Arabidopsis PCR2 is a zinc exporter involved in both zinc extrusion and long-distance zinc transport.
Plants strictly regulate the uptake and distribution of Zn, which is essential for plant growth and development. Here, we show that Arabidopsis thaliana PCR2 is essential for Zn redistribution and Zn detoxification. The pcr2 loss-of-function mutant was compromised in growth, both in Zn-excessive and -deficient conditions. The roots of pcr2 accumulated more Zn than did control plants, whereas the roots of plants overexpressing PCR2 contained less Zn, indicating that PCR2 removes Zn from the roots. Consistent with a role for PCR2 as a Zn-efflux transporter, PCR2 reduced the intracellular concentration of Zn when expressed in yeast cells. PCR2 is located mainly in epidermal cells and in the xylem of young roots, while it is expressed in epidermal cells in fully developed roots. Zn accumulated in the epidermis of the roots of pcr2 grown under Zn-limiting conditions, whereas it was found in the stele of wild-type roots. The transport pathway mediated by PCR2 does not seem to overlap with that mediated by the described Zn translocators (HMA2 and HMA4) since the growth of pcr2 hma4 double and pcr2 hma2 hma4 triple loss-of-function mutants was more severely inhibited than the individual single knockout mutants, both under conditions of excess or deficient Zn. We propose that PCR2 functions as a Zn transporter essential for maintaining an optimal Zn level in Arabidopsis.


HNO binding in a heme protein: structures, spectroscopic properties, and stabilities.
HNO can interact with numerous heme proteins, but atomic level structures are largely unknown. In this work, various structural models for the first stable HNO heme protein complex, MbHNO (Mb, myoglobin), were examined by quantum chemical calculations. This investigation led to the discovery of two novel structural models that can excellently reproduce numerous experimental spectroscopic properties. They are also the first atomic level structures that can account for the experimentally observed high stabilities. These two models involve two distal His conformations as reported previously for MbCNR and MbNO. However, a unique dual hydrogen bonding feature of the HNO binding was not reported before in heme protein complexes with other small molecules such as CO, NO, and O(2). These results shall facilitate investigations of HNO bindings in other heme proteins.


A measure of mortality risk for elderly patients with acute myocardial infarction.
The objective of this study was to derive and validate a simple scoring system that predicts risk of short-term mortality in elderly patients hospitalized with acute myocardial infarction (AMI) and to compare this derived score with the MedisGroups admission severity score. A myocardial infarction severity score (MISS) was derived from a database of clinical information abstracted using MedisGroups and follow-up information on 30-day mortality status. The MISS was validated and compared with the MedisGroups Admission Severity Groups (ASGs) in a separate database. The derivation set included 2,037 Medicare patients 65 years old or older with confirmed AMI who were randomly selected from patients discharged from hospitals in seven states during 1985. The validation set consisted of 6,323 patients from the 1988 MedisGroups comparative database who were at least 65 years of age and had confirmed AMI. Multivariate logistic regression analysis found a set of nine abnormal patient characteristics that independently predict 30-day mortality. There was good agreement between mortality rates predicted by the logistic model and observed mortality rates in the validation population. This regression model was then simplified to an additive score where eight of the characteristics were weighted as one point and one characteristic was weighted as two points. The MISS is the sum of the points for each patient. In the validation dataset, the 1,373 patients with the lowest MISS scores had a mortality rate of 4.6% and the 400 patients with the highest MISS scores had a mortality rate of 64%.(ABSTRACT TRUNCATED AT 250 WORDS)


Learning language with the wrong neural scaffolding: the cost of neural commitment to sounds.
Does tuning to one's native language explain the "sensitive period" for language learning? We explore the idea that tuning to (or becoming more selective for) the properties of one's native-language could result in being less open (or plastic) for tuning to the properties of a new language. To explore how this might lead to the sensitive period for grammar learning, we ask if tuning to an earlier-learned aspect of language (sound structure) has an impact on the neural representation of a later-learned aspect (grammar). English-speaking adults learned one of two miniature artificial languages (MALs) over 4 days in the lab. Compared to English, both languages had novel grammar, but only one was comprised of novel sounds. After learning a language, participants were scanned while judging the grammaticality of sentences. Judgments were performed for the newly learned language and English. Learners of the similar-sounds language recruited regions that overlapped more with English. Learners of the distinct-sounds language, however, recruited the Superior Temporal Gyrus (STG) to a greater extent, which was coactive with the Inferior Frontal Gyrus (IFG). Across learners, recruitment of IFG (but not STG) predicted both learning success in tests conducted prior to the scan and grammatical judgment ability during the scan. Data suggest that adults' difficulty learning language, especially grammar, could be due, at least in part, to the neural commitments they have made to the lower level linguistic components of their native language.


Genetic deletion of a single immunodominant T-cell response confers susceptibility to virus-induced demyelination.
An important question in neuropathology involves determining the antigens that are targeted during demyelinating disease. Viral infection of the central nervous system (CNS) leads to T-cell responses that can be protective as well as pathogenic. In the Theiler's murine encephalomyelitis virus (TMEV) model of demyelination it is known that the immune response to the viral capsid protein 2 (VP2) is critical for disease pathogenesis. This study shows that expressing the whole viral capsid VP2 or the minimal CD8-specific peptide VP2(121-130) as "self" leads to a loss of VP2-specific immune responses. Loss of responsiveness is caused by T cell-specific tolerance, as VP2-specific antibodies are generated in response to infection. More importantly, these mice lose the CD8 T-cell response to the immunodominant peptide VP2(121-130), which is critical for the development of demyelinating disease. The transgenic mice fail to clear the infection and develop chronic demyelinating disease in the spinal cord white matter. These findings demonstrate that T-cell responses can be removed by transgenic expression and that lack of responsiveness alters viral clearance and CNS pathology. This model will be important for understanding the mechanisms involved in antigen-specific T-cell deletion and the contribution of this response to CNS pathology.


Pedestrian collective motion in competitive room evacuation.
When a sizable number of people evacuate a room, if the door is not large enough, an accumulation of pedestrians in front of the exit may take place. This is the cause of emerging collective phenomena where the density is believed to be the key variable determining the pedestrian dynamics. Here, we show that when sustained contact among the individuals exists, density is not enough to describe the evacuation, and propose that at least another variable -such as the kinetic stress- is required. We recorded evacuation drills with different degrees of competitiveness where the individuals are allowed to moderately push each other in their way out. We obtain the density, velocity and kinetic stress fields over time, showing that competitiveness strongly affects them and evidencing patterns which have been never observed in previous (low pressure) evacuation experiments. For the highest competitiveness scenario, we detect the development of sudden collective motions. These movements are related to a notable increase of the kinetic stress and a reduction of the velocity towards the door, but do not depend on the density.


Visual pigments, oil droplets and cone photoreceptor distribution in the european starling (Sturnus vulgaris)
Microspectrophotometric measurements of retinal photoreceptors from the European starling (Sturnus vulgaris) revealed four classes of single cone, containing visual pigments with wavelengths of maximum absorbance (max) at 563, 504, 449 and close to 362 nm. The two longer-wave-sensitive single cones contained brightly coloured oil droplets which cut off light below 572 and 514 nm, respectively. The 449 nm max pigment was associated with a 'colourless' oil droplet with peak measured absorptance below 400 nm. The ultraviolet-sensitive visual pigment was paired with a transparent oil droplet which showed no significant absorption above 350 nm. A single class of double cone was identified, both members of which contained the longwave-sensitive (max 563 nm) visual pigment. The principal member of the double cone contained an oil droplet with a topographically variable cut-off wavelength below 471 nm; the oil droplet found in the accessory member was only measured in the ventral retina and displayed three distinct peaks of absorption at approximately 430, 450 and 480 nm. Rod photoreceptors had a max at 503 nm. A new polynomial for fitting visual pigment templates to ultraviolet-sensitive visual pigment data is given. Topographic density measurements of the different cone classes were made using Nitroblue-tetrazolium chloride to label selectively bleached photoreceptors. The two classes of shortwave-sensitive single cone were more abundant in the dorsal retina, and longwave-sensitive single cones were notably less abundant in the dorso-temporal region of the retina, which subserves binocular vision.


Classification of object size in retinotectal microcircuits.
A principal task of the visual system is to detect and classify moving objects in the visual environment. Information about the size of an object is critical for selecting appropriate behavioral responses. Object size is encoded in retinal ganglion cell (RGC) activity. Little is known, however, about how inputs from the multitude of RGC subtypes are distributed to higher visual centers and how information is combined from these feature-selective inputs. Here we show that in the zebrafish optic tectum, prey- or predator-like moving targets evoke activity in distinct groups of RGC fibers dependent on target size, demonstrating a retinal origin of tectal size classification. Small-size-selective retinal inputs are relatively more frequent in the most superficial layer of the tectal neuropil, whereas large-size-selective inputs predominate in deeper layers. Monostratified superficial interneurons (SINs) process large-size- and small-size-selective signals dependent on their dendritic target layer, consistent with the retinal input organization. Further downstream, small- and large-sized objects are encoded in population activity of separate sets of tectal neurons. Ethologically relevant size classes are preferentially processed in different layers of the tectal neuropil. The tectum categorizes visual targets on the basis of retinally computed size information, suggesting a critical role in visually guided response selection.


MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential.
MicroRNAs (miRNAs) are emerging as key control molecules in the regulation of gene expression, and their role in heart disease is becoming increasingly evident. Given the critical role of Ca(2+) handling and signaling proteins in the maintenance of cardiac function, the targeting of such proteins by miRNAs would be expected to have important consequences. miRNAs have indeed been shown to control the expression of genes encoding important Ca(2+) handling and signaling proteins, and are themselves regulated by Ca(2+)-dependent processes. Ca(2+)-related miRNAs have been found to be significant pathophysiological contributors in conditions like myocardial ischemic injury, cardiac hypertrophy, heart failure, ventricular arrhythmogenesis, and atrial fibrillation. This review is a comprehensive analysis of the present knowledge concerning miRNA regulation of Ca(2+) handling processes, the participation of Ca(2+)-regulating miRNAs in the evolution of heart disease, the mutual relationship between Ca(2+) signaling and miRNAs in the control of cardiac function, and the potential value of miRNA-control of Ca(2+) handling as a therapeutic target.


CLMSVault: A Software Suite for Protein Cross-Linking Mass-Spectrometry Data Analysis and Visualization.
Protein cross-linking mass spectrometry (CL-MS) enables the sensitive detection of protein interactions and the inference of protein complex topology. The detection of chemical cross-links between protein residues can identify intra- and interprotein contact sites or provide physical constraints for molecular modeling of protein structure. Recent innovations in cross-linker design, sample preparation, mass spectrometry, and software tools have significantly improved CL-MS approaches. Although a number of algorithms now exist for the identification of cross-linked peptides from mass spectral data, a dearth of user-friendly analysis tools represent a practical bottleneck to the broad adoption of the approach. To facilitate the analysis of CL-MS data, we developed CLMSVault, a software suite designed to leverage existing CL-MS algorithms and provide intuitive and flexible tools for cross-platform data interpretation. CLMSVault stores and combines complementary information obtained from different cross-linkers and search algorithms. CLMSVault provides filtering, comparison, and visualization tools to support CL-MS analyses and includes a workflow for label-free quantification of cross-linked peptides. An embedded 3D viewer enables the visualization of quantitative data and the mapping of cross-linked sites onto PDB structural models. We demonstrate the application of CLMSVault for the analysis of a noncovalent Cdc34-ubiquitin protein complex cross-linked under different conditions. CLMSVault is open-source software (available at https://gitlab.com/courcelm/clmsvault.git ), and a live demo is available at http://democlmsvault.tyerslab.com/ .


A molecular time-scale for eukaryote evolution recalibrated with the continuous microfossil record.
Recent attempts to establish a molecular time-scale of eukaryote evolution failed to provide a congruent view on the timing of the origin and early diversification of eukaryotes. The major discrepancies in molecular time estimates are related to questions concerning the calibration of the tree. To limit these uncertainties, we used here as a source of calibration points the rich and continuous microfossil record of dinoflagellates, diatoms and coccolithophorids. We calibrated a small-subunit ribosomal RNA tree of eukaryotes with four maximum and 22 minimum time constraints. Using these multiple calibration points in a Bayesian relaxed molecular clock framework, we inferred that the early radiation of eukaryotes occurred near the Mesoproterozoic-Neoproterozoic boundary, about 1100 million years ago. Our results indicate that most Proterozoic fossils of possible eukaryotic origin cannot be confidently assigned to extant lineages and should therefore not be used as calibration points in molecular dating.


Quantum dot infrared photodetector enhanced by surface plasma wave excitation.
Up to a thirty-fold detectivity enhancement is achieved for an InAs quantum dot infrared photodetector (QDIP) by the excitation of surface plasma waves (SPWs) using a metal photonic crystal (MPC) integrated on top of the detector absorption region. The MPC is a 100 nm-thick gold film perforated with a 3.6 microm period square array of circular holes. A bare QDIP shows a bias-tunable broadband response from approximately 6 to 10 microm associated with the quantum confined Stark (QCS) effect. On the other hand, an MPC-integrated QDIP exhibits a dominant peak at 11.3 microm with a approximately 1 microm full width at half maximum and the highly enhanced detectivity at the bias polarity optimized for long wavelength. This is very different from the photoresponse of the bare QDIP but fully consistent with the direct coupling of the QDs in the detector absorption region to the SPWs excited at the MPC/detector interface by incident photons. The SPW resonance wavelength, lambda, for the smallest coupling wavevector of the array in the MPC is close to 11.3 microm. The response also shows other SPW-coupled peaks: a significant peak at 8.1 microm (approximately lambda/radical2) and noticeable peaks at 5.8 microm (approximately lambda/2) and 5.4 microm (approximately lambda/ radical5) which correspond to higher-order coupling wavevectors. For the opposite bias, the MPC-integrated QDIP shows the highest response at 8.1 microm, providing a dramatic voltage tunability that is associated with QCS effect. SPWs propagate with TM (x, z) polarization along the MPC/detector interface. The enhanced detectivity is explained by these characteristics which increase both the effective absorption cross section with propagation and the interaction strength with TM polarization in the coupling to the QDs. Simulations show good qualitative agreement with the observed spectral behavior.


Low expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) indicates a shorter survival after resection in patients with adenocarcinoma of the lung.
It has been reported that an endogenous matrix metalloproteinase (MMP) inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), is able to inhibit tumour angiogenesis, invasion, and metastasis through inhibition of MMP-2, MMP-9, and membrane type-1 (MT1)-MMP (MMP-14) secretion and activity. In this study, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR), we have analysed RECK expression levels in resected non-small-cell lung cancer (NSCLC) tissue and compared these data with the clinicopathological features of these patients to investigate the role of RECK in NSCLC. We have also analysed the expression of MMP-2, MMP-9, and MMP-14 and compared the data with those for RECK expression. Tissue samples of primary lung cancers were obtained from a total of 83 patients [46 with adenocarcinomas (ADC) and 37 with squamous cell carcinomas (SCC)] who underwent curative resection. The samples were taken from 83 tumours and 20 matched normal lung tissue samples as controls. Expressions of RECK in ADC and SCC were significantly lower than in the control. In ADC tissue, the expression of RECK was higher in stage IA than in stage IB-IIIA. There was no such a correlation in SCC. In ADC, univariate analysis for relapse-free survival using Cox regression analysis identified low RECK expression (p=0.036), low MMP-14 expression (p=0.038), and tumour T2 (p=0.034) as significant negative prognostic predictors. However, in SCC, none of the clinicopathological factors assessed, including RECK expression, had prognostic value. In conclusion, our study suggests that suppression of RECK expression is involved in the progression of ADC of the lung and that RECK expression in resected ADC of the lung is a favorable predictor of patients' prognosis.


Web-based internet searches for digital health products in the United Kingdom before and during the COVID-19 pandemic: a time-series analysis using app libraries from the Organisation for the Review of Care and Health Applications (ORCHA).
To explore if consumer interest in digital health products (DHPs), changed following the COVID-19 pandemic and the lockdown measures that ensued. Retrospective time-series analysis of web-based internet searches for DHPs in the UK, split over two periods, pre-COVID-19 lockdown (January 2019-23 March 2020) and post-COVID-19 lockdown (24 March 2020-31 December 2020). The UK. Members of the UK general population using health-app libraries provided by the Organisation for the Review of Care and Health Applications. The primary outcome was volume of searches for DHPs. Secondary outcomes considered search volumes for 25 different therapeutic areas. Outcomes were assessed for significance using a two-stage Poisson test. There were 126 640 searches for DHPs over the study period. Searches for DHPs increased by 343% from 2446 per month prior to COVID-19 lockdown measures being introduced to 8996 per month in the period following the first COVID-19 lockdown in the UK. In total, 23/25 (92%) of condition areas experienced a significant increase in searches for DHPs, with the greatest increases occurring in the first 2 months following lockdown. Musculoskeletal conditions (2.036%), allergy (1.253%) and healthy living DHPs (1.051%) experienced the greatest increases in searches compared with pre-lockdown. Increased search volumes for DHPs were sustained in the 9 months following the introduction of lockdown measures, with 21/25 (84%) of condition areas experiencing monthly search volumes at least 50% greater than pre-lockdown levels. The COVID-19 pandemic has profoundly disrupted the routine delivery of healthcare, making face-to-face interaction difficult, and contributing to unmet clinical needs. This study has demonstrated significant increases in internet searches for DHPs by members of the UK population since COVID-19, signifying an increased interest in this potential therapeutic medium. Future research should clarify whether this increased interest has resulted in increased acceptance and utilisation of these technologies also.


Functional morphology of ductus venosus in human fetus.
The morphology of region umbilical vein, umbilical sinus and ductus venosus of human fetuses have been investigated. 26 human fetuses between 20 and 40 weeks' gestation were examined by morphological methods. The umbilical vein, DV and the portal vein were obtained after termination of gestation. Tissue samples have been fixed in phormaldehyde solution (pH 7,2) and were embedded in paraffin. The paraffin sections (5-7 micro k) were stained with hematoxylin and eosin, silver impregnation by Bilchovski, orcein, pikrofuchsin. Measurement of the angle between ductus venosus and the portal vein was obtained with alidade. Anatomical scheme of the region of umbilical vein, umbilical sinus and DV indicating two different patterns. The first: DV has situated into line with umbilical vein (22 cases). The second: umbilical vein has rotated before umbilical sinus, forming the turn in right (4 cases). The double-layer wall of ductus venosus (DV) contained the elastic, collagen and argyrophilic fibers. Around isthmus region of DV vasa vasorum and nervi vasorum have been found. The specific anatomical finding of the ductal isthmus was an accumulation of smooth muscle cells as intimal pillow, which were protruded into the vascular lumen. The double-layer wall of portal sinus (intima and adventitia) have been as the internal elastic membrane. The smooth muscle cells have been revealed in the walls, were not formed the tunica media at term 20-40 weeks of gestation. By the contrast the umbilical vein showed multiple, circularly running smooth muscle bundles. In this study, the ductal thickness was consistently bigger in the inlet than in the outlet. The tunica adventitia was greatest in the junction with the portal sinus and the inferior vena cava compared with the part arranged in the liver parenchyma. The wall thickness of the portal sinus and of the umbilical vein was significantly higher than of the duclal wall. The vascular muscle-elastic cells of intimal hyperplasia ("intimal pillow") in wall of DV, probably, executes the role of the fortification of resistant behaviours of vessel wall in connection with DV and portal sinus with high hemodynamics load in this area. The maximum thickness of adventicia in the field of joints also witnesses an hemodynamic in favour of particularities. The angle between DV and left branches of portal vein in dominate cases was sharp and right that reflects the general regularity of architectonics of the vascular riverbed.


