multidrug-resistant E. faecium strains that asymptomatically colonized five patients with the aim of describing the genome dynamics of this species. The patients were hospitalized on multiple occasions and isolates were collected over periods ranging from 15 months to 6.5 years. Ninety-five of the sequenced isolates belonged to E. faecium clade A1, which was previously determined to be responsible for the vast majority of clinical infections. The clade A1 strains clustered into six clonal groups of highly similar isolates, three of which consisted entirely of isolates from a single patient. We also found evidence of concurrent colonization of patients by multiple distinct lineages and transfer of strains between patients during hospitalization. We estimated the evolutionary rate of two clonal groups that each colonized single patients at 12.6 and 25.2 single-nucleotide polymorphisms (SNPs)/genome/year. A detailed analysis of the accessory genome of one of the clonal groups revealed considerable variation due to gene gain and loss events, including the chromosomal acquisition of a 37 kbp prophage and the loss of an element containing carbohydrate metabolism-related genes. We determined the presence and location of 12 different insertion sequence (IS) elements, with ISEfa5 showing a unique pattern of location in 24 of the 25 isolates, suggesting widespread ISEfa5 excision and insertion into the genome during gut colonization. Our findings show that the E. faecium genome is highly dynamic during asymptomatic colonization of the human gut. We observed considerable genomic flexibility due to frequent horizontal gene transfer and recombination, which can contribute to the generation of genetic diversity within the species and, ultimately, can contribute to its success as a nosocomial pathogen.


Ethical issues of unrelated hematopoietic stem cell transplantation in adult thalassemia patients.
Beta thalassemia major is a severe inherited form of hemolytic anemia that results from ineffective erythropoiesis. Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative therapy. Unfortunately, the subgroup of adult thalassemia patients with hepatomegaly, portal fibrosis and a history of irregular iron chelation have an elevated risk for transplantation-related mortality that is currently estimated to be about 29 percent. Thalassemia patients may be faced with a difficult choice: they can either continue conventional transfusion and iron chelation therapy or accept the high mortality risk of HSCT in the hope of obtaining complete recovery.Throughout the decision making process, every effort should be made to sustain and enhance autonomous choice. The concept of conscious consent becomes particularly important. The patient must be made fully aware of the favourable and adverse outcomes of HSCT. Although it is the physician's duty to illustrate the possibility of completely restoring health, considerable emphasis should be put on the adverse effects of the procedure. The physician also needs to decide whether the patient is eligible for HSCT according to the "rule of descending order". The patient must be given full details on self-care and fundamental lifestyle changes and be fully aware that he/she will be partly responsible for the outcome. Only if all the aforesaid conditions are satisfied can it be considered reasonable to propose unrelated HSCT as a potential cure for high risk thalassemia patients.


Mechanisms underlying partial (focal, or lesional) epilepsy.
Neuronal mechanisms underlying focal convulsions and secondary generalised convulsions have been extensively investigated at many different levels, from the biochemical, through the cellular to the intact brain. Numerous pathogenic processes relevant to epilepsy are now known. Experimental models suggest that alterations to the shape, connectivity and receptor-chemistry of individual neurons increase their excitability and the resultant increases in activity lead to changes of the local ionic environment that further causes enhanced excitability. As a consequence of the latter, neuronal firing rates increase and there is a shift from single-firing- to burst-firing-behaviours in populations of neurons and, possibly, also several changes in the way populations of neurons communicate, namely, from 'synaptic' to 'electric' and from orthodromic to antidromic. As a consequence, massive neuronal synchronisation occurs, the correlate of the focal or secondarily generalised attack. Because of experimental difficulties in studying the widespread and evolving neuronal activities in freely behaving animals, a precise correlation between states of neuronal activation and convulsive behaviour is still unclear.


Microphysiological Conditions Do Not Affect MDR1-Mediated Transport of Rhodamine 123 above an Artificial Proximal Tubule.
Despite disadvantages, such as high cost and their poor predictive value, animal experiments are still the state of the art for pharmaceutical substance testing. One reason for this problem is the inability of standard cell culture methods to emulate the physiological environment necessary to recapitulate in vivo processes. Microphysiological systems offer the opportunity to close this gap. In this study, we utilize a previously employed microphysiological system to examine the impact of pressure and flow on the transportation of substances mediated by multidrug resistance protein 1 (MDR1) across an artificial cell-based tubular barrier. By using a miniaturized fluorescence measurement device, we could continuously track the MDR1-mediated transport of rhodamine 123 above the artificial barrier over 48 h. We proved that applying pressure and flow affects both active and passive transport of rhodamine 123. Using experimental results and curve fittings, the kinetics of MDR1-mediated transport as well as passive transport were investigated; thus, a kinetic model that explains this transport above an artificial tubular barrier was identified. This kinetic model demonstrates that the simple Michaelis-Menten model is not an appropriate model to explain the MDR1-mediated transport; instead, Hill kinetics, with Hill slope of n = 2, is a better fit. The kinetic values, Km, Vmax, and apparent permeability (Papp), obtained in this study are comparable with other in vivo and in vitro studies. Finally, the presented proximal tubule-on-a-chip can be used for pharmaceutical substance testing and to investigate pharmacokinetics of the renal transporter MDR1.


Factors influencing compliance in long-term proton pump inhibitor therapy in general practice.
Long-term proton pump inhibitor (PPI) prescribing in general practice is common, but only a minority of patients request their prescriptions regularly. This study determined factors linked with compliance using questionnaires and diary cards. The chief factors determining whether or not patients took their PPIs were the presence or severity of symptoms and the desire to remain in personal control, together with a fear of side-effects and lack of knowledge about the drugs. As most such prescribing is for uncomplicated gastro-oesophageal reflux disease, on-demand therapy should now be formally advocated.


What Proportion of East African Refugees Report Musculoskeletal Problems? A Cross-sectional Survey.
Musculoskeletal conditions are the leading cause of disability worldwide and disproportionally affect individuals in low-income and middle-income countries. There is a dearth of evidence on musculoskeletal problems among refugees, 74% of whom reside in low-income and middle-income countries. (1) What proportion of refugees in Nyarugusu Camp, Kigoma, western Tanzania, are affected by musculoskeletal problems and what are the characteristics of those individuals? (2) What are the characteristics of these musculoskeletal problems, including their causes, location, and duration? (3) What forms of healthcare do those with musculoskeletal problems seek, including those for both musculoskeletal and nonmusculoskeletal problems? We conducted a cross-sectional study among refugees in Nyarugusu Camp, using the Surgeons OverSeas Assessment of Surgical Need tool. The Surgeons OverSeas Assessment of Surgical Need tool is a validated population-based survey tool developed for use in limited-resource settings that is intended to determine the prevalence of surgical disease in a community. It uses a cluster random sampling methodology with house-to-house data collection in the form of a verbal head-to-toe examination that is performed by a trained community healthcare worker. A total of 99% responded, and 3574 records were analyzed. The mean age of respondents was 23 ± 18 years, with under 18 as the most-represented age group (44% [1563]). A total of 57% (2026) of respondents were women, 79% (2802 of 3536) were generally healthy, and 92% (3297 of 3570) had visited a camp medical facility. Only records endorsing musculoskeletal problems (extremity or back) were included in this analysis. Using all refugees surveyed as our denominator and refugees who endorsed a musculoskeletal problem (extremity or back) as the numerator, we calculated the proportion of refugees who endorsed a musculoskeletal problem. We then analyzed the characteristics of those endorsing musculoskeletal problems, including their healthcare-seeking behavior, and the characteristics of the musculoskeletal problems themselves. Among 3574 refugees interviewed, 22% (769) reported musculoskeletal problems, with 17% (609) reporting extremity problems and 7% (266) reporting back problems. Among all people surveyed, 8% (290) reported current extremity problems while 5% (188) reported current back problems. Among those reporting musculoskeletal problems, respondents younger than 18 years were the most-represented age group (28% [169 of 609]) whereas respondents between 30 and 44 years of age were the most-represented age group for back problems (29% [76 of 266]). Wounds from an injury or trauma (24% [133 of 557]) and acquired disability (24% [133 of 557]) were the most-common causes of extremity problems, whereas acquired disability (53% [97 of 184]) followed by a wound not from injury or trauma (25% [45 of 184]) were the most common causes of back problems. Fifty percent (303) of those with extremity problems characterized it as disabling, whereas 76% (203) of those with back problems did. Over one of five refugees endorsed musculoskeletal problems, which are most often caused by acquired disease and injury. These musculoskeletal problems are often characterized as disabling, yet only slightly more than half have sought treatment for problems. This warrants further research on care-seeking behavior in this setting, and emphasizes that investing in the spectrum of musculoskeletal health systems, including medical management and rehabilitation services, is critical to decreasing disability caused by musculoskeletal problems. Level IV, prognostic study.


Physostigmine reversal of scopolamine-induced hypofrontality.
The muscarinic receptor antagonist scopolamine produces a transient memory deficit in healthy humans. This deficit has been offered as a model of the cholinergic deficit of Alzheimer's disease (AD). However, we have previously shown that scopolamine produces a deficit of cortical perfusion maximal in the frontal lobe, dissimilar to the parietal cortex deficit characteristic of AD. The current experiment was aimed at replicating and extending this observation by critically testing the central cholinergic origin of both cognitive and perfusion deficits. Nine healthy subjects participated in regional cerebral blood flow (rCBF) measurements at baseline, after scopolamine (7.2 micrograms/kg i.v.), and after both physostigmine (22 micrograms/kg i.v.) and neostigmine (7 or 11 micrograms/kg i.v.). rCBF was quantified by the xenon 133 inhalation method. As expected, scopolamine reduced cortical perfusion, mainly in the frontal cortex, and produced a memory deficit. Physostigmine, but not neostigmine, reversed all three variables partially or completely. These results support the hypothesis that all three consequences of scopolamine, namely, reduction of mean flow, frontal deficit, and memory impairment, are cholinergically mediated. Furthermore, because neostigmine poorly crosses the blood-brain barrier, these findings confirm that the effect is centrally mediated and cannot be explained by peripheral effects. However, they also confirm the frontal cortex locus of action for both scopolamine and its reversal by physostigmine and therefore suggest a major dissimilarity to the characteristic rCBF appearance of AD. This study extends our previous preliminary findings with tacrine and strengthens the suggestion that only nicotinic receptors are associated with the characteristic parietal deficit of AD.


