Tailored treatment of patients with hepatocellular carcinoma with portal vein invasion: experience from a multidisciplinary hepatobiliary tumor program within a NCI comprehensive cancer center.
Hepatocellular carcinoma (HCC) with portal vein invasion (PVI) has a poor prognosis with limited treatment options. Intra-arterial brachytherapy (IAB) and transarterial chemoembolization (TACE) yield local control but risk accelerating liver dysfunction. The outcomes, survival, and safety of selective liver-directed treatment are reported. Thirty-seven consecutive patients with HCC and PVI treated between 2009 and 2015 were reviewed from a prospectively collected database. Univariate analysis, Kaplan-Meier plots using the log-rank method, and multivariate analyses were performed. Statistical significance was defined as P<0.05. Overall survival was reported in months (median; 95% CI). Most patients (59%) had PVI identified at initial HCC diagnosis. The liver-directed therapy group (n=22) demonstrated a survival advantage versus the systemic/supportive care group (n=14) [23.6 (5.8, 30.9) vs. 6.0 (3.5, 8.8) months]. Patients indicated for liver directed therapy had unilateral liver involvement (100% vs. 43%, P<0.0001), lower median alkaline phosphatase (105.5 vs. 208.0, P=0.002), and lower mean Child-Turcotte-Pugh (CTP) score (5.9 vs. 7.2, P=0.04) and tolerated treatment without serious complications. In HCC patients presenting with PVI, liver-directed therapy was safely performed in patients with limited venous involvement and preserved liver function. Liver-directed therapy extended survival for these patients indicated for palliative chemotherapy by traditional guidelines.


Comanagement of hospitalized surgical patients by medicine physicians in the United States.
Comanagement of surgical patients by medicine physicians (generalist physicians or internal medicine subspecialists) has been shown to improve efficiency and to reduce adverse outcomes. We examined the extent to which comanagement is used during hospitalizations for common surgical procedures in the United States. We conducted a retrospective cohort study of Medicare fee-for-service beneficiaries hospitalized for 1 of 15 inpatient surgical procedures from 1996 to 2006 (n = 694 806). We also calculated the proportion of Medicare beneficiaries comanaged by medicine physicians (generalist physicians or internal medicine subspecialists) during hospitalization. Comanagement was defined by relevant physicians (generalist or internal medicine subspecialist) submitting a claim for evaluation and management services on 70% or more of the days that the patients were hospitalized. Between 1996 and 2006, 35.2% of patients hospitalized for a common surgical procedure were comanaged by a medicine physician: 23.7% by a generalist physician and 14% by an internal medicine subspecialist (2.5% were comanaged by both). The percentage of patients experiencing comanagement was relatively unchanged from 1996 to 2000 and then increased sharply. The increase was entirely attributable to a surge in comanagement by generalist physicians. In a multivariable multilevel analysis, comanagement by generalist physicians increased 11.4% per year from 2001 to 2006. Patients with advanced age, with more comorbidities, or receiving care in nonteaching, midsize (200-499 beds), or for-profit hospitals were more likely to receive comanagement. All of the growth in comanagement was attributed to increased comanagement by hospitalist physicians. Medical comanagement of Medicare beneficiaries hospitalized for a surgical procedure is increasing because of the increasing role of hospitalists. To meet this growing need for comanagement, training in internal medicine should include medical management of surgical patients.


Plasma levels of tumour necrosis factor alpha and transforming growth factor beta-1 in children with dengue 2 virus infection in French Polynesia.
The pathogenesis of dengue haemorrhagic fever (DHF) is not well understood. In the absence of predictive clinical or biological criteria, the management of DHF patients remains difficult. The role played by cytokines in the occurrence of DHF has been suggested by several authors. In this study, we determined the plasma levels of tumour necrosis factor alpha (TNF alpha) and transforming growth factor beta-1 (TGF beta-1) in 52 children with laboratory-confirmed dengue virus infection admitted to hospital during the recent dengue 2 outbreak in French Polynesia. Thirty-three children were classified as having dengue fever (DF) and 19 as DHF. The plasma of both DF and DHF patients contained similar levels of TNF alpha. By contrast, plasma obtained from children with DHF had significantly higher levels of TGF beta-1 than plasma from children with DF, especially from days 1 to 3 after the onset of fever.


Selection for higher gene copy number after different types of plant gene duplications.
The evolutionary origins of the multitude of duplicate genes in the plant genomes are still incompletely understood. To gain an appreciation of the potential selective forces acting on these duplicates, we phylogenetically inferred the set of metabolic gene families from 10 flowering plant (angiosperm) genomes. We then compared the metabolic fluxes for these families, predicted using the Arabidopsis thaliana and Sorghum bicolor metabolic networks, with the families' duplication propensities. For duplications produced by both small scale (small-scale duplications) and genome duplication (whole-genome duplications), there is a significant association between the flux and the tendency to duplicate. Following this global analysis, we made a more fine-scale study of the selective constraints observed on plant sodium and phosphate transporters. We find that the different duplication mechanisms give rise to differing selective constraints. However, the exact nature of this pattern varies between the gene families, and we argue that the duplication mechanism alone does not define a duplicated gene's subsequent evolutionary trajectory. Collectively, our results argue for the interplay of history, function, and selection in shaping the duplicate gene evolution in plants.


Evaluation of the Olfactory Function With the "Sniffin' Sticks" Test After Endoscopic Transsphenoidal Pituitary Surgery.
The aim of this study was to evaluate the olfactory function of patients who had undergone endoscopic transsphenoidal pituitary surgery. In this prospective study, the "Sniffin' Sticks" test was performed between June 2016 and April 2017 at Izmir Katip Celebi University Ataturk Training and Research Hospital. Thirty patients who were scheduled to undergo endoscopic transsphenoidal pituitary surgery were evaluated preoperatively and 8 weeks postoperatively using the Sniffin' Sticks test battery for olfactory function, odor threshold, smell discrimination, and odor identification. The patients were evaluated preoperatively by an otolaryngologist. The patients' demographic data and olfactory functions were analyzed with a t test and Wilcoxon-labeled sequential test. The study group comprised 14 women (46.7%) and 16 men (53.3%) patients. The mean age of the patients was 37.50 ± 9.43 years (range: 16-53 years). We found a significant difference in the preoperative and postoperative values of the odor recognition test (P = 0.017); however, there was no significant difference between the preoperative and postoperative odor threshold values (P = 0.172) and odor discrimination values (P = 0.624). The threshold discrimination identification test scores were not significant (P = 0.110). The olfactory function of patients who were normosmic preoperatively was not affected postoperatively. This study shows that the endoscopic transsphenoidal technique for pituitary surgery without nasal flap has no negative effect on the olfactory function.


A new osteichthyan from the late Silurian of Yunnan, China.
Our understanding of early gnathostome evolution has been hampered by a generally scant fossil record beyond the Devonian. Recent discoveries from the late Silurian Xiaoxiang Fauna of Yunnan, China, have yielded significant new information, including the earliest articulated osteichthyan fossils from the Ludlow-aged Kuanti Formation. Here we describe the partial postcranium of a new primitive bony fish from the Kuanti Formation that represents the second known taxon of pre-Devonian osteichthyan revealing articulated remains. The new form, Sparalepis tingi gen. et sp. nov., displays similarities with Guiyu and Psarolepis, including a spine-bearing pectoral girdle and a placoderm-like dermal pelvic girdle, a structure only recently identified in early osteichthyans. The squamation with particularly thick rhombic scales shares an overall morphological similarity to that of Psarolepis. However, the anterior flank scales of Sparalepis possess an unusual interlocking system of ventral bulges embraced by dorsal concavities on the outer surfaces. A phylogenetic analysis resolves Sparalepis within a previously recovered cluster of stem-sarcopterygians including Guiyu, Psarolepis and Achoania. The high diversity of osteichthyans from the Ludlow of Yunnan strongly contrasts with other Silurian vertebrate assemblages, suggesting that the South China block may have been an early center of diversification for early gnathostomes, well before the advent of the Devonian "Age of Fishes".


Research challenges arising from changes in worklife.
Great challenges for occupational health research are set by the rapid changes in the world of work as a consequence of globalization, new technologies, demographic workforce changes, fragmentation of enterprises and work contracts, high time pressures, high demands for learning new skills, and growing worker mobility. The occupational health problems are of 2 types, the persistent and reemerging old problems of occupational injuries and diseases and new challenges from psychological stress, musculoskeletal disorders caused by computerized work, cognitive ergonomics in information-intensive work, the work ability of aging workers, and new trends in occupational allergies. The 3 roles of research, improvement of knowledge, improvement of understanding, and support of the development of work conditions in practice, all call for new initiatives in occupational health research. The new comprehensive strategy for the development and promotion of work ability has been found to respond effectively to these new needs.


Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied α4β7 integrin-MADCAM1 axis. Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-α therapy goes through downregulation of certain adhesion molecules.


Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis.
Natural products have been an important source of therapeutic agents and chemical tools. The recent realization that many natural product biosynthetic genes are silent or sparingly expressed during standard laboratory growth has prompted efforts to investigate their regulation and develop methods to induce their expression. Because it is difficult to intuit signals that induce a given biosynthetic locus, we recently implemented a forward chemical-genetic approach to identify such inducers. In the current work, we applied this approach to nine silent biosynthetic loci in the model bacterium Burkholderia thailandensis to systematically screen for elicitors from a library of Food and Drug Administration-approved drugs. We find that β-lactams, fluoroquinolones, antifungals, and, surprisingly, calcimimetics, phenothiazine antipsychotics, and polyaromatic antidepressants are the most effective global inducers of biosynthetic genes. Investigations into the mechanism of stimulation of the silent virulence factor malleicyprol by the β-lactam piperacillin allowed us to elucidate the underlying regulatory circuits. Low-dose piperacillin causes oxidative stress, thereby inducing redox-sensing transcriptional regulators, which activate malR, a pathway-specific positive regulator of the malleicyprol gene cluster. Malleicyprol is thus part of the OxyR and SoxR regulons in B. thailandensis, allowing the bacterium to initiate virulence in response to oxidative stress. Our work catalogs a diverse array of elicitors and a previously unknown regulatory input for secondary metabolism in B. thailandensis.


Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.
Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia.


Myostatin signals through Pax7 to regulate satellite cell self-renewal.
Myostatin, a Transforming Growth Factor-beta (TGF-beta) super-family member, has previously been shown to negatively regulate satellite cell activation and self-renewal. However, to date the mechanism behind Myostatin function in satellite cell biology is not known. Here we show that Myostatin signals via a Pax7-dependent mechanism to regulate satellite cell self-renewal. While excess Myostatin inhibited Pax7 expression via ERK1/2 signaling, an increase in Pax7 expression was observed following both genetic inactivation and functional antagonism of Myostatin. As a result, we show that either blocking or inactivating Myostatin enhances the partitioning of the fusion-incompetent self-renewed satellite cell lineage (high Pax7 expression, low MyoD expression) from the pool of actively proliferating myogenic precursor cells. Consistent with this result, over-expression of Pax7 in C2C12 myogenic cells resulted in increased self-renewal through a mechanism which slowed both myogenic proliferation and differentiation. Taken together, these results suggest that increased expression of Pax7 promotes satellite cell self-renewal, and furthermore Myostatin may control the process of satellite cell self-renewal through regulation of Pax7. Thus we speculate that, in addition to the intrinsic factors (such as Pax7), extrinsic factors both positive and negative in nature, will play a major role in determining the stemness of skeletal muscle satellite cells.


Studies on fractions of methanol extracts of tubercle bacilli. II. Toxic and allergenic properties of fractions employed as antituberculous vaccine.
Fractions of methanol extract which had been previously demonstrated to increase the resistance of mice to experimental tuberculosis have been subjected to an examination of their toxic and allergenic properties. The criteria for toxicity were: (a) production of inflammatory skin reactions in guinea pigs; (b) induction of weight loss in mice by intraperitoneal injection; and (c) depression of resistance to staphylococcus infections in mice. Allergenicity of a preparation was investigated by (a) its ability to evoke a hypersensitive skin response in guinea pigs previously sensitized with whole tubercle bacilli; and (b) its capacity to induce hypersensitivity to one or more of its components when injected under appropriate conditions into guinea pigs. Fraction F I, a preparation precipitated from methanol extract by slow concentration at 45 degrees C., was found to possess some toxicity and some allergenicity by all of the criteria employed. Subfraction F I-P, precipitated from aqueous suspensions of F I by 33 per cent ethanol and 0.5 per cent NaCl, was apparently the F I component responsible for these activities. The saline-ethanol-soluble subfraction, F I-S, was neither toxic nor allergenic by the tests performed. These findings were considered of particular interest inasmuch as F I-S, despite its small yield, had been shown earlier to be the most active single substance used as vaccine to increase resistance to experimental tuberculosis in mice.


ZnO-Al2O3 and ZnO-TiO2 core-shell nanowire dye-sensitized solar cells.
We describe the construction and performance of dye-sensitized solar cells (DSCs) based on arrays of ZnO nanowires coated with thin shells of amorphous Al(2)O(3) or anatase TiO(2) by atomic layer deposition. We find that alumina shells of all thicknesses act as insulating barriers that improve cell open-circuit voltage (V(OC)) only at the expense of a larger decrease in short-circuit current density (J(SC)). However, titania shells 10-25 nm in thickness cause a dramatic increase in V(OC) and fill factor with little current falloff, resulting in a substantial improvement in overall conversion efficiency, up to 2.25% under 100 mW cm(-2) AM 1.5 simulated sunlight. The superior performance of the ZnO-TiO(2) core-shell nanowire cells is a result of a radial surface field within each nanowire that decreases the rate of recombination in these devices. In a related set of experiments, we have found that TiO(2) blocking layers deposited underneath the nanowire films yield cells with reduced efficiency, in contrast to the beneficial use of blocking layers in some TiO(2) nanoparticle cells. Raising the efficiency of our nanowire DSCs above 2.5% depends on achieving higher dye loadings through an increase in nanowire array surface area.


Smaller future floods imply less habitat for riparian plants along a boreal river.
Climate-change projections suggest large changes in riverine flow regime, which will likely alter riparian communities. In northern Europe, forecasts propose lower annual spring flood peaks and higher winter flows, resulting in narrower riparian zones. To estimate the impact of climate change on habitat extent of riparian plants, we developed a framework estimating the sensitivity and exposure of individual species to streamflow change, and surveyed five reaches along the free-flowing Vindel River in northern Sweden. We modeled the hydrologic niche of riparian plant species based on the probability of occurrence along gradients of flood frequency and duration and used predicted future water-level fluctuations (based on climate models and IPCC emission scenarios) to calculate changes in flow-related habitat availability of individual species. Despite projected increases in runoff, we predict most species to decrease in riparian elevational extent by on average 12-29% until the end of the century, depending on scenario. Species growing in the upper, spring-flood-controlled part of the riparian zone will likely lose most habitat, with the largest reductions in species with narrow ranges of inundation duration tolerance (decreases of up to 54%). In contrast, the elevational extent of most amphibious species is predicted to increase, but conditions creating isoëtid vegetation will become rarer or disappear: isoëtid vegetation is presently found in areas where ice formed in the fall settles on the riverbank during the winter as water levels subside. Higher winter flows will make these conditions rare. We argue that our framework is useful to project the effects of hydrologic change caused by climate change as well as other stressors such as flow regulation also in other regions. With few rivers remaining unaffected by dams and other human stressors, these results call for monitoring to detect species declines. Management to alleviate species losses might include mitigation of habitat degradation from land-use activities, more environmentally friendly flow schemes, and more intensive management options such as mowing riparian meadows no longer regularly maintained by recurrent floods.


Timing the radiations of leaf beetles: hispines on gingers from latest cretaceous to recent.
Stereotyped feeding damage attributable solely to rolled-leaf hispine beetles is documented on latest Cretaceous and early Eocene ginger leaves from North Dakota and Wyoming. Hispine beetles (6000 extant species) therefore evolved at least 20 million years earlier than suggested by insect body fossils, and their specialized associations with gingers and ginger relatives are ancient and phylogenetically conservative. The latest Cretaceous presence of these relatively derived members of the hyperdiverse leaf-beetle clade (Chrysomelidae, more than 38,000 species) implies that many of the adaptive radiations that account for the present diversity of leaf beetles occurred during the Late Cretaceous, contemporaneously with the ongoing rapid evolution of their angiosperm hosts.


The impact of routine outcome measurement on treatment processes in community mental health care: approach and methods of the MECCA study.
Three issues characterise the background to the MECCA study: A) Throughout Europe, most patients with severe forms of psychotic disorders are cared for in the community. The challenge now is to make processes in community mental health care more effective. B) There are widespread calls to implement regular outcome measurement in routine settings. This, however, is more likely to happen, if it provides a direct benefit to clinicians and patients. C) Whilst user involvement is relatively easy to achieve on a political level, new mechanisms may have to be established to make the views of patients feed into individual treatment decisions. The MECCA study is a cluster randomised controlled trial following the same protocol in community mental health teams in six European countries. In the experimental group, patients' subjective quality of life, treatment satisfaction and wishes for different or additional help are assessed in key worker-patient meetings every two months and intended to inform the therapeutic dialogue and treatment decisions. The trial tests the hypothesis that the intervention--as compared to current best standard practice--will lead to a better outcome in terms of quality of life and other criteria in patients with psychotic disorders over a one year period. This more favourable outcome is assumed to be mediated through different treatment input based on more appropriate joint decisions or a more positive therapeutic relationship in line with a partnership model of care or both. Moreover, the study will hopefully reveal new insights into how therapeutic processes in community mental health care work and how they can be optimised.


