Sentinel lymph node identification in breast cancer patients.
To evaluate the predictive value of sentinel lymph node biopsy versus axillary node dissection on lymph node status in patients with T1-T2 breast cancer. Twenty-nine patients with T1 and 12 with T2 breast carcinoma and clinically N0 axillary lymph nodes, underwent lymphoscintigraphy following the administration of 99mTc-human albumin nanocolloids. The tracer was injected subdermally, over the tumor mass, in the 34 patients with palpable lesions and peritumorally (n=3) or intratumorally (n=4), under stereotactic or ultrasound guidance, in the 7 patients with non-palpable lesions. Anterior and lateral planar images were acquired 15 min after the injection of the tracer and repeated every 30 min up to 3 hr until identification of sentinel lymph node. At the end of the scintigraphic study, sentinel node skin projection was marked using a dermographic pen. Eighteen hours after lymphoscintigraphy, sentinel lymph node was identified and removed during surgery by hand-held gamma probe, then, the remaining axillary lymph nodes were dissected. All surgical specimens underwent histologic examination. Sentinel lymph nodes free of metastasis at histology, underwent additional examination with immunohistochemistry using monoclonal antibodies against cytokeratin and EMA to search for micrometastases. Sentinel lymph node was identified in the 34 patients injected subdermally and in the 3 patients injected peritumorally, while it remained undetected in the 4 patients injected intratumorally except for one case in which it was isolated by radioguided surgery but not scintigraphically. Sentinel nodes resulted free of metastases both at histology and immunohistochemistry in 32 cases and metastatic in 6. In the 32 patients with non-metastatic sentinel lymph nodes the other axillary nodes were also free of metastases. Among the 6 metastatic sentinel lymph nodes, in 3 cases they were the only metastatic nodes of the axilla while in the other 3 cases metastases were spread to other axillary nodes. In agreement with previous studies, our results showed that sentinel lymph node radioguided biopsy is a simple and reliable method for predicting axillary lymph nodes status and for avoiding axillary dissection in early breast cancer patients with sentinel node free of metastases.


11beta-hydroxysteroid dehydrogenase type 2 in mouse aorta: localization and influence on response to glucocorticoids.
Both isozymes of 11beta-hydroxysteroid dehydrogenase, which interconvert active and inactive glucocorticoids, are expressed in the mouse aortic wall. Mice deficient in 11HSD type 2 (which converts active corticosterone into inert 11-dehydrocorticosterone) have hypertension and impaired endothelial nitric oxide activity. It has been suggested that 11HSD2 influences vascular function directly by limiting glucocorticoid-mediated inhibition of endothelium-derived nitric oxide. This study sought to determine (1) the cellular distribution of the 11HSD isozymes within the mouse aortic wall and (2) the influence of 11HSD2 on direct glucocorticoid-mediated changes in aortic function. Mouse aortas were separated into their component layers and RNA extracted for RT-PCR. Both types of corticosteroid (mineralocorticoid and glucocorticoid) receptors and both 11HSD isozymes were expressed in the aortic wall. 11HSD1 expression colocalized with alpha-smooth muscle actin (a marker for smooth muscle cells), whereas 11HSD2 colocalized with TIE-2 (a marker for endothelial cells). Functional relaxation responses of mouse aortic rings were unaltered after exposure to glucocorticoids for 24 hours. In the presence of l-arginine, glucocorticoids produced an endothelium-independent reduction of contraction; similar results were obtained with aortas from mice with genetic inactivation of 11HSD2. Incubation in medium containing l-arginine reversed the endothelial cell dysfunction associated with 11HSD2 inactivation. Thus, 11HSD2 is appropriately sited to modulate endothelial cell function, but endothelial dysfunction in 11HSD2 knockout mice cannot be explained simply by increased access of corticosterone to endothelial cell corticosteroid receptors. Therefore, additional mechanisms, possibly involving indirect effects of enhanced corticosterone action in the kidney and the resultant hypertension, must be involved.


Global Stroke Statistics 2023: Availability of reperfusion services around the world.
Disparities in the availability of reperfusion services for acute ischaemic stroke are considerable globally, and require urgent attention. Contemporary data on the availability of reperfusion services in different countries provide the necessary evidence to prioritise where access to acute stroke treatment is needed. To provide a snapshot of published literature on the provision of reperfusion services globally, including when facilitated by telemedicine or mobile stroke unit services. Methods: We searched PubMed to identify original papers, published up to January 2023, with the most recent, representative and relevant data for each country. Keywords included thrombolysis and telemedicine. We also screened reference lists of review papers, citation history of papers, and the grey literature. The information is provided as a narrative summary. Of 11,222 potentially eligible papers retrieved, 148 were included for review following de-duplications and full text review. Data were also obtained from national stroke clinical registry reports, Registry of Stroke Care Quality (RES-Q) and Pre-hospital Stroke Treatment Organization (PRESTO) repositories, and other national sources. Overall, we found evidence of the provision of intravenous thrombolysis services in 70 countries (6463% high-income countries (HICs)) and endovascular thrombectomy services in 33 countries (68% HICs), corresponding to far less than half of the countries in the world. Recent data (from 2019 or later) were lacking for 35 of 67 countries with known year of data (52%). We found published data on 74 different stroke telemedicine programs (93% in HICs) and 14 active mobile stroke unit pre-hospital ambulances services (80% in HICs) around the world. Despite remarkable advancements in reperfusion therapies for stroke, it is evident from available data that their availability remains unevenly distributed globally. Contemporary published data on availability of reperfusion services remain scarce, even in HICs, thereby making it difficult to reliably ascertain current gaps in the provision of this vital acute stroke treatment around the world.


Diguanylate cyclase null mutant reveals that C-Di-GMP pathway regulates the motility and adherence of the extremophile bacterium Acidithiobacillus caldus.
An understanding of biofilm formation is relevant to the design of biological strategies to improve the efficiency of the bioleaching process and to prevent environmental damages caused by acid mine/rock drainage. For this reason, our laboratory is focused on the characterization of the molecular mechanisms involved in biofilm formation in different biomining bacteria. In many bacteria, the intracellular levels of c-di-GMP molecules regulate the transition from the motile planktonic state to sessile community-based behaviors, such as biofilm development, through different kinds of effectors. Thus, we recently started a study of the c-di-GMP pathway in several biomining bacteria including Acidithiobacillus caldus. C-di-GMP molecules are synthesized by diguanylate cyclases (DGCs) and degraded by phosphodiesterases (PDEs). We previously reported the existence of intermediates involved in c-di-GMP pathway from different Acidithiobacillus species. Here, we report our work related to At. caldus ATCC 51756. We identified several putative-ORFs encoding DGC and PDE and effector proteins. By using total RNA extracted from At. caldus cells and RT-PCR, we demonstrated that these genes are expressed. We also demonstrated the presence of c-di-GMP by mass spectrometry and showed that genes for several of the DGC enzymes were functional by heterologous genetic complementation in Salmonella enterica serovar Typhimurium mutants. Moreover, we developed a DGC defective mutant strain (Δc1319) that strongly indicated that the c-di-GMP pathway regulates the swarming motility and adherence to sulfur surfaces by At. caldus. Together, our results revealed that At. caldus possesses a functional c-di-GMP pathway which could be significant for ores colonization during the bioleaching process.


[Taxotere and methylnitrosourea: experimental appraisal of combination chemotherapy].
The effectiveness of taxotere and methylnitrosourea (MNU) combined application against murine P388 leukemia has been studied. Antitumor drugs were administered separately or in combination in doses of 50, 60 or 70 mg/kg per day, i/p, beginning from day 1 after tumor transplantation. Combined administration was shown to potentiate antitumor effect, which also largely depended on schedule. Survival increase varied within 50-130% of control values. Optimal effect was observed with the following schedules: taxotere + MNU, 24-hour interval between injections, and MNU-taxotere, 4-day interval between injections. Synergism was in evidence since the therapeutic effect of combination treatment was significantly higher than that of either drug administered alone.


Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma.
Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin's lymphoma (NHL). Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti-B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board-approved questionnaire sent to the referring oncologists. Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy. Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.