Fragmentation mechanisms of protonated benzylamines. Electrospray ionisation-tandem mass spectrometry study and ab initio molecular orbital calculations.
Our research into neurotransmitters in a biological fluid presented an opportunity to investigate the fragmentations under low collision energy characterising benzyl-amines protonated under electrospray ionisation (ESI) conditions in a triple quadrupole mass spectrometer. In this work we present the breakdown graphs of protonated 3,4-dihydroxybenzylamine, DHBAH(+), and 3-methoxy, 4-hydroxybenzylamine, HMBAH(+), at various source temperatures and various pressures in the collision cell, the collision energy varying from 0 to 46 eV in the laboratory frame. Both parent ions eliminate first NH(3) at very low collision energy. The fragmentations of [MH - NH(3)](+) occur at high collision energy and are quite different for DHBAH(+) and HMBAH(+): formation of [MH - NH(3) - H(2)O - CO](+) for the former; formation of the radical cation [MH - NH(3) - CH(3)](+.) for the latter. These fragmentations are interpreted by means of ab initio calculations up to the B3LYP/6-311+G(2d,2p) level of theory. The successive losses of H(2)O and CO involve first the rearrangement in two steps of benzylic ions formed by loss of NH(3) into tropylium ions. The transition states associated with this rearrangement are very high in energy (about 400 kJ mol(-1) above MH(+)) explaining (i). the absence of an ion corresponding to [DHBAH - NH(3) - H(2)O](+). The determining steps associated with the losses of H(2)O and with H(2)O + CO are located lower in energy than the transition states associated with the isomerisation of benzylic ions into tropylium ions; explaining (ii). the formation of the radical cation [MH - NH(3) - CH(3)](+.). The homolytic cleavage of CH(3)-O requires less energy than does the rearrangement.


[Not Available].
J.-F. Emile Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumours of the digestive tract. They can arise anywhere in the gastrointestinal tract, from oesophagus to anus, and rarely from peritoneal cavity or mesentery. GIST usually remain asymptomatic for a long time. Therefore 10 to 20% are found incidentally at endoscopy or at time of surgery for others reasons and metastases are found in 15 to 50% of cases at diagnonis. Histologicaly, they are characterized by a cellular proliferation constituted of either spindle or epithelioid cells. Diagnosis has to be confirmed by immunohistochemistry, with positivity of KIT in 95% of cases, or by molecular biology, with "gain of function" mutations of KIT or PDGFRA in 85% of cases. Primary localization, mitotic activity and tumor size are the main prognostic factors. Metastases occur in 30 to 50% of patients with GIST. GIST are highly resistant to conventional chemotherapy and results obtained with new targeted therapies like Imatinib constitute one of the major progress in oncology during the decade.


Application of X-ray grating interferometry for the imaging of joint structures.
Conventional X-ray absorption contrast imaging does not depict soft tissues, such as cartilage, in sufficient detail. For visualization of the soft tissues, X-ray phase-contrast imaging is more sensitive than absorption-contrast imaging. The basic concept of the X-ray phase-contrast imaging used in this study is similar to that of differential interference contrast (Nomarski) microscopy. We applied Talbot-Lau X-ray interferometry to visualize the joint structures in the right hand and knee of a donated cadaver. This imaging system simultaneously produced three different types of images: an absorption image, a differential phase image, and a visibility image. The interface between the articular cartilage of the metacarpo-phalangeal joint and fluid or the bony cortex was clearly demonstrated on the differential phase image, whereas this interface was unclear on the absorption image. Within the knee joint, the surface of the articular cartilage was demonstrated both on the differential phase and visibility images; the medial collateral ligament and medial meniscus were also visualized successfully. These results are clinically significant for the diagnosis and therapeutic estimation of rheumatoid arthritis and related joint diseases. This feasibility study on the clinical application of this imaging tool was a collaborative effort of researchers in the fields of physics, radiology, and gross anatomy.


Hearing Loss in Alzheimer's Disease Is Associated with Altered Serum Lipidomic Biomarker Profiles.
Recent data have found that aging-related hearing loss (ARHL) is associated with the development of Alzheimer's Disease (AD). However, the nature of the relationship between these two disorders is not clear. There are multiple potential factors that link ARHL and AD, and previous investigators have speculated that shared metabolic dysregulation may underlie the propensity to develop both disorders. Here, we investigate the distribution of serum lipidomic biomarkers in AD subjects with or without hearing loss in a publicly available dataset. Serum levels of 349 known lipids from 16 lipid classes were measured in 185 AD patients. Using previously defined co-regulated sets of lipids, both age- and sex-adjusted, we found that lipid sets enriched in phosphatidylcholine and phosphatidylethanolamine showed a strong inverse association with hearing loss. Examination of biochemical classes confirmed these relationships and revealed that serum phosphatidylcholine levels were significantly lower in AD subjects with hearing loss. A similar relationship was not found in normal subjects. These data suggest that a synergistic relationship may exist between AD, hearing loss and metabolic biomarkers, such that in the context of a pathological state such as AD, alterations in serum metabolic profiles are associated with hearing loss. These data also point to a potential role for phosphatidylcholine, a molecule with antioxidant properties, in the underlying pathophysiology of ARHL in the context of AD, which has implications for our understanding and potential treatment of both disorders.


Writing a PACS program statement.
Medical telecommunications is becoming a necessity for maintaining the quality of care and delivering services on a timely basis in the current environment of cutting services and specialists to reduce costs. (Vanden Brink 1994). Picture archiving and communications systems (PACS) and teleradiology are increasingly viable because there is easier connectivity among modalities and manufacturers. Agreement on the DICOM Standard is one step toward greater connectivity. Two-thirds of the 350 radiology administrators, radiologists, hospital administrators and MIS directors interviewed for the 1994 IMACS/PACS Tracking Study believe that the use of image telecommunication technology is growing. In 1993, Vanderbilt University Medical Center (VUMC) formed a committee to evaluate the need for PACS and to compile a program statement. The principal purpose of the program statement is to provide fundamental information that can be understood easily by individuals outside the radiology department. It outlines the benefits of PACS and includes a financial analysis of the purchase and installation of a system. Key elements of the program statement include a description and analysis of the existing film library system, advantages of PACS, implementation plan, financial proforma and integration with the hospital information system. These and other topics are covered in detail in the following article.


[Cerebral imaging for Wilson disease].
Wilson disease is an autosomal recessive inherited copper metabolic disorder that is characterized by diminished biliary excretion of copper and a raised serum level of free copper. This leads to a toxic copper accumulation, particularly in the liver and the brain. Therefore, clinical symptoms are dominated by hepatic and extrapyramidal symptoms. Untreated Wilson disease has an unfavorable outcome. Cerebral changes are depicted most sensitively by magnetic resonance tomography. Pathological findings mainly focus on the basal ganglia, the midbrain and the brainstem. Depending on the therapy and the severity of the neurological symptoms, signal increase as well as signal decrease may be observed in T1-weighted (T1w) and T2-weighted (T2w) images and can be reversible when using an appropriate therapy. Hyperintense areas in T2-weighted images are induced by edema, gliosis, demyelinisation or cystic degeneration. Signal increase in T1-weighted images are found in patients with hepatic insufficiency and are probably due to manganese deposits. Signal decrease in T2-weighted images is probably caused by the paramagnetic effect of the copper accumulation. Furthermore, recent studies show a correlation between the clinical severity and changes in diffusion-weighted sequences. Although cross-section imaging plays a rather subordinate role in the primary diagnostics of Wilson disease, the described cerebral changes in patients with extrapyramidal disturbances should include Wilson disease in the differential. Persistent or progressive hyperintense lesions in T2-weighted images reflect therapy failure, and clinical recovery correlates to an improvement in MR images. Therefore, repeat MR imaging can be used to monitor medical therapy.


A comparison of the signalling properties of two tyramine receptors from Drosophila.
In invertebrates, the phenolamines, tyramine and octopamine, mediate many functional roles usually associated with the catecholamines, noradrenaline and adrenaline, in vertebrates. The α- and β-adrenergic classes of insect octopamine receptor are better activated by octopamine than tyramine. Similarly, the Tyramine 1 subgroup of receptors (or Octopamine/Tyramine receptors) are better activated by tyramine than octopamine. However, recently, a new Tyramine 2 subgroup of receptors was identified, which appears to be activated highly preferentially by tyramine. We examined immunocytochemically the ability of CG7431, the founding member of this subgroup from Drosophila melanogaster, to be internalized in transfected Chinese hamster ovary (CHO) cells by different agonists. It was only internalized after activation by tyramine. Conversely, the structurally related receptor, CG16766, was internalized by a number of biogenic amines, including octopamine, dopamine, noradrenaline, adrenaline, which also were able to elevate cyclic AMP levels. Studies with synthetic agonists and antagonists confirm that CG16766 has a different pharmacological profile to that of CG7431. Species orthologues of CG16766 were only found in Drosophila species, whereas orthologues of CG7431 could be identified in the genomes of a number of insect species. We propose that CG16766 represents a new group of tyramine receptors, which we have designated the Tyramine 3 receptors.


