Comparison of Aesthetic and Functional Outcomes of Spreader Graft and Autospreader Flap in Rhinoplasty.
Although the assignment and suturing of the spreader graft to the septum is a routine part of rhinoplasty, it is a time wasting procedure and some problems may occur. Rather, autospreader flap is a new method that the dorsal part of the upper lateral cartilage is used as its own graft. In the present study, we intended to compare the functional and aesthetic outcomes of these two techniques of rhinoplasty. In a clinical trial, patients who referred to 15 Khordad Hospital for elective rhinoplasty during 2013-2014 were enrolled. The functional and aesthetic outcomes were compared between the two techniques of spreader graft and autospreader flap using rhinomanometry and satisfaction questionnaire in two stages before and one months after the surgery. Total nasal airway resistance increased significantly by both spreader graft and autospreader flap, but the difference between the two methods was not statistically significant. The total nasal flow before and after the surgery significantly decreased using both techniques, but this reduction was not significant between the two methods of surgery. When questioned about the satisfaction with the surgery outcomes, 18 subjects (36%) had complete aesthetic satisfaction, 25 (50%) were partial satisfied and 7 subjects (14%) were unsatisfied from aesthetic results. The rate of patient's satisfaction in both groups was higher for functional outcome. Overall, 32 (64%) subjects were completely satisfied, 13 (26%) were partially satisfied and 5 (10%) subjects did not report satisfaction. Loss of respiratory function in both groups was inevitable due to short time post-operative period. Both spreader graft and autospreader flap techniques can be used in the preservation and restoration of the normal internal nasal valve angle, as well as restoration of dorsal aesthetic lines of the nasal dorsum.


On the epidemiology of influenza.
The epidemiology of influenza swarms with incongruities, incongruities exhaustively detailed by the late British epidemiologist, Edgar Hope-Simpson. He was the first to propose a parsimonious theory explaining why influenza is, as Gregg said, "seemingly unmindful of traditional infectious disease behavioral patterns." Recent discoveries indicate vitamin D upregulates the endogenous antibiotics of innate immunity and suggest that the incongruities explored by Hope-Simpson may be secondary to the epidemiology of vitamin D deficiency. We identify - and attempt to explain - nine influenza conundrums: (1) Why is influenza both seasonal and ubiquitous and where is the virus between epidemics? (2) Why are the epidemics so explosive? (3) Why do they end so abruptly? (4) What explains the frequent coincidental timing of epidemics in countries of similar latitude? (5) Why is the serial interval obscure? (6) Why is the secondary attack rate so low? (7) Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport? (8) Why does experimental inoculation of seronegative humans fail to cause illness in all the volunteers? (9) Why has influenza mortality of the aged not declined as their vaccination rates increased? We review recent discoveries about vitamin D's effects on innate immunity, human studies attempting sick-to-well transmission, naturalistic reports of human transmission, studies of serial interval, secondary attack rates, and relevant animal studies. We hypothesize that two factors explain the nine conundrums: vitamin D's seasonal and population effects on innate immunity, and the presence of a subpopulation of "good infectors." If true, our revision of Edgar Hope-Simpson's theory has profound implications for the prevention of influenza.


Nursing staff interactions during the older residents' transition into long-term care facility in a nursing home in rural Norway: an ethnographic study.
Future challenges in many countries are the recruitment of competent staff in long-term care facilities, and the use of unlicensed staff. Our study describes and explores staff interactions in a long-term care facility, which may facilitate or impede healthy transition processes for older residents in transition. An ethnographic study based on fieldwork following ten older residents admission day and their initial week in the long-term care facility, seventeen individual semi-structured interviews with different nursing staff categories and the leader of the institution, and reading of relevant documents. The interaction among all staff categories influenced the new residents' transition processes in various ways. We identified three main themes: The significance of formal and informal organization; interpersonal relationships and cultures of care; and professional hierarchy and different scopes of practice. The continuous and spontaneous staff collaborations were key activities in supporting quality care in the transition period. These interactions maintained the inclusion of all staff present, staff flexibility, information flow to some extent, and cognitive diversity, and the new resident's emerging needs appeared met. Organizational structures, staff's formal position, and informal staff alliances were complex and sometimes appeared contradictory. Not all the staff were necessarily included, and the new residents' needs not always noticed and dealt with. Paying attention to the playing out of power in staff interactions appears vital to secure a healthy transition process for the older residents.


The VAMPIRE challenge: A multi-institutional validation study of CT ventilation imaging.
CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities. The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA-SPECT, and 4 sheep imaged with Xenon-CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). Seven research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B-splines, Free-form, Diffeomorphisms, or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel-wise Spearman coefficient rS , and Dice similarity coefficients evaluated for low function lung ( DSClow ) and high function lung ( DSChigh ). A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant-submitted DIR motion fields using the in-house software, VESPIR. The rS and DSC results reveal a high degree of inter-algorithm and intersubject variability among the validation subjects, with algorithm rankings changing by up to ten positions depending on the choice of evaluation metric. The algorithm with the highest overall cross-modality correlations used a biomechanical model-based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27-0.73) for rS , 0.52 (0.36-0.67) for DSClow , and 0.45 (0.28-0.62) for DSChigh . All other algorithms exhibited at least one negative rS value, and/or one DSC value less than 0.5. The VAMPIRE Challenge results demonstrate that the cross-modality correlation between CTVIs and the RefVIs varies not only with the choice of CTVI algorithm but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a "gold standard," highlights the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts.


Novel Microbial-Based Immunotherapy Approach for Crohn's Disease.
Background: Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health outcomes for patients. Aims: To assess safety, efficacy, and tolerability of a novel microbial-derived immunotherapy, QBECO, that aims to restore rather than suppress immune function in CD. Methods: A randomized, double-blind, placebo-controlled trial was conducted in 68 patients with moderate-to-severe CD. Primary endpoints: safety and Week 8 clinical improvement. Secondary endpoints: Week 8 clinical response and remission. Week 8 responders continued blinded treatment through Week 16; non-responders received open-label QBECO from Weeks 9-16. Exploratory analyses included immune biomarker and genotype assessments. Results: QBECO was well-tolerated. Mean reduction in Crohn's Disease Activity Index (CDAI) score was -68 for QBECO vs. -31 for placebo at Week 8. Improvement with QBECO continued through Week 16 (-130 CDAI reduction). Week 8 QBECO clinical response, improvement and remission rates were 41.2%, 32.4%, 29.4% vs. 26.5%, 23.5%, 23.5% for placebo. TNFα inhibitor-naïve subjects achieved higher response rates at Week 8 with QBECO (64%) vs. placebo (26%). Specific immune biomarkers were identified that linked to QBECO response. Conclusion: This proof-of-concept study supports further investigation for the use of QBECO as a novel immunotherapy approach for CD. Biomarker analyses suggests it may be feasible to personalize CD treatment with QBECO. Larger trials are now needed to confirm clinical improvement and the unique biological findings. Clinical Trial Number: NCT01809275 (https://clinicaltrials.gov/ct2/show/NCT01809275).


Improved static lung preservation with corticosteroids and hypothermia.
With methylprednisolone as a chemical inhibitor of leukocytes, extended preservation was conducted with an isolated rabbit lung model. The heart-lung blocks of 39 New Zealand white rabbits were flushed in situ with 100 ml of Euro-Collins' solution, harvested, inflated (70%), and preserved at 4 degrees C. Lungs immediately reperfused with whole blood (control lungs, group 1) were compared with lungs preserved without methylprednisolone for 5, 12, and 24 hours (groups 2 to 4) and those preserved with methylprednisolone for 12 and 24 hours (groups 5 and 6, respectively). Methylprednisolone (30 mg/kg) was administered before harvest and was used as an additive to the flush and in the blood reperfusate. Hypothermia and Euro-Collins' flush alone provided adequate preservation for up to 5 hours; however, lung edema was evident by 12 hours of cold ischemia and became severe by 24 hours. By all measured parameters, the lungs in group 5 (treated with methylprednisolone) demonstrated values equal to or better than control lungs. By 24 hours of preservation the beneficial effects of the steroid treatment were no longer evident. Histologic evaluation revealed mild to moderate injury after 5 hours of cold ischemia; progressive edema and hemorrhage were found after 12 and 24 hours of preservation. This injury was significantly ameliorated by methylprednisolone treatment at 12 hours but not at 24 hours. This study suggests that static preservation for up to 5 hours is possible with hypothermia and a Euro-Collins' flush and that extended preservation to 12 hours is possible with pharmacologic dosages of methylprednisolone.(ABSTRACT TRUNCATED AT 250 WORDS)


Cognitive-behavioral self-help for binge eating disorder: a controlled effectiveness study.
The aim of this study was to evaluate the effectiveness of 2 methods of administering a cognitive-behavioral self-help program for binge eating disorder. The study was designed to reproduce many of the conditions that apply in settings in which self-help interventions are most relevant. Seventy-two women with binge eating disorder were randomly assigned to 1 of 3 conditions for 12 weeks: pure self-help (PSH), guided self-help (GSH), or a waiting list (WL) control condition (followed by PSH or GSH). They were then followed up for 6 months. Both PSH and GSH had a substantial and sustained impact with almost half the participants ceasing to binge eat. There was little change in the WL condition. Cognitive-behavioral self-help may be of value both as an initial treatment for binge eating disorder and as a form of secondary prevention.


