Real-time nanomicroscopy via three-dimensional single-particle tracking.
We developed a new method for real-time, three-dimensional tracking of fluorescent particles. The instrument is based on a laser-scanning confocal microscope where the focus of the laser beam is scanned or orbited around the particle. Two confocal pinholes are used to simultaneously monitor regions immediately above and below the particle and a feedback loop is used to keep the orbit centered on the particle. For moderate count rates, this system can track particles with 15 nm spatial resolution in the lateral dimensions and 50 nm in the axial dimension at a temporal resolution of 32 ms. To investigate the interaction of the tracked particles with cellular components, we have combined our orbital tracking microscope with a dual-color, wide-field setup. Dual-color fluorescence wide-field images are recorded simultaneously in the same image plane as the particle being tracked. The functionality of the system was demonstrated by tracking fluorescent-labeled artificial viruses in tubulin-eGFP expressing HUH7 cells. The resulting trajectories can be used to investigate the microtubule network with super resolution.


Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy.
High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with β-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 μg) of (177)Lu-DOTA-Tyr(3)-octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n ≥ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of (99m)Tc-dimercaptosuccinic acid ((99m)Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA) and 50 MBq of (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) at 100-120 d after therapy. (111)In-DTPA and (99m)Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced (111)In-DTPA, (99m)Tc-MAG3, and (99m)Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of (99m)Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Quantitative dynamic dual-isotope imaging using both (111)In-DTPA and (99m)Tc-MAG3 and static (99m)Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. (99m)Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or (99m)Tc-DMSA scintigraphy.


Hematology Laboratory Abnormalities in Patients with Coronavirus Disease 2019 (COVID-19).
Over the past few months, Coronavirus Disease 2019 (COVID-19) has spread across much of the world leading to a pandemic. Many infected individuals do not experience signs or symptoms, or experience only mild symptoms, whilst a subset experience severe disease, which is often fatal. A number of laboratory tests have been found to be abnormal in hospitalized patients, and some studies suggest some of these tests can predict an unfavorable outcome. These include markers of acute phase reaction (elevated C-reactive protein, erythrocyte sedimentation rate, white blood cell count, fibrinogen, procalcitonin, factor VIII, von Willebrand factor), signs of tissue injury (elevated lactic dehydrogenase, alanine aminotransferase, cardiac troponins), changes in hemostasis and coagulation (elevated D-dimer, prolonged prothrombin time, decreased platelets, decreased antithrombin, elevated factor VIII and von Willebrand factor), and decreased lymphocytes. Additional studies are needed to confirm the most ideal panel of tests, and to confirm the efficiency of laboratory tests to predict clinical outcome, as well as the ideal anticoagulation management.


Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation.
DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a-c and 4a-c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.


Models of charge pair generation in organic solar cells.
Efficient charge pair generation is observed in many organic photovoltaic (OPV) heterojunctions, despite nominal electron-hole binding energies which greatly exceed the average thermal energy. Empirically, the efficiency of this process appears to be related to the choice of donor and acceptor materials, the resulting sequence of excited state energy levels and the structure of the interface. In order to establish a suitable physical model for the process, a range of different theoretical studies have addressed the nature and energies of the interfacial states, the energetic profile close to the heterojunction and the dynamics of excited state transitions. In this paper, we review recent developments underpinning the theory of charge pair generation and phenomena, focussing on electronic structure calculations, electrostatic models and approaches to excited state dynamics. We discuss the remaining challenges in achieving a predictive approach to charge generation efficiency.


Goos-Hänchen shifts due to spin-orbit coupling in the carbon nanotube quantum dot nanostructures.
The properties of Goos-Hänchen (GH) shifts for transmitted and reflected light pulses in a cavity with an intracavity medium consist of carbon nanotube quantum dot nanostructures, which have been discussed theoretically by using the stationary phase theory. Our findings show that due to the presence of spin-orbit coupling, the maximum negative and positive shifts can be realized by modifying the absorption and dispersion properties of the intracavity medium. Moreover, the effect of the transverse magnetic field has been also considered as a new parameter for controlling the GH shifts in reflected and transmitted light beams. We hope that our proposed structure may be suitable for the generation of future all-optical system devices based on carbon nanotube quantum dot nanostructures.


Genetic analysis of incident HIV-1 strains among injection drug users in Bangkok: evidence for multiple transmission clusters during a period of high incidence.
During 1995-1996, 1,209 HIV-1-negative injection drug users (IDUs) attending methadone treatment clinics operated by the Bangkok Metropolitan Administration in Bangkok, Thailand, were enrolled in a prospective cohort study. Through 1998, 133 of these IDUs had seroconverted to HIV-1; 130 of these seroconverters were included in this study. HIV-1 CRF01_AE and subtype B strains accounted for 79% and 21% of the incident infections, respectively. To examine phylogenetic relationships among these incident HIV-1 strains, we used several phylogenetic inference methodologies to analyze the env (C2-V4) sequences in blood samples collected soon after seroconversion. These analyses consistently revealed eight phylogenetic clusters comprising 21 incident strains (bootstrap method, >80%; six CRF01_AE and two subtype B clusters). Two factors were found to be associated with the eight clusters. The first factor was temporal: seven of the eight clusters comprised 17 sequences from IDUs whose estimated dates of seroconversion were within a period of high incidence from July 1996 through January 1997. The second factor was a possible geographic association: four clusters were observed among IDUs who had attended the same methadone treatment clinics. These phylogenetic clusters likely represent subgroups within larger HIV transmission networks among IDUs in Bangkok. Despite prevention efforts, the incidence of HIV-1 infection among the Bangkok IDU population continues to be high. A better understanding of transmission networks and factors associated with such networks can help guide prevention efforts.


Ecological and immunological determinants of dengue epidemics.
The management of infectious diseases is an increasingly important public health issue, the effective implementation of which is often complicated by difficulties in teasing apart the relative roles of extrinsic and intrinsic factors influencing transmission. Dengue, a vector-borne strain polymorphic disease, is one such infection where transmission dynamics are affected by environmental variables as well as immune-mediated serotype interactions. To understand how alternative hypotheses concerning dengue infection and transmission may explain observed multiannual cycles in disease incidence, we adopt a theoretical approach that combines both ecological and immunological mechanisms. We demonstrate that, contrary to perceived wisdom, patterns generated solely by antibody-dependent enhancement or heterogeneity in virus virulence are not consistent with serotype-specific notification data in important ways. Furthermore, to generate epidemics with the characteristic signatures observed in data, we find that a combination of seasonal variation in vector demography and, crucially, a short-lived period of cross-immunity is sufficient. We then show how understanding the persistence and eradication of dengue serotypes critically depends on the alternative assumed mechanisms.


An indirect method to monitor the fraction of people ever infected with COVID-19: An application to the United States.
The number of COVID-19 infections is key for accurately monitoring the pandemics. However, due to differential testing policies, asymptomatic individuals and limited large-scale testing availability, it is challenging to detect all cases. Seroprevalence studies aim to address this gap by retrospectively assessing the number of infections, but they can be expensive and time-intensive, limiting their use to specific population subgroups. In this paper, we propose a complementary approach that combines estimated (1) infection fatality rates (IFR) using a Bayesian melding SEIR model with (2) reported case-fatality rates (CFR) in order to indirectly estimate the fraction of people ever infected (from the total population) and detected (from the ever infected). We apply the technique to the U.S. due to their remarkable regional diversity and because they count with almost a quarter of all global confirmed cases and deaths. We obtain that the IFR varies from 1.25% (0.39-2.16%, 90% CI) in Florida, the most aged population, to 0.69% in Utah (0.21-1.30%, 90% CI), the youngest population. By September 8, 2020, we estimate that at least five states have already a fraction of people ever infected between 10% and 20% (New Jersey, New York, Massachussets, Connecticut, and District of Columbia). The state with the highest estimated fraction of people ever infected is New Jersey with 17.3% (10.0, 55.8, 90% CI). Moreover, our results indicate that with a probability of 90 percent the fraction of detected people among the ever infected since the beginning of the epidemic has been less than 50% in 15 out of the 20 states analyzed in this paper. Our approach can be a valuable tool that complements seroprevalence studies and indicates how efficient have testing policies been since the beginning of the outbreak.