Trophic networks improve the performance of microbial anodes treating wastewater.
Microbial anodes represent a distinct ecological niche that is characterized mainly by the terminal electron acceptor, i.e., the anode potential, and the substrate, i.e., the electron source. Here, we determine the performance and the biofilm community of anode microbiomes while using substrates of increasing complexity (organic acids or organic acids and sugar or real domestic wastewater) to mimic different, practically relevant, trophic levels. α-Diversity values increased with substrate complexity. In addition, the higher abundance value of Deltaproteobacteria in the biofilms corresponds to higher reactor performance (i.e., COD removal, current density, and Coulombic efficiency). In reactors exploiting real wastewater, the diversity of the planktonic microorganisms was only little affected. Microbiome network analysis revealed two important clusters for reactor performance as well as performance-independent pathogen-containing clusters. Interestingly, Geobacter was not found to be integrated in the network underlining its outstanding individual ecological role in line with its importance for the efficiency of the electron harvest for all reactors. The microbiome analysis of different trophic levels and their temporal development from initial colonization to stable treatment demonstrate important principles for the implementation of microbial anodes for wastewater treatment.


Tracing retinal fiber trajectory with a method of transposon-mediated genomic integration in chick embryo.
We report convenient retinal fiber tracing by transfecting the tracer cDNA by in ovo electroporation. Long-term and stable expression of tracer proteins such as green fluorescent protein is achieved by transposon-mediated genome integration of the tracer protein expression cassette. We carried out coelectroporation of a plasmid containing CAGGS-tracer cDNA flanked by the Tol2 transposable element along with a transposase expression vector to the optic vesicle of chick embryos at stage 11. By selecting electrodes, we can label a large group of retinal ganglion cells, or a small group of retinal ganglion cells; parallel electrodes assure transfection of large areas of the retina, and needle type electrodes label small areas of the retina. The retinal fiber trajectory and terminal zone (TZ) could be detected in the precise retinotopic manner on the contra-lateral side of the optic tectum. The method has advantage in that we can show the retinal fiber trajectory in relation to the molecules that are responsible for pathfinding for the retinal fibers in the same specimen.


Thermal erosion of cratonic lithosphere as a potential trigger for mass-extinction.
The temporal coincidence between large igneous provinces (LIPs) and mass extinctions has led many to pose a causal relationship between the two. However, there is still no consensus on a mechanistic model that explains how magmatism leads to the turnover of terrestrial and marine plants, invertebrates and vertebrates. Here we present a synthesis of ammonite biostratigraphy, isotopic data and high precision U-Pb zircon dates from the Triassic-Jurassic (T-J) and Pliensbachian-Toarcian (Pl-To) boundaries demonstrating that these biotic crises are both associated with rapid change from an initial cool period to greenhouse conditions. We explain these transitions as a result of changing gas species emitted during the progressive thermal erosion of cratonic lithosphere by plume activity or internal heating of the lithosphere. Our petrological model for LIP magmatism argues that initial gas emission was dominated by sulfur liberated from sulfide-bearing cratonic lithosphere before CO2 became the dominant gas. This model offers an explanation of why LIPs erupted through oceanic lithosphere are not associated with climatic and biotic crises comparable to LIPs emitted through cratonic lithosphere.


The pH dependence of kinetic isotope effects in monoamine oxidase A indicates stabilization of the neutral amine in the enzyme-substrate complex.
A common feature of all the proposed mechanisms for monoamine oxidase is the initiation of catalysis with the deprotonated form of the amine substrate in the enzyme-substrate complex. However, recent steady-state kinetic studies on the pH dependence of monoamine oxidase led to the suggestion that it is the protonated form of the amine substrate that binds to the enzyme. To investigate this further, the pH dependence of monoamine oxidase A was characterized by both steady-state and stopped-flow techniques with protiated and deuterated substrates. For all substrates used, there is a macroscopic ionization in the enzyme-substrate complex attributed to a deprotonation event required for optimal catalysis with a pK(a) of 7.4-8.4. In stopped-flow assays, the pH dependence of the kinetic isotope effect decreases from approximately 13 to 8 with increasing pH, leading to assignment of this catalytically important deprotonation to that of the bound amine substrate. The acid limb of the bell-shaped pH profile for the rate of flavin reduction over the substrate binding constant (k(red)/K(s), reporting on ionizations in the free enzyme and/or free substrate) is due to deprotonation of the free substrate, and the alkaline limb is due to unfavourable deprotonation of an unknown group on the enzyme at high pH. The pK(a) of the free amine is above 9.3 for all substrates, and is greatly perturbed (DeltapK(a) approximately 2) on binding to the enzyme active site. This perturbation of the substrate amine pK(a) on binding to the enzyme has been observed with other amine oxidases, and likely identifies a common mechanism for increasing the effective concentration of the neutral form of the substrate in the enzyme-substrate complex, thus enabling efficient functioning of these enzymes at physiologically relevant pH.


National clinical practice guidelines for allergen immunotherapy: An international assessment applying AGREE-II.
Since 1988, numerous allergen immunotherapy guidelines (AIT-GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely underused. To evaluate AIT-GLs with AGREE-II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL quality. Allergist, from different continents, knowledgeable in AIT and AGREE-II trained were selected into the project team. The project received methodologists' guidance. AIT-GLs in any language were sought from 1980 to 2016; AIT-GLs were AGREE II-evaluated by at least 2 team members, independently; discrepancies were resolved in a second round, by team discussion or methodologists' consulting. We found 31 AIT-GLs (15 post-2010), ranging from local consensus reports to international position papers (EAACI, AAAAI-ACAAI, WAO). Pre-2010 GLs scored 1.6-4.6 (23%-67%) and post-2010 GLs scored 2.1-6 (30%-86%), on a 7-point Likert scale. The highest scores went to: German-Austrian-Swiss (6.0), Mexican (5.1), and the AAAAI/ACAAI AIT-GL (4.7). These were also the only 3 GLs that received "yes" of both evaluators to the item: "I would recommend this GL for use." The domains of "Stakeholder involvement" and "Rigor of Development" only scored 3/7, and "Applicability" scored the lowest. Strikingly, newer GLs only scored clearly better in "Editorial independence" and "Global evaluation." In AIT-GLs, there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the "Scientific rigor" domain flawed. When resources are limited, transculturizing a high-quality GL might be preferable over developing a GL from zero. Our study and AGREE-II could help to select the best candidate. We here evaluate allergen immunotherapy guideline (AIT-GL) quality. Only high-quality AIT-GLs should be consulted for AIT management decisions. In low-resource settings, transculturization of these is preferred over developing low-quality guidelines.


What Does Diabetes "Taste" Like?
The T1R2 (taste type 1 receptor, member 2)/T1R3 (taste type 1 receptor, member 3) sweet taste receptor is expressed in taste buds on the tongue, where it allows the detection of energy-rich carbohydrates of food. This single receptor responds to all compounds perceived as sweet by humans, including natural sugars and natural and artificial sweeteners. Importantly, the T1R2/T1R3 sweet taste receptor is also expressed in extra-oral tissues, including the stomach, pancreas, gut, liver, and brain. Although its physiological role remains to be established in numerous organs, T1R2/T1R3 is suspected to be involved in the regulation of metabolic processes, such as sugar sensing, glucose homeostasis, and satiety hormone release. In this review, the physiological role of the sweet taste receptor in taste perception and metabolic regulation is discussed by focusing on dysfunctions leading to diabetes. Current knowledge of T1R2/T1R3 inhibitors making this receptor a promising therapeutic target for the treatment of type 2 diabetes is also summarized and discussed.


[State of the endothelium of the aorta during chronic stress].
In 50 white male rats (18-control and 32-experimental) using morphometrical and stereological methods for film preparations of endothelium, the state of the internal aortal lining at various stages of chronic stress developing during muscular activity has been studied. The data obtained are statistically treated by the sliding averages method, reliability of the differences is estimated according to the value of nonparametrical criterion of Wilcoxon-Mann-Whitney. For objective periodization of the endothelial reaction to stress, centered moving averages curves are performed with subsequent calculation of the coefficient of variation for the aligned ordinates of the approximated values in every temporal point. The aortal endothelium reaction to the stress is of phasic character. During the alarm reaction, destructive changes predominate; they are accompanied with an increased mitotic activity of endotheliocytes up to 2.2%. The resistance stage increases compensatory-adaptive rearrangements, which are manifested not only as cellular hyperplasia, but as hyperthrophy of nuclei, increasing number of strangulated nuclei, nucleoli, as well as binuclear and trinucler cells. To the exhaustion period the increase of alternative and restorative transformations of the tissue corresponds.


Eternal work place change: Chaplains' response.
A detailed chronology of a unique response to organizational change is explored and discussed through the example of the Chaplaincy Staff Support Service at Hamilton Health Sciences. Highlighted are the corporate and staff benefits of using chaplains' skills, training and existing roles in hospital life. A summary of the specific methodologies are provided to clarify the theoretical discussion. It is concluded that this is a fiscally efficient means of supporting staff to live out the highest organizational principles in difficult times.


Persistent cell motion in the absence of external signals: a search strategy for eukaryotic cells.
Eukaryotic cells are large enough to detect signals and then orient to them by differentiating the signal strength across the length and breadth of the cell. Amoebae, fibroblasts, neutrophils and growth cones all behave in this way. Little is known however about cell motion and searching behavior in the absence of a signal. Is individual cell motion best characterized as a random walk? Do individual cells have a search strategy when they are beyond the range of the signal they would otherwise move toward? Here we ask if single, isolated, Dictyostelium and Polysphondylium amoebae bias their motion in the absence of external cues. We placed single well-isolated Dictyostelium and Polysphondylium cells on a nutrient-free agar surface and followed them at 10 sec intervals for approximately 10 hr, then analyzed their motion with respect to velocity, turning angle, persistence length, and persistence time, comparing the results to the expectation for a variety of different types of random motion. We find that amoeboid behavior is well described by a special kind of random motion: Amoebae show a long persistence time ( approximately 10 min) beyond which they start to lose their direction; they move forward in a zig-zag manner; and they make turns every 1-2 min on average. They bias their motion by remembering the last turn and turning away from it. Interpreting the motion as consisting of runs and turns, the duration of a run and the amplitude of a turn are both found to be exponentially distributed. We show that this behavior greatly improves their chances of finding a target relative to performing a random walk. We believe that other eukaryotic cells may employ a strategy similar to Dictyostelium when seeking conditions or signal sources not yet within range of their detection system.