The Need and Importance of Incorporating Academic Research Results in to the Curricula of Ayurveda in India.
Every year a noticeable number of MD and PhD students pass out from various Ayurveda colleges across the country. Each of these Post Graduate (PG) and doctoral students do submit a research thesis as a part of fulfillment of their respective degrees. As on 01/04/2015 there were 98 PG Ayurveda colleges in India with an admission capacity of 2441 seats each year. Moreover many of the post graduate institutes provide doctoral level (PhD) education which is primarily involved with research thesis. Such meticulous research carried out under the supervision of an academic expert should not go in vein and hence the research findings need to be slotted in to the respective areas and disciplines of Ayurveda syllabus. This will help in bringing in the latest scientific trends of Ayurveda to graduate students. Distressingly such practices are not in vogue in Ayurveda education system and most of the colleges follow the same stereotypic pedagogy using the classical texts of Ayurveda or their respective commentaries written decades back. Use of classical treatises and their respective commentaries offers very limited access to the recent scientific developments of Ayurveda as these commentaries are mostly one time efforts and do not undergo repeated revisions thus limiting the inclusion of present day innovations. In this commentary an effort has been made to understand the source, output, need and importance of such academic research finding with reference to their incorporation in to curricula of Ayurveda.


Effect of time zone and game time changes on team performance: National Football League.
To determine the effect of time zone and game time changes on NFL team performance, win-loss records from 1978-1987 were analyzed. Twenty-seven NFL teams were grouped by time zone and possible anti-jet lag adjustments. Among all intra-time zone rivals, home teams won 56.6%, away teams won 43.8%, for a home vs away winning percentage change of -12.8% (P < 0.001). West teams (N = 5) displayed fluctuations in home vs away team performance in association with trans-meridian travel. The change in winning percentage was found to be 0.0% vs West teams, -14.1% vs Central teams (N = 8) (P < 0.05), -16.3% vs East (N = 14) (P < 0.05) for West teams (N = 4) flying about 42 h pregame and +2.3% vs East for the one West team advancing practices 3-4 h to match East coast game time in addition to 48 h pregame flights. For night games within the same time zone, home vs away team winning percentage changed -23.8% (P < 0.01). West teams displayed uniformly high home winning percentages (75.0% and 68.4%) when playing Central and East teams, respectively, with little or no fall in away winning percentages (67.7% and 68.8%). For day games, a 3-h phase advance may decrease West coast team performance. In one small subset, anti-jet lag adjustments appeared to eliminate the expected decrement in performance. For night games, West coast teams, whether home or away, appear to be at a distinct advantage over East and Central teams.


Expression of haematopoietic stem cell markers, CD133 and CD34 on human corneal keratocytes.
To study the expression of CD133 and CD34 antigens on cultured human keratocytes over time. Primary cultures of human corneal stromal cells were established from explants derived from cadaver eye donors. The cultures were sorted for CD133+ and CD34+ cells using magnetic beads. Both the primary cultures and secondary passages of sorted cells were further analysed by flow cytometry and western blot analysis for expression of the same antigens over time. Four different cell populations-namely, CD133+, CD133-, CD34+ and CD34-, were identified in the culture samples. Two further specific subgroups were identified by flow cytometry: CD133+/CD34- cells and CD133+/CD34+ cells. Expression of CD133 declines more than CD34 with time in cell cultures. Although most cells lost expression of these markers, small populations retained staining up to 5 weeks in culture. Human keratocytes express the haematopoietic stem cell markers CD133 and CD34. This expression decreases with time in culture, with most but not all cells losing expression. On the basis of these markers, the corneal stroma shows a heterogeneous population of cells. Expression or down regulation of expression of these molecules could represent different stages of activation of these cells.


Afterpulse-like phenomenon of superconducting single photon detector in high speed quantum key distribution system.
We discuss our estimates of the performance of a superconducting single photon detector (SSPD) in a high speed quantum key distribution (QKD) system. We find that at high repetition operation reflections from the readout circuit at room temperature causes an afterpulse-like phenomenon, and drastically increases the quantum bit error rate (QBER). Such effects are not seen during low frequency operation. By using an amplifier with a small reflection coefficient S11, we succeed in reducing the afterpulse-like phenomenon and increasing a secure key rate.


A Multiple Object Geometric Deformable Model for Image Segmentation.
Deformable models are widely used for image segmentation, most commonly to find single objects within an image. Although several methods have been proposed to segment multiple objects using deformable models, substantial limitations in their utility remain. This paper presents a multiple object segmentation method using a novel and efficient object representation for both two and three dimensions. The new framework guarantees object relationships and topology, prevents overlaps and gaps, enables boundary-specific speeds, and has a computationally efficient evolution scheme that is largely independent of the number of objects. Maintaining object relationships and straightforward use of object-specific and boundary-specific smoothing and advection forces enables the segmentation of objects with multiple compartments, a critical capability in the parcellation of organs in medical imaging. Comparing the new framework with previous approaches shows its superior performance and scalability.


'The man who believed he had AIDS was cured': AIDS and sexually-transmitted infection treatment-seeking behaviour in rural Mwanza, Tanzania.
Most people living with AIDS in sub-Saharan Africa have had neither a biomedical diagnosis nor antiretroviral medication, leading to the question of how individuals understand and treat AIDS. This study examined general illness, sexually-transmitted infection (STI) and AIDS treatment-seeking behaviour in rural Mwanza, Tanzania. From 1999-2002, participant observation was carried out in nine villages for a total of 158 person-weeks. Treatments were pluralistic and opportunistic, usually beginning with home remedies (western or traditional), followed by visits to traditional healers (THs) and/or health facilities (HFs). THs were sometimes preferred over HFs because of familiarity, trust, accessibility, expense, payment plans, and the perceived cause, nature and severity of the illness, e.g. only THs were believed to successfully treat bewitchment. Some people, particularly young girls, delayed or avoided seeking treatment for STIs for fear of stigma. Most STIs were attributed to natural causes, but AIDS was sometimes attributed to witchcraft. Locally available biomedical care of people with AIDS-like symptoms consisted of basic treatment of opportunistic infections. Most such individuals repeatedly visited THs and HFs, but many stopped attending HFs because they came to believe they could not be cured there. Some THs claimed to cure witchcraft-induced, AIDS-like illnesses. There is an urgent need for improved biomedical services, and TH interventions could be important in future HIV/AIDS education and care.


Block of human CaV3 channels by the diuretic amiloride.
Previous studies in native T-type currents have suggested the existence of distinct isoforms with dissimilar pharmacology. Amiloride was the first organic blocker to selectively block the native T-type calcium channel, but the potency and mechanism of block of this drug on the three recombinant T-type calcium channels (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3) have not been systematically determined. The aim of the present study was to investigate whether there is differential block of Ca(V)3 channels by amiloride, to establish the mechanism of block, and to obtain insights into the amiloride putative binding sites in Ca(V)3 channels. By performing whole-cell patch-clamp recordings of human embryonic kidney 293 cells stably expressing human Ca(V)3 channels, we found that amiloride blocked the human Ca(V)3 channels in a concentration-response manner; the IC₅₀ for Ca(V)3.2 channels (62 μM) was 13-fold lower than that for Ca(V)3.1 and Ca(V)3.3. Block is voltage-independent (except for Ca(V)3.3 channels) and targets mainly closed-state channels, although a small use-dependent component was observed in Ca(V)3.1 channels. In addition, amiloride block of Ca(V)3.2 channels is mainly due to an extracellular effect, whereas in Ca(V)3.1 and Ca(V)3.3 channels, the amiloride inhibition is equally effective from both sides of the membrane. The results demonstrate that amiloride blocks human Ca(V)3 channels differentially through a mechanism involving mainly the closed state of the channel and suggest a negative allosteric interaction with at least two putative binding sites with different affinities. The preferential block of Ca(V)3.2 channels labels amiloride as the only organic blocker to be selective for any T-type channel.


