Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future.
Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide with an estimated 432 242 deaths occurring in 2018. This estimate, in conjunction with the findings that pancreatic ductal adenocarcinoma incidence is rising and that pancreatic ductal adenocarcinoma has the highest case-fatality rate of any solid tumour, highlights the urgency for designing novel therapeutic strategies to combat this deadly disease. Through the efforts of the global research community, our knowledge of the factors that lead to the development of pancreatic ductal adenocarcinoma, its progression, and the interplay between tumour cells and their surrounding microenvironment have improved substantially. Although these scientific advances have not yet translated into targeted or immunotherapy strategies that are effective for most patients with pancreatic ductal adenocarcinoma, important incremental progress has been made particularly for the treatment of specific molecular subgroups of tumours. Although PD-1 inhibitors for mismatch-repair-deficient tumours and NTRK inhibitors for tumours containing NTRK gene fusions are the most recent targeted agents approved by the US Food and Drug Administration, olaparib for germline BRCA-mutated pancreatic ductal adenocarcinoma is expected to be approved soon in the maintenance setting. These recent advances show the accelerated pace at which pancreatic ductal adenocarcinoma drugs are achieving successful clinical outcomes. Here we review the current understanding of the pathophysiology of pancreatic ductal adenocarcinoma, recent advances in the understanding of the stromal microenvironment, current standard-of-care treatment, and novel therapeutic targets and strategies that hold promise for improving patient outcomes. We predict that there will be major breakthroughs in the treatment of pancreatic ductal adenocarcinoma in the next 5-10 years. These breakthroughs will result from the increased understanding of the treatment barriers imposed by the tumour-associated stroma, and from the development of novel approaches to re-engineer the tumour microenvironment in favour of effective anticancer responses.


Deep Learning Solutions for Classifying Patients on Opioid Use.
Opioid analgesics, as commonly prescribed medications used for relieving pain in patients, are especially prevalent in US these years. However, an increasing amount of opioid misuse and abuse have caused lots of consequences. Researchers and clinicians have attempted to discover the factors leading to opioid long-term use, dependence, and abuse, but only limited incidents are understood from previous works. Motivated by recent successes of deep learning and the abundant amount of electronic health records, we apply state-of-the-art deep and recurrent neural network models on a dataset of more than one hundred thousand opioid users. Our models are shown to achieve robust and superior results on classifying opioid users, and are able to extract key factors for different opioid user groups. This work is also a good demonstration on adopting novel deep learning methods for real-world health care problems.


Multilocular cystic renal cell carcinoma: pathological t staging makes no difference to favorable outcomes and should be reclassified. Bhatt JR, Jewett MA, Richard PO, Kawaguchi S, Timilshina N, Evans A, Alibhai S, Finelli A.J Urol. November 2016;196(5):1350-1355.
We evaluated survival outcomes of cystic/multilocular cystic renal cell carcinomas in a long-term population-based study based on size and pathological tumor stage. We, retrospectively, reviewed a provincial cancer registry of all histologically proven cases of multilocular cystic renal cancers treated surgically between 1995 and 2008. All cases of cystic necrosis were excluded from study. Primary end points were overall- and cancer-specific survival estimated using Kaplan-Meier curves. Cox proportional hazards models of univariable and multivariable analyses were used to assess for factors associated with survival. Of 172 cases of cystic renal cancers 168 with complete data were analyzed, of which 98% were multilocular cystic. Median patient age at treatment was 55 years and 58% of the patients were male. More than 40% of cases were pT1b or greater, 15% were pT2 or greater and most cases were low Fuhrman grade (1-2). At a median follow-up of 9.75-years overall- and cancer-specific survival was 82.1% and 100%, respectively. No difference was noted in higher pathological T stage, size, or grade. Limitations inherent in population-based studies include under ascertainment of cause of death, lack of data on histologically benign cysts that are treated surgically and a lack of central pathology review. Multilocular cystic renal cell carcinoma has an excellent prognosis, which remains unchanged regardless of tumor size or pathological T stage. This suggests a strong case for nephron and adrenal sparing surgery when indicated, and nonsurgical management when feasible. As postoperative follow-up protocols are dictated by staging, we propose that for this entity pathological T staging should be abandoned or reassigned as pT1c to guide clinicians.


