Weighing the stigma of weight: An fMRI study of neural reactivity to the pain of obese individuals.
Explicit negative attitudes and blameful beliefs (e.g. poor diet, laziness) towards obese individuals are well documented and are pervasive even among health professionals. Here we sought to determine whether obesity stigma is reflected in a fundamental feature of intersubjectivity namely the automatic neural resonance with others' affective experiences. During fMRI, normal-weight female participants observed short clips depicting normal-weight (NW) and obese (Ob) models experiencing pain. Importantly, participants believed that half of the Ob were overweight due to a hormonal disorder (HormOb) and ignored the cause of obesity of the remaining models (Unknown obese models; UnkOb). Analyses of hemodynamic responses showed reduced activity to the pain of Ob compared to that of NW in areas associated with pain processing and early visual processing. The comparison between the two Ob conditions revealed a further decrease of activity to HormOb's pain compared to UnkOb's (and NW) pain in the right inferior frontal gyrus, an area associated with emotional resonance. Our study demonstrates that stigma for obese individuals can be observed at implicit levels, and that it is modulated by knowledge concerning the etiology of obesity, with the seemingly surprising result that obesity due to disease may result in greater stigmatization. Moreover, the perceived similarity with the models and the ambivalent emotion of pity may index biased brain responses to obese individuals' pain. The study highlights a possibly important neural link between resonance with the pain of others and obesity stigma.


Reference-free single-pass EPI Nyquist ghost correction using annihilating filter-based low rank Hankel matrix (ALOHA).
MR measurements from an echo-planar imaging (EPI) sequence produce Nyquist ghost artifacts that originate from inconsistencies between odd and even echoes. Several reconstruction algorithms have been proposed to reduce such artifacts, but most of these methods require either additional reference scans or multipass EPI acquisition. This article proposes a novel and accurate single-pass EPI ghost artifact correction method that does not require any additional reference data. After converting a ghost correction problem into separate k-space data interpolation problems for even and odd phase encoding, our algorithm exploits an observation that the differential k-space data between the even and odd echoes is a Fourier transform of an underlying sparse image. Accordingly, we can construct a rank-deficient Hankel structured matrix, whose missing data can be recovered using an annihilating filter-based low rank Hankel structured matrix completion approach. The proposed method was applied to EPI data for both single and multicoil acquisitions. Experimental results using in vivo data confirmed that the proposed method can completely remove ghost artifacts successfully without prescan echoes. Owing to the discovery of the annihilating filter relationship from the intrinsic EPI image property, the proposed method successfully suppresses ghost artifacts without a prescan step. Magn Reson Med 76:1775-1789, 2016. © 2016 International Society for Magnetic Resonance in Medicine.


Use of group treatment among case managers in Department of Veterans Affairs supported housing program.
Because the predominant supported housing model includes individual intensive community-based case management, use of group treatments in supported housing has not been adequately studied. This study examined practices and attitudes about groups among case managers in the Department of Housing and Urban Development-Department of Veterans Affairs Supportive Housing (HUD-VASH) program. We examined national administrative HUD-VASH data and an online survey of case managers from eight sites in the New England region, where dissemination of a new group-based model is in progress. Compared with other sites nationally, sites in the New England region had more group contacts, possibly reflecting the dissemination project. Among the New England sites (n = 8), administrative data showed that a higher percentage of group contacts was associated with a greater number of clients served and with more contacts per client. Although case manager survey data (n = 55) showed generally positive attitudes about using groups, particularly about the potential effectiveness of groups and peer support, greater reported use of groups was not associated with more positive attitudes about groups. These findings suggest providing group treatments in supported housing programs may help case managers stay connected to clients and case managers appear receptive to using groups, though further research is needed.


Collaborative care psychiatrists' views on treating bipolar disorder in primary care: a qualitative study.
To understand collaborative care psychiatric consultants' views and practices on making the diagnosis of and recommending treatment for bipolar disorder in primary care using collaborative care. We conducted a focus group at the University of Washington in December 2013 with nine psychiatric consultants working in primary-care-based collaborative care in Washington State. A grounded theory approach with open coding and the constant comparative method revealed categories where emergent themes were saturated and validated through member checking, and a conceptual model was developed. Three major themes emerged from the data including the importance of working as a collaborative care team, the strengths of collaborative care for treating bipolar disorder and the need for psychiatric consultants to adapt specialty psychiatric clinical skills to the primary care setting. Other discussion topics included gathering clinical data from multiple sources over time, balancing risks and benefits of treating patients indirectly, tracking patient care outcomes with a registry and effective care. Experienced psychiatric consultants working in collaborative care teams provided their perceptions regarding treating patients with bipolar illness including identifying ways to adapt specialty psychiatric skills, developing techniques for providing team-based care and perceiving the care delivered through collaborative care as high quality.


The three-dimensional structure of an arachidonic acid 15-lipoxygenase.
In mammals, the hydroperoxidation of arachidonic acid by lipoxygenases leads to the formation of leukotrienes and lipoxins, compounds that mediate inflammatory responses. Lipoxygenases are dioxygenases that contain a nonheme iron and are present in many animal cells. Soybean lipoxygenase-1 is a single-chain, 839-residue protein closely related to mammalian lipoxygenases. The structure of soybean lipoxygenase-1 solved to 2.6 angstrom resolution shows that the enzyme has two domains: a 146-residue beta barrel and a 693-residue helical bundle. The iron atom is in the center of the larger domain and is coordinated by three histidines and the COO- of the carboxyl terminus. The coordination geometry is nonregular and appears to be a distorted octahedron in which two adjacent positions are not occupied by ligands. Two cavities, in the shapes of a bent cylinder and a frustum, connect the unoccupied positions to the surface of the enzyme. The iron, with two adjacent and unoccupied positions, is poised to interact with the 1,4-diene system of the substrate and with molecular oxygen during catalysis.


Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors.
1. KCNQ1-4 potassium channels were expressed in mammalian Chinese hamster ovary (CHO) cells stably transfected with M1 muscarinic acetylcholine receptors and currents were recorded using the whole-cell perforated patch technique and cell-attached patch recording. 2. Stimulation of M1 receptors by 10 microM oxotremorine-M (Oxo-M) strongly reduced (to 0-10%) currents produced by KCNQ1-4 subunits expressed individually and also those produced by KCNQ2 + KCNQ3 and KCNQ1 + KCNE1 heteromers, which are thought to generate neuronal M-currents (IK,M) and cardiac slow delayed rectifier currents (IK,s), respectively. 3. The activity of KCNQ2 + KCNQ3, KCNQ2 and KCNQ3 channels recorded with cell-attached pipettes was strongly and reversibly reduced by Oxo-M applied to the extra-patch membrane. 4. It is concluded that M1 receptors couple to all known KCNQ subunits and that inhibition of KCNQ2 + KCNQ3 channels, like that of native M-channels, requires a diffusible second messenger.


Effect of 16 weeks of resistance training on fatigue resistance in men and women.
The purpose of this study was to investigate the effect of hypertrophy-type resistance training (RT) on upper limb fatigue resistance in young adult men and women. Fifty-eight men (22.7±3.7 years, 70.6±9.3 kg, and 176.8±6.4 cm) and 65 women (21.6±3.7 years, 58.8±11.9 kg, and 162.6±6.2 cm) underwent RT for 16 weeks. Training consisted of 10-12 whole body exercises with 3 sets of 8-12 repetitions maximum performed 3 times per week. Before and after the RT intervention participants were submitted to 1RM testing, as well as a fatigue protocol consisting of 4 sets at 80% 1RM on bench press (BP) and arm curl (AC). The sum of the number of repetitions accomplished in the 4 sets in each exercise was used to indicate fatigue resistance. There was a significant (p<0.05) time-by-group interaction in 1RM BP (men=+16%, women=+26%), however in 1RM AC no significant time-by-group interaction was observed (men=+14%, women=+23%). For the total number of repetitions, men and women showed a significant increase in BP (men=+16.3%, women=+10.5%) with no time-by-group interaction. The results suggest that the adaptation in maximal strength is influenced by sex in BP. On the other hand, for fatigue resistance, the individual's sex does not seem to influence outcomes either in BP or AC.