A free-response evaluation determining value in the computed tomography attenuation correction image for revealing pulmonary incidental findings: a phantom study.
The purpose of this study was to compare lesion-detection performance when interpreting computed tomography (CT) images that are acquired for attenuation correction when performing single photon emission computed tomography/computed tomography (SPECT/CT) myocardial perfusion studies. In the United Kingdom, there is a requirement that these images be interpreted; thus, it is necessary to understand observer performance on these images. An anthropomorphic chest phantom with inserted spherical lesions of different sizes and contrasts was scanned on five different SPECT/CT systems using site-specific CT protocols for SPECT/CT myocardial perfusion imaging. Twenty-one observers (0-4 years of CT experience) searched 26 image slices (17 abnormal, containing 1-3 lesions, and 9 normal, containing no lesions) for each CT acquisition. The observers marked and rated perceived lesions under the free-response paradigm. Four analyses were conducted using jackknife alternative free-response receiver operating characteristic (JAFROC) analysis: (1) 20-pixel acceptance radius (AR) with all 21 readers, abbreviated to 20/ALL analysis, (2) 40-pixel AR with 21 readers (40/ALL), (3) 20-pixel AR with 14 readers experienced in CT (20/EXP), and (4) 20-pixel AR with 7 readers with no CT experience (20/NOT). The significance level of the test was set so as to conservatively control the overall probability of a type I error to <0.05. The mean JAFROC figure of merit (FOM) for the five CT acquisitions for the 20/ALL study were 0.602, 0.639, 0.372, 0.475, and 0.719 with a significant difference in lesion-detection performance evident between all individual treatment pairs (P < .0001) with the exception of the 1-2 pairing, which was not significant (these differed only in milliamp seconds). System 5, which had the highest performance, had the smallest slice thickness and the largest matrix size. For the other analyses, the system orderings remained unchanged, and the significance of FOM difference findings remained identical to those for 20/ALL, with one exception: for 20/EXP analysis the 1-2 difference became significant with the higher milliamp seconds superior. Improved detection performance was associated with a smaller slice thickness, increased matrix size, and, to a lesser extent, increased tube charge. Protocol variations for CT-based attenuation correction (AC) in SPECT/CT imaging have a measurable impact on lesion-detection performance. The results imply that z-axis resolution and matrix size had the greatest impact on lesion detection, with a weaker but detectable dependence on the product of milliamp and seconds.


The Emerging Ecological and Biogeochemical Importance of Sponges on Coral Reefs.
With the decline of reef-building corals on tropical reefs, sponges have emerged as an important component of changing coral reef ecosystems. Seemingly simple, sponges are highly diverse taxonomically, morphologically, and in terms of their relationships with symbiotic microbes, and they are one of nature's richest sources of novel secondary metabolites. Unlike most other benthic organisms, sponges have the capacity to disrupt boundary flow as they pump large volumes of seawater into the water column. This seawater is chemically transformed as it passes through the sponge body as a consequence of sponge feeding, excretion, and the activities of microbial symbionts, with important effects on carbon and nutrient cycling and on the organisms in the water column and on the adjacent reef. In this review, we critically evaluate developments in the recently dynamic research area of sponge ecology on tropical reefs and provide a perspective for future studies.


Evidence of Polygenic Adaptation in the Systems Genetics of Anthropometric Traits.
Many signals of natural selection have been identified in the human genome. However, except for some single-locus mechanisms, most molecular processes generating these adaptation signals are still unknown. We developed an approach that integrates datasets related to genome-wide association studies (GWAS) with information about systems biology and genetic signatures of natural selection to identify evidence of polygenic adaptation. Specifically, we focused on five anthropometric measurements: body mass index (BMI), height, waist-to-hip ratio adjusted for BMI (WHR), and waist circumference adjusted for BMI (WC), and sex differences for WHR and WC. We performed an enrichment analysis for signals of natural selection in protein interaction networks associated with anthropometric traits in European populations. The adaptation signals-enriched gene networks associated highlighted epistatic interactions in the context of polygenic selection for the investigated traits. These polygenic mechanisms indicated intriguing selective mechanisms related to the anthropometric traits: adult locomotory behavior for BMI, infection resistance for height, interplay between lipid transport and immune systems for WHR, and female-specific polygenic adaptation for WHR and WC. In conclusion, we observed evidence of polygenic adaptation in the context of systems genetics of anthropometric traits that indicates polygenic mechanisms related to the natural selection in European populations.


Towards Environmental RF-EMF Assessment of mmWave High-Node Density Complex Heterogeneous Environments.
The densification of multiple wireless communication systems that coexist nowadays, as well as the 5G new generation cellular systems advent towards the millimeter wave (mmWave) frequency range, give rise to complex context-aware scenarios with high-node density heterogeneous networks. In this work, a radiofrequency electromagnetic field (RF-EMF) exposure assessment from an empirical and modeling approach for a large, complex indoor setting with high node density and traffic is presented. For that purpose, an intensive and comprehensive in-depth RF-EMF E-field characterization study is provided in a public library study case, considering dense personal mobile communications (5G FR2 @28 GHz) and wireless 802.11ay (@60 GHz) data access services on the mmWave frequency range. By means of an enhanced in-house deterministic 3D ray launching (3D-RL) simulation tool for RF-EMF exposure assessment, different complex heterogenous scenarios of high complexity are assessed in realistic operation conditions, considering different user distributions and densities. The use of directive antennas and MIMO beamforming techniques, as well as all the corresponding features in terms of radio wave propagation, such as the body shielding effect, dispersive material properties of obstacles, the impact of the distribution of scatterers and the associated electromagnetic propagation phenomena, are considered for simulation. Discussion regarding the contribution and impact of the coexistence of multiple heterogeneous networks and services is presented, verifying compliance with the current established international regulation limits with exposure levels far below the aforementioned limits. Finally, the proposed simulation technique is validated with a complete empirical campaign of measurements, showing good agreement. In consequence, the obtained datasets and simulation estimations, along with the proposed RF-EMF simulation tool, could be a reference approach for the design, deployment and exposure assessment of the current and future wireless communication technologies on the mmWave spectrum, where massive high-node density heterogeneous networks are expected.


Anterior optic pathway pathology in CNS demyelinating diseases.
The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.


A novel regulatory mechanism of naringenin through inhibition of T lymphocyte function in contact hypersensitivity suppression.
Naringenin, a flavonoid in grapefruits and citrus fruits, has been reported to exhibit anti-inflammatory and anti-oxidative activities. Contact hypersensitivity (CHS) is a T cell-mediated immune reaction, and the factors released from macrophages also contribute to this response. Previous studies showed that naringenin suppressed CHS by inhibiting activation and migration of macrophages. However, little is known about naringenin's effects on T lymphocytes. Our study indicated that naringenin potently suppressed picryl chloride (PCl)-induced contact hypersensitivity by inhibiting the proliferation and activation of T lymphocytes. In vitro, both of the activated hapten-specific T cells and the T cells stimulated with anti-CD3/anti-CD28 showed growth arrest after naringenin treatment. Furthermore, naringenin reduced CD69 (the protein level) and cytokines such as IL-2, TNF-alpha, and IFN-gamma (the mRNA level) expressions which highly expressed by activated T cells. Meanwhile, naringenin also induced T cell apoptosis by upregulation of Bax, Bad, PARP, cleaved-caspase 3 and downregulation of phosphorylated Akt, Bcl-2. These findings suggest that, besides its anti-inflammatory activities in macrophages, naringenin also showed inhibitory effects on the activation and proliferation of T cells to alleviate symptoms of contact hypersensitivity.