The primary structure of coho salmon growth hormone and its cDNA.
Total RNA was extracted from coho salmon growth hormone (sGH) cell regions and used to synthesize double-stranded cDNA, which was inserted into a plasmid vector and used to transform Escherichia coli HB101. The total RNA was also separated according to size by electrophoresis on agarose gels and the fraction that directed the cell-free synthesis of protein in the size range of GHs of other species was isolated and used to screen the transformed colonies of E. coli. A clone containing the putative sGH cDNA was identified and its nucleotide sequence was determined. To verify that the cDNA was that of sGH, the GH cell region of coho pituitary glands was incubated in organ culture. The secreted GH was purified by HPLC and the sequence of its 42 amino-terminal amino acids was determined. Comparison of this sequence with the amino acid sequence derived from the cDNA showed that it encoded sGH. Medium containing the presumptive sGH as the only prominent protein was active in a GH radioreceptor assay that involved labeled bovine GH and pregnant mouse liver membranes: the sGH was approximately 10% as active as the bGH standard. RNA blotting analysis showed that sGH was the major species of RNA produced by the GH cell region of the salmon pituitary. The mRNA of sGH differed from those of human, rat, and bovine GH in that its 3'-untranslated region was unusually large (about 500 nucleotides) but the coding region showed significant homology with mammalian GHs and resembled them in having a strong (78%) preference for G and C in the third positions of the codons. The amino acid sequence of sGH showed 32-34% and 19-22% identical homology with mammalian GHs and prolactins, respectively. Several conserved regions between sGH and mammalian GH and PRL molecules were also revealed that could indicate conservation of structurally and/or functionally important domains. Hydropathy analysis disclosed that although sGH and the GH of a representative mammal (pig) had similar profiles in some regions, the sGH was overall more hydrophobic than the pig (p) GH. Similarities and differences, were also noted in the predicted secondary structure of sGH and pGH.


Does ethnicity contribute to the control of cardiovascular risk factors among patients with type 2 diabetes?
This study aimed to examine the control of cardiovascular risk factors among the ethnic groups with type 2 diabetes in Malaysia. The authors analyzed the data of 70 092 adults from the Malaysian diabetes registry database. Malays had the worst achievement of target for most of the risk factors. Indians had poor achievement of control for waist circumference (odds ratio [OR] = 0.6, 95% confidence interval [CI] = 0.6-0.7) and high-density lipoprotein cholesterol (OR = 0.5, 95% CI = 0.4-0.5). As compared with the Malays, the Chinese had a better achievement of target control for the risk factors, including the following: body mass index (OR = 1.3, 95% CI = 1.2-1.4), blood pressure (OR = 1.3, 95% CI = 1.3-1.4), total cholesterol (OR = 1.7, 95% CI = 1.6-1.8), low-density lipoprotein cholesterol (OR = 1.7, 95% CI = 1.6-1.8), glycated hemoglobin A1c (OR = 1.4, 95% CI = 1.3-1.4) and fasting blood glucose (OR = 1.4, 95% CI = 1.3-1.5). Ethnicity, sociocultural factors, and psychobehavioral factors should be addressed in designing and management strategies for the control of cardiovascular risk factors among type 2 diabetes patients.


