Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery.
Centuries since it was first described, tuberculosis (TB) remains a significant global public health issue. Despite ongoing holistic measures implemented by health authorities and a number of new oral treatments reaching the market, there is still a need for an advanced, efficient TB treatment. An adjunctive, host-directed therapy designed to enhance endogenous pathways and hence compliment current regimens could be the answer. The integration of drug repurposing, including synthetic and naturally occurring compounds, with a targeted drug delivery platform is an attractive development option. In order for a new anti-tubercular treatment to be produced in a timely manner, a multidisciplinary approach should be taken from the outset including stakeholders from academia, the pharmaceutical industry, and regulatory bodies keeping the patient as the key focus. Pre-clinical considerations for the development of a targeted host-directed therapy are discussed here.


Diagnosis and management of microscopic colitis: current perspectives.
Collagenous colitis and lymphocytic colitis, together constituting microscopic colitis, are common causes of chronic diarrhea. They are characterized clinically by chronic nonbloody diarrhea and a macroscopically normal colonic mucosa where characteristic histopathological findings are seen. Previously considered rare, they now have emerged as common disorders that need to be considered in the investigation of the patient with chronic diarrhea. The annual incidence of each disorder is five to ten per 100,000 inhabitants, with a peak incidence in 60- to 70-year-old individuals and a predominance of female patients in collagenous colitis. The etiology and pathophysiology are not well understood, and the current view suggests an uncontrolled mucosal immune reaction to various luminal agents in predisposed individuals. Clinical symptoms comprise chronic diarrhea, abdominal pain, fatigue, weight loss, and fecal incontinence that may impair the patient's health-related quality of life. An association is reported with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. The best-documented treatment, both short-term and long-term, is budesonide, which induces clinical remission in up to 80% of patients after 8 weeks' treatment. However, after successful budesonide therapy is ended, recurrence of clinical symptoms is common, and the best possible long-term management deserves further study. The long-term prognosis is good, and the risk of complications, including colonic cancer, is low. We present an update of the epidemiology, pathogenesis, diagnosis, and management of microscopic colitis.


Characterization of Phytophthora spp. on Floriculture Crops in North Carolina.
Isolates of Phytophthora in floriculture crops were collected from North Carolina commercial greenhouse facilities in 2007 and 2008, identified, and characterized for mating type and mefenoxam sensitivity. In all, 163 isolates from 13 host species at 11 locations were identified primarily as Phytophthora nicotianae (59%), P. drechsleri (23%), P. cryptogea (9%), and P. tropicalis (4%). Multiple Phytophthora spp. were found at five locations. DNA sequencing was more reliable for differentiating P. cryptogea and P. drechsleri. Only the A1 mating type of P. drechsleri was collected; however, both mating types of P. nicotianae, P. cryptogea, and P. tropicalis were found. Overall, 66% of Phytophthora isolates were resistant or intermediate in resistance to mefenoxam at 1 μg a.i./ml. Three groups of P. drechsleri isolates had effective concentration of mefenoxam providing 50% growth inhibition (EC50) estimates over 700 μg a.i./ml. EC50 estimates for P. nicotianae ranged from 246 to 435 μg a.i./ml. Isolates of P. nicotianae exhibited phenotypic heterogeneity at several locations, suggesting multiple separate introductions to the facilities. In contrast, P. nicotianae and P. drechsleri isolates from two locations were phenotypically identical to a previous survey, suggesting that the facilities have Phytophthora spp. established onsite.


Regioisomeric allene dimer formation by the reaction of tetraarylbutatrienes with tetracyanoethene.
The reaction of tetraarylbutatrienes (tetraaryl[3]cumulenes) with tetracyanoethene (TCNE), a strong electron-accepting molecule, at room temperature yielded novel four-membered ring compounds (head-to-tail unsymmetrically substituted diarylallene dimers) by [2 + 2] cycloaddition of the central C=C bond of the butatrienes. This reaction proceeded through a head-to-head symmetrically substituted diarylallene dimer intermediate. Unsymmetrical butatriene also formed a small amount of another head-to-tail dimer. Although the allene dimer is stable in nonpolar solvents, it converts to other bicyclic and tricyclic compounds in MeOH or CH3CN at room temperature.


Active and water-soluble form of lipidated Wnt protein is maintained by a serum glycoprotein afamin/α-albumin.
Wnt plays important role during development and in various diseases. Because Wnts are lipidated and highly hydrophobic, they can only be purified in the presence of detergents, limiting their use in various in vitro and in vivo assays. We purified N-terminally tagged recombinant Wnt3a secreted from cells and accidentally discovered that Wnt3a co-purified with a glycoprotein afamin derived from the bovine serum included in the media. Wnt3a forms a 1:1 complex with afamin, which remains soluble in aqueous buffer after isolation, and can induce signaling in various cellular systems including the intestical stem cell growth assay. By co-expressing with afamin, biologically active afamin-Wnt complex can be easily obtained in large quantity. As afamin can also solubilize Wnt5a, Wnt3, and many more Wnt subtypes, afamin complexation will open a way to put various Wnt ligands and their signaling mechanisms under a thorough biochemical scrutiny that had been difficult for years.


[Santiago, a terror-stricken city].
The general purpose of this article is to determine how citizens' fear of lack of safety affects the use of public spaces. In an evaluation such as this, it is necessary to analyze two types of relationships pertaining to violence: the one between victimization and a perception of being unsafe, and the one that exists between social attitudes and the peaceful resolution of national conflicts. To this end, an analysis was performed of different variables--victimization, feeling unsafe, use of physical spaces, attitudes toward the established political and social institutions and toward the resolution of national conflicts--and of potential associations between these variables. The data for the study came from a survey of 1,200 persons between 18 and 70 years old who were residents of Santiago. Results show that Santiago's citizens live in fear and that their perception of a lack of safety has grown more intense, despite the fact that victimization rates remained relatively stable over the years preceding the survey. Fear is associated with an abandonment of both physical and sociopolitical public spaces, as well as with seeking refuge in private spaces and private life. There is a widespread attitude in favor of resolving conflicts through non-peaceful means, and such an attitude is more often associated with feeling unsafe, having negative attitudes toward democracy, and lacking hope in the nation's future. The results of this study support the notion that, in order to overcome their fear, people tend to adapt to reality by adopting a conformist attitude, taking on standard beliefs and behaviors, and overestimating the use of force as a way of resolving their differences.


Reconstructive management of cranial base defects after tumor ablation.
Successful reconstruction after cranial base tumor ablation is paramount in preventing potentially life-threatening complications. The purpose of this study was to evaluate experiences of cranial base reconstruction and to identify reconstructive management principles that may assist in achieving successful cranial base reconstruction. All cranial base reconstructions performed by the Department of Plastic Surgery at the University of Texas M. D. Anderson Cancer Center between January of 1993 and September of 1999 were reviewed. Analyses were performed to assess the impact of location of defect, type of reconstruction, type of dural repair, and history of preoperative radiation and chemotherapy on rates of complications, and patient survival. The 77 patients who underwent cranial base reconstruction after tumor ablation during the study period had a mean age of 52 years (6 to 84 years). The mean follow-up period was 28.7 months (1 to 76 months). Squamous cell carcinoma, the most common histopathologic type, was present in 24 patients (31 percent), and 35 patients (45 percent) presented with recurrent disease. Location of defects involved region I (anterior) in 31 patients (40 percent), region II (anterior-lateral) in 18 (23 percent), region III (lateral-posterior) in six (8 percent), and more than one region in 22 (29 percent). Reconstructive methods included free flaps in 52 patients (68 percent), temporalis muscle flaps in 14 (18 percent), pericranial flaps in eight (10 percent), and other local flaps (two galeal, one scalp) in three (4 percent). Of the 52 free flaps, 18 (35 percent) were used in region I, 14 (27 percent) in region II, six (12 percent) in region III, and 14 (27 percent) in defects involving more than one region. Of the 14 temporalis muscle flaps, 13 (93 percent) were used for defects involving regions I or II and one (7 percent) was used for a defect involving region III. Of the 11 pericranial and other local flaps, nine (82 percent) were used in region I, one (9 percent) in region II, and one (9 percent) in a combination of regions II and III. Complications occurred in 21 patients (27 percent): three total flap losses (4 percent), three partial flap losses (4 percent), two cerebrospinal fluid leaks (3 percent), two cases of meningitis (3 percent), two abscesses (3 percent), five cases of delayed wound healing (6 percent), two hematomas (3 percent), one wound infection (1 percent), and one cerebrovascular accident (1 percent). Overall survival was 77 percent at 2 years and 58 percent at 4 years. The type of reconstruction, location of defect, type of dural repair, and history of preoperative radiation and chemotherapy had no significant association with the incidence of complications. Neither the type of reconstruction nor the location of defect showed a significant effect on patient survival. In this experience, local flaps, such as pericranial or temporalis muscle flaps, are good choices for reconstruction of smaller anterior or lateral cranial base defects. For defects that require larger amounts of soft tissue, free flaps are appropriate. With proper patient selection, successful cranial base reconstruction can be performed with either local or free flaps with a low incidence of complications.


