Na,K-ATPase alpha isoforms at the blood-cerebrospinal fluid-trigeminal nerve and blood-retina interfaces in the rat.
Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted. Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively. The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and -3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier. Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer.


Patterns of coronary heart disease mortality over the 20th century in England and Wales: Possible plateaus in the rate of decline.
Coronary heart disease (CHD) rates in England and Wales between 1950 and 2005 were high and reasonably steady until the mid 1970s, when they began to fall. Recent work suggests that the rate of change in some groups has begun to decrease and may be starting to plateau or even reverse. Data for all deaths between 1931 and 2005 in England and Wales were grouped by year, sex, age at death and contemporaneous ICD code for CHD as cause of death. CHD mortality rates by calendar year and birth cohort were produced for both sexes and rates of change were examined. The pattern of increased burden of CHD mortality within older age groups has only recently emerged in men, whereas it has been established in women for far longer. CHD mortality rates among younger people showed little variation by birth cohort. For younger women (49 and under), the rate of change in CHD mortality has reversed in the last 20 years, indicating a future plateau and possible reversal of previous improvement in CHD mortality rates. Among younger men the rate of change in CHD mortality has been consistent for the past 15 years indicating that rates in this group have continued to fall steadily. Although CHD mortality rates continue to drop in older age groups the actual burden of coronary heart disease is increasing due to the ageing of the population. The rate of improvement in CHD mortality appears to be beginning to decline and may even be reversing among younger women.


Fiber Surface/Interfacial Engineering on Wearable Electronics.
Surface/interfacial engineering is an essential technique to explore the fiber materials properties and fulfil new functionalities. An extensive scope of current physical and chemical treating methods is reviewed here together with a variety of real-world applications. Moreover, a new surface/interface engineering approach is also introduced: self-assembly via π-π stacking, which has great potential for the surface modification of fiber materials due to its nondestructive working principle. A new fiber family member, metal-oxide framework (MOF) fiber shows promising candidacy for fiber based wearable electronics. The understanding of surface/interfacial engineering techniques on fiber materials is advanced here and it is expected to guide the rational design of future fiber based wearable electronics.


Postpartum hemorrhage with associated placenta previa in a kidney transplant recipient: A case report.
The efficacy and safety of uterine artery embolization (UAE) and prophylactic resuscitative endovascular balloon occlusion of the aorta (REBOA) against postpartum hemorrhage (PPH) in pregnant women after kidney transplantation have not been reported. Here, we describe a case of PPH associated with placenta previa in pregnancy following kidney transplantation, which was managed with UAE and prophylactic REBOA. A 35-year-old, gravida 2, para 1 woman with total placenta previa presented with vaginal bleeding (460 mL) at 33 weeks and 3 days of gestation. Previously, she underwent a living-donor kidney transplantation for IgA nephropathy, and the renal artery of the transplanted kidney was anastomosed with the right internal iliac artery. An emergency cesarean section with prophylactic REBOA was performed under general anesthesia. A balloon catheter was introduced via the left femoral artery and positioned above the aortic bifurcation (Aortic zone 3). Upon confirming fetal delivery, the balloon was immediately inflated, and the total aortic occlusion time was 20 min. However, following aortic balloon deflation, atonic bleeding continued despite Bakri balloon usage and uterotonic drug administration. Subsequently, UAE was performed for the refractory PPH, the left uterine artery was embolized using a gelatin sponge, and hemostasis was successfully achieved. The patient recovered uneventfully and was discharged on postoperative day 7. In pregnancies following kidney transplantation, prophylactic REBOA controls bleeding; however, it decreases blood flow to the transplanted kidney. Furthermore, uterine nutrient vasculature alterations are observed, necessitating a thorough understanding of the uterine artery supply pathways during UAE.


[Diagnosis and treatment of Sturge-Weber syndrome associated with retinal detachment].
To access the diagnosis and treatment of Sturge-Weber syndrome at late stage. The male patient aged 65 visited the eye clinic with presenting symptom of visual loss of the left eye for 2 months. Ocular examination disclosed a facial hemangioma with the size of 2 cm x 3 cm on the nasal side of the left upper eyelid associated with engorged bulbar conjunctival and episcleral vessels in the upper nasal quadrant. Ophthalmoscopy revealed total detachment of the retina. Esotropia was measured as 10 degrees. Intraocular pressure was 24 mmHg. Electroretinogram (ERG) demonstrated an indistinguished pattern. Posterior trans-scleral and ciliary body cryocoagulation was applied followed by external release of the subretinal fluid. The retina became reattached with visual acuity of 0.3 and intraocular pressure was 15 mmHg of the left eye at 5 months postoperatively. Fluorescein angiographical findings were consistent with diffuse hemangioma of the choroid. Follow-up study for 6 years revealed that the retina remained attached with visual acuity of 0.8 and essentially normal electroretinogram. The small facial hemangioma was the clue for the diagnosis of Sturge-Weber syndrome and cryocoagulation was the procedure of choice for the treatment of retinal detachment with favorable visual outcome.


A new method to assess the fluidodynamic behaviour of an angiographic contrast agent.
To propose a new method for the assessment of the fluidodynamic behaviour of angiographic contrast agents. The method enables measurement of the spatial distribution and time dependence of the contrast agent along a pseudo-vessel on images obtained with an X-ray image intensifier. A particular phantom was devised consisting of a plexiglas box with an insert into which a latex tube with a 0.4 cm in diameter was placed in order to simulate the tortuous flow of a blood vessel. The box, which is filled with water to simulate the thickness of a normal patient, is connected to an injection and pumping system which serve to keep the contrast agent flowing in the pseudo-vessel tube. The pseudo-vessel tube was filled with plain water in one case and with saline solution in another case to assess their different dilution capabilities. The phantom and the flow of contrast agent were imaged with a conventional X-ray image intensifier system and the images were stored in digital format during 35 second acquisitions at a speed of 4 frames per second; for any frame it is possible to measure the mathematical contrast in any position in the image. Further, a diagram showing the time dependence of the spatial distribution of the mathematical contrast is proposed. The X axis shows the spatial distribution of the mathematical contrast, whereas the Y axis shows its temporal variation with a gray level proportional to the mathematical contrast value. By building an horizontal profile of this diagram one can obtain the spatial distribution at a fixed time, while by building a vertical profile one can obtain the temporal variation at a fixed point. Several different contrast agents were so tested. The proposed method allows different fluido-dynamic behaviour patterns of contrast agents and flowing media to be shown. Owing to the different chemical characteristics of water and saline solution these media have different dilution capabilities (higher for water) and this is well demonstrated by the diagram profiles obtained for each. The system has also allowed the detection of a particular behaviour of some contrast agents, whose spatial distribution was non uniform even in the last frames, thus showing a tendency to maintain their bolus-nature over time. An interesting feature which can be noticed in all the temporal profiles is the presence of a "pre-bolus", i.e. the contrast is higher at the very beginning of the flow, then decreases and after some time starts to increase again. Though the initial contrast value obviously depends on the iodine concentration employed, the method shows the contrast variation as a function of time is different for different contrast agents. The method and the equipment proposed provide a good description of the fluidodynamic behaviour of different contrast agents, but do not constitute a reference method for testing haemodynamic behaviour which, "in vivo", is obviously affected by several other chemical and metabolic factors. However, the method allows evaluation of the contrast agents from a physical and fluidodynamic point of view, showing that the iodine content is not the only feature affecting their behaviour. The method can be used in quality control to test the constancy of the physical behaviour of different contrast agents.


Validation of a medium-throughput method for evaluation of intracellular growth of Mycobacterium tuberculosis.
Intracellular pathogens such as Mycobacterium tuberculosis have adapted to a life inside host cells, in which they utilize host nutrients to replicate and spread. Ineffective methods for the evaluation of growth of intracellular pathogens in their true environment pose an obstacle for basic research and drug screening. Here we present the validation of a luminometry-based method for the analysis of intramacrophage growth of M. tuberculosis. The method, which is performed in a medium-throughput format, can easily be adapted for studies of other intracellular pathogens and cell types. The use of host cells in drug-screening assays dedicated to find antimicrobials effective against intracellular pathogens permits the discovery of not only novel antibiotics but also compounds with immunomodulatory and virulence-impairing activities, which may be future alternatives or complements to antibiotics.