Histopathology of bronchiolar disorders.
Bronchiolar pathologic lesions result from the interplay between inflammatory and mesenchymal cells following injury to bronchioles. Offending agents include viruses, bacteria, fungi, cigarette smoke, toxic inhalants, inorganic dusts, allergens, and systemic or localized autoimmune or inflammatory processes. Bronchiolar pathologic lesions also arise in the context of allograft transplantation and pathology of the large airways and in the setting of an idiopathic disorder. Given the great variety of sources of injury and diversity of clinical, radiological, and functional patterns that result, it is no surprise that most morphological abnormalities of the bronchioles are not specific. They thus represent a diagnostic challenge to the surgical pathologist, and the necessity of a multidisciplinary (clinical/radiological/pathologic) approach cannot be overemphasized. After a survey of the normal histology of bronchioles, we present a pragmatic classification that reflects the spectrum of bronchiolar pathology, illustrating the intimate interdependence of clinical, radiological, and pathologic findings in assessing the significance of bronchiolar lesions. This classification is intended to be applicable to surgical pathology material that can be correlated with clinical disease syndromes. It includes asthma-associated bronchiolar changes, chronic bronchitis/emphysema-associated bronchiolar changes, cellular bronchiolitis, respiratory bronchiolitis, bronchiolitis obliterans with intraluminal polyps/ BOOP, constrictive bronchiolitis, mineral dust small airway disease, peribronchiolar fibrosis and bronchiolar metaplasia, and bronchiolocentric nodules.


Detection of radial crossbridge force by lattice spacing changes in intact single muscle fibers.
Time-resolved lattice spacing changes were measured (10-millisecond time resolution) by x-ray diffraction of synchrotron radiation in single intact muscle fibers of the frog Rana temporaria undergoing electrically stimulated tension development during application of stretches and releases. Ramp releases, which decreased fiber length at constant speed, caused a lattice expansion. After the ramp, increasing tension during recovery was accompanied by lattice compression. Ramp stretches caused a compression of the lattice. While the fiber was held at a constant length after the stretch, tension decreased and lattice spacing increased. These observations demonstrate the existence of a previously undetected radial component of the force generated by a cycling crossbridge. At sarcomere lengths of 2.05 to 2.2 micrometers, the radial force compresses the myofilament lattice. Hence, the myofilament lattice does not maintain a constant volume during changes in force.


Longevity of duodenal and peripheral T-cell and humoral responses to live-attenuated Salmonella Typhi strain Ty21a.
We have previously demonstrated that polyfunctional Ty21a-responsive CD4+ and CD8+ T cells are generated at the duodenal mucosa 18 days following vaccination with live-attenuated S. Typhi (Ty21a). The longevity of cellular responses has been assessed in peripheral blood, but persistence of duodenal responses is unknown. We vaccinated eight healthy adults with Ty21a. Peripheral blood and duodenal samples were acquired after a median of 1.5 years (ranging from 1.1 to 3.7 years) following vaccination. Cellular responses were assessed in peripheral blood and at the duodenal mucosa by flow cytometry. Levels of IgG and IgA were also assessed in peripheral blood by enzyme-linked immunosorbent assay. No T-cell responses were observed at the duodenal mucosa, but CD4+ T-cell responses to Ty21a and FliC were observed in peripheral blood. Peripheral anti-lipopolysaccharide IgG and IgA responses were also observed. Early immunoglobulin responses were not associated with the persistence of long-term cellular immune responses. Early T-cell responses which we have previously observed at the duodenal mucosa 18 days following oral vaccination with Ty21a could not be detected at a median of 1.5 years. Peripheral responses were observed at this time. Immunoglobulin responses observed shortly after vaccination were not associated with cellular immune responses at 1.5 years, suggesting that the persistence of cellular immunity is not associated with the strength of the initial humoral response to vaccination.


Carbon assimilation in crops at high temperatures.
Global temperatures are rising, and higher rates of temperature increase are projected over land areas that encompass the globe's major agricultural regions. In addition to increased growing season temperatures, heat waves are predicted to become more common and severe. High temperatures can inhibit photosynthetic carbon gain of crop plants and thus threaten productivity, the effects of which may interact with other aspects of climate change. Here, we review the current literature assessing temperature effects on photosynthesis in key crops with special attention to field studies using crop canopy heating technology and in combination with other climate variables. We also discuss the biochemical reactions related to carbon fixation that may limit crop photosynthesis under warming temperatures and the current strategies for adaptation. Important progress has been made on several adaptation strategies demonstrating proof-of-concept for translating improved photosynthesis into higher yields. These are now poised to test in important food crops.


Serum sialic acid concentration and cardiovascular mortality.
To determine whether serum sialic acid concentration may be used to predict short and long term cardiovascular mortality. Prospective study on all men and women who had their serum sialic acid concentration measured as part of a general health survey in 1964 or in 1965. All were followed up for an average of 20.5 years. Geographical part of the county of Värmland, Sweden. Residents in the area participating in a health check up in 1964-5 (27,065 men and 28,037 women), of whom 372 men (169 with incomplete data and 203 lost to follow up) and 345 women (143 and 202 respectively) were excluded; thus 26,693 men and 27,692 women entered the study. The study sample was restricted to subjects aged 40-74 during any of the 20 years' follow up. Serum sialic acid concentration, serum cholesterol concentration, diastolic blood pressure, body mass index at the general health survey visit; cardiovascular and non-cardiovascular deaths during three periods of follow up (0-6 years, 7-13 years, and 14-20 years), according to the Swedish mortality register, in subjects aged 45-74. Mean serum sialic acid concentration (mg/100 ml) was 68.8 (SD 8.0) for men and 69.2 (8.0) for women; the average concentration increasing with age in both sexes. A total of 5639 (21%) men and 3307 (12%) women died during the follow up period, in whom death in 3052 (54%) men and 1368 (41%) women was from cardiovascular causes. During short (0-6 years), medium (7-13 years), and long (14-20 years) term follow up the relative risk of death from cardiovascular disease increased with increasing serum sialic acid concentration. The relative risk (95% confidence interval) associated with the highest quartile of sialic acid concentration compared with the lowest quartile was 2.38 (2.01 to 2.83) in men and 2.62 (1.93 to 3.57) in women. Similar results were found for deaths from non-cardiovascular disease with relative risks of 1.50 (1.34 to 2.68) in men and 1.89 (1.57 to 2.28) in women, but these relative risks were significantly lower than those for deaths from cardiovascular disease (p less than 0.001 and p less than 0.005 respectively). In multivariate analysis of total mortality and of cardiovascular mortality with sialic acid concentration, serum cholesterol concentration, diastolic blood pressure, and body mass index as independent variables the impact of sialic acid concentration was virtually the same as in univariate analysis. Serum sialic acid concentration is a strong predictor of cardiovascular mortality. A possible explanation of these findings is that the serum sialic acid concentration may reflect the existence or the activity of an atherosclerotic process, and this may warrant further investigation.


Cracking the genome's second code: enhancer detection by combined phylogenetic footprinting and transgenic fish and frog embryos.
Genes involved in vertebrate development are unusually enriched for highly conserved non-coding sequence elements. These regions are readily detected in silico, by genome-wide sequence comparisons between different vertebrates, from mammals to fish (phylogenetic footprinting). It follows that sequence conservation must be the result of positive selection for an essential physiological role. An obvious possibility is that these conserved sequences possess regulatory or structural functions important for gene expression and, thus, an in vivo assay becomes necessary. We have developed a rapid testing system using zebrafish and Xenopus laevis embryos that allows us to assign transcriptional regulatory functions to conserved non-coding sequence elements. The sequences are cloned into a vector containing a minimal promoter and the GFP reporter, and are assayed for their putative cis-regulatory activity in zebrafish or Xenopus transgenic experiments. Vectors used include plasmid DNA and the Tol2 transposon system in fish and X. laevis. We have followed this logic to detect and analyze conserved elements in an intergenic region present in the Iroquois (Irx) gene clusters of zebrafish, Xenopus tropicalis, Fugu rubripes and mouse. We have assayed approximately 50 of these conserved elements and shown that the majority behave as modular positive regulatory elements (enhancers) that contribute to specific temporal and spatial domains that are part of the endogenous gene expression pattern. Moreover, comparison of the activity of cognate Irx enhancers from different organisms demonstrates that conservation of sequence is accompanied by in vivo functional conservation across species. Finally, for some of the most conserved elements, we have been able to identify a critical core sequence, essential for correct enhancer function.


3D Shape Perception in Posterior Cortical Atrophy: A Visual Neuroscience Perspective.
Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.