Recurrent pump thrombosis is common after axial continuous-flow left ventricular assist device exchange.
In selected patients with left ventricular assist device-associated infection or malfunction, pump exchange may become necessary after conservative treatment options fail and heart transplantation is not readily available. We examined the survival and complication rate in patients (⩾19 years of age) who underwent HeartMate II to HeartMate II exchange at our institution from 1 January 2010 to 28 February 2018. Clinical outcomes were analyzed and compared for patients who underwent exchange for pump thrombosis (14 patients), breach of driveline integrity (5 patients), and device-associated infection (2 patients). There were no differences in 30-day mortality (p = 0.58), need for temporary renal replacement therapy (p = 0.58), right ventricular mechanical support (p = 0.11), and postoperative stroke (p = 0.80) among groups. Survival at 1 year was 90% ± 7% for the whole cohort and 85% ± 10% for those who underwent exchange for pump thrombosis. In patients exchanged for device thrombosis, freedom from re-thrombosis and survival free from pump re-thrombosis at 1 year were 49% ± 16% and 42% ± 15%, respectively. No association of demographic and clinical variables with the risk of recurrent pump thrombosis after the first exchange was identified. Survival after left ventricular assist device exchange compares well with published results after primary left ventricular assist device implantation. However, recurrence of thrombosis was common among patients who required a left ventricular assist device exchange due to pump thrombosis. In this sub-group, consideration should be given to alternative strategies to improve the outcomes.


The Two Weapons against Bacterial Biofilms: Detection and Treatment.
Bacterial biofilms are defined as complex aggregates of bacteria that grow attached to surfaces or are associated with interfaces. Bacteria within biofilms are embedded in a self-produced extracellular matrix made of polysaccharides, nucleic acids, and proteins. It is recognized that bacterial biofilms are responsible for the majority of microbial infections that occur in the human body, and that biofilm-related infections are extremely difficult to treat. This is related with the fact that microbial cells in biofilms exhibit increased resistance levels to antibiotics in comparison with planktonic (free-floating) cells. In the last years, the introduction into the market of novel compounds that can overcome the resistance to antimicrobial agents associated with biofilm infection has slowed down. If this situation is not altered, millions of lives are at risk, and this will also strongly affect the world economy. As such, research into the identification and eradication of biofilms is important for the future of human health. In this sense, this article provides an overview of techniques developed to detect and imaging biofilms as well as recent strategies that can be applied to treat biofilms during the several biofilm formation steps.


Contamination-free high capacity converging waves sonoreactors for the chemical industry.
A new sonoreactor technology is presented here which should give a decisive impulse to sonochemistry in various areas of chemical processing. These exclusive systems use high power converging acoustic waves in a tube to produce a relatively large volume confined acoustic cavitation zone in flowing liquid reagents under pressure. It is well known that numerous chemical reactions are strongly accelerated when they take place inside such a zone. The new cylindrical sonoreactors do not contaminate the processed liquids with erosion products as most other devices do since the cavitation zone is maintained away from the wall of the tube. The processing conditions can be widely varied with pressure, power, temperature, and flow rate. The processing capacity of the largest models may be up to several tons per hour, depending on the required cavitation energy per unit volume to produce the desired process enhancement, using an electric power input of about 50 kW.


The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women.
We examined the association of bone mineral density (BMD) with a polymorphism in the gene encoding the vitamin D receptor (VDR) that causes a change in the predicted protein sequence. The polymorphism results from a C-to-T transition and creates an initiation codon (ATG) three codons proximal to a downstream start site. The polymorphism can be defined by a restriction fragment length polymorphism (RFLP) using the restriction endonuclease FokI. The presence of a FokI site, designated f, allows protein translation to initiate from the first ATG. The allele lacking the site (designated F), initiates from a second ATG site. Thus, translation products from these alleles are predicted to differ by three amino acids with the f variant elongated. In a group of 100 postmenopausal Mexican-American Caucasian women, subjects with the ff genotype (15% of the study population) had a 12.8% lower BMD at the lumbar spine than FF subjects (37% of the population) (p = 0.01). Heterozygote (Ff) subjects (48% of the population) had an intermediate BMD. This association between BMD and genotype was not apparent at the femoral neck or forearm. Over a 2-year follow-up period, a decrease in BMD at the femoral neck was greater in ff compared with FF subjects (-4.7% vs. -0.5%, p = 0.005). This trend was not apparent at the lumbar spine or forearm. There were no differences between genotype groups in measurements of 25-hydroxyvitamin D (25(OH)D), calcitriol, parathyroid hormone (PTH), osteocalcin, or urinary pyridinolines. We conclude that the FokI polymorphism of the VDR gene correlates significantly with decreased BMD at the lumbar spine and with an increased rate of bone loss at the hip in ff subjects. We emphasize that these initial data should be interpreted with caution but that the utility of this polymorphism as a genetic marker to determine BMD and osteoporosis risk warrants further study in larger populations with subjects of diverse ethnic backgrounds.


Age reprogramming and epigenetic rejuvenation.
Age reprogramming represents a novel method for generating patient-specific tissues for transplantation. It bypasses the de-differentiation/redifferentiation cycle that is characteristic of the induced pluripotent stem (iPS) and nuclear transfer-embryonic stem (NT-ES) cell technologies that drive current interest in regenerative medicine. Despite the obvious potential of iPS and NT-ES cell-based therapies, there are several problems that must be overcome before these therapies are safe and routine. As an alternative, age reprogramming aims to rejuvenate the specialized functions of an old cell without de-differentiation; age reprogramming does not require developmental reprogramming through an embryonic stage, unlike the iPS and NT-ES cell-based therapies. Tests of age reprogramming have largely focused on one aspect, the epigenome. Epigenetic rejuvenation has been achieved in vitro in the absence of de-differentiation using iPS cell reprogramming factors. Studies on the dynamics of epigenetic age (eAge) reprogramming have demonstrated that the separation of eAge from developmental reprogramming can be explained largely by their different kinetics. Age reprogramming has also been achieved in vivo and shown to increase lifespan in a premature ageing mouse model. We conclude that age and developmental reprogramming can be disentangled and regulated independently in vitro and in vivo.


Carbon dioxide versus normal saline in outpatient hysteroscopy.
The aim of this prospective randomized study was to measure patients' discomfort after hysteroscopy with CO(2) or normal saline. A total of 415 patients was randomized to two groups according to distension medium (CO(2), n = 201; normal saline, n = 214). The nature of randomization was to alternate distension media on a weekly basis. After hysteroscopy, women were asked to rate the pain experienced on a 100-mm visual analogue scale (0 = no pain; 100 = worst imaginable pain). Pain scores were expressed as mean +/- SD (0-40 = minimal; 41-70 = moderate; 71-100 = severe). Data were analysed using Student's t-test. Irrespective of the distension medium used, pelvic discomfort was worse in nulliparous women (pain score 39.0 +/- 26.5) than in multiparous women (30.4 +/- 25.9) (P < 0.05), especially if they were premenopausal. For all patients and both distension media, pelvic discomfort was generally minimal but higher in patients who had undergone hysteroscopy with normal saline (P < 0.05). CO(2) and normal saline were comparable with regard to patient discomfort, but in terms of the high frequency of abnormal uterine bleeding, normal saline may be the most appropriate distension medium for outpatient hysteroscopy.


Transdermal scopolamine in the prevention of motion sickness at sea.
Studies were conducted to evaluate the efficacy of scopolamine, absorbed through intact skin, in preventing motion sickness at sea. Efficacy of transdermal scopolamine was compared with oral dimenhydrinate and placebo. Transdermal applications were made 4 to 16 hr before exposure to motion. Dimenhydrinate or placebo was given 1.5 hr before motion and again 2.5 hr after motion began. Comparison with placebo indicated that transdermal scopolamine provided protection against motion sickness at a significance level of p = 0.0001 and oral dimenhydrinate at a level of p = 0.05. Dry mouth, drowsiness, and blurred vision associated with transdermal scopolamine therapy were minimal.


Interaction between lymphocytes and inflammatory exudate cells. II. A proteolytic enzyme released by PMN as a possible mediator for enhancement of thymocyte response.
Mouse polymorphonuclear leukocytes (PMN) were harvested from the peritoneal cavity stimulated with sodium caseinate. The cells were cultivated in vitro and the supernatant of these cultures (SUP) was tested for enhancing potency on DNA synthesis by syngeneic thymocytes stimulated with phytohemagglutinin (PHA). The enhancing potency of the SUP was markedly influenced by duration of the donor cultures of PMN, population density of the cultures, and protein concentrations in the medium, respectively. The enhancing factor in the SUP was found to be non-dialysable, heat-labile, and stable in the pH ranging between 3 and 9 but labile in the pH below 2 or above 10; its m.w. was approximately 19.000 when measured by gel-filtration on Sephadex G-75. The factor had a proteolytic activity on 3H-acetyl hemoglobin (3HHb) at neutral pH (7.2). Both the proteolytic activity and thymocyte-helping potency of the SUP were similarly abolished by adding protease inhibitor (Trasylol) in soluble form, or by passing through a column of the inhibitor insolubilized. It was thus assumed that the enhancing effect of PMN on thymocyte response was associated with a neutral protease released from the cells: it may be termed a lymphocyte-helping protease (LHP).


Toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea in human cell lines with different DNA repair phenotypes.
We examined the toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea (ENU) in three Epstein-Barr virus-transformed human lymphoblastoid cell lines, each with a different DNA repair phenotype. One cell line lacks O6-alkylguanine-DNA alkyltransferase (AGT) activity; another, derived from a patient with xeroderma pigmentosum, complementation group A, lacks nucleotide exicision repair (NER) capability, and the third is competent in both repair functions. ENU-induced toxicity and mutagenicity at the hypoxanthine-guanine phosphoribosyltransferase locus were increased to a similar degree relative to the repair-competent cells in both AGT-deficient and NER-deficient cells. We determined the mutational spectra for ENU by identifying DNA sequence changes at the hypoxanthine-guanine phosphoribosyltransferase locus in at least 26 clones resistant to 6-thioguanine from each cell line. Of the characterized mutations, 89% were single-base pair substitutions. Transitions and transversions were found at AT and GC base pairs in all three cell lines. The biggest difference within the spectra was in the rate of transitions at GC base pairs. Compared to the repair-competent cell line, this mutation was elevated about 8-fold in the AGT-deficient cells and about 3-fold in the NER-deficient cells. We conclude that both AGT and NER play an important role in protecting human cells from the toxic and mutagenic effects of ENU. Furthermore, the mutational spectra suggest that both of these repair systems participate in the repair of O6-ethylguanine adducts.