Accepting Medication Therapy Management Recommendations to Add ACEIs or ARBs in Diabetes Care.
National guidelines and initiatives have promoted the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for patients with diabetes. The University of Arizona Medication Management Center (UA-MMC) is contracted by Medicare health plans, pharmacy benefit managers (PBMs), and multiple commercial health insurance plans to provide medication therapy management (MTM) services for plan members. As part of the MTM program, recommendations have been made for those patients who may benefit from the addition of an ACEI/ARB. Although the intervention benefits and guidelines for using ACEIs/ARBs are clear, real-world evidence is needed to understand and potentially increase uptake of guideline interventions among eligible patients. To (a) identify patient characteristics that predict acceptance of guideline recommendations to add ACEI/ARB medications to diabetic treatment via MTM services and (b) examine how well different case characteristics (i.e., patient age and sex, type and number of recommendation attempts, type of health care plan) predict the odds of adding ACEI/ARB medications to diabetic regimens when recommended through an MTM call center. This was a retrospective analysis of secondary data provided by the UA-MMC. The de-identified national data included adult plan members with diabetes who the UA-MMC recommended adding an ACEI/ARB prescription based on 2012 national guidelines. The UA-MMC made recommendations by either patient letters, patient phone calls, physician faxes, or any combination thereof. We conducted a binary logistic regression analysis to assess the impact of case characteristics on the likelihood of accepting recommendations to add ACEI/ARB medications. The outcome variable was recommendation acceptance (yes/no), defined as new prescription claims for an ACEI/ARB within 120 days following the recommendation. Five predictor variables were assessed: (1) patient's age quartile; (2) method of communicating recommendations (letter, phone call, fax, or some combination thereof); (3) whether recommendations were made once or twice on separate dates; (4) patient's sex; and (5) type of health care plan. Recommendations were made for 31,495 members of health plans or PBMs that contracted with the UA-MMC. Patients' ages ranged from 19-90 (Mean =72.01; SD =10.21), with females comprising 56% of the sample. The recommendation to add ACEI/ARB medications was accepted for 14.5% (4,559) of patients. In most cases (73%), recommendations occurred via a letter to patients together with a fax to their providers. The fitted model, containing 3 predictor variables (age quartile, type of contact to communicate the recommendations, and whether recommendation contacts were made twice), was statistically significant, χ(2) (10; N = 31,495) = 112.82 (P < 0.001), indicating that the model was able to distinguish between those who did and did not accept UA-MMC's recommendations to add ACEI/ARB medications. The likelihood of recommendation acceptance decreased as patient age increased compared with patients in the first age quartile (ages 19-67; P ≤ 0.005 at all levels). Compared with sending only a provider fax, patients who received all 3 types of contact (provider fax with patient phone call and letter) were estimated to be 1.34 times more likely (34% increase) to have recommendation acceptance ( P = 0.004; 95% CI = 1.10-1.63). Similarly, patients who received only letters were also 1.32 times more likely (32% increase) than provider faxes alone to result in recommendation acceptance ( P = 0.003; 95% CI = 1.10-1.59). Patients for whom recommendations were made twice were less likely to have recommendation acceptance than for those contacted once, controlling for all other predictor variables in the model ( P < 0.001; OR = 0.77; 95% CI = 0.69-0.86). Recommendations to add an ACEI/ARB to diabetic regimens are more likely to be accepted for younger patients and those who receive recommendations through all 3 communication types (provider fax combined with patient phone call and letter) or just letters than provider faxes alone. Further research is needed to understand why prescribers are not accepting MTM recommendations.


Goos-Hänchen shifts of partially coherent light fields.
The Goos-Hänchen (GH) shift refers to a lateral displacement (from the path expected from geometrical optics) along an interface in totally internal reflection. This phenomenon results from a coherence effect. In order to bring to light the role of coherence, the reflection of partially coherent light fields was investigated within the framework of the theory of coherence. A formal expression for the GH shifts of partially coherent light fields is obtained in terms of Mercer's expansion. It is shown that both the spatial coherence and the beam width have an important effect on the GH shift, especially near the critical angles (such as totally reflection angle). These results are important to observe the GH shifts of the beams with imperfect coherence, like x-ray and matter-wave beams.


Effect of magnetic anisotropy on direct chiral discrimination in paramagnetic NMR spectroscopy.
We present and analyse a complete analytic expression for the generalized shielding polarizability third-rank tensor Φαβγ, whose isotropic average, the pseudoscalar [capital Phi, Greek, macron], is proportional to a chiral macroscopic electric polarization P measurable in a pulsed nuclear magnetic resonance (NMR) experiment probing molecules with an arbitrarily degenerate ground state, in solution. We have recently predicted that [capital Phi, Greek, macron] can be measurable at room temperature in chiral paramagnetic molecules, and identified strong magnetic anistropy (as featured e.g. in lanthanide complexes) as a crucial molecular property to achieve room temperature chiral discrimination using NMR spectroscopy. As previously proposed, the components of Φαβγ are obtained as analytical third derivatives of the electronic free energy. Here we present the explicit calculation of these derivatives, which provide working expressions for the explicit accurate ab initio calculation of Φαβγ. We apply our theory by performing ab initio multiconfigurational calculations of all contributions to Φαβγ, for a set of ten DyIII complexes, characterized by a strongly axial ground Kramers doublet, but also by thermally accessible excited Kramers doublets at room temperature. The results show that the thermally populated excited state contributions, while generally reducing the value of [capital Phi, Greek, macron] calculated on the assumption of a thermally isolated ground state, still confirm the room temperature detectability of this property for all ten studied complexes. Trends on the relative sign of dominant contributions are then discussed on the basis of a crystal field model electrostatic potential splitting a ground spin-orbit multiplet, which provides an insight into the properties of the generalized shielding polarizability tensor for open shell species.


A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis.
The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.


Current therapy of HIV.
Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/microl CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers.


Grain sizes, surface areas, and porosities of vapor-deposited H2O ices used to simulate planetary icy surfaces.
Mean grain sizes and specific surface areas (SSAs) of ice substrates formed by vapor deposition at low temperatures are of importance in simulating external surfaces of icy satellites in the solar system. Environmental scanning electron microscopy (ESEM) was used to obtain granule sizes and to observe the phase of ice granules prepared on borosilicate, silicon, and metallic plates. Ices prepared at a temperature lower than 140 K appear to be amorphous, and their granule sizes are typically submicrometer. At slightly warmer temperatures, near 180-200 K, ice films are composed of either hexagonal or cubic granules with sizes up to a few micrometers. When briefly annealed to even warmer temperatures, ice granule sizes approach approximately 10 microm. SSAs of ice substrates were determined from BET (Brunauer, Emmett, and Teller) analysis of gas adsorption isotherms in the temperature range from 83.5 to 261 K. SSAs decrease drastically from 102 m2/g at 83.5 K to 0.87 m2/g at 150 K and further decrease slowly to 0.22 m2/g at 261 K, suggesting that the transition from amorphous to crystalline forms occurs at approximately 150 K. The overall decrease in SSAs is primarily due to metamorphism and sintering. These results are comparable to recent field and laboratory measurements. Possible implications for theoretical models of icy satellites of outer planets using remote sensing techniques are also discussed.


Meglumine antımoniate-TiO2@Ag nanoparticle combinations reduce toxicity of the drug while enhancing its antileishmanial effect.
Currently, the treatment of leishmaniasis is increasingly insufficient as current antileishmanial drugs have many disadvantages such as toxic side effects, high cost, and growing drug resistance. In order to overcome these disadvantages, researchers have recently focused on combination therapy by using pentavalent antimonials in conjunction with other antileihmanial compounds. Our previous study found that TiO2@Ag nanoparticles (TiAgNps) demonstrated significant antileishmanial effects. However, a lethal dose of TiAgNps on L. topica promastigotes was found to be toxic for macrophage cells. Moreover, non-toxic concentrations of TiAgNps were ineffective in inhibiting L. topica promastigotes and amastigotes. Thus, we propose the use of TiAgNps in combination with other antileishmanial compounds like meglumine antimoniate (MA) at non-toxic concentrations, which may increase the efficacies of both agents and decrease their toxicities. Therefore, the aim of this study was to determine in vitro and in vivo antileishmanial efficacies of TiAgNps-MA combinations at non-toxic concentrations and develop a new approach for treatment that lowers the toxicities of pentavalent antimonials to minimal levels and enhances their effectiveness. In vitro screening was performed on L. topica promastigote and amastigote-macropage culture by using MTT assay to determine proliferation, perform infection index analysis, and to conduct a Griess reaction for nitric oxide production, while in vivo antileishmanial assays were applied on Balb/c mice with CL models. The results demonstrated that combinations including TiAgNps and MA at non-toxic concentrations were highly efficacious against both promastigotes and amastigotes, while MA application alone did not show any inhibitory effects. It was determined that combination applications decreased the proliferation of L. topica promastigotes 2- to 5-fold in contrast to use of MA alone, and was dependent on concentrations. Moreover, the use of combinations led to inhibition of L. topica amastigotes at rates ranging between 80% and 95%. Additionally, combinations were found to decrease metabolic activities of each form of the parasite at ranges between 7- to 20-fold, causing programmed-cell death and stimulation of macrophages for intensive production of nitric oxide, which is accepted as an important antileishmanial agent (p<0.05). Furthermore, Σ FIC analysis demonstrated that the tested combinations composed little additive, but mostly synergistic effects for inhibition of promastigotes and amastigotes. According to in vivo screening results, the combinations displayed high antileishmanial activities by successfully healing lesions and significantly reducing parasite burdens. Combined, these results show that TiAgNps-MA combinations were much more effective than use of MA alone at non-toxic concentrations and they possess high potential for development of new antileishmanial drugs to fight against leishmaniasis.


Lipid species profiling of bronchoalveolar lavage fluid cells of horses housed on two different bedding materials.
The lipidome of equine BALF cells has not been described. The objectives of this prospective repeated-measures study were to explore the BALF cells' lipidome in horses and to identify lipids associated with progression or resolution of airway inflammation. BALF cells from 22 horses exposed to two bedding materials (Peat 1-Wood shavings [WS]-Peat 2) were studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The effects of bedding on lipid class and species compositions were tested with rmANOVA. Correlations between lipids and cell counts were examined. The BALF cells' lipidome showed bedding-related differences for molar percentage (mol%) of 60 species. Whole phosphatidylcholine (PC) class and its species PC 32:0 (main molecular species 16:0_16:0) had higher mol% after Peat 2 compared with WS. Phosphatidylinositol 38:4 (main molecular species 18:0_20:4) was higher after WS compared with both peat periods. BALF cell count correlated positively with mol% of the lipid classes phosphatidylserine, sphingomyelin, ceramide, hexosylceramide, and triacylglycerol but negatively with PC. BALF cell count correlated positively with phosphatidylinositol 38:4 mol%. In conclusion, equine BALF cells' lipid profiles explored with MS-based lipidomics indicated subclinical inflammatory changes after WS. Inflammatory reactions in the cellular lipid species composition were detected although cytological responses indicating inflammation were weak.