[Genotoxic damage among artisanal and small-scale mining workers exposed to mercury].
To determine the genotoxic damage among artisanal and small-scale mining workers exposed to mercury. Observational cross-sectional study which evaluated mercury-exposed workers (n=83), whose cells were collected by mouth swab for further staining, microscopic observance, micronuclei count, and other nuclear alterations. 24-hour urine was also collected for the determination of inorganic mercury. 68.7% of participants were male, the mean age being 43 ± 12,4 years (range: 16-76). The average time of occupational exposure to mercury was 12,1 ± 6,7 years, and the contact with mercury was 4,1 ± 3,6 kg per person per day. 93% of participants failed to wear personal protection gear while handling mercury. Results of biological monitoring showed that 17% of participants had concentrations of mercury in urine higher than 2,5 µg/L, this value being the detection limit of the measurement technique used. Results of the genotoxic evaluation evidenced that 15% of people with labor exposure to mercury presented micronuclei in mouth epithelial cells, and other indicators of nuclear alteration such as nucleoplasmic bridges, gemmation and binucleation were found, which are also considered genotoxic events associated to the exposure of physical or chemical risk agents. The finding of micronuclei in mouth epithelial cells reflects genotoxic damage associated to the labor exposure of mercury used in artisanal and small-scale mining activities.


Protein purification by multidimensional liquid chromatography.
Recently Giddings discussed the prospect of combining two separation mechanisms in such a way that when "a sample is subjected to two displacement processes oriented at right angles to one another" a two-dimensional separation is carried out. In this review I have focused attention on the various ramifications of this concept in terms of combining two or more chromatographic techniques on-line to conduct MDLC for the purpose of purifying proteins. In general, the MDLC approaches discussed here were classified into two major categories. The first category involves the placement of several separation mechanisms in the same chromatographic work space (the chromatographic column). In this case the displacement processes are collinear. It is hoped that these new chromatographic packings and columns will display surface characteristics capable of a wide range of highly discriminating selectivities that can be modulated by mobile-phase changes to a greater extent than the nonspecific chromatographic techniques such as IEC and HIC. The ability to modulate the mobile phase to generate new selectivities is important in expanding the usefulness of these packings in comparison to the very high selectivity of affinity chromatography, which usually has little use outside its initial intended purpose to purify a particular protein. The second category involves the on-line physical coupling of two or more chromatography columns, each packed with a different chromatography material. Again the idea is to create or design a simple self-contained system that is capable of generating a wide range of high selectivities. Indeed, the on-line coupling of two different chromatographic packings for the purification of a single protein represents a line trace through "a discrete independent 2-dimensional system". These systems are highly attractive in large-scale purification, especially when using "on-off" chromatography, which eliminates the need for sophisticated gradient elution hardware. The purification of a single protein from its biological matrix is usually a multidimensional process utilizing several different separation technologies. By nature this leads to lengthy purifications that are frequently labor-intensive and expensive to scale up. It is my belief that future developments in the concept of on-line MDLC techniques involving complex chromatographic materials and column coupling will merge to create significant improvements in the protein purification process.


Separation and characterization of monoglucuronides of vitamin D(3) and25-hydroxyvitamin D(3) in rat bile by high-performance liquid chromatography.
The separation and characterization of vitamin D(3)- and 25-hydroxyvitamin D(3)-monoglucuronides, biliary metabolites obtained from rats dosed with D(3) and 25-hydroxyvitamin D(3) per os, respectively, were carried out by HPLC. The glucuronide fractions were obtained from bile specimens by the combined use of a Bond Elut C18 cartridge, for solid phase extraction, and a lipophilic gel (piperidinohydroxypropyl Sephadex LH-20), for ion-exchange chromatography. Each glucuronide was identified by comparison with an authentic sample in three ways: its chromatographic behavior, that of its fluorescent labeled derivative using 4-[4-(6-methoxy-2-benzoxazolyl)phenyl]-1,2,4-triazoline-3,5- dione and data obtained following enzymatic hydrolysis using beta-glucuronidase.


Contextual features and behavioral functions of self-mutilation among adolescents.
Adolescent self-mutilative behavior (SMB) is a pervasive and dangerous problem, yet factors influencing the performance of SMB are not well understood. The authors examined the contextual features and behavioral functions of SMB in a sample of 89 adolescent psychiatric inpatients. SMB typically was performed impulsively, in the absence of physical pain, and without the use of alcohol or drugs. Moreover, analyses supported the construct validity of a functional model in which adolescents reported engaging in SMB for both automatic and social reinforcement. Considering the functions of SMB clarified the relations between SMB and other clinical constructs reported in previous studies such as suicide attempts, posttraumatic stress, and social concerns and has direct implications for the assessment and treatment of SMB.