Development of a multiplexed bead-based suspension array for the detection and discrimination of pospiviroid plant pathogens.
Efficient and reliable diagnostic tools for the routine indexing and certification of clean propagating material are essential for the management of pospiviroid diseases in horticultural crops. This study describes the development of a true multiplexed diagnostic method for the detection and identification of all nine currently recognized pospiviroid species in one assay using Luminex bead-based suspension array technology. In addition, a new data-driven, statistical method is presented for establishing thresholds for positivity for individual assays within multiplexed arrays. When applied to the multiplexed array data generated in this study, the new method was shown to have better control of false positives and false negative results than two other commonly used approaches for setting thresholds. The 11-plex Luminex MagPlex-TAG pospiviroid array described here has a unique hierarchical assay design, incorporating a near-universal assay in addition to nine species-specific assays, and a co-amplified plant internal control assay for quality assurance purposes. All assays of the multiplexed array were shown to be 100% specific, sensitive and reproducible. The multiplexed array described herein is robust, easy to use, displays unambiguous results and has strong potential for use in routine pospiviroid indexing to improve disease management strategies.


Motor intracortical inhibition in PD: L-DOPA modulation of high-frequency rTMS effects.
Dopaminergic drugs and deep brain stimulation restore cortical inhibition in Parkinson disease (PD) patients. High-frequency rTMS was also found to increase cortical inhibition in PD but its therapeutic effect is still controversial. Here we hypothesize that, if dopaminergic drugs reverse to normal cortical excitability in M1, the effect of high-frequency (hf)-rTMS in PD patients could depend on whether they are in a medicated or unmedicated state. The present study aims to explore the lasting effects of sub-threshold hf rTMS trains over M1 on cortical inhibition in patients with "on" and without "off" L-DOPA treatment. Fourteen PD patients were examined twice while "on" and "off" medication. In both conditions, a paired-pulse paradigm was used to evaluate short intracortical inhibition (SICI) and long intracortical inhibition (LICI) that were evaluated before and after hf rTMS trains applied on the motor cortex. The results were compared with those obtained from normal controls. In baseline condition, SICI and LICI were significantly reduced in "off" compared to "on" patients and controls. hf-rTMS over the motor cortex significantly increased SICI and LICI in "off" medication PD patients. Magnetic stimulation proved to be ineffective when the same patients were in "on" state. The results showed that hf-rTMS affected intracortical inhibition (ICI) only in unmedicated patients. By restoring cortical inhibitory circuits dopaminergic drugs, normalize the excitability changes in M1 subsequent to motor rTMS. Whether patients are in a medicated or an unmedicated state would therefore appear to be critical for rTMS effects in PD patients. If a positive correlation exists between increased cortical inhibition and clinical improvement, hf-rTMS during the "off" state could be regarded as a potential add-on treatment to reduce the need of L-dopa and thus delay the adverse effects of its chronic use.


Prevalence and risk factors for heart disease among males with hemophilia.
There have been conflicting reports in the literature about the protective effect of hemophilia on the occurrence of ischemic heart disease (IHD). Circulatory disease has been reported as the second most common cause of death in persons with hemophilia in the United States. In addition to diabetes and hypertension, high levels of FVIII, as may occur during factor concentrate infusions, may increase IHD risk in this population. To estimate the prevalence of heart disease and examine factors associated with IHD and other heart diseases among persons with hemophilia, we analyzed data collected from the medical records of 3,422 males with hemophilia living in six U.S. states from 1993 to 1998. Heart disease cases were ascertained from among 2,075 persons who were hospitalized at least once during the 6-year period. Of these, 48 were diagnosed with IHD and 106, with other types of heart disease. The age-specific prevalence of IHD ranged from 0.05% in those under 30 years to 15.2% in those 60 years or older. Hospital discharge rates in males with hemophilia with IHD and other types of heart disease were lower compared to rates in age-matched U.S. males. In our cohort, as in the general population, IHD was independently associated with age, hypertension, diabetes, and hyperlipidemia. Other heart diseases were associated with HIV infection, hypertension, hemophilia B, and diabetes. In summary, persons with hemophilia have unique risk factors such as infusion of factor concentrates and infection with HIV that may predispose them to heart disease as their life expectancy increases.


Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents?
Co-infection has been reported in patients with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, but there is limited knowledge on co-infection among patients with coronavirus disease 2019 (COVID-19). The prevalence of co-infection was variable among COVID-19 patients in different studies, however, it could be up to 50% among non-survivors. Co-pathogens included bacteria, such as Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumonia, Legionella pneumophila and Acinetobacter baumannii; Candida species and Aspergillus flavus; and viruses such as influenza, coronavirus, rhinovirus/enterovirus, parainfluenza, metapneumovirus, influenza B virus, and human immunodeficiency virus. Influenza A was one of the most common co-infective viruses, which may have caused initial false-negative results of real-time reverse-transcriptase polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory and imaging findings alone cannot help distinguish co-infection from SARS-CoV-2 infection. Newly developed syndromic multiplex panels that incorporate SARS-CoV-2 may facilitate the early detection of co-infection among COVID-19 patients. By contrast, clinicians cannot rule out SARS-CoV-2 infection by ruling in other respiratory pathogens through old syndromic multiplex panels at this stage of the COVID-19 pandemic. Therefore, clinicians must have a high index of suspicion for coinfection among COVID-19 patients. Clinicians can neither rule out other co-infections caused by respiratory pathogens by diagnosing SARS-CoV-2 infection nor rule out COVID-19 by detection of non-SARS-CoV-2 respiratory pathogens. After recognizing the possible pathogens causing co-infection among COVID-19 patients, appropriate antimicrobial agents can be recommended.


New separation tools for comprehensive studies of protein expression by mass spectrometry.
Mass spectrometry has emerged as a core technique for protein identification and characterization because of its high sensitivity, accuracy, and speed of analysis. The most widespread strategy for studying global protein expression in biological systems employs analytical two-dimensional polyacrylamide gel electrophoresis (2D PAGE) followed by enzymatic degradation of isolated protein spots, peptide mapping, and bioinformatics searches. Using this method, thousands of proteins can be resolved in a gel and their expression quantified. However, certain types of proteins possessing important cellular functions are not easily analyzed using this strategy. These proteins include membrane, low copy number, highly basic, and very large (> 150 kDa) and small (< 10 kDa) proteins. To meet the growing need to simultaneously monitor all types of proteins in a biological system, new separation strategies have emerged that are amenable to hyphenation to mass spectrometric techniques. This article will review these new techniques and examine their usefulness in studies of protein expression.


Hearing aid benefit in patients with high-frequency hearing loss.
Patients with hearing loss limited to frequencies above 2 kHz are often considered borderline candidates for hearing aids. In this study, we used the Profile of Hearing Aid Benefit to access 134 patients' perceived benefit with a variety of linear hearing aids, some more capable than others at achieving prescribed frequency gain targets. We also sought to explore various audiologic and subject factors that might have led patients to report different degrees of success or failure with their hearing aids. Results demonstrate that subjects with hearing loss limited to frequencies above 2 kHz benefit significantly from amplification. However, the amount of benefit reported is mostly unrelated to the hearing aid gain and frequency response. Of numerous audiologic and demographic factors explored in the present study, the number of hours of hearing aid use per day turned out to be the most important single factor that was significantly related to the amount of reported hearing aid benefit. However, the predictive value of knowing how many hours per day subjects wore their aids, or any other combination of factors explored, was quite limited and only accounted for a small amount of the variability observed in user benefit.


Escherichia coli as a platform microbial host for systems metabolic engineering.
Bio-based production of industrially important chemicals and materials from non-edible and renewable biomass has become increasingly important to resolve the urgent worldwide issues including climate change. Also, bio-based production, instead of chemical synthesis, of food ingredients and natural products has gained ever increasing interest for health benefits. Systems metabolic engineering allows more efficient development of microbial cell factories capable of sustainable, green, and human-friendly production of diverse chemicals and materials. Escherichia coli is unarguably the most widely employed host strain for the bio-based production of chemicals and materials. In the present paper, we review the tools and strategies employed for systems metabolic engineering of E. coli. Next, representative examples and strategies for the production of chemicals including biofuels, bulk and specialty chemicals, and natural products are discussed, followed by discussion on materials including polyhydroxyalkanoates (PHAs), proteins, and nanomaterials. Lastly, future perspectives and challenges remaining for systems metabolic engineering of E. coli are discussed.


Curcumin, a component of turmeric: from farm to pharmacy.
Curcumin, an active polyphenol of the golden spice turmeric, is a highly pleiotropic molecule with the potential to modulate the biological activity of a number of signaling molecules. Traditionally, this polyphenol has been used in Asian countries to treat such human ailments as acne, psoriasis, dermatitis, and rash. Recent studies have indicated that curcumin can target newly identified signaling pathways including those associated with microRNA, cancer stem cells, and autophagy. Extensive research from preclinical and clinical studies has delineated the molecular basis for the pharmaceutical uses of this polyphenol against cancer, pulmonary diseases, neurological diseases, liver diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, and numerous other chronic diseases. Multiple studies have indicated the safety and efficacy of curcumin in numerous animals including rodents, monkeys, horses, rabbits, and cats and have provided a solid basis for evaluating its safety and efficacy in humans. To date, more than 65 human clinical trials of curcumin, which included more than 1000 patients, have been completed, and as many as 35 clinical trials are underway. Curcumin is now used as a supplement in several countries including the United States, India, Japan, Korea, Thailand, China, Turkey, South Africa, Nepal, and Pakistan. In this review, we provide evidence for the pharmaceutical uses of curcumin for various diseases.


