Persistent West Nile virus associated with a neurological sequela in hamsters identified by motor unit number estimation.
To investigate the hypothesis that neurological sequelae are associated with persistent West Nile virus (WNV) and neuropathology, we developed an electrophysiological motor unit number estimation (MUNE) assay to measure the health of motor neurons temporally in hamsters. The MUNE assay was successful in identifying chronic neuropathology in the spinal cords of infected hamsters. MUNE was suppressed at days 9 to 92 in hamsters injected subcutaneously with WNV, thereby establishing that a long-term neurological sequela does occur in the hamster model. MUNE suppression at day 10 correlated with the loss of neuronal function as indicated by reduced choline acetyltransferase staining (R(2) = 0.91). Between days 10 and 26, some alpha-motor neurons had died, but further neuronal death was not detected beyond day 26. MUNE correlated with disease phenotype, because the lowest MUNE values were detected in paralyzed limbs. Persistent WNV RNA and foci of WNV envelope-positive cells were identified in the central nervous systems of all hamsters tested from 28 to 86 days. WNV-positive staining colocalized with the neuropathology, which suggested that persistent WNV or its products contributed to neuropathogenesis. These results established that persistent WNV product or its proteins cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is effectively detected by MUNE. Inasmuch as WNV-infected humans can also experience a poliomyelitis-like disease where motor neurons are damaged, MUNE may also be a sensitive clinical or therapeutic marker for those patients.


Evaluation of load carriage systems used by active duty police officers: Relative effects on walking patterns and perceived comfort.
This study aimed to examine the effects of two different load carriage systems on gait kinematics, temporospatial gait parameters and self-reported comfort in Swedish police. 21 active duty police officers were recruited for this crossover study design. Biomechanical and self-report data was collected on two testing occasions. On occasion 1, three dimensional kinematic data was collected while police wore a/no equipment (control), b/their standard issues belt and ballistic protection vest and c/a load bearing vest with ballistic protection vest. Police then wore the load bearing vest for a minimum of 3 months before the second testing occasion. The load bearing vest was associated with a significant reduction in range of motion of the trunk, pelvis and hip joints. Biomechanical changes associated with the load bearing vest appeared to reduce with increased wear time. In both the standard issue belt condition and the load bearing vest condition, police walked with the arms held in a significantly greater degree of abduction. Self-report data indicated a preference for the load bearing vest. The two load carriage designs tested in this study were found to significantly alter gait kinematics. The load bearing vest design was associated with the greatest number of kinematic compensations however these reduced over time as police became more accustomed to the design. Results from this study do not support selection of one load carriage design over the other and providing individuals with the option to choose a load carriage design is considered appropriate.


SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: online resources and useful tools - a compass in the land of biomarker discovery.
Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies.


Do surgical clips interfere with radiofrequency thermal ablation?
This study sought to evaluate whether surgical clips affect tissue conductivity and thereby alter the induction of radiofrequency ablation lesions and to determine whether therapy is safe after previous placement of clips in the liver. An ex vivo porcine hepatic model was used. Three clips were placed around a radiofrequency electrode at 10, 20, and 30 mm from the point of insertion. Clips were arranged in a plane either perpendicular or parallel to the electrode track. After placement of the liver specimen on a grounding pad, radiofrequency energy was applied in a standardized manner for 5 min. Lesion growth and morphology were documented for each minute. Radiofrequency lesions appeared circular and homogeneous after 5 min. Lesion diameter perpendicular to the radiofrequency electrode averaged 30 mm. However, lesion formation was irregular during the early phase of the radiofrequency ablation. The lesion extended irregularly toward the 1-cm clip after 60 sec of ablation. During the second minute, a distinct lesion was observed around the clip 1 cm from the electrode; the primary lesion had not yet reached the clip. During the final 3 min, the primary lesion reached the 1-cm clip and ultimately incorporated the satellite lesion. No lesions were detected surrounding the more distant clips. Our data suggest that with the parameters applied in our study, radiofrequency ablation can be safely performed in patients with implanted clips. No aberrant conduction is observed around surgical clips that are located 20 mm and further from the radiofrequency electrode.


Tranexamic acid for upper gastrointestinal bleeding.
Background Tranexamic acid reduces haemorrhage through its antifibrinolytic effects. In a previous version of the present review, we found that tranexamic acid may reduce mortality. This review includes updated searches and new trials.Objectives To assess the effects of tranexamic acid versus no intervention, placebo or other antiulcer drugs for upper gastrointestinal bleeding.Search methods We updated the review by performing electronic database searches (Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE, Science Citation Index) and manual searches in July 2014.Selection criteriaRandomised controlled trials, irrespective of language or publication status.Data collection and analysis We used the standard methodological procedures of the The Cochrane Collaboration. All-cause mortality, bleeding and adverse events were the primary outcome measures. We performed fixed-effect and random-effects model meta-analyses and presented results as risk ratios (RRs) with 95% confidence intervals (CIs) and used I² as a measure of between-trial heterogeneity. We analysed tranexamic acid versus placebo or no intervention and tranexamic acid versus antiulcer drugs separately. To analyse sources of heterogeneity and robustness of the overall results, we performed subgroup, sensitivity and sequential analyses.Main results We included eight randomised controlled trials on tranexamic acid for upper gastrointestinal bleeding. Additionally, we identified one large ongoing pragmatic randomised controlled trial from which data are not yet available. Control groups were randomly assigned to placebo (seven trials) or no intervention (one trial). Two trials also included a control group randomly assigned to antiulcer drugs(lansoprazole or cimetidine). The included studies were published from 1973 to 2011. The number of participants randomly assigned ranged from 47 to 216 (median 204). All trials reported mortality. In total, 42 of 851 participants randomly assigned to tranexamic acid and 71 of 850 in the control group died (RR 0.60, 95% CI 0.42 to 0.87; P value 0.007; I² = 0%). The analysis was not confirmed when all participants in the intervention group with missing outcome data were included as treatment failures, or when the analysis was limited to trials with low risk of attrition bias. Rebleeding was diagnosed for 117 of 826 participants in the tranexamic acid group and for 146 of 825 participants in the control group (RR 0.80, 95% CI 0.64 to 1.00; P value 0.07; I² = 49%).We were able to evaluate the risk of serious adverse events on the basis of only four trials. Our analyses showed 'no evidence of a difference between tranexamic acid and control interventions regarding the risk of thromboembolic events.' Tranexamic acid appeared to reduce the risk of surgery ina fixed-effect meta-analysis (RR 0.73, 95% CI 0.56 to 0.95), but this result was no longer statistically significant in a random-effects meta-analysis (RR 0.61, 95% CI 0.35 to 1.04; P value 0.07). No difference was apparent between tranexamic acid and placebo in the assessment of transfusion (RR 1.02, 95% CI 0.94 to 1.11; I² = 0%), and meta-analyses that compared tranexamic acid versus antiulcer drugs did not identify beneficial or detrimental effects of tranexamic acid for any of the outcomes assessed.Authors' conclusions This review found that tranexamic acid appears to have a beneficial effect on mortality, but a high dropout rate in some trials means that we cannot be sure of this until the findings of additional research are published. At the time of this update in 2014, one large study(8000 participants) is in progress, so this review will be much more informative in a few years. Further examination of tranexamic acid would require inclusion of high-quality randomised controlled trials. Timing of randomisation is essential to avoid attrition bias and to limit the number of withdrawals. Future trials may use a pragmatic design and should include all participants with suspected bleeding or with endoscopically verified bleeding, as well as a tranexamic placebo arm and co-administration of pump inhibitors and endoscopic therapy. Assessment of outcome measures in such studies should be clearly defined. Endoscopic examination with appropriate control of severe bleeding should be performed, as should endoscopic verification of clinically significant rebleeding. In addition, clinical measures of rebleeding should be included. Other important outcome measures include mortality (30-day or in-hospital), need for emergency surgery or blood transfusion and adverse events (major or minor).


Apical ridge dependent and independent mesodermal domains of GHox-7 and GHox-8 expression in chick limb buds.
The homeobox-containing genes GHox-7 and GHox-8 have been proposed to play fundamental roles in limb development. The expression of GHox-8, by the apical ridge cells, and GHox-7, in the subridge mesoderm, suggests the involvement of these two genes in limb outgrowth and proximo-distal pattern formation. A straightforward way to test this is to remove the apical ridge. Here we report the relationship between the mesodermal expression of GHox-7 and GHox-8 and the apical ectodermal ridge in the chick limb bud. The data from ridge removal experiments indicate that there are at least two domains of GHox-7 expression in the apical limb bud mesoderm. The posterior subridge GHox-7 domain in the progress zone requires the influence of the apical ridge for continued expression, while the anterior GHox-7 domain continues expression after ridge removal. Posterior subridge mesoderm is exquisitely sensitive to the loss of the ridge in that GHox-7 expression by these cells is reduced in only two hours and undetectable by three hours after ridge removal. It would appear that one of the ways progress zone cells respond to the apical ridge signal is by expressing GHox-7. The loss of ridge influence whether by growth at the apex or by ridge removal is followed by an unusually rapid decline in detectable GHox-7 transcripts. Maintenance of GHox-8 expression by the anterior mesoderm appears to be independent of the presence of the apical ridge.(ABSTRACT TRUNCATED AT 250 WORDS)


Sleep disturbances in older adults with mild cognitive impairment.
Normal aging and dementia are characterized by increased prevalence of sleep disorders and alterations of both sleep continuity and architecture. However, little is still known about the nature of sleep in mild cognitive impairment (MCI), which is presumably situated on the continuum from healthy aging to dementia. This unsystematic review summarizes the current literature on the prevalence and severity of sleep disturbances in MCI. Eighteen studies addressing sleep/night-time disturbances among other neuropsychiatric symptoms in individuals with MCI were identified through a search of databases and an examination of reference lists of selected papers. Fifteen of those studies reported data on prevalence or severity of sleep/night-time disturbances. Results indicated that 14-59% of patients with MCI had sleep disturbances. These disturbances were often identified as one of the four most prevalent neuropsychiatric symptoms of MCI and were considered as clinically significant in some studies. In addition, there was some evidence that the prevalence of sleep disturbances in MCI is intermediate between that of normal aging and dementia. Longitudinal data suggest that sleep problems are associated with both incident MCI and dementia. These findings support the hypothesis that sleep disturbances are one of the core non-cognitive symptoms of MCI. It remains to be known whether sleep problems could help to identify those individuals with MCI who will eventually develop dementia. Studies characterizing sleep more systematically are needed to verify this proposition and to clarify the associations between sleep disturbances and other neuropsychiatric symptoms of MCI.