Role of oxidative stress in carbon nanotube-generated health effects.
The development of products containing carbon nanotubes (CNTs) is a major achievement of nanotechnology, although concerns regarding risk of toxic effects linger if the hazards associated with these materials are not thoroughly investigated. Exposure to CNTs has been associated with depletion of antioxidants, increased intracellular production of reactive oxygen species and pro-inflammatory signaling in cultured cells with primary function in the immune system as well as epithelial, endothelial and stromal cells. Pre-treatment with antioxidants has been shown to attenuate these effects, indicating a dependency of oxidative stress on cellular responses to CNT exposure. CNT-mediated oxidative stress in cell cultures has been associated with elevated levels of lipid peroxidation products and oxidatively damaged DNA. Investigations of oxidative stress endpoints in animal studies have utilized pulmonary, gastrointestinal, intravenous and intraperitoneal exposure routes, documenting elevated levels of lipid peroxidation products and oxidatively damaged DNA nucleobases especially in the lungs and liver, which to some extent occur concomitantly with altered levels of components in the antioxidant defense system (glutathione, superoxide dismutase or catalase). CNTs are biopersistent high aspect ratio materials, and some are rigid with lengths that lead to frustrated phagocytosis and pleural accumulation. There is accumulating evidence showing that pulmonary exposure to CNTs is associated with fibrosis and neoplastic changes in the lungs, and cardiovascular disease. As oxidative stress and inflammation responses are implicated in the development of these diseases, converging lines of evidence indicate that exposure to CNTs is associated with increased risk of cardiopulmonary diseases through generation of a pro-inflammatory and pro-oxidant milieu in the lungs.


Treatment of Dupuytren's contracture: a systematic review.
Dupuytren's contracture is a benign, myoproliferative condition affecting the palmar fascia that results in progressive contractures of the fingers. Despite increased knowledge of the cellular and connective tissue changes involved, neither a cure nor an optimum form of treatment exists. The aim of this systematic review was to summarize the best available evidence on the management of this condition. A comprehensive database search for randomized controlled trials (RCTs) was performed until August 2017. We studied RCTs comparing open fasciectomy with percutaneous needle aponeurotomy (PNA), collagenase clostridium histolyticum (CCH) with placebo, and CCH with PNA, in addition to adjuvant treatments aiming to improve the outcome of open fasciectomy. A total of 20 studies, involving 1584 patients, were included. PNA tended to provide higher patient satisfaction with fewer adverse events, but had a higher rate of recurrence compared with limited fasciectomy. Although efficacious, treatment with CCH had notable recurrence rates and a high rate of transient adverse events. Recent comparative studies have shown no difference in clinical outcome between patients treated with PNA and those treated with CCH. Currently there remains limited evidence to guide the management of patients with Dupuytren's contracture. Cite this article: Bone Joint J 2018;100-B:1138-45.


Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.
Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.


Intentional inhibition but not source memory is related to hallucination-proneness and intrusive thoughts in a university sample.
Proneness to unusual perceptual states - such as auditory or visual hallucinations - has been proposed to exist on a continuum in the general population, but whether there is a cognitive basis for such a continuum remains unclear. Intentional cognitive inhibition (the ability to wilfully control thoughts and memories) is one mechanism that has been linked to auditory hallucination susceptibility, but most evidence to date has been drawn from clinical samples only. Moreover, such a link has yet to be demonstrated over and above relations to other cognitive skills (source monitoring) and cognitive states (intrusive thoughts) that often correlate with both inhibition and hallucinations. The present study deployed two tests of intentional inhibition ability - the Inhibition of Currently Irrelevant Memories (ICIM) task and Directed Forgetting (DF) task - and one test of source monitoring (a source memory task) to examine how cognitive task performance relates to self-reported i) auditory hallucination-proneness and ii) susceptibility to intrusive thoughts in a non-clinical student sample (N = 76). Hierarchical regression analyses were used to assess the independent and combined contributions of task performance to proneness scores. ICIM performance but not DF or source memory scores were significantly related to both hallucination-proneness and intrusive thoughts. Further analysis suggested that intrusive thoughts may mediate the link between intentional inhibition skills and auditory hallucination-proneness, suggesting a potential pathway from inhibition to perception via intrusions in cognition. The implications for studying cognitive mechanisms of hallucination and their role in "continuum" views of psychosis-like experiences are discussed.


Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression.
The achaete-scute genes encode essential transcription factors in normal Drosophila and vertebrate nervous system development. Human achaete-scute homolog-1 (hASH1) is constitutively expressed in a human lung cancer with neuroendocrine (NE) features, small cell lung cancer (SCLC), and is essential for development of the normal pulmonary NE cells that most resemble this neoplasm. Mechanisms regulating achaete-scute homolog expression outside of Drosophila are presently unclear, either in the context of the developing nervous system or in normal or neoplastic cells with NE features. We now provide evidence that the protein hairy-enhancer-of-split-1 (HES-1) acts in a similar manner as its Drosophila homolog, hairy, to transcriptionally repress achaete-scute expression. HES-1 protein is detected at abundant levels in most non-NE human lung cancer cell lines which lack hASH1 but is virtually absent in hASH1-expressing lung cancer cells. Moreover, induction of HES-1 in a SCLC cell line down-regulates endogenous hASH1 gene expression. The repressive effect of HES-1 is directly mediated by binding of the protein to a class C site in the hASH1 promoter. Thus, a key part of the process that determines neural fate in Drosophila is conserved in human lung cancer cells. Furthermore, modulation of this pathway may underlie the constitutive hASH1 expression seen in NE tumors such as SCLC, the most virulent human lung cancer.


Care staff attributions for violent incidents involving male and female patients: a field study.
This article presents a study of naturally occurring attributions recorded by care staff following incidents of restraint in a psychiatric secure unit. The relationship between control for patient, control for staff and behavioural outcomes including use of medication, seclusion and duration of restraint were explored for male and female patients. In all, 557 forms documenting incidents of control and restraint, and completed over a four-year period by nurses in a UK psychiatric hospital, were content analysed using the Leeds Attributional Coding System (LACS; Munton, Silvester, & Hanks, 1999). Additional information concerning duration of restraint, severity of injuries sustained by patient and care staff, use of medication and seclusion, and patient was also gathered. It was hypothesized that perceived patient control over causes of the restraint incident would be associated with duration of restraint, use of seclusion and medication. It was also predicted that male patients would be perceived as having more control over incidents, and thus be more likely to be secluded and less likely to be prescribed medication, than female patients. Seclusion was associated with controllable attributions for patient and uncontrollable attributions for care staff. Use of medication was associated with uncontrollable attributions for patient, but only for male patients. Contrary to prediction, female patients were more likely to be secluded than males and less likely to receive medication. Staff were also more likely to state that they had 'no explanation' for restraint incidents involving female patients. The investigation of naturally occurring attributions raises important questions regarding the relationship between patient gender and attributional models of helping behaviour. The results are discussed in terms of their potential implications for future research and health care practice.


Micelle structure in a deep eutectic solvent: a small-angle scattering study.
In recent years many studies into green solvents have been undertaken and deep eutectic solvents (DES) have emerged as sustainable and green alternatives to conventional solvents since they may be formed from cheap non-toxic organic precursors. In this study we examine amphiphile behaviour in these novel media to test our understanding of amphiphile self-assembly within environments that have an intermediate polarity between polar and non-polar extremes. We have built on our recently published results to present a more detailed structural characterisation of micelles of sodium dodecylsulfate (SDS) within the eutectic mixture of choline chloride and urea. Here we show that SDS adopts an unusual cylindrical aggregate morphology, unlike that seen in water and other polar solvents. A new morphology transition to shorter aggregates was found with increasing concentration. The self-assembly of SDS was also investigated in the presence of water; which promotes the formation of shorter aggregates.


The action of a mast cell protease on the cuticular collagens of Necator americanus.
Collagen-like proteins, thought to be responsible for maintaining the structural integrity of the nematode cuticle, were isolated from adult Necator americanus and shown to be susceptible to digestion by purified mast cell proteases. Although these collagens would appear normally to be masked by superficially expressed (surface) antigens, it is suggested that a sufficiently avid and specific immune response could remove this potentially protective coat, rendering the structurally important underlying layers open to immune attack.


Genome Sequencing and Annotation of Bacillus subtilis UBBS-14 to Ensure Probiotic Safety.
Bacillus subtilis is a rod shaped, gram positive, spore producing bacterium. They are the normal flora of gastrointestinal tract of humans and it is the best characterized model organism for endospore formation. It has the ability to withstand environmental stress, and synthesize beneficial compounds, therefore, it is recognized as a high-quality probiotic supplement. To ensure the probiotic safety and the efficiency, we report the whole genome sequence (WGS) of Bacillus subtilis UBBS-14 strain. The draft genome sequence of Bacillus subtilis UBBS-14 consists of 4,048,984 bp and 4,017 genes, respectively. Bacillus subtilis UBBS-14 does not carry any antibiotic resistant genes containing plasmid, nor it contains any harmful putative virulence factors coding genes, therefore, it confirms the probiotic safety of the respective strain at genome level.


Dynamic Exchange During Triplet Transport in Nanocrystalline TIPS-Pentacene Films.
The multiplication of excitons in organic semiconductors via singlet fission offers the potential for photovoltaic cells that exceed the Shockley-Quiesser limit for single-junction devices. To fully utilize the potential of singlet fission sensitizers in devices, it is necessary to understand and control the diffusion of the resultant triplet excitons. In this work, a new processing method is reported to systematically tune the intermolecular order and crystalline structure in films of a model singlet fission chromophore, 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS-Pn), without the need for chemical modifications. A combination of transient absorption spectroscopy and quantitative materials characterization enabled a detailed examination of the distance- and time-dependence of triplet exciton diffusion following singlet fission in these nanocrystalline TIPS-Pn films. Triplet-triplet annihilation rate constants were found to be representative of the weighted average of crystalline and amorphous phases in TIPS-Pn films comprising a mixture of phases. Adopting a diffusion model used to describe triplet-triplet annihilation, the triplet diffusion lengths for nanocrystalline and amorphous films of TIPS-Pn were estimated to be ∼75 and ∼14 nm, respectively. Importantly, the presence of even a small fraction (<10%) of the amorphous phase in the TIPS-Pn films greatly decreased the ultimate triplet diffusion length, suggesting that pure crystalline materials may be essential to efficiently harvest multiplied triplets even when singlet fission occurs on ultrafast time scales.