Cerebral vasoconstrictor responses to serotonin after dietary treatment of atherosclerosis: implications for transient ischemic attacks.
Serotonin, which is released when platelets aggregate at carotid lesions, may contribute to cerebral ischemia. Our goal was to test the hypothesis that dietary treatment of atherosclerosis reverses the augmented cerebral vasoconstrictor response to serotonin. We studied normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were fed a normal (regression) diet for 18 months. Morphometric studies indicated that the regression diet reduced intimal area in the carotid arteries by about 50-75%. Cerebral blood flow was measured with microspheres, and microvascular pressure was measured with a micropipette in pial arteries that were approximately 300 micron in diameter. Values for cerebral blood flow and arteriolar pressure were used to calculate resistance of large cerebral arteries (greater than 300 micron diameter). Infusion of serotonin produced a modest increase in the resistance of large cerebral arteries in normal monkeys. Vasoconstrictor responses to serotonin were increased more than fivefold in atherosclerotic monkeys. The major finding of the study is that dietary treatment of atherosclerosis abolishes augmented cerebral responses to serotonin.


Epithelial-mesenchymal transition and colorectal cancer: gaining insights into tumor progression using LIM 1863 cells.
In addition to allowing epithelial cells to escape the structural constraints imposed by tissue architecture and adopt a phenotype more amenable to cell movement, it is now recognized that the epithelial-mesenchymal transition (EMT) may also represent a critical component permitting the progression of carcinomas towards invasive and metastatic disease. However, data supporting the actual occurrence of EMT in specific solid tumors and its relevance to the process of progression of these cancers has been scant. Despite an extensive knowledge of the genetic basis for colorectal cancer, the translation of this information into effective treatments has been limited. Clearly, there is a desperate need for new and improved therapies and since the switch to a metastatic phenotype is critical for outcome, it is of paramount importance to elucidate the biology that underlies the progression of this disease. Thus, the unique LIM 1863 model for studying the EMT of colorectal carcinoma has been used to both substantiate the importance of the transition for this cancer type and to identify molecular events that contribute to disease progression. Importantly, it has emerged that not only does EMT enhance migratory capacity, but also elicits additional selective advantages to colonic tumor cells. Specifically, the acquisition of autocrine growth factor signaling loops, mechanisms to evade apoptosis, and expression of specific integrins allowing invasive cells to interact with interstitial matrices and sustain activation of TGF-beta combine to provide a compelling new biochemical framework for understanding how EMT contributes to tumor evolution.


Serologic autoantibodies as diagnostic cancer biomarkers--a review.
Current diagnostic techniques used for the early detection of cancers are successful but subject to detection bias. A recent focus lies in the development of more accurate diagnostic tools. An increase in serologic autoantibody levels has been shown to precede the development of cancer disease symptoms. Therefore, autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers. Their clinical application has, however, been hindered by low sensitivity, specificity, and low predictive value scores. These scores have been shown to improve when panels of multiple diagnostic autoantibody biomarkers are used. A five-marker biomarker panel has been shown to increase the sensitivity of prostate cancer diagnosis to 95% as compared with 12.2% for prostate-specific antigen alone. New potential biomarker panels were also discovered for lung, colon, and stomach cancer diagnosis with sensitivity of 76%, 65.4%, and 50.8%, respectively. Studies in breast and liver cancer, however, seem to favor single markers, namely α-2-HS-glycoprotein and des-γ-carboxyprothrombin with sensitivities of 79% and 89% for the early detection of the cancers. The aim of this review is to discuss the relevance of autoantibodies in cancer diagnosis and to outline the current methodologies used in the detection of autoantibodies. The review concludes with a discussion of the autoantibodies currently used in the diagnosis of cancers of the prostate, breast, lung, colon, stomach, and liver. A discussion of the potential future use of autoantibodies as diagnostic cancer biomarkers is also included in this review.


Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts.
Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection. Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay. We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo. This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells.


Statistically induced phase transitions and anyons in 1D optical lattices.
Anyons--particles carrying fractional statistics that interpolate between bosons and fermions--have been conjectured to exist in low-dimensional systems. In the context of the fractional quantum Hall effect, quasi-particles made of electrons take the role of anyons whose statistical exchange phase is fixed by the filling factor. Here we propose an experimental setup to create anyons in one-dimensional lattices with fully tuneable exchange statistics. In our setup, anyons are created by bosons with occupation-dependent hopping amplitudes, which can be realized by assisted Raman tunnelling. The statistical angle can thus be controlled in situ by modifying the relative phase of external driving fields. This opens the fascinating possibility of smoothly transmuting bosons via anyons into fermions and of inducing a phase transition by the mere control of the particle statistics as a free parameter. In particular, we demonstrate how to induce a quantum phase transition from a superfluid into an exotic Mott-like state where the particle distribution exhibits plateaus at fractional densities.


MK-801 induced retrieval, but not acquisition, deficits for passive avoidance conditioning.
Two experiments using a state-dependent retention (SDR) design determined whether MK-801 blocked the acquisition and retention of an avoidance response. In Experiments 1 and 2, rats were trained and tested 30 min after injections of either saline or MK-801 (0.05 and 0.10 mg/kg, respectively). Two minutes after training, subjects were immediately tested, and in both experiments, the avoidance response was acquired. The 24-h retention tests for Experiment 1 revealed that the data marginally supported a SDR interpretation. In Experiment 2, the dose of MK-801 was increased to 0.10 mg/kg, and the results showed that MK-801 rendered passive avoidance (PA) state-dependent. These experiments indicate that neither the 0.05 nor 0.10 mg/kg doses of MK-801 prevented acquisition of the avoidance response and that the latter dose rendered memory for PA training state-dependent. It is suggested that doses of MK-801 that did not impair PA learning can function as a cue state and influence expression of memory for PA.


Soft tissue manipulation for single implant restorations.
Achievement of optimal aesthetics on implants in the anterior region can be difficult due to inherent differences to the natural dentition. An important consideration is the peri-implant soft tissues which can be modified to create a more natural emergence profile and contour. The methods with which this can be achieved vary as can methods for recording soft tissue changes and relaying this to technician colleagues. This review appraises some techniques available for the manipulation of the soft tissue profile on single implant restorations.


Heat-killed cells of lactobacilli skew the immune response toward T helper 1 polarization in mouse splenocytes and dendritic cell-treated T cells.
It is believed that probiotics play an important role for the health of the host, including modulation of immune responses. Most studies have focused on the immunomodulatory effects of viable cells of lactic acid bacteria; however, we investigated those of heat-killed cells of lactic acid bacteria in this study. We first observed the effects on immune functions via stimulating splenocytes with three heat-killed Lactobacillus strains. Furthermore, we also investigated the effect of mouse dendritic cells (DCs) treated with these heat-killed Lactobacillus strains on T cell responses. The results showed that these Lactobacillus strains were able to stimulate cell proliferation and interleukin (IL)-10, IL-12 p70, and interferon (IFN)-gamma production but not transforming growth factor (TGF)-beta in splenocytes. In addition, these heat-killed Lactobacillus strains also stimulated high-level secretion of IL-12 p70 in DCs and switched T cells to T helper (Th) 1 immune responses, as evidenced by the elevated secretion of IFN-gamma but not IL-5, IL-13, and TGF-beta. These results showed that lactobacilli play a potentially important role in modulating immune responses and allergic reactions.


Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages.
The concentrations of ATP and the ATP/AMP concentration ratios were maintained in thioglycollate-elicited mouse peritoneal macrophages incubated in vitro for 90 min in the presence or absence of added substrate: rates of glycolysis, lactate formation and glutamine utilization were approximately linear with time for at least 60 min of incubation. The rate of oxygen consumption by macrophages was only increased above the basal rate (i.e. that in the absence of added substrate) by addition of succinate or pyruvate, or by addition of the uncoupling agent carboxyl cyanide m-chlorophenylhydrazone ('CCCP'); it was decreased by 75% by the addition of KCN. These findings suggest that metabolism of endogenous substrate can provide most, if not all, of the energy requirement of these cells, at least for a short period. The rates of glucose and glutamine utilization by incubated macrophages were approx. 300 and 100 nmol/min per mg of protein respectively. A large proportion of the glutamine that is utilized is converted into glutamate and aspartate, and very little (perhaps less than 10%) is oxidized. Similarly almost all of the glucose that is utilized is converted into lactate and very little is oxidized. This characteristic is similar to that of resting lymphocytes and rapidly dividing cells; in non-proliferating macrophages it may be a mechanism to provide precision in control of the rate of biosynthetic processes that utilize intermediates of these pathways, e.g. purines and pyrimidines for mRNA for the synthesis of secretory proteins and glycerol 3-phosphate for phospholipid synthesis for membrane recycling. No utilization of acetoacetate or 3-hydroxybutyrate by macrophages was detected. In contrast, both butyrate and oleate were oxidized. The rate of [14C]oleate conversion into 14CO2 (1.3 nmol/h per mg of protein) could account for most of the oxygen consumption by incubated macrophages, suggesting that long-chain fatty acids might provide an important fuel in situ. This may be one explanation for the secretion of lipoprotein lipase by these cells, to provide fatty acids for oxidation from the degradation of local triacylglycerol.