Social health insurance for the poor: lessons from a health insurance programme in Karnataka, India.
Life-saving technology used to treat catastrophic illnesses such as heart disease and cancer is often out of reach for the poor. As life expectancy increases in poor countries and the burden from chronic illnesses continues to rise, so will the unmet need for expensive tertiary care. Understanding how best to increase access to and reduce the financial burden of expensive tertiary care is a crucial task for the global health community in the coming decades. In 2010, Karnataka, a state in India, rolled out the Vajpayee Arogyashree scheme (VAS), a social health insurance scheme focused on increasing access to tertiary care for households below the poverty line. VAS was rolled out in a way that allowed for robust evaluation of its causal effects and several studies have examined various impacts of the scheme on poor households. In this analysis article, we summarise the key findings and assess how these findings can be used to inform other social health insurance schemes. First, the evidence suggests that VAS led to a substantial reduction in mortality driven by increased tertiary care utilisation as well as use of better quality facilities and earlier diagnosis. Second, VAS significantly reduced the financial burden of receiving tertiary care. Third, these benefits of social health insurance were achieved at a reasonable cost to society and taxpayers. Several unique features of VAS led to its success at improving health and financial well-being including effective outreach via health camps, targeting expensive conditions with high disease burden, easy enrolment process, cashless treatment, bundled payment for hospital services, participation of both public and private hospitals and prior authorisation to improve appropriateness of care.


Hantavirus pulmonary syndrome in Santa Cruz, Bolivia: outbreak investigation and antibody prevalence study.
We report the results of an investigation of a small outbreak of hantavirus pulmonary syndrome in 2002 in the Department of Santa Cruz, Bolivia, where the disease had not previously been reported. Two cases were initially reported. The first case was a physician infected with Laguna Negra virus during a weekend visit to his ranch. Four other persons living on the ranch were IgM antibody-positive, two of whom were symptomatic for mild hantavirus pulmonary syndrome. The second case was a migrant sugarcane worker. Although no sample remained to determine the specific infecting hantavirus, a virus 90% homologous with Río Mamoré virus was previously found in small-eared pygmy rice rats (Oligoryzomys microtis) trapped in the area. An antibody prevalence study conducted in the region as part of the outbreak investigation showed 45 (9.1%) of 494 persons to be IgG positive, illustrating that hantavirus infection is common in Santa Cruz Department. Precipitation in the months preceding the outbreak was particularly heavy in comparison to other years, suggesting a possible climatic or ecological influence on rodent populations and risk of hantavirus transmission to humans. Hantavirus infection appears to be common in the Santa Cruz Department, but more comprehensive surveillance and field studies are needed to fully understand the epidemiology and risk to humans.


The role of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test blood and urine samples for the toxicological investigation of drug-facilitated crimes.
The authors present an overview of the drug-facilitated crime (DFC) phenomenon, especially in France. Recently, there has been an increase in reports of incidents (mainly sexual assaults and robbery) as well as in scientific publications and congress presentations on the topic. From enquiries conducted nationally, a list of drugs reportedly associated with DFC was established and includes benzodiazepines and benzodiazepine-like drugs (zolpidem, zopiclone), minor tranquilizers and neuroleptics, barbiturates, narcotics, hallucinogens, and anaesthetics. Some of these molecules are specific to France in DFC cases. A study using healthy volunteers who had taken benzodiazepines (lorazepam, bromazepam, flunitrazepam, clonazepam), zolpidem and zopiclone, showed that the only way to increase the duration of detection of these drugs is to use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test blood and urine samples. The very high sensitivity of this method appears to be an essential condition to document the cases, because the drugs tested were still detectable in urine at least 6 days after the ingestion of one therapeutic dose. Limits of detection were always lower than 0.5 ng/mL in urine. The actual list of molecules and metabolites the authors screened for in urine and blood by LC-MS/MS, in every DFC, is given in detail: 25 benzodiazepines and benzodiazepine-like drugs, 11 minor tranquilizers and neuroleptics, 2 barbiturates, 12 narcotics, 4 hallucinogens, and 1 anaesthetic. However, the distinction between continual therapeutic use of a psychotropic drug or illegal narcotic and a single ingestion has to be documented by sequential analysis of hair, again with LC-MS/MS.


IL-17-producing alveolar macrophages mediate allergic lung inflammation related to asthma.
IL-17 is a pivotal proinflammatory molecule in asthmatics. However, the cellular source of IL-17 in asthma has not been identified to date. In this study, we report that macrophages rather than Th17 cells are the main producer of IL-17 in allergic inflammation related to asthma. After OVA challenge in a mouse model mimicking allergic asthma, the increased IL-17(+) cells in the lung were mainly CD11b(+)F4/80(+) macrophages, instead of T cells or others. Importantly, IL-17(+) alveolar macrophages (AMs), but not IL-17(+) interstitial macrophages, were significantly increased after allergen challenge. The increase of IL-17(+) AMs was not due to the influx of IL-17(+) macrophages from circulation or other tissues, but ascribed to the activation of AMs by mediator(s) secreted by IgE/OVA-activated mast cells. Depleting alveolar macrophages or neutralizing IL-17 prevented the initiation of OVA-induced asthma-related inflammation by inhibiting the increase of inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid. Th2 cytokine IL-10 could down-regulate IL-17 expression in alveolar macrophages. The increased IL-17 and the decreased IL-10 in bronchoalveolar lavage fluid were further confirmed in asthmatic patients. These findings suggest that IL-17 is mainly produced by macrophages but not Th17 cells in allergic inflammation related to asthma. Mast cell-released mediators up-regulate the expression of IL-17 by macrophages, whereas IL-10 down-regulates IL-17 expression.


Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment.
By using stable isotope methodology, we studied the disposition of ibuprofen after the first and last dose of a 4-week regimen of 800 mg of racemic ibuprofen every 8 hr in three groups of subjects: 1) young healthy volunteers (n = 8); 2) healthy elderly volunteers (n = 14); and 3) elderly patients with creatinine clearance between 30 and 70 ml/min (n = 13). Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated S- and nondeuterated R- and S-ibuprofen in serum up to 24 hr after the first and last doses. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24-hr postdose by stereoselective high-performance liquid chromatography. Stereoselective serum protein binding was determined by ultrafiltration. Both elderly groups had significantly decreased binding of S-ibuprofen compared to the young group. The S-ibuprofen pharmacokinetics were significantly different in the elderly patients with renal impairment compared to the young volunteers: the T1/2 was increased, the unbound clearance was decreased and the unbound concentration at steady state was increased. Fraction inverted was similar for all groups, but unbound clearances of glucuronidation and hydroxylation were reduced in the elderly patients with renal impairment. These results suggest that the disposition of ibuprofen enantiomers is altered in elderly persons with renal impairment; these changes may increase the risk for nonsteroidal anti-inflammatory drug-associated adverse effects in such patients.


Retrievable covered nitinol stents: experiences in 108 patients with malignant esophageal strictures.
The authors report their experience with three types of retrievable covered nitinol stents in patients with malignant esophageal strictures. Three types of retrievable covered nitinol stents were designed. Type A stents were placed in 45 patients, type B stents were placed in 29 patients, and type C stents were placed in 34 patients. The stents were removed with use of a stent retrieval set under fluoroscopic guidance when the stents caused complications. Stent patency, symptom relief, survival rate, and complications were analyzed relative to stent type and radiation therapy. The timing of radiation and the stent type have significant effects on occurrence of complications such as stent migration and fistula formation (P =.002 and P = 0.029, respectively). Complications were significantly more frequent in patients with the type B stent than those with type A or type C stents (P =.008). Patients who underwent radiation therapy before stent placement or who underwent no radiation therapy experienced substantially less complications than those who underwent radiation therapy after stent placement (P =.005 and P <.001, respectively). The survival period was significantly longer in patients who underwent radiation therapy after stent placement than in the other groups (P =.034). Stents were removed from 15 patients (14%) 2 days to 16 weeks (mean, 4 weeks) after stent placement as a result of severe pain (n = 7), stent migration (n = 6), or stent deformity (n = 2). Stent removal was well tolerated in all patients. Use of retrievable covered nitinol stents seems to be a safe and effective method of treatment in patients with malignant esophageal strictures. However, removal of the stents was needed in 14% of the patients because of complications. Patients who underwent radiation therapy after stent placement and those with the type B stent experienced more complications than other patients.