The Middle Road Less Taken: Electronic-Structure-Inspired Design of Hybrid Photocatalytic Platforms for Solar Fuel Generation.
The development of efficient solar energy conversion to augment other renewable energy approaches is one of the grand challenges of our time. Water splitting, or the disproportionation of H2O into energy-dense fuels, H2 and O2, is undoubtedly a promising strategy. Solar water splitting involves the concerted transfer of four electrons and four protons, which requires the synergistic operation of solar light harvesting, charge separation, mass and charge transport, and redox catalysis processes. It is unlikely that individual materials can mediate the entire sequence of charge and mass transport as well as energy conversion processes necessary for photocatalytic water splitting. An alternative approach, emulating the functioning of photosynthetic systems, involves the utilization of hybrid systems wherein different components perform the various functions required for solar water splitting. The design of such hybrid systems requires the multiple components to operate in lockstep with optimal thermodynamic driving forces and interfacial charge transfer kinetics. This Account describes a new class of nanoscale heterostructures comprising M xV2O5 nanowires, where M is a p-block cation with a ( n - 1) d10 ns2 np0 electronic configuration characterized by a stereoactive lone pair of electrons and x is its stoichiometry, interfaced with II-VI semiconductor quantum dots (QDs). Photocatalytic water splitting involves the transfer of excited-state holes from QDs to mid-gap states (derived from the stereoactive lone pairs of p-block cations) of nanowires, hole transport through nanowires, the reduction of protons at a QD-immobilized catalyst, and water oxidation at an anode. The M xV2O5/QD architectures provide a vast design space for evolutionary optimization of function with considerable tunability of composition and structure of the individual components as well as of the interfacial structure, thereby facilitating programmability of absorption spectra, energetic offsets, and charge-transfer reactivity. The available design space spans choice of the p-block cation M, its stoichiometry x, the composition and size of various QDs, and the nature of the nanowire/QD interface. This multivariate parameter space has been navigated by integrating first-principles modeling, diversified synthesis, spectroscopic measurements, and catalytic evaluation to facilitate the rational design of several generations of heterostructures and the systematic improvement of their photocatalytic performance. The electronic structures of the target heterostructures are predicted by DFT calculations in light of the revised lone pair model of stereoactive structural distortions and evaluated by hard X-ray photoelectron spectroscopy such as to systematically tune the interfacial band offsets. Central to this approach is the development of a topochemical "etch-a-sketch" intercalation approach that allows for facile installation of p-block cations in metastable polymorphs of V2O5. The interfacial charge transfer kinetics of M xV2O5/QD heterostructures is further evaluated by transient absorption spectroscopy to measure excited-state charge-transfer dynamics and is found to depend sensitively on interfacial structure and the thermodynamic driving forces in accordance with Marcus theory. The integration of theory and experiment has allowed for the design of viable photocatalytic architectures exemplified by the exceptional catalytic performance of β-Pb xV2O5/CdX (X= S, Se) architectures, which has subsequently been elaborated to other lone-pair M xV2O5 compounds, demonstrating the effective exploitation of the opportunities for programmability available in the design space.


Xylazine-pentobarbital anesthesia in dogs and its antagonism by yohimbine.
Once a week for 4 weeks, 5 dogs were given IM injections of xylazine (2.2 mg/kg of body weight) followed in 10 minutes by IV injections of pentobarbital (14 mg/kg). The resultant duration of anesthesia, absence of pedal reflex, and time from return of consciousness to ambulation were consistent from week to week. The mean times were 137.3, 111.8, and 56.9 minutes, respectively. A second experiment using 5 other dogs was performed to evaluate the antagonistic effect of yohimbine on the anesthesia induced by the xylazine-pentobarbital combination. When yohimbine (0.1 mg/kg, IV) was administered 10, 60, and 120 minutes after the xylazine-pentobarbital injection (given as in the 1st experiment), it abolished or markedly reduced the duration of anesthesia, absence of pedal reflex, and the time from return of consciousness to ambulation. After being given yohimbine, the dogs had a smooth recovery without postanesthetic excitement. In experiment 3, IM xylazine injections caused bradycardia without changing mean arterial blood pressure. Subsequent IV pentobarbital administration abolished xylazine-induced bradycardia for approximately 20 minutes and decreased arterial blood pressure slightly and gradually. Respiration was markedly depressed for the first 20 minutes of xylazine-pentobarbital anesthesia and gradually decreased during the rest of the 50-minute monitoring period. Yohimbine injection at postpentobarbital dosing minute 50 reversed the resumed xylazine-induced bradycardia and relieved other signs of respiratory depression associated with xylazine-pentobarbital anesthesia. The xylazine-pentobarbital combination was safe and effective for inducing and maintaining up to 2 hours of anesthesia in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)


Inferences on the kinetics of asbestos deposition and clearance among chrysotile miners and millers.
The health effects of asbestos are intimately related to the fate of inhaled fibers in the lungs. The kinetics of asbestos fibers have been studied primarily in rodents. The objective of this study was to explore the application of these kinetic models to human autopsy data. We analyzed the asbestos fiber content of the lungs of 72 Quebec chrysotile miners and millers and 49 control subjects using analytical transmission electron microscopy. Statistical methods included standard multivariate linear regression and locally weighted regression methods. The lung burdens of asbestos bodies and chrysotile and tremolite fibers were correlated, as were the concentrations of short, medium, and long fibers of each asbestos variety. There were significant associations between the duration of occupational exposure and the burdens of chrysotile and tremolite. The concentration of chrysotile decreased with the time since last exposure but the concentration of tremolite did not. The clearance rate varied inversely with the length of chrysotile fibers. For fibers greater than 10 mu in length the clearance half-time was estimated to be 8 years. The patterns in our data are compatible with both of the hypotheses suggested from rodent experiments; the existence of a long-term sequestration compartment and overload of clearance mechanisms in this compartment.


Prostate-Specific Membrane Antigen in Low-Grade Fibromatosis.
We report a case of fibromatosis demonstrating prostate-specific membrane antigen (PSMA)-positive scan. A 76-year-old man was under assessment because of rising prostate-specific antigen level. Bone scan showed abnormal soft tissue uptake of Tc-MDP adjacent to the right scapula, compatible with a mass in MRI, thereafter. Because of the unavailability of Ga-PSMA scan in our department and also high cost in other centers, the patient underwent Lu-PSMA for more assessment, which revealed PSMA-avid mass. Pathologic examination confirmed the diagnosis of low-grade fibromatosis. This report demonstrates another false-positive result of PSMA scan and highlights the importance of pathologic examination.


Role of the blood-spinal cord barrier in posttraumatic syringomyelia.
Posttraumatic syringomyelia produces a significant burden of pain and neurological deficits in patients with spinal cord injury. The mechanism of syrinx formation is unknown and treatment is often ineffective. A possible explanation for syrinx formation is fluid leakage from the microcirculation in the presence of a compromised blood-spinal cord barrier (BSCB). The aim of this study was to investigate the structural and functional integrity of the BSCB in a model of posttraumatic syringomyelia. The excitotoxic amino acid and arachnoiditis model of syringomyelia was used in 27 Sprague-Dawley rats. Structural integrity of the BSCB was assessed using immunoreactivity to endothelial barrier antigen (EBA), and loss of functional integrity was assessed by extravasation of intravascular horseradish peroxidase. Animals were studied after 3 days, or at 1, 3, 6, or 12 weeks after surgery. There were laminectomy-only and saline injection control animals for comparison at each time point. Syrinxes formed in 16 of the 17 animals injected with excitotoxic amino acid. Loss of structural and functional integrity of the BSCB in syrinx animals was noted at all time points. Disruption of the BSCB was most dramatic in tissue adjacent to the syrinx, and in the central and dorsal gray matter. Changes in EBA expression generally corresponded with altered vascular permeability, although in the acute stages, widespread vascular permeability occurred without a corresponding decrease in EBA expression. At the later time points (3-12 weeks) EBA expression was often absent, although no vascular leakage was observed. This study demonstrated a prolonged structural and functional disruption of the BSCB in this model of posttraumatic syringomyelia. Loss of functional integrity of the BSCB, with fluid entering the interstitial space of the spinal cord, may contribute to initial cyst formation after spinal cord injury and subsequent enlargement of the cyst, to produce posttraumatic syringomyelia.


An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis.
To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.


Development and present status of concentrate therapy for hemophilia and von Willebrand's disease.
A brief review of the current status of treatment of two severe bleeder diseases, hemophilia A and von Willebrand's disease, with factor VIII concentrate is given. The functional activities deficient in the two diseases, antihemophilic factor (AHF) or coagulant factor VIII (F. VIII:C) in hemophilia, and the von Willebrand factor(s) (vWF; F.VIII R: Ag) in von Willebrand's disease, are present in a very large protein moiety of plasma, the macromolecular factor VIII complex. The rationale for replacement therapy of hemophilia depends on assessment of the severity of a given hemorrhagic episode followed by single, multiple, or continuous infusions of factor VIII concentrates sufficient to raise the plasma AHF to the hemostatic level (15 - less than 50%, depending on the severity of hemorrhage). Prophylactic regimens prevent hemorrhage but are expensive. Despite many problems in their use, the success of factor VIII concentrates in controlling severe hemorrhage and in preventing crippling by arthropathies is evident in many ways including the demand for concentrates, which now exceed the economic value of two other main products of plasma fractionation, albumin and gamma globulin. The rationale for therapy of von Willebrand's disease is dependent on the formation of the hemostatic platelet plug, which includes adhesion of platelets to a vascular site of bleeding, followed by platelet aggregation to give the hemostatic thrombus. The very large molecular weight arrays of the factor VIII complex contained in cryoprecipitate appear needed for development of the hemostatic plug. A new test for determining the plasma platelet-aggregating vWF, the Botrocetin test, appears superior to the ristocetin test. An activator factor in Bothrops snake venom is used. Some prospects for improving the factor VIII therapeutic preparations through recombinant DNA technology and through altering procedures for fractionation are outlined.


Building-Related Environmental Intolerance and Associated Health in the General Population.
People frequently attribute adverse symptoms to particular buildings when exposure to pollutants is low, within nonhazardous levels. Our aim was to characterize building-related intolerance (BRI) in the general population. Data were derived from two population-based questionnaire surveys, the Västerbotten and Österbotten Environmental Health Study. We identified cases of BRI if respondents reported symptoms emerging from residing in certain buildings, when most other people had none. The questionnaires covered lifestyle factors, perceived general health, BRI duration and symptom frequency, the emotional and behavioral impact of BRI, coping strategies, and physician-diagnosed diseases. From the total of 4941 participants, we formed two case groups, 275 (5.6%) fulfilled criteria for self-reported BRI, and 123 (2.5%) for BRI with wide-ranging symptoms. Individuals in both case groups were significantly more often female, single, and perceived their general health as poorer than the referents, i.e., those reporting no BRI symptoms. The mean duration of BRI was 12 years. In both case groups, avoidance behavior was found in over 60%, and nearly half of the sample had sought medical care. BRI with wide-ranging symptoms was associated with elevated odds for all studied comorbidities (somatic and psychiatric diseases and functional somatic syndromes). The perceived health of individuals with BRI is poorer and comorbidities are more frequent than among referents. BRI seems to be similar to other environmental intolerances and shares features with functional somatic syndromes.