Rapid and real-time identification of fungi up to species level with long amplicon nanopore sequencing from clinical samples.
The availability of long-read technologies, like Oxford Nanopore Technologies, provides the opportunity to sequence longer fragments of the fungal ribosomal operon, up to 6 Kb (18S-ITS1-5.8S-ITS2-28S) and to improve the taxonomy assignment of the communities up to species level and in real-time. We assess the applicability for taxonomic assignment of amplicons targeting a 3.5 Kb region (V3 18S-ITS1-5.8S-ITS2-28S D2) and a 6 Kb region (V1 18S-ITS1-5.8S-ITS2-28S D12) with the What's in my pot (WIMP) classifier. We used the ZymoBIOMICSTM mock community and different microbiological fungal cultures as positive controls. Long amplicon sequencing correctly identified Saccharomyces cerevisiae and Cryptococcus neoformans from the mock community and Malassezia pachydermatis, Microsporum canis and Aspergillus fumigatus from the microbiological cultures. Besides, we identified Rhodotorula graminis in a culture mislabelled as Candida spp. We applied the same approach to external otitis in dogs. Malassezia was the dominant fungal genus in dogs' ear skin, whereas Ma. pachydermatis was the main species in the healthy sample. Conversely, we identified a higher representation of Ma. globosa and Ma. sympodialis in otitis affected samples. We demonstrate the suitability of long ribosomal amplicons to characterize the fungal community of complex samples, either healthy or with clinical signs of infection.


First detection of a plasmid-encoded New-Delhi metallo-beta-lactamase-1 (NDM-1) producing Acinetobacter baumannii using whole genome sequencing, isolated in a clinical setting in Benin.
Carbapenem-resistant Acinetobacter baumannii is considered a top priority pathogen by the World Health Organization for combatting increasing antibiotic resistance and development of new drugs. Since it was originally reported in Klebsiella pneumoniae in 2009, the quick spread of the blaNDM-1 gene encoding a New-Delhi metallo-beta-lactamase-1 (NDM-1) is increasingly recognized as a serious threat. This gene is usually carried by large plasmids and has already been documented in diverse bacterial species, including A. baumannii. Here, we report the first detection of a NDM-1-producing A. baumannii strain isolated in Benin. A 31-year-old woman was admitted to a surgical unit with a diagnosis of post-cesarean hematoma. An extensively-drug resistant A. baumannii strain solely susceptible to amikacin, colistin and ciprofloxacin, and resistant to several other antibiotics including ceftazidime, imipenem, meropenem, gentamicin, tobramycin, ceftazidime/avibactam, and sulfamethoxazole-trimethoprim, was isolated from the wound. Production of NDM-1 was demonstrated by immunochromatographic testing. Whole genome sequencing of the isolate confirmed the presence of blaNDM-1, but also antibiotic resistance genes against multiple beta-lactamases and other classes of antibiotics, in addition to several virulence genes. Moreover, the blaNDM-1 gene was found to be present in a Tn125 transposon integrated on a plasmid. The discovery of this extensively-drug resistant A. baumannii strain carrying blaNDM-1 in Benin is worrying, especially because of its high potential risk of horizontal gene transfer due to being integrated into a transposon located on a plasmid. Strict control and prevention measures should be taken, once NDM-1 positive A. baumannii has been identified to prevent transfer of this resistance gene to other Enterobacterales. Capacity building is required by governmental agencies to provide suitable antibiotic treatment options and strategies, in combination with strengthening laboratory services for detection and surveillance of this pathogen.


An evaluation of Ontario trauma outcomes and the development of regional norms for Trauma and Injury Severity Score (TRISS) analysis.
Outcomes analysis of patient care programs has become increasingly necessary for a variety of reasons in recent years. This has been particularly true for trauma programs. The Trauma and Injury Severity Score (TRISS) methodology was developed for this purpose in the context of the Major Trauma Outcome Study (MTOS). It provides an estimate of the probability of survival for individual patients, based on anatomic, physiologic, and etiologic factors. In addition, it allows hospitals and groups of hospitals to compare survival rates with other hospitals submitting data to the data base. However, the published coefficients for TRISS analysis have been derived from the MTOS data base. Patterns of practice, time to treatment, and other variables may be significantly different in other jurisdictions. To compare outcomes among similar hospitals within the province of Ontario, Canada, a regression analysis was performed to develop TRISS coefficients specific to the province. Data were obtained from the 12 trauma centers in the province treating the most severely injured patients (Injury Severity Score > 12). A total of 3,880 cases were eligible for TRISS analysis, over a 3-year period. Of these, 3,672 were patients with blunt trauma, and 208 were victims of penetrating injury. Standard TRISS analysis of the patients with blunt trauma revealed z scores ranging from -10.260 to +1.849, with a mean of -6.648. Four centers had negative z scores that were significant (an absolute value of > 1.96 is considered statistically significant). Using Ontario TRISS coefficients, z scores ranged from -4.125 to +2.782, with a mean of 0.000. Four scores were significant with the Ontario coefficients, only one of which had been significant using the MTOS norms. The other three z scores were all positive, indicating more deaths than would have been predicted, but they were not significant when compared to the MTOS norms. The mean was also, of course, no longer significant. The area under the receiver operating characteristic curve analysis was strongly positive, and the Hosmer-Lemeshow Goodness-of-Fit analysis indicated good calibration. The new coefficients were subsequently validated by applying them to a subsequent year's data from patient records that did not form part of the original data set. This resulted in slightly improved z scores overall, and in most of the hospitals. This use of regional norms allows comparison with outcomes of patients cared for in hospitals within the same jurisdiction that are more similar to one another than to those in the MTOS, and helps to identify unexpected outcomes and outliers.


Bovine IgG can aggregate at conditions simulating pasteurization and binds to some human Fc gamma receptors.
The ability of bovine IgG preparations to bind to the various distinct human leukocyte Fc gamma receptors was studied. In experiments using intact cells and isolated Fc gamma receptors, it was demonstrated that bovine IgG can bind to Fc gamma receptors of four human cell types but not to Fc gamma receptors of human neutrophils. 125I-labeled Fc gamma receptors purified on human IgG-Sepharose columns from human B and T lymphocytes, monocytes and eosinophils were able to rebind specifically to insolubilized bovine IgG. In contrast, radioiodinated human neutrophil Fc gamma receptors did not rebind to bovine IgG-Sepharose. A similar pattern of specificity was demonstrated in studies of the binding of 125I-labeled heat-aggregated bovine IgG to various human leukocyte populations. The labeled aggregated bovine IgG bound to peripheral blood mononuclear cells, to B cells from chronic lymphocytic leukemia patients and to macrophage-like U-937 cells, but bound poorly to normal human granulocytes. Labeled non-aggregated bovine IgG was not appreciably bound to any of the cell populations. Since bovine IgG in dietary sources is frequently exposed to heat, the effect of heating on the physical state and Fc-binding properties of bovine IgG was examined. The data show that heating bovine IgG at concns of 0.9-3.6 mg/ml at 63 degrees C for 30 min in neutral buffer causes aggregation of bovine immunoglobulin (10-16% aggregation) and increases the ability of bovine IgG preparations to bind to human Fc gamma receptors of intact cells. Gel filtration studies suggest the possibility that bovine IgG may also be aggregated during the pasteurization of raw milk.


Estimating the size of hidden populations from register data.
Prevalence estimates of drug use, or of its consequences, are considered important in many contexts and may have substantial influence over public policy. However, it is rarely possible to simply count the relevant individuals, in particular when the defining characteristics might be illegal, as in the drug use case. Consequently methods are needed to estimate the size of such partly 'hidden' populations, and many such methods have been developed and used within epidemiology including studies of alcohol and drug use. Here we introduce a method appropriate for estimating the size of human populations given a single source of data, for example entries in a health-care registry. The setup is the following: during a fixed time-period, e.g. a year, individuals belonging to the target population have a non-zero probability of being "registered". Each individual might be registered multiple times and the time-points of the registrations are recorded. Assuming that the population is closed and that the probability of being registered at least once is constant, we derive a family of maximum likelihood (ML) estimators of total population size. We study the ML estimator using Monte Carlo simulations and delimit the range of cases where it is useful. In particular we investigate the effect of making the population heterogeneous with respect to probability of being registered. The new estimator is asymptotically unbiased and we show that high precision estimates can be obtained for samples covering as little as 25% of the total population size. However, if the total population size is small (say in the order of 500) a larger fraction needs to be sampled to achieve reliable estimates. Further we show that the estimator give reliable estimates even when individuals differ in the probability of being registered. We also compare the ML estimator to an estimator known as Chao's estimator and show that the latter can have a substantial bias when applied to epidemiological data. The population size estimator suggested herein complements existing methods and is less sensitive to certain types of dependencies typical in epidemiological data.