Cultural neurobiology and the family: Evidence from the daily lives of Latino adolescents.
Culturally linked family influences during adolescence are important predictors of health and well-being for Latino youth, yet few studies have examined whether these familial influences are associated with indicators of typical physiological stress processes. Following a cultural neurobiology framework, we examined the role of family in the everyday lives of Latino adolescents (N = 209; Mage = 18.10; 85.1% Mexican descent; 64.4% female) by investigating familism values and perceptions of parent support as well as daily family assistance behaviors in relation to hypothalamic-pituitary-adrenal axis diurnal patterns, indexed by salivary cortisol five times a day for 3 weekdays. Three-level growth curve analyses revealed that perceptions of parental support were associated with greater cortisol awakening responses, whereas familism values were not associated with diurnal cortisol patterns. In day-to-day analyses, assisting family during the day (compared to not assisting family) was associated with lower waking cortisol levels and flatter diurnal slopes the next day. Our findings highlight the dynamic associations and multiple time courses between cultural values and behaviors, daily experiences, and physiological stress processes for Latino adolescents. Further, we identified important cultural risk and promotive factors associated with physiological regulation in daily life and potential pathways toward health outcomes in adulthood.


The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells.
Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors such as nitric oxide (NO) or endothelin-1 (ET-1) results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. The results were that, in cells, calcitriol increased ET-1 and NO productions, which were measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), their protein expressions (Western-blot), and their promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific to VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each upregulation differed. ECE-1 upregulation depended on AP-1 activation, whereas eNOS upregulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single ip injection of 400 ng/kg calcitriol and euthanized 24 h later. Results confirmed those observed in cells, that production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. We conclude that calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 upregulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases in blood pressure.


Investigation on the gastroprotective and antidiarrhoeal properties of Aegle marmelos unripe fruit extract.
The Study was designed to verify the gastroprotective and antidiarrhoeal effects of unripe fruit extract of Aegle marmelos Corr. The gastroprotective function of this extract was evaluated in rats against gastric mucosal damage induced by hypothermic restraint stress, absolute ethanol, and indomethacin, whereas the antidiarrhoeal activity was investigated by studying the influence on gastrointestinal transit as measured by a charcoal marker and on castor oil-induced accumulation of intestinal fluid in mice and also on contractile responses evoked by acetylcholine, histamine, serotonin, and barium chloride in isolated guinea-pig ileum, the results demonstrated that pretreatment of animals with unripe fruit extract (50 and 100 mg/kg, i.p.) produces a significant inhibition of gastric lesion induced by ethanol but not those induced by restraint stress or indomethacin and suggest a probable involvement of a prostaglandin-independent mechanism of gastroprotection. At similar doses, both the intestinal transit as well as the accumulation of intestinal fluids induced by castor oil in mice were significantly inhibited by raw fruit extract. Furthermore, the extract antagonized the contractile responses evoked by different agonists on guinea-pig ileum in vitro and its inhibitory potential for the drugs are in the order of acetylcholine > histamine > serotonin > barium chloride. Taken together, these results point out a possible antidiarrhoeal effect of unripe fruit extract of A. marmelos Corr., since inhibition of intestinal motility and secretion can control clinical diarrhoea.


Coronary heart disease in relation to age, sex, and the menopause.
Examination of the Registrar General's mortality data suggested that women do not lose protection from coronary heart disease (CHD) after the menopause. Apparently, at around the age of 50 men begin to lose a factor that had previously put them at increased risk of developing CHD compared with women. Male sex hormones may be risk factors for CHD, and further studies are needed to clarify their role in the aetiology of CHD in men.


[Decentralization, AIDS, and harm reduction: the implementation of public policies in Rio de Janeiro, Brazil].
This paper assesses how decentralization of resources and initiatives by the Brazilian National SDT/AIDS Program has impacted the transfer of funds for programs to prevent HIV/AIDS among injecting drug users in Rio de Janeiro, Brazil (1999-2006). The effects of the decentralization policy on Rio de Janeiro's Syringe Exchange Programs (SEPs) are assessed in detail. Decentralization effectively took place in Rio de Janeiro in 2006, with the virtual elimination of any direct transfer from the Federal government. The elimination of direct transfers forced SEPs to seek alternative funding sources. The structure of local SEPs appears to be weak and has been further undermined by current funding constraints. Of 22 SEPs operating in 2002, only two are still operational in 2006, basically funded by the State Health Secretariat and one municipal government. The current discontinuity of SEP operations may favor the resurgence of AIDS in the IDU population. A more uniform, regulated decentralization process is thus needed.


Are Thai MSM willing to take PrEP for HIV prevention? An analysis of attitudes, preferences and acceptance.
We aimed to understand the attitudes, preferences and acceptance of oral and parenteral PrEP among men who have sex with men (MSM) in Thailand. Pre-exposure prophylaxis (PrEP), the use of antiretrovirals to prevent HIV acquisition, has shown promising results in recent trials. To assess the potential impact of this new HIV prevention method, in addition to efficacy data, we need to understand which psychosocial factors are likely to determine its uptake among members of potential user groups. Surveys of willingness to use PrEP products were administered to MSM. Spearman's rank tests were used to uncover associations between questionnaire items. Mann-Whitney tests were performed to ascertain differences between groups. Conjoint analysis was used to examine the attitudes and preferences of MSM towards PrEP attributes. Most participants were willing to consider taking PrEP (39.2% "yes, definitely" and 49.2% "yes, probably") and perceived PrEP as giving them new possibilities in their lives (38.5% "a lot of hope" and 55.8% "some hope"), even after being instructed of potential side effects and costs. HIV testing was considered the most important attribute and a daily pill and longer lasting injection in the arm were the preferred routes of administration. Despite its multiple challenges, MSM in Thailand would be willing to take PrEP, even if they had to experience inconvenience and expense. If PrEP were to be implemented in Thailand, our findings show that its uptake could be considerable.


Molybdenum limitation of microbial nitrogen assimilation in aquatic ecosystems and pure cultures.
Molybdenum (Mo) is an essential micronutrient for biological assimilation of nitrogen gas and nitrate because it is present in the cofactors of nitrogenase and nitrate reductase enzymes. Although Mo is the most abundant transition metal in seawater (107 nM), it is present in low concentrations in most freshwaters, typically <20 nM. In 1960, it was discovered that primary productivity was limited by Mo scarcity (2-4 nM) in Castle Lake, a small, meso-oligotrophic lake in northern California. Follow up studies demonstrated that Mo also limited primary productivity in lakes in New Zealand, Alaska, and the Sierra Nevada. Research in the 1970s and 1980s showed that Mo limited primary productivity and nitrate uptake in Castle Lake only during periods of the growing season when nitrate concentrations were relatively high because ammonium assimilation does not require Mo. In the years since, research has shifted to investigate whether Mo limitation also occurs in marine and soil environments. Here we review studies of Mo limitation of nitrogen assimilation in natural microbial communities and pure cultures. We also summarize new data showing that the simultaneous addition of Mo and nitrate causes increased activity of proteins involved in nitrogen assimilation in the hypolimnion of Castle Lake when ammonium is scarce. Furthermore, we suggest that meter-scale Mo and oxygen depth profiles from Castle Lake are consistent with the hypothesis that nitrogen-fixing cyanobacteria in freshwater periphyton communities have higher Mo requirements than other microbial communities. Finally, we present topics for future research related to Mo bioavailability through time and with changing oxidation state.


Effects of the 5-HT(4) receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels.
The 5-HT(4) receptor modulates activity of serotonergic neurons and is a new potential target for antidepressant treatment. This microdialysis study evaluated the effect of the 5-HT(4) receptor agonist, RS67333, on extracellular serotonin (5-hydroxytryptamine, 5-HT) and 5-HIAA levels in rat ventral hippocampus during chloral hydrate anaesthesia, and explored the ability of RS67333 to augment the effect of the selective serotonin reuptake inhibitor paroxetine. The effect of RS67333 was examined after acute and subchronic (3 days) administration. Acute RS67333 (1.5mg/kg i.v.) had no effect on extracellular 5-HT or 5-HIAA levels, while acute paroxetine (0.5mg/kg i.v.) increased 5-HT levels by 299+/-16% and decreased 5-HIAA levels by 25+/-4%. Administration of RS67333 80 min after paroxetine caused an additional transient increase in 5-HT levels (to 398+/-52% of baseline). Subchronic RS67333 administration (1.5mg/kg i.p.) increased basal 5-HT levels by 73+/-15% and decreased 5-HIAA levels by 27+/-13%. In conclusion, the 5-HT(4) receptor agonist RS67333 augmented the acute effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, and after 3 days increased basal hippocampal 5-HT levels.