Critique of the linear theory of carcinogenesis.
1) Present data on human leukemogenesis by radiation fail to indicate a linear relation between dose and effect. Because data are scanty, such a hypothesis cannot be ruled out statistically, but it is less probable than a nonlinear or threshold relation. 2) Other instances in which carcinogenic agents have been examined from the standpoint of dose and dose-rate relations show many clear instances where the relation is nonlinear and none in which linearity is unquestionably demonstrated. 3) Theoretical consideration of the probability that a single critical molecular event, such as a mutation, will give rise to cancer indicate that a malignant change must be an extraordinarily improbable result of such a perturbation. It is also very difficult to reconcile this mechanism with the rather comparable spontaneous and induced-cancer incidences in species with greatly different numbers of cells. 4) Any scheme in which multiple events caused by the carcinogen are required to produce a tumor is incompatible with a linear relation, while, if a disordered state of tissue is an important factor, a true threshold may even occur. There is much evidence, from cancer research of all sorts, indicating that one or both of these conditions is involved in the carcinogenic process.


Systemic arterial air embolism: positive pressure ventilation can be fatal in a patient with blunt trauma.
Systemic air embolism is a potentially fatal condition. Although venous embolism is commonly reported after deep sea diving or neurosurgical procedures, arterial embolism is rare. It usually occurs because of lung trauma after biopsy or lung resection but can rarely affect patients of blunt or penetrating trauma to chest managed on positive pressure ventilation. We report a case of road traffic accident with head injury, with normal primary survey of chest and abdomen who developed fatal systemic arterial air embolism immediately after intubation. Postmortem CT scan revealed huge amounts of air in left side of the heart, ascending aorta, arch of aorta, bilateral internal carotids and all right-sided intracranial arteries. In emergency departments of non-specialised centres, such complications are universally fatal. Thus, extreme caution needs to be exercised while managing patients of blunt trauma on mechanical ventilation even if the chest and abdominal examinations are normal.


Associations of objectively measured sitting and standing with low-back pain intensity: a 6-month follow-up of construction and healthcare workers.
Objectives This study aimed to determine the associations between objectively measured sitting and standing duration and intensity of low-back pain (LBP) among Norwegian construction and healthcare workers. Methods One-hundred and twenty-four workers wore two accelerometers for 3-4 consecutive days, during work and leisure. Minutes of sitting and standing was calculated from accelerometer data. We obtained self-reported LBP intensity (0-3) at the time of objective measurement and after six months. We examined associations with linear mixed models and presented results per 100 minutes. Results For healthcare workers, the duration of sitting during work [β= -0.33, 95% confidence interval (95% CI) -0.55- -0.10] and during full-day (work + leisure) (β= -0.21, 95% CI -0.38- -0.04) was associated with baseline LBP intensity. Furthermore, minutes of sitting at work (β=-0.35, 95% CI -0.57- -0.13) and during the full day (β=-0.20, 95% CI -0.37- -0.04) were significantly associated with LBP intensity at six months. Associations were attenuated when adjusting for work-related mechanical and psychosocial covariates and objectively measured exposure during leisure time. No significant associations between sitting and LBP intensity were found for construction workers. Standing at work was not consistently associated with LBP intensity at baseline or after six months for any work sector. Conclusions This study suggests that a long duration of sitting at work is associated with lower levels of LBP intensity among healthcare workers. Standing duration had no consistent associations with LBP intensity.


Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis.
Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3-/-), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3-/- mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3-/- mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3-/- mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.


Neural injury, repair, and adaptation in the GI tract. IV. Pathophysiology of GI motility related to interstitial cells of Cajal.
Our understanding of the physiological roles played by interstitial cells of Cajal (ICC) in relation to gastrointestinal (GI) motility is still rudimentary. Nevertheless, studies into the pathophysiology of ICC are emerging at a rapid pace. Caution should be exercised, however, in assuming correlations between changes in Kit immunoreactivity, findings of ultrastructural abnormalities in ICC, and the pathophysiology and symptoms of the patients. Recent studies have revealed reduced numbers or the absence of ICC in small intestine and colon that do not exhibit normal peristaltic activity. Furthermore, important evidence is emerging that motor abnormalities in newborns may be associated with delayed maturation of the ICC network. These preliminary clinical studies provide plausible hypotheses toward the pathophysiology of certain motor disorders and strongly encourage basic scientific studies directed toward discovering the intrinsic properties of ICC as well as obtaining a deeper understanding of the physiological roles played by these cells.


Mouse Zfx protein is similar to Zfy-2: each contains an acidic activating domain and 13 zinc fingers.
The Zfy gene is located on the Y chromosome of placental mammals and encodes a zinc finger protein which may serve as the primary sex-determining signal. A related gene, Zfx, is similarly conserved on the X chromosome. Unlike that in most mammals, the mouse genome contains four homologous zinc finger loci: Zfy-1, Zfy-2, Zfx, and Zfa (on an autosome). We report that, in contrast to the mouse Zfy genes, Zfx is widely transcribed in embryos, newborns, and adults, both male and female. Moreover, Zfx transcripts contain long 3' untranslated sequences which are phylogenetically conserved. Zfa is a processed gene derived from Zfx. An analysis of cDNA clones demonstrated that Zfx encodes a 799-amino-acid protein that is 70% identical to the mouse Zfy-1 and Zfy-2 proteins. Zfx, Zfy-1, and Zfy-2 contain highly acidic amino-terminal domains and carboxy-terminal regions containing 13 zinc fingers. When fused to the DNA-binding domain of GAL4, the acidic domains of Zfx and Zfy-2 activated transcription in yeast cells.


Baby-OSCAR: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies-a statistical analysis plan for short-term outcomes.
The Baby-OSCAR trial is a multi-centre, randomised, placebo-controlled parallel group trial of early treatment of large patent ductus arteriosus (PDA) with ibuprofen in extremely preterm infants. This paper describes the statistical analysis plan for the short-term health outcomes of the Baby-OSCAR trial. This is a randomised controlled trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies improves short and long-term health and economic outcomes. Infants born between 23+0 and 28+6 weeks of gestation, confirmed by echocardiography as having a large PDA (with a diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern), with parental informed consent, were randomly allocated to receive either ibuprofen or placebo within 72 h of birth. The primary outcome is a composite of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Baseline demographic and clinical characteristics will be described by randomised group. The primary analysis will be on the modified intention to treat (ITT) population. Counts and percentages will be presented for binary and categorical variables, and mean and standard deviation or median and interquartile range will be presented for continuous variables. For binary outcomes, risk ratios and confidence intervals will be calculated using log binomial or Poisson regression with a robust variance estimator. Continuous outcomes will be analysed using linear regression models, or quantile regression models if skewed. Analyses will be adjusted for all minimisation factors where technically possible, and correlation between siblings from multiple births will be accounted for by nesting the clusters as a random effect. Both crude and adjusted effect estimates will be presented, with the primary inference based on the adjusted estimates. Ninety-five per cent confidence intervals will be used for all pre-specified outcome comparisons. This paper describes the statistical analysis plan for short-term health outcomes of the trial, including the analysis principles, definitions of important outcomes, methods for primary analysis, pre-specified subgroup analysis, and secondary analysis. The plan was finalised prior to completion of short-term follow-up. ISRCTN registry ISRCTN84264977 . Registered on 15 September 2010.


Characterization of a calcium/calmodulin-regulated SR/CAMTA gene family during tomato fruit development and ripening.
Fruit ripening is a complicated development process affected by a variety of external and internal cues. It is well established that calcium treatment delays fruit ripening and senescence. However, the underlying molecular mechanisms remain unclear. Previous studies have shown that calcium/calmodulin-regulated SR/CAMTAs are important for modulation of disease resistance, cold sensitivity and wounding response in vegetative tissues. To study the possible roles of this gene family in fruit development and ripening, we cloned seven SR/CAMTAs, designated as SlSRs, from tomato, a model fruit-bearing crop. All seven genes encode polypeptides with a conserved DNA-binding domain and a calmodulin-binding site. Calmodulin specifically binds to the putative targeting site in a calcium-dependent manner. All SlSRs were highly yet differentially expressed during fruit development and ripening. Most notably, the expression of SlSR2 was scarcely detected at the mature green and breaker stages, two critical stages of fruit development and ripening; and SlSR3L and SlSR4 were expressed exclusively in fruit tissues. During the developmental span from 10 to 50 days post anthesis, the expression profiles of all seven SlSRs were dramatically altered in ripening mutant rin compared with wildtype fruit. By contrast, only minor alterations were noted for ripening mutant nor and Nr fruit. In addition, ethylene treatment of mature green wildtype fruit transiently stimulated expression of all SlSRs within one to two hours. This study indicates that SlSR expression is influenced by both the Rin-mediated developmental network and ethylene signaling. The results suggest that calcium signaling is involved in the regulation of fruit development and ripening through calcium/calmodulin/SlSR interactions.


Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups.
The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.