Human and novel coronavirus infections in children: a review.
Coronaviruses, seven of which are known to infect humans, can cause a spectrum of clinical presentations ranging from asymptomatic infection to severe illness and death. Four human coronaviruses (hCoVs)-229E, HKU1, NL63 and OC43-circulate globally, commonly infect children and typically cause mild upper respiratory tract infections. Three novel coronaviruses of zoonotic origin have emerged during the past two decades: severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV) and the recently discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. These novel coronaviruses are known to cause severe illness and death predominantly in older adults and those with underlying comorbidities. Consistent with what has been observed during the outbreaks of SARS and MERS, children with COVID-19 are more likely to be asymptomatic or to have mild-to-moderate illness, with few deaths reported in children globally thus far. Clinical symptoms and laboratory and radiological abnormalities in children have been similar to those reported in adults but are generally less severe. A rare multisystem inflammatory syndrome in children (MIS-C) which has resulted in critical illness and some deaths has recently been described. Clinical trials for therapeutics and vaccine development should include paediatric considerations. Children may play an important role in the transmission of infection and outbreak dynamics and could be a key target population for effective measures to control outbreaks. The unintended consequences of the unprecedented scale and duration of pandemic control measures for children and families around the world should be carefully examined.Abbreviations: 2019-nCoV, 2019 novel coronavirus; ADEM, acute demyelinating encephalomyelitis; AAP, American Academy of Pediatrics; ACE-2, angiotensin-converting enzyme 2; ARDS, acute respiratory distress syndrome; BCG, bacillus Calmette-Guérin; BNP, brain natriuretic peptide; CDC, Centers for Disease Control and Prevention; CRP, C-reactive protein; CSF, cerebrospinal fluid; COVID-19, coronavirus disease 2019; CT, computed tomography; CXR, chest X-ray; DOL, day of life; hCoV, human coronavirus; ICU, intensive care unit; IL, interleukin; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; LDH, lactate dehydrogenase; MERS, Middle East respiratory syndrome; MERS-CoV, Middle East respiratory syndrome coronavirus; MEURI, monitored emergency use of unregistered and experimental interventions; MIS-C, multi-system inflammatory syndrome in children; PCR, polymerase chain reaction; PICU, paediatric intensive care unit; RNA, ribonucleic acid; RCT, randomised-controlled trial; RSV, respiratory syncytial virus; SARS, severe acute respiratory syndrome; SARS-CoV-1, severe acute respiratory syndrome coronavirus 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-alpha, tumour necrosis factor alpha; UK United Kingdom; UNICEF, United Nations Children's Fund; USA, United States of America; WHO, World Health Organization.


Central corneal thickness and intraocular pressure in patients of primary open angle glaucoma and normal population in Nepalese population: A hospital based study.
Central corneal thickness (CCT) is a powerful predictor of primary open angle glaucoma. Individualized risk assessment is critical for early diagnosis and management of glaucoma. To compare CCT and intraocular pressure in patients of primary openangle glaucoma (POAG) with those of normal population. A Comparative Cross-Sectional Study was performed in Ophthalmology department of B. P. Koirala Institute of Health Sciences, Nepal. Newly diagnosed cases of primary glaucoma (open angle, normal tension) of 18 years and above, without known systemic diseases were included. Out of a total of 291 subjects (582 eyes), 105 subjects (210 eyes) were with primary glaucoma and 186 (382 eyes) were normal subjects. There was no significant difference in CCT between glaucomatous (533.57 μm) and normal (530.06 μm) eyes (p=0.1). Cornea was thinner (518.±18.03 μm) in eyes with severe glaucomatous damage (cup:disc ratio > 0.8) than in moderate glaucomatous damage (cup:disc ratio=0.5-0.8)(p=0.003). There was a statistically significant difference of 22.05 μm in CCT between POAG and NTG (p<0.001). A positive correlation was found between IOP & CCT in both cases and control group (p=0.000; r = 0.355, 0.254; r2 =0.126, 0.064 respectively). Majority of studied Nepalese population have CCT less than 550 μm, thus increasing the risk of POAG. CCT decreases with age, and females with glaucoma have significantly thicker cornea than men. There is a significant positive correlation between CCT and IOP, and IOP will have to be adjusted for CCT for proper diagnosis and monitoring of glaucomatous damage in Nepalese population too.


[Circumflex coronary artery fistula during staphylococcal aortic valve endocarditis].
We presented a very rare case of the fistula to coronary artery during staphylococcal aortic valve endocarditis in a young man. The tranesophageal echocardiography detected vegetation on aortic valve leaflets and large regurgitatin. During transesophageal echocardiography the peri-anular multi-chamber abscess formation and fistulous communication to circumflex coronary artery was detected.


[Membranoreceptor disorders in the pathogenesis of bronchial asthma].
The purpose of the work was to study some characteristic features of the membranoreceptor complex in patients suffering from atopic bronchial asthma (BA) and infection-dependent BA. That was done with the aid of the erythrocytic model (phytohemagglutinin /PHA/ reception, electrophysical analysis of the membranous properties). Electrophoretic mobility (EPM) of red blood cells and red blood cell sedimentation under the action of PHA were determined. The data obtained indicate that in patients with infection-dependent BA, the membranoreceptor complex is characterized by a decrease of EPM of red blood cells, inhibition of red blood cell sedimentation in the presence of PHA. The results of studying the membranoreceptor complex in BA patients are summarized as are the marker characteristics of atopic and infection-dependent BA, reflecting pathology of reception, glycocalyx, and lipid matrix.


Spermitin: a novel mitochondrial protein in Drosophila spermatids.
Mitochondria, important energy centers in the cell, also control sperm cell morphogenesis. Drosophila spermatids have a remarkably large mitochondrial formation called the nebenkern. Immediately following meiosis during sperm development, the mitochondria in the spermatid fuse together into two large aggregates which then wrap around one another to produce the spherical nebenkern: a giant mitochondrion about 6 micrometers in diameter. The fused mitochondria play an important role in sperm tail elongation by providing a structural platform to support the elongation of sperm cells. We have identified a novel testis-specific protein, Spermitin (Sprn), a protein with a Pleckstrin homology-like (PH) domain related to Ran-binding protein 1 at its C-terminus. Fluorescence microscopy showed that Sprn localizes at mitochondria in transfected Kc167 cells, and in the nebenkern throughout spermatid morphogenesis. The role of Sprn is unclear, as sprn mutant males are fertile, and have sperm tail length comparable to the wild-type.


Crystal Structure of the GRAS Domain of SCARECROW-LIKE7 in Oryza sativa.
GRAS proteins belong to a plant-specific protein family with many members and play essential roles in plant growth and development, functioning primarily in transcriptional regulation. Proteins in the family are minimally defined as containing the conserved GRAS domain. Here, we determined the structure of the GRAS domain of Os-SCL7 from rice (Oryza sativa) to 1.82 Å. The structure includes cap and core subdomains and elucidates the features of the conserved GRAS LRI, VHIID, LRII, PFYRE, and SAW motifs. The structure is a dimer, with a clear groove to accommodate double-stranded DNA. Docking a DNA segment into the groove to generate an Os-SCL7/DNA complex provides insight into the DNA binding mechanism of GRAS proteins. Furthermore, the in vitro DNA binding property of Os-SCL7 and model-defined recognition residues are assessed by electrophoretic mobility shift analysis and mutagenesis assays. These studies reveal the structure and preliminary DNA interaction mechanisms of GRAS proteins and open the door to in-depth investigation and understanding of the individual pathways in which they play important roles.


Molecular analysis of enrichment cultures of ammonia oxidizers from the Salar de Huasco, a high altitude saline wetland in northern Chile.
We analyzed enrichment cultures of ammonia-oxidizing bacteria (AOB) collected from different areas of Salar de Huasco, a high altitude, saline, pH-neutral water body in the Chilean Altiplano. Samples were inoculated into mineral media with 10 mM NH4+ at five different salt concentrations (10, 200, 400, 800 and 1,400 mM NaCl). Low diversity (up to three phylotypes per enrichment) of beta-AOB was detected using 16S rDNA and amoA clone libraries. Growth of beta-AOB was only recorded in a few enrichment cultures and varied according to site or media salinity. In total, five 16S rDNA and amoA phylotypes were found which were related to Nitrosomonas europaea/Nitrosococcus mobilis, N. marina and N. communis clusters. Phylotype 1-16S was 97% similar with N. halophila, previously isolated from Mongolian soda lakes, and phylotypes from amoA sequences were similar with yet uncultured beta-AOB from different biofilms. Sequences related to N. halophila were frequently found at all salinities. Neither gamma-AOB nor ammonia-oxidizing Archaea were recorded in these enrichment cultures.


Cytotoxic xanthone-anthraquinone heterodimers from an unidentified fungus of the order Hypocreales (MSX 17022).
Two new xanthone-anthraquinone heterodimers, acremoxanthone C (5) and acremoxanthone D (2), have been isolated from an extract of an unidentified fungus of the order Hypocreales (MSX 17022) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Two known related compounds, acremonidin A (4) and acremonidin C (3) were also isolated, as was a known benzophenone, moniliphenone (1). The structures of these isolates were determined via extensive use of spectroscopic and spectrometric tools in conjunction with comparisons to the literature. All compounds (1-5) were evaluated against a suite of biological assays, including those for cytotoxicity, inhibition of the 20S proteasome, mitochondrial transmembrane potential and nuclear factor-κB.