Cardiovascular pharmacology of purines.
1. This review focuses on the extracellular actions of ATP and adenosine, and in particular their role in cardiovascular regulation. 2. ATP serves as a co-transmitter within the sympathetic nervous system, and is also released from endothelium and aggregating thrombocytes. ATP acts on P2x purinoceptors on vascular smooth muscle cells to induce vasoconstriction. Stimulation of P2y purinoceptors on endothelial cells releases endothelium-derived relaxing factors and causes vasodilatation. This dual action of ATP may have pathophysiological importance by inducing vasospasm at sites of impaired endothelial function and thrombus formation. 3. Adenosine is generated by enzymic degradation of ATP. Its formation is enhanced during ischaemia. Adenosine inhibits noradrenaline release from sympathetic nerve endings, causes vasodilatation via endothelium-dependent and endothelium-independent actions, has important anti-arrhythmic properties and prevents deleterious sequelae of ischaemia. In humans, adenosine evokes a sympatho-excitatory reflex mediated by chemically sensitive receptors and afferent nerves in the kidney, heart and forearm. This reflex may be active during exercise and ischaemia and, because of its potential adverse consequences, it should be considered when developing new therapies to potentiate the anti-ischaemic actions of endogenous adenosine in humans. Adenosine appears to mediate ischaemia-induced pain; a reduced sensitivity to adenosine may underlie silent ischaemia. 4. New drugs that interact with adenosine formation or degradation or with adenosine receptors are under development. These have potential therapeutic application in the treatment of ischaemia and other circulatory disorders.


Macromolecular and electrical coupling between inner hair cells in the rodent cochlea.
Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 30% of the IHCs are electrochemically coupled in 'mini-syncytia'. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca2+-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D electron microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca2+-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding.


A new plan quality index for dose painting radiotherapy.
Dose painting radiotherapy is considered a promising radiotherapy technology that enables more targeted dose delivery to tumor rich regions while saving critical normal tissues. Obviously, dose painting planning would be more complicated and hard to be evaluated with current plan quality index systems that were developed under the paradigm of uniform dose prescription. In this study, we introduce a new plan quality index, named "index of achievement (IOA)" that assesses how close the planned dose distribution is to the prescribed one in a dose painting radiotherapy plan. By using voxel-based comparison between planned and prescribed dose distributions in its formulation, the index allows for a single-value evaluation regardless of the number of prescribed dose levels, which cannot be achieved with the conventional indices such as conventional homogeneity index. Benchmark calculations using patient data demonstrated feasibility of the index not only for contour-based dose painting plans, but also for dose painting by numbers plans. Also, it was shown that there is strong correlation between the new index and conventional indices, which indicates a potential of the new index as an alternative to conventional ones in general radiotherapy plan evaluation.


Exploring the light-induced dynamics in solvated metallogrid complexes with femtosecond pulses across the electromagnetic spectrum.
Oligonuclear complexes of d4-d7 transition metal ion centers that undergo spin-switching have long been developed for their practical role in molecular electronics. Recently, they also have appeared as promising photochemical reactants demonstrating improved stability. However, the lack of knowledge about their photophysical properties in the solution phase compared to mononuclear complexes is currently hampering their inclusion into advanced light-driven reactions. In the present study, the ultrafast photoinduced dynamics in a solvated [2 × 2] iron(II) metallogrid complex are characterized by combining measurements with transient optical-infrared absorption and x-ray emission spectroscopy on the femtosecond time scale. The analysis is supported by density functional theory calculations. The photocycle can be described in terms of intra-site transitions, where the FeII centers in the low-spin state are independently photoexcited. The Franck-Condon state decays via the formation of a vibrationally hot high-spin (HS) state that displays coherent behavior within a few picoseconds and thermalizes within tens of picoseconds to yield a metastable HS state living for several hundreds of nanoseconds. Systematic comparison with the closely related mononuclear complex [Fe(terpy)2]2+ reveals that nuclearity has a profound impact on the photoinduced dynamics. More generally, this work provides guidelines for expanding the integration of oligonuclear complexes into new photoconversion schemes that may be triggered by ultrafast spin-switching.


Retroperitoneal hemorrhage associated with bone marrow trephine biopsy.
Male, 19 FINAL DIAGNOSIS: Hyperleukocytosis • thrombocytosis Hyperleukocytosis • retroperitoneal hemorrhage • thrombocytosis - Clinical Procedure: Bone marrow trephine biopsy Specialty: Hematology • Radiology. Diagnostic/therapeutic accidents. Bone marrow (BM) trephine biopsy is generally a safe procedure, but adverse events such as retroperitoneal hemorrhage (RPH) may occur. We report 3 cases of this complication. A 19-year-old male with thrombocytopenia and coagulopathy underwent BM trephine biopsy to confirm relapse of acute lymphoblastic leukemia. Two hours later, he developed severe hypotension and a CT scan revealed a massive RPH, and was treated conservatively. The RPH recurred 2 weeks after chemotherapy and was successfully treated with gel foam embolization. A 55-year-old male with coagulopathy underwent BM trephine biopsy for hyperleukocytosis and thrombocytosis. He developed a large RPH preceded by left lumbar dermatome sensory neuropathy. He was treated conservatively. A 56-year-old overweight woman on aspirin underwent BM trephine biopsy for polycythemia. Twelve hours later she developed severe abdominal pain with hypotension. A CT scan showed a massive RPH and secondary hemothorax. She was treated conservatively and the RPH resolved after several months. We and others showed that myeloproliferative neoplasm, quantitative or qualitative platelet abnormalities, aspirin, coagulopathy, and obesity are associated with development of RPH following BM trephine biopsy. Early diagnosis and intervention are crucial. Correction of coagulopathy and cessation of anti-platelet treatment prior to biopsy can prevent this serious complication.


Opening the Random Forest Black Box of the Metabolome by the Application of Surrogate Minimal Depth.
For the untargeted analysis of the metabolome of biological samples with liquid chromatography-mass spectrometry (LC-MS), high-dimensional data sets containing many different metabolites are obtained. Since the utilization of these complex data is challenging, different machine learning approaches have been developed. Those methods are usually applied as black box classification tools, and detailed information about class differences that result from the complex interplay of the metabolites are not obtained. Here, we demonstrate that this information is accessible by the application of random forest (RF) approaches and especially by surrogate minimal depth (SMD) that is applied to metabolomics data for the first time. We show this by the selection of important features and the evaluation of their mutual impact on the multi-level classification of white asparagus regarding provenance and biological identity. SMD enables the identification of multiple features from the same metabolites and reveals meaningful biological relations, proving its high potential for the comprehensive utilization of high-dimensional metabolomics data.


Homotetrameric structure of the SNAP-23 N-terminal coiled-coil domain.
SNARE proteins mediate intracellular membrane fusion by forming a coiled-coil complex to merge opposing membranes. A "fusion-active" neuronal SNARE complex is a parallel four-helix bundle containing two coiled-coil domains from SNAP-25 and one coiled-coil domain each from syntaxin-1a and VAMP-2. "Prefusion" assembly intermediate complexes can also form from these SNAREs. We studied the N-terminal coiled-coil domain of SNAP-23 (SNAP-23N), a non-neuronal homologue of SNAP-25, and its interaction with other coiled-coil domains. SNAP-23N can assemble spontaneously with the coiled-coil domains from SNAP-23C, syntaxin-4, and VAMP-3 to form a heterotetrameric complex. Unexpectedly, pure SNAP-23N crystallizes as a coiled-coil homotetrameric complex. The four helices have a parallel orientation and are symmetrical about the long axis. The complex is stabilized through the interaction of conserved hydrophobic residues comprising the a and d positions of the coiled-coil heptad repeats. In addition, a central, highly conserved glutamine residue (Gln-48) is buried within the interface by hydrogen bonding between glutamine side chains derived from adjacent subunits and to solvent molecules. A comparison of the SNAP-23N structure to other SNARE complex structures reveals how a simple coiled-coil motif can form diverse SNARE complexes.


Use of Smartphone-Based Head-Mounted Display Devices to View a Three-Dimensional Dissection Model in a Virtual Reality Environment: Pilot Questionnaire Study.
Virtual reality (VR) technology has started to gain attention as a form of surgical support in medical settings. Likewise, the widespread use of smartphones has resulted in the development of various medical applications; for example, Google Cardboard, which can be used to build simple head-mounted displays (HMDs). However, because of the absence of observed and reported outcomes of the use of three-dimensional (3D) organ models in relevant environments, we have yet to determine the effects of or issues with the use of such VR technology. The aim of this paper was to study the issues that arise while observing a 3D model of an organ that is created based on an actual surgical case through the use of a smartphone-based simple HMD. Upon completion, we evaluated and gathered feedback on the performance and usability of the simple observation environment we had created. We downloaded our data to a smartphone (Galaxy S6; Samsung, Seoul, Korea) and created a simple HMD system using Google Cardboard (Google). A total of 17 medical students performed 2 experiments: an observation conducted by a single observer and another one carried out by multiple observers using a simple HMD. Afterward, they assessed the results by responding to a questionnaire survey. We received a largely favorable response in the evaluation of the dissection model, but also a low score because of visually induced motion sickness and eye fatigue. In an introspective report on simultaneous observations made by multiple observers, positive opinions indicated clear image quality and shared understanding, but displeasure caused by visually induced motion sickness, eye fatigue, and hardware problems was also expressed. We established a simple system that enables multiple persons to observe a 3D model. Although the observation conducted by multiple observers was successful, problems likely arose because of poor smartphone performance. Therefore, smartphone performance improvement may be a key factor in establishing a low-cost and user-friendly 3D observation environment.