Primary care clinician adherence to guidelines for the management of chronic musculoskeletal pain: results from the study of the effectiveness of a collaborative approach to pain.
We assessed primary care clinician-provided guideline-concordant care as documented in patients' medical records, predictors of documented guideline-concordant care, and its association with pain-related functioning. Patients were participants in a randomized trial of collaborative care for chronic musculoskeletal pain. The intervention featured patient and primary care clinician education, symptom monitoring and feedback to clinicians by the intervention team. To assess concordance with the evidence-based treatment guidelines upon which our intervention was based, we developed an 8-item chart review tool, the Pain Process Checklist (PPC). We then reviewed electronic medical records for 365 veteran patients treated by 42 primary care clinicians over 12 months. Intervention status, demographic, and clinical variables were tested as predictors of PPC scores using generalized estimating equations (GEE). GEE was also used to test whether PPC scores predicted treatment response (≥30% decrease in Roland-Morris Disability Questionnaire score). Rates of documented guideline-concordant care varied widely among PPC items, from 94% of patients having pain addressed to 17% of patients on opioids having side effects addressed. Intervention status was unrelated to item scores, and PPC-7 totals did not differ significantly between intervention and treatment-as-usual patients (61.2%, standard error [SE] = 3.3% vs 55.2%, SE = 2.6%, P = 0.15). In a multivariate model, higher PPC-7 scores were associated with receiving a prescription for opioids (odds ratio [OR] = 1.07, P = 0.007) and lower PPC-7 scores with patient age (10-year difference OR = 0.97, P = 0.004). Finally, intervention patients who received quantitative pain and depression assessments were less likely to respond to treatment (assessed vs not: 18% vs 33%, P = 0.008, and 13% vs 28%, P = 0.001, respectively). As measured by medical record review, additional training and clinician feedback did not increase provision of documented guideline-concordant pain care, and adherence to guidelines by primary care clinicians did not improve clinical outcomes for patients with chronic musculoskeletal pain.


Quantifying asthma patient preferences for onset of effect of combination inhaled corticosteroids and long-acting beta2-agonist maintenance medications.
The Onset-of-Effect Questionnaire (OEQ) is a self-administered instrument used to assess patient perception of how quickly asthma maintenance medications begin to work. This study was designed to quantify the relative importance that patients using combination inhaled corticosteroid and long-acting beta(2)-agonist (ICS/LABA) maintenance medication place on the onset-of-effect outcomes. Patients aged >or=18 years with a self-reported diagnosis of asthma, currently using combination ICS/LABA maintenance medication, completed an Internet-based SC conjoint survey instrument that included 10 choice trade-off tasks. In four choice tasks, patients were asked to choose between two hypothetical medications. In six choice tasks, patients were asked to choose among two hypothetical medications and their current medication. Each choice alternative was defined by response levels of the five OEQ statements and out-of-pocket cost. We used random-parameters logit methods to estimate the relative importance of outcomes assessed by the OEQ. Five hundred nine patients completed the study. Satisfied was the most important OEQ outcome and physical sensations were the least important. When offered a choice, 80% (95% CI, 75-85%) of patients preferred a maintenance medication for which they are satisfied with how quickly they feel it begins to work and 62% (95% CI: 57-67%) of patients preferred a maintenance medication that they feel begins to work right away. Combination maintenance medications with rapid onset of effect, especially those that impact a patients' ability to feel the medication work right away and patient satisfaction with how quickly the medication works, may increase the use of and adherence to maintenance medications.


[Early contrast-enhanced MR imaging assessment of femoral head viability after femoral neck fracture].
To evaluate the use of MR imaging, before and after i.v. administration of Magnevist, for assessing the femoral head perfusion after femoral neck fracture. Evaluation of femoral head viability is important because the outcome of internal fixation is adversely affected by the development of capital osteonecrosis. We performed MRI of the femoral head in 48 hours of injury, on 10 patients with femoral neck fracture. Five patients underwent MR imaging of the hip utilizing fat-suppressed (STIR) sequences and the others, T1-weighted spin-echo sequences before and after i.v. contrast administration. MR findings were correlated with radiographic follow-up for at least 12 months. Radiographic follow-up showed femoral head osteonecrosis in two patients. On contrast-enhanced MR images of these patients, the femoral head did not enhance and was lower in signal intensity than were the enhancing femoral shaft and neck distal to the fracture and the enhancing femoral head on the unaffected side. In the patients with persistent perfusion, contrast-enhanced MR images showed a uniform increase in signal intensity in the femoral shaft and neck as well as the femoral head; the femoral head on the fractured side showed contrast enhancement similar to that on the healthy side. These preliminary results indicate that contrast-enhanced MR imaging may be useful for noninvasive evaluation of femoral head perfusion after femoral neck fracture. MR findings also may aid the clinician in deciding between joint-preserving therapy and hip arthroplasty.


Validity and reliability of using a self-lavaging device for cytology and HPV testing for cervical cancer screening: findings from a pilot study.
Self-sampling could increase cervical cancer screening uptake. While methods have been identified for human papillomavirus (HPV) testing, to date, self-sampling has not provided adequate specimens for cytology. We piloted the validity and reliability of using a self-lavaging device for cervical cytology and HPV testing. We enrolled 198 women in New York City in 2008-2009 from three ambulatory clinics where they received cervical cancer screening. All were asked to use the Delphi Screener™ to self-lavage 1-3 months after clinician-collected index cytological smear (100 normal; 98 abnormal). Women with abnormal cytology results from either specimen underwent colposcopy; 10 women with normal results from both specimens also underwent colposcopy. We calculated sensitivity of self-collected cytology to detect histologically confirmed high grade lesions (cervical intraepithelial neoplasia, CIN, 2+); specificity for histology-negative (CIN 1 or lower), paired cytology negative, or a third cytology negative; and kappa for paired results. One hundred and ninety-seven (99.5%) women self-collected a lavage. Seventy-five percent had moderate to excellent cellularity, two specimens were unsatisfactory for cytology. Seven of 167 (4%) women with definitive results had CIN2+; one had normal and six abnormal cytology results with the self-lavage (sensitivity = 86%, 95% Confidence Interval, CI: 42, 100). The kappa for paired cytology was low (0.36; 95% CI: 0.25, 0.47) primarily due to clinician specimens with atypical squamous cells of undetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) coded as normal using Screener specimens. However, three cases of HSIL were coded as ASC-US and one as normal using Screener specimens. Seventy-three women had paired high-risk HPV tests with a kappa of 0.66 (95% CI: 0.49, 0.84). Based on these preliminary findings, a larger study to estimate the performance of the Screener for co-testing cytology and HPV or for HPV testing with cytology triage is warranted. ClinicalTrials.gov NCT00702208.


Global environmental change and the nature of aboveground net primary productivity responses: insights from long-term experiments.
Many global change drivers chronically alter resource availability in terrestrial ecosystems. Such resource alterations are known to affect aboveground net primary production (ANPP) in the short term; however, it is unknown if patterns of response change through time. We examined the magnitude, direction, and pattern of ANPP responses to a wide range of global change drivers by compiling 73 datasets from long-term (>5 years) experiments that varied by ecosystem type, length of manipulation, and the type of manipulation. Chronic resource alterations resulted in a significant change in ANPP irrespective of ecosystem type, the length of the experiment, and the resource manipulated. However, the pattern of ecosystem response over time varied with ecosystem type and manipulation length. Continuous directional responses were the most common pattern observed in herbaceous-dominated ecosystems. Continuous directional responses also were frequently observed in longer-term experiments (>11 years) and were, in some cases, accompanied by large shifts in community composition. In contrast, stepped responses were common in forests and other ecosystems (salt marshes and dry valleys) and with nutrient manipulations. Our results suggest that the response of ANPP to chronic resource manipulations can be quite variable; however, responses persist once they occur, as few transient responses were observed. Shifts in plant community composition over time could be important determinants of patterns of terrestrial ecosystem sensitivity, but comparative, long-term studies are required to understand how and why ecosystems differ in their sensitivity to chronic resource alterations.