A systematic review exploring the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose levels and metabolic complications in type 2 diabetes mellitus.
Citrus bioflavonoids are polyphenolic compounds that are derived from citrus fruits and vegetables. Although they are well known for their powerful antioxidant properties, their effects on glycemic control are not well understood. This review aims to highlight the potential benefits of using citrus bioflavonoids in patients with type 2 diabetes mellitus and its metabolic complications, as well as the medicinal effects of known subclasses of naturally occurring citrus bioflavonoids. In this systematic review, a survey of studies was conducted from January 2012 to February 2023 using various databases (PubMed, Medline, Google Scholar, and Scopus) to determine the effects of citrus bioflavonoid supplementation on reducing oxidative stress, improving lipid profiles, and glycemic index in patients with diabetes mellitus, as well as the proposed mechanisms of action. The results of the survey indicate that citrus bioflavonoids may have a positive impact on reducing oxidative stress levels in patients with type 2 diabetes mellitus. In addition to reducing oxidative stress, citrus bioflavonoids may also have a positive impact on other markers of diabetes. For example, studies have shown that they can reduce non-enzymatic protein glycation, which is a process that occurs when glucose molecules bind to proteins in the body. The reduction in oxidative stress that can be achieved using citrus bioflavonoids may help to maintain antioxidant levels in the body, thereby reducing the severity of diabetes and its complications. These findings suggest that citrus bioflavonoids may be a useful complementary therapy for patients with diabetes.


[Fixed-Drug Combination Amlodipine, Indapamide and Perindopril: New Horizons of Antihypertensive Therapy].
High prevalence of arterial hypertension and low rate of blood pressure (BP) control in patients with arterial hypertension require more intensive approaches to antihypertensive therapy. Every patient with arterial hypertension is characterized by different predominant pathophysiologic mechanisms in different periods of his life. Because of impact on different pathophysiologic mechanisms combined antihypertensive therapy allows to achieve more pronounced BP reduction, decrease heterogeneity of response and alleviate side effects of each component. Use of fixed drug combinations improves adherence to treatment and thus its efficacy. Novel fixed-dose combination of amlodipine, indapamide and perindopril fully realizes principles underlying modern antihypertensive therapy. Antihypertensive effectiveness of components of this combination has been confirmed by the results of international trials.


Structural analysis of the elongation factor G protein from the low-temperature-adapted bacterium Arthrobacter globiformis SI55.
The first structural analysis of elongation factor G (EF-G) from a cold-adapted bacterium is presented. EF-G is an essential protein involved in the elongation process during protein synthesis and is therefore thought to play a crucial role in the low-temperature adaptation of cold-adapted microorganisms. To define its importance, the EF-G gene (fus) from the psychrotolerant bacterium Arthrobacter globiformis SI55 was cloned and sequenced. The deduced primary structure of the elongation factor is composed of 700 amino acids with a predicted molecular mass of 77.4 kDa. A three-dimensional model of the protein was constructed based on the known crystal structures of structurally homologous proteins. Structural features that might potentially be important for activity and flexibility at low temperature were deduced by comparisons with models of the EF-G proteins from the closely related mesophiles Micrococcus luteus and Mycobacterium tuberculosis. These features include a loss in the number of salt bridges in intradomain and interdomain positions, increased solvent interactions mediated by greater charge and polarity on domain surfaces, loop insertions, loss of proline residues in loop structures, and an increase of hydrophobicity in core regions. Specific changes have also been identified in the catalytic domain (G domain) and sites of potential ribosome interaction, which may directly affect guanosine triphosphate (GTP) hydrolysis and elongation rates at low temperature.


Effects of a best-possible-self mental imagery exercise on mood and dysfunctional attitudes.
Dispositional optimism has been related to positive physical and mental health outcomes, increased positive mood ratings and cognitions about the future. In order to determine the causal relation between optimism and mood and cognitions optimism should be manipulated experimentally. The current study tested the effects of a best-possible-self mental imagery exercise on affect and mood ratings and dysfunctional cognitions following a sad mood induction in undergraduate students (N=40). Participants in the experimental condition wrote about their best possible self in the future for 15 min and engaged in a mental imagery task about their best possible self in the future for 5 min in order to experimentally induce optimism. Participants in the control condition wrote about a typical day for 15 min and engaged in mental imagery about a typical day for 5 min. We assessed affect, mood and dysfunctional cognitions before and after the experimental manipulation. Participants in the experimental condition had higher positive mood ratings and higher positive affect compared to participants in the control condition. Participants in the control condition reported decreased dysfunctional cognitions whereas dysfunctional cognitions in the experimental group remained unchanged. Future studies should replicate these findings in clinical groups with more profound levels of negative affect and dysfunctional cognitions.


Association of US Centers for Medicare and Medicaid Services Hospital 30-Day Risk-Standardized Readmission Metric With Care Quality and Outcomes After Acute Myocardial Infarction: Findings From the National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines.
The US Centers for Medicare and Medicaid Services Hospital Readmissions Reduction Program penalizes hospitals with higher-than-expected risk-adjusted 30-day readmission rates (excess readmission ratio [ERR] > 1) after acute myocardial infarction (MI). However, the association of ERR with MI care processes and outcomes are not well established. To evaluate the association between ERR for MI with in-hospital process of care measures and 1-year clinical outcomes. Observational analysis of hospitalized patients with MI from National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines centers subject to the first cycle of the Hospital Readmissions Reduction Program between July 1, 2008, and June 30, 2011. The ERR for MI (MI-ERR) in 2011. Adherence to process of care measures during index hospitalization in the overall study population and risk of the composite outcome of mortality or all-cause readmission within 1 year of discharge and its individual components among participants with available Centers for Medicare and Medicaid Services-linked data. The median ages of patients in the MI-ERR greater than 1 and tertiles 1, 2, and 3 of the MI-ERR greater than 1 groups were 64, 63, 64, and 63 years, respectively. Among 380 hospitals that treated a total of 176 644 patients with MI during the study period, 43% had MI-ERR greater than 1. The proportions of patients of black race, those with heart failure signs at admission, and bleeding complications increased with higher MI-ERR. There was no significant association between adherence to MI performance measures and MI-ERR (adjusted odds ratio, 0.94; 95% CI, 0.81-1.08, per 0.1-unit increase in MI-ERR for overall defect-free care). Among the 51 453 patients with 1-year outcomes data available, higher MI-ERR was associated with higher adjusted risk of the composite outcome and all-cause readmission within 1 year of discharge. This association was largely driven by readmissions early after discharge and was not significant in landmark analyses beginning 30 days after discharge. The MI-ERR was not associated with risk for mortality within 1 year of discharge in the overall and 30-day landmark analyses. During the first cycle of the Hospital Readmissions Reduction Program, participating hospitals' risk-adjusted 30-day readmission rates following MI were not associated with in-hospital quality of MI care or clinical outcomes occurring after the first 30 days after discharge.


[Transfusion related acute lung injury (TRIALI)--case report].
Transfusion related acute lung injury (TRALI) is a relatively rare but potentially severe complication of blood transfusion. Acute respiratory distress syndrome in this case is due to noncardiogenic pulmonary oedema without hypervolaemia. The passive transfer of anti-human leukocyte antigen (HLA) or antineutrophil antibodies in the donated blood products are responsible for the pathophysiological process in TRALI. Less commonly, the recipient may have antibodies which interact with white cells in the donor products. Most commonly TRALI may appear during whole blood, packed cells and fresh frozen plasma transfusions. The increased risk of TRALI is observed when a donors are multiparous women and additionally when older, stored blood components are used for transfusion. The only therapy which can be recommended as standard treatment of TRALI is ventilatory assistance and saline infusion. The case of 70-year-old woman with the fracture of the right femoral bone, who developed TRALI after transfusion of packed red cells is presented in the paper. It is the first case of TRIALI reported in our department.


The role of fibronectin in cell adhesion to spiral patterned TiO2 nanoparticles.
Spiral micropatterned surfaces of decreasing dimensions were produced by photo-immobilizing a photo-reactive hyaluronan (Hyal) derivative on TiO2 nanoparticles. The microstructured surfaces were characterized by both scanning electron microscopy and atomic force microscopy analysis. The behavior, of both endothelial cells (HCAEC) and tumoral mouse fibroblasts (NIH3T3) on the patterned surfaces was evaluated. HCAEC adhered only to the TiO2 nanoparticles avoiding contact with the Hyal. NIH3T3 adhered to and completely covered the TiO2 spiral but prolonging the culture time, it also covered the external photo-immobilized Hyal surface. The role of fibronectin to mediate cell adhesion to the TiO2 pattern surfaces was evaluated by experiments with blocked fibronectin membrane receptors on both HCAEC and NIH3T3. The results showed the absence of any adhering cells. Therefore, fibronectin seemed to be the only key protein in mediating cell adhesion to these TiO2 substrates.


The incidence of clinically diagnosed versus research-identified autism in Olmsted County, Minnesota, 1976-1997: results from a retrospective, population-based study.
Autism prevalence studies have often relied on administrative prevalence or clinical diagnosis as case-identification strategies. We report the incidence of clinical diagnoses of autism spectrum disorders (ASD), versus research-identified autism among residents of Olmsted County, Minnesota, age < or =21 years, from 1976-1997. The incidence of clinically diagnosed ASD (with 95% CI) was 1.5 per 100,000 (0.0-3.7) in 1980-1983 and 33.1 (22.8-43.3) in 1995-1997, a 22.1-fold increase. In contrast, the incidence of research-identified autism increased from 5.5 (1.4-9.5) per 100,000 to 44.9 (32.9-56.9), an 8.2-fold increase. Only 46.8% of research-identified cases received a clinical diagnosis of ASD. These findings demonstrate the potential for misleading interpretation of results from epidemiologic studies that rely on clinical diagnosis of autism to identify cases.