A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans.
Prematurity is more prevalent in African Americans than in European Americans. We investigated the contribution of a functional SNP in the promoter of the SERPINH1 gene, enriched among those of African ancestry, to preterm premature rupture of membranes (PPROM), the leading identifiable cause of preterm birth. SERPINH1 encodes heat-shock protein 47, a chaperone essential for collagen synthesis. The SERPINH1 -656 minor T allele had a greater frequency in African populations and African Americans than in European Americans (7.4% [corrected] vs. 4.1%). The -656 T allele displayed significantly reduced promoter activity compared to the major -656 C allele in amnion fibroblasts, which lay down the fibrillar collagen that gives tensile strength to the amnion. An initial case-control study demonstrated that the -656 T allele is significantly more frequent in African-American neonates (P < 0.0009) born from pregnancies complicated by PPROM compared with controls (odds ratio of 3.22, 95% confidence interval 1.50, 7.22). There was no significant difference in ancestry among cases and controls using a dihybrid model based on 29 ancestry-informative markers. Adjusting the results of the case-control study for admixture still yielded a statistically significant association between the -656 T allele and PPROM (P < 0.002). A follow-up case-control study gave similar results. The combined case-control findings showed a highly significant (P < 0.0000045) association between the -656 T allele and PPROM. The SERPINH1 -656 T allele is the first example of an ancestry-informative marker associated with preterm birth in African Americans.


Predator nonconsumptive effects on prey recruitment weaken with recruit density.
We investigated the nonconsumptive effects (NCEs) of predatory dogwhelks (Nucella lapillus) on intertidal barnacle (Semibalanus balanoides) recruitment through field experiments on the Gulf of St. Lawrence coast and the Atlantic coast of Nova Scotia, Canada. We studied the recruitment seasons (May-June) of 2011 and 2013. In 2011, the Gulf coast had five times more nearshore phytoplankton (food for barnacle larvae and recruits) during the recruitment season and yielded a 58% higher barnacle recruit density than the Atlantic coast at the end of the recruitment season. In 2013, phytoplankton levels and barnacle recruit density were similar on both coasts and also lower than for the Gulf coast in 2011. Using the comparative-experimental method, the manipulation of dogwhelk presence (without allowing physical contact with prey) revealed that dogwhelk cues limited barnacle recruitment under moderate recruit densities (Atlantic 2011/2013 and Gulf 2013) but had no effect under a high recruit density (Gulf 2011). Barnacle recruits attract settling larvae through chemical cues. Thus, the highest recruit density appears to have neutralized dogwhelk effects. This study suggests that the predation risk perceived by settling larvae may decrease with increasing recruit density and that prey food supply may indirectly influence predator NCEs on prey recruitment.


Congenital and acquired thrombocytopenia.
The diagnosis and management of thrombocytopenia is a growing component in the practice of hematology. The frequency with which hematologists are called in consultation for thrombocytopenia continues to increase with the advent of routine automated platelet determinations and the introduction of new medications. For most patients, such as those with inherited and auto-immune thrombocytopenia, emphasis is focused on efforts to treat or forestall bleeding without excess drug-induced toxicity or burden to the patient. However, in disorders such as heparin-induced thrombocytopenia (HIT), avoidance of thrombotic complications is the key to management. In this chapter, we provide the pediatric and adult hematologist with new insights into the pathogenesis and recognition of congenital inherited thrombocytopenias (CTP), a hitherto difficult to comprehend constellation of clinical entities. We also highlight new approaches to the diagnosis and treatment of two of the more common thrombocytopenic conditions encountered in practice, autoimmune or idiopathic thrombocytopenic purpura (ITP) and HIT. In Section I, Dr. James Bussel discusses CTPs and their distinction from childhood ITP. He emphasizes the clinical features that enable the pediatrician and hematologist to suspect the diagnosis of CTP and those that are of use to subcategorize the various entities, where possible. He also emphasizes newer molecular markers that afford definitive diagnosis in some cases and provide insight into platelet production. This section highlights the characteristic associated findings and differences in the natural history and approaches to management of the various entities. In Section II, Dr. Robert McMillan discusses adult chronic ITP. He revisits the utility of platelet antibody determination in diagnosis and review new insights into pathogenesis. The role of Helicobacter pylori infection and the timing of splenectomy in the management of acute and emergent ITP are examined. New insights into the natural history of ITP post-splenectomy and management strategies for patients with severe, chronic, refractory ITP are discussed. In Section III, Dr. James Zehnder updates us on HIT. He emphasizes new insights into the clinical presentation and pathogenesis of this condition. He critically reviews the utility of laboratory testing for heparin-dependent antibodies. Recent studies on the use of direct thrombin inhibitors are examined and the management of cardiopulmonary bypass surgery in patients with HIT is discussed.


Glacier protection laws: Potential conflicts in managing glacial hazards and adapting to climate change.
The environmental, socioeconomic and cultural significance of glaciers has motivated several countries to regulate activities on glaciers and glacierized surroundings. However, laws written to specifically protect mountain glaciers have only recently been considered within national political agendas. Glacier Protection Laws (GPLs) originate in countries where mining has damaged glaciers and have been adopted with the aim of protecting the cryosphere from harmful activities. Here, we analyze GPLs in Argentina (approved) and Chile (under discussion) to identify potential environmental conflicts arising from law restrictions and omissions. We conclude that GPLs overlook the dynamics of glaciers and could prevent or delay actions needed to mitigate glacial hazards (e.g. artificial drainage of glacial lakes) thus placing populations at risk. Furthermore, GPL restrictions could hinder strategies (e.g. use of glacial lakes as reservoirs) to mitigate adverse impacts of climate change. Arguably, more flexible GPLs are needed to protect us from the changing cryosphere.


Nickel(II), copper(II) and zinc(II) metallo-intercalators: structural details of the DNA-binding by a combined experimental and computational investigation.
We present a thorough characterization of the interaction of novel nickel(II) (1), copper(II) (2) and zinc(II) (3) Schiff base complexes with native calf thymus DNA (ct-DNA), in buffered aqueous solution at pH 7.5. UV-vis absorption, circular dichroism (CD) and viscometry titrations provided clear evidence of the intercalative mechanism of the three square-planar metal complexes, allowing us to determine the intrinsic DNA-binding constants (K(b)), equal to 1.3 × 10(7), 2.9 × 10(6), and 6.2 × 10(5) M(-1) for 1, 2 and 3, respectively. Preferential affinity, of one order of magnitude, toward AT compared to GC base pair sequences was detected by UV-vis absorption titrations of 1 with [poly(dG-dC)]2 and [poly(dA-dT)]2. Structural details of the intercalation site of the three metal complexes within [dodeca(dA-dT)]2 were obtained by molecular dynamics (MD) simulations followed by density functional theory/molecular mechanics (DFT/MM) calculations. The calculations revealed that three major intermolecular interactions contribute to the strong affinity between DNA and the three metal complexes: (1) the electrostatic attraction between the two positively charged triethylammoniummethyl groups of the metal complexes and the negatively charged phosphate groups of the DNA backbone; (2) the intercalation of the naphthalene moiety within the four nitrogen bases of the intercalation site; (3) the metal coordination by exocyclic donor atoms of the bases, specifically the carbonyl oxygen and amine nitrogen atoms. Remarkably, the Gibbs formation free energy calculated for the intercalation complexes of 1, 2 and 3 with [dodeca(dA-dT)]2 in the implicit water solution is in agreement with the experimental Gibbs free energy values obtained from the DNA-binding constants as ΔG° = -RT ln(K(b)). In particular, the DNA-binding affinity trend, 1 > 2 > 3, is reproduced. Finally, the first shell coordination distances calculated for the intercalation complex 3/[dodeca(dA-dT)]2 are in excellent agreement with the experimental distances extracted from the extended X-ray absorption fine structure (EXAFS) spectrum of the corresponding 3/ct-DNA solutions. The latter results provided the first evidence of metal ion coordination by native DNA in aqueous solution.


Physiotherapy and a Homeopathic Complex for Chronic Low-back Pain Due to Osteoarthritis: A Randomized, Controlled Pilot Study.
Osteoarthritis (OA) is a common cause of chronic low-back pain (CLBP) and can be managed with drug therapy and physiotherapy. Homeopathic remedies may assist managing OA; however, research that supports their effectiveness is limited. The study aimed to investigate the efficacy of a homeopathic complex in combination with physiotherapy in treating CLBP due to OA. The study was a 6-wk, randomized, double-blind, placebo-controlled pilot. The study took place in a private physiotherapy practice in Gauteng, South Africa. The participants were 30 males and females, aged 45-75 y, who were receiving physiotherapy treatment for OA of the lumbar spine from a therapist in private practice. The intervention and control groups both received standard physiotherapy treatment-massage, thermal therapy, and joint mobilization-every 2 wk. In addition, the treatment group received a homeopathic complex-6cH each of Arnica montana, Bryonia alba, Causticum, Kalmia latifolia, Rhus toxicodendron, and Calcarea fluorica. The control group a received a placebo. The primary measure was a visual analogue scale (VAS) for pain. Secondary outcome measures included the Oswestry Disability Index (ODI), an evaluation of each patient's range of motion (ROM) of the lumbar spine, and a determination of each patient's need for pain medication. Intergroup analysis revealed that the treatment group significantly outperformed the control group with regard to pain, daily functioning, and ROM. No difference existed between the groups, however, in the need for conventional pain medication. The study was too small to be conclusive, but results suggest the homeopathic complex, together with physiotherapy, can significantly improve symptoms associated with CLBP due to OA.