Increased CD39 nucleotidase activity on microparticles from patients with idiopathic pulmonary arterial hypertension.
Idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease characterized by increased pulmonary vascular resistance, smooth muscle and endothelial cell proliferation, perivascular inflammatory infiltrates, and in situ thrombosis. Circulating intravascular ATP, ADP, AMP and adenosine activate purinergic cell signaling pathways and appear to induce many of the same pathologic processes that underlie IPAH. Extracellular dephosphorylation of ATP to ADP and AMP occurs primarily via CD39 (ENTPD1), an ectonucleotidase found on the surface of leukocytes, platelets, and endothelial cells. Microparticles are micron-sized phospholipid vesicles formed from the membranes of platelets and endothelial cells. Studies here examine whether CD39 is an important microparticle surface nucleotidase, and whether patients with IPAH have altered microparticle-bound CD39 activity that may contribute to the pathophysiology of the disease. Kinetic parameters, inhibitor blocking experiments, and immunogold labeling with electron microscopy support the role of CD39 as a major nucleotidase on the surface of microparticles. Comparison of microparticle surface CD39 expression and nucleotidase activity in 10 patients with advanced IPAH and 10 healthy controls using flow cytometry and thin layer chromatograph demonstrate the following: 1) circulating platelet (CD39(+)CD31(+)CD42b(+)) and endothelial (CD39(+)CD31(+)CD42b(-)) microparticle subpopulations in patients with IPAH show increased CD39 expression; 2) microparticle ATPase and ADPase activity in patients with IPAH is increased. We demonstrate for the first time increased CD39 expression and function on circulating microparticles in patients with IPAH. Further research is needed to elucidate whether these findings identify an important trigger for the development of the disease, or reflect a physiologic response to IPAH.


Gradient-based adaptation of general gaussian kernels.
Gradient-based optimizing of gaussian kernel functions is considered. The gradient for the adaptation of scaling and rotation of the input space is computed to achieve invariance against linear transformations. This is done by using the exponential map as a parameterization of the kernel parameter manifold. By restricting the optimization to a constant trace subspace, the kernel size can be controlled. This is, for example, useful to prevent overfitting when minimizing radius-margin generalization performance measures. The concepts are demonstrated by training hard margin support vector machines on toy data.


Eating behaviors among low-income obese adults in the United States: Does health care provider's advice carry any weight.
The U.S. Preventive Task Force recommends that all patients be screened for obesity and given appropriate weight loss advice, if needed, as nutrition counseling by primary care physicians is a key objective for Healthy People 2020. This study assesses the association between health care provider's (HCP) advice to lose weight and eating behaviors among obese individuals. Data were collected using a household survey of adults in five New Jersey cities in 2009-10. Analyses presented are limited to 548 obese participants. Negative-binomial regression analysis determined the association of participants' eating behaviors and HCP's advice to lose weight, after adjusting for the participant's attempt to lose weight and demographic variables. Despite being obese, only 48% of the participants received weight loss advice from their HCP while 68% stated they were attempting to lose weight. HCP's advice to lose weight was associated with increased salad and fruit consumption (PR 1.3, 95% CI 1.06-1.61; PR 1.23, 95% CI 1.02-1.48). Attempting to lose weight was positively associated with a higher consumption of fruit (PR 1.39, 95% CI 1.13-1.72), vegetables (PR 1.22, 95% CI 1.07-1.39), and with eating fruits and vegetables as snacks (PR 1.62, 95% CI 1.28-2.05). Attempting to lose weight was negatively associated with consumption of sweet snacks (PR 0.68, 95% CI 0.49-0.94), sugar sweetened beverages (PR 0.71, 95% CI 0.58-0.87) and fast food (PR 0.77, 95% CI 0.62-0.97). There were no significant interactions between HCP's advice and attempts to lose weight. Obese adult's attempt to lose weight, and not HCP's advice to lose weight, was a predictor for healthy eating behaviors. Interventions in medical practices should train HCPs on effective strategies for motivating obese patients to adopt healthier lifestyles.


Impact of enteropathogens on faltering growth in a resource-limited setting.
Environmental enteropathy is an important contributor to childhood malnutrition in the developing world. Chronic exposure to fecal pathogens leads to alteration in intestinal structure and function, resulting in impaired gut immune function, malabsorption, and growth faltering leading to environmental enteropathy. A community-based intervention study was carried out on children till 24 months of age in Matiari district, Pakistan. Blood and fecal specimens were collected from the enrolled children aged 3-6 and 9 months. A real-time PCR-based TaqMan array card (TAC) was used to detect enteropathogens. Giardia, Campylobacter spp., enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), Enterotoxigenic Escherichia coli (ETEC), and Cryptosporidium spp. were the most prevailing enteropathogens in terms of overall positivity at both time points. Detection of protozoa at enrollment and 9 months was negatively correlated with rate of change in height-for-age Z (ΔHAZ) scores during the first and second years of life. A positive association was found between Giardia, fecal lipocalin (LCN), and alpha 1-Acid Glycoprotein (AGP), while Campylobacter spp. showed positive associations with neopterin (NEO) and myeloperoxidase (MPO). Protozoal colonization is associated with a decline in linear growth velocity during the first 2 years of life in children living in Environmental enteric dysfunction (EED) endemic settings. Mechanistic studies exploring the role of cumulative microbial colonization, their adaptations to undernutrition, and their influence on gut homeostasis are required to understand symptomatic enteropathogen-induced growth faltering.


Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas.
The recent emergence and spread of dengue hemorrhagic fever in the Americas have been a major source of concern. Efforts to control this disease are dependent on understanding the pathogenicity of dengue viruses and their transmission dynamics. Pathogenicity studies have been hampered by the lack of in vitro or in vivo models of severe dengue disease. Alternatively, molecular epidemiologic studies which associate certain dengue virus genetic types with severe dengue outbreaks may point to strains with increased pathogenicity. The comparison of nucleotide sequences (240 bp) from the E/NS1 gene region of the dengue virus genome has been shown to reflect evolutionary relationships and geographic origins of dengue virus strains. This approach was used to demonstrate an association between the introduction of two distinct genotypes of dengue type 2 virus and the appearance of dengue hemorrhagic fever in the Americas. Phylogenetic analyses suggest that these genotypes originated in Southeast Asia and that they displaced the native, American genotype in at least four countries. Vaccination and other control efforts should therefore be directed at decreasing the transmission of these "virulent" genotypes.


Patterns of PrPCWD accumulation during the course of chronic wasting disease infection in orally inoculated mule deer (Odocoileus hemionus).
Patterns of abnormal prion protein (PrP) accumulation during the course of chronic wasting disease (CWD) infection were studied and the distribution and timing of disease-associated PrP (PrP(CWD)) deposition and lesions in 19 mule deer (Odocoileus hemionus) 90-785 days after oral inoculation were described. PrP(CWD) deposition occurred relatively rapidly and widely in lymphoid tissues, later in central and peripheral nervous tissues and sporadically in a variety of tissues and organs in terminal disease stages. Development of spongiform encephalopathy lagged behind PrP(CWD) deposition in the central nervous system (CNS), but occurred in the same neuroanatomical locations. PrP(CWD) deposition in the lymphatic and nervous systems tended to be consistent and progressive in specific organs and tissues. Locations of PrP(CWD) deposition were similar between deer of two PrP genotypes (225SS and 225SF), but the time course differed between genotypes: in 225SF deer, PrP(CWD) accumulated more slowly in lymphatic tissues than in 225SS animals, but that disparity was small in comparison to the disparity between genotypes in timing of deposition in CNS tissue. These data confirm retropharyngeal lymph node and medulla oblongata at the level of the obex as early sites of PrP(CWD) accumulation in mule deer with CWD. Data on the relative time frames for and genetic influences on PrP(CWD) accumulation may also offer insights about epidemic dynamics and potential control strategies.


Rapid axonal transport of sulfated mucopolysaccharide proteins.
When sulfur-35-labeled sodium sulfate is injected intraocularly in the goldfish, labeled sulfated mucopolysaccharides rapidly appear in the contra-lateral optic tectum of the brain, demonstrating the axonal flow of sulfated mucopolysaccharides. The transport rate is the same as that observed for proteins labeled after intraocular injection of tritiated proline. Treatment of the sulfur-35-labeled material with precipitants and enzymes reveals the presence of substances with properties similar to those of heparan sulfate (the major component) and chondroitin sulfate. Dermatan sulfate was not detected.