High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine.
We determined the effect of coingestion of caffeine (Caff) with carbohydrate (CHO) on rates of muscle glycogen resynthesis during recovery from exhaustive exercise in seven trained subjects who completed two experimental trials in a randomized, double-blind crossover design. The evening before an experiment subjects performed intermittent exhaustive cycling and then consumed a low-CHO meal. The next morning subjects rode until volitional fatigue. On completion of this ride subjects consumed either CHO [4 g/kg body mass (BM)] or the same amount of CHO + Caff (8 mg/kg BM) during 4 h of passive recovery. Muscle biopsies and blood samples were taken at regular intervals throughout recovery. Muscle glycogen levels were similar at exhaustion [ approximately 75 mmol/kg dry wt (dw)] and increased by a similar amount ( approximately 80%) after 1 h of recovery (133 +/- 37.8 vs. 149 +/- 48 mmol/kg dw for CHO and Caff, respectively). After 4 h of recovery Caff resulted in higher glycogen accumulation (313 +/- 69 vs. 234 +/- 50 mmol/kg dw, P < 0.001). Accordingly, the overall rate of resynthesis for the 4-h recovery period was 66% higher in Caff compared with CHO (57.7 +/- 18.5 vs. 38.0 +/- 7.7 mmol x kg dw(-1) x h(-1), P < 0.05). After 1 h of recovery plasma Caff levels had increased to 31 +/- 11 microM (P < 0.001) and at the end of the recovery reached 77 +/- 11 microM (P < 0.001) with Caff. Phosphorylation of CaMK(Thr286) was similar after exercise and after 1 h of recovery, but after 4 h CaMK(Thr286) phosphorylation was higher in Caff than CHO (P < 0.05). Phosphorylation of AMP-activated protein kinase (AMPK)(Thr172) and Akt(Ser473) was similar for both treatments at all time points. We provide the first evidence that in trained subjects coingestion of large amounts of Caff (8 mg/kg BM) with CHO has an additive effect on rates of postexercise muscle glycogen accumulation compared with consumption of CHO alone.


Genetic patterns in European geometrid moths revealed by the Barcode Index Number (BIN) system.
The geometrid moths of Europe are one of the best investigated insect groups in traditional taxonomy making them an ideal model group to test the accuracy of the Barcode Index Number (BIN) system of BOLD (Barcode of Life Datasystems), a method that supports automated, rapid species delineation and identification. This study provides a DNA barcode library for 219 of the 249 European geometrid moth species (88%) in five selected subfamilies. The data set includes COI sequences for 2130 specimens. Most species (93%) were found to possess diagnostic barcode sequences at the European level while only three species pairs (3%) were genetically indistinguishable in areas of sympatry. As a consequence, 97% of the European species we examined were unequivocally discriminated by barcodes within their natural areas of distribution. We found a 1:1 correspondence between BINs and traditionally recognized species for 67% of these species. Another 17% of the species (15 pairs, three triads) shared BINs, while specimens from the remaining species (18%) were divided among two or more BINs. Five of these species are mixtures, both sharing and splitting BINs. For 82% of the species with two or more BINs, the genetic splits involved allopatric populations, many of which have previously been hypothesized to represent distinct species or subspecies. This study confirms the effectiveness of DNA barcoding as a tool for species identification and illustrates the potential of the BIN system to characterize formal genetic units independently of an existing classification. This suggests the system can be used to efficiently assess the biodiversity of large, poorly known assemblages of organisms. For the moths examined in this study, cases of discordance between traditionally recognized species and BINs arose from several causes including overlooked species, synonymy, and cases where DNA barcodes revealed regional variation of uncertain taxonomic significance.


GWAS of epigenetic aging rates in blood reveals a critical role for TERT.
DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.


Induction of Terpenoid Synthesis in Cotton Roots and Control of Rhizoctonia solani by Seed Treatment with Trichoderma virens.
ABSTRACT Research on the mechanisms employed by the biocontrol agent Trichoderma virens to suppress cotton (Gossypium hirsutum) seedling disease incited by Rhizoctonia solani has shown that mycoparasitism and antibiotic production are not major contributors to successful biological control. In this study, we examined the possibility that seed treatment with T. virens stimulates defense responses, as indicated by the synthesis of terpenoids in cotton roots. We also examined the role of these terpenoid compounds in disease control. Analysis of extracts of cotton roots and hypocotyls grown from T. virens-treated seed showed that terpenoid synthesis and peroxidase activity were increased in the roots of treated plants, but not in the hypocotyls of these plants or in the untreated controls. Bioassay of the terpenoids for toxicity to R. solani showed that the pathway intermediates desoxyhemigossypol (dHG) and hemigossypol (HG) were strongly inhibitory to the pathogen, while the final product gossypol (G) was toxic only at a much higher concentration. Strains of T. virens and T. koningii were much more resistant to HG than was R. solani, and they thoroughly colonized the cotton roots. A comparison of biocontrol efficacy and induction of terpenoid synthesis in cotton roots by strains of T. virens, T. koningii, T. harzianum, and protoplast fusants indicated that there was a strong correlation (+0.89) between these two phenomena. It, therefore, appears that induction of defense response, particularly terpenoid synthesis, in cotton roots by T. virens may be an important mechanism in the biological control by this fungus of R. solani-incited cotton seedling disease.


11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.
Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11β-HSD1 null background. 11β-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11β-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-α (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-α, and interferon-γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11β-11β-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11β-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-α-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Adequacy of prescribing nasal continuous positive airway pressure therapy for the sleep apnoea/hypopnoea syndrome on the basis of night time respiratory recording variables.
The increased demand of full polysomnographic studies, not only for diagnostic purposes but also for continuous positive airway pressure (CPAP) titration, has produced long waiting lists. Simpler methods are therefore needed to avoid having to refer all patients for full polysomnography. The hypothesis that CPAP therapy for the sleep apnoea/hypopnoea syndrome (SAHS) can be performed exclusively on the basis of recording night time respiratory variables was tested. The level of CPAP in a group of 41 patients (three women) of mean (SD) age 52 (10) years, body mass index 31.5 (4.4) kg/m2, and apnoea/hypopnoea index (AHI) 53(16) events/hour was measured. During a two week period CPAP titration was performed in a random order in two settings: (1) in the sleep laboratory using full polysomnography; and (2) in the respiratory ward using equipment which continuously recorded and displayed pulse oximetry, airflow, chest and abdominal motion, and body position. The level of CPAP was increased progressively until apnoea, hypopnoea, snoring, and thoraco-abdominal paradox disappeared. No differences in CPAP levels (9.34(2.2) versus 9.68 (2.1) cm H2O) were found between full polysomnography and night time respiratory recordings. The accuracy of the measurement of both procedures showed good agreement. Only one patient showed a significant difference in CPAP level requirements between the two methods. Night time respiratory recording is sufficient to permit a reasonable choice of CPAP levels to abolish all the respiratory disturbances in most of the patients studied.


Duodenal perfusion with sodium taurocholate inhibits biliary but not pancreatic secretion in man.
1. A standard duodenal perfusion technique was used to study the effects of luminally perfused sodium taurocholate on basal and stimulated biliary and pancreatic secretion and gastrointestinal hormone release in man. 2. During duodenal perfusion with sodium taurocholate alone, both basal and caerulein/secretin-stimulated bilirubin secretion were suppressed. A successive perfusion with a mixture of the bile salt and essential amino acids in combination overcame the biliary suppression and biliary secretion rose above basal levels. A further increase in bilirubin secretion was not observed in a subsequent perfusion with essential amino acids alone in these studies. 3. No inhibitory effect on basal or caerulein/secretin-stimulated trypsin secretion was observed during the bile salt perfusion; basal trypsin secretion was in fact slightly increased during a prolonged (4 h) perfusion of the bile salt. 4. During bile salt perfusion, basal bicarbonate secretion remained unchanged but caerulein/secretin-stimulated bicarbonate secretion was slightly increased. 5. Plasma levels of pancreatic polypeptide, gastric inhibitory peptide and gastrin did not change significantly during duodenal perfusion with bile salt, but plasma levels of motilin were suppressed. 6. These results support the view that bile salts in the duodenum may regulate biliary and pancreatic secretion in man and affect plasma levels of motilin.