Inactivation of Wnt/β-catenin/renin angiotensin axis by tumor necrosis factor-alpha inhibitor, infliximab, ameliorates CKD induced in rats.
Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate β-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/β-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/β-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1β (IL1β). DOX decreased the renal expression of klotho which in turn increased Wnt1, active β-catenin/total β-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active β-catenin/total β-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/β-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/β-catenin/renin angiotensin axis.


Lumbar vertebra morphometry and stereological assesment of intervertebral space volumetry: a methodological study.
The use of technology in the treatment of degenerative spinal diseases has undergone rapid clinical and scientific development. It has been extensively studied in combination with various techniques for spinal stabilization from both the anterior and posterior approach. Minimally invasive and instrumental approach via posterior fixation is increasingly being used for the treatment of adult degenerative disc disease, stenosis, and deformity of the lumbar vertebrae. Posterior access to the lumbar disc spaces for posterolateral fusion scan has been technically challenging, frequently requiring the use of an approach surgery for adequate exposure. For successful surgery and suitable instrumental design, adequate anatomical knowledge of the lumbar vertebra is also needed. Anatomic features of lumbar vertebrae are of importance for posterior screw fixation technique. The morphometry of L1-L5 has been studied to facilitate the safe application of pedicle screws. Thus, we aimed to evaluate the morphometric landmarks of lumbar vertebrae such as pedicle, vertebral body, vertebral foramen, intervertebral space height and volume for safe surgical intervention using a posterior fixation approach to offer anatomical supports for lumbar discectomy, stenosis and cases of deformity. The features of the L1-L5 vertebral body, the detailed morphometric parameters of lumbar vertebrae and the intervertebral space were analyzed using computerized tomography scan, magnetic resonance imaging and also dry lumbar vertebrae. Additionally, intervertebral space volumes were measured using stereological methods to ensure safe surgical intervention.


PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.
In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.


[Retinal vascular occlusion in antithrombin III deficiency].
Deficiency of Antithrombin III (AT III), which is one of the main inhibitors of blood coagulation, may lead to severe thrombosis and embolism. The authors detected AT III deficiency in two patients with retinal vessel occlusion. Both patients were otherwise healthy. One had recurrent retinal vein thrombosis, the other cilioretinal occlusion. To the authors' knowledge, only one case of retinal vessel occlusion with AT III deficiency has been reported in literature. Furthermore, in the patients reported here retinal vessel occlusion may have been caused by AT III deficiency, which has considerable therapeutic and prophylactic consequences for patients with this disorder. AT III should therefore be determined in retinal vessel occlusion of unknown cause.


11-year follow-up study of resin-bonded fixed partial dentures.
The clinical performance of 325 resin-bonded fixed partial dentures (RBFPD) placed between 1984 and 1995 was reviewed. The primary indications of the 264 patients treated were trauma and aplasia. Two hundred eighty-three of the resin-bonded fixed partial dentures were primary restorations, and 42 of the restorations were secondary and tertiary after the loss of the primary resin-bonded fixed partial denture. Including the rebonded restorations, the survival rate calculated using the Kaplan-Meier method was 76% after 5 years and 60% after 10 years. Analysis of the data showed that casting alloy, pretreatment of the bonding surfaces, luting agent, and mobility of the abutment teeth were decisive prognostic factors for success. Base metal alloys, silicoating, mesh retention, and immobile abutments were positive factors. In contrast to other reports in the literature, retentive abutment preparation did not result in a higher survival rate than unprepared abutments. Small restorations in the bonding area did not affect the survival. No differences in survival rate were found for resin-bonded fixed partial dentures in the maxillae or mandible, or in the anterior and posterior regions. Multiunit resin-bonded fixed partial dentures had a smaller probability of survival than three-unit resin-bonded fixed partial dentures. Carious lesions were found on 4% of the abutment teeth.


Flagellimonas maritima sp. nov., isolated from surface seawater.
An aerobic, non-motile, rod-shaped and Gram-stain-negative marine bacterium, designated as HME9304T, was isolated from surface seawater of the Yellow Sea. Growth was observed at 10-35 °C (optimum, 30 °C), pH 6-8 (pH 7) and with 1-5 % NaCl (2 %). The major fatty acids of strain HME9304T were iso-C15 : 1 G, iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c). The only respiratory quinone was menaquinone-6. The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids, one unidentified glycolipid and five unidentified polar lipids. Results of phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain HME9304T was affiliated with the genus Flagellimonas. Its closest type strains were Flagellimonas aquimarina ECD12T (95.5 % sequence similarity), Flagellimonas flava A11T (95.4 %), Flagellimonas pacifica SW169T (94.9 %) and Flagellimonas eckloniae DOKDO 007T (94.6 %). The DNA G+C content of the genomic DNA was 38.1 mol%. Phylogenetic, phenotypic and chemotaxonomic characteristics suggested that strain HME9304T represents a novel species of the genus Flagellimonas within the family Flavobacteriaceae, for which the name  Flagellimonas maritima sp. nov. is proposed. The type strain is HME9304T (=KCTC 32464T=KACC 17618T=CECT 8418T).


Using a hybrid model to investigate the comorbidity and symptom overlap between social phobia and the other anxiety disorders and unipolar mood disorders.
New hybrid models of psychopathology have been proposed that combine the current categorical approach with symptom dimensions that are common across various disorders. The present study investigated the new hybrid model of social anxiety in a large sample of participants with anxiety disorders and unipolar mood disorders to improve understanding of the comorbidity and symptom overlap between social phobia (SOC) and the other anxiety disorders and unipolar mood disorders. Six hundred and eighty two participants from a specialized outpatient clinic for anxiety treatment completed a semi-structured diagnostic interview and the Multidimensional Assessment of Social Anxiety (MASA). A hybrid model symptom profile was identified for SOC and compared with each of the other principal diagnoses. Significant group differences were identified on each of the MASA scales. Differences also were identified when common sets of comorbidities were compared within participants diagnosed with SOC. The findings demonstrated the influence of both the principal diagnosis of SOC and other anxiety disorders and unipolar mood disorders as well as the influence of comorbid diagnoses with SOC on the six symptom dimensions. These findings highlight the need to shift to transdiagnostic assessment and treatment practices that go beyond the disorder-specific focus of the current categorical diagnostic systems.


Familial hypercholesterolemia. Evidence for a newly recognized mutation determining increased fibroblast receptor affinity but decreased capacity for low density lipoprotein in two siblings.
Cultured skin fibroblasts were obtained from two siblings with classic clinical features of homozygous familial hypercholesterolemia. Plasma cholesterol values were 970 and 802 mg/100 ml in the siblings, 332 mg/100 ml in the mother, and 426 mg/100 ml in the father. Fibroblast receptor-specific capacity for binding and degradation of (125)I-low density lipoprotein (LDL) at 37 degrees C was 11% of normal, consistent with the diagnosis of "homozygous LDL receptor-defective" hypercholesterolemia, a disorder in which LDL binding activity is low but detectable. The residual LDL receptor activity was clearly qualitatively abnormal. The Michaelis constant (K(m)) for (125)I-LDL was reduced to 20-40% of normal, indicating a substantially increased affinity for LDL. Increased affinity and reduced capacity for (125)I-LDL are also found when normal fibroblasts are assayed at 4 degrees C. As the temperature is raised to 37 degrees C surface LDL binding affinity decreases while capacity increases. At 4 degrees C the fibroblasts of our subjects had an affinity for LDL indistinguishable from normal cells assayed at that temperature and a binding capacity 23% of normal. However, only small changes in affinity and capacity occurred upon increasing the temperature to 37 degrees C. When (125)I-apoprotein E-phospholipid vesicles were bound at 37 degrees C the receptor deficiency appeared only half as severe as when (125)I-LDL was used as ligand.A family study suggests that the siblings are genetic compounds rather than homozygotes, having inherited a mutant maternal gene causing absent or silent LDL receptors and a mutant paternal gene resulting in qualitatively altered LDL receptors. It is not clear whether these defects are present at the same or different genetic loci. The altered receptors are characterized by increased affinity and moderately reduced capacity for LDL at 37 degrees C and are accompanied by hypercholesterolemia at least as severe as that associated with familial hypercholesterolemia with absent or nonfunctional LDL receptors.


N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma.
--Melasma is a difficult medical problem to treat. Hydroquinone is administered to many patients, but it is unstable and local irritation and dermatitis may develop after a prolonged use at a high concentration. This study introduces a new depigmenting agent, N-acetyl-4-S-cysteaminylphenol, for better management of melanoderma in patients with melasma. --Our study, based on a retrospective observation of 12 patients using 4% N-acetyl-4-S-cysteaminylphenol in oil-in-water emulsion, showed a complete loss (8%), a marked improvement (66%), or a moderate improvement (25%) of melasma lesions. Visible changes of melanoderma can be seen in 2 to 4 weeks after daily topical application. This depigmentation was associated with a decrease in the number of functioning melanocytes and in the number of melanosomes transferred to keratinocytes. N-acetyl-4-S-cysteaminylphenol is the tyrosinase substrate, and, on exposure to tyrosinase, it formed a melanin-like pigment. --A phenolic thioether, N-acetyl-4-S-cysteaminylphenol, is a new type of depigmenting agent for the better management of melasma. It is much more stable and less irritating to the skin than hydroquinone, and it is specific to melanin-synthesizing cells.