The impact of uncross-matched blood transfusion on the need for massive transfusion and mortality: analysis of 5,166 uncross-matched units.
The objective of this study was to analyze the outcomes associated with uncross-matched blood transfusion during trauma resuscitation. Our hypothesis was that uncross-matched blood transfusion is a predictor of the need for massive transfusion and mortality. All injured patients receiving packed red blood cell (PRBC) transfusion during a 6-year period ending December 2005 were identified from the blood bank database at a level I trauma center. Uncross-matched red blood cell (URBC) and cross-matched red blood cells, plasma and platelet utilization, and injury demographics were abstracted for each patient. Of 25,599 trauma patients, 4,241 (16.6%) patients received 29,375 units of PRBC and 1,236 (29.1%) of the transfused patients received 5,166 units of URBC during their resuscitation. Patients requiring URBC had a higher mortality (39.6% vs. 11.9%, p < 0.001) and were more likely to require massive (> or = 10 PRBC during 12 hours) transfusion (29.3% vs. 1.8%, p < 0.001). There was a stepwise increase in mortality with increasing URBC transfusion. After adjusting for age, gender, mechanism, hypotension at admission, emergency department intubation, initial hemoglobin, Glasgow Coma Scale, Abbreviated Injury Scale, Injury Severity Score, and amount of blood products received; URBC remained an independent predictor of mortality (adjusted odds ratio 2.15; 95% confidence interval 1.58-2.94; p < 0.001) and massive transfusion (adjusted odds ratio, 11.87; 95% confidence interval, 8.43-16.7; p < 0.001). Patients receiving URBC also utilized more blood components (11.9 +/- 12.7 vs. 4.9 +/- 5.8 units of PRBC, p < 0.001; 5.1 +/- 8.9 vs. 2.0 +/- 4.8 units of plasma, p < 0.001; and 1.1 +/- 2.5 vs. 0.4 +/- 1.6 units of platelets, p < 0.001). The requirement for uncross-matched blood during the acute resuscitation of trauma patients is an independent predictor of mortality and the need for massive transfusion. A URBC request during resuscitation should be considered by the blood bank as a potential trigger to prepare for massive transfusion.


Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD.
The Na+/H+ antiporter, which regulates intracellular pH in virtually all cells, is one of the best examples of a mitogen- and oncogene-activated membrane target whose activity rapidly changes on stimulation. The activating mechanism is unknown. A Na+/H+ antiporter complementary DNA fragment was expressed in Escherichia coli as a beta-galactosidase fusion protein, and a specific antibody to the fusion protein was prepared. Use of this antibody revealed that the Na+/H+ antiporter is a 110-kilodalton glycoprotein that is phosphorylated in growing cells. Mitogenic activation of resting hamster fibroblasts and A431 human epidermoid cells with epidermal growth factor, thrombin, phorbol esters, or serum, stimulated phosphorylation of the Na+/H+ antiporter with a time course similar to that of the rise in intracellular pH.


The role of ecological feedbacks in the evolution of host defence: what does theory tell us?
Hosts have evolved a diverse range of defence mechanisms in response to challenge by infectious organisms (parasites and pathogens). Whether defence is through avoidance of infection, control of the growth of the parasite once infected, clearance of the infection, tolerance to the disease caused by infection or innate and/or acquired immunity, it will have important implications for the population ecology (epidemiology) of the host-parasite interaction. As a consequence, it is important to understand the evolutionary dynamics of defence in the light of the ecological feedbacks that are intrinsic to the interaction. Here, we review the theoretical models that examine how these feedbacks influence the nature and extent of the defence that will evolve. We begin by briefly comparing different evolutionary modelling approaches and discuss in detail the modern game theoretical approach (adaptive dynamics) that allows ecological feedbacks to be taken into account. Next, we discuss a number of models of host defence in detail and, in particular, make a distinction between 'resistance' and 'tolerance'. Finally, we discuss coevolutionary models and the potential use of models that include genetic and game theoretical approaches. Our aim is to review theoretical approaches that investigate the evolution of defence and to explain how the type of defence and the costs associated with its acquisition are important in determining the level of defence that evolves.


Bifurcations and chaos in semiconductor superlattices with a tilted magnetic field.
We study the effects of dissipation on electron transport in a semiconductor superlattice with an applied bias voltage and a magnetic field that is tilted relative to the superlattice axis. In previous work, we showed that, although the applied fields are stationary, they act like a terahertz plane wave, which strongly couples the Bloch and cyclotron motion of electrons within the lowest miniband. As a consequence, the electrons exhibit a unique type of Hamiltonian chaos, which creates an intricate mesh of conduction channels (a stochastic web) in phase space, leading to a large resonant increase in the current flow at critical values of the applied voltage. This phase-space patterning provides a sensitive mechanism for controlling electrical resistance. In this paper, we investigate the effects of dissipation on the electron dynamics by modifying the semiclassical equations of motion to include a linear damping term. We demonstrate that, even in the presence of dissipation, deterministic chaos plays an important role in the electron transport process. We identify mechanisms for the onset of chaos and explore the associated sequence of bifurcations in the electron trajectories. When the Bloch and cyclotron frequencies are commensurate, complex multistability phenomena occur in the system. In particular, for fixed values of the control parameters several distinct stable regimes can coexist, each corresponding to different initial conditions. We show that this multistability has clear, experimentally observable, signatures in the electron transport characteristics.


Competence in Teaching Mindfulness-Based Courses: Concepts, Development and Assessment.
There has been a groundswell of interest in the UK in Mindfulness-Based Stress Reduction (MBSR) and its derivatives, particularly Mindfulness-Based Cognitive Therapy (MBCT). Many health, education and social work practitioners have sought ways to develop their competencies as mindfulness-based teachers, and increasing numbers of organisations are developing mindfulness-based training programmes. However, the rapid expansion of interest in mindfulness-based approaches has meant that those people offering training for MBSR and MBCT teachers have had to consider some quite fundamental questions about training processes, standards and competence. They also need to consider how to develop a robust professional context for the next generation of mindfulness-based teachers. The ways in which competencies are addressed in the secular mainstream contexts in which MBSR and MBCT are taught are examined to enable a consideration of the particularities of mindfulness-based teaching competence. A framework suggesting how competencies develop in trainees is presented. The current status of methodologies for assessing competencies used in mindfulness-based training and research programmes is reviewed. We argue that the time is ripe to continue to develop these dialogues across the international community of mindfulness-based trainers and teachers.


Acute phase gene expression in rainbow trout (Oncorhynchus mykiss) after exposure to a confinement stressor: A comparison of pooled and individual data.
This study set out to investigate whether differential expression of genes for acute phase proteins in rainbow trout (Oncorhynchus mykiss) could be induced by confinement stress, a non-invasive method of activating the neuroendocrine stress response. In addition, a second objective was to assess the variation in gene expression between individual fish within the population of stressed fish in an attempt to identify APP genes having uniform and consistent changes in expression during stress. The liver was chosen for this investigation as it is the primary site of acute phase protein synthesis. Relative expression of the eight genes including transferrin, fibrinogen-like protein 2 (flp2), alpha-1-anti-proteinase-like protein (alpha1-antiprot), leukocyte cell-derived chemotaxin 2 (LECT2), pentraxin, serum amyloid A (SAA), haptoglobin (Hp), and differentially regulated trout protein 1 (DRTP1) was analysed by quantitative real-time PCR (qPCR) over 5 experimental time points spanning the course of a week. The results showed that the expression of three genes, SAA, haptoglobin and DRTP1, were most altered as a result of exposure to confinement stress. A correlation was identified between the expression of haptoglobin and DRTP1. Gene expression analyses in individual fish found that the transcript levels of haptoglobin and DRTP1 genes varied much less between individuals than was the case for SAA. The increase of haptoglobin and DRTP1 gene expression and its uniformity in response to stress make these genes potential biomarkers for stress in trout.


Cycles in epilepsy.
Epilepsy is among the most dynamic disorders in neurology. A canonical view holds that seizures, the characteristic sign of epilepsy, occur at random, but, for centuries, humans have looked for patterns of temporal organization in seizure occurrence. Observations that seizures are cyclical date back to antiquity, but recent technological advances have, for the first time, enabled cycles of seizure occurrence to be quantitatively characterized with direct brain recordings. Chronic recordings of brain activity in humans and in animals have yielded converging evidence for the existence of cycles of epileptic brain activity that operate over diverse timescales: daily (circadian), multi-day (multidien) and yearly (circannual). Here, we review this evidence, synthesizing data from historical observational studies, modern implanted devices, electronic seizure diaries and laboratory-based animal neurophysiology. We discuss advances in our understanding of the mechanistic underpinnings of these cycles and highlight the knowledge gaps that remain. The potential clinical applications of a knowledge of cycles in epilepsy, including seizure forecasting and chronotherapy, are discussed in the context of the emerging concept of seizure risk. In essence, this Review addresses the broad question of why seizures occur when they occur.