Cancer survival in Kampala, Uganda.
Epidemiological data on the occurrence of cancer in sub-Saharan Africa are sparse, and population-based cancer survival data are even more difficult to obtain due to various logistic difficulties. The population-based Cancer Registry of Kampala, Uganda, has followed up the vital status of all registered cancer patients with one of the 14 most common forms of cancer, who were diagnosed and registered between 1993 and 1997 in the study area. We report 5-year absolute and relative survival estimates of the Ugandan patients and compare them with those of black American patients diagnosed in the same years and included in the SEER Program of the United States. In general, the prognosis of cancer patients in Uganda was very poor. Differences in survival between the two patient populations were particularly dramatic for those cancer types for which early diagnosis and effective treatment is possible. For example, 5-year relative survival was as low as 8.3% for colorectal cancer and 17.7% for cervical cancer in Uganda, compared with 54.2 and 63.9%, respectively, for black American patients. The collection of good-quality follow-up data was possible in the African environment. The very poor prognosis of Ugandan patients is most likely explained by the lack of access to early diagnosis and treatment options in the country. On the policy level, the results underscore the importance of the consistent application of the national cancer control programme guidelines as outlined by the World Health Organization.


Human resources for emergency obstetric care in northern Tanzania: distribution of quantity or quality?
Health care agencies report that the major limiting factor for implementing effective health policies and reforms worldwide is a lack of qualified human resources. Although many agencies have adopted policy development and clinical practice guidelines, the human resources necessary to carry out these policies towards actual reform are not yet in place. The goal of this article is to evaluate the current status of human resources quality, availability and distribution in Northern Tanzania in order to provide emergency obstetric care services to specific districts in this area. The article also discusses the usefulness of distribution indicators for describing equity in the decision-making process. We conducted a quantitative facility survey in six districts of Northern Tanzania. We collected data from all 129 facilities that provide delivery services in the study area. The data includes information on the emergency obstetric care indicators, as described by the WHO/UNICEF/UFPA guidelines for monitoring the provision of obstetric care. The inventory also includes information on the numbers of qualified health personnel at the basic and comprehensive emergency obstetric care level. We analysed the distribution and workload of the available human resources in a wider policy context with a particular focus on equity, use and quality, by means of descriptive statistics and the Spearman's correlation test. We determined that there are adequate human resources allocated for health care provision in Tanzania, according to national standards. Compared to similar countries however, Tanzania has a very low availability of health care staff. Most qualified staff are concentrated in a few centralized locations, while those remaining are inequitably and inefficiently distributed in rural areas and lower-level services. Rural districts have restricted access to government-run health care, because these facilities are understaffed. In fact, voluntary agency facilities in these districts have more staff than the government facilities. There is a statistical correlation between availability of qualified human resources and use of services, but the availability of qualified human resources does not automatically translate into higher availability of qualified emergency obstetric care services. National guidelines for human resources for health care in Tanzania require focused revisions in order to reflect the quality indicators more adequately when monitoring and setting criteria for HR distribution. Availability of qualified personnel as well as institutional management and capacity determine the quality of emergency obstetric care services and personnel. The current wide distribution of staff of inadequate quality should be reconsidered. The use of distribution indicators alone is not useful to properly monitor equity. This article suggests increasing access to high-quality health care instead of distributing low-quality services widely.


Propagation of an Airy beam through the atmosphere.
In this paper, the effect of thermal blooming of an Airy beam propagating through the atmosphere is examined, and the effect of atmospheric turbulence is not considered. The changes of the intensity distribution, the centroid position and the mean-squared beam width of an Airy beam propagating through the atmosphere are studied by using the four-dimensional (4D) computer code of the time-dependent propagation of Airy beams through the atmosphere. It is shown that an Airy beam can't retain its shape and the structure when the Airy beam propagates through the atmosphere due to thermal blooming except for the short propagation distance, or the short time, or the low beam power. The thermal blooming results in a central dip of the center lobe, and causes the center lobe to spread and decrease. In contrast with the center lobe, the side lobes are less affected by thermal blooming, such that the intensity maximum of the side lobe may be larger than that of the center lobe. However, the cross wind can reduce the effect of thermal blooming. When there exists the cross wind velocity vx in x direction, the dependence of centroid position in x direction on vx is not monotonic, and there exists a minimum, but the centroid position in y direction is nearly independent of vx.


Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress.
Research interest has grown around the potential therapeutic use of cannabidiol in mood-related disorders, due to its anxiolytic and antidepressant-like effects. These have been partially attributed to its action as an allosteric modulator of 5-HTR1A. However, the exact mechanism supporting cannabidiol properties remains unclear. To assess the effects of cannabidiol on different targets of the hypothalamus-pituitary-adrenal axis under baseline and stress conditions. We administered cannabidiol (5 mg/kg, 15 mg/kg or 30 mg/kg, intraperitoneally) or vehicle to male C57BL/6J mice 90 min before single restraint stress exposure (20 min). Using real-time polymerase chain reaction analysis, we measured alterations in the relative gene expression of corticotropin-releasing factor in the paraventricular nucleus, pro-opiomelanocortin in the arcuate nucleus of the hypothalamus, glucocorticoid receptor in the hippocampus, and serotonin 5-HTR1A receptor in the hippocampus and amygdala. Under baseline conditions, cannabidiol did not modify any element of the hypothalamus-pituitary-adrenal axis. In contrast, all doses induced alterations in 5-HTR1A in the amygdala and hippocampus. Interestingly, cannabidiol at low (5 mg/kg) and intermediate doses (15 mg/kg) successfully blocked the effects induced by acute stress on corticotropin-releasing factor, pro-opiomelanocortin and glucocorticoid receptor gene expression. Also, restraint stress induced the opposite effects in 5-HTR1A gene expression in the hippocampus and amygdala, an effect not seen in mice treated with cannabidiol at low doses. Taken together, these data suggest the ability of cannabidiol to regulate acute stress hypothalamus-pituitary-adrenal axis activation might be explained, at least in part, by its action on 5-HTR1A receptors.


Social desirability bias in sexual behavior reporting: evidence from an interview mode experiment in rural Malawi.
Social desirability bias is problematic in studies that rely on self-reported sexual behavior data. Where gender norms create different expectations about socially acceptable behavior, males and females face distinct pressures in reporting certain outcomes, which can distort assessments of risk for HIV and STIs. In 2009, relationship and sexual behavior data were collected from 1,750 never-married males and females aged 16-18 via audio computer-assisted self-interviewing (audio-CASI) during the third round of the Malawi Schooling and Adolescent Study. A comparison group of 311 youth completed an identical questionnaire in face-to-face interviews. To assess whether interview mode may have influenced participants' reporting of sensitive behavior, reports of sexual experience in the two groups were compared. Multiple logistic regression analysis was used to identify associations between interview mode and reports of these behaviors, by gender. In adjusted regression models, males were less likely to report ever having had a girlfriend in audio-CASI than in face-to-face interviews (odds ratio, 0.4), but they were more likely to report having had sex with a relative or teacher (3.5). For females, reports of ever having had a boyfriend or having had sex did not differ between modes. A small proportion of females reported ever having had sex with a relative or teacher in audio-CASI, while none did so in face-to-face interviews. The method used for collecting relationship and sexual behavior data may influence the reported prevalence of some key behaviors, particularly among males. Further research is needed to improve methods of collecting sensitive data.


Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism.
UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens. The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism. Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney. A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2Δexon3) was investigated, with UGT2A2Δexon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined. UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx. Cell homogenates prepared from human embryonic kidney (HEK)293 cells overexpressing wild-type UGT2A2 (termed UGT2A2_i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy-(OH)-pyrene, 1-naphthol, and hydroxylated benzo(a)pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol. Activity assays showed the UGT2A2Δexon3 protein (termed UGT2A2_i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2_i2 negatively modulates UGT2A2_i1 activity. Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines. These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites.


NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.
Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr-/- mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.


Evidence for miRNA-mediated modulation of the host transcriptome in cnidarian-dinoflagellate symbiosis.
Reef-building corals and other cnidarians living in symbiotic relationships with intracellular, photosynthetic dinoflagellates in the genus Symbiodinium undergo transcriptomic changes during infection with the algae and maintenance of the endosymbiont population. However, the precise regulatory mechanisms modulating the host transcriptome are unknown. Here, we report apparent post-transcriptional gene regulation by miRNAs in the sea anemone Aiptasia, a model system for cnidarian-dinoflagellate endosymbiosis. Aiptasia encodes mainly species-specific miRNAs, and there appears to have been recent differentiation within the Aiptasia genome of miRNAs that are commonly conserved among anthozoan cnidarians. Analysis of miRNA expression showed that both conserved and species-specific miRNAs are differentially expressed in response to endosymbiont infection. Using cross-linking immunoprecipitation of Argonaute, the central protein of the miRNA-induced silencing complex, we identified miRNA binding sites on a transcriptome-wide scale and found that the targets of the miRNAs regulated in response to symbiosis include genes previously implicated in biological processes related to Symbiodinium infection. Our study shows that cnidarian miRNAs recognize their mRNA targets via high-complementarity target binding and suggests that miRNA-mediated modulations of genes and pathways are important during the onset and maintenance of cnidarian-dinoflagellate endosymbiosis.