Emerging Memristive Artificial Synapses and Neurons for Energy-Efficient Neuromorphic Computing.
Memristors have recently attracted significant interest due to their applicability as promising building blocks of neuromorphic computing and electronic systems. The dynamic reconfiguration of memristors, which is based on the history of applied electrical stimuli, can mimic both essential analog synaptic and neuronal functionalities. These can be utilized as the node and terminal devices in an artificial neural network. Consequently, the ability to understand, control, and utilize fundamental switching principles and various types of device architectures of the memristor is necessary for achieving memristor-based neuromorphic hardware systems. Herein, a wide range of memristors and memristive-related devices for artificial synapses and neurons is highlighted. The device structures, switching principles, and the applications of essential synaptic and neuronal functionalities are sequentially presented. Moreover, recent advances in memristive artificial neural networks and their hardware implementations are introduced along with an overview of the various learning algorithms. Finally, the main challenges of the memristive synapses and neurons toward high-performance and energy-efficient neuromorphic computing are briefly discussed. This progress report aims to be an insightful guide for the research on memristors and neuromorphic-based computing.


Task Context Influences Brain Activation during Music Listening.
In this paper, we examined brain activation in subjects during two music listening conditions: listening while simultaneously rating the musical piece being played [Listening and Rating (LR)] and listening to the musical pieces unconstrained [Listening (L)]. Using these two conditions, we tested whether the sequence in which the two conditions were fulfilled influenced the brain activation observable during the L condition (LR → L or L → LR). We recorded high-density EEG during the playing of four well-known positively experienced soundtracks in two subject groups. One group started with the L condition and continued with the LR condition (L → LR); the second group performed this experiment in reversed order (LR → L). We computed from the recorded EEG the power for different frequency bands (theta, lower alpha, upper alpha, lower beta, and upper beta). Statistical analysis revealed that the power in all examined frequency bands increased during the L condition but only when the subjects had not had previous experience with the LR condition (i.e., L → LR). For the subjects who began with the LR condition, there were no power increases during the L condition. Thus, the previous experience with the LR condition prevented subjects from developing the particular mental state associated with the typical power increase in all frequency bands. The subjects without previous experience of the LR condition listened to the musical pieces in an unconstrained and undisturbed manner and showed a general power increase in all frequency bands. We interpret the fact that unconstrained music listening was associated with increased power in all examined frequency bands as a neural indicator of a mental state that can best be described as a mind-wandering state during which the subjects are "drawn into" the music.


Mutations at the Qo Site of the Cytochrome bc1 Complex Strongly Affect Oxygen Binding.
The homodimeric bc1 protein complex is embedded in membranes of mitochondria and photosynthetic bacteria, where it transports protons across the membrane to maintain an electrostatic potential used to drive ATP synthesis as part of the respiratory or photosynthetic pathways. The reaction cycle of the bc1 complex is driven by series of redox processes involving substrate molecules from the membrane, but occasional side reactions between an intermediate semiquinone substrate and molecular oxygen are suspected to be a source of toxic superoxide, which is believed to be a factor in aging. The present investigation employs molecular dynamics simulations to study the effect of mutations in the Qo binding sites of the bc1 complex on the ability of oxygen molecules to migrate to and bind at various locations within the complex. It is found that the mutations strongly affect the ability of oxygen to bind at the Qo sites, and moreover, different behavior of the two monomers of the bc1 complex is observed. The conformational differences at the Qo sites of the two monomers are studied in detail and discussed. The anionic form of semiquinone was identified as leading to the greatest opportunity for side reactions with oxygen.


Extended-release injectable naltrexone for opioid use disorder: a systematic review.
To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol® ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined. We searched PubMed and used Google Scholar for forward citation searches of peer-reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR-NTX were included. We identified and included 34 studies. Pooled estimates showed that XR-NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5-70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0-90.1%); 44.2% (95% CI = 33.1-55.9%) of individuals took all scheduled injections of XR-NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6-month rates: 46.7%, 95% CI = 34.5-59.2% versus 10.5%, 95% CI = 4.6-22.4%, respectively). Compared with referral to treatment, XR-NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR-NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR-NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification. Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most who do start XR-NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.


Systematic evaluation of written health information on PSA based screening in Germany.
Prostate-specific antigen (PSA) based screening for early detection of prostate cancer is common although it is associated with both benefits and potential harms (e.g., the risk of overdiagnosis). Evidence-based health information could help individuals make informed decisions about whether to undergo PSA testing or not. This evaluation aimed to determine whether the written health information materials available in Germany provide appropriate information for informed decision-making on PSA based screening. A list of criteria was developed and used to systematically assess the quality of information on the benefits and harms of prostate cancer screening included in written health information materials. Fourteen information materials identified by information requests and online searches were evaluated independently by two of three reviewers. Consensus was achieved with a third reviewer. Of the 14 information materials evaluated, 10 (71%) list the ability to reduce the absolute risk of death from prostate cancer as a benefit of PSA testing, 9 (64%) point out the risks of follow-up diagnostics, 13 (93%) describe the risks of the available prostate cancer treatments, and all 14 specify the risk of overdiagnosis. The minority provide numerical data on benefits and risks. Partially mismatched framing was identified in four cases: two information materials report only the relative frequencies of benefits, and two report only the absolute frequencies of harms. Half of the materials encouraged participation using downplaying or frightening language. The majority of health information materials in Germany describe the benefits and harms of PSA based screening, including overdiagnosis, but often lack adequate balance, neutrality and numbers.


Phosphoproteomics of Retinoblastoma: A Pilot Study Identifies Aberrant Kinases.
Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.


The expression and tyrosine phosphorylation of E-cadherin/catenin adhesion complex, and focal adhesion kinase in invasive cervical carcinomas.
The present study aimed to confirm the hypothesis that the expression and phosphorylation status of the E-cadherin/catenin adhesion complex is related to cervical carcinogenesis and cervical cancer invasion, and to investigate the expression and the tyrosine phosphorylation of focal adhesion kinase (FAK) and its relation with E-cadherin/catenin adhesion complex. The expression of E-cadherin, alpha- and beta-catenin, and FAK were studied by a western blot analysis with 26 cervical carcinomas, nine normal cervices, and five carcinomas in situ of cervix. The tyrosine phosphorylation of alpha- and beta-catenin and FAK were examined by an immunoprecipitation. The expressions of alpha- and beta-catenin and E-cadherin were reduced in cervical carcinoma, and the tyrosine phosphorylation of alpha- and beta-catenin in cervical carcinoma was higher than in normal cervix and carcinoma in situ of cervix. Tyrosine phosphorylation of FAK was elevated in cervical carcinoma although the expression of FAK was not significantly different. Moreover, alpha- and beta-catenin were coimmunoprecipitated with FAK. We conclude that the loss of E-cadherin/catenin proteins and the tyrosine phosphorylation of E-cadherin/catenin are involved in cervical carcinogenesis and cancer invasion. Tyrosine phosphorylation of focal adhesion kinase is also related to the cervical cancer invasion. The E-cadherin/catenin complex and FAK may be related functionally and structurally.


Controls on methane emissions from Alnus glutinosa saplings.
Recent studies have confirmed significant tree-mediated methane emissions in wetlands; however, conditions and processes controlling such emissions are unclear. Here we identify factors that control the emission of methane from Alnus glutinosa. Methane fluxes from the soil surface, tree stem surfaces, leaf surfaces and whole mesocosms, pore water methane concentrations and physiological factors (assimilation rate, stomatal conductance and transpiration) were measured from 4-yr old A. glutinosa trees grown under two artificially controlled water-table positions. Up to 64% of methane emitted from the high water-table mesocosms was transported to the atmosphere through A. glutinosa. Stem emissions from 2 to 22 cm above the soil surface accounted for up to 42% of total tree-mediated methane emissions. Methane emissions were not detected from leaves and no relationship existed between leaf surface area and rates of tree-mediated methane emissions. Tree stem methane flux strength was controlled by the amount of methane dissolved in pore water and the density of stem lenticels. Our data show that stem surfaces dominate methane egress from A. glutinosa, suggesting that leaf area index is not a suitable approach for scaling tree-mediated methane emissions from all types of forested wetland.


The neural correlates of Fitts's law in action observation: an fMRI study.
Previous neuroimaging studies support the assumption of a strong link between perception and action, demonstrating that the motor system is involved when others' actions are observed. One question that is still open to debate is which aspects of observed actions engage the motor system. The present study tested whether motor activation corresponds to the difficulty of the observed action, using Fitts's law. This law postulates that the difficulty of any movement (ID) is a function of the distance to the target (A) and the target width (W). In an observation task, the ID of the observed action was manipulated orthogonally to W (by using five different As). The results revealed activity in the primary motor cortex, the supplementary motor area, and the basal ganglia in response to increasing ID levels, but not in response to different levels of A or W. Thus, activation in the motor system during action observation is not driven by perceptual parameters but by the motor difficulty of the observed action.


Incidence and prevalence of antibody to hepatitis C virus in FDNY first responders before and after work at the World Trade Center disaster site.
The goals of this study were to assess the impact of work at the World Trade Center (WTC) site in relation to new, post-9/11/2001 (9/11) antibody to hepatitis C Virus (anti-HCV); and, evaluate secular trends in WTC-exposed male Fire Department of New York City (FDNY) Firefighters and Emergency Medical Services (EMS) responders. FDNY monitors responder health through physical exams and routine blood work. We used descriptive statistics to compare trans-9/11 and post-9/11 incidence and to assess trends in prevalence from 2000 to 2012. Trans-9/11 incidence of new anti-HCV was 0.42 per 100 persons compared with post-9/11 incidence of 0.34 (P = 0.68). Overall seroprevalence was 1.3%; rates declined from 1.79 per 100 to 0.49 per 100 over time (P < 0.0001). Work at the WTC was not associated with new infection. Biennial seroprevalence in responders declined over time, supporting the FDNY decision to discontinue routine annual testing in this cohort.