Monitoring newt communities in urban area using eDNA metabarcoding.
Newts are amphibians commonly present in small ponds or garden pools in urban areas. They are protected in many countries and their presence is monitored through visual observation and/or trapping. However, newts are not easy to spot as they are small, elusive and often hidden at the bottom of water bodies. In recent years, environmental DNA (eDNA) has become a popular tool for detecting newts, with a focus on individual species using qPCR assays. Here, we assess the effectiveness of eDNA metabarcoding compared to conventional visual surveys of newt diversity in 45 ponds within urban areas of Geneva canton, Switzerland. We designed newt-specific mitochondrial 16S rRNA primers, which assign the majority of amplicons to newts, and were able to detect four species known to be present in the region, including the invasive subspecies Lissotriton vulgaris meridionalis, native to the Italian peninsula, that has been introduced in the Geneva area recently. The obtained eDNA results were congruent overall with conventional surveys, confirming the morphological observations in the majority of cases (67%). In 25% of cases, a species was only detected genetically, while in 8% of cases, the observations were not supported by eDNA metabarcoding. Our study confirms the usefulness of eDNA metabarcoding as a tool for the effective and non-invasive monitoring of newt community and suggests its broader use for the survey of newt diversity in urban area at larger scales.


Validation of the Greek translation of the Nursing Dimensions Inventory questionnaire (NDI-35).
The concept of care is a fundamental issue in nursing science. Therefore the development and the use of tools for assessing care is an imperative for the nursing profession. The NDI-35 questionnaire is one such tool for assessing the nursing care. The purpose of this paper is to adapt and use the NDI-35 questionnaire in Greek nursing practice. A translation and validation of NDI-35 questionnaire is performed. Exploratory factor analyses, as well as internal consistency and test-retest analyses, were conducted. Forward translations from English were produced by three independent Greek translators and then back translations by five independent bilingual translators. The Greek NDI-35 questionnaire that was produced was administered to 200 nurses (144 women and 56 men) from tertiary and secondary health care facilities. Data were analyzed using principal component analysis and Cronbach's alpha. One hundred and eighty four nurses that answered the NDI-35 questionnaire were graduates from the Technological Educational Institute (T.E.I.) and 64% of the respondents had more than 15 years of professional experience. Two subscales arbitrarily called "clinical work" and "patient needs" emerged, with the mean "clinical work" subscale score being at 70.16 ±12.90 (a maximum of 85) and mean "patient needs" subscale at 21.49± 6.16. Considerable differences in scoring among different items were observed when the NDI-35 answers were compared to their Greek counterparts'. Results confirmed that: (a) the translated versions are an accurate translation of the original, (b) factor analyses established similar factor solutions as that of the English versions, (c) reliability coefficients are satisfactory (i.e., Cronbach's ? coefficients and test-retests), and (d) construct validity revealed similarities between English and Greek versions, replications consistent with past research, as well as differences explained through theoretical frameworks. Therefore, both scales were accepted as valid and reliable measures in Greek-speaking populations. Alphas and test-retest correlation suggest the Greek translated and validated NDI-35 questionnaire is a reliable tool for assessing nursing care. Factor analysis and focus group input suggest it is a valid tool. Nurses in different settings may perceive nursing care differently. The findings of the current paper are discussed in the context of nurse education and assessment of care.


An analysis of global research funding for the frontotemporal dementias: 1998-2008.
To better understand the status of frontotemporal dementia (FTD) research, and identify opportunities to accelerate translational research, we analyzed international funding for FTD and related dementias between 1998 and 2008. Search terms were compiled to define the clinical spectrum of FTD and all known mechanisms. Funders were asked to return grants that contained these search terms in the title or abstract. Grants were classified according to the most reasonably achieved stated aim using a classification scheme of research activities that was developed to map grants along the continuum from basic research to clinical trials of treatments. This analysis captured 613 grants ($432,167,275), from 19 private and public funders from 7 countries and the European Union. National Institutes of Health contributed $360 million (MM), 53% of grants and 83% of total funding. Foundations contributed $43 MM, 35% of grants and 10% of total funding, an increase in recent years. A total of $319 MM (74%, funding) went toward basic research, of which 10% was dedicated to preclinical treatment development, clinical treatment evaluation, and developing detection, diagnostic, and imaging technologies and reagents. FTD received moderate funding over the past decade, which has decreased almost five-fold during this period. A sizable proportion of FTD funding supported mechanisms shared with Alzheimer's disease. Few programs advanced past validating target models and into drug discovery and preclinical development, indicating that the knowledge gained from recent research has still not advanced into treatment development. Quantitative analysis of funding highlighted under-resourced areas as well as redundant efforts, enabling a more strategic approach toward advancing FTD drug discovery and development.


First Report of Mycosphaerella pini Causing Red Band Needle Blight on Scots Pine in Norway.
During a survey conducted in August 2009 in northern Norway, symptoms typical for red band needle blight (1) were observed in four young Scots pine (Pinus sylvestris) stands. The stands, less than 15 years old, were located in humid sites near rivers in Bardu and Målselv municipalities, Troms County. Many of the oldest needles (2- to 3-yearsold) in the lower part of young trees were partially or completely brown, but still attached, and red bands could be observed. Aggregations of conidial stromata were often seen in the red bands. Conidia were hyaline, smooth, thin walled, and filiform, 1.9 to 2.6 μm wide and 12 to 36 μm long. Isolations were made from conidiomata and the identity of Mycosphaerella pini was confirmed by partial sequencing of the internal transcribed spacer (ITS) region of a sample from Målselv (69°00'N, 18°51'E) (GenBank Accession No. JF796109). In June 2010, a survey was done in southeastern Norway where nearly 100 stands with young Scots pine, up to 20 years old, were inspected and typical symptoms of red band needle blight were observed in 10 stands in three municipalities in Hedmark County (Eidskog, Kongsvinger, and Trysil), less than 25 km from the Swedish border, and in one stand in Buskerud County (Nedre Eiker). Lower branches of up to 5 m tall trees had symptoms of red band needle blight, mainly on the oldest needles. In the red bands, acervuli of Dothistroma septosporum, the anamorph of M. pini, appeared. Typical conidia from acervuli were germinated in water agar and resulting mycelium was transferred to modified orange serum agar. Two isolates were sequenced as above and both herbarium samples and isolates (Kongsvinger, 60°06'N, 12°04'E; GenBank Accession No. JF796108 and Trysil, 61°14'N, 12°22'E; GenBank Accession No. JF796107) were deposited at the Norwegian Forest and Landscape Institute. To fulfill Koch's postulates, symptoms were reproduced by artificial inoculation onto 1-year-old Scots pine seedlings. In June 2010, a pooled conidial suspension (2.4 to 3.8 × 103 conidia per ml) from two single-conidium cultures was sprayed to runoff onto 128 seedlings and 64 seedlings were mock sprayed with distilled water. First symptoms (brown segments and red bands) appeared on inoculated seedlings 1 month later and acervuli appeared after another 6 to 8 weeks. M. pini was reisolated from the acervuli. Three months after inoculation, 90% of inoculated seedlings showed symptoms while all uninoculated seedlings were healthy. Damage caused by M. pini has increased in the northern hemisphere during the last 15 to 20 years, possibly because of climate change (4). In 2006, the fungus was recorded in Estonia (2), in 2008 in Finland (3), and by 2009, the disease had spread over large areas in Finland including the region near the Norwegian border in the north. The disease has been in Sweden for a few years (J. Stenlid, personnel communication). In southern Norway, the disease has mainly been observed near the Swedish border so here the disease may originate from Sweden. So far, however, only small areas of Norway have been surveyed. Both natural spread and human transport dissemination may be occurring. References: (1) Anonymous. OEPP/EPPO Bull. 35, 303, 2005. (2) M. Hanso and R. Drenkhan. Plant Pathol. 57:170, 2008. (3) M. Müller et al. Plant Dis. 93:322, 2009. (4) A. Woods et al. BioScience 55:761, 2005.


Unravelling the distinct strains of Tharu ancestry.
The northern region of the Indian subcontinent is a vast landscape interlaced by diverse ecologies, for example, the Gangetic Plain and the Himalayas. A great number of ethnic groups are found there, displaying a multitude of languages and cultures. The Tharu is one of the largest and most linguistically diverse of such groups, scattered across the Tarai region of Nepal and bordering Indian states. Their origins are uncertain. Hypotheses have been advanced postulating shared ancestry with Austroasiatic, or Tibeto-Burman-speaking populations as well as aboriginal roots in the Tarai. Several Tharu groups speak a variety of Indo-Aryan languages, but have traditionally been described by ethnographers as representing East Asian phenotype. Their ancestry and intra-population diversity has previously been tested only for haploid (mitochondrial DNA and Y-chromosome) markers in a small portion of the population. This study presents the first systematic genetic survey of the Tharu from both Nepal and two Indian states of Uttarakhand and Uttar Pradesh, using genome-wide SNPs and haploid markers. We show that the Tharu have dual genetic ancestry as up to one-half of their gene pool is of East Asian origin. Within the South Asian proportion of the Tharu genetic ancestry, we see vestiges of their common origin in the north of the South Asian Subcontinent manifested by mitochondrial DNA haplogroup M43.


Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair.
Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.


Hydroxyapatite cement. II. Obliteration and reconstruction of the cat frontal sinus.
Frontal sinus obliteration and reconstruction can be performed with autogenous grafts or synthetic implants, each of which has significant limitations. Hydroxyapatite cement, which can be shaped intraoperatively and sets to a microporous hydroxyapatite implant, was applied to this problem. Nine cats had the anterior table of their frontal sinus unilaterally removed and the sinus cavity stripped of its mucosa. Hydroxyapatite cement was used to obliterate the cavity and reconstruct the overlying anterior table defect. The unoperated side served as the control, and the animals were sacrificed up to 18 months postoperatively. There were no adverse reactions, infections, mucoceles, or implant extrusions. The normal anatomic contour of the forehead region overlying the hydroxyapatite cement implants was maintained in all animals. Histologic examination of undecalcified whole sinus sections revealed progressive replacement of the implants with woven bone without a loss of volume. Replacement of the hydroxyapatite cement by woven bone is postulated to occur through a combination of implant resorption coupled with osteoconduction. The use of hydroxyapatite cement proved successful for the reconstruction and obliteration of cat frontal sinuses, and may be appropriate for the same application in humans.


Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting.
Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common. To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting. A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado). Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records. Incident CBC based on long-term systematic follow-up. Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive. Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor-positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.


Soy immunotherapy for peanut-allergic mice: modulation of the peanut-allergic response.
Allergen-specific immunotherapy (IT) is an effective therapeutic modality to prevent further anaphylactic episodes in patients with insect sting hypersensitivity and is being investigated for peanut allergy. So far, peanut-specific IT has been unsuccessful because of the side effects of therapy. Soybean seed storage proteins share significant homology with the respective peanut allergens. This study was undertaken in mice to investigate whether specific doses of soybean would desensitize peanut-allergic mice. C3H/HeJ mice were sensitized to peanut with 3 intraperitoneal (IP) injections of crude peanut extract. The mice were desensitized by IP injections with either crude peanut or soybean extract for 4 weeks, 3 times a week. Controls included placebo desensitization with PBS and naive mice. After 2 weeks of rest, mice were challenged IP with crude peanut extract. Thirty minutes later, symptom scores and body temperatures were recorded. Serum immunoglobulins, peanut-induced splenocyte proliferation, and secreted cytokines were measured before and after desensitization. The clinical symptoms in the soybean- and peanut-desensitized animals were markedly reduced compared with the placebo-treated mice. Specific IgG1 levels to crude peanut were significantly lower in the soy IT group than in the peanut IT group. The cellular response to crude peanut was also downregulated in the soy IT group, as shown by decreased peanut-specific stimulation indices and a cytokine profile skewed toward a T H 1 response. Soy IT can be used to desensitize/downregulate peanut-specific response in peanut-allergic mice and could provide a new therapeutic intervention for peanut allergy.


Polymorphisms of lipid metabolism enzyme-coding genes in patients with diabetic dyslipidemia.
The polymorphisms/mutations of genes encoding proteins and enzymes involved in lipoprotein metabolism play important roles in the development of diabetic dyslipidemia. The aim of our study was to investigate the effects of LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), PON1 (rs662), and MNSOD (rs4880) gene polymorphisms on lipid metabolism and diabetic dyslipidemia. This case-control study included 217 patients with diabetic dyslipidemia and 212 healthy age- and gender-matched individuals. Genomic DNA isolation was performed from blood samples, and genotype analysis was performed using melting curve analysis on a LightCycler® 480 Instrument. The chi-square test was used to compare genotype distribution and allele frequencies between the groups. Significant associations were observed between LPL (rs320) (p<0.001), LIPC (rs2070895) (p<0.001), SCARB1 (rs5888) (p<0.001), LCAT (rs2292318) (p<0.001), CETP (rs708272) (p<0.001), ADIPOQ (rs1501299) (p=0.01), RETN (rs3745367) (p<0.001), and MNSOD (rs4880) (p<0.001) polymorphisms and diabetic dyslipidemia. However, no association was observed between PON1 (rs662) polymorphisms and diabetic dyslipidemia (p=0.611). LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), and MNSOD (rs4880) polymorphisms play an important role in basic molecular metabolism in diabetic dyslipidemia. Therefore, these polymorphisms may be used as a predictive marker for diabetic dyslipidemia in high-risk patients.


Exploiting conformational dynamics to facilitate formation and trapping of electron-transfer photoproducts in metal complexes.
Three new photoinduced electron donor-acceptor (D-A) systems are reported which juxtapose a Ru(II) excited-state donor with a bipyridinium acceptor via a conformationally active asymmetric aryl-substituted bipyridine ligand participating in the bridge between D and A. Across the series of complexes 1-3, steric bulk is sequentially added to tune the inter-ring dihedral angle theta between the bipyridine and the aryl substituent. Driving forces for photoinduced electron transfer (DeltaG(ET)) and back electron transfer (DeltaG(BET)) are reported based on electrochemical measurements of 1-3 as well as Franck-Condon analysis of emission spectra collected for three new donor model complexes 1'-3'. These preserve the substitution patterns on the aryl substituent in their respective D-A complexes but remove the bipyridinium acceptor. Both DeltaG(ET) and DeltaG(BET) are invariant to within 0.02 eV across the series. Upon visible photoexcitation of each of the D-A systems with approximately 100 fs laser pulses at 500 +/- 10 nm, an electron-transfer (ET) photoproduct is observed to form with a time constant of tau(ET) = 29 ps (1), 37 ps (2), and 57 ps (3). That ET remains relatively rapid throughout this series, even as steric bulk significantly increases the inter-ring dihedral angle theta, is attributed to the effects of ligand-based torsional dynamics driven by intraligand electron delocalization in the D*-A excited state manifold prior to ET. The lifetimes of the charge-separated states (tau(BET)) are also reported with tau(BET) = 98 ps (1), 217 ps (2), and 789 ps (3), representing a more than 8-fold increase across the series. This is attributed to reverse conformational dynamics in D(+)-A(-) driven by steric repulsions, which serves to minimize electronic coupling to the ground state. Steric control of ligand geometry and the range over which theta changes during conformational dynamics provides a new strategy to facilitate the formation and storage of charge-separated excited states.


Simple and highly sensitive measurement method for detection of glass transition temperatures of polymers: application of ESR power saturation phenomenon with conventional spin-probe technique.
A combination of the microwave power saturation (MPS) method of electron spin resonance (ESR) and spin probing is proposed as a simple and practical technique for detecting the glass transition temperatures, T(g), of polymers with high sensitivity. Effects of the spin-probe size and concentration on the T(g) value of polystyrene (PS) determined by MPS, T(g,ESR), were first evaluated. Spin-probed PS with four types of nitroxides, namely, di-tert-butyl nitroxide (DBN), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl (BZONO), and 4',4'-dimethyl-spiro(5α-cholestane-3,2'-oxazolidin)-3'-yloxy free radical (CHOL), having molecular weights of 144, 156, 276, and 473, respectively, and spin-labeled PS with TEMPO were prepared. The T(g,ESR) values for the spin-probed PS with DBN, TEMPO, BZONO, and CHOL and spin-labeled PS were determined to 360, 363, 374, 374, and 375 K, respectively, within experimental uncertainties of 2 K, whereas the glass transition temperature determined by DSC, T(g,DSC), was 375 K for all samples. A significant decrease in T(g,ESR) for small spin probes was shown to be due to decoupling between the mobilities of small spin probes and PS segments. Concerning the concentration, a decrease in the saturation factor, S, induced by shortening of the spin-spin relaxation time was observed for the spin-probed PS with CHOL when the concentration of CHOL was more than 1.0 wt %. Furthermore, T(g,ESR) decreased slightly with increasing weight fraction of CHOL because of the "plasticizer effect" of CHOL. However, the T(g,ESR) and T(g,DSC) values corresponded for each concentration. Thus, large spin probes, such as CHOL and BZONO, are appropriate for the determination of T(g,ESR) values; the concentration of the spin probes does not affect the T(g,ESR) value unless the overall T(g) value is reduced by blending of excess spin probes. Finally, measurements of T(g,ESR) in PS/silica composites containing more than 95 wt % silica are shown as an application example of the present method. T(g,ESR) was clearly determined even for the PS/silica composites with 98 wt % silica; a decrease in T(g,ESR) with increasing silica content was observed.