Soy food consumption and lung cancer risk: a meta-analysis using a common measure across studies.
A published meta-analysis pooled individual studies by using the study-specific odds ratio (OR) or relative risk (RR) for the highest vs. lowest category of soy or isoflavone intake from each study, but it should be problematic to make comparison between studies/populations for lung cancer risk as the quantiles are so different from different studies/populations. Therefore, we conducted a meta-analysis to explore the association between exposure of estimated daily soy protein intake in grams and lung cancer risk. We extracted ORs or RRs and 95% confidence intervals (CIs), converted them to the estimated ones for daily soy protein intake and pooled them using fixed or random effects models from 11 epidemiologic studies. Overall, the inverse association between daily grams of soy protein intake and risk of lung cancer was borderline statistically significant (OR = 0.98, 95% CI = 0.96 to 1.00); the inverse association was statistically significant in nonsmokers (OR = 0.96; 95% CI = 0.93 to 0.99) and stronger than in smokers (P for difference <0.05). No statistical significance for the associations was observed between genders, the origin of the participants, study design and types of soy intake. This study suggests a borderline reduction in risk of lung cancer with daily soy protein intake in grams, and a significant inverse association in nonsmokers.


Immunoglobulin E and bullous pemphigoid.
Clinical features and histological findings in bullous pemphigoid (BP) suggest a Th2-oriented inflammatory reaction, especially in the early stages of the disease. Elevated total serum IgE levels, blood eosinophilia, and elevated serum levels of different soluble inflammatory Th2 response mediators have been described in large cohorts of patients with classic clear-cut BP manifestations. Direct immunofluorescence, indirect immunofluorescence, and anti-BP230 and anti-BP180 IgE ELISA testing show self-reactive IgE autoantibodies in a consistent number of BP patients. Both IgE autoantibodies and a Th2-oriented immune response may play a role in the initial phases of BP and atypical cases of BP, such as severe erythematous and urticarial forms of BP, as well as blister formation. Two recently reported experimental murine models employing IgE autoantibodies against BP180 have been reported and the successful treatment of bullous pemphigoid with the anti-IgE antibody, omalizumab, supports the roles played by IgE autoantibodies in BP pathogenesis.


Exponential vaporization fronts and critical heat flux in pool boiling.
Here we study the inception and propagation of vaporization fronts and transition to the critical heat flux (CHF) and film-boiling regime triggered by a steep, almost instantaneous increase in the heat release from a strip heater submerged in Novec 7300 liquid. The propagation path of the resulting vaporization front along the strip heater is measured and shown to be exponentially increasing in time, in distinction from the previous reports in literature claiming that the increase is only linear. Since the previous experiments employed such liquids as water, refrigerants, acetone, ethanol, and alkali metals, which possess relatively high latent heat of evaporation and thus require a relatively high power to be supplied, the heater burnout at the inception of the CHF and film boiling was too fast to allow for longer-time observations. Accordingly, the previous works observed only an extremely short-time asymptotics of the propagation process, which means the short-time expansion of the exponential function, which is linear. On the other hand, in the experiments with Novec 7300 liquid, the heater burnout is delayed due to a much lower latent heat of evaporation, thus allowing for a much longer observation of the propagation path, which appears to be exponentially increasing in time. The experiments were preceded by our theoretical prediction of such a behavior, and this theory is also described in the present work. Due to the fact that this theory has been corroborated by the experimental data, the theory yields an adequate explanation and description of the CHF trigger and film boiling inception.


Estimating Flight Distance of Platypus koryoensis (Coleoptera: Curculionidae) by Mark-Release-Recapture and Its Validation by Field Observation.
Korean oak wilt (KOW) is vectored by the beetle Platypus koryoensis (Murayama) (Coleoptera: Curculionidae), a native species of Korea, whose dispersal distance is a key factor determining the spread of damage by KOW. To estimate dispersal distance at stand level, we conducted a mark-release-recapture (MRR) experiment and validated its results using an independent data. Sticky traps were attached to the trunks of oak trees up to 48.8 m from the release point. Beetles were marked with different three fluorescent powders by date and released, and the number of recaptured beetles was counted 90 min after release. To validate the flight distance, annual mean dispersal distance of P. koryoensis population was analyzed using GPS coordinates of oak trees with the symptom of KOW recorded in the field from 2012 to 2014 in independent oak stands that have been damaged by KOW since 2012. The beetles were recaptured only on the day they were released, suggesting that the beetles only make one flight. The percentage of recaptured beetles was 6.0 ± 1.6%. The mean dispersal distance was 18.0 ± 1.3 m, and more than 85% of recaptured beetles were caught within 25 m. Annual movement distances in infested stands were 24.1 and 19.9 m from 2012 to 2013 and 2013 to 2014, respectively, similar to the dispersal distance obtained from our MRR experiment. Our results showed that the dispersal distance of P. koryoensis estimated by MRR is a useful process for predicting the spread of areas damaged by KOW.


Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease.
The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals. TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed. Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies. Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.


Computer-generated microcooled reflection holograms in silicon for material processing with a CO(2) laser.
We report on the design, fabrication, and testing of multilevel computer-generated reflection holograms in Si for CO(2) laser material processing for laser intensities of <2 kW/cm(2). The holograms are designed with an iterative method based on scalar diffraction theory. In this case the reconstructed intensity distribution is independent of the incident high-power laser mode. For achieving high diffraction efficiencies, multilevel staircase surface topologies are fabricated by multimask and reactive ion-etching technology on the front side of a polished Si wafer. For efficient hologram cooling, a gratinglike structure of microchannels is chemically etched on the back side of the Si wafer. Absorption and deformation measurements have been carried out on both a microcooled flat mirror and a reflection hologram. The maximum deformation amounts to 200 nm and is 10 times smaller than comparable conventional uncoated Cu mirrors. A diffraction efficiency of 88% is achieved with an eight-level reflection hologram and a 30-mm-diameter CO(2) laser beam with a power of 5 kW.


Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies.
Previous evidence suggests that higher circulating 25-hydroxyvitamin D (25[OH]D) levels are variably associated with lower breast cancer risk; however, prospective studies and clinical trials have been inconsistent, particularly between older and younger women of differing menopausal status. We conducted a quantitative nonlinear dose-response meta-analysis of prospective studies evaluating the association between circulating 25(OH)D and breast cancer risk, stratified by menopause. A systematic search of MEDLINE and EMBASE included studies published through May 2011. We reviewed references from retrieved articles and contacted relevant investigators for additional data from prospective studies on circulating 25(OH)D levels and incident breast cancers. Prospective studies of circulating vitamin D and breast cancer risk were reviewed, and no language restrictions were imposed. Information on study population, menopausal status, 25(OH)D levels, and relative risk (RR) estimates were extracted using a standardized protocol.A total of 9 prospective studies were included, comprising 5206 cases and 6450 controls. Data were pooled using dose-response random-effects meta-regression models. Identifying nonlinear effects, spline models were optimized for thresholds. The relationship between circulating 25(OH)D and breast cancer risk differed by menopausal status (p = 0.05 for effect modification). While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women. Notably, a flat association was observed in the lowest range of 25(OH)D levels <27 ng/mL (RR = 1.01 per 5 ng/mL; 95% confidence interval [CI], 0.98-1.04). In contrast, postmenopausal breast cancer risk decreased with 25(OH)D levels 27-<35 ng/mL (p = 0.02 for nonlinear risk change), where a 5 ng/mL increase in 25(OH)D was associated with a 12% lower risk of breast cancer (RR = 0.88 per 5 ng/mL; 95% CI, 0.79-0.97), with suggestive flattening at higher doses >35 ng/mL. The significant inverse association did not appear to vary across strata of invasive/in-situ cases, body mass index adjustment, region, postmenopausal hormone use, or assay method.In summary, this dose-response meta-analysis of prospective studies of plasma 25(OH)D suggested a breast cancer risk differential by menopause, whereby a step-wise inverse association was observed beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL, in postmenopausal women. These findings help resolve prior inconsistent findings and may carry important clinical and public health implications.


An adaptable system for improving transposon-based gene expression in vivo via transient transgene repression.
Transposons permit permanent cellular genome engineering in vivo. However, transgene expression falls rapidly postdelivery due to a variety of mechanisms, including immune responses. We hypothesized that delaying initial transgene expression would improve long-term transgene expression by using an engineered piggyBac transposon system that can regulate expression. We found that a 2-part nonviral Tet-KRAB inducible expression system repressed expression of a luciferase reporter in vitro. However, we also observed nonspecific promoter-independent repression. Thus, to achieve temporary transgene repression after gene delivery in vivo, we utilized a nonintegrating version of the repressor plasmid while the gene of interest was delivered in an integrating piggyBac transposon vector. When we delivered the luciferase transposon and repressor to immunocompetent mice by hydrodynamic injection, initial luciferase expression was repressed by 2 orders of magnitude. When luciferase expression was followed long term in vivo, we found that expression was increased >200-fold compared to mice that received only the luciferase transposon and piggyBac transposase. We found that repression of early transgene expression could prevent the priming of luciferase-specific T cells in vivo. Therefore, transient transgene repression postgene delivery is an effective strategy for inhibiting the antitransgene immune response and improving long-term expression in vivo without using immunosuppression.