Forty-five good things: a prospective pilot study of the Three Good Things well-being intervention in the USA for healthcare worker emotional exhaustion, depression, work-life balance and happiness.
High rates of healthcare worker (HCW) burn-out have led many to label it an 'epidemic' urgently requiring interventions. This prospective pilot study examined the efficacy, feasibility and evaluation of the 'Three Good Things' (3GT) intervention for HCWs, and added burn-out and work-life balance to the set of well-being metrics. 228 HCWs participated in a prospective, repeated measures study of a web-based 15-day long 3GT intervention. Assessments were collected at baseline and 1, 6 and 12-month post-intervention. The primary measure of efficacy was a derivative of the emotional exhaustion subscale of the Maslach Burnout Inventory. The secondary measures were validated instruments assessing depression symptoms, subjective happiness, and work-life balance. Paired samples t-tests and Cohen's d effect sizes for correlated samples were used to examine the efficacy of the intervention. 3GT participants exhibited significant improvements from baseline in emotional exhaustion, depression symptoms and happiness at 1 month, 6 months and 12 months, and in work-life balance at 1 month and 6 months (effect sizes 0.16-0.52). Exploratory subgroup analyses of participants meeting 'concerning' criteria at baseline revealed even larger effects at all assessment points (0.55-1.57). Attrition rates were similar to prior 3GT interventions. 3GT appears a promising low-cost and brief intervention for improving HCW well-being. This study is approved by the Institutional Review Board of Duke University Health System (Pro00063703). All participants are required to give their informed consent prior to any study procedure.


Comparison of the potency of three Brazilian Bothrops antivenoms using in vivo rodent and in vitro assays. BIASG (Butantan Institute Antivenom Study Group).
Three Brazilian polyspecific Bothrops antivenoms were compared using standard W.H.O. rodent in vivo and in vitro assays of their ability to neutralize the principal venom activities of pooled whole Bothrops jararaca venom. On a volume basis, the antivenoms were equally effective in neutralizing lethal activity in mice, and there were only minor differences in their ability to neutralize venom-induced haemorrhage, necrosis and procoagulant activity. Antivenom efficacy in neutralizing defibrinogenation varied. However, when equal amounts of antivenom IgG were compared, it was found that the FUNED antivenom best neutralized lethality, haemorrhage, necrosis and fibrinogen clotting activity. Vital Brazil and FUNED antivenoms were equally effective in neutralizing plasma coagulant activity but Vital Brazil antivenom was the more effective in neutralizing defibrinogenation.


Biomechanical study of ligaments around the elbow joint.
The ligamentous contribution to elbow joint stability is a product of morphology and biologic parameters of each of the collateral ligaments. Better understanding of these characteristics is of paramount importance for successful ligament reconstruction in the surgery for joint replacement and traumatic injury. Two experiments were performed. In the first, the arc of elbow flexion where the individual ligament was either taut or slack was measured; in the second, the structural properties of each collateral ligament were determined by using bone-ligament-bone preparations. The anterior medial collateral ligament (AMCL) and radial collateral ligament (RCL) were taut throughout most of the entire arc of flexion. The posterior medial collateral ligament (PMCL) was taut only when the elbow was in a flexed position. Among the collateral ligaments, the AMCL was the strongest and stiffest with an average failure load of 260 N. The palmaris longus tendon, the most frequently used graft for elbow ligament reconstruction, was similar in strength (357 N).


Adverse effects of hypoxaemia on diastolic filling in humans.
1. Abnormalities of myocardial relaxation may occur as a consequence of myocyte hypoxia. We have therefore examined the effects of hypoxaemia on right and left ventricular diastolic function in 10 healthy male subjects. 2. After resting to reach baseline haemodynamics, subjects were rendered hypoxaemic by breathing a variable nitrogen/oxygen mixture. Oxygen saturation (SaO2) was maintained at 85-90% for 20 min and then at 75-80% for a further 20 min. Haemodynamic and diastolic filling parameters were measured noninvasively at baseline and at the end of each period of hypoxaemia. 3. Diastolic filling of both ventricles was significantly impaired by hypoxaemia. In comparison with baseline, left ventricular isovolumic relaxation time and transmitral E-wave deceleration time corrected for heart rate were significantly prolonged at SaO2 75-80%: mean difference in corrected relaxation time, 9.8 ms (95% confidence interval 1-19); mean difference in corrected deceleration time, 34 ms (95% confidence interval 11-56). Similarly, right ventricular isovolumic relaxation time and transtricuspid E-wave deceleration time were significantly prolonged at SaO2 values of 75-80% compared with baseline: mean difference in relaxation time, 20.3 ms (95% confidence interval 3-38); mean difference in deceleration time, 33 ms (95% confidence interval 11-55). 4. During hypoxaemia there were dose-related increases in heart rate, cardiac output and mean pulmonary artery pressure, but no effects on mean arterial pressure. 5. Hypoxaemia significantly impairs relaxation of left and right ventricles in normal humans. These changes may reflect impairment of intracellular calcium transport secondary to the effects of myocyte hypoxia.


Normal human CD4(+) helper T cells express Kv1.1 voltage-gated K(+) channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway.
TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 ± 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNFα secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion; (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFα injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFα in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFα to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFα-induced increased permeability of organ's barriers.


Quality of life and quality adjusted survival for breast cancer patients receiving adjuvant therapy. Eastern Cooperative Oncology Group (ECOG).
The objective was to compare health related quality of life (QOL) in hormone receptor negative, node-positive breast cancer patients receiving adjuvant chemotherapy to determine whether a more intensive chemotherapy regimen has an adverse effect upon QOL that is not balanced by improvements in disease control or survival. Increased physical symptoms, including fatigue and the inconvenience of the dose intensive 16-week regimen, were expected to have a negative impact on QOL. QOL was measured in 163 patients, randomized to either a standard cyclophosphamide, doxorubicin and 5-flurouracil (CAF) or a 16-week multidrug regimen, using the Breast Chemotherapy Questionnaire (BCQ). The 30 item BCQ was self-administered prior to therapy, during therapy, and 4 months post treatment. BCQ scores decreased (worsened) more during therapy on the 16-week regimen, median change -1.4, than on CAF, median change -0.8 (p < 0.001). By 4 months post treatment, BCQ scores were higher than pre-treatment and equal in the two arms (CAF: 8.1 and 16 weeks: 8.2, p = 0.6). Over a period of 48 months, patients on the 16-week regimen averaged 1.4 fewer months of treatment with toxicity, 4.0 more months without symptoms and 0.7 fewer months post recurrence compared to patients on the CAF regimen. Given typical values for these health states, the gain in Q-TWiST observed for the CAF regimen during treatment shifted to the 16-week regimen after 1 year, with a gain of 2.0 to 2.4 months after 4 years. The hypothesized negative impact of the dose intensive 16-week regimen was confirmed by the BCQ assessments. However, Q-TWiST analysis suggests a small gain for the 16-week regimen. The later results should be interpreted with caution with the limited follow-up of 4 years.


Public health law in India: a framework for its application as a tool for social change.
Public health law focuses on the nexus between law, public health and the legal tools applicable to public health issues. Though there have been consistent interventions to address public health concerns in the past, there exists a need for a contemporary framework to appropriately use modern legal tools for complex health challenges. We identify a checklist of imperative indicators to assess whether public health legislations would be an effective form of intervention to bring about the desired social change.


Structural analysis of botulinum neurotoxin type G receptor binding .
Botulinum neurotoxin (BoNT) binds peripheral neurons at the neuromuscular junction through a dual-receptor mechanism that includes interactions with ganglioside and protein receptors. The receptor identities vary depending on BoNT serotype (A-G). BoNT/B and BoNT/G bind the luminal domains of synaptotagmin I and II, homologous synaptic vesicle proteins. We observe conditions under which BoNT/B binds both Syt isoforms, but BoNT/G binds only SytI. Both serotypes bind ganglioside G(T1b). The BoNT/G receptor-binding domain crystal structure provides a context for examining these binding interactions and a platform for understanding the physiological relevance of different Syt receptor isoforms in vivo.