A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice.
Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.


Physical activity and immunity in HIV-infected individuals.
The purpose of this study was to determine what relationship exists among physical activity levels and viral load and CD4+ cell count in HIV-infected individuals. Increased viral load is associated with disease progression and symptom severity. A convenience sample of 66 male and female subjects between the ages of 18 and 64 years of age (mean 39 +/- 8) was recruited from a hospital-based HIV/AIDS clinic. Components of PA were assessed for three continuous days using a mini-motion logger wrist actigraph. These components included mean PA level, and PA index and acceleration index. Pearson's correlational analysis was used to test the strength of association between PA components and viral load or CD4+ cell count. A significant inverse relationship was found between mean PA level and viral load (p=0.047). An inverse relationship was also observed between PA index and viral load (p=0.0061). Neither mean PA nor PA index scores correlated with CD4+ cell counts. Acceleration index, a measure of PA intensity, showed no correlation to viral load or CD4+ cell counts. These findings suggest that increasing levels of physical activity might have beneficial effects on viral load in HIV-infected individuals.


Comparison of data sets for surveillance of work-related injury in Victoria, Australia.
To investigate differences and similarities between three sources of work-related injury information: workers compensation claims, emergency department (ED) presentation data and hospital admissions data. This population-based, retrospective descriptive analysis of non-fatal, work-related injuries of workforce participants in Victoria, Australia, has compared data from workers compensation claims and ED presentation and hospital admission data sets for the period 2004-2011. Work-related injury case frequency and rate were compared across study years according to gender, age, geographical location and injury type. Injury rates were expressed as cases per million hours worked. Rates of hospital admissions for treatment of work-related injury increased over the study period, compared with decreasing rates of injury in compensation claims and ED data. The highest rate of injuries to younger workers was captured in ED data. There was greater capture of musculoskeletal injuries by workers' compensation data, and of open wound and burn injury by the ED data. Broad similarities were noted for temporal trends according to gender, for the distribution of cases across older age groups and for rates of fracture injuries. These study findings inform use of workers' compensation, ED presentation and hospital admission data sets as sources of information for surveillance of work-related injuries in countries where these types of data are routinely collected. Choice of data source for investigation of work-related injury should take into consideration the population and injury types of interest.


Time course of adaptation to stimuli presented along cardinal lines in color space.
Visual sensitivity is a process that allows the visual system to maintain optimal response over a wide range of ambient light levels and chromaticities. Several studies have used variants of the probe-flash paradigm to show that the time course of adaptation to abrupt changes in ambient luminance depends on both receptoral and postreceptoral mechanisms. Though a few studies have explored how these processes govern adaptation to color changes, most of this effort has targeted the L-M-cone pathway. The purpose of our work was to use the probe-flash paradigm to more fully explore light adaptation in both the L-M- and the S-cone pathways. We measured sensitivity to chromatic probes presented after the onset of a 2-s chromatic flash. Test and flash stimuli were spatially coextensive 2 degrees fields presented in Maxwellian view. Flash stimuli were presented as excursions from white and could extended in one of two directions along an equiluminant L-M-cone or S-cone line. Probes were presented as excursions from the adapting flash chromaticity and could extend either toward the spectrum locus or toward white. For both color lines, the data show a fast and slow adaptation component, although this was less evident in the S-cone data. The fast and slow components were modeled as first- and second-site adaptive processes, respectively. We find that the time course of adaptation is different for the two cardinal pathways. In addition, the time course for S-cone stimulation is polarity dependent. Our results characterize the rapid time course of adaptation in the chromatic pathways and reveal that the mechanics of adaptation within the S-cone pathway are distinct from those in the L-M-cone pathways.


Geometry parameterization and multidisciplinary constrained optimization of coronary stents.
Coronary stents are tubular type scaffolds that are deployed, using an inflatable balloon on a catheter, most commonly to recover the lumen size of narrowed (diseased) arterial segments. A common differentiating factor between the numerous stents used in clinical practice today is their geometric design. An ideal stent should have high radial strength to provide good arterial support post-expansion, have high flexibility for easy manoeuvrability during deployment, cause minimal injury to the artery when being expanded and, for drug eluting stents, should provide adequate drug in the arterial tissue. Often, with any stent design, these objectives are in competition such that improvement in one objective is a result of trade-off in others. This study proposes a technique to parameterize stent geometry, by varying the shape of circumferential rings and the links, and assess performance by modelling the processes of balloon expansion and drug diffusion. Finite element analysis is used to expand each stent (through balloon inflation) into contact with a representative diseased coronary artery model, followed by a drug release simulation. Also, a separate model is constructed to measure stent flexibility. Since the computational simulation time for each design is very high (approximately 24 h), a Gaussian process modelling approach is used to analyse the design space corresponding to the proposed parameterization. Four objectives to assess recoil, stress distribution, drug distribution and flexibility are set up to perform optimization studies. In particular, single objective constrained optimization problems are set up to improve the design relative to the baseline geometry-i.e. to improve one objective without compromising the others. Improvements of 8, 6 and 15% are obtained individually for stress, drug and flexibility metrics, respectively. The relative influence of the design features on each objective is quantified in terms of main effects, thereby suggesting the design features which could be altered to improve stent performance. In particular, it is shown that large values of strut width combined with smaller axial lengths of circumferential rings are optimal in terms of minimizing average stresses and maximizing drug delivery. Furthermore, it is shown that a larger amplitude of the links with minimum curved regions is desirable for improved flexibility, average stresses and drug delivery.


[Uterine Rupture at 18 Weeks of Pregnancy in the Context of Malformed Uterus].
Birth defects of the female genital tract are relatively common and often asymptomatic. Despite the pregnancy outcome can be favorable, adverse obstetric outcomes are described in women with uterine malformations. The authors report the case of an obstetric emergency which enhances the possibility of a very adverse and rare outcome of uterine rupture in a left hemi-cavity of a bicornuate uterus away from the term, at 18 weeks of pregnancy, in a pregnant woman with history of caesarean in the right hemi-cavity and with placenta increta. A malformed uterus with a primitive type cavity has lower distensibility of the wall with the progression of the pregnancy and facilitates the development of abnormal placentation forms, increasing the risk of uterine rupture in the first and second trimesters. The knowledge of the existence of a congenital uterine anomaly in the preconceptional period is of primary importance.


Accuracy of cytology for diagnosis of lipomatous tumors: comparison with magnetic resonance and computed tomography findings in 175 cases.
To assess the value of fine-needle aspiration cytology in the diagnostic work-up of lipomatous tumors of the extremities and trunk, and to identify specific radiological features that could aid in the preoperative evaluation. 175 patients with subfascial lipomatous tumors who had undergone preoperative magnetic resonance imaging or computed tomography and fine-needle aspiration cytology were studied. The percentage of fat within the lesion was visually graded from the images as: none, 1-75%, 75-95%, or 95-100%. The histological and cytological diagnoses were compared and in discordant cases the radiological images were re-reviewed. There was cytological and histological concordance in 96% of lipomas and in 85% of atypical lipomatous tumors (ALT) and liposarcomas. Most discordant cases exhibited 1-75% fat. Radiological review suggested that cytological sampling problems due to tumor heterogeneity were the main cause of diagnostic difficulties. The majority of tumors with less than 75% fat were liposarcomas, and in no liposarcoma was the fat content higher than 75%. Both ALT and lipoma were found in the 95-100% group. Cytology can be highly accurate in the diagnosis of lipomatous tumors, including ALT; however, critical comparison with the radiological findings increases diagnostic security. In tumors with fat content visually assessed as less than 75% of the tumor volume, liposarcoma is the most likely diagnosis and a cytological diagnosis of ALT or lipoma should be questioned. In lesions with 75-95% fat, liposarcoma is unlikely, but FNAC is still indicated for safety. In lesions with 95-100% fat, FNAC is only indicated if the differentiation between lipoma and ALT influences the treatment strategy.


MEIS1 regulates early erythroid and megakaryocytic cell fate.
MEIS1 is a transcription factor expressed in hematopoietic stem and progenitor cells and in mature megakaryocytes. This biphasic expression of MEIS1 suggests that the function of MEIS1 in stem cells is distinct from its function in lineage committed cells. Mouse models show that Meis1 is required for renewal of stem cells, but the function of MEIS1 in human hematopoietic progenitor cells has not been investigated. We show that two MEIS1 splice variants are expressed in hematopoietic progenitor cells. Constitutive expression of both variants directed human hematopoietic progenitors towards a megakaryocyte-erythrocyte progenitor fate. Ectopic expression of either MEIS1 splice variant in common myeloid progenitor cells, and even in granulocyte-monocyte progenitors, resulted in increased erythroid differentiation at the expense of granulocyte and macrophage differentiation. Conversely, silencing MEIS1 expression in progenitor cells induced a block in erythroid expansion and decreased megakaryocytic colony formation capacity. Gene expression profiling revealed that both MEIS1 splice variants induce a transcriptional program enriched for erythroid and megakaryocytic genes. Our results indicate that MEIS1 expression induces lineage commitment towards a megakaryocyte-erythroid progenitor cell fate in common myeloid progenitor cells through activation of genes that define a megakaryocyte-erythroid-specific gene expression program.