Mapping Power Law Distributions in Digital Health Social Networks: Methods, Interpretations, and Practical Implications.
Social networks are common in digital health. A new stream of research is beginning to investigate the mechanisms of digital health social networks (DHSNs), how they are structured, how they function, and how their growth can be nurtured and managed. DHSNs increase in value when additional content is added, and the structure of networks may resemble the characteristics of power laws. Power laws are contrary to traditional Gaussian averages in that they demonstrate correlated phenomena. The objective of this study is to investigate whether the distribution frequency in four DHSNs can be characterized as following a power law. A second objective is to describe the method used to determine the comparison. Data from four DHSNs—Alcohol Help Center (AHC), Depression Center (DC), Panic Center (PC), and Stop Smoking Center (SSC)—were compared to power law distributions. To assist future researchers and managers, the 5-step methodology used to analyze and compare datasets is described. All four DHSNs were found to have right-skewed distributions, indicating the data were not normally distributed. When power trend lines were added to each frequency distribution, R(2) values indicated that, to a very high degree, the variance in post frequencies can be explained by actor rank (AHC .962, DC .975, PC .969, SSC .95). Spearman correlations provided further indication of the strength and statistical significance of the relationship (AHC .987. DC .967, PC .983, SSC .993, P<.001). This is the first study to investigate power distributions across multiple DHSNs, each addressing a unique condition. Results indicate that despite vast differences in theme, content, and length of existence, DHSNs follow properties of power laws. The structure of DHSNs is important as it gives insight to researchers and managers into the nature and mechanisms of network functionality. The 5-step process undertaken to compare actor contribution patterns can be replicated in networks that are managed by other organizations, and we conjecture that patterns observed in this study could be found in other DHSNs. Future research should analyze network growth over time and examine the characteristics and survival rates of superusers.


Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.
Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10(-5)). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10(-5)), and 43% ID rate increase (CI: [23%, 67%], p<6×10(-5)). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10(-16)).


The reward-based eating drive scale: a self-report index of reward-based eating.
Why are some individuals more vulnerable to persistent weight gain and obesity than are others? Some obese individuals report factors that drive overeating, including lack of control, lack of satiation, and preoccupation with food, which may stem from reward-related neural circuitry. These are normative and common symptoms and not the sole focus of any existing measures. Many eating scales capture these common behaviors, but are confounded with aspects of dysregulated eating such as binge eating or emotional overeating. Across five studies, we developed items that capture this reward-based eating drive (RED). Study 1 developed the items in lean to obese individuals (n = 327) and examined changes in weight over eight years. In Study 2, the scale was further developed and expert raters evaluated the set of items. Study 3 tested psychometric properties of the final 9 items in 400 participants. Study 4 examined psychometric properties and race invariance (n = 80 women). Study 5 examined psychometric properties and age/gender invariance (n = 381). Results showed that RED scores correlated with BMI and predicted earlier onset of obesity, greater weight fluctuations, and greater overall weight gain over eight years. Expert ratings of RED scale items indicated that the items reflected characteristics of reward-based eating. The RED scale evidenced high internal consistency and invariance across demographic factors. The RED scale, designed to tap vulnerability to reward-based eating behavior, appears to be a useful brief tool for identifying those at higher risk of weight gain over time. Given the heterogeneity of obesity, unique brief profiling of the reward-based aspect of obesity using a self-report instrument such as the RED scale may be critical for customizing effective treatments in the general population.


A multistate outbreak of infections caused by Yersinia enterocolitica transmitted by pasteurized milk.
In June and July 1982, a large interstate outbreak of Yersinia enterocolitica infections caused by an unusual serotype occurred in Tennessee, Arkansas, and Mississippi. Eighty-six percent of cases had enteritis characterized by fever, abdominal pain, and diarrhea. In three separate case-control studies, drinking milk pasteurized by plant A was statistically associated with illness. In a survey of randomly chosen households, 8.3% of persons who recalled having drunk milk from plant A during the suspect period experienced a yersiniosislike illness. Inspection of the plant and cultures of the available raw and pasteurized milk did not reveal the source or mechanism of contamination or a breach in normal pasteurizing technique. Although outbreaks of enteric disease caused by pasteurized milk are rare in the United States, the ability of Y enterocolitica to grow in milk at refrigeration temperatures makes pasteurized milk a possible vehicle for virulent Y enterocolitica. The extent to which milk is responsible for sporadic cases of yersiniosis is unknown.


Single-Molecule Insights Into the Dynamics of Replicative Helicases.
Helicases are molecular motors that translocate along single-stranded DNA and unwind duplex DNA. They rely on the consumption of chemical energy from nucleotide hydrolysis to drive their translocation. Specialized helicases play a critically important role in DNA replication by unwinding DNA at the front of the replication fork. The replicative helicases of the model systems bacteriophages T4 and T7, Escherichia coli and Saccharomyces cerevisiae have been extensively studied and characterized using biochemical methods. While powerful, their averaging over ensembles of molecules and reactions makes it challenging to uncover information related to intermediate states in the unwinding process and the dynamic helicase interactions within the replisome. Here, we describe single-molecule methods that have been developed in the last few decades and discuss the new details that these methods have revealed about replicative helicases. Applying methods such as FRET and optical and magnetic tweezers to individual helicases have made it possible to access the mechanistic aspects of unwinding. It is from these methods that we understand that the replicative helicases studied so far actively translocate and then passively unwind DNA, and that these hexameric enzymes must efficiently coordinate the stepping action of their subunits to achieve unwinding, where the size of each step is prone to variation. Single-molecule fluorescence microscopy methods have made it possible to visualize replicative helicases acting at replication forks and quantify their dynamics using multi-color colocalization, FRAP and FLIP. These fluorescence methods have made it possible to visualize helicases in replication initiation and dissect this intricate protein-assembly process. In a similar manner, single-molecule visualization of fluorescent replicative helicases acting in replication identified that, in contrast to the replicative polymerases, the helicase does not exchange. Instead, the replicative helicase acts as the stable component that serves to anchor the other replication factors to the replisome.


Dense deposit disease in Korean children: a multicenter clinicopathologic study.
The purpose of this study was to investigate the clinical, laboratory, and pathologic characteristics of dense deposit disease (DDD) in Korean children and to determine whether these characteristics differ between Korean and American children with DDD. In 2010, we sent a structured protocol about DDD to pediatric nephrologists throughout Korea. The data collected were compared with previously published data on 14 American children with DDD. Korean children had lower 24-hr urine protein excretion and higher serum albumin levels than American children. The light microscopic findings revealed that a higher percentage of Korean children had membranoproliferative glomerulonephritis patterns (Korean, 77.8%; American, 28.6%, P = 0.036), whereas a higher percentage of American children had crescents (Korean, 0%; American, 78.6%, P < 0.001). The findings from the electron microscopy revealed that Korean children were more likely to have segmental electron dense deposits in the lamina densa of the glomerular basement membrane (Korean, 100%; American, 28.6%, P = 0.002); mesangial deposit was more frequent in American children (Korean, 66.7%; American, 100%, P = 0.047). The histological findings revealed that Korean children with DDD were more likely to show membranoproliferative glomerulonephritis patterns than American children. The degree of proteinuria and hypoalbuminemia was milder in Korean children than American children.


Fractionation of the component processes underlying successful episodic encoding: a combined fMRI and divided-attention study.
Considerable evidence suggests that attentional resources are necessary for the encoding of episodic memories, but the nature of the relationship between attention and neural correlates of encoding is unclear. Here we address this question using functional magnetic resonance imaging and a divided-attention paradigm in which competition for different types of attentional resources was manipulated. Fifteen volunteers were scanned while making animacy judgments to visually presented words and concurrently performing one of three tasks on auditorily presented words: male/female voice discrimination (control task), 1-back voice comparison (1-back task), or indoor/outdoor judgment (semantic task). The 1-back and semantic tasks were designed to compete for task-generic and task-specific attentional resources, respectively. Using the "remember/know" procedure, memory for the study words was assessed after 15 min. In the control condition, subsequent memory effects associated with later recollection were identified in the left dorsal inferior frontal gyrus and in the left hippocampus. These effects were differentially attenuated in the two more difficult divided-attention conditions. The effects of divided attention seem, therefore, to reflect impairments due to limitations at both task-generic and task-specific levels. Additionally, each of the two more difficult divided-attention conditions was associated with subsequent memory effects in regions distinct from those showing effects in the control condition. These findings suggest the engagement of alternative encoding processes to those engaged in the control task. The overall pattern of findings suggests that divided attention can impact later memory in different ways, and accordingly, that different attentional resources, including task-generic and task-specific resources, make distinct contributions to successful episodic encoding.