The response of the lymphatic system to the human skin resident bacteria.
We designed a study to identify skin bacterial strains producing most intensive changes in lymphoid tissue of the draining nodes and analyse the node cell phenotypes reacting to bacterial antigens. The obtained results were expected to help in establishing rational therapy in recipients of hand allografts. The highest level of activation of lymphoid tissue was found after inoculation with S. epidermidis, Acinetobacter, Enterobacter and Aerococcus. There was an increase in weight and cell concentration of nodes, intense expression of W3/25+ (CD4), OX6+ (class II), EDI+ (CD14), CD54+ and OX62+ cells in the paracortex and medulla 7 days after bacterial inoculation. The most advanced changes were seen after recall bacterial stimulation. Taken together, evident differences in the intensity of response to the investigated bacterial strains were found. The obtained information can be useful for establishing rational antibiotic therapy after composite graft transplantation.


Molecular chemotherapy for breast cancer.
Gene therapy for breast cancer initially involves local or systemic delivery. Local delivery may be intrapleural or via direct injection to lesions. However, systemic delivery remains the greatest challenge with targeting, although methods using antibodies or growth factor receptor ligands have been demonstrated in preclinical models. This review focuses on the next step of using tissue-specific promoters such as Muc-1, CEA, PSA, HER-2, Myc, L-plastin and secretory leukoproteinase inhibitor promoters. All of these have demonstrated differential upregulation in breast cancer and additional specificity may be obtained by using physiological stimuli that are more frequently expressed in cancers, such as glucose regulated promoters and hypoxia response elements or radiation inducible elements. Amongst the later are the EGR-1, p21 and tissue type plaminogen activator promoters. Potential therapy genes include the prodrug activation system 5-fluorocytosine and other analogues of antimetabolites, but all of these need gap junctions to transfer the phosphorylated metabolites. Other approaches involving more freely diffusible products include cyclophosphamide, ifosfamide and thymidine phosphorylase to activate 5-deoxy-5-fluoruridine to fluorouracil. The bystander effect is important both for cell killing and for immunological and antivascular effects. Breast cancer is one type of tumour where a major clinical research effort is underway using local delivery methods. For prodrug activation systems, the use of human enzymes is desirable to prevent an immunological response that would eventually eliminate cells producing the prodrug activation system. The use of alkylating agents has an advantage over antimetabolites in that they are cytotoxic to cycling and noncycling cells, and the cytotoxic products can diffuse across cell membranes without the need for gap junctions. They also have a much steeper dose response curve than antimetabolites.


Trophic structure and community stability in an overfished ecosystem.
Since the collapse of the pelagic fisheries off southwest Africa in the late 1960s, jellyfish biomass has increased and the structure of the Benguelan fish community has shifted, making the bearded goby (Sufflogobius bibarbatus) the new predominant prey species. Despite increased predation pressure and a harsh environment, the gobies are thriving. Here we show that physiological adaptations and antipredator and foraging behaviors underpin the success of these fish. In particular, body-tissue isotope signatures reveal that gobies consume jellyfish and sulphidic diatomaceous mud, transferring "dead-end" resources back into the food chain.


The Heterogeneity, Distribution, and Environmental Associations of Borrelia burgdorferi Sensu Lato, the Agent of Lyme Borreliosis, in Scotland.
Lyme borreliosis is an emerging infectious human disease caused by the Borrelia burgdorferi sensu lato complex of bacteria with reported cases increasing in many areas of Europe and North America. To understand the drivers of disease risk and the distribution of symptoms, which may improve mitigation and diagnostics, here we characterize the genetics, distribution, and environmental associations of B. burgdorferi s.l. genospecies across Scotland. In Scotland, reported Lyme borreliosis cases have increased almost 10-fold since 2000 but the distribution of B. burgdorferi s.l. is so far unstudied. Using a large survey of over 2200 Ixodes ricinus tick samples collected from birds, mammals, and vegetation across 25 sites we identified four genospecies: Borrelia afzelii (48%), Borrelia garinii (36%), Borrelia valaisiana (8%), and B. burgdorferi sensu stricto (7%), and one mixed genospecies infection. Surprisingly, 90% of the sequence types were novel and, importantly, up to 14% of samples were mixed intra-genospecies co-infections, suggesting tick co-feeding, feeding on multiple hosts, or multiple infections in hosts. B. garinii (hosted by birds) was considerably more genetically diverse than B. afzelii (hosted by small mammals), as predicted since there are more species of birds than small mammals and birds can import strains from mainland Europe. Higher proportions of samples contained B. garinii and B. valaisiana in the west, while B. afzelii and B. garinii were significantly more associated with mixed/deciduous than with coniferous woodlands. This may relate to the abundance of transmission hosts in different regions and habitats. These data on the genetic heterogeneity within and between Borrelia genospecies are a first step to understand pathogen spread and could help explain the distribution of patient symptoms, which may aid local diagnosis. Understanding the environmental associations of the pathogens is critical for rational policy making for disease risk mitigation and land management.


Reduction of oral corticosteroids in patients with severe eosinophilic asthma treated with Benralizumab: could it represent a marker of treatment efficacy?
Introduction: Subjects with severe Th2-high endotype usually respond to oral corticosteroids (OCS). However, they often require high dosages with incremental side effects and health-care costs. The advent of biological therapies provides an effective strategy to improve asthma control, as well as reduce OCS use. Various molecules have been developed, each targeting different pathways. We analyzed the two anti-IL-5 strategies, benralizumab and mepolizumab, based on pivotal trials (RCTs), mechanisms of action and their possible role on the steroid-sparing effect. Areas covered: This review analyzes the data from the benralizumab and mepolizumab RCTs, focusing on the advantages of each drug on clinical efficacy and the steroid-sparing effect. Expert opinion: Benralizumab may represent a promising therapeutic option in the treatment of eosinophilic asthma, due to its mechanism of action, which rapidly allows a reduction in the eosinophils' number, and a greater steroid-sparing effect.


Ameliorative influence of Urtica dioica L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma.
Cisplatin (CP) is a widely used cytotoxic agent against cancer, and high doses of CP have been known to cause nephrotoxicity and hepatotoxicity. Some reports claim that antioxidants can reduce CP-induced toxicity. This study investigated the hepatoprotective, nephroprotective, and antioxidant activity of Urtica dioica L methanolic extract (UDME) against CP toxicity in Erhlich ascites tumor (EAT)-bearing mice. Levels of serum hepatic enzymes, renal function markers, and oxidant/antioxidant parameters of liver tissue were measured. Mice were inoculated with EAT on day 0 and treated with nothing else for 24 hours. After a single dose of CP administration on day 1, the extract was given at the doses of 50, 100, 200, and 400 mg/kg body weight daily during 6 days. Almost all doses of UDME performed a significant (P < 0.05) preventive role against CP toxicity by decreasing aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, lipid peroxidation, protein oxidation levels, and myeloperoxidase activity, as well as increasing reduced glutathione content, superoxide dismutase, catalase, glutathione S-transferase, and glutathione peroxidase activities. This suggests that UDME has a protective capacity and antioxidant activity against CP toxicity in EAT-bearing mice, probably by promoting antioxidative defense systems.


Tertiary structure checkpoint at anticodon loop modification in tRNA functional maturation.
tRNA precursors undergo a maturation process, involving nucleotide modifications and folding into the L-shaped tertiary structure. The N1-methylguanosine at position 37 (m1G37), 3' adjacent to the anticodon, is essential for translational fidelity and efficiency. In archaea and eukaryotes, Trm5 introduces the m1G37 modification into all tRNAs bearing G37. Here we report the crystal structures of archaeal Trm5 (aTrm5) in complex with tRNA(Leu) or tRNA(Cys). The D2-D3 domains of aTrm5 discover and modify G37, independently of the tRNA sequences. D1 is connected to D2-D3 through a flexible linker and is designed to recognize the shape of the tRNA outer corner, as a hallmark of the completed L shape formation. This interaction by D1 lowers the K(m) value for tRNA, enabling the D2-D3 catalysis. Thus, we propose that aTrm5 provides the tertiary structure checkpoint in tRNA maturation.


A new surrogate variable for erectile dysfunction status in the Massachusetts male aging study.
Erectile dysfunction (ED) is the subject of a vast clinical literature, but little information has been gathered from random samples of the general public. The Massachusetts Male Aging Study (MMAS) addressed this important aspect of men's health. The MMAS was conducted in two waves, with baseline data collection in 1987-1989 and follow-up in 1995-1997. Subsequent to the baseline MMAS survey, a consensus developed that subjective measures are optimal for defining ED. Unfortunately, the baseline questionnaire did not ask subjects directly about their erectile functioning. Thus, we previously assigned the MMAS subjects a degree of impotence at baseline using a series of related questions, employing a discriminant formula constructed from a separate sample of urology clinic patients. At follow-up the men classified themselves directly in addition to answering the original series of related questions. In the present article, we report the results of a new discriminant function, based on the MMAS men at follow-up. We also compare the two methods and discuss our reasons for preferring the internally calibrated method.