A conserved truncated isoform of the ATR-X syndrome protein lacking the SWI/SNF-homology domain.
Mutations in the ATRX gene cause a severe X-linked mental retardation syndrome that is frequently associated with alpha thalassemia (ATR-X syndrome). The previously characterized ATRX protein (approximately 280 kDa) contains both a Plant homeodomain (PHD)-like zinc finger motif as well as an ATPase domain of the SNF2 family. These motifs suggest that ATRX may function as a regulator of gene expression, probably by exerting an effect on chromatin structure, although the exact cellular role of ATRX has not yet been fully elucidated. Here we characterize a truncated (approximately 200 kDa) isoform of ATRX (called here ATRXt) that has been highly conserved between mouse and human. In both species, ATRXt arises due to the failure to splice intron 11 from the primary transcript, and the use of a proximal intronic poly(A) signal. We show that the relative expression of the full length and ATRXt isoforms is subject to tissue-specific regulation. The ATRXt isoform contains the PHD-like domain but not the SWI/SNF-like motifs and is therefore unlikely to be functionally equivalent to the full length protein. We used indirect immunofluorescence to demonstrate that the full length and ATRXt isoforms are colocalized at blocks of pericentromeric heterochromatin but unlike full length ATRX, the truncated isoform does not associate with promyelocytic leukemia (PML) nuclear bodies. The high degree of conservation of ATRXt and the tight regulation of its expression relative to the full length protein suggest that this truncated isoform fulfills an important biological function.


John Burns Brooksby CBE: 25 December 1914 - 17 December 1998.
John Brooksby was an outstanding veterinary virologist, who worked at the Animal Virus Disease Research Institute, Pirbright, for 40 years, for 16 of which he was Director of the Institute. He will be remembered for his contributions to the diagnosis of foot-and-mouth disease, for his discovery of four new types, for the classification of subtypes and for fundamental studies of the virus. As Deputy Director and Director he was responsible for programmes on fundamental investigations of foot-and-mouth disease virus and other viruses exotic to the UK and for the application of the results both in the UK and worldwide. His advice on the distribution and the control of foot-and-mouth disease was sought by international organizations and by individual countries and was responsible for reducing the risk of spread of disease.


Allelotype of colorectal carcinomas.
To examine the extent and variation of allelic loss in a common adult tumor, polymorphic DNA markers were studied from every nonacrocentric autosomal arm in 56 paired colorectal carcinoma and adjacent normal colonic mucosa specimens. This analysis was termed an allelotype, in analogy with a karyotype. Three major conclusions were drawn from this analysis: (i) Allelic deletions were remarkably common; one of the alleles of each polymorphic marker tested was lost in at least some tumors, and some tumors lost more than half of their parental alleles. (ii) In addition to allelic deletions, new DNA fragments not present in normal tissue were identified in five carcinomas; these new fragments contained repeated sequences of the variable number of tandem repeat type. (iii) Patients with more than the median percentage of allelic deletions had a considerably worse prognosis than did the other patients, although the size and stage of the primary tumors were very similar in the two groups. In addition to its implications concerning the genetic events underlying tumorigenesis, tumor allelotype may provide a molecular tool for improved estimation of prognosis in patients with colorectal cancer.


Anti-hepatitis C virus T-cell immunity in the context of multiple exposures to the virus.
Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype-specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T-cell targets, and their adapted form, were used in individualised IFN-γ ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV-seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV-infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design.


Functional anatomy of the Achilles tendon.
The Achilles tendon is the strongest and thickest tendon in the human body. It is also the commonest tendon to rupture. It begins near the middle of the calf and is the conjoint tendon of the gastrocnemius and soleus muscles. The relative contribution of the two muscles to the tendon varies. Spiralisation of the fibres of the tendon produces an area of concentrated stress and confers a mechanical advantage. The calcaneal insertion is specialised and designed to aid the dissipation of stress from the tendon to the calcaneum. The insertion is crescent shaped and has significant medial and lateral projections. The blood supply of the tendon is from the musculotendinous junction, vessels in surrounding connective tissue and the osteotendinous junction. The vascular territories can be classified simply in three, with the midsection supplied by the peroneal artery, and the proximal and distal sections supplied by the posterior tibial artery. This leaves a relatively hypovascular area in the mid-portion of the tendon where most problems occur. The Achilles tendon derives its innervation from the sural nerve with a smaller supply from the tibial nerve. Tenocytes produce type I collagen and form 90% of the cellular component of the normal tendon. Evidence suggests ruptured or pathological tendon produce more type III collagen, which may affect the tensile strength of the tendon. Direct measurements of forces reveal loading in the Achilles tendon as high as 9 KN during running, which is up to 12.5 times body weight.


The experience of emotional wellbeing for patients with physical injury: A qualitative follow-up study.
Traumatic physical injury is abrupt, painful, debilitating, costly and life-altering. The experience of emotional wellbeing following traumatic physical injury has not been well investigated, and the role of health services and how services can support the emotional recovery of injured patients has not been well understood. This has impacted on care provision and contributed to a lack of evidence-informed guidance for clinicians to support patients' emotional wellbeing. To explore the patient experience of emotional wellbeing following injury and to understand how injured patients manage their emotional wellbeing. The study comprises the follow-up qualitative phase of a mixed-methods explanatory sequential study. Semi-structured interviews were conducted with a purposive sample of 14 participants admitted to hospital following physical injury. Participants were purposely selected where they had reported high levels of depression, anxiety and stress on the DASS-21 at 3 and 6-months after injury. The qualitative data were analysed using thematic analysis. Three main themes were identified: experiencing the many impacts of injury; facing the emotional journey following injury; and being supported and managing the impacts of injury. Key findings were the extreme negative emotional responses experienced many months after the injury; a strong physical link between the emotional and physical aspects of health; participant reluctance to seek emotional support; a lack of emotional support provision by the health service and a subsequent need for individual and group support in order to develop resilience in the injured person. Finally, male participants who reported extreme emotional responses after injury, including suicidality, were less likely to seek help for their symptoms. Injured patients can experience substantial negative emotional responses following injury. The lack of support provided by health services to injured patients identified highlights the importance of in-hospital screening for emotional wellbeing and follow-up post-discharge, and a support network for patients to reduce the negative impacts of injury on their mental health. There is a need for anticipatory guidance frameworks for clinicians.


Impact of chromosome 14q loss on survival in primary head and neck squamous cell carcinoma.
We screened 73 primary head and neck squamous cell carcinoma (HNSCC) specimens for loss of heterozygosity (LOH) on chromosome 14q. Analysis of 20 polymorphic microsatellite markers identified 29 (40%) HNSCCs exhibiting LOH of 14q in at least one locus. Six tumors had probable monosomy of 14q, displaying allelic loss for all informative markers tested, and 23 demonstrated partial losses on 14q. Fine mapping with 1-10 additional markers revealed two poorly defined regions of loss (4-7 cM) at 14q13-21 and 14q31-32.1 in seven tumors. In 53 patients with previously untreated tumors treated with curative intent, LOH of 14q in these tumors correlated with poor survival. Compared to patients with tumors that retain heterozygosity of 14q, those with 14q LOH had a 3-fold increased risk of death in multivariate analysis (hazards ratio, 3.2; 95% confidence interval = 1.2-8.4). These data have confirmed a high frequency of chromosome 14q loss in HNSCC and suggest that LOH of any region on chromosome 14q is an indicator of poor outcome.