Rising signal intensity observed in extra-axial brain tumours - a potential pitfall in perfusion MR imaging.
Dynamic perfusion magnetic resonance (MR) techniques may be used to track the susceptibility effects of gadolinium contrast material as it passes through the brain. We describe three intracranial tumours that showed progressively rising signal intensity above the baseline during first-pass contrast-enhanced echo-planar imaging (EPI) MR imaging. Multiphase acquisition using single-shot EPI was performed during rapid bolus contrast injection. Ten studies, using either spin-echo or gradient-echo EPI sequences, were carried out in eight patients with intracranial tumours. Time-signal intensity graphs and regional cerebral blood volume (rCBV) were reviewed. In seven studies, the signal intensity within the tumour showed initial signal drop and quick recovery to baseline and increased rCBV. Three studies revealed progressively rising signal intensity. These patients were all imaged using a spin-echo EPI method and subsequent histology revealed meningioma, hemangiopericytoma and pinealblastoma. Dynamic perfusion MR methods may be used to study intracranial tumours. However, in short relaxation time spin-echo EPI, the T1- effect of gadolinium becomes noticeable during the first-pass acquisition in extra-axial tumours that lack a well-developed blood-brain barrier. Careful selection of patients and pulse sequence is essential to avoid this potential pitfall.


Single-molecule imaging of transcription dynamics in somatic stem cells.
Molecular noise is a natural phenomenon that is inherent to all biological systems1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states-akin to a transcriptional priming phenomenon-the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness.


Protocol for a single-centre randomised controlled trial of multimodal periarticular anaesthetic infiltration versus single-agent femoral nerve blockade as analgesia for total knee arthroplasty: Perioperative Analgesia for Knee Arthroplasty (PAKA).
Total knee arthroplasty (TKA) surgery causes postoperative pain. The use of perioperative injections around the knee containing local anaesthetic, opiates and non-steroidal anti-inflammatory drugs has increased in popularity to manage pain. Theoretical advantages include reduced requirements for analgesia and earlier mobilisation. We propose a single-centre randomised controlled trial of multimodal periarticular anaesthetic infiltration versus femoral nerve anaesthetic blockade as analgesia for TKA. The aim is to determine, in patients undergoing TKA, if there is a difference in patient-reported pain scores on the visual analogue scale (VAS) prior to physiotherapy on day 1 postoperatively between treatment groups. Patients undergoing a primary unilateral TKA at University Hospitals Coventry and Warwickshire Hospitals will be assessed for eligibility. A total of 264 patients will provide 90% power to detect a difference of 12 mm on the VAS on day 1 postoperatively at the 5% level. The trial will use 1:1 randomisation, stratified by mode of anaesthetic. Primary outcome measure will be the VAS for pain prior to physiotherapy on day 1. Secondary outcome measures include VAS on day 2, total use of opiate analgesia up to 48 h, ordinal pain scores up to 40 min after surgery, independent functional knee physiotherapist assessment on days 1 and 2. Oxford knee Scores (OKS), EuroQol (EQ-5D) and Douleur Neuropathic Pain Scores (DN2) will be recorded at baseline, 6 weeks and 12 months. Adverse events will be recorded up to 12 months. Analysis will investigate differences in VAS on day 1 between the two treatment groups on an intention-to-treat basis. Tests will be two-sided and considered to provide evidence for a significant difference if p values are less than 0.05. NRES Committee West Midlands, 23 September 2013 (ref: 13/WM/0316). The results will be disseminated via peer-reviewed publications and conference presentations. ISRCTN 60611146 and EUDRACT Number 2013-002439-10 (protocol code number PAKA-33601-AS117013); Pre-results.


Ringing ears: the neuroscience of tinnitus.
Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved. A brain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing.


Fatty liver promotes fibrosis in monkeys consuming high fructose.
Nonalcoholic fatty liver diseases (NAFLD) are related to development of liver fibrosis which currently has few therapeutic options. Rodent models of NAFLD inadequately model the fibrotic aspects of the disease and fail to demonstrate the spectrum of cardiometabolic diseases without genetic manipulation. This study aimed to document a monkey model of fatty liver and fibrosis, which naturally develop cardiometabolic disease pathophysiologies. Twenty-seven cynomolgus monkeys (Macaca fascicularis) fed diets either low or high in simple carbohydrates, supplied as fructose [control and high-fructose diet (HRr)], on low-fat, cholesterol-free background were studied. The HFr was consumed for up to 7 years, and liver tissue was histologically evaluated for fat and fibrosis extent. The HFr diet increased steatosis, and its extent was related to duration of fructose exposure. Lipid droplet size also increased with HFr duration; however, compared with control, the lipid droplets were smaller on average. Fibrosis extent was significantly greater with fructose feeding and was predicted by fructose exposure, extent of fatty liver, and age. These data are the first to demonstrate that high-carbohydrate diets alone can generate both liver fat and fibrosis and thus allow further study of mechanisms and therapeutic options in the translational animal model.


A mobile care system with alert mechanism.
Hypertension and arrhythmia are chronic diseases, which can be effectively prevented and controlled only if the physiological parameters of the patient are constantly monitored, along with the full support of the health education and professional medical care. In this paper, a role-based intelligent mobile care system with alert mechanism in chronic care environment is proposed and implemented. The roles in our system include patients, physicians, nurses, and healthcare providers. Each of the roles represents a person that uses a mobile device such as a mobile phone to communicate with the server setup in the care center such that he or she can go around without restrictions. For commercial mobile phones with Bluetooth communication capability attached to chronic patients, we have developed physiological signal recognition algorithms that were implemented and built-in in the mobile phone without affecting its original communication functions. It is thus possible to integrate several front-end mobile care devices with Bluetooth communication capability to extract patients' various physiological parameters [such as blood pressure, pulse, saturation of haemoglobin (SpO2), and electrocardiogram (ECG)], to monitor multiple physiological signals without space limit, and to upload important or abnormal physiological information to healthcare center for storage and analysis or transmit the information to physicians and healthcare providers for further processing. Thus, the physiological signal extraction devices only have to deal with signal extraction and wireless transmission. Since they do not have to do signal processing, their form factor can be further reduced to reach the goal of microminiaturization and power saving. An alert management mechanism has been included in back-end healthcare center to initiate various strategies for automatic emergency alerts after receiving emergency messages or after automatically recognizing emergency messages. Within the time intervals in system setting, according to the medical history of a specific patient, our prototype system can inform various healthcare providers in sequence to provide healthcare service with their reply to ensure the accuracy of alert information and the completeness of early warning notification to further improve the healthcare quality. In the end, with the testing results and performance evaluation of our implemented system prototype, we conclude that it is possible to set up a complete intelligent healt care chain with mobile monitoring and healthcare service via the assistance of our system.


Immunologic and Virologic Progression in HIV Controllers: The Role of Viral "Blips" and Immune Activation in the ANRS CO21 CODEX Study.
Some HIV controllers (HICs) experience CD4+T cell count loss and/or lose their ability to control HIV. In this study, we investigated the rate of immunologic and/or virologic progression (ImmP/VirP) and its determinants in the ANRS CO21/CODEX cohort. Immunologic progression was defined as a lasting fall in CD4+T cell count below 350/mm(3) or more than 200/mm(3) with a baseline count below 600/mm(3). Virologic progression was defined as a HIV viral load (VL) above 2000 copies/mL on two consecutive determinations. Clinical characteristics, immune activation, ultrasensitive HIV VL and total HIV DNA were analyzed. Disease progression was observed in 15 of the 217 patients followed up between 2009 and 2013 (ImmP, n = 10; VirP, n = 5). Progressors had higher ultrasensitive HIV RNA levels at inclusion (i.e. 1-2 years before progression) than non-progressors. ImmP had also lower CD4+T cell nadir and CD4+T cell count at inclusion, and VirP had higher HIV DNA levels in blood. T cell activation and IP10 levels at inclusion were significantly higher in ImmP than in non-progressors. In summary, the lasting loss of CD4+T cells, residual HIV replication and basal levels of immune activation appear to be major determinants of progression in HICs. These factors should be considered for adjusting their follow-up.