Acupuncture for joint symptoms related to aromatase inhibitor therapy in postmenopausal women with early-stage breast cancer: a narrative review.
Aromatase inhibitor-induced musculoskeletal syndrome (AIMSS) leads to discontinuation of aromatase inhibitor therapy in a significant proportion of patients with breast cancer. Acupuncture is popular among cancer patients and has previously been shown to improve symptoms in a range of musculoskeletal complaints. To determine the effectiveness and safety of acupuncture for the management of AIMSS in postmenopausal women with early-stage breast cancer. A literature search was carried out for randomised controlled trials (RCTs) on acupuncture for AIMSS in postmenopausal women with early-stage breast cancer. Characteristics of trials and outcomes were extracted from the retrieved articles, which were also assessed for risk of bias and quality of reporting. Four RCTs were retrieved of sample size 32-67 (totalling 190 participants). Compliance with treatment was high and rates of adverse events were low. Of the three two-arm RCTs, two found no difference between acupuncture and sham acupuncture and one found that acupuncture was statistically superior to sham acupuncture. The fourth RCT, which incorporated three arms, found acupuncture and sham acupuncture to be statistically superior to usual care but there was no difference between true and sham acupuncture. Three trials that used non-penetrating sham as the control found no effect of acupuncture over sham, but the one trial that used superficial needle insertion found acupuncture to be superior. Acupuncture is safe and results in improvement in AIMSS symptoms, but similar benefits are also elicited by non-penetrating sham acupuncture. Future research should seek to establish the durability of improvements.


Absence of Dbp2p alters both nonsense-mediated mRNA decay and rRNA processing.
Dbp2p, a member of the large family of DEAD-box proteins and a yeast homolog of human p68, was shown to interact with Upf1p, an essential component of the nonsense-mediated mRNA decay pathway. Dbp2p:Upf1p interaction occurs within a large conserved region in the middle of Upf1p that is largely distinct from its Nmd2p and Sup35/45p interaction domains. Deletion of DBP2, or point mutations within its highly conserved DEAD-box motifs, increased the abundance of nonsense-containing transcripts, leading us to conclude that Dbp2p also functions in the nonsense-mediated mRNA decay pathway. Dbp2p, like Upf1p, acts before or at decapping, is predominantly cytoplasmic, and associates with polyribosomes. Interestingly, Dbp2p also plays an important role in rRNA processing. In dbp2Delta cells, polyribosome profiles are deficient in free 60S subunits and the mature 25S rRNA is greatly reduced. The ribosome biogenesis phenotype, but not the mRNA decay function, of dbp2Delta cells can be complemented by the human p68 gene. We propose a unifying model in which Dbp2p affects both nonsense-mediated mRNA decay and rRNA processing by altering rRNA structure, allowing specific processing events in one instance and facilitating dissociation of the translation termination complex in the other.


Computational reprogramming of homing endonuclease specificity at multiple adjacent base pairs.
Site-specific homing endonucleases are capable of inducing gene conversion via homologous recombination. Reprogramming their cleavage specificities allows the targeting of specific biological sites for gene correction or conversion. We used computational protein design to alter the cleavage specificity of I-MsoI for three contiguous base pair substitutions, resulting in an endonuclease whose activity and specificity for its new site rival that of wild-type I-MsoI for the original site. Concerted design for all simultaneous substitutions was more successful than a modular approach against individual substitutions, highlighting the importance of context-dependent redesign and optimization of protein-DNA interactions. We then used computational design based on the crystal structure of the designed complex, which revealed significant unanticipated shifts in DNA conformation, to create an endonuclease that specifically cleaves a site with four contiguous base pair substitutions. Our results demonstrate that specificity switches for multiple concerted base pair substitutions can be computationally designed, and that iteration between design and structure determination provides a route to large scale reprogramming of specificity.


The circulating cell-free microRNA profile in systemic sclerosis is distinct from both healthy controls and systemic lupus erythematosus.
To evaluate the expression profile of cell-free circulating microRNA (miRNA) in systemic sclerosis (SSc), healthy controls (HC), and systemic lupus erythematosus (SLE). Total RNA was purified from plasma and 45 different, mature miRNA were measured using quantitative PCR assays after reverse transcription. Samples (n = 189) were from patients with SSc (n = 120), SLE (n = 29), and from HC (n = 40). Expression data were clustered by principal components analysis, and diagnostically specific miRNA profiles were developed by leave-one-out cross-validation. Diagnostic probability scores were derived from stepwise logistic regression. Thirty-seven miRNA specificities were consistently detected and 26 of these were unaffected by SSc sample age and present in more than two-thirds of SSc samples. SSc cases showed a distinct expression profile with 14/26 miRNA significantly decreased (false discovery rate < 0.05) and 5/26 increased compared with HC. A 21-miRNA classifier gave optimum accuracy (80%) for discriminating SSc from both HC and SLE. The discrimination between HC and SSc (95% accuracy) was strongly driven by miRNA of the 17 ∼ 92 cluster and by miR-16, -223, and -638, while SLE and SSc differed mainly in the expression of miR-142-3p, -150, -223, and -638. Except for a weak correlation between anti-Scl-70 and miR-638 (p = 0.048), there were no correlations with other patient variables. Circulating miRNA profiles are characteristic for SSc compared with both HC and SLE cases. Some of the predicted targets of the differentially regulated miRNA are of relevance for transforming growth factor-β signaling and fibrosis, but need to be validated in independent studies.


The lipoxygenase metabolite, 12(S)-HETE, induces a protein kinase C-dependent cytoskeletal rearrangement and retraction of microvascular endothelial cells.
We previously reported that a lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], induced large vessel endothelial cell (EC) retraction and increased tumor cell adhesion to exposed extracellular matrix (Honn et al., FASEB J. 3, 2285-2293, 1989). Here, we present evidence that 12(S)-HETE induces the retraction of microvascular ECs in a time- and concentration-dependent manner. The EC retraction was observed 15 min after 12(S)-HETE treatment and reached a peak level between 1 and 2 h. The monolayer reformed by 24 h. Silver staining and "gap-FRAP" experiments suggest that 12(S)-HETE altered the normally apposed cell junctions and impaired gap junction-mediated cell-cell communication. It appears that the 12(S)-HETE effect was mediated by cytoskeletal alteration. The first observed alteration in EC cytoskeleton following 12(S)-HETE stimulation is vimentin bundling, followed by the rearrangement and disruption of vinculin-containing adhesion plaques and/or simultaneous redistribution of alpha-actinin and disruption of spectrin. These changes are accompanied by progressive microfilament dissolution. During the same time interval, alpha-actinin is mobilized to the cell periphery at cell "ruffles." However, 12(S)-HETE showed little or no effects on actin-binding proteins filamin and tropomyosin or on microtubules. 12(S)-HETE effects on these cytoskeletal elements were fully reversible by 24 h and appeared to be mediated through enhancing protein phosphorylation. Following 12(S)-HETE (0.1 microM) treatment increased phosphorylation of proteins that comigrated with myosin light chain (20 kDa), actin (42 kDa), and vimentin (57 kDa) were observed. The enhanced phosphorylation of these cytoskeletal proteins was confirmed by 2D gel analysis. The phosphorylation-promoting effect of 12(S)-HETE on cytoskeletal proteins could be totally abolished by calphostin C, partially inhibited by staurosporine, but was not influenced by N-[2-(methylamine)ethyl]-5-isoquinolinesilfonamide dihydrochloride (HS), suggesting that the 12(S)-HETE effect was mediated via protein kinase C. This was further substantiated by quantitative experiments demonstrating that calphostin C, but not H8, inhibited 12(S)-HETE-induced EC retraction.


Effects of partial substitution of fish meal by soybean meal with or without heat-killed Lactobacillus plantarum (LP20) on growth performance, digestibility, and immune response of amberjack, Seriola dumerili juveniles.
A 56-day feeding trial was conducted to evaluate the effects of supplemented diets with heat-killed Lactobacillus plantarum (HK-LP) with graded levels of soybean meal (SBM) on growth, digestibility, blood parameters, and immune response of Seriola dumerili (initial weight, 25.05 ± 0.1 g). Seven isonitrogenous and isolipidic practical diets were formulated to contain 0%, 15%, 30%, and 45% SBM, and each SBM level was supplemented with HK-LP at 0.0 and 0.1%. Fish fed diet which contains 30% SBM with HK-LP grew significantly faster than the other groups with notable feed intake and protein retention. Further, protein gain, whole body protein content, protease activity, protein, and lipid digestibility were significantly increased for all fish groups except for fish fed diet which contains 45% SBM with or without HK-LP. Interestingly, lysozyme activity was significantly enhanced in fish fed diets that contain 15% and 30% SBM with HK-LP. Hematocrit, peroxidase, and bactericidal activities revealed a significant increase in 30% SBM with HK-LP group. In addition, fish fed diets which contain 0% and 30% SBM with HK-LP showed higher tolerance against low-salinity stress compared with other groups. In conclusion, the addition of HK-LP to amberjack diets appeared to improve SBM utilization, immune response, and stress resistance.


Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation.
One of the major limitations for understanding the biology of human mesenchymal stem cells (hMSCs) is the absence of prospective markers needed for distinguishing them from other cells and for monitoring lineage-specific differentiation. Mass spectrometry (MS)-based proteomics has proven extremely useful for analyzing complex protein expression patterns and, when applied quantitatively, can be used to resolve subtle differences between samples. Thus, we used MS to characterize changes in expression of membrane protein markers before and after short-term induction of osteoblast (OB) differentiation in a cell model of hMSCs established by overexpression of human telomerase reverse-transcriptase gene. We identified 463 unique proteins with extremely high confidence, including all known markers of hMSCs (e.g., SH3 [CD71], SH2 [CD105], CD166, CD44, Thy1, CD29, and HOP26 [CD63]) among 148 integral membrane or membrane-anchored proteins and 159 membrane-associated proteins. Twenty-nine integrins and cell adhesion molecules, 20 receptors, and 18 Ras-related small GTPases were also identified. Upon OB differentiation, the expression levels of 83 proteins increased by at least twofold whereas the levels of another 21 decreased by at least twofold. For example, alkaline phosphatase (ALP), versican core protein, and tenascin increased 27-, 12-, and 4-fold, respectively, and fatty acid synthase decreased sixfold. The observed increases in veriscan and ALP were confirmed using immunocytochemistry and cytochemistry. Quantitative real-time reverse transcription-polymerase chain reaction confirmed the presence of mRNA of these membrane proteins. However, with the exception of ALP, no concordance was detected between the changes in levels of gene and protein expression during OB differentiation. In conclusion, MS-based proteomics can reveal novel markers for MSCs that can be used for their isolation and for monitoring OB differentiation.