Designing an integrated drug benefit for the elderly.
The elderly are hit hard by high out-of-pocket expenses for medicines, but a stand-alone pharmaceutical benefit could cost the country billions and still not improve older Americans' quality of care. Such a benefit should be coordinated with patients' overall medical benefits. A systems-based pharmaceutical benefit is financially feasible through a combination of premiums and cost sharing, market-driven price reductions, and cost savings achieved through integrated managed care programs and improved outcomes.


Dissociation of event-based prospective memory and time-based prospective memory in patients with prostate cancer receiving androgen-deprivation therapy: a neuropsychological study.
The primary purpose of this study was to evaluate the event-based prospective memory (EBPM) and time-based prospective memory (TBPM) in androgen-deprivation therapy (ADT)-induced cognitive impairment in patients with prostate cancer (PC). Participants included PC patients who had undergone ADT (ADT group, n = 43) or patients who did not undergo ADT (non-ADT group, n = 35), as well as age and education-matched healthy controls (HC group, n = 40). All participants were administered with a battery of neuropsychological tests including EBPM and TBPM tasks. Our results indicated that during the EBPM task, the ADT group obtained significantly lower scores than the non-ADT and HC group did, while no significant differences in the TBPM task scores were found among these three groups. Additionally, the ADT group demonstrated significantly lower scores in several cognitive tasks, including attention, memory, and information processing, when compared with the other two groups. This study demonstrated that PC patients receiving ADT may have selective reductions in EBPM performance but unimpaired TBPM performance and that these deficits may result from the changes of function and structure of the pre-frontal cortex induced by ADT.


Should selecting saviour siblings be banned?
By using tissue typing in conjunction with preimplantation genetic diagnosis doctors are able to pick a human embryo for implantation which, if all goes well, will become a "saviour sibling", a brother or sister capable of donating life-saving tissue to an existing child. This paper addresses the question of whether this form of selection should be banned and concludes that it should not. Three main prohibitionist arguments are considered and found wanting: (a) the claim that saviour siblings would be treated as commodities; (b) a slippery slope argument, which suggests that this practice will lead to the creation of so-called "designer babies"; and (c) a child welfare argument, according to which saviour siblings will be physically and/or psychologically harmed.


Constitutional promoter methylation and risk of familial melanoma.
Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P<0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility.


Vanadium extraction from steel slag: Generation, recycling and management.
The metal vanadium has superior physical and chemical properties and has a wide range of applications in many fields of modern industry. The increasing demand for vanadium worldwide has led to the need to guarantee sustainable vanadium production. The smelting process of vanadium and titanium magnetite produces vanadium-bearing steel slag, a key material for vanadium extraction. Herein, vanadium production, consumption, and steel slag properties are discussed. A detailed review of methods for extracting vanadium from vanadium-bearing steel slag is presented, including the most commonly used roasting and leaching method, and direct leaching, bioleaching and enhanced leaching methods are also described. Finally, the rules and regulations of steel slag management are introduced. In general, it is necessary to further develop environmentally friendly vanadium extraction methods and technologies from vanadium containing solid wastes. This study provides research directions for the technology of vanadium extraction from steel slag.


Multiple co-circulating HIV-1 subtypes in the Middle East and North Africa.
HIV-1 incidence has been increasing more rapidly in the Middle East and North Africa than in any other global region. Despite this trend, HIV epidemiology in the region remains poorly defined. We conducted an analysis of 3284 publicly available HIV-1 sequences from 15 countries in the Middle East and North Africa to better characterize the regional epidemic. A phylogenetic tree based on the reverse transcriptase gene revealed a complex mosaic of diverse HIV subtypes and circulating recombinant forms across the region.


Investigation of Non-contact Electrodes for Electrocardiogram Monitoring.
This work investigates the use of an active noncontact electrode to monitor electrocardiogram (ECG) signals in the chest region of the human body across different interface materials. Non-contact electrodes provide an advantage over wet gel electrodes as they do not require direct contact with the skin which can lead to skin irritation. The key aspects and parameters of non-contact electrodes were discussed. Additionally, a printed circuit board (PCB) electrode was designed and prototyped. Experimental evaluations were performed to demonstrate the feasibility of the design as well as the impact of various interface materials. Results showed that R-peaks can be detected through all materials tested. The highest noise levels were observed in polyester, resulting in the highest signal standard deviation, followed by merino and cotton. The patch sensor with just a solder mask as an insulation layer provided the clearest ECG signal, with 100% accuracy on Rpeak detection.Clinical relevance- Non-contact electrodes offer a more comfortable solution for long-term heart monitoring with minimal discomfort due to less skin irritation when compared to conventional electrodes.


Histocompatibility-2 system in wild mice. II. H-2 haplotypes of t-bearing mice.
As a first step in the study of the possible relationship between the T/t and H-2 complexes, the H-2 antigenic composition of the strains carrying factors t12, tw32, tw2, tw8, t1, t0, t6, tw1, tw71, tw73, tw12, tw5, tw75, and t38 was studied by using a battery of antisera containing antibodies against inbred-derived H-2 antigens. In addition, five t strains (t12, t6, tw5, tw1, and tw2) were selected for the production of antisera against the H-2 complexes carried by t chromosomes. Spleen, lymph node, and thymus cells from H-2b/t heterozygotes and tw2/tw2 homozygotes were injected into appropriate F1 hybrids between two inbred strains that carried the inbred-derived H-2 antigens of the donor. Four new H-2 antigens and one Ia antigen were uncovered and were assigned the symbols H-2.106 through H-2.109, and Ia.101, respectively. Three new H-2 haplotypes were also described, based upon the H-2 antigenic pattern of three t factors, t12, tw1, and tw5. These new haplotypes were given the symbols H-2t12, H-2tw1, and H-2tw5. When the t factors were grouped according to their H-2 haplotypes, their distribution, with certain exceptions, corresponded to the complementation groups. Thus, t chromosomes in the same complementation group carried similar, if not identical, H-2 haplotypes, despite the fact that these chromosomes were derived from widely separated geographic areas. Such an association between the t and H-2 complexes is most unusual in light of what is known of the polymorphism of H-2 haplotypes in wild mice populations. It suggests more than a casual relationship, at least at the population level, between the t and H-2 loci.


[Healthcare practices in Nursing and Communication: a review of the literature].
Changes in nurse healthcare practices, especially for projects such as Brazil's Family Health Program, prompted us to study the related communication processes. A review of the literature from January 1994 through to December 2004 examined 26 papers in Brazilian and international periodicals, four dissertations, three theses and four books in the BIREME data-bases (LILACS and SCIELO-Br). Using 'Communication', 'Family Health Program' and 'Nursing' as key words, 373 mentions were found for 'Communication' and 'Nursing', twelve mentions for 'Family Health Program' and 'Communication' (LILACS); eighteen mentions for 'Communication' and 'Nursing'; and no mentions for 'Family Health Program' and 'Communication' (SCIELO-Br). In order to analyze these findings, the publications located through this search were grouped under four trends in the links between Communication and Nursing practices: Communication within the Family Health Program teams; Communication in professional Nursing practice; Communication as a leadership tool for Nurses; and Communication in Nursing education. This study showed that although the most usual communication model for healthcare practices is still unilinear, there is already a clear trend towards more dialogue, which poses a challenge for nursing practices in the Family Health Program.


[Effect of ethanol on protein synthesis in the tissues of various organs of guinea pigs].
Long-term administration (for three months) of ethanol has been studied for its effect on the composition and synthesis of electrophoretic fractions of soluble proteins of the liver, brain, heart, kidneys and adrenals tissues in the guinea pigs. The obtained data permit supposing that the quantitative redistribution of the fractions under study as influenced by ethanol is due to their aggregation. Most of the studied tissues demonstrate a decrease in specific radioactivity of total proteins and 5 of 8-9 recorded electrophoretic fractions. Only one fraction in the heart and brain has been characterized by an increase of the protein synthesis level. The authors' results and data from literature make it possible to conclude that while analyzing pathogenesis of the chronic intoxication by ethanol and alcoholism the quantitative redistribution of soluble proteins and suppression of their synthesis in various tissues should be taken into account.


Leishmania infantum isolates exhibit high infectivity and reduced susceptibility to amphotericin B.
Leishmaniasis is a neglected disease caused by a protozoan parasite of the Leishmania species in over 98 countries in five continents. Visceral leishmaniasis is one of the main forms of the disease and is mainly caused by Leishmania infantum, whose main vector is the dipteran Lutzomyia longipalpis. The presence of the vector in Uruguay was recorded for the first time in 2010 and an autochthonous outbreak of canine visceral leishmaniasis occurred in the northern locality of the country in 2015. We report the isolation in blood-free FBS-supplemented defined media of five isolates responsible for the referred outbreak, and characterize them in terms of their growth as promastigotes, infectivity and replication in human derived monocytes and drug resistance. Results indicate similar promastigote growth among the strains, enhanced infectivity and replication for the five strains isolated from the Uruguayan outbreak when compared with reference strains from South America, equivalent drug susceptibility for miltefosine and nifurtimox and a significant difference in IC50 values for amphotericin B between the Uruguayan strains, 3-4 fold higher than the reference strain.