Role of new antibiotics for KPC-producing Klebsiella pneumoniae.
Klebsiella pneumoniae has accumulated a wide range of resistance determinants and has evolved into a difficult-to-treat pathogen that poses an increasing healthcare threat. KPC is an important marker for extensively drug-resistant (XDR) organisms with limited treatment options. In response to the medical need for new treatment options, several new antibiotics have been developed and registered recently. The β-lactamase inhibitor (BLI) combinations ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam, the cephalosporin-siderophore conjugate cefiderocol, the aminoglycoside derivative plazomicin and the tetracycline derivative eravacycline, focus on carbapenem-resistant Enterobacterales. These modified agents from old antibiotic classes illustrate the challenges of this requirement to address class-specific resistance mechanisms while critical gaps and some cross-resistance within a class, or to unrelated antibiotic classes, remain. The diverse molecular mechanisms and increasing diversification of carbapenem resistance among Klebsiella isolates requires improved rapid molecular diagnostic capabilities and stringent stewardship programmes to preserve the efficacy of new antibiotics for as long as possible.


Interchannel interaction of optical solitons.
We study interaction between two solitons from different frequency channels propagating in an optical fiber. The interaction may be viewed as an inelastic collision, in which energy is lost to continuous radiation due to small but finite third order dispersion. We develop a perturbation theory with two small parameters: the third order dispersion coefficient d(3), and the reciprocal of the interchannel frequency difference, 1/beta. We find that amplitude of the leading contribution to radiation emitted during the collision is proportional to d(3)/beta(2). The source term for this radiation is of the form that would be generated by a variation in the second order dispersion coefficient. In addition, the only other effects up to the combined third order of the perturbation theory are phase changes and position shifts of the solitons. Solitons propagating in a given frequency channel interact via radiation emitted due to collisions with many solitons from other frequency channels. We show that this intrachannel interaction effect, induced by many interchannel collisions, is identical to the radiation mediated intrachannel interaction effect observed for solitons propagating under the influence of disorder in the second order dispersion coefficient.


Impact of elevated Ca(2+)/Mg(2+) concentrations of reverse osmosis membrane desalinated seawater on the stability of water pipe materials.
Hardness and alkalinity are known factors influencing the chemical stability of desalinated water. This study was carried out to investigate the effect of Ca(2+) and Mg(2+) on corrosion and/or scale formation on the surface of different water distribution pipe materials under tropical conditions. The corrosion rates of ductile iron, cast iron and cement-lined ductile iron coupons were examined in reverse osmosis (RO) membrane desalinated seawater which was remineralised using different concentrations of Ca(2+) and Mg(2+). The changes in water characteristics and the coupon corrosion rates were studied before and after the post-treatment. The corrosion mechanisms and corrosion products were examined using scanning electron microscope and X-ray diffraction, respectively. We found that the combination of Ca(2+) and Mg(2+) (60/40 mg/L as CaCO3) resulted in lower corrosion rates than all other treatments for the three types of pipe materials, suggesting that Ca(2+)/Mg(2+) combination improves the chemical stability of desalinated seawater rather than Ca(2+) only.


Confirmation of mutations in PROSC as a novel cause of vitamin B 6 -dependent epilepsy.
Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPL or ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPO explain a major fraction of cases. Very recently biallelic mutations in PROSC were shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6 plasma profiles on pyridoxine did not enable the differentiation of patients with PROSC mutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with PROSC mutations was indistinguishable from ALDH7A1 and PNPO deficiency. We therefore confirm PROSC as a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6 profile under pyridoxine treatment.


Levamisole-induced leukocytoclastic vasculitis and neutropenia in a patient with cocaine use: an extensive case with necrosis of skin, soft tissue, and cartilage.
Levamisole-induced vasculitis is a relatively new entity in people who use cocaine. We describe a 44-year-old woman with a history of cocaine use who presented with a complaint of a painful rash of 2-3 month's duration on her extremities, cheeks, nose, and earlobes. She had not experienced fever, weight loss, alopecia, dry eyes, oral ulcers, photosensitivity, or arthralgia. Examination revealed tender purpuric eruptions with central necrosis on her nose, cheeks, earlobes, and extremities. Laboratory investigations revealed neutropenia, an elevated erythrocyte sedimentation rate (ESR), presence of lupus anticoagulant, low complement component 3 (C3), and presence of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA). A urine toxicology screen was positive for cocaine, and gas chromatography-mass spectrometry was positive for levamisole. Skin biopsy showed leukocytoclastic vasculitis and small vessel thrombosis. Necrotic lesions of the nose led to its self-amputation. Large bullae on the lower extremities ruptured, leading to wound infection and extensive necrosis that required multiple surgical debridements. When necrosis progressed despite debridement, bilateral above-knee amputation of the legs was performed. Once new lesions stopped appearing, the patient was discharged home. Two months later, she had a recurrence related to cocaine use. To the best of our knowledge, this is only the second reported case of levamisole-induced vasculitis that required above-knee amputation.


Comparative Analysis of Driver Mutations and Transcriptomes in Papillary Thyroid Cancer by Region of Residence in South Korea.
Radiation exposure is a well-known risk factor for papillary thyroid cancer (PTC). South Korea has 24 nuclear reactors in operation; however, no molecular biological analysis has been performed on patients with PTC living near nuclear power plants. We retrospectively included patients with PTC (n=512) divided into three groups according to their place of residence at the time of operation: inland areas (n=300), coastal areas far from nuclear power plants (n=134), and nuclear power plant areas (n=78). After propensity score matching (1:1:1) by age, sex, and surgical procedure, the frequency of representative driver mutations and gene expression profiles were compared (n=50 per group). Epithelial-mesenchymal transition (EMT), BRAF, thyroid differentiation, and radiation scores were calculated and compared. No significant difference was observed in clinicopathological characteristics, including radiation exposure history and the frequency of incidentally discovered thyroid cancer, among the three groups. BRAFV600E mutation was most frequently detected in the groups, with no difference among the three groups. Furthermore, gene expression profiles showed no statistically significant difference. EMT and BRAF scores were higher in our cohort than in cohorts from Chernobyl tissue bank and The Cancer Genome Atlas Thyroid Cancer; however, there was no difference according to the place of residence. Radiation scores were highest in the Chernobyl tissue bank but exhibited no difference according to the place of residence. Differences in clinicopathological characteristics, frequency of representative driver mutations, and gene expression profiles were not observed according to patients' region of residence in South Korea.


Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives.
Psilocybin is a tryptamine-derived psychoactive alkaloid found mainly in the fungal genus Psilocybe, among others, and is the active ingredient in so-called "magic mushrooms". Although its notoriety originates from its psychotropic properties and popular use as a recreational drug, clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. In this work, we demonstrate the de novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae by expression of a heterologous biosynthesis pathway sourced from Psilocybe cubensis. Additionally, we achieve improved product titers by supplementing the pathway with a novel cytochrome P450 reductase from P. cubensis. Further rational engineering resulted in a final production strain producing 627 ± 140 mg/L of psilocybin and 580 ± 276 mg/L of the dephosphorylated degradation product psilocin in triplicate controlled fed-batch fermentations in minimal synthetic media. Pathway intermediates baeocystin, nor norbaeocystin as well the dephosphorylated baeocystin degradation product norpsilocin were also detected in strains engineered for psilocybin production. We also demonstrate the biosynthetic production of natural tryptamine derivative aeruginascin as well as the production of a new-to-nature tryptamine derivative N-acetyl-4-hydroxytryptamine. These results lay the foundation for the biotechnological production of psilocybin in a controlled environment for pharmaceutical applications, and provide a starting point for the biosynthetic production of other tryptamine derivatives of therapeutic relevance.


3D Bioprinting Human Induced Pluripotent Stem Cell Constructs for In Situ Cell Proliferation and Successive Multilineage Differentiation.
The ability to create 3D tissues from induced pluripotent stem cells (iPSCs) is poised to revolutionize stem cell research and regenerative medicine, including individualized, patient-specific stem cell-based treatments. There are, however, few examples of tissue engineering using iPSCs. Their culture and differentiation is predominantly planar for monolayer cell support or induction of self-organizing embryoids (EBs) and organoids. Bioprinting iPSCs with advanced biomaterials promises to augment efforts to develop 3D tissues, ideally comprising direct-write printing of cells for encapsulation, proliferation, and differentiation. Here, such a method, employing a clinically amenable polysaccharide-based bioink, is described as the first example of bioprinting human iPSCs for in situ expansion and sequential differentiation. Specifically, we have extrusion printed the bioink including iPSCs, alginate (Al; 5% weight/volume [w/v]), carboxymethyl-chitosan (5% w/v), and agarose (Ag; 1.5% w/v), crosslinked the bioink in calcium chloride for a stable and porous construct, proliferated the iPSCs within the construct and differentiated the same iPSCs into either EBs comprising cells of three germ lineages-endoderm, ectoderm, and mesoderm, or more homogeneous neural tissues containing functional migrating neurons and neuroglia. This defined, scalable, and versatile platform is envisaged being useful in iPSC research and translation for pharmaceuticals development and regenerative medicine.


A genome-wide association study of renal cell carcinoma among African Americans.
Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AA), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNP) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases and 543 controls). The 12p11.23 variant rs10771279, located 77 kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P = 1.2 × 10(-7)) but did not replicate (P = 0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [OR, 0.76, 95% confidence interval (CI), 0.64-0.91; P = 0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07, respectively, among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR, 0.56; P = 7.4 × 10(-7)) and absent for cases of other or unknown histology (OR, 1.02; P = 0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92, respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to clear-cell RCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.