The health advantage of a vegan diet: exploring the gut microbiota connection.
This review examines whether there is evidence that a strict vegan diet confers health advantages beyond that of a vegetarian diet or overall healthy eating. Few studies include vegan subjects as a distinct experimental group, yet when vegan diets are directly compared to vegetarian and omnivorous diets, a pattern of protective health benefits emerges. The relatively recent inclusion of vegan diets in studies of gut microbiota and health allows us the opportunity to assess whether the vegan gut microbiota is distinct, and whether the health advantages characteristic of a vegan diet may be partially explained by the associated microbiota profile. The relationship between diet and the intestinal microbial profile appears to follow a continuum, with vegans displaying a gut microbiota most distinct from that of omnivores, but not always significantly different from that of vegetarians. The vegan gut profile appears to be unique in several characteristics, including a reduced abundance of pathobionts and a greater abundance of protective species. Reduced levels of inflammation may be the key feature linking the vegan gut microbiota with protective health effects. However, it is still unclear whether a therapeutic vegan diet can be prescribed to alter the gut microflora for long-term health benefits.


Ionescu-Shiley bovine pericardial bioprostheses. Histologic and ultrastructural studies.
Studies were done on the structural changes that develop in Ionescu-Shiley valves that are used as replacement heart valves for 4 to 8 years. These changes were compared with those found in similarly used porcine aortic valve (PAV) bioprostheses. A variety of morphologic differences were observed between bovine pericardial valve (BPV) and PAV bioprostheses after orthotopic implantation including: primary tissue failure associated with the use of an alignment suture, thickening of valve leaflet, leaflet tissue delamination, leaflet calcification, and dystrophic alterations of collagen. These findings indicate that valve design criteria directly influence the durability of pericardial valves. However, other factors unique to pericardial tissue also affect the durability and performance of BPVs. These factors include the inability of pericardial tissue to accommodate dynamic stresses; the extensive insudation of plasma proteins and lipids; and the inability to reduce leaflet calcification using agents that effectively mitigate calcification in PAV bioprostheses.


Effects of mass and body composition on fasting fuel utilisation in grey seal pups (Halichoerus grypus Fabricius): an experimental study using supplementary feeding.
This study used supplementary feeding to test the hypothesis that fuel partitioning during the postweaning fast in grey seal pups is affected by size and composition of energy reserves at weaning, and by extra provisioning. Mass and body composition changes were measured during suckling and fasting to investigate the effect of natural differences in energy reserves at weaning on subsequent allocation of fat and protein to energy use. We fed seven pups for 5 days after weaning, to investigate the effect of increased fuel availability, and particularly protein, on fuel utilisation. After correcting for protein used during the moult, the proportional contribution of fat was 86-99% of total energy use. Pups with greater energy reserves, i.e. those that were heavier and fatter at weaning, had higher rates of fat and energy use. There was no significant relationship between adiposity at weaning and proportional contribution of fat to energy use, perhaps due to a limited sample size or range of body masses and adiposity. Supplemented individuals used energy, specifically fat, much faster and utilised proportionally less of their endogenous protein by departure than non-supplemented individuals. Fat metabolism contributed a similar percentage to daily energy use in both groups. These findings show that pups spare protein, even when energy use is dramatically increased. Pups that receive greater maternal provisioning and lay down more protein may have increased survival chances at sea. This study highlights the importance of protein reserves in first year survival of grey seal pups.


Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)


The beta3 subunit of the Na+,K+-ATPase mediates variable nociceptive sensitivity in the formalin test.
It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the beta3 subunit of the Na+,K+-ATPase pump (Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, beta3 protein expression, and biophysical properties of the Na+,K+ pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the beta3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the beta3 subunit of the Na+,K+-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.


Mouse ghrelin-O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption.
Ghrelin is a unique peptide gut hormone that requires post-translational modification to stimulate both feeding and growth hormone release. Ghrelin O-acyltransferase (GOAT) was identified as a specific acyl-transferase for ghrelin, and recent genetic deletion studies of the Goat gene (Goat(-/-)) uncovered the role of ghrelin in the regulation of glucose homeostasis. To further understand the physiological functions of the GOAT/ghrelin system, we have conducted a metabolomic and microarray profile of Goat-null mice, as well as determined Goat expression in different tissues using the lacZ reporter gene. Serum metabolite profile analysis revealed that Goat(-/-) mice exhibited increased secondary bile acids >2.5-fold. This was attributed to increased mRNA and protein expression of the ileal sodium-dependent bile acid transporter (ISBT) in the intestinal and biliary tract. Increased expression of additional solute carrier proteins, including Slc5a12 (>10-fold) were also detected in the small intestine and bile duct. Goat staining was consistently observed in the pituitary glands, stomach, and intestines, and to a lesser extent in the gallbladder and pancreatic duct. This is the first report that the GOAT/ghrelin system regulates bile acid metabolism, and these findings suggest a novel function of GOAT in the regulation of intestinal bile acid reabsorption..


Effects of feed intake and genetics on tissue nitrogen-15 enrichment and feed conversion efficiency in sheep.
This study investigated the effects of sheep genetics and feed intake on nitrogen isotopic fractionation (ΔN) and feed conversion efficiency (FCE; live weight gain/DMI), using a 2 × 2 factorial design, with 2 levels of genetic merit for growth (high vs. low) and 2 levels of feed intake (110 vs. 170% of ME for maintenance [MEm]). No effect of genetic merit was detected for live weight gain ( = 0.64), FCE ( = 0.46), plasma urea nitrogen ( = 0.52), plasma glucose ( = 0.78), and ΔN of wool ( = 0.45), blood ( = 0.09), and plasma ( = 0.51). Sheep receiving 170% of MEm had 175% higher live weight gain ( < 0.001) and 77% higher FCE ( < 0.001) than sheep receiving 110% of MEm. There was no difference among treatments at the beginning of the study for either blood or plasma ∆N, but the treatment groups started to diverge in blood and plasma ∆N at 21 and 7 d, respectively. Blood, plasma, and wool samples were enriched in N compared with feed. There was a higher blood, plasma, and wool ∆N for the low feed intake group than the high feed intake group ( < 0.001 in all cases). Across the 4 treatment groups, higher FCE in sheep was associated with lower ∆N for plasma, blood, and wool. Overall, the results are consistent with the potential of ∆N as a rapid, low-cost biomarker of FCE in sheep, despite there being no effects of genetic treatment on FCE and ∆N.


An exploration of when urban background medical students become interested in rural practice.
While it is well recognized that rural background medical students are more likely to enter rural practice than urban background, students' research shows that 34% to 67% of rural doctors have urban backgrounds. This article explores the factors influencing urban background medical students' interest in rural practice. The study used a qualitative design employing focus groups and semi-structured interviews. Data were collected at three Australian universities and a national student rural health conference, and the participants were 82 first and final year medical students who participated in focus groups, and 49 who were interviewed individually. Data were analysed using the N6 computer package to manage the data. Forty-three urban background students indicated an interest in rural practice and the data presented in this article relate to this group of students. This article presents an analysis of data from one part of a larger project conducted from 2002 to 2004 investigating medical student career choice. The students' level of interest in rural practice depends on an interaction between student and location factors and other external influences with students seeking to match their needs and interests with locations. Some are 'predisposed' to develop interest in rural practice via their familiarity with rural areas, level of altruism, interest in generalist work, and interest in certain leisure activities. Exposure to rural locations provides knowledge about different places. Students recognize differences between rural locations in relation to the size of town and the remoteness of the town, and they seek specific rural locations which will match their values and interests. Existing social relationships can be enabling or limiting factors in the student's ability to follow through their interest in rural practice and to enter rural practice, and are important in the students finding a match between themselves and an appropriate location. Exposure of urban background students to rural practice and a range of rural locations generates an interest in rural practice among many urban background students. This exposure may increase the number of students who become interested in rural practice and decide to enter rural practice. Further quantitative research is required to test the findings from this exploratory qualitative study.