Benzo(a)pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes.
We investigated whether the presence of (+)-anti-benzo(a)pyrene diolepoxide adducts to serum albumin (BPDE-SA) among workers exposed to benzo(a)pyrene (BaP) and unexposed reference controls was influenced by genetic polymorphisms of cytochrome P4501A1 (CYP1A1), microsomal epoxide hydrolase (EHPX), glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), all involved in BaP metabolism. Exposed workers had significantly higher levels of adducts (0.124 ± 0.02 fmol BPTmg(-1) SA, mean ± SE) and a higher proportion of detectable adducts (40.3%) than controls (0.051 ± 0.01 fmol BPT mg(-1) SA; 16.1%) (p = 0:014 and p = 0:012). Smoking increased adduct levels only in occupationally exposed workers with the GSTM1 deletion (GSTM1 null) (p = 0:034). Smokers from the exposed group had higher adduct levels when they were CYP1A1 *1/*1 wild-type rather than heterozygous and homozygous for the variant alleles (CYP1A1 *1/*2 plus *2/*2) (p = 0:01). The dependence of BPDE-SA adduct levels and frequency on the CYP1A1 *1/*1 genotype was most pronounced in GSTM1-deficient smokers. Exposed workers with GSTM1 null/GSTP1 variant alleles had fewer detectable adducts than those with the GSTM1 null/GSTP1*A wild-type allele, supporting for the first time the recent in vitro finding that GSTP1 variants may be more effective in the detoxification of BPDE than the wild-type allele. Logistic regression analysis indicated that occupational exposure, wild-type CYP1A1*1/*1 allele and the combination of GSTM1 null genotype+EHPX genotypes associated with predicted low enzyme activity were significant predictors of BPDE-SA adducts. Though our findings should be viewed with caution because of the relatively limited size of the population analysed, the interaction between these polymorphic enzymes and BPDE-SA adducts seems to be specific for high exposure and might have an impact on the quantitative risk estimates for exposure to polycyclic aromatic hydrocarbons.


Cloaking by coating: how effectively does a thin, stiff coating hide a soft substrate?
From human tissue to fruits, many soft materials are coated by a thin layer of a stiffer material. While the primary role of such a coating is often to protect the softer material, the thin, stiff coating also has an important effect on the mechanical behaviour of the composite material, making it appear significantly stiffer than the underlying material. We study this cloaking effect of a coating for the particular case of indentation tests, which measure the 'firmness' of the composite solid: we use a combination of theory and experiment to characterize the firmness quantitatively. We find that the indenter size plays a key role in determining the effectiveness of cloaking: small indenters feel a mixture of the material properties of the coating and of the substrate, while large indenters sense largely the unadulterated substrate.


Serine/threonine protein phosphatases and regulation of K-Cl cotransport in human erythrocytes.
Activation of K-Cl cotransport is associated with activation of membrane-bound serine/threonine protein phosphatases (S/T-PPases). We characterize red blood cell S/T-PPases and K-Cl cotransport activity regarding protein phosphatase inhibitors and response to changes in ionic strength and cell size. Protein phosphatase type 1 (PP1) activity is highly sensitive to calyculin A (CalA) but not to okadaic acid (OA). PP2A activity is highly sensitive to CalA and OA. CalA completely inhibits K-Cl cotransport activity, whereas OA partially inhibits K-Cl cotransport. Membrane PP1 and membrane PP2A activities are elevated in cells suspended in hypotonic solutions, where K-Cl cotransport is elevated. Increases in membrane PP1 activity (62 +/- 10% per 100 meq/l) result from decreases in intracellular ionic strength and correlate with increases in K-Cl cotransport activity (54 +/- 10% per 100 meq/l). Increases in membrane PP2A activity (270 +/- 77% per 100 mosM) result from volume increases and also correlate with increases in K-Cl cotransport activity (420 +/- 47% per 100 mosM). The characteristics of membrane-associated PP1 and PP2A are consistent with a role for both phosphatases in K-Cl cotransport activation in human erythrocytes.


Alterations of the CD58 gene in classical Hodgkin lymphoma.
Immune evasion plays a central role in the pathophysiology of classical Hodgkin lymphoma (cHL). As mutations of the CD58 gene contribute to immune evasion of diffuse large B cell lymphoma tumor cells, we studied whether alterations of the CD58 gene also occur in Hodgkin and Reed/Sternberg (HRS) cells of cHL. Single nucleotide polymorphism chip analysis revealed homozygous deletions within the CD58 gene in two cHL cell lines (SUP-HD1 and U-HO1). Sequencing of the CD58 gene in seven cHL cell lines disclosed in addition a homozygous splice site mutation in cell line KM-H2. None of the three mutated lines expressed CD58 protein on their surface. Thus, three of seven cHL cell lines analyzed harbor destructive CD58 mutations. Molecular analysis of isolated HRS cells from 10 primary cases of cHL; however, did not reveal any case with a CD58 mutation. A FICTION study indicated heterozygous deletions of CD58 in 3 of 13 cHL analyzed. Overall, we report frequent inactivating mutations of CD58 in cHL cell lines, but their rare occurrence in primary HRS cells. As the three cHL cell lines with CD58 mutations were all established from HRS cells located in pleural effusions, i.e., outside the normal lymph node microenvironment, in end-stages of the disease, CD58 inactivation in cHL might be predominantly prevalent to such situations.


A prototype knowledge base and SMART app to facilitate organization of patient medications by clinical problems.
Increasing use of electronic health records requires comprehensive patient-centered views of clinical data. We describe a prototype knowledge base and SMART app that facilitates organization of patient medications by clinical problems, comprising a preliminary step in building such patient-centered views. The knowledge base includes 7,164,444 distinct problem-medication links, generated from RxNorm, SNOMED CT, and NDF-RT within the UMLS Metathesaurus. In an evaluation of the knowledge base applied to 5000 de-identified patient records, 22.4% of medications linked to an entry in the patient's active problem list, compared to 32.6% of medications manually linked by providers; 46.5% of total links were unique to the knowledge base, not added by providers. Expert review of a random patient subset estimated a sensitivity of 37.1% and specificity of 98.9%. The SMART API successfully utilized the knowledge base to generate problem-medication links for test patients. Future work is necessary to improve knowledge base sensitivity and efficiency.


Alteration of the α1β2/α2β1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice.
Deer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant. Highland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 Å. Using the smaller unit cell crystal, the structure was solved at 2.2 Å resolution. The asymmetric unit contained two tetrameric hemoglobin molecules. The analyses revealed that αPro50 in the highland hemoglobin variant promoted a stable interaction between αHis45 and heme that was not seen in the αHis50 lowland variant. The αPro50 mutation also altered the nature of atomic contacts at the α1β2/α2β1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites.


Prevalence and characterization of occult hepatitis B infection among blood donors in central Saudi Arabia.
To evaluate the prevalence of occult hepatitis B viral infections (OBIs) among blood donors considering the clinical and epidemiological importance of identifying OBIs. A cross-sectional study conducted at King Khalid University Hospital, Riyadh, Saudi Arabia between January 2011 and January 2012. Blood donors (n=8501) were screened for Hepatitis B virus surface antigen (HBsAg) and hepatitis B core antibodies (HBcAb). All HBsAg-negative and HBcAb-positive samples were tested further for hepatitis B surface antibodies (HBsAb), hepatitis B virus (HBV)-DNA, and HBV genotyping. Of the 8501 serum samples tested, 56 (0.7%) were positive and 8445 (99.3%) were negative for HBsAg. Among the HBsAg-negative samples, 198 (2.3%) were positive for HBcAb and these patients were suspected to have OBIs. Among the HBcAb-positive samples, 119 (60.1%) were positive while 79 (39.9%) were negative for HBsAb. Analysis of HBV-DNA for the suspected OBIs showed that 17 out of 198 samples (8.6%) yielded positive results, and all of them were HBsAb-negative. The viral load was low (less than 20-186 IU/mL) in all OBIs. Hepatitis B virus genotyping showed that 15 out of 17 samples (88.2%) were genotype D, and the other 2 samples (11.8%) were genotype E. The prevalence of OBIs among blood donors in Riyadh was 0.2%. Therefore, it is recommended that HBV molecular testing should be incorporated with serological assays for screening of blood donors.


Encapsulating Polyethyleneimine-DNA Nanoplexes into PEGylated Biodegradable Microparticles Increases Transgene Expression In Vitro and Reduces Inflammatory Responses In Vivo.
Encapsulating genetic material into biocompatible polymeric microparticles is a means to improving gene transfection while simultaneously decreasing the tendency for inflammatory responses; and can be advantageous in terms of delivering material directly to the lungs via aerosolization for applications such as vaccinations. In this study, we investigated the advantages of using polymeric microparticles carrying the luciferase reporter gene in increasing transfection efficiency in the readily transfectable HEK293 cell line and the difficult to transfect RAW264.7 cell line. The results indicated that there was a limit to the ratio of nitrogen in polyethylenimine (PEI) to phosphate in DNA (N/P ratio) beyond which further increases in transgene expression no longer, or only marginally, occurred. Microparticles encapsulating PEI:DNA nanoplexes induced cellular toxicity in a dose-dependent manner. PEGylation increased transgene expression, likely related to enhanced degradation of particles. Furthermore, intra-tracheal instillation in rats allowed us to investigate the inflammatory response in the lung as a function of PEGylation, porosity, and size. Porosity did not influence cell counts in bronchoalveolar lavage fluid in the absence of PEG, but in particles containing PEG, non-porous particles recruited fewer inflammatory cells than their porous counterparts. Finally, both 1 μm and 10 μm porous PLA-PEG particles recruited more neutrophils than 4 μm particles. Thus, we have shown that PEGylation and lack of porosity are advantageous for faster release of genetic cargo from microparticles and a reduced inflammatory response, respectively.