Psychophysiological reactivity: mechanisms and pathways to cardiovascular disease.
This article examines possible sources of heightened psychophysiological reactivity in relation to risk for hypertension and coronary artery disease. The idea that exaggerated reactions to psychological stress may predict greater risk for future disease has some support in the psychosomatic and behavioral medicine literature. However, the pathways by which exaggerated reactivity could arise in a given person and the implications of different sources of reactivity for potential disease relationships have received little attention. This topic is approached through a selective literature review and by means of a neurophysiologically based model of individual differences in physiological reactivity. Temperament characteristics, cognitive processes, neurophysiology, and peripheral physiology are used to indicate three levels that could contribute to exaggerated physiological reactivity. At the top level in the model, activity of the frontal cortex and limbic system establish cognitive-emotional sources of activation that may underlie exaggerated physiological reactivity. In the absence of these influences, large responses may be more likely when exaggerated subcortical response tendencies are present via the hypothalamus or brain stem. Finally, peripheral alterations may account for larger reactions in persons who have otherwise normal emotional and hypothalamic and brainstem response tendencies. Cognitive-emotional and hypothalamic-brainstem sources of altered reactivity may cause or aggravate disease. In contrast, altered peripheral reactivity suggests that a pathophysiologic process may be present, serving as a marker for disease. These three levels of analysis allow for organization of existing data in the area of cardiovascular reactivity and for planning future studies in a hypothesis-building framework.


Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: A cohort study.
Non-alcoholic fatty liver disease (NAFLD) has been associated with chronic kidney disease (CKD), but cohort studies are limited. We investigated the longitudinal association of NAFLD and its severity with the development of CKD. We performed a retrospective cohort study of 41,430 adult men and women (average age, 48.9y) without CKD at baseline who underwent repeated health check-up examinations from January 1, 2003, through December 31, 2013. NAFLD status was assessed by ultrasonography, and NAFLD severity was assessed by the NAFLD fibrosis score (NFS). The outcome was an incident CKD, defined as an estimated glomerular filtration rate less than 60ml/min/1.73m2. During 200,790 person-years of follow-up (median follow-up of 4.15years), we identified 691 incident CKD cases. The multivariable-adjusted hazard ratio for CKD comparing participants with and without NAFLD was 1.22 (95% confidence interval [CI] 1.04-1.43). The risk of CKD increased progressively with increased NAFLD severity. The multivariable-adjusted hazard ratios for CKD comparing participants with NFS <-1.455 and those with NFS ≥-1.455 to participants without NAFLD were 1.09 (95% CI 0.91-1.32) and 1.58 (95% CI 1.30-1.92), respectively. The association was consistent across clinically relevant subgroups. In a large cohort of adult men and women without CKD, NAFLD was associated with an increased risk of CKD development. NAFLD may adversely affect renal function and patients may need to be carefully monitored for an increased risk of CKD. The presence of fatty liver is associated with the future decline of renal function. Thus, fatty liver patients need to be monitored regularly for renal function.


Awake craniotomy for tumor resection.
Surgical treatment of brain tumors, especially those located in the eloquent areas such as anterior temporal, frontal lobes, language, memory areas, and near the motor cortex causes high risk of eloquent impairment. Awake craniotomy displays major rule for maximum resection of the tumor with minimum functional impairment of the Central Nervous System. These case reports discuss the use of awake craniotomy during the brain surgery in Alzahra Hospital, Isfahan, Iran. A 56-year-old woman with left-sided body hypoesthesia since last 3 months and a 25-year-old with severe headache of 1 month duration were operated under craniotomy for brain tumors resection. An awake craniotomy was planned to allow maximum tumor intraoperative testing for resection and neurologic morbidity avoidance. The method of anesthesia should offer sufficient analgesia, hemodynamic stability, sedation, respiratory function, and also awake and cooperative patient for different neurological test. Airway management is the most important part of anesthesia during awake craniotomy. Tumor surgery with awake craniotomy is a safe technique that allows maximal resection of lesions in close relationship to eloquent cortex and has a low risk of neurological deficit.


DNA variation in the phenotypically-diverse brown alga Saccharina japonica.
Saccharina japonica (Areschoug) Lane, Mayes, Druehl et Saunders is an economically important and highly morphologically variable brown alga inhabiting the northwest Pacific marine waters. On the basis of nuclear (ITS), plastid (rbcLS) and mitochondrial (COI) DNA sequence data, we have analyzed the genetic composition of typical Saccharina japonica (TYP) and its two common morphological varieties, known as the "longipes" (LON) and "shallow-water" (SHA) forms seeking to clarify their taxonomical status and to evaluate the possibility of cryptic species within S. japonica. The data show that the TYP and LON forms are very similar genetically in spite of drastic differences in morphology, life history traits, and ecological preferences. Both, however, are genetically quite different from the SHA form. The two Saccharina lineages are distinguished by 109 fixed single nucleotide differences as well as by seven fixed length polymorphisms (based on a 4,286 bp concatenated dataset that includes three gene regions). The GenBank database reveals a close affinity of the TYP and LON forms to S. japonica and the SHA form to S. cichorioides. The three gene markers used in the present work have different sensitivity for the algal species identification. COI gene was the most discriminant gene marker. However, we have detected instances of interspecific COI recombination reflecting putative historical hybridization events between distantly related algal lineages. The recombinant sequences show highly contrasted level of divergence in the 5'- and 3'- regions of the gene, leading to significantly different tree topologies depending on the gene segment (5'- or 3'-) used for tree reconstruction. Consequently, the 5'-COI "barcoding" region (~ 650 bp) can be misleading for identification purposes, at least in the case of algal species that might have experienced historical hybridization events. Taking into account the potential roles of phenotypic plasticity in evolution, we conclude that the TYP and LON forms represent examples of algae phenotypic diversification that enables successful adaptation to contrasting shallow- and deep-water marine environments, while the SHA form is very similar to S. cichorioides and should be considered a different species. Practical applications for algal management and conservation are briefly considered.


Lack of an association of depression with n-3 polyunsaturated fatty acids in adipose tissue and serum phospholipids in healthy adults.
Studies have shown that depression relates to biomarkers of both short-term and long-term polyunsaturated fatty acid intake. However, it is not known which of these two biomarkers is more closely related to depression. The aim of this study was to examine the relationship of depression with both adipose tissue and serum phospholipid polyunsaturated fatty acids and to assess the importance of each of these two biomarkers in relating to depression. This is a cross-sectional study of healthy adults from the island of Crete. Subjects were examined by the Preventive Medicine and Nutrition Clinic of the University of Crete. Subjects were 394 healthy adults (175 males, 219 females) aged 18-60. The sample consisted of farmers from a number of rural communities of Crete. Fatty acids were determined by gas chromatography in adipose tissue and serum phospholipids. Information about depression was obtained through the Beck Depression Inventory (BDI) and Zung Self-rating Depression Scale (ZSRDS). Adipose tissue alpha-linolenic acid (ALA) (C18:3n-3) was inversely correlated to BDI (r=-0.17, p<0.02). Multiple linear regression analysis taking into account the possible confounding effect of age, gender, body mass index (BMI), smoking and educational level did not confirm this association. The other polyunsaturated fatty acids in adipose tissue were not related to depression. Serum phospholipid polyunsaturated fatty acids did not correlate with depression. This study did not show that the polyunsaturated fatty acids in the adipose tissue are better predictors of depression than those in serum phospholipids.


Oculomotor nerve palsy precipitating acute angle-closure glaucoma. A case report.
A case of acute angle-closure glaucoma precipitated by oculomotor nerve palsy in a patient with shallow anterior chambers is reported. The different ways in which a palsy of the oculomotor nerve can influence the intra-ocular pressure are discussed.


Hidden female physiological resistance to male accessory gland substances in a simultaneous hermaphrodite.
To increase fertilization chances compared with rivals, males are favoured to transfer accessory gland proteins to females during mating. These substances, by influencing female physiology, cause alteration of her sperm usage and remating rate. Simultaneously hermaphroditic land snails with love-darts are a case in point. During courtship, a love-dart is pierced through the partner's body wall, thereby introducing accessory mucous gland products. This mucus physiologically increases paternity by inhibiting the digestion of donated sperm. The sperm, which are packaged in a spermatophore, are exchanged and received in an organ called the diverticulum. Because of its length, this organ was previously proposed to be a female anatomical adaptation that may limit the dart interference with the recipient's sperm usage. For reproductive success of the donor, an anatomically long spermatophore, relative to the partner's diverticulum, is beneficial as sperm can avoid digestion by exiting through the spermatophore's tail safely. However, the snail Eobania vermiculata possesses a diverticulum that is three times longer than the spermatophore it receives. Here, we report that the love-dart mucus of this species contains a contraction-inducing substance that shortens the diverticulum, an effect that is only properly revealed when the mucus is applied to another helicid species, Cornu aspersum This finding suggests that E. vermiculata may have evolved a physiological resistance to the manipulative substance received via the love-dart by becoming insensitive to it. This provides useful insight into the evolution of female resistance to male manipulations, indicating that it can remain hidden if tested on a single species.


Thermal conductivity of monolayer molybdenum disulfide obtained from temperature-dependent Raman spectroscopy.
Atomically thin molybdenum disulfide (MoS2) offers potential for advanced devices and an alternative to graphene due to its unique electronic and optical properties. The temperature-dependent Raman spectra of exfoliated, monolayer MoS2 in the range of 100-320 K are reported and analyzed. The linear temperature coefficients of the in-plane E2g 1 and the out-of-plane A1g modes for both suspended and substrate-supported monolayer MoS2 are measured. These data, when combined with the first-order coefficients from laser power-dependent studies, enable the thermal conductivity to be extracted. The resulting thermal conductivity κ = (34.5(4) W/mK at room temperature agrees well with the first principles lattice dynamics simulations. However, this value is significantly lower than that of graphene. The results from this work provide important input for the design of MoS2-based devices where thermal management is critical.