Using an electronic medical record to improve communication within a prenatal care network.
In 2002, the Institute of Medicine called for the introduction of information technologies in health care settings to improve quality of care. We conducted a review of hospital charts of women who delivered before and after the implementation of an intranet-based computerized prenatal record in an inner-city practice. Our objective was to assess whether the use of this record improved communication among the outpatient office, the ultrasonography unit, and the labor floor. The charts of patients who delivered in August 2002 and August 2003 and received their prenatal care at the Comprehensive Family Care Center at Montefiore Medical Center were analyzed. Data collected included the presence of a copy of the prenatal record in the hospital chart, the date of the last documented prenatal visit, and documentation of any prenatal ultrasonograms performed. Forty-three charts in each group were available for review. The prenatal chart was absent in 16% of the charts of patients from August 2002 compared with only 2% in August 2003 charts (P < .05). Among charts with prenatal records available, the median length of time between the last documented prenatal visit and delivery was significantly longer for August 2002 patients compared with August 2003 patients (36 compared with 4 days, respectively, P < .001). All patients received prenatal ultrasonograms, but documentation of the ultrasonogram was missing from 16% of the August 2002 charts compared with none of the August 2003 charts (P = .01). The use of a paperless, hospital intranet-based prenatal chart significantly improves communication among providers.


Aging Triggers H3K27 Trimethylation Hoarding in the Chromatin of Nothobranchius furzeri Skeletal Muscle.
Aging associates with progressive loss of skeletal muscle function, sometimes leading to sarcopenia, a process characterized by impaired mobility and weakening of muscle strength. Since aging associates with profound epigenetic changes, epigenetic landscape alteration analysis in the skeletal muscle promises to highlight molecular mechanisms of age-associated alteration in skeletal muscle. This study was conducted exploiting the short-lived turquoise killifish Nothobranchius furzeri (Nfu), a relatively new model for aging studies. The epigenetic analysis suggested a less accessible and more condensed chromatin in old Nfu skeletal muscle. Specifically, an accumulation of heterochromatin regions was observed as a consequence of increased levels of H3K27me3, HP1α, polycomb complex subunits, and senescence-associated heterochromatic foci (SAHFs). Consistently, euchromatin histone marks, including H3K9ac, were significantly reduced. In this context, integrated bioinformatics analysis of RNASeq and ChIPSeq, related to skeletal muscle of Nfu at different ages, revealed a down-modulation of genes involved in cell cycle, differentiation, and DNA repair and an up-regulation of inflammation and senescence genes. Undoubtedly, more studies are needed to disclose the detailed mechanisms; however, our approach enlightened unprecedented features of Nfu skeletal muscle aging, potentially associated with swimming impairment and reduced mobility typical of old Nfu.


Role of the microRNA-17-92 cluster in the endothelial differentiation of stem cells.
MicroRNAs (miRs) are small non-coding RNAs that recently emerged as potent regulators of gene expression. The members of the miR-17-92 cluster have been shown to control endothelial cell functions and neovascularization; however, the regulation and function of the cluster in endothelial cell lineage commitment has not been explored. This project aimed to test the role of the miR-17-92 cluster during endothelial differentiation. We demonstrate that miR-17, miR-18, miR-19 and miR-20 are increased upon the induction of endothelial cell differentiation of murine embryonic stem cells or induced pluripotent stem cells. In contrast, miR-92a and the primary miR-17-92 transcript were downregulated. The inhibition of each individual miR of the cluster by cholesterol-modified antagomirs did not affect endothelial marker gene expression. Moreover, the combination of all antagomirs had no effect. These findings illustrate that although the miR-17-92 cluster regulates vascular integrity and angiogenesis, none of the members has a significant impact on the endothelial differentiation of pluripotent stem cells.


Assessment and risk analysis of casing and cement impairment in oil and gas wells in Pennsylvania, 2000-2012.
Casing and cement impairment in oil and gas wells can lead to methane migration into the atmosphere and/or into underground sources of drinking water. An analysis of 75,505 compliance reports for 41,381 conventional and unconventional oil and gas wells in Pennsylvania drilled from January 1, 2000-December 31, 2012, was performed with the objective of determining complete and accurate statistics of casing and cement impairment. Statewide data show a sixfold higher incidence of cement and/or casing issues for shale gas wells relative to conventional wells. The Cox proportional hazards model was used to estimate risk of impairment based on existing data. The model identified both temporal and geographic differences in risk. For post-2009 drilled wells, risk of a cement/casing impairment is 1.57-fold [95% confidence interval (CI) (1.45, 1.67); P < 0.0001] higher in an unconventional gas well relative to a conventional well drilled within the same time period. Temporal differences between well types were also observed and may reflect more thorough inspections and greater emphasis on finding well leaks, more detailed note taking in the available inspection reports, or real changes in rates of structural integrity loss due to rushed development or other unknown factors. Unconventional gas wells in northeastern (NE) Pennsylvania are at a 2.7-fold higher risk relative to the conventional wells in the same area. The predicted cumulative risk for all wells (unconventional and conventional) in the NE region is 8.5-fold [95% CI (7.16, 10.18); P < 0.0001] greater than that of wells drilled in the rest of the state.


Gender differences in the prevalence of impaired fasting glycaemia and impaired glucose tolerance in Mauritius. Does sex matter?
To examine gender differences in the characteristics and prevalence of various categories of glucose tolerance in a population study in Mauritius. In 1998, a community-based cross-sectional survey was conducted in Mauritius. Categories of glucose metabolism were determined in 5388 adults, with an oral glucose tolerance test given to those who did not have previously diagnosed diabetes (n=4036). Other cardiovascular risk factors were assessed among those without known diabetes. For men and women the prevalence of diabetes (22.0 vs. 21.8%, respectively) and the prevalence of coexisting impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (3.2 vs. 2.9%) were similar. However, men were twice as likely as women to have isolated IFG [5.1% (4.2-6.0) vs. 2.9% (2.3-3.5)], despite being younger, thinner and with lower plasma insulin but higher lipids. Conversely, the prevalence of isolated IGT was lower in men [9.0% (7.9-10.2) vs. 13.9% (12.6-15.1)]. Among non-diabetic individuals, fasting glucose was higher in men than women, whereas 2-h glucose was higher in women. In people without diabetes, women had significantly higher body mass index, beta cell function (HOMA-B), fasting and 2-h insulin than men and significantly lower waist-hip ratios, waist circumference, insulin sensitivity (HOMA-S) and triglycerides. In Mauritius, the distribution of impaired glucose metabolism differs by sex. The observation that IFG is more prevalent in men and IGT more prevalent in women raises important questions about their underlying aetiology and the ability of the current glucose thresholds to equally identify men and women at high-risk of developing diabetes. IFG should be seen as a complimentary category of abnormal glucose tolerance, rather than a replacement for IGT.


Influence of compacted hydrophobic and hydrophilic colloidal silicon dioxide on tableting properties of pharmaceutical excipients.
The effect of noncompacted and compacted hydrophilic as well as hydrophobic colloidal silicon dioxide (CSD) on tableting properties of three different pharmaceutical excipients used for direct compression, namely, Avicel PH 101, Starch 1500, and Tablettose 80, was investigated. Binary powder mixtures containing 0.5% CSD and 99.5% excipient were compressed on an instrumented single-punch tablet press, and the radial tensile strength/compaction load profiles were examined. The Ryshkewitch-Duckworth relationship shows that the influence of CSD on tablet strength was dependent on the hydrophobic and hydrophilic nature of the CSD and on the compaction characteristics of the excipients. Tablets from each excipient with and without CSDs were subjected to different levels of relative humidity at 20 degrees C for 7 days. The sorption isotherms and the radial tensile strengths of the tablets after the storage period showed that neither hydrophilic nor hydrophobic CSD influenced the tablet properties of Avicel PH 101, Starch 1500, and Tablettose 80. Moreover, ternary powder mixtures containing magnesium stearate as a third component were compressed in order to study the influence of CSD on the deleterious effect of magnesium stearate on the interparticle bonding. The radial tensile strength/compaction load profiles and the residual and ejection forces of tablets made from ternary mixtures showed that CSD eliminated the negative effect of magnesium stearate on interparticle bonding while maintaining the lubrication action, in a manner that was affected by its hydrophobicity/hydrophilicity and by the particle deformation properties of the excipient upon compression.


Hypertension and proteinuria: long-term sequelae of uninephrectomy in humans.
Renal function and blood pressure were assessed in 52 renal allograft donors 10 years or more following uninephrectomy, and their current function compared to their pre-uninephrectomy function as well as to age- and sex-matched control subjects consisting of inpatient potential renal donors and a normal "outpatient" population. The results show no significant deterioration in renal function as determined by serum creatinine or creatinine clearance, as a function of years post-uninephrectomy or age at the time of donation. A higher incidence of proteinuria and hypertension was found in male donors as compared to their pre-uninephrectomy values and to age- and sex-matched, inpatient and outpatient control subjects. Female donors had increased proteinuria when compared to pre-uninephrectomy and to age-matched, inpatient potential donors. However, the extent of proteinuria and hypertension was not significantly different from outpatient age-matched females with two kidneys. In our population, uninephrectomy is associated with mild proteinuria and hypertension.


Contribution of vertebral [corrected] bodies, endplates, and intervertebral discs to the compression creep of spinal motion segments.
Spinal segments show non-linear behavior under axial compression. It is unclear to what extent this behavior is attributable to the different components of the segment. In this study, we quantified the separate contributions of vertebral bodies and intervertebral discs to creep of a segment. Secondly, we investigated the contribution of bone and osteochondral endplate (endplates including cartilage) to the deformation of the vertebral body. From eight porcine spines a motion segment, a disc and a vertebral body were dissected and subjected to mechanical testing. In an additional test, cylindrical samples, machined from the lowest thoracic vertebrae of 11 porcine spines, were used to compare the deformation of vertebral bone and endplate. All specimens were subjected to three loading cycles, each comprising a loading phase (2.0 MPa, 15 min) and a recovery phase (0.001 MPa, 30 min). All specimens displayed substantial time-dependent height changes. Average creep was the largest in motion segments and smallest in vertebral bodies. Bone samples with endplates displayed substantially more creep than samples without. In the early phase, behavior of the vertebra was similar to that of the disc. Visco-elastic deformation of the endplate therefore appeared dominant. In the late creep phase, behavior of the segment was similar to that of isolated discs, suggesting that in this phase the disc dominated creep behavior, possibly by fluid flow from the nucleus. We conclude that creep deformation of vertebral bodies contributes substantially to creep of motion segments and that within a vertebral body endplates play a major role.