Community Health Workers in Hawai'i: A Scoping Review and Framework Analysis of Existing Evidence.
Introduction: Community health workers (CHWs) play a vital role in health across Hawai'i, but the scope of this work is not comprehensively collated. This scoping review describes the existing evidence of the roles and responsibilities of CHWs in Hawai'i. Methods: Between May and October 2018, researchers gathered documents (eg, reports, journal articles) relevant to Hawai'i CHWs from health organizations, government entities, colleges/universities, and CHWs. Documents were reviewed for overall focus and content, then analyzed using the Centers for Disease Control and Prevention's 10 Essential Public Health Services as well as the Community Health Worker Core Consensus Project roles to identify workplace roles and gaps. Results: Of 92 documents received, 68 were included for review. The oldest document dated to 1995. Document types included curricula outlines, unpublished reports, and peer-reviewed articles. Documents discussed trainings, certification programs, CHWs' roles in interventions, and community-, clinical-, and/or patient-level outcomes. Cultural concordance parity between CHWs and patients, cost savings, and barriers to CHW work were noted. Most roles named by the Community Health Worker Core Consensus Project were mentioned in documents, but few were related to the roles of "community/policy advocacy" and "participation in research and evaluation." Workplace roles, as determined using the 10 Essential Public Health Services, focused more on "assuring workforce competency" and "evaluation," and less on "policy development," and "enforcing laws." Discussion: CHWs are an important part of Hawaii's health system and engage in many public health functions. Although CHW roles in Hawai'i mirrored those identified by the CHW Core Consensus Project and 10 Essential Public Health Services frameworks, there is a noticeable gap in Hawai'i CHW professional participation in research, evaluation, and community advocacy.


Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency.
Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.


Hemorrhagic complications in pediatric hematologic malignancies.
Hematologic malignancies account for almost 40% of all cancers in children. Hemorrhage is the most common cause of early death in children with leukemia. Furthermore, major bleeding episodes lead to shorter survival and increased resource use. Potential risk factors for bleeding include hyperleukocytosis, immunophenotype of leukemia (especially acute promyelocytic leukemia), thrombocytopenia, and associated infections. Successful management of a bleeding episode is dependent on prompt identification of a child at high risk for bleeding, and should be directed at the replacement of blood products as well as to the aggressive therapy for underlying risk factors. Although in recent years there is a favorable decline in the hemorrhage-related mortality, the overall prevalence and the extent of morbidity posed by this potentially fatal complication, including disease outcome in children with hematologic malignancy, is largely unknown. In addition, there are no evidence-based guidelines for prophylactic blood or blood product transfusions. Prospective studies are required to define the epidemiology and risk factors predisposing children with hematologic malignancy to bleeding and to develop management guidelines.


Standardised alcohol screening in primary health care services targeting Aboriginal and Torres Strait Islander peoples in Australia.
Aboriginal and Torres Strait Islander Community Controlled Health Services (ACCHSs) around Australia have been asked to standardise screening for unhealthy drinking. Accordingly, screening with the 3-item AUDIT-C (Alcohol Use Disorders Identification Test-Consumption) tool has become a national key performance indicator. Here we provide an overview of suitability of AUDIT-C and other brief alcohol screening tools for use in ACCHSs. All peer-reviewed literature providing original data on validity, acceptability or feasibility of alcohol screening tools among Indigenous Australians was reviewed. Narrative synthesis was used to identify themes and integrate results. Three screening tools-full AUDIT, AUDIT-3 (third question of AUDIT) and CAGE (Cut-down, Annoyed, Guilty and Eye-opener) have been validated against other consumption measures, and found to correspond well. Short forms of AUDIT have also been found to compare well with full AUDIT, and were preferred by primary care staff. Help was often required with converting consumption into standard drinks. Researchers commented that AUDIT and its short forms prompted reflection on drinking. Another tool, the Indigenous Risk Impact Screen (IRIS), jointly screens for alcohol, drug and mental health risk, but is relatively long (13 items). IRIS has been validated against dependence scales. AUDIT, IRIS and CAGE have a greater focus on dependence than on hazardous or harmful consumption. Detection of unhealthy drinking before harms occur is a goal of screening, so AUDIT-C offers advantages over tools like IRIS or CAGE which focus on dependence. AUDIT-C's brevity suits integration with general health screening. Further research is needed on facilitating implementation of systematic alcohol screening into Indigenous primary healthcare.


Capturing norovirus transmission.
Human norovirus is a leading cause of gastroenteritis and is efficiently transmitted between humans and around the globe. The burden of norovirus infections in the global community and in health-care settings warrant the availability of outbreak prevention strategies and control measures that are tailored to the pathogen, outbreak setting and population at risk. A better understanding of viral and host determinants of transmission would aid in developing and fine-tuning such efforts. Here, we describe mechanisms of transmission, available model systems for studying norovirus transmission and their strengths and weaknesses as well as future research strategies.


[Early prediction of severity in acute pancreatitis].
To identify the score that best predicts early severity in patients with acute pancreatitis. A prospective cohort study was performed from December 2009 to December 2011. Cases of pancreatitis were classified as mild or severe based on the organ failure criteria and/or local complications according to the Atlanta Symposium. APACHE-II, BISAP and urea were calculated using data from the first 24 hours. Ranson was calculated using data from the first 48 hours. Hemoconcentratión was assessed 24 hours from admission, after adequate hydration. To assess the predictive value of the different scores the area under the curve ROC was used. 329 patients with acute pancreatitis were included: 214 women (65%) and 115 males (35%). The most common etiology was biliary 245 (74.3%). Two hundred and forty were mild cases of pancreatitis (73%) and 89 were severe (27%). The areas under the curve ROC were: APACHE-II: 0.74; BISAP: 0.78; Ranson: 0.48; urea: 0.70; hemoconcentratión: 0.73. There were 10 deaths (mortality: 3%). There were no significant differences between BISAP and APACHE-II, urea or hemoconcentration, but a significant difference existed with Ranson score. BISAP is a simple score that applied early in the emergency room identifies patients with severe pancreatitis with an efficacy similar to APACHE-II, urea and hemoconcentration, and acute pancreatitis, BISAP, severity, prognostic scoring.


Predictors of timing of adjuvant chemotherapy in older women with hormone receptor-negative, stages II-III breast cancer.
Adherence to consensus guidelines for cancer care may vary widely across health care settings and contribute to differences in cancer outcomes. For some women with breast cancer, omission of adjuvant chemotherapy or delays in its initiation may contribute to differences in cancer recurrence and mortality. We studied adjuvant chemotherapy use among women with stage II or stage III, hormone receptor-negative breast cancer to understand health system and socio-demographic correlates of underuse and delayed adjuvant chemotherapy. We used Surveillance Epidemiology and End Results (SEER)-Medicare linked data to examine the patterns of care for 6,678 women aged 65 and older diagnosed with stage II or stage III hormone receptor-negative breast cancer in 1994-2002, with claims data through 2007. Age-stratified logistic regression was employed to examine the potential role of socio-demographic and structural/organizational health services characteristics in explaining differences in adjuvant chemotherapy initiation. Overall utilization of guideline-recommended adjuvant chemotherapy peaked at 43% in this population. Increasing age, higher co-morbidity burden, and low-income status were associated with lower odds of chemotherapy initiation within 4 months, whereas having positive lymph nodes, more advanced disease, and being married were associated with higher odds (P < 0.05). Health system-related structural/organizational characteristics and race/ethnicity offered little explanatory insight. Timely initiation of guideline-recommended adjuvant chemotherapy was low, with significant variation by age, income, and co-morbidity status. Based on these findings, future studies should seek to explore the more nuanced reasons why older women do not receive chemotherapy and why delays in care occur.


PKA-type I selective constrained peptide disruptors of AKAP complexes.
A-Kinase Anchoring Proteins (AKAPs) coordinate complex signaling events by serving as spatiotemporal modulators of cAMP-dependent protein kinase activity in cells. Although AKAPs organize a plethora of diverse pathways, their cellular roles are often elusive due to the dynamic nature of these signaling complexes. AKAPs can interact with the type I or type II PKA holoenzymes by virtue of high-affinity interactions with the R-subunits. As a means to delineate AKAP-mediated PKA signaling in cells, we sought to develop isoform-selective disruptors of AKAP signaling. Here, we report the development of conformationally constrained peptides named RI-STapled Anchoring Disruptors (RI-STADs) that target the docking/dimerization domain of the type 1 regulatory subunit of PKA. These high-affinity peptides are isoform-selective for the RI isoforms, can outcompete binding by the classical AKAP disruptor Ht31, and can selectively displace RIα, but not RIIα, from binding the dual-specific AKAP149 complex. Importantly, these peptides are cell-permeable and disrupt Type I PKA-mediated phosphorylation events in the context of live cells. Hence, RI-STAD peptides are versatile cellular tools to selectively probe anchored type I PKA signaling events.