Novel approaches to the treatment of acute renal failure.
Acute renal failure (ARF) occurs frequently in hospitalised patients and is associated with significant morbidity and mortality. Many therapeutic strategies have been undertaken both to prevent acute renal injury and, once ARF occurs, to improve renal function and reduce mortality. Among the available pharmacological options, no specific therapy has been shown to alter the course of ARF. This article reviews the efficacy of several strategies in experimental renal disease and raises the possibility that similar interventions might be available to the clinician in the near future for the prevention and management of ARF. The prospect of these novel strategies, together with the ever-increasing understanding of the complex pathophysiology of ARF, offers the promise of effective and more physiological therapeutic interventions in this new millennium.


Role of glucocorticoids and catecholamines on hepatic thiobarbituric acid reactants in basal and stress conditions in the rat.
Thiobarbituric acid-reactants (TBARs) are considered to be an index of lipid peroxidation. In the present experiments, the effect of stress and hormones on hepatic TBARs levels was studied in Sprague-Dawley rats. In unstressed conditions adrenalectomized rats showed higher TBARs levels than sham-adrenalectomized rats. The effect of adrenalectomy was reverted by the administration of corticosterone but not by that of aldosterone, indicating that glucocorticoids exert a negative role on the regulation of liver TBARs. The effect of these hormones appears to be a permissive one, since the administration of a long lasting ACTH preparation did not reduce liver TBARs. In contrast to that observed in unstressed rats, glucocorticoids appeared to increase liver TBARs in stressed rats. Nevertheless, other alternative explanations are possible. Finally, no evidence for a role of catecholamines in the regulation of hepatic TBARs was found.


Morphology of First Zoeal Stage of Four Genera of Alvinocaridid Shrimps from Hydrothermal Vents and Cold Seeps: Implications for Ecology, Larval Biology and Phylogeny.
Alvinocaridid shrimps are endemic species inhabiting hydrothermal vents and/or cold seeps. Although indirect evidences (genetic and lipid markers) suggest that their larval stages disperse widely and support large scale connectivity, larval life and mechanisms underlying dispersal are unknown in alvinocaridids. Here we provide for the first time detailed descriptions of the first larval stage (zoea I) of four alvinocaridid species: Rimicaris exoculata and Mirocaris fortunata from the Mid-Atlantic Ridge, Alvinocaris muricola from the Congo Basin and Nautilocaris saintlaurentae from the Western Pacific. The larvae were obtained from onboard hatching of brooding females (either at atmospheric pressure or at habitat pressure in hyperbaric chambers) and from the water column near adult habitats, sampled with plankton pumps or sediment traps. Major characteristics of the alvinocaridid larvae include undeveloped mandible and almost complete absence of setation in the inner margin of the mouth parts and maxillipeds. Although the larvae are very similar between the four species studied, some morphological features could be used for species identification. In addition, undeveloped mouthparts and the large amount of lipid reserves strongly support the occurrence of primary lecithotrophy in the early stage of alvinocaridids. Although lecithotrophy in decapod crustaceans is usually associated with abbreviated larval development, as a mechanism of larval retention, morphological and physiological evidences suggest the occurrence of an extended and lecithotrophic larval stage in the Alvinocarididae. These traits permit the colonization of widely dispersed and fragmented environments of hydrothermal vents and cold seeps. Distribution of larval traits along the phylogenetic reconstruction of the Alvinocarididae and related families suggest that lecithotrophy/planktotrophy and extended/abbreviated development have evolved independently along related families in all potential combinations. However, the Alvinocarididae is the only taxa with a combination of lecithotrophy and extended larval development.


Application of sequential and orthogonalised-partial least squares (SO-PLS) regression to predict sensory properties of Cabernet Sauvignon wines from grape chemical composition.
The current study determined the applicability of sequential and orthogonalised-partial least squares (SO-PLS) regression to relate Cabernet Sauvignon grape chemical composition to the sensory perception of the corresponding wines. Grape samples (n = 25) were harvested at a similar maturity and vinified identically in 2013. Twelve measures using various (bio)chemical methods were made on grapes. Wines were evaluated using descriptive analysis with a trained panel (n = 10) for sensory profiling. Data was analysed globally using SO-PLS for the entire sensory profiles (SO-PLS2), as well as for single sensory attributes (SO-PLS1). SO-PLS1 models were superior in validated explained variances than SO-PLS2. SO-PLS provided a structured approach in the selection of predictor chemical data sets that best contributed to the correlation of important sensory attributes. This new approach presents great potential for application in other explorative metabolomics studies of food and beverages to address factors such as quality and regional influences.


Quantitative single molecule RNA-FISH and RNase-free cell wall digestion in Neurospora crassa.
Single molecule RNA-FISH (smFISH) is a valuable tool for analysis of mRNA spatial patterning in fixed cells that is underutilized in filamentous fungi. A primary complication for fixed-cell imaging in filamentous fungi is the need for enzymatic cell wall permeabilization, which is compounded by considerable variability in cell wall composition between species. smFISH adds another layer of complexity due to a requirement for RNase free conditions. Here, we describe the cloning, expression, and purification of a chitinase suitable for supplementation of a commercially available RNase-free enzyme preparation for efficient permeabilization of the Neurospora cell wall. We further provide a method for smFISH in Neurospora which includes a tool for generating numerical data from images that can be used in downstream customized analysis protocols.


Permanent Working Group of European Junior Hospital Doctors. Policy statement on postgraduate medical education in general practice. Prepared by the Subcommittee on Postgraduate Medical Training.
The Permanent Working Group of European Junior Hospital Doctors' Policy Statement on Postgraduate Medical Education reviewed the regulations governing postgraduate training in the European Communities and set out educational principles which the Group believed were applicable in all medical disciplines. Recognizing that the training of general practitioners poses some specific problems, the PWG has adopted this further statement on training in general practice. It reaffirms the need for trainees to have a model of good practice, extensive experience, theoretical teaching, critical scrutiny and regular, unambiguous feedback regarding progress. In addition, it argues for the availability of an appropriate number of posts for GP trainees both in hospitals and in practices and an awareness among hospital-based trainers of the educational needs of trainees who intend a career in general practice.


Anthocyanins and Human Health: An In Vitro Investigative Approach.
Anthocyanin pigments and associated flavonoids have demonstrated ability to protect against a myriad of human diseases, yet they have been notoriously difficult to study with regard to human health. Anthocyanins frequently interact with other phytochemicals to potentiate biological effects, thus contributions from individual components are difficult to decipher. The complex, multicomponent structure of compounds in a bioactive mixture and the degradation of flavonoids during harsh extraction procedures obscure the precise assignment of bioactivity to individual pigments. Extensive metabolic breakdown after ingestion complicates tracking of anthocyanins to assess absorption, bioavailability, and accumulation in various organs. Anthocyanin pigments and other flavonoids that are uniformly, predictably produced in rigorously controlled plant cell culture systems can be a great advantage for health and nutrition research because they are quickly, easily isolated, lack interferences found in whole fruits, can be elicited to provoke rapid and prolific accumulation, and are amenable to biolabeling so that metabolic fate can be investigated after ingestion.


Physicians' ability to predict the risk of coronary heart disease.
Coronary heart disease (CHD) is the leading cause of death in the United States. Previous research examining physicians ability to estimate cardiovascular risk has shown that physicians' generally overestimate the absolute risk of CHD events. This question has, however, only studied risk prediction for a limited number of patient care scenarios. The aim of this study is to measure the ability of physicians to estimate the risk of CHD events in patients with no previous history of coronary heart disease. Twelve primary prevention scenarios with a 5-year risk of CHD events were developed. This questionnaire was surveyed at 3 university teaching hospitals where the participants were a convenience sample of internal medicine residents and fellows or attending physicians in general internal medicine or cardiology. For each scenario, physicians were asked to estimate the baseline 5-year risk of a coronary heart disease event and the revised risk if the patient were to receive lipid-lowering drug therapy. Estimates of the baseline 5-year risk were compared with values calculated from Framingham risk equations. Inaccurate responses were defined as those with a ratio of estimated to actual risk of more than 1.5 or less than 0.67. Physicians' estimates of the relative risk reduction with therapy were considered to be accurate if they were between 25% and 40%. 79 physicians (53 residents, 8 fellows, 18 attending physicians) completed the survey. Only 24% of physicians' risk estimates were accurate. In most cases, physicians overestimated the absolute risk of cardiovascular events without therapy (proportion overestimating ranged from 32-92% for the 12 individual scenarios). Physicians made larger errors in patient scenarios involving patients with high total or LDL cholesterol levels. Physicians' estimates of the relative risk reduction from treatment were more accurate: 43% of estimates were between 25 and 40%. Over 85% of physicians recommended treatment in 10 of 12 scenarios. Physicians overestimate the absolute risk of CHD events and the potential absolute benefit of drug therapy.