Aptamer Efficacies for In Vitro and In Vivo Modulation of αC-Conotoxin PrXA Pharmacology.
The medical staff is often powerless to treat patients affected by drug abuse or misuse and poisoning. In the case of envenomation, the treatment of choice remains horse sera administration that poses a wealth of other medical conditions and threats. Previously, we have demonstrated that DNA-based aptamers represent powerful neutralizing tools for lethal animal toxins of venomous origin. Herein, we further pursued our investigations in order to understand whether all toxin-interacting aptamers possessed equivalent potencies to neutralize αC-conotoxin PrXA in vitro and in vivo. We confirmed the high lethality in mice produced by αC-conotoxin PrXA regardless of the mode of injection and further characterized myoclonus produced by the toxin. We used high-throughput patch-clamp technology to assess the effect of αC-conotoxin PrXA on ACh-mediated responses in TE671 cells, responses that are carried by muscle-type nicotinic receptors. We show that 2 out of 4 aptamers reduce the affinity of the toxin for its receptor, most likely by interfering with the pharmacophore. In vivo, more complex responses on myoclonus and mice lethality are observed depending on the type of aptamer and mode of administration (concomitant or differed). Concomitant administration always works better than differed administration indicating the stability of the complex in vivo. The most remarkable conclusion is that an aptamer that has no or a limited efficacy in vitro may nevertheless be functional in vivo probably owing to an impact on the biodistribution or pharmacokinetics of the toxin in vivo. Overall, the results highlight that a blind selection of aptamers against toxins leads to efficient neutralizing compounds in vivo regardless of the mode of action. This opens the door to the use of aptamer mixtures as substitutes to horse sera for the neutralization of life-threatening animal venoms, an important WHO concern in tropical areas.


The brief psychiatric rating scale: effect of scaling system on clinical response assessment.
The Brief Psychiatric Rating Scale (BPRS) is an 18-item rating scale frequently used to assess change in psychopathology in schizophrenic patients in antipsychotic drug trials. BPRS items may be rated by the use of either a 1 to 7 or 0 to 6 scaling system, with the 1 or 0 rating indicating no pathology, respectively. When percent change in BPRS total score is used as an index of change, measurement considerations indicate that the 0 to 6 scaling system is preferable. Furthermore, when the 1 to 7 scaling system is used, patients whose initial BPRS values fall at the lower end of the range are classified as responders at a lower rate than are patients with higher initial scores. The adoption of the 0 to 6 scaling system for the BPRS and other rating scales, such as the Positive and Negative Syndrome Scale, is advocated.


Absorption microscopy of enzymatically treated cell-free chloroplasts.
Monochromatic light microscopy at 435 mmicro shows in Euglena gracilis, the distribution of chlorophyll and the general orientation and geometry of chloroplasts in vivo. In addition it discloses, in swelling chloroplasts, a lamellar pigmented structure. Changes in this structure are observed in extruded swollen chloroplasts treated with lipolytic or proteolytic enzymes. Lipolytic enzymes produce an increase in the number of visible lamellae while proteolytic enzymes disrupt the lamellar array. Correlation of chloroplast swelling behavior and the effects of enzymatic degradation with current electron microscope observations support the following: (1) the pigment lamellae observed in vivo consist of component laminae; (2) the lamellae are separated by sites of swelling; and (3) the integrity of the lamellar structure is primarily dependent upon the intact state of the protein.


Hepatoprotective effect of chrysin on prooxidant-antioxidant status during ethanol-induced toxicity in female albino rats.
To evaluate the effect of chrysin, a natural, biologically active compound extracted from many plants, honey and propolis, on the tissue and circulatory antioxidant status, and lipid peroxidation in ethanol-induced hepatotoxicity in rats. Rats were divided into four groups. Groups 1 and 2 received isocaloric glucose. Groups 3 and 4 received 20% ethanol, equivalent to 5 g/kg bodyweight every day. Groups 2 and 4 received chrysin (20 mg/kg bodyweight) dissolved in 0.5% dimethylsulfoxide. The results showed significantly elevated levels of tissue and circulatory thiobarbituric acid reactive substances, conjugated dienes and lipid hydroperoxides, and significantly lowered enzymic and non-enzymic antioxidant activity of superoxide dismutase, catalase and glutathione-related enzymes such as glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in ethanol-treated rats compared with the control. Chrysin administration to rats with ethanol-induced liver injury significantly decreased the levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, and significantly elevated the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and the levels of reduced glutathione, vitamin C and vitamin E in the tissues and circulation compared with those of the unsupplemented ethanol-treated rats. The histological changes observed in the liver and kidney correlated with the biochemical findings. Chrysin offers protection against free radical-mediated oxidative stress in rats with ethanol-induced liver injury.


Late Post-Conditioning with Sevoflurane after Cardiac Surgery--Are Surrogate Markers Associated with Clinical Outcome?
In a recent randomized controlled trial our group has demonstrated in 102 patients that late post-conditioning with sevoflurane performed in the intensive care unit after surgery involving extracorporeal circulation reduced damage to cardiomyocytes exposed to ischemia reperfusion injury. On the first post-operative day the sevoflurane patients presented with lower troponin T values when compared with those undergoing propofol sedation. In order to assess possible clinical relevant long-term implications in patients enrolled in this study, we performed the current retrospective analysis focusing on cardiac and non-cardiac events during the first 6 months after surgery. All patients who had successfully completed the late post-conditioning trial were included into this follow-up. Our primary and secondary endpoints were the proportion of patients experiencing cardiac and non-cardiac events, respectively. Additionally, we were interested in assessing therapeutic interventions such as initiation or change of drug therapy, interventional treatment or surgery. Of 102 patients analyzed in the primary study 94 could be included in this follow-up. In the sevoflurane group (with 41 patients) 16 (39%) experienced one or several cardiac events within 6 months after cardiac surgery, in the propofol group (with 53 patients) 19 (36%, p=0.75). Four patients (9%) with sevoflurane vs. 7 (13%) with propofol sedation had non-cardiac events (p=0.61). While a similar percentage of patients suffered from cardiac and/or non-cardiac events, only 12 patients in the sevoflurane group compared to 20 propofol patients needed a therapeutic intervention (OR: 0.24, 95% CI: 0.04-1.43, p=0.12). A similar result was found for hospital admissions: 2 patients in the sevoflurane group had to be re-admitted to the hospital compared to 8 in the propofol group (OR 0.23, 95% CI: 0.04-1.29, p=0.10). Sevoflurane does not seem to provide protection with regard to the occurrence of cardiac and non-cardiac events in the 6-month period following cardiac surgery with the use of extracorporeal circulation. However, there was a clear trend towards fewer interventions (less need for treatment, fewer hospital admissions) associated with sevoflurane post-conditioning in patients experiencing any event. Such results might encourage launching large multicenter post-conditioning trials with clinical outcome defined as primary endpoint.


Established donepezil treatment modulates task relevant regional brain activation in early Alzheimer's disease.
Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.


Bystander resuscitation attempts at heroin overdose: does it improve outcomes?
To document the characteristics and effectiveness of cardiopulmonary resuscitation (CPR) at non-fatal heroin overdose events in Melbourne, Australia. A retrospective analysis of a computerised database of ambulance attendance records at non-fatal heroin overdose cases for the period 1/12/1998 to 31/7/2000 was undertaken. The main outcome measure was the rate of patient hospitalisation. The rate of CPR administration at heroin overdose cases was also examined, along with characteristics of the attendance, such as the age and sex of the overdose case, the relationship of person providing CPR to the overdose case as well as the location, time and date of the event. CPR was administered prior to ambulance arrival in 579 heroin overdose cases (9.4% of total heroin overdose cases attended) between 1/12/98 and 31/7/2000. A greater proportion of female overdose cases were administered CPR than males and CPR administrations were evenly distributed across attendances occurring in private and public locations. Bystander administration of CPR prior to ambulance attendance resulted in a significantly lower rate of heroin user hospitalisation (14.5%) compared to cases where bystander CPR was not administered (18.8%). While CPR administration prior to ambulance attendance at heroin overdose events is relatively uncommon (especially compared to out-of-hospital cardiac arrest), such administration was associated with a statistically significant improvement in clinical outcomes in cases of non-fatal heroin overdose. These findings suggest that the provision of CPR training to people likely to come into contact with heroin overdose events may be an effective strategy at minimising consequent overdose-related harm.