The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study.
Vertebral fractures are a common complication of osteoporosis and may have a negative effect on health-related quality of life (HRQOL). We investigated the effect of prevalent vertebral fractures on HRQOL in patients with osteoporosis. A cross-sectional multicenter study was carried out among postmenopausal women with primary osteoporosis attending primary care centers and hospital outpatient clinics: 234 women with vertebral fractures and 244 asymptomatic women. Women with secondary osteoporosis or taking medications that affect bone metabolism were excluded. All patients were questioned using the mini-Osteoporosis Quality of Life Questionnaire (mini-OQLQ), Medical Outcomes Study Short Form-36 (SF-36), and the EuroQuol-5D, after assessment of all clinical variables and anthropometric data. To assess comorbidity we used the Self-Administered Comorbidity Questionnaire (SCQ). Diagnosis of osteoporosis was confirmed in all patients by bone mineral density using dual energy x-ray absorptiometry. Radiographic evaluation was performed by a musculoskeletal radiologist. A total of 483 postmenopausal women, randomly matched for age out of 1579 healthy controls, were chosen to compare the SF-36 scores with respect to patients with and without vertebral fractures due to osteoporosis. A multivariable regression analysis was conducted to identify the strongest determinant for low HRQOL, adjusted for potential confounding variables such as comorbid conditions, education level, and psychosocial status. The vertebral fracture group had significantly lower scores than patients without fractures and controls in all domains of the generic and specific questionnaires. Women with only 1 prevalent fracture had statistically significantly lower HRQOL scores than those without fractures on SF-36 measures of bodily pain, physical functioning, and role function physical (all p < 0.01). HRQOL scores were lower in women with lumbar fractures compared with women with thoracic fractures only when the physical functioning and bodily pain dimensions approached statistical significance. Based on the multivariate analysis, the strongest determinant for low HRQOL was physical functioning (explained by number of vertebral fractures) followed by comorbidity score and age. Adjusted R2 in the final model was 35.9%. Using the SF-36 summary scales, comorbid conditions predominantly affected either mental or physical health (p < 0.0001). A significant correlation (p <0.0001) was found between total score on the mini-OQLQ and the mean SCQ comorbidity score. Our results confirm previous findings that HRQOL, assessed by generic and osteoporosis-specific instruments, is decreased in patients with vertebral fractures due to osteoporosis as a function of the number of vertebral fractures, presence of comorbid conditions, and age.


Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon.
Cathepsin K has been shown to exhibit antimicrobial and anti-inflammatory activities in the mouse colon. To further elucidate its role, we used Ctsk-/- mice and demonstrated that the absence of cathepsin K was accompanied by elevated protein levels of related cysteine cathepsins (cathepsins B, L, and X) in the colon. In principle, such changes could result in altered subcellular localization; however, the trafficking of cysteine cathepsins was not affected in the colon of Ctsk-/- mice. However, cathepsin K deficiency affected the extracellular matrix constituents, as higher amounts of collagen IV and laminin were observed. Moreover, the localization pattern of the intercellular junction proteins E-cadherin and occludin was altered in the colon of Ctsk-/- mice, suggesting potential impairment of the barrier function. Thus, we used an ex vivo method for assessing the mucus layers and showed that the absence of cathepsin K had no influence on mucus organization and growth. The data of this study support the notion that cathepsin K contributes to intestinal homeostasis and tissue architecture, but the lack of cathepsin K activity is not expected to affect the mucus-depending barrier functions of the mouse colon. These results are important with regard to oral administration of cathepsin K inhibitors that are currently under investigation in clinical trials.


Effect of ethanolic extract of Lepidium meyenii Walp on serum hormone levels in ovariectomized rats.
To evaluate the effect of long-term ethanol extract of Lepidium meyenii (Maca) on serum hormone levels in ovariectomized (OVX) rats and compare them with the effect of diethylstilbestrol. Fifty female Sprague-Dawley rats were ovariectomized or sham operated. Both sham and OVX control groups (n = 10, respectively) received the vehicle. The remaining OVX rats were oral administrated with ethanol extract of Maca (0.096, or 0.24g/kg; n = 10, respectively) and diethylstilbestrol (0.05 mg/kg; n = 10). The treatment continued for 28 weeks. At week 12 and week 28, the blood of rats was collected and serum hormone levels, including estradiol (E2), testosterone (T) and follicle-stimulating hormone (FSH) were measured by radioimmunoassay. At week 12, the levels of serum E2 were slightly higher in Maca groups than that in OVX group; T levels were significantly decreased; and FSH levels were advanced slightly in Maca groups than that in sham group. After 28 weeks administration, serum E2 levels in Maca-treated animals did not differ significantly from sham control, the low dose of Maca increased serum E2 levels, and Maca prevented increase in serum FSH levels compared with OVX group. Long-term Maca supply modulates endocrine hormone balance in OVX rats, especially it decreases enhanced FSH levels. It is proposed that Maca may become a potential choice for postmenopausal women.


Knowledge of pregnant women on transmission of HIV infection through breast feeding.
Although breast-feeding is nature's way of providing nutrition to the baby, in HIV positive mothers this has been identified as one of the means through which HIV infection is transmitted from the mother to the child. In Africa where children under the age of 5 are killed by preventable diseases like diarrhoea, the issue of HIV transmission through breast feeding poses an added huge problem. Research has, however shown that exclusive infant feeding, be it breast or formula, reduces the risk substantially. It is imperative that mothers be informed about safer methods of infant feeding so that HIV infection is kept to a minimum. The objective of the study was to explore and describe the knowledge that pregnant women had about mother to child transmission of HIV infection through breast-feeding. A non-experimental quantitative exploratory and descriptive research design was used to explore the knowledge women had on mother to child transmission of HIV infection through breast-feeding. From the data collected, it showed that although women were aware of the susceptibility of children to HIV infection if fed on breast and formula feeds simultaneously by HIV positive mothers, exclusive feeding was a problem as people associated the practise with a positive HIV status. Women who had not disclosed their HIV status and were HIV positive, found it difficult to comply with the requirement to exclusively feed their infants. These either continued with complementary feeds or did not collect the free formula milk supply preferring instead to buy the formula feeds privately. In this study it was recommended that information on transmission of HIV infection from mother to child through breast -feeding including the benefits of exclusive infant feeding, be it breast or formula, for the first three to six months be provided to the community so that relatives can support the mother on infant feeding method of choice.


Patient-physician e-mail: an opportunity to transform pediatric health care delivery.
The objectives of this study were to assess the patterns of patients who use a patient-physician e-mail service, measure physician time required to answer a patient question via e-mail compared with that via telephone, and determine the satisfaction of families who are provided e-mail access to their child's rheumatologist. A consecutive series of patients' families were offered e-mail access during a 2-year period. Data regarding patient e-mail use were collected, including urgency of message, subject matter, message volume, and time of day of messaging. The duration of the pediatric rheumatologist's e-mail interactions and telephone interactions with patients was measured using a stopwatch. After 1 year of enrollment in the patient-physician e-mail service, families were mailed a 12-item satisfaction survey regarding their e-mail experience. A total of 306 of 328 families who were offered patient-physician e-mail access enrolled, and 121 used the service. The patients sent 40% of their e-mails outside business hours. Messages that were urgent (notification of disease flare, notification of new symptoms, or parent expectation of same-day response) made up 5.7% of the e-mails sent to the physician. Messages that required emergent attention made up 0.002% of the e-mails to the physician. Answering patient questions by e-mail was 57% faster than using the telephone for the physician. The physician received 1.2 e-mails per day from patients. The families who responded to the survey agreed that patient-physician e-mail increased access to the physician and improved the quality of care. The families did not find that patient-physician e-mail distanced them from their child's doctor. Patient-physician e-mail is a service that patients will use given the opportunity. The e-mail service enables physicians to answer medical questions with less time spent compared with telephone messaging. In our experience in an academic pediatric subspecialty practice, patients reported enhanced communication and access with the e-mail service.


A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma.
Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482-95. ©2015 AACR.


Stimulatory effect of Brazilian propolis on hair growth through proliferation of keratinocytes in mice.
Propolis is a natural honeybee hive product with the potential for use in the treatment of dermatological conditions, such as cutaneous abrasions, burns, and acne. In this study, we investigated whether propolis stimulates hair growth in mice. Ethanol-extracted propolis, which contains various physiologically active substances such as caffeic acid and kaempferol, stimulated anagen induction in shaved back skin. Anagen induction occurred without any detectable abnormalities in the shape of the hair follicles (HFs), hair stem cells in the bulge, proliferating hair matrix keratinocytes in the hair bulb, or localization of versican in the dermal papilla. Propolis treatment also stimulated migration of hair matrix keratinocytes into the hair shaft in HFs during late anagen in the depilated back skin. Organotypic culture of skin containing anagen stage HFs revealed significant stimulation of hair matrix keratinocyte proliferation by propolis. Furthermore, propolis facilitated the proliferation of epidermal keratinocytes. These results indicate that propolis stimulates hair growth by inducing hair keratinocyte proliferation.