Characterization of NADPH Diaphorase- and Doublecortin-Positive Neurons in the Lizard Hippocampal Formation.
The lizard cortex has remarkable similarities with the mammalian hippocampus. Both regions process memories, have similar cytoarchitectural properties, and are important neurogenic foci in adults. Lizards show striking levels of widespread neurogenesis in adulthood and can regenerate entire cortical areas after injury. Nitric oxide (NO) is an important regulatory factor of mammalian neurogenesis and hippocampal function. However, little is known about its role in nonmammalian neurogenesis. Here, we analyzed the distribution, morphology, and dendritic complexity (Neurolucida reconstructions) of NO-producing neurons through NADPH diaphorase (NADPHd) activity, and how they compare with the distribution of doublecortin-positive (DCX+) neurons in the hippocampal formation of the neotropical lizard Tropidurus hispidus. NADPHd-positive (NADPHd+) neurons in the dorsomedial cortex (DMC; putatively homologous to mammalian CA3) were more numerous and complex than the ones in the medial cortex (MC; putatively homologous to the dentate gyrus). We found that NADPHd+ DMC neurons send long projections into the MC. Interestingly, in the MC, NADPHd+ neurons existed in 2 patterns: small somata with low intensity of staining in the outer layer and large somata with high intensity of staining in the deep layer, a pattern similar to the mammalian cortex. Additionally, NADPHd+ neurons were absent in the granular cell layer of the MC. In contrast, DCX+ neurons were scarce in the DMC but highly numerous in the MC, particularly in the granular cell layer. We hypothesize that NO-producing neurons in the DMC provide important input to proliferating/migrating neurons in the highly neurogenic MC.


Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer.
Although tobacco smoking is the primary risk factor for lung cancer, low dietary folate intake and suboptimal DNA repair capacity also contribute to lung cancer risk. Thymidylate synthase (TYMS) is involved in the metabolism of folate and the provision of nucleotides needed for DNA synthesis and repair. Thus, a variation in TYMS functions likely plays a role in the etiology of lung cancer. The TYMS gene has a tandem repeat polymorphism (two or three 28 bp) in the TYMS enhancer region (TSER) and a 6 bp deletion/insertion polymorphism in the TS 3'-untranslated region (TS3'UTR or 1494del6). We investigated the frequencies of these two polymorphisms in a hospital-based case-control study of 1055 lung cancer patients and 1140 cancer-free controls in a non-Hispanic white population and genotyped for these two polymorphisms. We found that the TS3'UTR, but not the TSER, variant was associated with the risk of lung cancer. Compared with homozygotes for the TS3'UTR 6 bp deletion (0bp/0bp), the 6bp/0bp+6bp/6bp genotypes were associated with a significantly increased risk of lung cancer [odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.12-2.06]. In stratification analysis the risk associated with the 0bp/6bp+6bp/6bp genotype was more pronounced in subjects who were >55 years old (OR = 1.57, 95% CI = 1.10-2.23), males (OR = 1.88, 95% CI = 1.22-2.89), current (OR = 2.04, 95% CI = 1.26-3.29) and heavy smokers (OR = 1.73, 95% CI = 1.10-2.70) and current drinkers (OR = 3.17, 95% CI = 1.78-5.64).Furthermore, significant gene-dietary interactions were found between TS3'UTR and alcohol consumption and between TSER and vitamin B(12) intake. In conclusion, the polymorphisms of TYMS are likely to contribute to the risk of lung cancer in non-Hispanic whites and interact with dietary factors in lung cancer development.


A Preference-Based Model of Care: An Integrative Theoretical Model of the Role of Preferences in Person-Centered Care.
Knowledge of individuals' everyday preferences is a cornerstone of person-centered care (PCC). Initial evidence demonstrates the positive impact of honoring preferences in care for older adults receiving long-term services and supports (LTSS). Yet, the mechanisms through which preference-based care affects individual well-being remain poorly understood. This article proposes a theoretical model of PCC entitled the Preference-Based Model of Care that integrates the Theory of Human Motivation, Self-determination Theory, the Competence-Press Model of person and environment fit, the Living Systems Framework, and the Broaden-and-Build theory of positive emotions to deepen our understanding of the processes through which preference-based care affects well-being among older adults receiving LTSS. The Preference-Based Model of Care illustrates how goal-directed behaviors facilitate need fulfillment through the expression of individual preferences and how these behaviors mediate the relationship between person-environment fit and affect balance within a particular social, cultural, and political context. The Preference-Based Model of Care can advance research on PCC in LTSS and can inform LTSS clinical practice guidelines for older adults, regardless of functional or cognitive capacity.


Trends in the Management of Small Renal Masses: A Survey of Members of the Endourological Society.
Treatment modalities for small renal masses (SRMs) include open or minimally invasive radical or partial nephrectomy, and laparoscopic or percutaneous ablations. Members of the Endourological Society were surveyed to evaluate how practitioner and clinical practice characteristics may be associated with the management of SRMs over time. The survey assessed characteristics of urologists (recency of residency and fellowship training, clinical practice type and location, and treatment modalities available) and their management of SRMs over the past year and over the course of the year 5 years prior. Of the 1495 surveys e-mailed, there were 129 respondents (8.6%). Comparing the past year to 5 years prior, there was increasing utilization of robotic partial nephrectomy (p < 0.001) and robotic radial nephrectomy (p = 0.031). In contrast, there was decreasing utilization of open partial nephrectomy (p < 0.001), open radical nephrectomy (p = 0.039), laparoscopic partial nephrectomy (p = 0.002), and laparoscopic radical nephrectomy (p = 0.041). Employment of laparoscopic ablation decreased (p = 0.001), but that of percutaneous ablation did not change significantly. For masses treated with image-guided therapy, there was increasing utilization of microwave ablation (p = 0.008) and decreasing usage of radiofrequency ablation (p = 0.002). Future studies should focus on the most effective treatment modalities based on provider, patient, and tumor characteristics.


In vivo induction of cardiac Purkinje fiber differentiation by coexpression of preproendothelin-1 and endothelin converting enzyme-1.
The rhythmic heart beat is coordinated by electrical impulses transmitted from Purkinje fibers of the cardiac conduction system. During embryogenesis, the impulse-conducting cells differentiate from cardiac myocytes in direct association with the developing endocardium and coronary arteries, but not with the venous system. This conversion of myocytes into Purkinje fibers requires a paracrine interaction with blood vessels in vivo, and can be induced in vitro by exposing embryonic myocytes to endothelin-1 (ET-1), an endothelial cell-associated paracrine factor. These results suggest that an endothelial cell-derived signal is capable of inducing juxtaposed myocytes to differentiate into Purkinje fibers. It remains unexplained how Purkinje fiber recruitment is restricted to subendocardial and periarterial sites but not those juxtaposed to veins. Here we show that while the ET-receptor is expressed throughout the embryonic myocardium, introduction of the ET-1 precursor (preproET-1) in the embryonic myocardium is not sufficient to induce myocytes to differentiate into conducting cells. ET converting enzyme-1 (ECE-1), however, is expressed preferentially in endothelial cells of the endocardium and coronary arteries where Purkinje fiber recruitment takes place. Retroviral-mediated coexpression of both preproET-1 and ECE-1 in the embryonic myocardium induces myocytes to express Purkinje fiber markers ectopically and precociously. These results suggest that expression of ECE-1 plays a key role in defining an active site of ET signaling in the heart, thereby determining the timing and location of Purkinje fiber differentiation within the embryonic myocardium.


Facts About Cracks in Teeth.
Examining the nature of stress distribution within the intact tooth can aid in understanding how natural tooth structures are able to resist mechanical forces during masticatory function. Identification of potential fractures in teeth on clinical examination is essential for correct diagnosis, particularly if there is pulpal involvement. This discussion will consider the different types of fracture, their identification and management. This paper will highlight management of tooth fractures, including identifying prognostic indicators, which are largely dependent on the extent of the fracture within the tooth structure.


Joint Goals in Older Couples: Associations With Goal Progress, Allostatic Load, and Relationship Satisfaction.
Older adults often have long-term relationships, and many of their goals are intertwined with their respective partners. Joint goals can help or hinder goal progress. Little is known about how accurately older adults assess if a goal is joint, the role of over-reporting in these perceptions, and how joint goals and over-reporting may relate to older partners' relationship satisfaction and physical health (operationally defined as allostatic load). Two-hundred-thirty-six older adults from 118 couples (50% female; M age = 71 years) listed their three most important goals and whether they thought of them as goals they had in common with and wanted to achieve together with their partner (self-reported joint goals). Two independent raters classified goals as "joint" if both partners independently listed open-ended goals of the same content. Goal progress and relationship satisfaction were assessed 1 week later. Allostatic load was calculated using nine different biomarkers. Results show that 85% self-reported at least one goal as joint. Over-reporting- the perception that a goal was joint when in fact it was not mentioned among the three most salient goals of the spouse - occurred in one-third of all goals. Multilevel models indicate that the number of externally-rated joint goals was related to greater goal progress and lower allostatic load, but only for adults with little over-reporting. More joint goals and higher over-reporting were each linked with more relationship satisfaction. In conclusion, joint goals are associated with goal progress, relationship satisfaction, and health, but the association is dependent on the domain of functioning.