The role of physical activity enjoyment in the pathways from the social and physical environments to physical activity of early adolescent girls.
Most girls experience a notable decline in physical activity (PA) in early adolescence, increasing their risk for harmful health outcomes. Enjoyment for PA (i.e., positive feelings toward PA) is a determinant of PA among girls during adolescence and sustained PA throughout adulthood. Previous studies recommended increasing girls' PA enjoyment in order to increase their PA, but did not include environmental-level strategies for how families, schools, or communities do this. To gain insight on such strategies, this study examines the role of PA enjoyment as a mediator of social and physical environments to moderate-to-vigorous intensity PA of early adolescent girls. Cross-sectional, secondary analyses, using structural equation modeling, were conducted on a U.S. national dataset of 1721 sixth grade girls from the Trial of Activity for Adolescent Girls in 2003. Mediation model fit parameters included χ2 (292, N = 1721) = 947.73 p < 0.001, CFI = 0.95, RMSEA = 0.04 (90% CI = 0.03, 0.04), and SRMR = 0.037 suggesting overall good fit. There were no indirect effects on PA through PA enjoyment from the social or physical environmental factors. To PA, there were significant direct effects only from social support from friends (β = 0.15, CI = 0.09, 0.22). To PA enjoyment, there were significant direct effects from social support from family (β = 0.15, CI = 0.08, 0.23), school climate (teachers β = 0.15, CI = 0.10, 0.21 and boys β = 0.15, CI = 0.09, 0.20), and neighborhood environment (β = 0.10, CI = 0.04, 0.17). The findings of this study identified several direct effects of the social and physical environment on PA enjoyment that can begin to inform environmental-level strategies for increasing PA enjoyment among early adolescent girls.


Oocyte-granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence.
Homologous gap junctions are generally recognized as a means of coordinating cellular behavior under developmental and homeostatic conditions. In the mammalian ovary, heterologous gap junctions between the oocyte and the granulosa cells have been widely implicated in the regulation of meiotic maturation late in oogenesis. However, the role of oocyte-granulosa cell gap junctions at earlier stages of oogenesis is poorly understood. Stage-specific defects in both oocyte and follicle development have been identified in juvenile mice deficient in heterologous oocyte-granulosa cell gap junctions due to targeted deletion of Gja4, the gene encoding connexin-37. Follicle development arrests at the type 4 preantral stage and although oocytes commence growth, oocyte growth ceases at a diameter of 52 microm (74.3% of control size). Analysis of cell cycle and cytoskeletal markers indicates that oocytes arrest in a G(2) state based on uniform decondensed GV chromatin, interphase microtubule arrays, and nonphosphorylated cytoplasmic centrosomes. Functional assays of meiotic competence confirm that oocytes from connexin-37-deficient mice are unable to enter M phase (initiate meiotic maturation) unless treated with the phosphatase inhibitor okadaic acid (OA). Unlike growing oocytes from heterozygous control animals, OA-treated oocytes from connexin-37-deficient mice respond acutely and progress rapidly to the circular bivalent stage of meiosis I and upon removal from OA rapidly revert to an interphase state. In contrast, OA-treated control incompetent oocytes are slow to respond, exhibit a lower proportion of chromosomal bivalent stage oocytes, but remain in and progress into meiotic M phase upon removal from OA. This study demonstrates that heterologous gap-junctional communication is required for the completion of oocyte growth and the acquisition of cytoplasmic meiotic competence.


An in vitro atomic force microscopic study of commercially available dental luting materials.
The aim of this in vitro study was to compare the surface roughness parameters of four different types of dental luting agents used for cementation of implant restorations. Five specimens (8 mm high and 1 mm thick) of each cement were made using metal ring steelless molds. Atomic Force Microscope was employed to analyze different surface texture parameters of the materials. Bearing ratio analysis was used to calculate the potential microgap size between the cement and implant material and to calculate the depth of the valleys on the cement surface, while power spectral density (PSD) measurements were performed to measure the percentage of the surface prone to bacterial adhesion. Glass ionomer cement showed significantly lower value of average surface roughness then the other groups of the materials (P < 0.05) which was in line with the results of Bearing ratio analysis. On the other side, PSD analysis showed that zinc phosphate cement experience the lowest percentage of the surface which promote bacterial colonization. Glas ionomer cements present the surface roughness parameters that are less favorable for bacterial adhesion than that of zinc phosphate, resin-modified glass ionomer and resin cements.


Isothermal amplification and fluorescent detection of SARS-CoV-2 and SARS-CoV-2 variant virus in nasopharyngeal swabs.
The COVID-19 pandemic caused by the SARS-CoV-2 is a serious health threat causing worldwide morbidity and mortality. Real-time reverse transcription PCR (RT-qPCR) is currently the standard for SARS-CoV-2 detection. Although various nucleic acid-based assays have been developed to aid the detection of SARS-CoV-2 from COVID-19 patient samples, the objective of this study was to develop a diagnostic test that can be completed in 30 minutes without having to isolate RNA from the samples. Here, we present an RNA amplification detection method performed using reverse transcription loop-mediated isothermal amplification (RT-LAMP) reactions to achieve specific, rapid (30 min), and sensitive (<100 copies) fluorescent detection in real-time of SARS-CoV-2 directly from patient nasopharyngeal swab (NP) samples. When compared to RT-qPCR, positive NP swab samples assayed by fluorescent RT-LAMP had 98% (n = 41/42) concordance and negative NP swab samples assayed by fluorescent RT-LAMP had 87% (n = 59/68) concordance for the same samples. Importantly, the fluorescent RT-LAMP results were obtained without purification of RNA from the NP swab samples in contrast to RT-qPCR. We also show that the fluorescent RT-LAMP assay can specifically detect live virus directly from cultures of both SARS-CoV-2 wild type (WA1/2020), and a SARS-CoV-2 B.1.1.7 (alpha) variant strain with equal sensitivity to RT-qPCR. RT-LAMP has several advantages over RT-qPCR including isothermal amplification, speed (<30 min), reduced costs, and similar sensitivity and specificity.


Low-Latency Line Tracking Using Event-Based Dynamic Vision Sensors.
In order to safely navigate and orient in their local surroundings autonomous systems need to rapidly extract and persistently track visual features from the environment. While there are many algorithms tackling those tasks for traditional frame-based cameras, these have to deal with the fact that conventional cameras sample their environment with a fixed frequency. Most prominently, the same features have to be found in consecutive frames and corresponding features then need to be matched using elaborate techniques as any information between the two frames is lost. We introduce a novel method to detect and track line structures in data streams of event-based silicon retinae [also known as dynamic vision sensors (DVS)]. In contrast to conventional cameras, these biologically inspired sensors generate a quasicontinuous stream of vision information analogous to the information stream created by the ganglion cells in mammal retinae. All pixels of DVS operate asynchronously without a periodic sampling rate and emit a so-called DVS address event as soon as they perceive a luminance change exceeding an adjustable threshold. We use the high temporal resolution achieved by the DVS to track features continuously through time instead of only at fixed points in time. The focus of this work lies on tracking lines in a mostly static environment which is observed by a moving camera, a typical setting in mobile robotics. Since DVS events are mostly generated at object boundaries and edges which in man-made environments often form lines they were chosen as feature to track. Our method is based on detecting planes of DVS address events in x-y-t-space and tracing these planes through time. It is robust against noise and runs in real time on a standard computer, hence it is suitable for low latency robotics. The efficacy and performance are evaluated on real-world data sets which show artificial structures in an office-building using event data for tracking and frame data for ground-truth estimation from a DAVIS240C sensor.


Nationwide Analysis of Changes in Medical Utilization Before and After a New Panic Disorder Diagnosis.
Panic disorder (PD) is associated with somatization and high medical utilization in primary care settings. Treatment of PD could reduce the frequency of panic attacks and visits to emergency departments, but the associated change in medical utilization is unknown. This study investigated the change in medical utilization before and after a PD diagnosis. This study identified 8722 patients with PD enrolled in the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2012. We used a case-crossover study design to compare medical utilizations with a 1-year time window before and after new PD diagnoses, including medical examinations, specialty visits, and medication used. A conditional logistic regression model was used to estimate changes in comorbidity before and after new PD diagnoses. The utilization of examinations-including electrocardiography, radiography, and sonography-decreased within 1 year after PD diagnosis compared with 1 year before PD diagnosis. Outpatient and emergency department visits to nonpsychiatric departments decreased (risk ratio [RR] = 0.989 [95% confidence interval {CI} = 0.985-0.993] and RR = 0.924 [95% CI = 0.894-0.956], respectively), whereas outpatient visits to psychiatric departments increased (RR = 1.193, 95% CI = 1.171-1.215). PD diagnosis is associated with increased use of antidepressants (RR = 12.65) and benzodiazepines (RR = 11.63), an increased ratio of comorbid depressive disorder (RR = 3.06) and bipolar disorder (RR = 1.77), and a decreased ratio of nonpanic anxiety disorder (RR = 0.69). New PD diagnoses are associated with decreased laboratory examination and nonpsychiatric service utilization, along with increased psychiatric service utilization. We suggest that PD should be detected earlier for mitigating potentially unnecessary use of nonpsychiatric examinations and services.