Wound healing activities of different extracts of Centella asiatica in incision and burn wound models: an experimental animal study.
The efficacy of Centella asiatica for incision and burn wounds are not fully understood. Here, we report the wound healing activities of sequential hexane, ethyl acetate, methanol, and water extracts of Centella asiatica in incision and partial-thickness burn wound models in rats. Male Sprague-Dawley rats weighing 250-300 g were randomly divided into incision and burn wound groups. Each group was stratified into seven subgroups: (1) untreated; (2) NSS-; (3) Tween 20®- (vehicle control); (4) hexane extract-; (5) ethyl acetate extract-; (6) methanol extract-; and (7) aqueous extract-treated groups. The test substances were applied topically once daily. The tensile strength of the incision wound was measured on the seventh day after wound infliction. The general appearance and degree of wound healing of the burn wound were assessed on Days 3, 7, 10 and 14 after burn injury and prior to histopathological evaluation. On the seventh day after wound infliction, the tensile strength of incision wound in all extract-treated groups was significantly higher than that of the vehicle control (Tween 20®), but comparable to the NSS-treated group. The degrees of healing in the burn wound with the four extracts were significantly higher than that of the control on Days 3, 10 and 14. Histopathological findings on Day 14 after burn injury revealed prominent fibrinoid necrosis and incomplete epithelialization in the control and untreated groups, whereas fully developed epithelialization and keratinization were observed in all extract-treated groups. Analysis by thin layer chromatography demonstrated that the phyto-constituents β-sitosterol, asiatic acid, and asiaticoside and madecassocide were present in the hexane, ethyl acetate and methanol extracts, respectively. All extracts of Centella asiatica facilitate the wound healing process in both incision and burn wounds. Asiatic acid in the ethyl acetate extract seemed to be the most active component for healing the wound.


Compact Viscometer Prototype for Remote In Situ Analysis of Sludge.
On the Sellafield site there are several legacy storage tanks and silos containing sludge of uncertain properties. While there are efforts to determine the chemical and radiological properties of the sludge, to clean out and decommission these vessels, the physical properties need to be ascertained as well. Shear behaviour, density and temperature are the key parameters to be understood before decommissioning activities commence. However, limited access, the congested nature of the tanks and presence of radioactive, hazardous substances severely limit sampling and usage of sophisticated characterisation devices within these tanks and therefore, these properties remain uncertain. This paper describes the development of a cheap, compact, and robust device to analyse the rheological properties of sludge, without the need to extract materials from the site in order to be analysed. Analysis of a sludge test material has been performed to create a suitable benchmark material for the rheological measurements with the prototype. Development of the device is being undertaken with commercial off the shelf (COTS) components and modern rapid prototyping techniques. Using these techniques, an initial prototype for measuring shear parameters of sludge has been developed, using a micro-controller for remote control and data gathering. The device is also compact enough to fit through a 75 mm opening, maximising deployment capabilities.


Manipulating the metazoan mitochondrial genome with targeted restriction enzymes.
High copy number and random segregation confound genetic analysis of the mitochondrial genome. We developed an efficient selection for heritable mitochondrial genome (mtDNA) mutations in Drosophila, thereby enhancing a metazoan model for study of mitochondrial genetics and mutations causing human mitochondrial disease. Targeting a restriction enzyme to mitochondria in the germline compromised fertility, but escaper progeny carried homoplasmic mtDNA mutations lacking the cleavage site. Among mutations eliminating a site in the cytochrome c oxidase gene, mt:CoI(A302T) was healthy, mt:CoI(R301L) was male sterile but otherwise healthy, and mt:CoI(R301S) exhibited a wide range of defects, including growth retardation, neurodegeneration, muscular atrophy, male sterility, and reduced life span. Thus, germline expression of mitochondrial restriction enzymes creates a powerful selection and has allowed direct isolation of mitochondrial mutants in a metazoan.


Endothelial dysfunction is associated with a greater depressive symptom score in a general elderly population: the Hoorn Study.
Endothelial dysfunction (ED), low-grade inflammation (LGI) and oxidative stress (OxS) may be involved in the pathobiology of depression. Previous studies on the association of these processes in depression have yielded contradictory results. We therefore investigated comprehensively, in a population-based cohort study, the association between ED, LGI and OxS on the one hand and depressive symptoms on the other. We used data from the Hoorn Study and determined biomarkers of ED [flow-mediated dilatation (FMD), von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble thrombomodulin and soluble endothelial selectin], LGI [C-reactive protein, tumour necrosis factor-α, interleukin 6, interleukin 8, serum amyloid A, myeloperoxidase (MPO) and sICAM-1] and OxS (oxidized low density lipoprotein and MPO). Depressive symptoms were quantified by the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire (n = 493; age 68 years; 49.9% female). Regression analyses were performed with the use of biomarker Z scores. Adjustments were made for age, sex and glucose metabolism status (cohort stratification variables) and prior cardiovascular disease, hypertension, waist-to-hip ratio, cholesterol levels, education level, physical activity, dietary habits, and the use of antihypertensive and/or lipid-lowering medication and/or metformin (potential confounders). After adjustment for age, sex and glucose metabolism status, one standard deviation increase in the ED Z score was associated with a 1.9 [95% confidence interval (CI) 0.7-3.1] higher CES-D score. Additional adjustments did not materially change this result. LGI and OxS were not associated with the CES-D score. ED, as quantified by an array of circulating biomarkers and FMD, was independently associated with depressive symptoms. This study supports the hypothesis that ED plays an important role in the pathobiology of depression.


Associations of body mass index and waist circumference with: energy intake and percentage energy from macronutrients, in a cohort of Australian children.
It is evident from previous research that the role of dietary composition in relation to the development of childhood obesity remains inconclusive. Several studies investigating the relationship between body mass index (BMI), waist circumference (WC) and/or skin fold measurements with energy intake have suggested that the macronutrient composition of the diet (protein, carbohydrate, fat) may play an important contributing role to obesity in childhood as it does in adults. This study investigated the possible relationship between BMI and WC with energy intake and percentage energy intake from macronutrients in Australian children and adolescents. Height, weight and WC measurements, along with 24 h food and drink records (FDR) intake data were collected from 2460 boys and girls aged 5-17 years living in the state of Queensland, Australia. Statistically significant, yet weak correlations between BMI z-score and WC with total energy intake were observed in grades 1, 5 and 10, with only 55% of subjects having a physiologically plausible 24 hr FDR. Using Pearson correlations to examine the relationship between BMI and WC with energy intake and percentage macronutrient intake, no significant correlations were observed between BMI z-score or WC and percentage energy intake from protein, carbohydrate or fat. One way ANOVAs showed that although those with a higher BMI z-score or WC consumed significantly more energy than their lean counterparts. No evidence of an association between percentage macronutrient intake and BMI or WC was found. Evidently, more robust longitudinal studies are needed to elucidate the relationship linking obesity and dietary intake.


Synaptic assembly of the brain in the absence of neurotransmitter secretion.
Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.


Type II protein secretion in gram-negative pathogenic bacteria: the study of the structure/secretion relationships of the cellulase Cel5 (formerly EGZ) from Erwinia chrysanthemi.
Erwinia chrysanthemi, a Gram-negative plant pathogen, secretes the cellulase Cel5 (formerly EGZ) via the type II secretion pathway (referred to as Out). Cel5 is composed of two domains, a large N-terminal catalytic domain (390 amino acid residues) and a small C-terminal cellulose-binding domain (62 amino acid residues) separated by a linker region. A combination of mutagenesis and structural analysis permitted us to investigate the structure/secretion relationships with respect to the catalytic domain of Cel5. The 3D structure of the catalytic domain was solved by molecular replacement at 2.3 A resolution. Cel5 exhibits the (beta/alpha)8 structural fold and two extra-barrel features. Our previous genetic study based upon tRNA-mediated suppression allowed us to predict positions of importance in the molecule in relation to structure and catalysis. Remarkably, all of the predictions proved to be correct when compared with the present structural information. Mutations of Arg57, which is located at the heart of the catalytic domain, allowed us to test the consequences of structural modifications on the secretion efficiency. The results revealed that secretability imposes remarkably strong constraints upon folding. In particular, an Arg-to-His mutation yielded a species that folded to a stable conformation close to, but distinct from the wild-type, which however was not secretable. We discuss the relationships between folding of a protein in the periplasm, en route to the cell exterior, and presentation of secretion information. We propose that different solutions have been selected for type II secreted exoproteins in order to meet the constraints imposed by their interaction with their respective secretion machineries. We propose that evolutionary pressure has led to the adaptation of different secretion motifs for different type II exoproteins.


microRNA arm-imbalance in part from complementary targets mediated decay promotes gastric cancer progression.
Strand-selection is the final step of microRNA biogenesis in which functional mature miRNAs are generated from one or both arms of precursor. The preference of strand-selection is diverse during development and tissue formation, however, its pathological effect is still unknown. Here we find that two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, are inversely expressed and play exactly opposite roles in gastric cancer progression. Higher-5p with lower-3p expression pattern is significantly correlated with higher TNM stages and poor prognosis of gastric cancer patients. The increase of miR-574-5p/-3p ratio, named miR-574 arm-imbalance is partially due to the dynamic expression of their highly complementary targets in gastric carcinogenesis, moreover, the arm-imbalance of miR-574 is in turn involved and further promotes gastric cancer progression. Our results indicate that miR-574 arm-imbalance contribute to gastric cancer progression and re-modification of the miR-574-targets homeostasis may represent a promising strategy for gastric cancer therapy.