Providing a computationally derived, mechanically optimised target correction during preoperative planning can improve joint contact mechanics of hip dysplasia treated with periacetabular osteotomy.
Preoperative identification of acetabular corrections that optimally improve joint stability and reduce elevated contact stresses could further reduce osteoarthritis progression in patients with hip dysplasia who are treated with periacetabular osteotomy (PAO). The purpose of this study was to investigate how providing patient-specific, mechanically optimal acetabular reorientations to the surgeon during preoperative planning affected the surgically achieved correction. Preoperative CT scans were used to create patient-specific hip models for 6 patients scheduled for PAO. A simulated acetabular fragment was extracted from the preoperative pelvis model and computationally rotated to simulate candidate acetabular reorientations. For each candidate, discrete element analysis was used to compute contact stresses during walking, which were summed over the gait cycle and scaled by patient age to obtain chronic contact stress-time exposure. The ideal patient-specific reorientation was identified using a cost function that balances minimising chronic stress exposures and achieving surgically acceptable acetabular coverage angles. The optimal reorientation angles and associated contact mechanics were provided to the surgeon preoperatively. After PAO was performed, a model of the surgically achieved correction was created from a postoperative CT scan. Radiographic coverage and contact mechanics were compared between preoperative, optimal, and surgically achieved orientations. While surgically achieved reorientations were not significantly different from optimal reorientations in radiographically measured lateral (p = 0.094) or anterior (p = 0.063) coverage, surgically achieved reorientations had significantly (p = 0.031) reduced total contact area compared to optimal reorientations. The difference in lateral coverage and peak chronic exposure between surgically achieved and optimal reorientations decreased with increasing surgeon experience using the models (R² = 0.758, R2 = 0.630, respectively). Providing hip surgeons with a patient-specific, computationally optimal reorientation during preoperative planning may improve contact mechanics after PAO, which may help reduce osteoarthritis progression in patients with hip dysplasia.


Selenoureas for anion binding as molecular logic gates.
The first example of a molecular logic gate based on selenourea/anion host-guest interaction that performs a ternary logic operation using an 1H-NMR easy to read response output is described here. Selenoureas are very versatile receptors for anion binding, capable of forming both mono- and bi-coordinated adducts at room temperature in solution.


The role of human herpes virus 6 and 7 in the pathogenesis of pityriasis rosea.
Pityriasis rosea (PR) is an acute exanthematous inflammatory skin disease in which many epidemiological studies suggest a viral infection in its pathogenesis. Several viruses such as picornaviruses, parvoviruses and herpes viruses were accused as causative agents in PR. Human herpes virus-6 (HHV-6) and HHV-7 are newly discovered members of herpesviridae family. Several diseases including roseola infantum and PR have been linked with HHV-6 and HHV-7 in dermatology. We aimed to investigate the role of HHV-6 and HHV-7 in the pathogenesis of PR. Blood samples from 35 patients with acute PR and 30 healthy volunteers were examined to obtain titres for HHV-6 and HHV-7 antibodies. Anti-HHV-6 and -HHV-7 immunoglobulin (Ig) G antibodies were detected by IFA. The high titres of anti-HHV-6 IgG were determined in four patients and anti-HHV-7 IgG in only two of four patients. In our study, we haven't found any significant relationship between HHV-6, HHV-7 and PR. Our results were supported with the data of several previous studies.


The invasion of southern South America by imported bumblebees and associated parasites.
The Palaearctic Bombus ruderatus (in 1982/1983) and Bombus terrestris (1998) have both been introduced into South America (Chile) for pollination purposes. We here report on the results of sampling campaigns in 2004, and 2010-2012 showing that both species have established and massively expanded their range. Bombus terrestris, in particular, has spread by some 200 km year(-1) and had reached the Atlantic coast in Argentina by the end of 2011. Both species, and especially B. terrestris, are infected by protozoan parasites that seem to spread along with the imported hosts and spillover to native species. Genetic analyses by polymorphic microsatellite loci suggest that the host population of B. terrestris is genetically diverse, as expected from a large invading founder population, and structured through isolation by distance. Genetically, the populations of the trypanosomatid parasite, Crithidia bombi, sampled in 2004 are less diverse, and distinct from the ones sampled later. Current C. bombi populations are highly heterozygous and also structured through isolation by distance correlating with the genetic distances of B. terrestris, suggesting the latter's expansion to be a main structuring factor for the parasite. Remarkably, wherever B. terrestris spreads, the native Bombus dahlbomii disappears although the reasons remain unclear. Our ecological and genetic data suggest a major invasion event that is currently unfolding in southern South America with disastrous consequences for the native bumblebee species.


Francisco Martinez de Castrillo: An Early Spanish Author.
Francisco Martinez de Castrillo was a pioneer Spanish dental author who wrote and published Coloquio Breve y Compendioso Sobre la Materia de la Dentadura y Maravillosa Obra de la Boca, the first book published ever in the Spanish language. However, his life and work is largely unknown to the history of the dental profession.


[Age-related seroprevalence of measles, mumps and rubella antibodies in 1996].
In 1996 the effects on the immunity profile of a Swiss population exposed to MMR vaccination, which has been recommended since 1985, were evaluated with an age-stratified seroprevalence study for measles, mumps and rubella (MMR). At the age of 1.5-2.5 years, seroprevalence attained 76% for measles and rubella, which is respectively 17% and 24% above the values observed in 1992. The seroprevalence for mumps attained only 55% at the same age, which could reflect the poor immunogenicity of this component of the MMR vaccine. The seroprevalence for measles IgG showed a slow but steady increase from vaccination age to adulthood, attaining nearly 100%. The concentrations of measles IgG were about 700 IU/l into adolescence and rose to a plateau at about 1500 IU/l during young adulthood. These observations are compatible with low endemic activity of measles in the last 20 years and a predominance of vaccine-induced immunity up to about 20 years of age. This corresponds to the time period when measles vaccines--single or as MMR--have been in use. In 1992, at the peak of epidemic activity, seroprevalence for mumps rose substantially faster than in 1996. In addition, the rapid increase in quantitative values during preschool age mirrors the ongoing wild virus circulation with minimal vaccine effect. In the vaccine cohort (2-12 years of age) the seroprevalence of rubella IgG reached 70-80%. That there is no rise in the curve during school age shows that the recommended catch-up vaccinations before or during school age have been neglected. The median concentrations of rubella IgG were about 65 IU/ml at vaccination, declined to 40-50 IU/ml during preschool age, and rose again during school age, suggesting wild virus circulation. These data show that the MMR vaccine cover in Swiss children is insufficient to interrupt virus circulation, and administration of a second dose of MMR for catch-up immunisation has been omitted. The poor efficacy of the mumps component of the MMR vaccine that has mainly been used in Switzerland is also evident. The average age at infection is therefore expected to rise, thus involving a risk of increasing age-dependent complications. Efforts to implement the MMR vaccination program in Switzerland should be improved.


In search for significant cognitive features in Klinefelter syndrome through cross-species comparison of a supernumerary X chromosome.
The behavioral characterization of animals that carry genetic disorder abnormalities in a controlled genetic and environmental background may be used to identify human deficits that are significant to understand underlying neurobiological mechanisms. Here, we studied whether previously reported object recognition impairments in mice with a supernumerary X chromosome relate to specific cognitive deficits in Klinefelter syndrome (47,XXY). We aimed to optimize face validity by studying temporal object recognition in human cognitive assays. Thirty-four boys with Klinefelter syndrome (mean age 12.01) were compared with 90 age-matched normal controls, on a broad range of visual object memory tasks, including tests for pattern and temporal order discrimination. The results indicate that subjects with Klinefelter syndrome have difficulty in the processing of visual object and pattern information. Visual object patterns seem difficult to discriminate especially when temporal information needs to be processed and reproduced. On the basis of cross-species comparison, we propose that impaired temporal processing of object pattern information is an important deficit in Klinefelter syndrome. The current study shows how cross-species behavioral characterization may be used as a starting point to understand the neurobiology of syndromal phenotypic expression. The features of this study may serve as markers for interventions in Klinefelter syndrome. Similar cross-species evaluations of standard mouse behavioral paradigms in different genetic contexts may be powerful tools to optimize genotype-phenotype relationships.


Cancer mortality and predictions for 2018 in selected Australasian countries and Russia.
Predicted cancer mortality figures and rates are useful for public health planning. We retrieved cancer death certification data for 10 major cancer sites and total cancers from the World Health Organization (WHO) database and population data from WHO and United Nations Population Division databases. We obtained figures for Russia, Israel, Hong Kong, Japan, the Philippines, Korea, and Australia in 1970-2015. We predicted numbers of deaths by age group and age-standardized rates (world population) for 2018 by applying a linear regression to mortality data of each age group over the most recent trend segment identified by a joinpoint regression model. Russia had the highest predicted total cancer mortality rates, 158.5/100 000 men and 84.1/100 000 women. Men in the Philippines showed the lowest rates for 2018 (84.6/100 000) and Korean males the most favourable predicted fall (21% between 2012 and 2018). Women in Korea had the lowest total cancer predicted rate (52.5/100 000). Between 1993 and 2018, i.e. by applying the 1993 rates to populations in subsequent years, a substantial number of cancer deaths was avoided in Russia (1 000 000 deaths, 821 000 in men and 179 000 in women), Israel (40 000 deaths, 21 000 in men and 19 000 in women), Hong Kong (63 000 deaths, 40 000 in men and 23 000 in women), Japan (651 000 deaths, 473 000 in men and 178 000 in women), Korea (327 000 deaths, 250 000 in men and 77 000 in women), and Australia (181 000 deaths, 125 000 in men and 56 000 in women). No appreciable reduction in cancer deaths was found in the Philippines. Overall, we predicted falls in cancer mortality. However, these are less marked and later compared with the European Union and United States. Substantial numbers of deaths were avoided in all countries considered except the Philippines. Lung cancer mortality remains exceedingly high in Russian men, despite recent falls.