Cross-sectional analysis of sexual function after prostate brachytherapy.
To assess sexual function after prostate brachytherapy and compare outcomes in different age groups. This cross-sectional study consisted of 96 sexually active patients (mean age 64 years) who underwent iodine-125 seed implantation between 1997 and 2003 to treat early-stage prostate cancer (Stage T1-T2). Patients completed a questionnaire adapted from the validated Rand 36-Item Health Survey and the University of California, Los Angeles, Prostate Cancer Index. The median follow-up was 2.5 years (range 3 months to 6.2 years). The mean value for sexual function was 54.8. The mean score for erectile function was 55.0, and the mean score for the ability to reach orgasm was 54.0. No significant relationship was found between sexual function and time since treatment (P = 0.9897). Pain on orgasm was reported after brachytherapy by 38 patients (40%) and hematospermia by 16 patients (17%). A negative correlation was observed between pain on orgasm and time since treatment (P = 0.021), but no significant relationship was found between hematospermia and time since treatment (P = 0.427). A significant difference in sexual function was observed between patients younger than 60 years and patients older than 60 years (66.3 +/- 7.0 versus 47.7 +/- 7.2; P = 0.002). A large variation in sexual potency is present after brachytherapy with no significant relationship to the time since treatment. Age is an indicator of sexual function after brachytherapy, with younger patients experiencing less sexual dysfunction than older patients. Other aspects of sexual function (pain on orgasm, hematospermia) are also significant side effects of brachytherapy and must be considered in the treatment decision for low-risk prostate cancer.


Insulin receptors in cultured human fibroblasts.
In order to study human insulin resistance, we have first characterized the interaction of insulin with specific insulin receptors in cultures of normal human fibroblasts. 125 I-insulin bound rapidly to human fibroblasts in suspension at 15 degrees, achieving steady state between one and three hours. Insulin was not degraded during the binding assays. In competitive binding experiments, 2 ng/ml. (3.3 X 10(-10) M) of unlabeled insulin reduced 125 I-insulin binding by 50 per cent. Insulin analogues competed for binding in proportion to their biologic potencies. A curvilinear Scatchard plot was obtained, suggesting the existence of negatively cooperative site-site interactions among the insulin receptors. This was confirmed directly by studies of the dissociation kinetics. The high affinity, specificity, and negative cooperativity of the fibroblast insulin receptor closely resembles the properties of other human insulin receptors. The cultuted human fibroblast should prove a useful tissue for the study of insulin-resistant states in man.


New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes.
Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5-methoxybiphenyl-2'-O-β-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver-Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics.


Analysis of clock-regulated genes in Neurospora reveals widespread posttranscriptional control of metabolic potential.
Neurospora crassa has been for decades a principal model for filamentous fungal genetics and physiology as well as for understanding the mechanism of circadian clocks. Eukaryotic fungal and animal clocks comprise transcription-translation-based feedback loops that control rhythmic transcription of a substantial fraction of these transcriptomes, yielding the changes in protein abundance that mediate circadian regulation of physiology and metabolism: Understanding circadian control of gene expression is key to understanding eukaryotic, including fungal, physiology. Indeed, the isolation of clock-controlled genes (ccgs) was pioneered in Neurospora where circadian output begins with binding of the core circadian transcription factor WCC to a subset of ccg promoters, including those of many transcription factors. High temporal resolution (2-h) sampling over 48 h using RNA sequencing (RNA-Seq) identified circadianly expressed genes in Neurospora, revealing that from ∼10% to as much 40% of the transcriptome can be expressed under circadian control. Functional classifications of these genes revealed strong enrichment in pathways involving metabolism, protein synthesis, and stress responses; in broad terms, daytime metabolic potential favors catabolism, energy production, and precursor assembly, whereas night activities favor biosynthesis of cellular components and growth. Discriminative regular expression motif elicitation (DREME) identified key promoter motifs highly correlated with the temporal regulation of ccgs. Correlations between ccg abundance from RNA-Seq, the degree of ccg-promoter activation as reported by ccg-promoter-luciferase fusions, and binding of WCC as measured by ChIP-Seq, are not strong. Therefore, although circadian activation is critical to ccg rhythmicity, posttranscriptional regulation plays a major role in determining rhythmicity at the mRNA level.


Hypnotics in insomnia: the experience of zolpidem.
One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator-controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated with rebound insomnia, complex sleep-related behaviors, and next-day residual effects (after middle-of-the-night dosing) on driving ability, memory, and psychomotor performance.


Ligand binding by the immunoglobulin superfamily recognition molecule CD2 is glycosylation-independent.
The evolutionary success of the immunoglobulin superfamily (IgSF) is thought to reflect the ability of IgSF protein domains to form stable structural units. The role of glycosylation in stabilizing these domains is controversial, however. In this study a systematic analysis of the effect of glycosylation on the ligand-binding properties of the cell-cell recognition molecule CD2, which consists of two IgSF domains, was undertaken. A form of human soluble CD2 (hsCD2) with single N-acetylglucosamine residues at each glycosylation site was produced by inhibiting glucosidase I with N-butyldeoxynojirimycin during expression in Chinese hamster ovary cells and digesting the expressed hsCD2 with endoglycosidase H. The ligand and antibody binding properties of this form of hsCD2 were indistinguishable from those of fully glycosylated hsCD2 as determined by surface plasmon resonance analyses. The protein also formed diffraction quality crystals and analysis of the 2.5-A resolution crystal structure indicated that the single N-acetylglucosamine residue present on domain 1 is unlikely to stabilize the ligand binding face of hsCD2. A second, fully deglycosylated form of hsCD2 also bound the ligand and antibodies although this form of the protein tended to aggregate. In contrast to the results of previous studies, the current data indicate that the structural integrity and ligand binding function of human CD2 are glycosylation-independent.


First sex pheromone of the order strepsiptera: (3R,5R,9R)-3,5,9-trimethyldodecanal in Stylops melittae KIRBY, 1802.
The twisted-wing parasites (Strepsiptera) are an unusual and small order of insects with about 600 known species. As obligate endoparasitoids, they develop and spend most of their lives living in other insects. Adults show an extreme sexual dimorphism: The free-living males have large eyes, branched antennae, reduced forewings, and well developed hind wings, while the neotenic females of most species lack all external characters that normally define an insect, remain endoparasitic, and only extrude the cephalothorax from the host. Due to the males' short life span of only a few hours, there must be an efficient means of mate finding. This is believed to be mediated by chemical cues released by virgin females. Here, we report the first identification and synthesis of a female-produced strepsipteran sex pheromone, (3R,5R,9R)-3,5,9-trimethyldodecanal, from Stylops melittae, a species parasitizing andrenid bees. We found this highly EAD-active compound to be present in cephalothoraxes of and released from unmated females, and synthetic samples proved to be extremely attractive when offered in the field during the swarming period of the males. The structural features of this new natural compound may further support the re-establishment of the Strepsiptera as the closest living relatives of the Coleoptera.


No evidence for individual recognition in threespine or ninespine sticklebacks (Gasterosteus aculeatus or Pungitius pungitius).
Recognition plays an important role in the formation and organization of animal groups. Many animals are capable of class-level recognition, discriminating, for example, on the basis of species, kinship or familiarity. Individual recognition requires that animals recognize distinct cues, and learn to associate these with the specific individual from which they are derived. In this study, we asked whether sticklebacks (Gasterosteus aculeatus and Pungitius pungitius) were capable of learning to recognize individual conspecifics. We have used these fish as model organisms for studying selective social learning, and demonstrating a capacity for individual recognition in these species would provide an exciting opportunity for studying how biases for copying specific individuals shape the dynamics of information transmission. To test for individual recognition, we trained subjects to associate green illumination with the provision of a food reward close to one of two conspecifics, and, for comparison, one of two physical landmarks. Both species were capable of recognizing the rewarded landmark, but neither showed a preference for associating with the rewarded conspecific. Our study provides no evidence for individual recognition in either species. We speculate that the fission-fusion structure of their social groups may not favour a capacity for individual recognition.


Venous thromboembolism in very elderly patients: findings from a prospective registry (RIETE).
Elderly patients with venous thromboembolism (VTE) have an increased rate of bleeding complications on therapeutic doses of anticoagulant therapy. Using data in RIETE, an international registry of consecutive patients with objectively confirmed, symptomatic acute VTE, we analyzed the clinical characteristics and outcome within 90 days of therapy of all enrolled patients aged > or = 80 years old. Of the 13,011 patients with VTE enrolled in RIETE up tp September 2005, 2890 (22%) were aged > or = 80 years old. During the study period 99 patients (3.4%) aged > or = 80 years, and 212 aged < 80 years (2.1%) had major bleeding events (odds ratio: 1.7; 95% CI: 1.3-2.1). Fatal bleeding occurred in 0.8% and 0.4%, respectively (odds ratio: 2.0; 95% CI: 1.2-3.4). The incidence of recurrent VTE was 2.1% and 2.8%. However, 3.7% of patients > or = 80 years and 1.1% < 80 years died of pulmonary embolism (PE) (odds ratio: 3.6; 95% CI: 2.7-4.7). On multivariate analysis, patients > or = 80 years with symptomatic PE, heart failure, long-term therapy with low-molecular-weight heparin (LMWH) or a vena cava filter had an increased risk of recurrent VTE. Those with recent bleeding, abnormal renal function, use of corticosteroids or long-term therapy with LMWH had an increased risk of major bleeding. In patients aged > or = 80 years old the 3.4% incidence of major bleeding exceeded the 2.1% incidence of VTE recurrences. However, the 3.7% incidence of fatal PE outweighed the 0.8% of fatal bleeding. Thus, there seems to be more reason to be concerned about fatal PE than about bleeding in elderly patients with VTE.


Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.
The regulation of insulin secretion from pancreatic beta-cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K+ channels (K(ATP) channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the K(ATP) channels in pancreatic beta-cells is regulated by changes in the ATP and ADP concentrations (ATP/ADP ratio) caused by glucose metabolism. Thus, the K(ATP) channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. K(ATP) channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic beta-cell K(ATP) channel, Kir6.2 (an inward rectifier K+ channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K+ ion-permeable pore and primarily confer inhibition of the channels by ATP, while SUR1 subunits confer activation of the channels by MgADP and K+ channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to ATP. To determine the physiological roles of K(ATP) channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 specifically in the pancreatic beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the K(ATP) channels in endocrine pancreatic function: 1) the K(ATP) channels are the major determinant of the resting membrane potential of pancreatic beta-cells, 2) both glucose- and sulfonylurea-induced membrane depolarization of beta-cells require closure of the K(ATP) channels, 3) both glucose- and sulfonylurea-induced rises in intracellular calcium concentration in beta-cells require closure of the K(ATP) channels, 4) both glucose- and sulfonylurea-induced insulin secretions are mediated principally by the K(ATP) channel-dependent pathway, 5) the K(ATP) channels are important for beta-cell survival and architecture of the islets, 6) the K(ATP) channels are important in the differentiation of islet cells, and 7) the K(ATP) channels in glucose-responsive cells generally participate in coupling glucose sensing with cell excitability. Interestingly, despite the severe defect in glucose-induced insulin secretion, Kir6.2 knockout mice show only a very mild impairment in glucose tolerance. However, when the knockout mice become obese with age, they develop fasting hyperglycemia and glucose intolerance, while neither fasting hyperglycemia nor glucose intolerance is evident in the aged knockout mice without obesity, suggesting that both the genetic defect in glucose-induced insulin secretion and the acquired insulin resistance due to environmental factors are necessary to develop diabetes in Kir6.2 knockout mice. Thus, Kir6.2G132S Tg mice and Kir6.2 knockout mice provide a model of type 2 diabetes and clarify the various roles of K(ATP) channels in endocrine pancreatic function.


p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant.
In response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation. We show that a commonly occurring p53 mutant, R248W, retains wild-type ability to support survival under serine starvation. R248W, but not R175H, can engage p21 and MDM2, which both function to limit oxidative stress and facilitate the switch to de novo serine synthesis. In vivo, the growth of R248W-expressing tumours is resistant to dietary depletion of serine and glycine, correlating with an increased capacity to limit ROS compared to tumours expressing R175H. Human cancers expressing this p53 mutant show a worse outcome. Our work shows that mutant p53s can selectively retain wild-type p53 functions that allow adaptation to serine starvation through the activation of antioxidant defence pathways. Tumours containing this p53 mutation are resistant to serine-limited conditions and less responsive to therapy.


Controlled trial of respiratory health worker visiting patients with chronic respiratory disability.
Seventy five patients with chronic respiratory disability were randomised to a group visited by a respiratory health worker (42) or control group (33). The first group was visited monthly by a respiratory nurse, who gave education and support. The effect of the intervention was assessed in terms of quality of life (by questionnaires), the number and duration of admissions to hospital, and the number of deaths. The questionnaires on quality of life showed no changes in either group during the study, but nearly all of the group visited by a respiratory health worker said that they valued the visits and wished them to continue. Their knowledge about their condition also improved compared with that of the controls. The duration of stay in hospital for respiratory reasons in the group visited by a respiratory health worker was longer than that of control patients. This was explained by their being scored as more ill than the controls on admission. Fewer patients died in the group visited by a respiratory health worker than in the control group (p = 0.11). The patients in the group visited by respiratory health workers may have survived longer because they sought help rather than dying at home. If confirmed this could have implications for the cost of their care.


Creating highly specific nucleases by fusion of active restriction endonucleases and catalytically inactive homing endonucleases.
Zinc-finger nucleases and TALE nucleases are produced by combining a specific DNA-binding module and a non-specific DNA-cleavage module, resulting in nucleases able to cleave DNA at a unique sequence. Here a new approach for creating highly specific nucleases was pursued by fusing a catalytically inactive variant of the homing endonuclease I-SceI, as DNA binding-module, to the type IIP restriction enzyme PvuII, as cleavage module. The fusion enzymes were designed to recognize a composite site comprising the recognition site of PvuII flanked by the recognition site of I-SceI. In order to reduce activity on PvuII sites lacking the flanking I-SceI sites, the enzymes were optimized so that the binding of I-SceI to its sites positions PvuII for cleavage of the composite site. This was achieved by optimization of the linker and by introducing amino acid substitutions in PvuII which decrease its activity or disturb its dimer interface. The most specific variant showed a more than 1000-fold preference for the addressed composite site over an unaddressed PvuII site. These results indicate that using a specific restriction enzyme, such as PvuII, as cleavage module, offers an alternative to the otherwise often used catalytic domain of FokI, which by itself does not contribute to the specificity of the engineered nuclease.


Does sterile or nonsterile technique make a difference in wounds healing by secondary intention?
After observing inconsistencies in care of acute surgical wounds healing by secondary intention and reviewing the potential cost savings of implementing clean dressing change technique policies, surgical nurses at a university-based medical center monitored supply usage and infection rates of these wounds using a nonexperimental, longitudinal study design. Staff from two acute care surgical units provided data for 3 months before and 3 months after standardization of wound care to a clean wound care technique. All adult patients requiring dressing changes three times per day with normal saline moistened gauze of their open surgical wound(s) participated in the study. Before changing the wound care procedures, nine (9) of 1,070 (0.84%) admissions to the two surgical units had a surgical site infection. During the 3 months following implementation of clean wound care protocols, eight (8) surgical site infections were documented in 963 admissions (rate.83%). Dressing supply costs were $380 less. In this study, using nonsterile wound care procedures for wounds healing by secondary intention did not negatively impact infection rates and saved supply costs.


Long-Term Follow-Up of Children Treated With Peginterferon and Ribavirin for Hepatitis C Virus Infection.
The aim of the study was to describe the 5-year follow-up of children who received peginterferon and ribavirin in a global, open-label study. A 5-year follow-up study of 107 children and adolescents ages 3 to 17 years with chronic hepatitis C virus infection who received peginterferon and ribavirin for 24 or 48 weeks. No drugs were administered during follow-up. Ninety-four patients were enrolled in the long-term follow-up portion of the study; the median duration of follow-up was 287 weeks (range, 73-339). Of 63 patients with sustained virologic response who were enrolled, 54 completed 5 years of follow-up; none had relapse in the 5-year follow-up period. Significant decreases in height z scores were observed during treatment. The effect of treatment on height z score was larger in patients treated for 48 weeks compared with those treated for 24 weeks (mean change from baseline to the end of treatment was -0.13 [P < 0.001] and -0.44 [P < 0.001] in the 24- and 48-week treatment groups, respectively). Among patients treated for 24 weeks, full recovery of height z scores to baseline was observed by 1 year of follow-up, whereas only partial recovery was observed during 5 years of follow-up in patients treated for 48 weeks (mean change from baseline to the final follow-up visit was -0.16 (P = NS) and -0.32 (P < 0.05) in the 24- and 48-week treatment groups, respectively). Similar patterns were observed for weight and body mass index z scores. Impairment of growth should be considered when assessing the risk-benefit profile of peginterferon/ribavirin therapy in children with hepatitis C virus infection. In deciding to treat children with chronic hepatitis C virus, considerations should include both deferring treatment in patients during optimal growth periods, and the possibility that interferon-free regimens may be available to children in the next 5 to 10 years.


[Development of Alzheimer's disease treatment based on the molecular mechanism of γ-secretase activity].
Genetic and biological studies provide strong evidence that the deposition of amyloid-β peptide (Aβ) contributes to the etiology of Alzheimer's disease (AD). Thus, drugs that regulate the brain Aβ levels could provide effective disease-modifying therapy for AD. Aβ is generated from amyloid-β precursor protein (APP) by β- and γ-secretases. Several γ-secretase inhibitors have been developed as AD therapeutics. However, simple inhibition of γ-secretase would have adverse consequences, as γ-secretase is involved in several signaling pathways including Notch signaling. In 2010, the development of semagacestat, a γ-secretase inhibitor, was halted. Preliminary results from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, semagacestat treatment was associated with an increased risk of skin cancer. Thus, alternative compounds that indirectly modulate γ-secretase activity without affecting Notch are attracting attention. However, molecular mechanism of these compounds still remains unclear. To develop therapeutics with superior specificity and high potency for AD, we have been analyzing the mode of actions of known compounds, structure-and-function relationship of the γ-secretase complex and possible rational design of γ-secretase inhibitors and modulators using chemical biology.