Dynamic nuclear polarization of water by a nitroxide radical: rigorous treatment of the electron spin saturation and comparison with experiments at 9.2 Tesla.
The interaction between nuclear and electronic spins is of interest for structural characterization of biomolecules and biomedical imaging based on nuclear magnetic resonance. The polarization of the nuclear spins can be increased significantly if the electron spin polarization is kept out of equilibrium. We employ semiclassical relaxation theory to analyze the electronic polarization of the two-spin system characteristic of nitroxide radicals. Atomistic molecular dynamics simulations of the nitroxide TEMPOL in water are performed to account for the effects of tumbling and spin-rotation coupling on the spin-spin and spin-lattice relaxation times. Concentration effects on the electron saturation are introduced by allowing for Heisenberg spin exchange between two nitroxides. Polarization enhancement profiles, calculated from the computed saturation, are directly compared with liquid-state dynamic nuclear polarization experiments conducted at 260 GHz/400 MHz. The contribution of the separate hyperfine lines to the saturation can be easily disentangled using the developed formalism.


Thromboprophylaxis for Hip Revision Arthroplasty: Can We Use the Recommendations for Primary Hip Surgery? A Cohort Study.
The risk of thromboembolic events after hip revision arthroplasty might be higher than in primary hip arthroplasty. However, evidence regarding the use of thromboprophylaxis in revisions is scarce. The purpose of this study is to determine whether thromboprophylaxis recommendations for primary arthroplasty produce similar results in hip revision arthroplasty. This comparative cohort study retrospectively analyzed consecutive patients undergoing primary hip arthroplasty and hip revision surgery between March 2004 and December 2015, who received thromboprophylaxis according to local clinical practice guidelines for primary hip arthroplasty. The prevalence of deep vein thrombosis and pulmonary embolism and the presence of major bleeding events were assessed during hospitalization and at 3 months after discharge and compared between groups. The overall prevalence of thromboembolic events in the hip revision surgery cohort and in the primary hip cohort was 1.62% and 1.35%, respectively ( P = .801). The 38.4% of hip revision patients and 20.3% of primary hip patients presented major bleeding events. Thromboembolic disease outcomes with the use of a standardized thromboprophylaxis regimen were similar in both cohorts, regardless of the high variability of hip revision surgery and the increased risk of complications. Implementation of this regimen is recommended in patients requiring joint replacement revision surgery.


Imaging the effects of oxygen saturation changes in voluntary apnea and hyperventilation on susceptibility-weighted imaging.
Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T. We performed SWI scans (3T; acquisition time of 1 minute, 28 seconds; centered on the anterior commissure and the posterior commissure) on 10 healthy male volunteers during baseline breathing as well as during simple voluntary hyperventilation and apnea challenges. The hyperventilation and apnea tasks were separated by a 5-minute resting period. SWI venograms were generated, and the signal changes on SWI before and after the respiratory stress tasks were compared by means of a paired Student t test. Changes in venous vasculature visibility caused by the respiratory challenges were directly visualized on the SWI venograms. The venogram segmentation results showed that voluntary apnea decreased the mean venous blood voxel number by 1.6% (P < .0001), and hyperventilation increased the mean venous blood voxel number by 2.7% (P < .0001). These results can be explained by blood CO2 changes secondary to the respiratory challenges, which can alter cerebrovascular tone and cerebral blood flow and ultimately affect venous oxygen levels. These results highlight the sensitivity of SWI to simple and noninvasive respiratory challenges and its potential utility in assessing cerebral hemodynamics and vasomotor responses.


Influence of the Gut Microbiome on Autoimmunity in the Central Nervous System.
Autoimmune disorders of the CNS have complex pathogeneses that are not well understood. In multiple sclerosis and neuromyelitis optica spectrum disorders, T cells destroy CNS tissue, resulting in severe disabilities. Mounting evidence suggests that reducing inflammation in the CNS may start with modulation of the gut microbiome. The lymphoid tissues of the gut are specialized for the induction of regulatory cells, which are directly responsible for the suppression of CNS-damaging autoreactive T cells. Whether cause or effect, the onset of dysbiosis in the gut of patients with multiple sclerosis and neuromyelitis optica provides evidence of communication along the gut-brain axis. Thus, current and future therapeutic interventions directed at microbiome modulation are of considerable appeal.


Promoting community participation in priority setting in district health systems: experiences from Mbarali district, Tanzania.
Community participation in priority setting in health systems has gained importance all over the world, particularly in resource-poor settings where governments have often failed to provide adequate public-sector services for their citizens. Incorporation of public views into priority setting is perceived as a means to restore trust, improve accountability, and secure cost-effective priorities within healthcare. However, few studies have reported empirical experiences of involving communities in priority setting in developing countries. The aim of this article is to provide the experience of implementing community participation and the challenges of promoting it in the context of resource-poor settings, weak organizations, and fragile democratic institutions. Key informant interviews were conducted with the Council Health Management Team (CHMT), community representatives, namely women, youth, elderly, disabled, and people living with HIV/AIDS, and other stakeholders who participated in the preparation of the district annual budget and health plans. Additionally, minutes from the Action Research Team and planning and priority-setting meeting reports were analyzed. A number of benefits were reported: better identification of community needs and priorities, increased knowledge of the community representatives about priority setting, increased transparency and accountability, promoted trust among health systems and communities, and perceived improved quality and accessibility of health services. However, lack of funds to support the work of the selected community representatives, limited time for deliberations, short notice for the meetings, and lack of feedback on the approved priorities constrained the performance of the community representatives. Furthermore, the findings show the importance of external facilitation and support in enabling health professionals and community representatives to arrive at effective working arrangement. Community participation in priority setting in developing countries, characterized by weak democratic institutions and low public awareness, requires effective mobilization of both communities and health systems. In addition, this study confirms that community participation is an important element in strengthening health systems.


A constitutively open potassium channel formed by KCNQ1 and KCNE3.
Mutations in all four known KCNQ potassium channel alpha-subunit genes lead to human diseases. KCNQ1 (KvLQT1) interacts with the beta-subunit KCNE1 (IsK, minK) to form the slow, depolarization-activated potassium current I(Ks) that is affected in some forms of cardiac arrhythmia. Here we show that the novel beta-subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly instantaneous and depend linearly on voltage. It also suppresses the currents of KCNQ4 and HERG potassium channels. In the intestine, KCNQ1 and KCNE3 messenger RNAs colocalized in crypt cells. This localization and the pharmacology, voltage-dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhoea and cystic fibrosis.


Genetic and molecular diversity in nondeletion Hb H disease.
Restriction endonuclease mapping of nondeletion alpha-thalassemia determinants from a variety of racial groups showed no detectable abnormalities within a 40-kilobase region of the zeta-alpha globin gene cluster. By using a zeta-specific probe, we defined three different types of interactions that give rise to Hb H disease, each involving a nondeletion alpha-thalassemia haplotype. mRNA analysis showed further diversity within these groups, indicating that there are at least three nondeletion determinations.


Quantitative imaging of complex samples by spiral phase contrast microscopy.
Recently a spatial spiral phase filter in a Fourier plane of a microscopic imaging setup has been demonstrated to produce edge enhancement and relief-like shadow formation of amplitude and phase samples. Here we demonstrate that a sequence of at least 3 spatially filtered images, which are recorded with different rotational orientations of the spiral phase plate, can be used to obtain a quantitative reconstruction of both, amplitude and phase information of a complex microscopic sample, i.e. an object consisting of mixed absorptive and refractive components. The method is demonstrated using a calibrated phase sample, and an epithelial cheek cell.


Binding of L7Ae protein to the K-turn of archaeal snoRNAs: a shared RNA binding motif for C/D and H/ACA box snoRNAs in Archaea.
Small nucleolar RNAs (designated as snoRNAs in Eukarya or sRNAs in Archaea) can be grouped into H/ACA or C/D box snoRNA (sRNA) subclasses. In Eukarya, H/ACA snoRNAs assemble into a ribonucleoprotein (RNP) complex comprising four proteins: Cbf5p, Gar1p, Nop10p and Nhp2p. A homolog for the Nhp2p protein has not been identified within archaeal H/ACA RNPs thus far, while potential orthologs have been identified for the other three proteins. Nhp2p is related, particularly in the middle portion of the protein sequence, to the archaeal ribosomal protein and C/D box protein L7Ae. This finding suggests that L7Ae may be able to substitute for the Nhp2p protein in archaeal H/ACA sRNAs. By band shift assays, we have analyzed in vitro the interaction between H/ACA box sRNAs and protein L7Ae from the archaeon Archaeoglobus fulgidus. We present evidence that L7Ae forms specific complexes with three different H/ACA sRNAs, designated as Afu-4, Afu-46 and Afu-190 with an apparent K(d) ranging from 28 to 100 nM. By chemical and enzymatic probing we show that distinct bases located within bulges or loops of H/ACA sRNAs interact with the L7Ae protein. These findings are corroborated by mutational analysis of the L7Ae binding site. Thereby, the RNA motif required for L7Ae binding exhibits a structure, designated as the K-turn, which is present in all C/D box sRNAs. We also identified four H/ACA RNAs from the archaeal species Pyrococcus which exhibit the K-turn motif at a similar position in their structure. These findings suggest a triple role for L7Ae protein in Archaea, e.g. in ribosomes as well as H/ACA and C/D box sRNP biogenesis and function by binding to the K-turn motif.