General practitioners' knowledge, attitude and prescribing of antibiotics for upper respiratory tract infections in Selangor, Malaysia: findings and implications.
Antibiotics are widely prescribed especially for upper respiratory tract infections (URTIs). Their irrational use can increase costs and resistance. Assess knowledge, attitude and prescribing of antibiotics for URTIs in Selangor, Malaysia, using a cross-sectional survey among general practitioners (GPs) working in private clinics in 2011. One hundred and thirty-nine physicians completed the questionnaire (response rate = 34.8%). 49.6% (n = 69) agreed antibiotics are helpful in treating URTIs, with most GPs agreeing antibiotics may reduce URTI duration and complications. The majority of GPs reported they felt patients expected antibiotics, with 36.7% (n = 51) agreeing patients would change doctors if they did not prescribe antibiotics and 21.6% (n = 30) agreeing when requested they prescribe antibiotics even if they believe them to be unnecessary. When assessed against six criteria, most GPs had a moderate level of knowledge of prescribing for URTIs. However, antibiotic prescriptions could be appreciably reduced. Further programs are needed to educate GPs and patients about antibiotics building on current initiatives.


Cognitive improvement following treatment in late-life depression: relationship to vascular risk and age of onset.
To test the hypothesis that the degree of vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late-life depression. Measurement of cognition both before and following 12 weeks of treatment with sertraline. University medical centers (Washington University and Duke University). One hundred sixty-six individuals with late-life depression. Sertraline treatment. The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2-based white matter hyperintensities using the Fazekas criteria. Both episodic memory and executive function demonstrated significant improvement among adults with late-life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental State Examination scores predicted less change in working memory. Furthermore, older age, later age of onset, and higher vascular risk scores predicted less change in executive function. These results have important clinical implications in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.


Predicting Future Suicide Attempts Among Adolescent and Emerging Adult Psychiatric Emergency Patients.
The purpose of this study was to longitudinally examine specific characteristics of suicidal ideation in combination with histories of suicide attempts and non-suicidal self-injury (NSSI) to best evaluate risk for a future attempt among high-risk adolescents and emerging adults. Participants in this retrospective medical record review study were 473 (53% female; 69% Caucasian) consecutive patients, ages 15 to 24 years (M=19.4 years) who presented for psychiatric emergency services during a 9-month period. These patients' medical records, including a clinician-administered Columbia-Suicide Severity Rating Scale, were coded at the index visit and at future visits occurring within the next 18 months. Logistic regression models were used to predict suicide attempts during this period. Socioeconomic status, suicidal ideation severity (i.e., intent, method), suicidal ideation intensity (i.e., frequency, controllability), a lifetime history of suicide attempt, and a lifetime history of NSSI were significant independent predictors of a future suicide attempt. Suicidal ideation added incremental validity to the prediction of future suicide attempts above and beyond the influence of a past suicide attempt, whereas a lifetime history of NSSI did not. Sex moderated the relationship between the duration of suicidal thoughts and future attempts (predictive for male patients but not female). Results suggest value in incorporating both past behaviors and current thoughts into suicide risk formulation. Furthermore, suicidal ideation duration warrants additional examination as a potential critical factor for screening assessments evaluating suicide risk among high-risk samples, particularly for male patients.


Contrarians Synchronize beyond the Limit of Pairwise Interactions.
We give evidence that a population of pure contrarian globally coupled D-dimensional Kuramoto oscillators reaches a collective synchronous state when the interplay between the units goes beyond the limit of pairwise interactions. Namely, we will show that the presence of higher-order interactions may induce the appearance of a coherent state even when the oscillators are coupled negatively to the mean field. An exact solution for the description of the microscopic dynamics for forward and backward transitions is provided, which entails imperfect symmetry breaking of the population into a frequency-locked state featuring two clusters of different instantaneous phases. Our results contribute to a better understanding of the powerful potential of group interactions entailing multidimensional choices and novel dynamical states in many circumstances, such as in social systems.


Manganese-enhanced MRI of human choroidal melanoma xenografts.
To test the hypothesis that the structure and function of an experimental human choroidal melanoma xenograft and neighboring non-tumor-bearing retina can be simultaneously assessed by using manganese-enhanced MRI (MEMRI). Spheroids grown from the human choroidal melanoma cell line C918 were implanted in the superior suprachoroidal space of 11 WAG/Nij-rnu nude rats. Two weeks later, MRI data were collected 4 hours after intraperitoneal injection of saline or MnCl(2), an MRI contrast agent that can act as a biomarker of cellular demand for ions, such as calcium. The following parameters were measured: (1) tumor signal intensity, (2) inner and outer retinal signal intensity in non-tumor-bearing inferior retina, and (3) whole and inner retinal thickness of inferior retina. Separate MEMRI experiments were performed on spheroids in vitro after MnCl(2) exposure and washing. In vitro, spheroids exposed to MnCl(2) retained sufficient Mn(2+) to demonstrate contrast enhancement during MEMRI. In vivo, injection of MnCl(2) resulted in a 30% increase in tumor signal intensity compared with tumors in rats injected with saline (P < 0.05). In inferior retina of tumor-bearing eyes, outer retinal signal intensity increased by 17% relative to a similar region in control eyes (P < 0.05), but there was no change in the inferior inner retinal intensity. Total retinal thickness of the inferior retina in the tumor-bearing eyes increased by 8%, compared with that in the non-tumor-bearing eyes (P < 0.05). The present identification of regions of enhanced Mn(2+) uptake in choroidal melanoma and a somewhat unexpected edema and increased outer retinal ion demand in neighboring non-tumor-bearing retina highlights MEMRI as a potentially powerful method for noninvasively monitoring tumor progression and treatment response and efficacy.


Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression.
Circulating tumor cells (CTCs) are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs' diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0-54 CTCs per 5 min). These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.


The genome of a Bacillus isolate causing anthrax in chimpanzees combines chromosomal properties of B. cereus with B. anthracis virulence plasmids.
Anthrax is a fatal disease caused by strains of Bacillus anthracis. Members of this monophyletic species are non motile and are all characterized by the presence of four prophages and a nonsense mutation in the plcR regulator gene. Here we report the complete genome sequence of a Bacillus strain isolated from a chimpanzee that had died with clinical symptoms of anthrax. Unlike classic B. anthracis, this strain was motile and lacked the four prohages and the nonsense mutation. Four replicons were identified, a chromosome and three plasmids. Comparative genome analysis revealed that the chromosome resembles those of non-B. anthracis members of the Bacillus cereus group, whereas two plasmids were identical to the anthrax virulence plasmids pXO1 and pXO2. The function of the newly discovered third plasmid with a length of 14 kbp is unknown. A detailed comparison of genomic loci encoding key features confirmed a higher similarity to B. thuringiensis serovar konkukian strain 97-27 and B. cereus E33L than to B. anthracis strains. For the first time we describe the sequence of an anthrax causing bacterium possessing both anthrax plasmids that apparently does not belong to the monophyletic group of all so far known B. anthracis strains and that differs in important diagnostic features. The data suggest that this bacterium has evolved from a B. cereus strain independently from the classic B. anthracis strains and established a B. anthracis lifestyle. Therefore we suggest to designate this isolate as "B. cereus variety (var.) anthracis".


Anti-aromatase chemicals in red wine.
Estrogen synthesized in situ plays a more important role in breast cancer cell proliferation than does circulating estrogen. Aromatase is the enzyme that converts androgen to estrogen and is expressed at a higher level in breast cancer tissue than in surrounding noncancer tissue. A promising route of chemoprevention against breast cancer may be through the suppression of in situ estrogen formation using aromatase inhibitors. A diet high in fruits and vegetables may reduce the incidence of breast cancer, because they contain phytochemicals that can act as aromatase inhibitors. In our previous studies, we found that grapes and wine contain potent phytochemicals that can inhibit aromatase. We show that red wine was more effective than white wine in suppressing aromatase activity. Interestingly, our results from white wine studies suggest a weak inductive effect of alcohol on aromatase activity. On the other hand, the potent effect of anti-aromatase chemicals in red wine overcomes the weak inductive effect of alcohol in wine. Several purification procedures were performed on whole red wine to separate active aromatase inhibitors from non-active compounds. These techniques included liquid-liquid extraction, silica gel chromatography, various solid phase extraction (SPE) columns, and high performance liquid chromatography. An active Pinot Noir red wine SPE C18 column fraction (20% acetonitrile:water) was more effective than complete Pinot Noir wine in suppressing aromatase assay. This red wine extract was further analyzed in a transgenic mouse model in which aromatase was over-expressed in mammary tissue. Our gavaged red wine extract completely abrogated aromatase-induced hyperplasia and other neoplastic changes in mammary tissue. These results suggest that red wine or red wine extract may be a chemopreventive diet supplement for postmenopausal women who have a high risk of breast cancer. Further research is underway to purify and characterize the active compounds in red wine that are responsible for the inhibition of aromatase.