The effects of midgut serine proteases on dengue virus type 2 infectivity of Aedes aegypti.
Dengue viruses (DENV) cause significant morbidity and mortality worldwide and are transmitted by the mosquito Aedes aegypti. Mosquitoes become infected after ingesting a viremic bloodmeal, and molecular mechanisms involved in bloodmeal digestion may affect the ability of DENV to infect the midgut. We used RNA interference (RNAi) to silence expression of four midgut serine proteases and assessed the effect of each RNAi phenotype on DENV-2 infectivity of Aedes aegypti. Silencing resulted in significant reductions in protease mRNA levels and correlated with a reduction in activity except in the case of late trypsin. RNA silencing of chymotrypsin, early and late trypsin had no effect on DENV-2 infectivity. However, silencing of 5G1 or the addition of soybean trypsin inhibitor to the infectious bloodmeals significantly increased midgut infection rates. These results suggest that some midgut serine proteases may actually limit DENV-2 infectivity of Ae. aegypti.


DA-6034-induced mucin secretion via Ca2+-dependent pathways through P2Y receptor stimulation.
We evaluated whether DA-6034 is involved in mucin secretion via P2Y receptor activation and/or intracellular Ca2+ concentration ([Ca2+]i) change. Also, we investigated the effect of P2Y receptor inhibitors or Ca2+ chelators on the DA-6034-induced mucin secretion and [Ca2+]i increases. Effects of DA-6034 on mucin expression in primary, cultured, conjunctival epithelial cells was studied using RT-PCR, Western blot analysis, and periodic acid-schiff (PAS) staining. To evaluate thin film layer thickness generated by mucin and fluid secretion, cells were incubated in DA-6034 with/without P2Y antagonists or extracellular/intracellular Ca2+ chelators, and were imaged with confocal microscope using Texas Red-dextran dye. In addition, DA-6034-induced Ca2+-dependent Cl- channels opening was evaluated using perforated patch clamp. Fluo-4/AM was used to measure changes in [Ca2+]i induced by DA-6034 in Ca2+-free or Ca2+-containing buffered condition, as well as P2Y antagonists. DA-6034 induced the expression of mucin genes, production of mucin protein, and increase of number of mucin-secreting cells. P2Y antagonists inhibited DA-6034-induced mucin and fluid secretion, which was also affected by extracellular/intracellular Ca2+ chelators. DA-6034 stimulated Cl- channel opening and [Ca2+]i elevation. Further, [Ca2+]i increases induced by DA-6034 were lacking in either P2Y antagonists or Ca2+-free buffered condition, and diminished when endoplasmic reticulum Ca2+ was depleted by cyclopiazonic acid in Ca2+-free buffered condition. This study demonstrated that DA-6034 has a potential to induce mucin secretion via Ca2+-dependent pathways through P2Y receptors in multilayer, cultured, human conjunctival epithelial cells.


Hinge axis determination of the temporomandibular joint and its interpretation: what do we really measure?
Terminal hinge axis (THA) determination is recommended in some clinical situations and for some diagnostic purposes. Different methods are described and are available for this task. In particular, circle fitting or iterative trace recording methods, in the conventional process known as the pantographic or Lauritzen method, have mostly been applied in clinical settings and have even been used as exact reference measures in many studies. The aim of this study was to investigate whether the conditions for THA determination by these methods principally allow for the differentiation between a pure rotational movement and a combined translational and rotational movement. A further question relates to how large the uncertainties are if an additional translational movement is present during the first phase of mouth opening or closing. These questions were investigated by an exact simulation. The methods under consideration are seen to be able to detect a pure rotational movement, if one or both of the following conditions are met: a) the traces recorded around the rotational center perform a circlelike motion, and b) a point or pin on the rotational center remains at rest during movement. It can be proven that in the relevant clinical situation these conditions also hold in the case of a combination of translational and rotational movement. Furthermore, small translations of 1.1 mm lead to a deviation of the THA of around ± 6.7 mm, and a translation of 2.2 mm to an uncertainty of even ± 13.5 mm. The significance of these results suggests that the commonly used methods for THA determination should be reevaluated, and the literature on this topic should be carefully scrutinized.


National anti-tuberculosis drug resistance study in Tanzania.
To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all diagnostic centres in the country. The survey enrolled 1019 new and 148 retreatment patients. The adjusted prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line drugs in new patients was 8.3%, while the prevalence of multidrug-resistant TB (MDR-TB) was 1.1%. In retreatment patients, the crude prevalence for any resistance and for MDR-TB was respectively 20.6% and 3.9%. The prevalence of drug resistance did not differ in relapse patients compared to failure patients. These estimates are among the lowest in those African countries with an estimated level of drug resistance in the last 5 years. The low levels of drug resistance in Tanzania are likely due to a well performing TB control programme and the absence of noticeable involvement of the private sector in TB treatment.


Gonorrhoea and gonococcal antimicrobial resistance surveillance networks in the WHO European Region, including the independent countries of the former Soviet Union.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae has emerged for essentially all antimicrobials following their introduction into clinical practice. During the latest decade, susceptibility to the last remaining options for antimicrobial monotherapy, the extended-spectrum cephalosporins (ESC), has markedly decreased internationally and treatment failures with these ESCs have been verified. In response to this developing situation, WHO and the European Centre for Disease Prevention and Control (ECDC) have published global and region-specific response plans, respectively. One main component of these action/response plans is to enhance the surveillance of AMR and treatment failures. This paper describes the perspectives from the diverse WHO European Region (53 countries), including the independent countries of the former Soviet Union, regarding gonococcal AMR surveillance networks. The WHO European Region has a high prevalence of resistance to all previously recommended antimicrobials, and most of the first strictly verified treatment failures with cefixime and ceftriaxone were also reported from Europe. In the European Union/European Economic Area (EU/EEA), the European gonococcal antimicrobial surveillance programme (Euro-GASP) funded by the ECDC is running. In 2011, the Euro-GASP included 21/31 (68%) EU/EEA countries, and the programme is further strengthened annually. However, in the non-EU/EEA countries, internationally reported and quality assured gonococcal AMR data are lacking in 87% of the countries and, worryingly, appropriate support for establishment of a GASP is still lacking. Accordingly, national and international support, including political and financial commitment, for gonococcal AMR surveillance in the non-EU/EEA countries of the WHO European Region is essential.


Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells.
Embryonic stem cells sustain a microenvironment that facilitates a balance of self-renewal and differentiation. Aggressive cancer cells, expressing a multipotent, embryonic cell-like phenotype, engage in a dynamic reciprocity with a microenvironment that promotes plasticity and tumorigenicity. However, the cancer-associated milieu lacks the appropriate regulatory mechanisms to maintain a normal cellular phenotype. Previous work from our laboratory reported that aggressive melanoma and breast carcinoma express the embryonic morphogen Nodal, which is essential for human embryonic stem cell (hESC) pluripotency. Based on the aberrant expression of this embryonic plasticity gene by tumor cells, this current study tested whether these cells could respond to regulatory cues controlling the Nodal signaling pathway, which might be sequestered within the microenvironment of hESCs, resulting in the suppression of the tumorigenic phenotype. Specifically, we discovered that metastatic tumor cells do not express the inhibitor to Nodal, Lefty, allowing them to overexpress this embryonic morphogen in an unregulated manner. However, exposure of the tumor cells to a hESC microenvironment (containing Lefty) leads to a dramatic down-regulation in their Nodal expression concomitant with a reduction in clonogenicity and tumorigenesis accompanied by an increase in apoptosis. Furthermore, this ability to suppress the tumorigenic phenotype is directly associated with the secretion of Lefty, exclusive to hESCs, because it is not detected in other stem cell types, normal cell types, or trophoblasts. The tumor-suppressive effects of the hESC microenvironment, by neutralizing the expression of Nodal in aggressive tumor cells, provide previously unexplored therapeutic modalities for cancer treatment.


Physical rehabilitation for critical illness myopathy and neuropathy.
Intensive care unit (ICU) acquired or generalised weakness due to critical illness myopathy (CIM) and polyneuropathy (CIP) are major causes of chronically impaired motor function that can affect activities of daily living and quality of life. Physical rehabilitation of those affected might help to improve activities of daily living. Our primary objective was to assess the effects of physical rehabilitation therapies and interventions for people with CIP and CIM in improving activities of daily living such as walking, bathing, dressing and eating. Secondary objectives were to assess effects on muscle strength and quality of life, and to assess adverse effects of physical rehabilitation. On 16 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register and on 14 July 2014 we searched CENTRAL, MEDLINE, EMBASE and CINAHL Plus. In July 2014, we searched the Physiotherapy Evidence Database (PEDro, http://www.pedro.org.au/) and three trials registries for ongoing trials and further data about included studies. There were no language restrictions. We also handsearched relevant conference proceedings and screened reference lists to identify further trials. We planned to include randomised controlled trials (RCTs), quasi-RCTs and randomised controlled cross-over trials of any rehabilitation intervention in people with acquired weakness syndrome due to CIP/CIM. We would have extracted data, assessed the risk of bias and classified the quality of evidence for outcomes in duplicate, according to the standard procedures of The Cochrane Collaboration. Outcome data collection would have been for activities of daily living (for example, mobility, walking, transfers and self care). Secondary outcomes included muscle strength, quality of life and adverse events. The search strategy retrieved 3587 references. After examination of titles and abstracts, we retrieved the full text of 24 potentially relevant studies. None of these studies met the inclusion criteria of our review. No data were suitable to be included in a meta-analysis. There are no published RCTs or quasi-RCTs that examine whether physical rehabilitation interventions improve activities of daily living for people with CIP and CIM. Large RCTs, which are feasible, need to be conducted to explore the role of physical rehabilitation interventions for people with CIP and CIM.