Medical bioremediation of age-related diseases.
Catabolic insufficiency in humans leads to the gradual accumulation of a number of pathogenic compounds associated with age-related diseases, including atherosclerosis, Alzheimer's disease, and macular degeneration. Removal of these compounds is a widely researched therapeutic option, but the use of antibodies and endogenous human enzymes has failed to produce effective treatments, and may pose risks to cellular homeostasis. Another alternative is "medical bioremediation," the use of microbial enzymes to augment missing catabolic functions. The microbial genetic diversity in most natural environments provides a resource that can be mined for enzymes capable of degrading just about any energy-rich organic compound. This review discusses targets for biodegradation, the identification of candidate microbial enzymes, and enzyme-delivery methods.


Microarray-based comparative genomic analyses of the human malaria parasite Plasmodium falciparum using Affymetrix arrays.
Microarray-based comparative genomic hybridization (CGH) provides a powerful tool for whole genome analyses and the rapid detection of genomic variation that underlies virulence and disease. In the field of Plasmodium research, many of the parasite genomes that one might wish to study in a high throughput manner are not laboratory clones, but clinical isolates. One of the key limitations to the use of clinical samples in CGH, however, is the miniscule amounts of genomic DNA available. Here we describe the successful application of multiple displacement amplification (MDA), a non-PCR-based amplification method that exhibits clear advantages over all other currently available methods. Using MDA, CGH was performed on a panel of NF54 and IT/FCR3 clones, identifying previously published deletions on chromosomes 2 and 9 as well as polymorphism in genes associated with disease pathology.


Short report: Antibody responses of mice immunized with a tetravalent dengue recombinant protein subunit vaccine.
Recombinant proteins containing the B domain of dengue virus serotypes 1-4 fused to the maltose binding protein (MBP) of Escherichia coli were evaluated individually and as a tetravalent vaccine candidate in mice. Sera from mice immunized with monovalent DEN-MBP recombinant protein vaccines developed high titers of serotype homologous antibody in the enzyme-linked immunosorbent assay and the plaque-reduction neutralization test. Cross-reactive antibody titers were either several dilutions lower or not detectable. Sera from mice immunized with the tetravalent DEN subunit vaccine neutralized all 4 DEN viruses in the plaque-reduction neutralization test. The neutralizing antibody titers to each individual serotype were significantly greater than any cross-reactive neutralizing antibody titers induced by the monovalent vaccines, providing evidence that the tetravalent DEN recombinant subunit vaccine produced specific neutralizing antibody to all 4 serotypes of dengue virus.


Usability of RemindMe - An Interactive Web-Based Mobile Reminder Calendar: A Professional's Perspective.
The aim of the study was to examine the usability of an interactive web-based mobile reminder calendar (RemindMe) developed for supporting individuals in organizing, planning and executing activities in everyday life, from the perspectives of professionals. Eleven professionals working in community services evaluated the usability of RemindMe in their clinical practice. Data were collected using semi-structured interviews and analysed with inductive qualitative analysis. The professionals perceived that RemindMe was useful, easy to use, and intuitive. There was a need among professionals for a web-based reminder calendar that requires the active acknowledgement of reminders. RemindMe's feedback system offering self-monitored information based on the user's interaction with the system supported the professionals in discussions, evaluation, and follow-up based on the needs of the persons with cognitive impairments. The results indicate that RemindMe may be potentially useful to professionals who provide support to individuals with cognitive impairments. However, further research is needed to evaluate experience of using RemindMe from the perspective of individuals with cognitive impairments.


Liver Fibrosis Marker and Postoperative Mortality in Patients Without Overt Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) can progress to advanced fibrosis, which, in the nonsurgical population, is associated with poor hepatic and extrahepatic outcomes. Despite its high prevalence, NAFLD and related liver fibrosis may be overlooked during the preoperative evaluation, and the role of liver fibrosis as an independent risk factor for surgical-related mortality has yet to be tested. The aim of this study was to assess whether fibrosis-4 (FIB-4), which consists of age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelets, a validated marker of liver fibrosis, is associated with postoperative mortality in the general surgical population. A historical cohort of patients undergoing general anesthesia at an academic medical center between 2014 and 2018 was analyzed. Exclusion criteria included known liver disease, acute liver disease or hepatic failure, and alcohol use disorder. FIB-4 score was categorized into 3 validated predefined categories: FIB-4 ≤1.3, ruling out advanced fibrosis; >1.3 and <2.67, inconclusive; and ≥2.67, suggesting advanced fibrosis. The primary analytic method was propensity score matching (FIB-4 was dichotomized to indicate advanced fibrosis), and a secondary analysis included a multivariable logistic regression. Of 19,861 included subjects, 1995 (10%) had advanced fibrosis per FIB-4 criteria. Mortality occurred intraoperatively in 15 patients (0.1%), during hospitalization in 272 patients (1.4%), and within 30 days of surgery in 417 patients (2.1%). FIB-4 ≥2.67 was associated with increased intraoperative mortality (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.25-10.58), mortality during hospitalization (OR, 3.14; 95% CI, 2.37-4.16), and within 30 days from surgery (OR, 2.46; 95% CI, 1.95-3.10), after adjusting for other risk factors. FIB-4 was related to increased mortality in a dose-dependent manner for the 3 FIB-4 categories ≤1.3 (reference), >1.3 and <2.67, and ≥2.67, respectively; during hospitalization (OR, 1.89; 95% CI, 1.34-2.65 and OR, 4.70; 95% CI, 3.27-6.76) and within 30 days from surgery (OR, 1.77; 95% CI, 1.36-2.31 and OR, 3.55; 95% CI, 2.65-4.77). In a 1:1 propensity-matched sample (N = 1994 per group), the differences in mortality remained. Comparing the FIB-4 ≥2.67 versus the FIB-4 <2.67 groups, respectively, mortality during hospitalization was 5.1% vs 2.2% (OR, 2.70; 95% CI, 1.81-4.02), and 30-day mortality was 6.6% vs 3.4% (OR, 2.26; 95% CI, 1.62-3.14). A simple liver fibrosis marker is strongly associated with perioperative mortality in a population without apparent liver disease, and may aid in future surgical risk stratification and preoperative optimization.


Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents.
Clinical trials that have excluded patients at high risk for cardiac events have led to commercial labeling approval of drug-eluting stents; nevertheless, such high-risk patients commonly undergo stent placement in clinical practice. The degree to which they experience cardiac events at a higher rate than non-high-risk patients is unclear. To assess the rates of major adverse cardiac events during the index admission and 1 year after the implantation of drug-eluting stents in patients with high-risk angiographic and clinical features. From July 2004 to September 2005, consecutive patients who underwent attempted stent placement at 42 different hospitals throughout the United States were enrolled in a prospective multicenter registry. We analyzed outcomes of 3323 patients who received at least 1 drug-eluting stent for a reason other than acute ST-segment elevation myocardial infarction. The study population was divided into 2 groups based on presence of at least 1 of 9 off-label characteristics based on the current US Food and Drug Administration-approved indications for sirolimus- and paclitaxel-eluting stents. The composite clinical outcomes of death, myocardial infarction, or target vessel revascularization during the index admission and death, myocardial infarction, or target lesion revascularization at 1 year were evaluated. Of the 3323 patients, 1817 (54.7%) had at least 1 off-label characteristic. During the index hospitalization, the composite clinical outcome occurred in 198 (10.9%) of patients in the off-label group and 76 (5.0%) of patients in the on-label group (adjusted odds ratio, 2.32; 95% confidence interval [CI], 1.75-3.07; P<.001). At 1 year, the composite clinical outcome occurred more often in the off-label group compared with the on-label group; 309 (17.5%) vs 131 (8.9%) (adjusted hazard ratio [HR], 2.16; 95% CI, 1.74-2.67; P<.001). Stent thrombosis also occurred more frequently among patients in the off-label group during the initial hospitalization (8 [0.4%] vs 0) and at 1 year: 29 (1.6%) vs 13 (0.9%), adjusted HR, 2.29 (95% CI, 1.02-5.16; P = .05). Compared with on-label use, off-label use of drug-eluting stents is associated with a higher rate of adverse outcomes during the index admission and at 1 year. Stent thrombosis occurred predominantly in patients who underwent off-label drug-eluting stent implantation. Clinicians should be cautious about extrapolating the benefits of drug-eluting stents over bare-metal stents observed in randomized clinical trials to higher-risk clinical settings that have not been assessed.


Imported malaria in the Bronx: review of 51 cases recorded from 1986 to 1991.
The cases of 51 patients with malaria seen at the Albert Einstein College of Medicine hospitals from January 1986 to June 1991 are reviewed. Thirty-five patients acquired infection on journeys to their country of origin. Of these 35 patients, 83% of whom had lived in the United States for > or = 2 years, only 17% received antimalarial prophylaxis. Ten of the 51 patients were born and raised in the United States, and 70% received prophylaxis (P < .01). Six of the 51 patients were visitors to the United States from areas endemic for malaria. Overall, 64% of patients acquired malaria in West Africa, south of the Sahara; 20% in Asia; 8% in Ecuador; 6% in Haiti; and 4% in the Middle East. The majority of infections were due to Plasmodium falciparum. Six patients traveled to a zone endemic for malaria while pregnant, and none received prophylaxis. In nine of 13 patients who received prophylaxis, there was inadequate dosing or poor compliance. Individuals born in regions endemic for malaria are at high risk of acquiring malaria on return to their countries of origin and are less aware of the need for malaria prophylaxis than are other travelers.