Angiogenesis and c-erbB-2 (HER2/neu) overexpression status in primary breast cancer patients: an analysis of 158 needle core biopsies.
Angiogenesis, formation of new blood vessels from a preexisting vascular bed is a complex multistep process, which may also permit metastasis. The subset of patients with breast cancer demonstrating a c-erbB-2 (HER2/neu)-positive status has aggressive tumors and a poor prognosis. To investigate how tumor angiogenesis correlates with c-erbB-2 (HER2/neu) overexpression in breast carcinoma diagnosed on core biopsy, microvessels were counted (and graded the density of microvessels) within the initial invasive carcinomas of 158 patients. Using light microscopy, the number of microvessels was counted manually in a subjectively selected hot spot (in the most active areas of neovascularization per 400x field), and their values were separated as above or below median (low and high), without knowledge of the outcome in the patient or any other pertinent variable. When the mean values of MVD of the various groups defined by c-erbB-2 (HER2/neu) overexpression were compared, significant difference was noted (P = 0.014818). When tumors were classified as high or low MVD, based on a cut-off value (30.70175 microvessels/mm(2)), cases with high MVD were significantly more numerous. MVD did show a relationship with groups defined by c-erbB-2 (HER2/neu) status (P = 0.002699) or c-erbB-2 (HER2/neu) score (P = 0.027589). The correlation of angiogenesis with c-erbB-2 (HER2/neu) overexpression may be a potential therapeutic target for the treatment and prevention of breast cancer, using antiangiogenic molecules.


Hemodynamic Function of Forearm Muscle in Postmenopausal Women With Type 2 Diabetes.
Changes in the hemodynamic function of muscle are speculated as a causal mechanism for reduced motor capabilities with aging in Type 2 diabetes mellitus (DM). The focus of this study was to evaluate changes in muscle oxygenation during sustained force production in postmenopausal women with DM compared with controls. Near-infrared spectroscopy was used to monitor deoxyhemoglobin and oxyhemoglobin in the flexor digitorum superficialis. Sensorimotor function and health state covariates were also assessed. Increased deoxyhemoglobin was found during force production, whereas oxyhemoglobin remained constant. Changes were found in the time structure of the hemodynamic data during force production. No between-group differences were found; instead, measures covaried with the health state. Sex-based differences in the manifestation of DM-related sensorimotor dysfunction are likely. These data indicate that basic cardiovascular health measures may be more beneficial to monitoring hyperemic status and muscle function in postmenopausal women with DM, compared with DM diagnosis.


Effect of hyaluronic acid on the excursion resistance of tendon grafts. A biomechanical study in a canine model in vitro.
The excursion resistance between the tendon and pulley is an important factor contributing to the limitation of function after surgery to the hand. The administration of hyaluronic acid (HA) in the early rehabilitation after tendon grafting may help to prevent adhesions. We evaluated changes in the excursion resistance between potential sources of flexor tendon grafts and the annular pulley in a canine model after administration of HA. The intrasynovial and extrasynovial tendons were soaked in 10 mg/ml of HA for five minutes. The excursion resistance between these tendons and the annular pulley of an intact proximal phalanx and that of the same tendons of the opposite foot without administration of HA were evaluated. The tendon of flexor digitorum profundus of the second toe without administration of HA was used as a control. The gliding resistance of canine tendons was significantly decreased after the administration of HA especially in the extrasynovial tendons. Our findings suggest that the administration of HA may improve the gliding function of a flexor tendon graft.


The yeast SEN1 gene is required for the processing of diverse RNA classes.
A single base change in the helicase superfamily 1 domain of the yeast Saccharomyces cerevisiae SEN1 gene results in a heat-sensitive mutation that alters the cellular abundance of many RNA species. We compared the relative amounts of RNAs between cells that are wild-type and mutant after temperature-shift. In the mutant several RNAs were found to either decrease or increase in abundance. The affected RNAs include tRNAs, rRNAs and small nuclear and nucleolar RNAs. Many of the affected RNAs have been positively identified and include end-matured precursor tRNAs and the small nuclear and nucleolar RNAs U5 and snR40 and snR45. Several small nucleolar RNAs co-immunoprecipitate with Sen1 but differentially associate with the wild-type and mutant protein. Its inactivation also impairs precursor rRNA maturation, resulting in increased accumulation of 35S and 6S precursor rRNAs and reduced levels of 20S, 23S and 27S rRNA processing intermediates. Thus, Sen1 is required for the biosynthesis of various functionally distinct classes of nuclear RNAs. We propose that Sen1 is an RNA helicase acting on a wide range of RNA classes. Its effects on the targeted RNAs in turn enable ribonuclease activity.


Addressing Evaluation Barriers with Early Innovation Development for Adolescent-Focused Sexual and Reproductive Health Interventions.
Most evidence-based teen pregnancy prevention programs focus on individual-level sexual health outcomes (e.g., STIs, pregnancy, teen births). To expand program and intervention approaches within teen pregnancy prevention (TPP), the Department of Health and Human Services funded two grantees, Innovative Teen Pregnancy Prevention Programs (iTP3) and Innovation Next (IN) to support and enable early innovation to advance adolescent health and prevent teen pregnancy. The pipeline to support and enable innovation in adolescent health is complex, resulting in barriers and challenges to research and evaluation of novel programs. This paper presents some of the barriers encountered by the grantees. Data for this paper was collected from key personnel and secondary data sources. Focus group participants included seven representatives (n = 7) across the two organizations. Focus group questions assessed barriers related to innovative intervention development and evaluation. Key findings include four barriers to evaluation when fostering innovative adolescent-focused pregnancy prevention interventions. These included (a) funding constraints on evaluation activities, (b) innovation readiness for rigorous testing, (c) evaluation knowledge and expertise on innovation-development teams, and (d) challenges with evaluation requirements. Novel and promising system- and technology-focused interventions with the potential to impact TPP require alternative tools and approaches for evaluation. This would allow research to focus on how systems-level change mechanisms (i.e., policy, access to care) impact sexual risk behaviors and better understand ecological and social determinants of health for the priority population. The advancement of approaches to impact adolescent health identifies the need to expand the focus of evidence-based interventions beyond the adolescent themselves and understand approaches that impact external contexts and environments related to reducing sexual and reproductive health (SRH) risk-taking.


Melatonin and malignant disease.
A possible role for the pineal and melatonin in malignant disease is suggested by the studies of hormone-dependent tumours presented here. The most dramatic observation of the effect of the pineal and melatonin in malignancy is that melatonin protects against, while pinealectomy enhances, 7,12-dimethylbenz[a]anthracene-induced mammary tumours in rats. Melatonin may protect against tumours through a suppressive effect on prolactin secretion or an action on oestrogen receptors. Melatonin can change the concentration of oestrogen receptors in hamsters, both juvenile and adults, and in a human breast cancer cell line. The long-term effect of melatonin in the ovariectomized adult hamster and in human breast cancer cells is to inhibit oestrogen-stimulated growth. A possible relationship between melatonin and oestrogen receptors was examined in women with breast cancer. An inverse correlation was observed between the oestrogen receptor concentration in each patient's tumour and her peak plasma melatonin level, suggesting that the more hormone dependent the breast cancer the more blunted the daily melatonin rhythm. Thus, the more robust the daily melatonin rhythm the greater the protective effect on hormone-dependent breast cancer. Unfortunately, this hypothesis is not easily tested as shown in a study of women at high risk for developing breast cancer. These women had daily melatonin profiles that did not differ from those of a normal population. Thus, the use of plasma melatonin as a screening tool for breast cancer risk is not reasonable; however the basic and clinical data argue that the role of melatonin in endocrine-related cancers requires more extensive clinical investigation.


[Tracers in oncology - preclinical and clinical evaluation].
In oncology, PET and PET/CT with tracers beyond FDG target more specific biological processes, such as proliferation (18F-3´-fluoro-3´-deoxy-L-thymidine; 18F-FLT), tumour hypoxia (18F-fluoromisonidazol; 18F-FMISO) and phospholipid metabolism (radioactively labelled choline derivates). FLT is a thymidine analogue which can be labelled with 18F. PET with 18F-FLT enables to non-invasively image and to quantify the proliferation fraction of tumours. Proliferation dependent accumulation of FLT has been demonstrated for a variety of solid and haematologic neoplasms including lung cancer, breast cancer, gastric cancer, colorectal cancer and malignant lymphoma. Furthermore, FLT has been suggested as surrogate marker for the assessment of response to treatment, especially when targeted drugs are utilized. PET imaging in particular has emerged as a promising non-invasive tool to accurately characterize tumour oxygenation. The great promise of PET/CT is its potential as a single imaging modality for whole body staging that provides anatomical and biological information on the disease as a whole. It allows a more precise estimation of the hypoxic tumour volume as well as comparisons on a voxel-by-voxel basis (parametric mapping). PET and PET/CT with hypoxia tracers thus offer the potential to optimize and individualize therapy for patients suffering from cancer. PET- and PET/CT-studies using 11C- or 18F-labeled choline derivates recently have shown promising results for re-staging prostate cancer in patients with biochemical recurrence and advanced prostate cancer. In patients with biochemical recurrence of prostate cancer after primary therapy the detection rate of 11C-choline-PET/CT shows a positive relationship with serum PSA-levels. In these patients 11C-choline PET/CT allows not only to diagnose but also to localize recurrent disease with implications on disease management (localised vs. systemic therapy). The clinical success of multimodal imaging with PET/CT is expected to promote the combination of MRI and PET in the future.