Treatment of Periprosthetic Joint Infection Using Antimicrobials: Dilute Povidone-Iodine Lavage.
Periprosthetic joint infections (PJI) remain a challenge for the orthopaedic surgeon to treat and remain a leading cause of failure of both primary and revision total joint arthroplasty. Once a PJI develops, surgical treatment is generally indicated and includes an aggressive irrigation and debridement. One component of the irrigation and debridement involves the use of an antiseptic irrigating solution. In primary and revision TJA, dilute povidone-iodine lavage can be performed prior to wound closure. Approximately 17.5mL of 10% povidone-iodine is diluted with 500-1000cc of normal saline. The wound is then irrigated with the dilute povidone-iodine for 3 minutes. The dilute povidone-iodine is then thoroughly irrigated and washed out of the wound with normal saline prior to wound closure. The use of dilute povidone-iodine lavage prior to wound closure has been shown to reduce the risk of deep surgical site infection in multiple surgical specialties. In primary TJA, it has been demonstrated to reduce the risk of infection, without any associated adverse effects. It is also included in multiple protocols for the surgical treatment of PJI. Dilute povidone-iodine lavage provides a safe and inexpensive method to reduce the rate of PJI in TJA.


Initial results of combined anterior mitral leaflet extension and myectomy in patients with obstructive hypertrophic cardiomyopathy.
The purpose of this study was to describe the clinical and functional results of combined anterior mitral leaflet extension and myectomy in patients with hypertrophic obstructive cardiomyopathy. Septal myectomy is the most commonly performed surgical procedure in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. Because of the role of the mitral valve in creating the outflow tract gradient, mitral valve replacement or plication is performed in selected cases in combination with myectomy, often with better hemodynamic results than those of myectomy alone. Mitral valve leaflet extension, in which a glutaraldehyde-preserved autologous pericardial patch is used to enlarge the mitral valve along its horizontal axis, is a novel surgical approach in patients with hypertrophic obstructive cardiomyopathy. Eight patients with hypertrophic obstructive cardiomyopathy were treated with mitral leaflet extension and myectomy. Preoperative and postoperative data (New York Heart Association functional class, number of drugs prescribed, width of the interventricular septum, severity of mitral valve regurgitation severity of systolic anterior motion of the mitral valve and outflow tract gradient) were compared with those of 12 patients undergoing myectomy alone. Preoperative evaluation demonstrated that mitral regurgitation and systolic anterior motion of the mitral valve were more severe in the group undergoing mitral valve extension (p < 0.001 and p < 0.05, respectively). There were no deaths associated with either surgical procedure. Two patients, both treated by myectomy alone, died during the follow-up period. Postoperatively, patients treated with mitral valve extension had less mitral regurgitation (p < 0.005), less residual systolic anterior motion (p < 0.001), greater improvement in functional class (p = 0.05) and greater reduction in the number of drugs (p < 0.005) and in septal thickness (p < 0.05). Mitral leaflet extension in combination with myectomy is a promising new surgical approach that may provide superior results to those of myectomy alone. Further studies are needed to determine the clinical value of this procedure.


External cavity tunable quantum cascade lasers and their applications to trace gas monitoring.
Since the first quantum cascade laser (QCL) was demonstrated approximately 16 years ago, we have witnessed an explosion of interesting developments in QCL technology and QCL-based trace gas sensors. QCLs operate in the mid-IR region (3-24 μm) and can directly access the rotational vibrational bands of most molecular species and, therefore, are ideally suited for trace gas detection with high specificity and sensitivity. These sensors have applications in a wide range of fields, including environmental monitoring, atmospheric chemistry, medical diagnostics, homeland security, detection of explosive compounds, and industrial process control, to name a few. Tunable external cavity (EC)-QCLs in particular offer narrow linewidths, wide ranges of tunability, and stable power outputs, which open up new possibilities for sensor development. These features allow for the simultaneous detection of multiple species and the study of large molecules, free radicals, ions, and reaction kinetics. In this article, we review the current status of EC-QCLs and sensor developments based on them and speculate on possible future developments.


Quantitative, dynamic 18F-FDG-PET for the evaluation of soft tissue sarcomas: relation to differential diagnosis, tumor grading and prediction of prognosis.
The purpose of this study was to evaluate soft tissue sarcomas by dynamic (18)F-FDG-PET studies, and to establish an index of kinetic parameters for evaluation of their malignancy, histological grade and prognosis, after surgical resection. One hundred and seventeen patients including 79 with histologically proven soft tissue malignancies, 14 with primary benign soft tissue tumors and 24 with postoperative scar tissues were examined. The (18)F-FDG studies were accomplished as a dynamic series for 60 min. The evaluation of the (18)F-FDG kinetics was performed using the following parameters: standardized uptake value (SUV), global influx (Ki), computation of transport constants (k1-k4) with consideration of the vascular fraction (VB) according to a two tissue compartment model, and fractal dimension (FD) based on the box-counting procedure (non-compartmental model). Discriminant analysis (DA) was used for data evaluation. Multivariate analysis was performed to assess the predictive value of each kinetic parameter on survival. Our results showed that in the primary cases (n=46), SUV, k1, Ki and FD were higher in sarcomas than benign tumors. The diagnostic sensitivity of 62.50%, a specificity of 92.86%, and an accuracy of 71.74% were achieved by using the combination of k1 and SUV as input variables for DA. In the postoperative cases (n=71), SUV, VB, k3, Ki, and FD were higher in recurrent lesions than in scar tissues. DA revealed a sensitivity of 80.85%, a specificity of 87.50%, and an accuracy of 83.10% by using the combination of SUV, Ki and FD. In liposarcoma patients (n=32), SUV and FD were higher in GII,III tumors as compared with GI. DA led to a sensitivity of 86.96%, a specificity of 55.56%, and an accuracy of 78.13% by using the combination of SUV and FD. By multivariate analysis of primary soft tissue sarcomas (n=26) after surgical resection, groups with k3>0.025 (P<0.0026) or FD>1.25 (P<0.0162) had significantly poor prognosis. In conclusion, the evaluation of full (18)F-FDG kinetics provides important information for the diagnosis of malignant lesions, histological grading and prognosis of soft tissue sarcomas.


Intentional modulation of the late positive potential in response to smoking cues by cognitive strategies in smokers.
Attentional bias is considered an important concept in addiction since it has been found to correlate with subjective craving and is strongly associated with relapse after periods of abstinence. Hence, investigating in ways to regulate attention for drug cues would be of major clinical relevance. The present study examined deliberate, cognitive modulation of motivated attention for smoking cues in smokers. The effects of three different reappraisal strategies on an electrophysiological measure of attentive processing were investigated. Early and late LPP components in response to passively viewed neutral and smoking pictures were compared with LPPs in response to smoking pictures that were reappraised with three different reappraisal strategies. Results show that when smokers actively imagine how pleasant it would be to smoke (pleasant condition), their early LPP in response to smoking cues increases, but when smokers actively focus on an alternative stimulus (distraction condition) or think of a rational, uninvolved interpretation of the situation (rational condition), smoking-related late LPP amplitude decreases to the processing level of neutral stimuli. Present results are the first to indicate that smoking cue-elicited LPP amplitudes can be modulated by cognitive strategies, suggesting that attentive processing of smoking cues can be intentionally regulated by smokers with various levels of dependence. Although cognitive strategies can lead to enhanced processing of smoking cues, it is not completely clear whether cognitive strategies are also successful in reducing smoking-related motivated attention. Although findings do point in this direction, present study is best considered preliminary and a starting point for other research on this topic. A focus on the distraction strategy is proposed, as there are indications that this strategy is more successful than the rational strategy in decreasing LPP amplitude.


A Rare Case of Mainly Unilateral Focal Dermal Hypoplasia (Goltz Syndrome) in an Adult Male: A Case Report and Review of the Literature.
Focal dermal hypoplasia (Goltz syndrome), is an exceedingly rare X-linked dominant genetic disorder. It is a multisystem disease, but it is hallmarked by characteristic skin changes. Focal dermal hypoplasia typically occurs in females (90%), and males are thought to only survive through having either a sporadic new mutation or somatic mosaicism. This report details a 48-year-old male diagnosed with predominately unilateral focal dermal hypoplasia that was reviewed decades post his initial diagnosis. He presented with multiple atrophic hyperpigmented macules and fat herniation along the lines of Blaschko, across primarily the right side of the body. Skin biopsy is the mainstay for the diagnosis and therefore dermatologists need to be aware of the classical cutaneous findings of familial dermal hypoplasia to ensure accurate diagnosis. Familial dermal hypoplasia is best managed through the collective minds of multidisciplinary teams.