Emboli in infective endocarditis: the prognostic value of echocardiography.
To determine whether vegetations visualized on two-dimensional echocardiography are an independent risk factor for the development of subsequent emboli in patients with infective endocarditis and to assess the timing of emboli relative to the initiation of antimicrobial therapy. Investigator-blinded, retrospective incidence cohort study. Tertiary referral center. Patients with left-sided native valve infective endocarditis who had two-dimensional echocardiography within 72 hours of beginning antimicrobial therapy. The crude incidence rate of first embolic events in patients receiving antimicrobial therapy was 6.2 per 1000 patient-days (95% CI, 4.2 to 9.2). The rates in patients with and without vegetations were 7.1 and 4.9 per 1000 patient-days, respectively (incidence rate ratio, 1.4; 95% CI, 0.6 to 3.3). The relation between vegetations and risk for emboli was microorganism-dependent: Stratified incidence rate ratios were 6.9 (95% CI, 1.1 to 42.5; P less than 0.05) and 1.0 (95% CI, 0.2 to 3.9) for viridans streptococcal and Staphylococcus aureus endocarditis, respectively. The rate of first embolic events diminished over time (P less than 0.001), falling from 13 per 1000 patient-days during the first week of therapy to less than 1.2 per 1000 patient-days after completion of the second week of therapy. Overall, the presence of vegetations on echocardiography was not associated with a significantly higher risk for embolus in patients with left-sided native valve infective endocarditis. The relative risk for embolic events associated with echocardiographically visualized vegetations may be microorganism-dependent, with a significantly increased risk seen only in patients with viridans streptococcal infection. The rate of embolic events declines with time after initiation of antimicrobial treatment.


Carbonized blood deposited on fibres during 810, 940 and 1,470 nm endovenous laser ablation: thickness and absorption by optical coherence tomography.
Endovenous laser ablation (EVLA) is commonly used to treat saphenous varicosities. Very high temperatures at the laser fibre tip have been reported during EVLA. We hypothesized that the laser irradiation deposits a layer of strongly absorbing carbonized blood of very high temperature on the fibre tip. We sought to prove the existence of these layers and study their properties by optical transmission, optical coherence tomography (OCT) and microscopy. We analysed 23 EVLA fibres, 8 used at 810 nm, 7 at 940 nm and 8 at 1,470 nm. We measured the transmission of these fibres in two wavelength bands (450-950 nm; 950-1,650 nm). We used 1,310 nm OCT to assess the thickness of the layers and the attenuation as a function of depth to determine the absorption coefficient. Microscopy was used to view the tip surface. All fibres showed a slightly increasing transmission with wavelength in the 450-950 nm band, and a virtually wavelength-independent transmission in the 950-1,650 nm band. OCT scans showed a thin layer deposited on all 13 fibres investigated, 6 used at 810 nm, 4 at 940 nm and 3 at 1,470 nm, some with inhomogeneities over the tip area. The average absorption coefficient of the 13 layers was 72 +/- 16 mm(-1). The average layer thickness estimated from the transmission and absorption measurements was 8.0 +/- 2.7 microm. From the OCT data, the average maximal thickness was 26 +/- 6 microm. Microscopy of three fibre tips, one for each EVLA wavelength, showed rough, cracked and sometimes seriously damaged tip surfaces. There was no clear correlation between the properties of the layers and the EVLA parameters such as wavelength, except for a positive correlation between layer thickness and total delivered energy. In conclusion, we found strong evidence that all EVLA procedures in blood filled veins deposit a heavily absorbing hot layer of carbonized blood on the fibre tip, with concomitant tip damage. This major EVLA mechanism is unlikely to have much wavelength dependence at similar delivered energies per centimetre of vein. Optical-thermal interaction between the vein wall and the transmitted laser light depends on wavelength.


Bitewing film quality: a clinical comparison of the loop vs. holder techniques.
To compare in vivo bitewing film quality using the holder versus the paper loop technique. Four bitewing films were taken from the right and left premolar and molar regions of 45 dental students using both the bitewing holder and paper loop techniques. A total of 360 films were taken and assessed by an experienced practitioner not apprised of the bitewing technique used. Of interest were: (1) the number of overlaps and the percentage of teeth showing the alveolar crest; (2) proper film positioning; and (3) the percentage of cone cutting. A Poisson regression using generalized estimating equations (GEEs) was used to estimate the difference in overlap between the two techniques. For proper positioning and cone cutting, logistic regressions using GEEs were used. The average number of horizontal overlaps for the loop and holder techniques at the right premolar, right molar, left premolar, and left molar were 1.64, 2.11, 2.16, 2.78, and 1.64, 2.00, 2.00, 2.18, respectively. The loop technique was 1.11 times more likely to cause overlapping than the holder technique. The highest percentage of teeth showing the alveolar crest by the loop technique was 97.8% in the mandibular second premolar and first molar. With respect to film positioning, the loop technique was 1.12 times more likely to cause improper positioning than the holder technique. Both techniques demonstrated minimal cone cutting (1 in the loop versus 0 in the holder). The quality of bitewing films taken by the loop and holder techniques was not significantly different.


The utility of cranial ultrasound as a screening tool for neonatal ECMO.
Background Neurologic complications including hemorrhage, ischemia, and infarction are often identified in neonates undergoing extracorporeal membrane oxygenation (ECMO) and may contribute to the high morbidity observed in ECMO survivors. Screening for intracranial complications is reliant on bedside transcranial ultrasound (CUS) prior to and during ECMO therapy, and advanced imaging [i.e. computed tomography (CT)/magnetic resonance imaging (MRI)] is recommended after completion of ECMO support. The goal of this study is to describe the correlation of intracranial complications identified on CUS during ECMO and MRI after completion of ECMO. Methods Fifty-five neonates underwent ECMO support at the Children's Hospital of Georgia at Augusta University from January 1, 2012 to December 31, 2017. Forty-four (80%) had a brain MRI performed prior to transfer or discharge. Ultrasound studies were reviewed by a single blinded pediatric radiologist and MRIs were reviewed by a single blinded neuro-radiologist. Results Of the 44 neonates with post-ECMO MRI, CUS during ECMO identified intracranial lesions in nine neonates, which were all confirmed on post-ECMO MRI. Sixteen subjects (46%) with unremarkable CUS during ECMO had identifiable lesions on post-ECMO MRI, yielding a sensitivity of 36% and a specificity of 100% for CUS in the detection of intracranial lesions. Despite the lack of correlation between CUS and MR, 84.6% of survivors exhibited normal development at 24 months of age. Conclusion While necessary for the identification of intracranial lesions during neonatal ECMO, CUS demonstrated low correlation with post-ECMO MRI in the identification of intracranial lesions, which supports Extracorporeal Life Support Organization (ELSO) recommendations.


Blood Pressure Complexity Discriminates Pathological Beat-to-Beat Variability as a Marker of Vascular Aging.
Background Beat-to-beat blood pressure variability (BPV) is associated with an increased risk of stroke but can be driven by both healthy physiological processes and failure of compensatory mechanisms. Blood pressure (BP) complexity measures structured, organized variations in BP, as opposed to random fluctuations, and its reduction may therefore identify pathological beat-to-beat BPV. Methods and Results In the prospective, population-based OXVASC (Oxford Vascular Study) Phenotyped Cohort with transient ischemic attack or minor stroke, patients underwent at least 5 minutes of noninvasive beat-to-beat monitoring of BP (Finometer) and ECG to derive the following: BPV (coefficient of variation) and complexity (modified multiscale entropy) of systolic BP and diastolic BP, heart rate variability (SD of R-R intervals), and baroreflex sensitivity (BRS; Welch's method), in low- (0.04-0.15 Hz) and high-frequency (0.15-0.4 Hz) bands. Associations between BPV or BP complexity with autonomic indexes and arterial stiffness were determined (linear regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. In 908 consecutive, consenting patients, BP complexity was inversely correlated with BPV coefficient of variation (P<0.001) and was similarly reduced in patients with hypertension or diabetes (P<0.001). However, although BPV coefficient of variation had a U-shaped relationship with age, BP complexity fell systematically across age quintiles (quintile 1: 15.1 [14.0-16.1] versus quintile 5: 13.8 [12.4-15.1]) and was correlated with markers of autonomic dysfunction (heart rate variability SD of R-R intervals: r = 0.20; BRS low frequency: 0.19; BRS high frequency: 0.26) and arterial stiffness (pulse wave velocity: -0.21; all P<0.001), even after adjustment for clinical variables (heart rate variability SD of R-R intervals: 0.12; BRS low frequency and BRS high frequency: 0.13 and 0.17; and pulse wave velocity: -0.07; all P<0.05). Conclusions Loss of BP complexity discriminates BPV because of pathological failure of compensatory mechanisms and may represent a less confounded and potentially modifiable risk factor for stroke.