Differential genetic expression in large versus small clear cell renal cell carcinoma: results from microarray analysis.
Tumor growth and progression requires multiple steps and genetic alterations. The molecular events that occur as tumors increase in size are unknown. Patients with von Hippel-Lindau (VHL) provide a unique opportunity to study molecular alterations during tumor growth as these patients develop multiple bilateral renal tumors. To better characterize biologic events associated with tumor growth, we evaluated the alterations in gene expression in large versus small renal tumors removed from the same kidney of the same individuals. We reviewed pathology reports from patients who underwent partial nephrectomies at the National Cancer Institute for multiple tumors. We identified 11 patients who fulfilled the following inclusion criteria: 1) The patient must have had a surgical resection of more than one solid tumor from the same kidney during the same operation; 2) Among the solid tumors at least one must have been greater than 3 cm in the largest dimension and at least one less than 2 cm; 3) the nuclear Furhman grade for both larger and smaller solid tumors was identical; 4) a portion of each tumor was procured and snap frozen after surgical removal; 5) Hematoxylin and eosin staining of the frozen sample confirmed clear cell carcinoma to be present in at least 80% of the section.Affymetrix platform and protocol for gene expression arrays were used. RNA from the frozen large and small tumor samples was extracted using Trizol-Chlorophorm method. The RNA was then reverse transcribed, labeled, fragmented, and hybridized on to an Affymetrix U133 Plus 2.0 array that contains 54,000 probe sets representing 24,568 genes. Analysis included unsupervised clustering and chromosomal analysis. The paired t-test was performed to compare gene expression levels in small and large tumors. P<0.01 was considered statistically significant. Gene expression profiles were assessed for 22 tumors (11 patients). Upon unsupervised clustering the pairs with larger tumor volume difference clustered separately from pairs with smaller volume difference. Chromosomal analysis revealed few consistent changes other than reduced expression of chromosome 3p25 among all tumors. Paired t-test showed 860 differentially expressed genes in the T1b vs T1a group, a number far greater than expected due to chance alone. When analyzed by gene function, most differences were observed in genes involved in DNA replication and in cytokine signaling. This study demonstrates that as tumors increase in size there is an increasing difference in gene expression. Unsupervised clustering analysis confirms that as the volume difference increases there are a distinct set of genes that are regulated either as a response to a tumor's growth or as an early event that causes the tumor to grow. While we did not observe chromosomal instability, we did note differences in expression of individual transcripts as tumors grew larger.


How should external human-machine interfaces behave? Examining the effects of colour, position, message, activation distance, vehicle yielding, and visual distraction among 1,434 participants.
External human-machine interfaces (eHMIs) may be useful for communicating the intention of an automated vehicle (AV) to a pedestrian, but it is unclear which eHMI design is most effective. In a crowdsourced experiment, we examined the effects of (1) colour (red, green, cyan), (2) position (roof, bumper, windshield), (3) message (WALK, DON'T WALK, WILL STOP, WON'T STOP, light bar), (4) activation distance (35 or 50 m from the pedestrian), and (5) the presence of visual distraction in the environment, on pedestrians' perceived safety of crossing the road in front of yielding and non-yielding AVs. Participants (N = 1434) had to press a key when they felt safe to cross while watching a random 40 out of 276 videos of an approaching AV with eHMI. Results showed that (1) green and cyan eHMIs led to higher perceived safety of crossing than red eHMIs; no significant difference was found between green and cyan, (2) eHMIs on the bumper and roof were more effective than eHMIs on the windshield, (3) for yielding AVs, perceived safety was higher for WALK compared to WILL STOP, followed by the light bar; for non-yielding AVs, a red bar yielded similar results to red text, (4) for yielding AVs, a red bar caused lower perceived safety when activated early compared to late, whereas green/cyan WALK led to higher perceived safety when activated late compared to early, and (5) distraction had no significant effect. We conclude that people adopt an egocentric perspective, that the windshield is an ineffective position, that the often-recommended colour cyan may have to be avoided, and that eHMI activation distance has intricate effects related to onset saliency.


Energetic consequences of prey type in little penguins (Eudyptula minor).
Investigation of foraging decisions can help understand how animals efficiently gather and exploit food. Prey chase and handling times are important aspects of foraging efficiency, influencing the net energy gain derived from a prey item. However, these metrics are often overlooked in studies of foraging behaviour due to the difficulty in observing them. The present study used animal-borne cameras to investigate the type, duration and energetic consequences of predator-prey interactions in little penguins (Eudyptula minor) (n = 32) from two colonies in Bass Strait, south-eastern Australia. A total of seven main prey items were observed and consumed by little penguins. Penguins were observed to consume prey types and use strategies that have not been previously documented. These included consumption of bellowsfish (Macroramphosus scolopax) and other fish species captured sheltering around jellyfish or extracted dead from the tentacles. Chase and handling time varied with prey type and lasted approximately 2 s for most prey. Profitability varied among prey types, with a greater amount of low profitable prey being consumed, suggesting a trade-off between minimizing energetic costs, and increasing capture rates. These results highlight the use of animal-borne video data loggers to further understand the foraging adaptations of important predators in the marine environment.


[Postmenopausal osteoporosis: therapeutic approaches].
The preventive and therapeutical measures to be implemented the post-menopausal osteoporosis are varied, although there is no clear, single protocol of intervention. ESTROGENS AND PROGESTOGENS: It si verify that the administration of estrogens and/or progestogens prevents bone loss with an action on mineral components of bone and on collagenic metabolism. BIPHOSPONATES: Operate inhibiting mineralization and, particularly, bone reabsorption. At present its use, in low dosages, is reserved to "fast bone loser" patients. CALCITONIN: It increases bone mass and significantly reduces the frequency of fractures in comparison with only calcium, but its use is limited by high costs. IPRIFLAVONE: Anti-reabsorption effects has on bone and stimulates osteoblastic activity; besides, it seems to developed the effect of estrogens on the bone. FLUORIDES: Fluorides also operate on both components of bone turnover, with a most important action on bone formation. An interesting approach is the association of low doses of monofluorophosphate with calcium. However, further confirmation of the "quality" of neoformed bone is necessary. CALCIUM: Calcium supplementation is obligatory where the alimentary supply of calcium is lower then 1 g/die or where an osteomalacic component coexists; only dosages higher than 15 g/die can produce/pharmacological effects on bone turnover. CALCITRIOL: The use is still disputed. The calcitriol-calcium association seems convincing haveved. ORG: OD 14. The efficacy of this synthetic steroid to prevent bone loss is probably superimposable on the efficacy of classic estrogen therapy.


Exploring visual-spatial working memory: a critical review of concepts and models.
The ability to retain and process an object's identity and spatial location is essential for many daily tasks, often referred to as visual-spatial working memory. Research investigating visual-spatial processing has concentrated on three aspects or mechanisms thought to sub-serve this process; perceptual processes, anatomical correlates and working memory functions. An approach integrating all three areas has largely been neglected. Hence, this review sought to (1) outline some of the advances made to the understanding by these three concepts or models of visual-spatial processing, (2) establish the relationship between these processes, and discuss the challenges faced by researchers attempting to dissociate this functions from other visual-spatial processes as well as other working memory functions. It is suggested that a more comprehensive and integrative understanding of visual-spatial working memory has implications for research seeking to investigate visual-spatial memory, and to relate visual-spatial memory to other cognitive functions, such as executive function and attention.


Use of BAC array CGH for evaluation of chromosomal stability of clinically used human mesenchymal stem cells and of cancer cell lines.
Array-based comparative genomic hybridization (aCGH) using bacterial artificial chromosomes (BAC) is a powerful method to analyze DNA copy number aberrations of the entire human genome. In fact, CGH and aCGH have revealed various DNA copy number aberrations in numerous cancer cells and cancer cell lines examined so far. In this report, BAC aCGH was applied to evaluate the stability or instability of cell lines. Established cell lines have greatly contributed to advancements in not only biology but also medical science. However, cell lines have serious problems, such as alteration of biological properties during long-term cultivation. Firstly, we investigated two cancer cell lines, HeLa and Caco-2. HeLa cells, established from a cervical cancer, showed significantly increased DNA copy number alterations with passage time. Caco-2 cells, established from a colon cancer, showed no remarkable differences under various culture conditions. These results indicate that BAC aCGH can be used for the evaluation and validation of genomic stability of cultured cells. Secondly, BAC aCGH was applied to evaluate and validate the genomic stabilities of three patient's mesenchymal stem cells (MSCs), which were already used for their treatments. These three MSCs showed no significant differences in DNA copy number aberrations over their entire chromosomal regions. Therefore, BAC aCGH is highly recommended for use for a quality check of various cells before using them for any kind of biological investigation or clinical application.