Incidence and risk factors of incisional hernia formation following abdominal organ transplantation.
Hernia formation is common following abdominal operations, and transplant patients are at increased risk due to postoperative immunosuppression. The purpose of this study was to estimate the incidence of incisional hernia formation following primary abdominal solid organ transplantation and identify clinical risk factors for hernia formation. We performed a single-institution retrospective review of a prospectively collected database to evaluate all patients who underwent primary liver, kidney, or pancreas transplantation between 2000 and 2011. The primary outcome was hernia formation at the transplant incision. Univariate and multivariate Cox proportional hazards models were used to identify risk factors for incisional hernia formation. A total of 3,460 transplants were performed during the study period: 2,247 kidney only, 718 liver only, and 495 pancreas or simultaneous pancreas and kidney (pancreas group). The overall incisional hernia rate was 7.5 %. The Kaplan-Meier rates of hernia formation at 1, 5, and 10 years were 2.5, 4.9, and 7.0 % for kidney; 4.5, 13.6, and 19.0 % for liver; and 2.5, 12.7, and 21.8 % for the pancreas groups. On univariate analysis, surgical site infection (SSI), body mass index (BMI) >25, delayed graft function, and withholding a calcineurin inhibitor or mycophenolate mofetil (MMF) were associated with hernia formation in the kidney group. SSI and BMI >25 were associated with hernia formation in the liver group. In the pancreas group, SSI, cyclosporine, and withholding MMF were all associated with hernia formation. On multivariate analysis, SSI was strongly associated with hernia formation in all groups. Hazard ratio: kidney = 24.71 (13.00-46.97); liver = 12.0 (6.40-22.52); pancreas = 12.95 (2.78-60.29). Incisional hernias are common following abdominal organ transplant with nearly one in five patients developing an incisional hernia 5 years after liver or pancreas transplantation. Strategies focusing on prevention and early treatment of SSI may help to decrease the risk of incisional hernia formation following abdominal organ transplantation.


Distress among matriculating medical students relative to the general population.
Many medical students experience distress during medical school. If matriculating medical students (MMSs) begin training with similar or better mental health than age-similar controls, this would support existing concerns about the negative impact of training on student well-being. The authors compared mental health indicators of MMSs versus those of a probability-based sample of the general U.S. population. In 2012 all MMSs at six U.S. medical schools were invited to participate in a survey during orientation. The research team surveyed a probability-based sample of U.S. individuals using the same questions in 2011. Individuals from the population sample who completed a four-year college degree and matched within the appropriate age strata (< 30, 31-35, 36-40, > 40) were compared with MMSs. Surveys included demographics and validated instruments to measure burnout; depression symptoms; and mental, emotional, physical, and overall of quality of life (QOL). Demographic characteristics of the 582/938 (62%) responding MMSs were similar to U.S. MMSs. Relative to 546 age-similar college graduates, MMSs had lower rates of burnout (27.3% versus 37.3%, P < .001) and depression symptoms (26.2% versus 42.4%, P < .0001) and higher scores across the four QOL domains assessed relative to controls (all P < .0001). These findings persisted on multivariate analysis after adjusting for age, sex, relationship status, and race/ethnicity. These findings, along with high rates of distress reported in medical students and residents, support concerns that the training process and environment contribute to the deterioration of mental health in developing physicians.


Time-Dependent Long-Range-Corrected Density-Functional Tight-Binding Method Combined with the Polarizable Continuum Model.
In this study, excited-state free energies and geometries were efficiently evaluated using a linear-response time-dependent long-range-corrected density-functional tight-binding method integrated with the polarizable continuum model (TD-LC-DFTB2/PCM). Although the LC-DFTB method required the evaluation of the exchange-type term, which was moderately computationally expensive, a single evaluation of the excited-state gradient for a system consisting of more than 1000 atoms in a vacuum was completed within 30 min using one CPU core. Benchmark calculations were conducted for 3-hydroxyflavone, which exhibits dual emission: the absorption and enol-form emission wavelengths calculated by TD-LC-DFTB2/PCM agreed well with those predicted based on the density functional theory using a long-range corrected functional; however, there was a large error in the predicted keto-form emission wavelength. Further benchmark calculations for more than 20 molecules indicated that the conventional TD-DFTB method underestimated the absorption and 0-0 transition energies compared with those which were measured experimentally, whereas the TD-LC-DFTB2 method systematically overestimated these metrics. Nevertheless, the agreement of the results of the TD-LC-DFTB2 method with those obtained by the CAM-B3LYP method demonstrates the potential of the TD-LC-DFTB2/PCM method. Moreover, changing the range separation parameter to 0.15 minimized this deviation.


Language delay aggregates in toddler siblings of children with autism spectrum disorder.
Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype. We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample. Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition. Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.


Beta burst coupling across the motor circuit in Parkinson's disease.
Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.


Prevalence and Risk Factors Associated with Use of QT-Prolonging Drugs in Hospitalized Older People.
The objective of this study was to evaluate the prevalence of the prescription of QT-prolonging drugs at hospital admission and discharge and the risk factors associated with their use in older people (aged 65 years and older). Data were obtained from the REPOSI (REgistro POliterapie SIMI [Società Italiana di Medicina Interna]) registry, which enrolled 4035 patients in 2008 (n = 1332), 2010 (n = 1380), and 2012 (n = 1323). Multivariable logistic regression was performed to determine the risk factors independently associated with QT-prolonging drug use. QT-prolonging drugs were classified by the risk of Torsades de Pointes (TdP) (definite, possible, or conditional) according to the Arizona Center for Education and Research on Therapeutics (AzCERT) classification. Specific drug combinations were also assessed. Among 3906 patients prescribed at least one drug at admission, 2156 (55.2%) were taking at least one QT-prolonging drug. Risk factors independently associated with the use of any QT-prolonging drugs were increasing age (odds ratio [OR] 1.02, 95% CI 1.01-1.03), multimorbidity (OR 2.69, 95% CI 2.33-3.10), hypokalemia (OR 2.79, 95% CI 1.32-5.89), atrial fibrillation (OR 1.66, 95% CI 1.40-1.98), and heart failure (OR 3.17, 95% CI 2.49-4.05). Furosemide, alone or in combination, was the most prescribed drug. Amiodarone was the most prescribed drug with a definite risk of TdP. Both the absolute number of QT-prolonging drugs (2890 vs. 3549) and the number of patients treated with them (2456 vs. 2156) increased at discharge. Among 1808 patients not prescribed QT-prolonging drugs at admission, 35.8% were prescribed them at discharge. Despite their risk, QT-prolonging drugs are widely prescribed to hospitalized older persons. The curriculum for both practicing physicians and medical students should be strengthened to provide more education on the appropriate use of drugs in order to improve the management of hospitalized older people.


Simple Vaginal Trachelectomy: A Valuable Fertility-Preserving Option in Early-Stage Cervical Cancer.
Radical trachelectomy is a valid alternative for the treatment of early-stage cervical cancer in young women who wish to preserve fertility potential. Recent data indicate that even less radical surgery could be performed in low-risk cases. The objective of our study was to evaluate the safety of simple vaginal trachelectomy and node assessment in patients with low-risk, early-stage cervical cancer (<2 cm). From May 2007 to July 2016, 35 women underwent a simple vaginal trachelectomy with laparoscopic sentinel lymph node mapping + pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meier estimate were used for analysis. Patients' median age was 29 years, and 24 (69%) were nulliparous. Eight had stage IA1 with lymphovascular space invasion, 9 a stage IA2, and 18 a stage IB1. Nineteen (54%) had squamous histology, 13 (37%) had adenocarcinoma, and 3 had other histologic findings. The median operating room time was 148 minutes (90-240 minutes), and median blood loss was 50 mL (25-200 mL). On final pathology, lymph nodes were negative in all patients, except 2 cases with isolated tumor cells. Twenty-two patients (63%) had either no residual disease in the trachelectomy specimen (n = 15) or residual dysplasia only (n = 7). With a median follow-up of 42 months (1-100 months), 1 local recurrence occurred treated initially with chemoradiation and then a pelvic exenteration. The recurrence-free survival at 48 months is 96.7%. There were 25 pregnancies: 5 (20%) ended in the first trimester, 2 delivered prematurely at 34.4 and at 35 weeks, and all the others (18 [72%]) delivered at more than 36 weeks. Based on our experience, simple trachelectomy and nodes appear to be a safe fertility-preserving surgery in well-selected patients with small-volume cervical cancer. Obstetric outcome appears favorable.