Immunologic basis of reproductive failure.
This article has reviewed the immunologic factors of human infertility and some of the animal models that have provided experimental evidence for the better understanding of these disorders. It is clear that definitive evidence for human autoimmune diseases of the gonads is still lacking. However, recent findings in infertile men represent tangible support for this possibility and should stimulate further studies. Insofar as these diseases are relatively rare, meaningful clinical investigations can best come from a multicenter effort based on patients with well-defined clinical and laboratory profiles. To arrive at a firmer immunologic basis for these human diseases, it will be helpful to extrapolate from experimental studies. For both testicular and ovarian diseases, it will be desirable to refine the methods for quantifying humoral and cellular immune responses to the organ-specific autoantigens in the testis and ovary. Immunohistochemical localization of immune reactants is likely to be successful when performed early in the disease process and on tissue from patients with active disease. The nature of the immune deposits in testes will need to be confirmed by the classic approach of elution of antibody from the tissue with dissociating agents, followed by quantitation. The large quantity of tissue required for study can come from orchiectomy specimens from infertile men with unilateral vasal stenosis. In addition to immunologic reactions that lead to inflammation, future studies should take into consideration the possible existence of autoantibodies that react against hormone receptors or other functional ligands involved in ovarian or testicular physiology. Despite the paucity of evidence for human autoimmune diseases of the gonads, the likelihood of existence of these diseases is also supported by the ease with which experimental autoimmune disease of the gonads can be induced. We have described the experimental models of gonadal autoimmune diseases in detail, since analysis of these diseases has led to some unique contributions to immunopathology research and the physiology of the gonads. It is anticipated that future studies will characterize the target antigens as well as the local and systemic mechanisms that prevent autoimmune disease of the gonads in normal individuals. Moreover, it is anticipated that the model of neonatal thymectomy and oophoritis/orchitis will help to define the intricate interplay among thymic function, tolerance mechanisms, and autoimmunity. It is important to emphasize that research on the maternal-fetal immunologic relationship is a rapidly moving and controversial field. Although we have tried to point out controversial areas, the reader may wish to consult several excellent recent reviews. The anatomy and function of the hemochorial placenta and decidua are extraordinarily complex.(ABSTRACT TRUNCATED AT 400 WORDS)


Complex population history of two Anopheles dirus mosquito species in Southeast Asia suggests the influence of Pleistocene climate change rather than human-mediated effects.
Anopheles dirus and Anopheles baimaii are closely related species which feed on primates, particularly humans, and transmit malaria in the tropical forests of mainland Southeast Asia. Here, we report an in-depth phylogeographic picture based on 269 individuals from 21 populations from mainland Southeast Asia. Analysis of 1537 bp of mtDNA sequence revealed that the population history of A. baimaii is far more complex than previously thought. An old expansion (pre-300 kyr BP) was inferred in northern India/Bangladesh with a wave of south-eastwards expansion arriving at the Thai border (ca 135-173 kyr BP) followed by leptokurtic dispersal very recently (ca 16 kyr BP) into peninsular Thailand. The long and complex population history of these anthropophilic species suggests their expansions are not in response to the relatively recent (ca 40 kyr BP) human expansions in mainland Southeast Asia but, rather, fit well with our understanding of Pleistocene climatic change there.


A Diagnostic Dilemma of Sinonasal T Cell Lymphoma: Report of A Unique Case and Literature Review.
Natural Killer/T-cell non-Hodgkin lymphomas are rare and aggressive disease of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction and necrosis. It has a strong association with Epstein-Barr virus (EBV) as the lymphoma cells are almost invariably infected with the clonal episomal form of EBV. Because of their rarity, it is a challenge to diagnose and treat them even to the experienced pathologists. The featured case describes a 40-year-old male who presented with symptoms suggestive for sinusitis. Further diagnostic investigation by the functional endoscopic sinus surgery (FESS) revealed a chronic sinusitis with multiple biopsies showing negative for malignancy, viral and bacterial infections and therefore undiagnosed for sinonasal NK/T-cell lymphoma. Subsequently after a month of surgery, he developed multiple lymph nodes in inguinal where biopsy revealed extranodal NK/T-cell non-Hodgkin lymphoma, high grade but in no time for treatment, he finally succumbed to the illness. The case presented here was initially diagnosed as a chronic sinusitis, not as sinonasal NK/Tcell lymphoma which later developed into extranodal NK/T-cell lymphoma. The prognosis showed improvement for nasal lymphomas but remains poor for disseminated and extranasal lymphomas which are more aggressive with lower survival rate. It is clinically important to differentiate diseases for proper staging and monitoring as they require completely different treatment strategies.


Response to anti-vascular endothelial growth factor of abnormal retinal vascular net in para foveal telangiectasia group II images on optical coherence tomography-angiography.
To identify optical coherence tomography-angiography (OCT-A) findings to predict treatment response during anti-vascular endothelial growth factor (VEGF) therapy in eyes with para foveal telangiectasia (PFT) group II. In this retrospective series, Twelve eyes of seven patients diagnosed with PFT group II without evidence of sub-retinal neovascular membrane (SRNVM) clinically or on spectral domain-OCT (SD-OCT) were included. All patients underwent OCT-A on the Topcon DRI OCT Triton® with 4.5 mm macula scans. The patients with abnormal vascular nets were further classified into type A and B nets and administered intravitreal anti-VEGF therapy. Visual acuity and size of type A and B nets were evaluated pre- and post-injection. Paired t- test and intraclass correlation were used to analyse data. Patients with type A net showed significant improvement in visual acuity (logMAR 0.38, P = 0.0047). The size of type A net showed statistically significant decrease (P = 0.0008) on 6 month follow up. Type B net did not show statistically significant difference in visual acuity or size following anti-VEGF therapy. OCT-A plays an important role in early detection of possible neovascular nets (type A), in the absence of obvious SRNVM. Treatment decisions based on OCT-A may be helpful to achieve better visual outcome.


Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus.
Much attention is being given to the identification of common disease genes through whole-genome linkage disequilibrium (LD) screens with single nucleotide polymorphisms (SNPs). Simulation studies have suggested that useful LD is unlikely to extend beyond 3 kb, and that > 500,000 SNPs may be needed for comprehensive coverage of the genome. The TCR alpha/delta locus on chromosome 14q contains many V, J and D segments that combine with constant domains to produce either an alpha or a delta chain of the T cell receptor. Multiple SNPs have been recognized within the V segments, and it has been suggested that variation within the locus may modify the course of autoimmune and allergic diseases. We have examined LD within an 850 kb section of the TCR alpha/delta locus on chromosome 14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and fifty-nine nuclear and extended families were genotyped in order to derive haplotypes, and the pair-wise LD between SNPs was investigated in 600 haplotypes from unrelated individuals (the parents). The mean extent of useful LD was much greater than suggested by simulations: significant LD was relatively common at 250 kb and was detectable beyond 500 kb. The mean extent of LD was twice as far between alleles of low frequency than between common alleles. The distribution of LD was highly irregular and concentrated in three distinct islands. The results differ from those obtained by simulation, and if they are typical of other genomic regions, suggest that the minimum number of markers necessary for comprehensive LD mapping may be reduced by at least an order of magnitude.


Anterior shift in gene expression precedes anteriormost digit formation in amniote limbs.
In tetrapod limbs, an anteriormost digit has common traits of small, short and less-phalange morphology. In this study, we focused on three genes, Mkp3, Sef and Tsukushi (TSK), which have anterior-specific or anterior-prominent expression patterns in the developing limb bud at the autopod-forming stage. The anterior expression is not fixed in the period of limb development, but the expression domains of Mkp3, Sef and TSK change considerably from the distal domain to the anterior domain. This change in expression domains, anterior shift, of these genes involves maintenance of gene expression in the anterior side and downregulation in the posterior side. Manipulated overdose of fibroblast growth factor (FGF) in the presumptive digit 2 region of chick forelimb bud results in elongation of cartilage elements of digit 2, suggesting that attenuated FGF signaling, which Mkp3, Sef, and TSK negatively regulate, provides digit 2-specific traits of morphology. The anterior expression of Mkp3 and Sef but not TSK is conserved also in limb buds of the mouse and gecko, and the anterior shift of these genes, accumulation of their transcripts in the anterior side and appropriate regulation of strength of FGF signaling may control species-specific morphology of the anteriormost digit.


Histoplasma variation and adaptive strategies for parasitism: new perspectives on histoplasmosis.
This review summarizes the biology of Histoplasma capsulatum in relation to a wide variety of corresponding pathologies in histoplasmosis. Features of these disease syndromes can be explained in part by natural variations within the fungal population and adaptations made by individual organisms to specific environments. H. capsulatum grows as mycelia and conidia in the soil; once inhaled, the organism undergoes a dramatic morphological and physiological conversion to a yeast form. The yeasts proliferate within the phagolysosomes of macrophages, using a variety of specific strategies for intracellular survival. Even avirulent strains or variants are able to avoid being killed by macrophages and instead establish inapparent or persistent infections. The ingested avirulent organisms assume enlarged shapes similar in appearance to those seen in histological sections of tissues from patients with histoplasmosis. Respiratory tract epithelial cells also appear to play a role in persistence: within them yeasts undergo phenotypic switching akin to the phase variation observed in other pathogens. This particular change involves the loss or modification of cell wall alpha-(1,3)-glucan, which is also correlated with the spontaneous appearance of avirulent variants. The repertoire of adaptive responses and natural variations within this species probably evolved from the need to adjust to a wide range of dynamic environments. In combination with the immune status of the host, these characteristics of H. capsulatum appear to influence the epidemiology, extent, and persistence of histoplasmosis.


Loco-regional interventional treatment of hepatocellular carcinoma: techniques, outcomes, and future prospects.
Loco-regional interventional treatments continue to evolve and to play a major role in the therapeutic management of hepatocellular carcinoma (HCC). Image-guided ablation is established as the treatment of choice for patients with early-stage HCC when transplantation or resection is precluded. Recent refinements in technique have substantially increased the ability of radiofrequency ablation to achieve sustained complete response of target tumors in properly selected patients, and new alternate thermal and nonthermal methods for local tumor treatment are currently under investigation. Transarterial chemoembolization (TACE) is the standard of care for patients with multinodular disease at the intermediate stage. The introduction of drug-eluting beads--that enhance drug delivery to the tumor and reduce systemic exposure--appears to improve anticancer activity and safety profile of TACE compared with conventional regimens. Despite these advances, the long-term outcomes of patients treated with loco-regional therapies remain unsatisfactory because of the high rate of tumor recurrence. The introduction of molecular targeted therapies that inhibit tumor proliferation and angiogenesis has opened new prospects in this regard. Clinical trials focused on combining interventional treatment with systemically active drugs are ongoing. The outcomes of such studies are eagerly awaited, as they have the potential to revolutionize treatment of HCC.