Measuring Mind Wandering During Online Lectures Assessed With EEG.
Mind wandering can inhibit learning in multimedia classrooms, such as when watching online lectures. One explanation for this effect is that periods of mind wandering cause learners' attention to be redirected from the learning material toward task-unrelated thoughts. The present study explored the relationship between mind wandering and online education using electroencephalography (EEG). Participants were asked to attend to a 75 minute educational video lecture, while task-irrelevant auditory tones played at random intervals. The tones were of two distinct pitches, with one occurring frequently (80%) and the other infrequently (20%). Participants were prompted at pseudo-random intervals during the lecture to report their degree of experienced mind wandering. EEG spectral power and event-related potentials (ERP) were compared between states of high and low degrees of self-reported mind wandering. Participants also performed pre/post quizzes based on the lecture material. Results revealed significantly higher delta, theta and alpha band activity during mind wandering, as well as a decreased P2 ERP amplitude. Further, learning scores (improvement on quizzes pre to post) were lower among participants who reported higher degrees of mind wandering throughout the video. The results are consistent with a view that mind wandering during e-learning is characterized by a shift in attention away from the external world and toward internal thoughts, which may be a cause of reduced learning.


[Degenerative osteoarthritis, osteoporosis and fractures: controversies and evidences].
Osteoarthritis and osteoporosis are both common conditions in the elderly but their association has long remained obscure. Recently published studies show that patients with osteoarthritis have higher bone mass but no corresponding decrease in fracture risk. This has been proposed to be due to an increased rate of falls in these patients. Multi-disciplinary interventions, vitamin D supplementation and bisphosphonates can play a role on preventing fractures among osteoarthritis patients, but evidence on their efficacy is scarce and of poor quality.


Volatile organic compounds concentrations in residential indoor and outdoor and its personal exposure in Korea.
To date, personal volatile organic compounds (VOCs) exposure and residential indoor and outdoor VOCs levels have not been characterized in Korea. In this study, residential indoor and outdoor VOCs concentrations were measured and compared simultaneously with the personal exposure for each of 30 participants in a medium city, Asan, and in a metropolitan city, Seoul. Factors that influence personal VOCs exposures were assessed in relation to house characteristics and time activity information. All VOC concentrations were measured using passive samplers during a 24-h period and analyzed using GC-MS. Ten target VOCs were benzene, trichloroethylene, toluene, o-xylene, p-xylene, ethylbenzene, MIBK, n-octane, styrene, and 1,2-dichlorobenzene. Residential indoor and outdoor VOCs concentrations measured in Seoul were significantly higher than those in Asan. Indoor/outdoor (I/O) ratios for all target compounds ranged from 0.94 to 1.51 and I/O ratios of Asan were a little higher than those of Seoul. Results indicate that time activity information can be used to predict personal exposures, although such predictions will result in an over estimation compared to measured exposures. Factors which influence the indoor VOCs level and its personal exposure in relation to house characteristics included house age, indoor smoking, and house type.


Insights into colour-tuning of chlorophyll optical response in green plants.
First-principles calculations within the framework of real-space time-dependent density functional theory have been performed for the complete chlorophyll (Chl) network of the light-harvesting complex from green plants, LHC-II. A local-dipole analysis method developed for this work has made possible the studies of the optical response of individual Chl molecules subjected to the influence of the remainder of the chromophore network. The spectra calculated using our real-space TDDFT method agree with previous suggestions that weak interaction with the protein microenvironment should produce only minor changes in the absorption spectrum of Chl chromophores in LHC-II. In addition, relative shifting of Chl absorption energies leads the stromal and lumenal sides of LHC-II to absorb in slightly different parts of the visible spectrum providing greater coverage of the available light frequencies. The site-specific alterations in Chl excitation energies support the existence of intrinsic energy transfer pathways within the LHC-II complex.


Sterol regulatory element-binding protein 2 couples HIV-1 transcription to cholesterol homeostasis and T cell activation.
Cholesterol plays an essential role in the life cycle of several enveloped viruses. Many of these viruses manipulate host cholesterol metabolism to facilitate their replication. HIV-1 infection of CD4(+) T cells activates the sterol regulatory element-binding protein 2 (SREBP2) transcriptional program, which includes genes involved in cholesterol homeostasis. However, the role of SREBP2-dependent transcription in HIV-1 biology has not been fully examined. Here, we identify TFII-I, a gene critical for HIV-1 transcription in activated T cells, as a novel SREBP2 target gene. We found TFII-I expression increased after HIV-1 infection or activation of human primary CD4(+) T cells. We show that inhibition of SREBP2 activity reduced TFII-I induction in response to these stimuli. More importantly, small interfering RNA (siRNA)-mediated gene silencing of either SREBP2 or TFII-I significantly reduced HIV-1 production in CD4(+) T cells. We also found that TFII-I potentiates Tat-dependent viral gene expression, consistent with a role at the level of HIV-1 transcription. Collectively, our results demonstrate for the first time that HIV-1 transcription in T cells is linked to cholesterol homeostasis through control of TFII-I expression by SREBP2.


Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation.
The broad and often contrasting effects of type I interferons (IFNs) in innate and adaptive immunity are belied by the signaling via a single receptor, IFN-alpha receptor (IFNAR). Here, we show that IFN-alpha/beta induces opposing effects on the immunologic outcome of antigen cross-presentation depending on dendritic cell (DC) maturation status. Despite equivalent IFNAR expression, immature conventional DCs (cDCs) activate STAT1 in response to IFN-alpha/beta, whereas exposure of mature DCs to IFN-alpha/beta results in signaling via STAT4. Microarray analysis revealed numerous transcriptional changes resulting from the altered signaling. Importantly, STAT1 signaling resulted in significant inhibition of CD40L-induced IL-12 production, accounting for the inhibition of CD8+ T-cell activation. These data provide evidence for a molecular switch in signaling pathways concomitant with DC maturation that offers a novel mechanism by which DCs modulate the integration of signals from the surrounding environment.


Development and validation of the automated imaging differentiation in parkinsonism (AID-P): a multicentre machine learning study.
Development of valid, non-invasive biomarkers for parkinsonian syndromes is crucially needed. We aimed to assess whether non-invasive diffusion-weighted MRI can distinguish between parkinsonian syndromes using an automated imaging approach. We did an international study at 17 MRI centres in Austria, Germany, and the USA. We used diffusion-weighted MRI from 1002 patients and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute space between Parkinson's disease and atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy) and between multiple system atrophy and progressive supranuclear palsy. For each comparison, models were developed on a training and validation cohort and evaluated in an independent test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic curves. The primary outcomes were free water and free-water-corrected fractional anisotropy across 60 different template regions. In the test cohort for disease-specific comparisons, the diffusion-weighted MRI plus MDS-UPDRS III model (Parkinson's disease vs atypical parkinsonism had an AUC 0·962; multiple system atrophy vs progressive supranuclear palsy AUC 0·897) and diffusion-weighted MRI only model had high AUCs (Parkinson's disease vs atypical parkinsonism AUC 0·955; multiple system atrophy vs progressive supranuclear palsy AUC 0·926), whereas the MDS-UPDRS III only models had significantly lower AUCs (Parkinson's disease vs atypical parkinsonism 0·775; multiple system atrophy vs progressive supranuclear palsy 0·582). These results indicate that a non-invasive imaging approach is capable of differentiating forms of parkinsonism comparable to current gold standard methods. This study provides an objective, validated, and generalisable imaging approach to distinguish different forms of parkinsonian syndromes using multisite diffusion-weighted MRI cohorts. The diffusion-weighted MRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 min across 3T scanners worldwide. The use of this test could positively affect the clinical care of patients with Parkinson's disease and parkinsonism and reduce the number of misdiagnosed cases in clinical trials. National Institutes of Health and Parkinson's Foundation.


A comprehensive production method of self-cryoprotected nano-liposome powders.
This study provided a convenient approach for large scale production of hydrogenated soya phosphatidylcholine nano-liposome powders using beclometasone dipropionate as a model drug and sucrose as proliposome carrier. Fluid-bed coating was employed to manufacture proliposomes by coating sucrose with the phospholipid (5%, 10%, 15% and 20% weight gains), followed by hydration, size reduction using high pressure homogenization, and freeze-drying to yield stable nano-vesicles. High pressure homogenization was compared with probe-sonication in terms of liposome size, zeta potential and drug entrapment. Furthermore, the effect of freeze-drying on vesicle properties generated using both size reduction methods was evaluated. Results have shown that high-pressure homogenization followed by freeze-drying and rehydration tended to yield liposomes smaller than the corresponding vesicles downsized via probe-sonication, and all size measurements were in the range of 72.64-152.50 nm, indicating that freeze-drying was appropriate, regardless of the size reduction technique. The liposomes, regardless of size reduction technique and freeze drying had slightly negative zeta potential values or were almost neutral in surface charge. The entrapment efficiency of BDP in homogenized liposomes was found to increase following freeze-drying, hence the drug entrapment efficiency values in rehydrated liposomes were 64.9%, 57%, 69.5% and 64.5% for 5%, 10%, 15% and 20% weight gains respectively. In this study, we have reported a reliable production method of nano-liposomes based on widely applicable industrial technologies such as fluid-bed coating, high pressure homogenization and freeze-drying. Moreover, sucrose played a dual role as a carrier in the proliposome formulations and as a cryoprotectant during freeze-drying.


The Roles of Lysosomes in Inflammation and Autoimmune Diseases.
Lysosomes perform a range of functions, some of which, such as degradation, are common to all cell types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve fusion of this organelle with the cell surface to release its contents. This review describes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also review the characteristic changes in lysosomal hydrolases and membrane proteins in common autoimmune diseases. Finally, future directions in lysosome research are proposed, with it being suggested that the role of lysosomes will continue to be of growing interest in immunity research.