Effects of imidazoline I(2) receptor agonists and morphine on schedule-controlled responding in rats.
Accumulating evidence indicates that imidazoline I(2) receptor agonists enhance the antinociceptive effects of opioids and therefore may be suitable for combination therapy with opioids for pain treatment. However, little is known of the effects of I(2) receptor agonists on other behavioral effects of opioids. This study used schedule-controlled responding and dose-addition analyses to examine interactions between the μ opioid receptor agonist morphine and two imidazoline I(2) receptor agonists, 2-BFI and BU224. In 8 rats responding under a fixed ratio 10 schedule of food presentation, morphine (3.2-17.8 mg/kg), 2-BFI (3.2-17.8 mg/kg), and BU224 (5.6-17.8 mg/kg) each dose-dependently decreased responding. The addition of fixed proportions of 2-BFI or BU224 shifted the morphine dose-effect curves leftward. The interactions between morphine and 2-BFI or BU224 were infra-additive when the same proportions of morphine and I(2) receptor agonists were mixed; however, the interaction between morphine and I(2) receptor agonists was additive when the drugs were mixed at other proportions. These results provide quantitative evidence that I(2) receptor agonists do not enhance the response rate-decreasing effect of morphine and suggest that the enhancement of morphine antinociception is selective. Together, these results further support the therapeutic potential of combining I(2) receptor agonists and opioids for pain control.


The functional organization of the lateral frontal cortex: conjecture or conjuncture in the electrophysiology literature?
While the importance of the prefrontal cortex for `higher-order' cognitive functions is largely undisputed, no consensus has been reached regarding the fractionation of functions within this region. Since Fuster and Alexander's first description of `working memory cells' the field has continued to be driven by electrophysiological recording studies, the results of which have provided the impetus for an abundance of studies using alternative methodologies, most notably, functional neuroimaging. However, even within the electrophysiological literature, there is considerable disagreement about how the functions of different prefrontal regions might best be described, a consideration that has implications for the interpretation of related studies in human subjects. In this article, we review the electrophysiological evidence for functional segregation within the frontal cortex in the context of related data from primate lesion studies and functional neuroimaging in humans, and attempt to reconcile the key findings with emerging cognitive models of lateral frontal lobe organization.


Concepts and technologies for tracking bioactive compounds in natural product extracts: generation of libraries, and hyphenation of analytical processes with bioassays.
Since the advent of high-throughput screening (HTS) in the early 1990s, a wealth of innovative technologies have been proposed and implemented for the effective localization and characterization of bioactive constituents in complex matrices. The latest developments in this field are reviewed under the perspective of their applicability to natural product-based drug discovery. The approaches discussed here include TLC-based bioautography, HPLC-based assays with on-line, at-line and off-line detection, as well as affinity-based methods, such as frontal affinity chromatography, pulsed ultrafiltration mass spectrometry, imprinted polymers, and affinity capillary electrophoresis. Selected practical examples are given to illustrate the strengths and limitations of these approaches in contemporary natural product lead discovery. In addition, compatibility issues of natural product extracts and HTS are addressed, and selected protocols for the generation of high quality libraries are presented.


Provider Role in Transmission of Carbapenem-Resistant Enterobacteriaceae.
OBJECTIVE We sought to evaluate the role healthcare providers play in carbapenem-resistant Enterobacteriaceae (CRE) acquisition among hospitalized patients. DESIGN A 1:4 case-control study with incidence density sampling. SETTING Academic healthcare center with regular CRE perirectal screening in high-risk units. PATIENTS We included case patients with ≥1 negative CRE test followed by positive culture with a length of stay (LOS) >9 days. For controls, we included patients with ≥2 negative CRE tests and assignment to the same unit set as case patients with a LOS >9 days. METHODS Controls were time-matched to each case patient. Case exposure was evaluated between days 2 and 9 before positive culture and control evaluation was based on maximizing overlap with the case window. Exposure sources were all CRE-colonized or -infected patients. Nonphysician providers were compared between study patients and sources during their evaluation windows. Dichotomous and continuous exposures were developed from the number of source-shared providers and were used in univariate and multivariate regression. RESULTS In total, 121 cases and 484 controls were included. Multivariate analysis showed odds of dichotomous exposure (≥1 source-shared provider) of 2.27 (95% confidence interval [CI], 1.25-4.15; P=.006) for case patients compared to controls. Multivariate continuous exposure showed odds of 1.02 (95% CI, 1.01-1.03; P=.009) for case patients compared to controls. CONCLUSIONS Patients who acquire CRE during hospitalization are more likely to receive care from a provider caring for a patient with CRE than those patients who do not acquire CRE. These data support the importance of hand hygiene and cohorting measures for CRE patients to reduce transmission risk. Infect Control Hosp Epidemiol 2017;38:1329-1334.


Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here?
A subset of patients treated for Lyme disease report persistent or recurrent symptoms of unknown etiology named post-treatment Lyme disease syndrome (PTLDS). This study aims to describe a cohort of participants with early, untreated Lyme disease, and characterize post-treatment symptomatology and functional impact of PTLDS over time. Sixty-three participants with erythema migrans and systemic symptoms were enrolled in a prospective cohort study. Participants underwent physical exams and clinical assessments, and completed the SF-36 (daily life functioning) and the Beck Depression Inventory, Second Edition (BDI-II) (depression), at each of five visits over a period of 6 months. Signs of Lyme disease disappeared post-treatment; however, new-onset patient-reported symptoms increased or plateaued over time. At 6 months, 36% of patients reported new-onset fatigue, 20% widespread pain, and 45% neurocognitive difficulties. However, less than 10% reported greater than "minimal" depression across the entire period. Those with PTLDS (36%) did not differ significantly from those without with respect to demographics, pre-treatment SF-36, and BDI-II scores. Statistically significant differences were found over time on the Role Physical, Vitality, Social Functioning, Role Emotional, and Mental Health subscales (with a trend toward significance for the remaining three subscales of Physical Functioning, Bodily Pain, and General Health) of the SF-36 between those with an eventual PTLDS diagnosis and those without when measured at 6 months. Unlike clinical signs of Lyme disease, new-onset symptoms are reported by a subset of participants without evidence of depressive symptomatology. Patients who developed PTLDS had significantly lower life functioning compared to those without PTLDS. We propose future avenues for researching infection-triggered symptoms resulting from multiple mechanisms.


Liquid crystal Fresnel zone lens based on single-side-patterned photoalignment layer.
In this article, we disclose a method to fabricate a liquid crystal (LC) Fresnel zone lens (FZL) with high efficiency. The LCFZL, based on patterned planar-aligned regions, has been prepared by means of a two-step photoalignment technique. The proposed binary-phase LCFZL manifests 39% diffraction efficiency at the focal point, which is close to the theoretical limit, 41%. Moreover, because of a lower driving voltage and faster response time, these elements could find application in many modern devices.


Follicular Growth Pattern Disease on Thyroid Fine-needle Aspiration Biopsy
Thyroid nodules are a common worldwide health problem and a diagnostic challenge for clinicians and cytopathologists. Follicular growth pattern constitutes the majority of thyroid lesions. Thyroid nodules can be neoplastic or non-neoplastic, and neoplastic nodules can be classified as benign, malignant, or gray zone. Gray zone lesions include different benign and malignant entities that might be resulted in unnecessary thyroidectomies with risk of morbidity and higher health care costs. Depending on the cellularity, most cases might fall into the follicular neoplasia (FN)/ suspicious for FN (SFN) category or follicular lesion of undetermined significance (FLUS) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Pathologists must be aware of the relationship between this diagnostic category and follow-up patient management and avoid over-diagnosing by mastering the diagnostic criteria.


Pathways for horizontal gene transfer in bacteria revealed by a global map of their plasmids.
Plasmids can mediate horizontal gene transfer of antibiotic resistance, virulence genes, and other adaptive factors across bacterial populations. Here, we analyze genomic composition and pairwise sequence identity for over 10,000 reference plasmids to obtain a global map of the prokaryotic plasmidome. Plasmids in this map organize into discrete clusters, which we call plasmid taxonomic units (PTUs), with high average nucleotide identity between its members. We identify 83 PTUs in the order Enterobacterales, 28 of them corresponding to previously described archetypes. Furthermore, we develop an automated algorithm for PTU identification, and validate its performance using stochastic blockmodeling. The algorithm reveals a total of 276 PTUs in the bacterial domain. Each PTU exhibits a characteristic host distribution, organized into a six-grade scale (I-VI), ranging from plasmids restricted to a single host species (grade I) to plasmids able to colonize species from different phyla (grade VI). More than 60% of the plasmids in the global map are in groups with host ranges beyond the species barrier.