Conserved and nonconserved residues in the substrate binding site of 7,8-diaminopelargonic acid synthase from Escherichia coli are essential for catalysis.
The vitamin B(6)-dependent enzyme 7,8-diaminopelargonic acid (DAPA) synthase catalyzes the antepenultimate step in the synthesis of biotin, the transfer of the alpha-amino group of S-adenosyl-l-methionine (SAM) to 7-keto-8-aminopelargonic acid (KAPA) to form DAPA. The Y17F, Y144F, and D147N mutations in the active site were constructed independently. The k(max)/K(m)(app) values for the half-reaction with DAPA of the Y17F and Y144F mutants are reduced by 1300- and 2900-fold, respectively, compared to the WT enzyme. Crystallographic analyses of these mutants do not show significant changes in the structure of the active site. The kinetic deficiencies, together with a structural model of the enzyme-PLP/DAPA Michaelis complex, point to a role of these two residues in recognition of the DAPA/KAPA substrates and in catalysis. The k(max)/K(m)(app) values for the half-reaction with SAM are similar to that of the WT enzyme, showing that the two tyrosine residues are not involved in this half-reaction. Mutations of the conserved Arg253 uniquely affect the SAM kinetics, thus establishing this position as part of the SAM binding site. The D147N mutant is catalytically inactive in both half-reactions. The structure of this mutant exhibits significant changes in the active site, indicating that this residue plays an important structural role. Of the four residues examined, only Tyr144 and Arg253 are strictly conserved in the available amino acid sequences of DAPA synthases. This enzyme thus provides an illustrative example that active site residues essential for catalysis are not necessarily conserved, i.e., that during evolution alternative solutions for efficient catalysis by the same enzyme arose. Decarboxylated SAM [S-adenosyl-(5')-3-methylthiopropylamine] reacts nearly as well as SAM and cannot be eliminated as a putative in vivo amino donor.


Use of U.S. croplands for biofuels increases greenhouse gases through emissions from land-use change.
Most prior studies have found that substituting biofuels for gasoline will reduce greenhouse gases because biofuels sequester carbon through the growth of the feedstock. These analyses have failed to count the carbon emissions that occur as farmers worldwide respond to higher prices and convert forest and grassland to new cropland to replace the grain (or cropland) diverted to biofuels. By using a worldwide agricultural model to estimate emissions from land-use change, we found that corn-based ethanol, instead of producing a 20% savings, nearly doubles greenhouse emissions over 30 years and increases greenhouse gases for 167 years. Biofuels from switchgrass, if grown on U.S. corn lands, increase emissions by 50%. This result raises concerns about large biofuel mandates and highlights the value of using waste products.


Triptolide induces s phase arrest and apoptosis in gallbladder cancer cells.
Gallbladder carcinoma is the most common malignancy of the biliary tract, with a very low 5-year survival rate and extremely poor prognosis. Thus, new effective treatments and drugs are urgently needed for the treatment of this malignancy. In this study, for the first time we investigated the effects of triptolide on gallbladder cancer cells and identified the mechanisms underlying its potential anticancer effects. The MTT assay showed that triptolide decreased cell viability in a dose- and time-dependent manner. The results of the colony formation assay indicated that triptolide strongly suppressed colony formation ability in GBC-SD and SGC-996 cells. Flow cytometric analysis revealed that triptolide induced S phase arrest in gallbladder cancer cells. In addition, triptolide induced apoptosis, as shown by the results of annexin V/propidium iodide double-staining and Hoechst 33342 staining. Furthermore, triptolide decreased mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Finally, western blot analysis of triptolide-treated cells revealed the activation of caspase-3, caspase-9, PARP, and Bcl-2; this result demonstrated that triptolide induced apoptosis in gallbladder cancer cells by regulating apoptosis-related protein expression, and suggests that triptolide may be a promising drug to treat gallbladder carcinoma.


Comparison of short-term rainfall forecasts for model-based flow prediction in urban drainage systems.
Forecast-based flow prediction in drainage systems can be used to implement real-time control of drainage systems. This study compares two different types of rainfall forecast - a radar rainfall extrapolation-based nowcast model and a numerical weather prediction model. The models are applied as input to an urban runoff model predicting the inlet flow to a waste water treatment plant. The modelled flows are auto-calibrated against real-time flow observations in order to certify the best possible forecast. Results show that it is possible to forecast flows with a lead time of 24 h. The best performance of the system is found using the radar nowcast for the short lead times and the weather model for larger lead times.


Risk factors for falling in home-dwelling older women with stroke: the Women's Health and Aging Study.
Much of our knowledge of risk factors for falls comes from studies of the general population. The aim of this study was to estimate the risk of falling associated with commonly accepted and stroke-specific factors in a home-dwelling stroke population. This study included an analysis of prospective fall reports in 124 women with confirmed stroke over 1 year. Variables relating to physical and mental health, history of falls, stroke symptoms, self-reported difficulties in activities of daily living, and physical performance tests were collected during home assessments. Risk factors for falling commonly reported in the general population, including performance tests of balance, incontinence, previous falls, and sedative/hypnotic medications, did not predict falls in multivariate analyses. Frequent balance problems while dressing were the strongest risk factor for falls (odds ratio, 7.0). Residual balance, dizziness, or spinning stroke symptoms were also a strong risk factor for falling (odds ratio, 5.2). Residual motor symptoms were not associated with an increased risk of falling. Interventions to reduce the frequency of balance problems during complex tasks may play a significant role in reducing falls in stroke. Clinicians should be aware of the increased risk of falling in women with residual balance, dizziness, or spinning stroke symptoms and recognize that risk assessments developed for use in the general population may not be appropriate for stroke patients.


What determines ageing of the transplanted liver?
Liver transplantation is used to treat patients with irreversible liver failure from a variety of causes. Long-term survival has been reported, particularly in the paediatric population, with graft survival longer than 20 years now possible. The goal for paediatric liver transplantation is to increase the longevity of grafts to match the normal life expectancy of the child. This paper reviews the literature on the current understanding of ageing of the liver and biomarkers that may predict long-term survival or aid in utilization of organs. Scientific papers published from 1950 to 2013 were sought and extracted from the MEDLINE, PubMed and University of Melbourne databases. Hepatocytes appear resistant to the ageing process, but are affected by both replicative senescence and stress-related senescence. These processes may be exacerbated by the act of transplantation. The most studied biomarkers are telomeres and SMP-30. There are many factors that play a role in the ageing of the liver. Further studies into biomarkers of ageing and their relationship to the chronological age of the liver are required to aid in predicting long-term graft survival and utilization of organs.


Pancreaticoduodenectomy with en bloc vein resection for locally advanced pancreatic cancer: a case series without venous reconstruction.
Resection with clean margin (R0 resection) is associated with better survival in patients with pancreatic cancer. Over the last decade, advancements in preoperative chemotherapy and radiation therapy in pancreatic cancer have led to expansion of indications for surgical resection. Current guidelines define pancreatic cancer with unreconstructable vascular involvement as locally advanced, or surgically unresectable. We present our experience in managing patients with locally advanced pancreatic cancer with a very unique series of patients who achieved R0 resection despite "unresectable" vascular involvement. Additionally, we review current guidelines, the ability to predict venous resection by imaging, outcomes after venous resection and reconstruction, published patency rates of venous reconstructions, and potential future implications of this novel technique.


Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial.
Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain. To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis. The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014. Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline). The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure. Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits. Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency. clinicaltrials.gov Identifier: NCT01408030.


Biventricular pacing for atrioventricular block and systolic dysfunction.
Right ventricular pacing restores an adequate heart rate in patients with atrioventricular block, but high percentages of right ventricular apical pacing may promote left ventricular systolic dysfunction. We evaluated whether biventricular pacing might reduce mortality, morbidity, and adverse left ventricular remodeling in such patients. We enrolled patients who had indications for pacing with atrioventricular block; New York Heart Association (NYHA) class I, II, or III heart failure; and a left ventricular ejection fraction of 50% or less. Patients received a cardiac-resynchronization pacemaker or implantable cardioverter-defibrillator (ICD) (the latter if the patient had an indication for defibrillation therapy) and were randomly assigned to standard right ventricular pacing or biventricular pacing. The primary outcome was the time to death from any cause, an urgent care visit for heart failure that required intravenous therapy, or a 15% or more increase in the left ventricular end-systolic volume index. Of 918 patients enrolled, 691 underwent randomization and were followed for an average of 37 months. The primary outcome occurred in 190 of 342 patients (55.6%) in the right-ventricular-pacing group, as compared with 160 of 349 (45.8%) in the biventricular-pacing group. Patients randomly assigned to biventricular pacing had a significantly lower incidence of the primary outcome over time than did those assigned to right ventricular pacing (hazard ratio, 0.74; 95% credible interval, 0.60 to 0.90); results were similar in the pacemaker and ICD groups. Left ventricular lead-related complications occurred in 6.4% of patients. Biventricular pacing was superior to conventional right ventricular pacing in patients with atrioventricular block and left ventricular systolic dysfunction with NYHA class I, II, or III heart failure. (Funded by Medtronic; BLOCK HF ClinicalTrials.gov number, NCT00267098.).