Quality of Stroke Patient Information Applied in Randomized Controlled Trials-Literature Review.
Background: Strokes have a huge impact on patients' quality of life. Although there are potentially effective secondary preventions and treatment options for stroke patients, adherence is mostly low. Low disease and treatment-related knowledge and, consequently, a lack of informed decision-making in stroke patients may contribute to this problem. However, stroke patient information did not seem to have relevant effects on patients' knowledge in randomized controlled trials. One contributing factor may be the lack of thoroughly developed patient information materials. Methods: We aimed to evaluate the quality of patient information materials for stroke patients by using randomized controlled trials, applying quality criteria for evidence-based patient information (EBPI). We conducted a literature search (MEDLINE, Embase, CINAHL, PsycINFO, and CENTRAL). To be included in the review, research had to be randomized controlled trials that provided stroke patient information, were published in English, and had knowledge assessed as the primary endpoint. Authors of primary studies were contacted and asked for information materials applied. Results: We screened 15,507 hits and identified 30 eligible studies. Information materials were available for only eight studies. Analyses revealed that all available materials had important shortcomings concerning EBPI quality criteria [concerning, for example, structural information (e.g., reporting conflicts of interest), content information (e.g., reporting sources of information), or comprehensive descriptions of treatment effects and side effects]. Frequently, treatment effects were reported only narratively without providing absolute numbers, values, or frequencies. Conclusion: Quality of materials differed, but none sufficiently fulfilled EBPI quality criteria. Unsatisfactory trial results concerning patient knowledge and patient involvement in decision-making may at least partially be explained by limitations of the provided materials. Future patient information should consider EBPI quality criteria.


The importance of effective risk communication and transparency: lessons from the dengue vaccine controversy in the Philippines.
In 2016 the Philippine Department of Health (DOH) introduced a novel dengue vaccine in a mass immunization program to reduce the substantial economic and social burden of the disease on households and the government. The vaccine manufacturer's announcement regarding new findings on the small but increased risk of severe dengue for vaccinated seronegative patients caused turmoil as various people claimed that the vaccine caused deaths and that health authorities are corrupt. While health department staff split-some having to preserve its reputation and others to monitor over 800,000 children administered the vaccine-communication between the frontline health workers and parents suffered. As a result, public confidence in vaccines dramatically dropped and the repercussions challenge the public health system. We examine factors that contributed to the crisis and argue for strengthening risk communication strategies and increasing transparency on decision making to counter misinformation and protect public health.


Pain Control and Functional Milestones in Total Knee Arthroplasty: Liposomal Bupivacaine versus Femoral Nerve Block.
Although pain management after total knee arthroplasty (TKA) affects rehabilitation, length of stay, and functional outcomes, pain management for patients undergoing TKA has yet to be standardized. Femoral nerve blocks (FNBs) are commonly used as an adjunct; however, these can result in transient quadriceps weakness and have been associated with in-hospital falls. Periarticular infiltration of liposomal bupivacaine has been recently introduced as a long-acting analgesic that can be administered without affecting motor function. (1) Does periarticular liposomal bupivacaine compared with FNB result in improved pain control as measured by pain scores and narcotic consumption? (2) How do liposomal bupivacaine and FNB compare in terms of gait and stairclimbing milestones and the proportion of patients who experienced a fall in the hospital? Between September 2013 and October 2014, a retrospective analysis was conducted involving 24 surgeons who performed a total of 1373 unilateral, primary TKAs. From September 2013 to April 2014, the routine approach to TKA pain management pathway consisted of preoperative administration of oral analgesics, intraoperative anesthesia (preferred spinal or general), an ultrasound-guided FNB, intraoperative analgesic cocktail injection, patient-controlled analgesia, and oral and IV narcotics for pain as needed. A total of 583 patients were included in this study group. Starting May 2014, FNBs were discouraged and there was department-wide adoption of liposomal bupivacaine. Liposomal bupivacaine became routinely used in all patients undergoing TKA with no other changes made to the multimodal analgesia protocol at that time, and 527 patients in this study group were compared with the FNB cohort. Chart review on a total of 1110 patients was conducted by a research assistant who was not participating in patient care. During the inpatient stay, pain scores during 8-hour intervals, narcotic use, and physical therapy milestones were compared. With the numbers available, we detected no clinically important difference in pain scores throughout the hospital stay; however, patients treated with liposomal bupivacaine consumed very slightly less narcotics overall (96 ± 62 versus 84 ± 73 eq mg of morphine; [95% confidence interval, 11-13 mg]; p = 0.004) through postoperative Day 2 of inpatient hospitalization. Seventy-seven percent (406 of 527) of patients receiving liposomal bupivacaine achieved their gait milestones of clearing 100 feet of ambulation versus 60% (349 of 583) of patients receiving FNB (p < 0.001) before discharge. Likewise, 94% (497 of 527) of patients receiving liposomal bupivacaine completed stairs compared with 73% (427 of 583) of patients receiving FNB (p < 0.001). Patients who received liposomal bupivacaine were less likely to experience a fall during the hospital stay than were patients treated with FNB (3 of 527 [0.6%] versus 12 of 583 [2%]; p = 0.03). In the absence of strong data supporting FNB over liposomal bupivacaine, we have modified our TKA pain management protocols by adopting liposomal bupivacaine in lieu of FNBs, facilitating rapid rehabilitation while providing adequate pain control. Level III, therapeutic study.


The art and science of weed mapping.
Land managers need cost-effective and informative tools for non-native plant species management. Many local, state, and federal agencies adopted mapping systems designed to collect comparable data for the early detection and monitoring of non-native species. We compared mapping information to statistically rigorous, plot-based methods to better understand the benefits and compatibility of the two techniques. Mapping non-native species locations provided a species list, associated species distributions, and infested area for subjectively selected survey sites. The value of this information may be compromised by crude estimates of cover and incomplete or biased estimations of species distributions. Incorporating plot-based assessments guided by a stratified-random sample design provided a less biased description of non-native species distributions and increased the comparability of data over time and across regions for the inventory, monitoring, and management of non-native and native plant species.


Pharmacological treatment of oro-facial pain - health technology assessment including a systematic review with network meta-analysis.
This health technology assessment evaluated the efficacy of pharmacological treatment in patients with oro-facial pain. Randomised controlled trials were included if they reported pharmacological treatment in patients ≥18 years with chronic (≥3 months) oro-facial pain. Patients were divided into subgroups: TMD-muscle [temporomandibular disorders (TMD) mainly associated with myalgia]; TMD-joint (TMD mainly associated with temporomandibular joint pain); and burning mouth syndrome (BMS). The primary outcome was pain intensity reduction after pharmacological treatment. The scientific quality of the evidence was rated according to GRADE. An electronic search in PubMed, Cochrane Library, and EMBASE from database inception to 1 March 2017 combined with a handsearch identified 1552 articles. After screening of abstracts, 178 articles were reviewed in full text and 57 studies met the inclusion criteria. After risk of bias assessment, 41 articles remained: 15 studies on 790 patients classified as TMD-joint, nine on 375 patients classified as TMD-muscle and 17 on 868 patients with BMS. Of these, eight studies on TMD-muscle, and five on BMS were included in separate network meta-analysis. The narrative synthesis suggests that NSAIDs as well as corticosteroid and hyaluronate injections are effective treatments for TMD-joint pain. The network meta-analysis showed that clonazepam and capsaicin reduced pain intensity in BMS, and the muscle relaxant cyclobenzaprine, for the TMD-muscle group. In conclusion, based on a limited number of studies, evidence provided with network meta-analysis showed that clonazepam and capsaicin are effective in treatment of BMS and that the muscle relaxant cyclobenzaprine has a positive treatment effect for TMD-muscle pain.


On the Coyne and Orr-igin of species: effects of intrinsic postzygotic isolation, ecological differentiation, x chromosome size, and sympatry on Drosophila speciation.
Coyne and Orr found that mating discrimination (premating isolation) evolves much faster between sympatric than allopatric Drosophila species pairs. Their meta-analyses established that this pattern, expected under reinforcement, is common and that Haldane's rule is ubiquitous in Drosophila species divergence. We examine three possible contributors to the reinforcement pattern: intrinsic postzygotic isolation, dichotomized as to whether hybrid males show complete inviability/sterility; host-plant divergence, as a surrogate for extrinsic postzygotic isolation; and X chromosome size, whether roughly 20% or 40% of the genome is X-linked. We focus on "young" species pairs with overlapping ranges, contrasted with allopatric pairs. Using alternative criteria for "sympatry" and tests that compare either level of prezygotic isolation in sympatry or frequency of sympatry, we find no statistically significant effects associated with X chromosome size or our coarse quantifications of intrinsic postzygotic isolation or ecological differentiation. Although sympatric speciation seems very rare in animals, the pervasiveness of the reinforcement pattern and the commonness of range overlap for close relatives indicate that speciation in Drosophila is often not purely allopatric. It remains to determine whether increased premating isolation with sympatry results from secondary contact versus parapatric speciation and what drives this pattern.


Perspectives on preoperative systemic treatment and breast conservative surgery: One step forward or two steps back?
Preoperative systemic therapy (PST) has become an accepted treatment not only for locally advanced but also for early stage breast cancer patients. Clinical trials have demonstrated that the use of PST is equally to adjuvant treatments in terms of overall survival, and has the advantage of increasing rates of breast conservative surgery and rates of pathologic complete response, a surrogate endpoint for the effectiveness of systemic therapy. Initial studies have suggested higher rates of locoregional recurrence with this approach. However, the optimization of systemic and targeted therapy and the multidisciplinary care is key to achieving optimal outcomes in this setting.