Rising trends and inequalities in cesarean section rates in Pakistan: Evidence from Pakistan Demographic and Health Surveys, 1990-2013.
Despite global efforts to improve maternal health, many developing countries including Pakistan have failed to achieve the target of a 75% reduction in maternal deaths by 2015. Addressing socioeconomic inequalities in access to emergency obstetric care is crucial for reducing the maternal mortality rate. This study was done to examine the time trends and socioeconomic inequalities in the utilization of cesarean section (C-section) in Pakistan during 1990-2013. We used data from the Pakistan Demographic and Health Surveys (PDHS) conducted during 1990 to 2013. All these surveys are nationally representative surveys of ever-married women aged 15-49 years with a sample size of 6611, 10,023, and 13,558 women in 1990-1991, 2006-2007, and 2012-2013, respectively, with an overall response rate of over 90%. The unit of analysis for this study was women with their most recent live birth in the five years preceding the surveys. Bivariate analyses and multivariable logistic regression models were employed to investigate the prevalence of cesarean sections according to selected sociodemographic characteristics of women. C-section rates were found to have increased during this period, with an especially significant rise from 2.7% in 1990-1991 to 15.8% in 2012-2013 with lower utilization among the non-educated women (7.5%), compared with the women with higher education (40.3%). C-section rates ranged from 5.5% in the poorest women to 35.3% in the richest women. Only 11.5% of the rural women had a C-section compared to 25.6% of the urban women. A greater likelihood of having a cesarean section was observed in the richest, highly educated, and urban-living women while there was no significant difference observed in cesarean section rates between the private and public sectors in all three surveys. To improve maternal health, routine monitoring and evaluation of the provision of emergency obstetric services are needed to address the underuse of C-section in poor and rural areas and overuse in rich and urban areas.


Metal-supported and -assisted stereoselective cooperative photoredox catalysis.
In this perspective, we review those stereoselective photocatalytic reactions that use synergy between photoredox catalysts and transition metal catalysts. In particular, we highlight the orchestrated interaction between two and more metals which not only enhance the turnover numbers, but also lead to increased selectivities. Aspects of green chemistry and sustainable developments are included. In this review, C-C, C-O, C-N and C-S forming reactions are discussed and a perspective on future developments is given.


[Hospitalization for pneumonia in adults. Lazio, 1997-1999].
The aim of this study is to define the burden of pneumonia requiring hospitalization among adults in Lazio region from 1997 to 1999 and to describe the characteristic of community acquired (CAP), suspected nosocomial (NP) and in AIDS pneumonia. The data source is the hospital discharge register. 30517 incident episodes of pneumonia hospitalization occurred in the three years period, 20497 CAP, 9760 NP and 964 in AIDS of which 704 supposed to be acquired in hospital; the mean age is 65, 69 and 38 years respectively. Standardized hospitalization rates for CAP do not show a clear geographical pattern, while for NPs and in AIDS they are higher in the city of Rome than in the rest of the region. There are peaks of incidence during the winter for CAPs and NPs but not for AIDS. Only 20% of pneumonias have etiological diagnosis. The proportional analysis of aetiological agents shows: pneumococcus, pseudomonas, staphylococci and influenza; the most frequent comorbidities are: circulatory diseases, chronic obstructive pulmonary disease (COPD), malignancies and diabetes. 3.9% of individuals in the study with CAP or NP had more than one episode of pneumonia during the study period, for those with pneumonia in AIDS this percentage was 14.8. In-hospital lethality is 9.4%, 29.3% and 11.2% for CAP, NP and in AIDS, respectively. Data from the hospital discharge registers can be used to give a cheap and rapid glimpse to the epidemiology of pathologies frequently requiring hospitalisation neglected from more analytical surveillance systems or registries.


Antimicrobial, anticancer and antioxidant activities of nano-heart of Phoenix dactylifera tree extract loaded chitosan nanoparticles: In vitro and in vivo study.
This study aimed to present a new heart of P. dactylifera (HP) extract loaded chitosan nanoparticles and estimate its anticancer, antimicrobial, antioxidant activity and free radical scavenger effect (in vitro). This nano-supplement may prevent doxorubicin cardiotoxicity and nephrotoxicity in rat model. The HP extract was loaded on chitosan nanoparticles producing HP-ChNPs, then characterized. The antioxidant properties of the HP-ChNPs was assessed in vitro. The antibacterial activity against three-gram positive bacteria and two gram-negative bacteria were done. The in vitro studies of cytotoxicity against MCF7, CaCo3, and Hela cell lines were also evaluated. Then, the protective effect of the HP-ChNPs (2 mg/kg, IP) was evaluated against doxorubicin induce organ toxicity in a rat model. The in vitro studies revealed the antibacterial, anticancer and antioxidant activities of the HP-ChNPs. The in vivo study demonstrates reduction of heart and kidney apoptosis with increased programmed cell death protein-1 (PD-1); as the major anticancer drug (doxorubicin) pathway is to release free radicals with decreased PD-1 levels and induction of apoptosis. In conclusion, the HP-ChNPs, in a very small dose, might be a promising supplement to avoid doxorubicin toxicity with improvment the antioxidant enzymes without affecting its anticancer activity.


Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis.
How hematopoietic stem cells (HSCs) coordinate their divisional axis and whether this orientation is important for stem cell-driven hematopoiesis is poorly understood. Single-cell RNA sequencing data from patients with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome, show that ARHGEF2, a RhoA-specific guanine nucleotide exchange factor and determinant of mitotic spindle orientation, is specifically downregulated in SDS hematopoietic stem and progenitor cells (HSPCs). We demonstrate that transplanted Arhgef2-/- fetal liver and bone marrow cells yield impaired hematopoietic recovery and a production deficit from long-term HSCs, phenotypes that are not the result of differences in numbers of transplanted HSCs, their cell cycle status, level of apoptosis, progenitor output, or homing ability. Notably, these defects are functionally restored in vivo by overexpression of ARHGEF2 or its downstream activated RHOA GTPase. By using live imaging of dividing HSPCs, we show an increased frequency of misoriented divisions in the absence of Arhgef2. ARHGEF2 knockdown in human HSCs also impairs their ability to regenerate hematopoiesis, culminating in significantly smaller xenografts. Together, these data demonstrate a conserved role for Arhgef2 in orienting HSPC division and suggest that HSCs may divide in certain orientations to establish hematopoiesis, the loss of which could contribute to HSC dysfunction in bone marrow failure.


Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes.
Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations. We explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11-12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1β, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aβ40 and Aβ42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities. Intervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1β and TNFα but not IL-6. MW150 treatment also increased the IBA1+ microglia within a 15 μm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aβ40 and Aβ42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells. Our results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.


A randomized pragmatic trial of telephone-delivered cognitive behavioral-therapy, modafinil, and combination therapy of both for fatigue in multiple sclerosis: The design of the "COMBO-MS" trial.
Fatigue is one of the most common and disabling chronic symptoms in multiple sclerosis (MS). Optimization of available treatments for MS-related fatigue has been stymied by lack of comparative effectiveness research that focuses on real-world treatment delivery methods and potential modification of treatment effect by other chronic MS symptoms or disability level. This report describes the design of a patient centered, comparative effectiveness trial of cognitive behavioral-therapy (CBT), modafinil, and combination therapy of both for fatigue in MS ("COMBO-MS"). We describe the methods of this pragmatic comparative effectiveness trial that is guided by a team of patient, family, provider, community, and payer stakeholders. Eligible participants with MS and significant fatigue severity are randomly assigned (1:1:1) to received either CBT, modafinil, or a combination of CBT and modafinil for 12 weeks. The primary outcome is change in fatigue impact as measured by the Modified Fatigue Impact Scale (MFIS) at 12 weeks. Secondary outcome measures include ecological momentary assessment (EMA) measures of fatigue intensity, fatigue interference, and fatigability (measured over 7 days' time at baseline and at 12 weeks), and change in MFIS score at 24 weeks. We hypothesize that combination therapy will more effectively ameliorate fatigue severity than either monotherapy, and that heterogeneity of treatment effects will be found based on depression status, presence of known or suspected sleep disorder, and disease severity. Study findings will assist patients, providers, payers, and policy makers to provide more effective care for managing fatigue in MS.


Synthesis of the phenoxonium cation of an alpha-tocopherol model compound crystallized with non-nucleophilic [B(C6F5)4]- and (CB11H6Br6)- anions.
The phenoxonium cation of a vitamin E model compound has been crystallized using the non-nucleophilic carborane and tetrakis(pentafluorophenyl)borate counteranions. The crystal structures confirm the assignment of the unusually stable phenoxonium cation and indicate that there is a substantial shortening of the carbon-oxygen bond lengths of the para-carbon atoms in the phenolic ring and a substantial increase of the carbon-oxygen bond length at the quaternary carbon. The crystallographic data are in excellent agreement with structural predictions from molecular orbital calculations.


Leuconostoc kimchii sp. nov., a new species from kimchi.
A Gram-positive, catalase-negative, facultatively anaerobic, coccus-shaped bacterium, designated IH25T, was isolated from kimchi, a traditional Korean vegetable product. Phylogenetic analysis based on almost complete 16S rDNA sequences placed the isolate in a monophyletic clade corresponding to the genus Leuconostoc. All validly described species in the genus Leuconostoc, with the exception of Leuconostoc fallax, showed high sequence identity of over 97%. The 16S rDNA sequence of strain IH25T showed the highest homology to those of Leuconostoc gelidum DSM 5578T (98.9%) and Leuconostoc citreum KCTC 3526T (98.3 %). However, DNA-DNA hybridization experiments indicated that the organism represents a novel genomic species in the genus, since the previously known leuconostocs share DNA homology with strain IH25T of less than 70%. In this work, it is proposed that isolate IH25T be classified in the genus Leuconostoc as Leuconostoc kimchii sp. nov. The type strain of Leuconostoc kimchii is IH25T (= KCTC 2386T = IMSNU 11154T).