Invasion biology in non-free-living species: interactions between abiotic (climatic) and biotic (host availability) factors in geographical space in crayfish commensals (Ostracoda, Entocytheridae).
In invasion processes, both abiotic and biotic factors are considered essential, but the latter are usually disregarded when modeling the potential spread of exotic species. In the framework of set theory, interactions between biotic (B), abiotic (A), and movement-related (M) factors in the geographical space can be hypothesized with BAM diagrams and tested using ecological niche models (ENMs) to estimate A and B areas. The main aim of our survey was to evaluate the interactions between abiotic (climatic) and biotic (host availability) factors in geographical space for exotic symbionts (i.e., non-free-living species), using ENM techniques combined with a BAM framework and using exotic Entocytheridae (Ostracoda) found in Europe as model organisms. We carried out an extensive survey to evaluate the distribution of entocytherids hosted by crayfish in Europe by checking 94 European localities and 12 crayfish species. Both exotic entocytherid species found, Ankylocythere sinuosa and Uncinocythere occidentalis, were widely distributed in W Europe living on the exotic crayfish species Procambarus clarkii and Pacifastacus leniusculus, respectively. No entocytherids were observed in the remaining crayfish species. The suitable area for A. sinuosa was mainly restricted by its own limitations to minimum temperatures in W and N Europe and precipitation seasonality in circum-Mediterranean areas. Uncinocythere occidentalis was mostly restricted by host availability in circum-Mediterranean regions due to limitations of P. leniusculus to higher precipitation seasonality and maximum temperatures. The combination of ENMs with set theory allows studying the invasive biology of symbionts and provides clues about biogeographic barriers due to abiotic or biotic factors limiting the expansion of the symbiont in different regions of the invasive range. The relative importance of abiotic and biotic factors on geographical space can then be assessed and applied in conservation plans. This approach can also be implemented in other systems where the target species is closely interacting with other taxa.


Optimizing antipseudomonal therapy in critical care.
Pseudomonas aeruginosa is a common and important pathogen in the critically ill. It combines environmental hardiness with genomic plasticity and is well adapted to the various niches available in the intensive care unit (ICU). Unresolved arguments over the value of dual versus monotherapy relate primarily to rapidity of killing and to the avoidance of therapeutic failure due to antibiotic resistance. Increasing resistance to conventional antibiotics means that we need to be aware of the factors that promote the success of this pathogen in the ICU, and of emerging alternative strategies. This review focuses on an understanding of the underlying issues and on the practical aspects of prescribing, particularly in the ICU.


Effects of Lifestyle Modification on Telomerase Gene Expression in Hypertensive Patients: A Pilot Trial of Stress Reduction and Health Education Programs in African Americans.
African Americans suffer from disproportionately high rates of hypertension and cardiovascular disease. Psychosocial stress, lifestyle and telomere dysfunction contribute to the pathogenesis of hypertension and cardiovascular disease. This study evaluated effects of stress reduction and lifestyle modification on blood pressure, telomerase gene expression and lifestyle factors in African Americans. Forty-eight African American men and women with stage I hypertension who participated in a larger randomized controlled trial volunteered for this substudy. These subjects participated in either stress reduction with the Transcendental Meditation technique and a basic health education course (SR) or an extensive health education program (EHE) for 16 weeks. Primary outcomes were telomerase gene expression (hTERT and hTR) and clinic blood pressure. Secondary outcomes included lifestyle-related factors. Data were analyzed for within-group and between-group changes. Both groups showed increases in the two measures of telomerase gene expression, hTR mRNA levels (SR: p< 0.001; EHE: p< 0.001) and hTERT mRNA levels (SR: p = 0.055; EHE: p< 0.002). However, no statistically significant between-group changes were observed. Both groups showed reductions in systolic BP. Adjusted changes were SR = -5.7 mm Hg, p< 0.01; EHE = -9.0 mm Hg, p < 0.001 with no statistically significant difference between group difference. There was a significant reduction in diastolic BP in the EHE group (-5.3 mm Hg, p< 0.001) but not in SR (-1.2 mm Hg, p = 0.42); the between-group difference was significant (p = 0.04). The EHE group showed a greater number of changes in lifestyle behaviors. In this pilot trial, both stress reduction (Transcendental Meditation technique plus health education) and extensive health education groups demonstrated increased telomerase gene expression and reduced BP. The association between increased telomerase gene expression and reduced BP observed in this high-risk population suggest hypotheses that telomerase gene expression may either be a biomarker for reduced BP or a mechanism by which stress reduction and lifestyle modification reduces BP. ClinicalTrials.gov NCT00681200.


A point-of-sale communications campaign to provide consumers safety information on drug-dietary supplement interactions: a pilot study.
Concurrent use of dietary supplements with over-the-counter and prescription pharmaceuticals has become increasingly common, and with this trend, so has the incidence of adverse drug-supplement interactions. In the current market, consumers have no way to distinguish between safe and potentially harmful supplements. Thus, the primary objective of this study was to test the hypothesis that messages designed to increase consumers' awareness of potential health risks of concurrent use of dietary supplements with over-the-counter and prescription pharmaceuticals would promote further consideration and action, as evidenced by (a) seeking additional information from an authoritative source or qualified health care professional and (b) changing dietary supplement usage patterns. To test this hypothesis, an innovative consumer information delivery system, referred to as the Buyer Information Network (BuyIN), was utilized. BuyIN uses currently available, Web-enabled point-of-sale (POS) technology to provide up-to-date, evidence-based, health- and safety-related messages to consumers at the retail checkout counter. Results showed that more than one-fourth (27.1%) of consumers (n = 199) who purchased targeted items reported they were aware of the messages. Of this subgroup of aware consumers, 11.2% reported that they sought additional information from a physician or pharmacist, 11.5% reported that they visited the website listed on the coupon, and 10.5% indicated that they changed their dietary supplement usage patterns as a result of the messages. Future research should include a large-scale study of a fully implemented and capable system at multiple test sites around the country, including investigating the utility of BuyIN in different retail settings.


Iron overload in patients with myelodysplastic syndromes: An updated overview.
Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication.


Ethics in Plastic Surgery: Applying the Four Common Principles to Practice.
The topic of ethics in plastic surgery remains underrepresented in the literature. By applying the four principles of biomedical ethics-respect for autonomy, beneficence, nonmaleficence, and justice-as described by Beauchamp and Childress to proposed ethical scenarios, this article attempts to provide plastic surgeons with a systematic approach to recognize and address ethical dilemmas as they present in day-to-day practice. Through the perspective of an experienced plastic surgeon and medical ethicist, this article is intended to spark discussion, reflection, and debate on ethical challenges in plastic surgery.


Cellular polypeptides overexpressed after herpes simplex infection permit virus subtyping and may help diagnose cervical cancer.
The synthesis of cellular macromolecules is inhibited after infection with herpes simplex viruses (HSV) although certain host proteins accumulate to high concentrations as identified by monoclonal antibody TG7A. By western blotting, a polypeptide with a relative molecular weight of 90 kilodaltons was identified in cells infected with type 2 viruses and a polypeptide of 40 kilodaltons relative molecular weight in type 1 infected cells, and virus typing was confirmed by restriction enzyme analysis of viral DNA. Thirty seven clinical isolates from the genital region were subtyped as HSV type 2 and 18 from the orofacial region as type 1 by the different intracellular location of the 90 kilodalton and 40 kilodalton proteins seen on immunofluorescent staining of cells infected with HSV. Expression of these proteins has been associated with cellular transformation due to gene products of HSV or other viruses. Overexpression of the cellular proteins identified by TG7A reactivity was shown to be a marker for cells in cervical smears from patients with CIN III that appeared to be dyskaryotic. Little or no reaction was observed in squamous epithelial cells found in normal or abnormal smears.