Carnosine is a novel peptide modulator of intracellular calcium and contractility in cardiac cells.
Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and systemic inflammatory states such as sepsis. Accumulating evidence indicates that contractile failure is associated with dysregulation of myoplasmic calcium levels. In a search for biochemical causes for contractile dysfunction, we found that the dipeptide carnosine improves cardiac contractility and tested the possibility that carnosine plays a role in the regulation of intracellular calcium. Carnosine increased contractility in a dose-dependent manner (1-10 mM) in isolated perfused rat hearts. and it also increased free intracellular calcium levels in isolated myocytes. Carnosine increased myocyte tension via calcium release from the ryanodine receptor calcium release channel in skinned myocardial fibers and increased open-state probability and dwell time of the isolated ryanodine receptor calcium release channel in lipid bilayers. In addition. we report that carnosine sensitizes the contractile proteins so calcium. These results suggest a novel role for carnosine as a modulator of intracellular calcium and contractility in cardiac tissue.


Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells.
The activation of cyclin-dependent kinases (cdks) has been implicated in apoptosis induced by various stimuli. We find that the Fas-induced activation of cdc2 and cdk2 in Jurkat cells is not dependent on protein synthesis, which is shut down very early during apoptosis before caspase-3 activation. Instead, activation of these kinases seems to result from both a rapid cleavage of Wee1 (an inhibitory kinase of cdc2 and cdk2) and inactivation of anaphase-promoting complex (the specific system for cyclin degradation), in which CDC27 homolog is cleaved during apoptosis. Both Wee1 and CDC27 are shown to be substrates of the caspase-3-like protease. Although cdk activities are elevated during Fas-induced apoptosis in Jurkat cells, general activation of the mitotic processes does not occur. Our results do not support the idea that apoptosis is simply an aberrant mitosis but, instead, suggest that a subset of mitotic mechanisms plays an important role in apoptosis through elevated cdk activities.


Enrichment of Innate Lymphoid Cell Populations in Gingival Tissue.
Innate lymphoid cells (ILCs) are a population of lymphocytes that act as the first line of immunologic defense at mucosal surfaces. The ILC family in the skin, lungs, and gastrointestinal tissues has been investigated, and there are reports of individual subsets of ILCs in the oral tissues. We sought to investigate the whole ILC population (group 1, 2, and 3 subsets) in the murine gingivae and the lymph nodes draining the oral cavity. We show that ILCs made up a greater proportion of the whole CD45+ lymphocyte population in the murine gingivae (0.356% ± 0.039%) as compared with the proportion of ILCs in the draining lymph nodes (0.158% ± 0.005%). Cytokine profiling of the ILC populations demonstrated different proportions of ILC subsets in the murine gingivae versus the regional lymph nodes. The majority of ILCs in the draining lymph nodes expressed IL-5, whereas there were equal proportions of IFN-γ- and IL-5 expressing ILCs in the oral mucosa. The percentage of IL-17+ ILCs was comparable between the murine gingivae and the oral draining lymph nodes. These data suggest an enrichment of ILCs in the murine gingivae, and these ILCs reflect a cytokine profile discrepant to that of the local draining lymph nodes. These studies indicate diversity and enrichment of ILCs at the oral mucosal surface. The function of ILCs in the oral cavity remains to be determined; here, we provide a premise of ILC populations that merits future consideration in investigations of mouse models and human tissues.


Prevention of artifactual protein oxidation generated during sodium dodecyl sulfate-gel electrophoresis.
Prevention of artifactual protein oxidation occurring during sodium dodecyl sulfate (SDS) acrylamide gel electrophoresis is critical for identifying physiological protein oxidation implicated in human diseases due to the routine use of gel electrophoresis to separate the multiple proteins in proteomic studies. To develop a methodology that completely prevents artifactual protein oxidation in SDS acrylamide gel electrophoresis, cytochrome c was electrophoresed on polyacrylamide gels and subjected to trypsin in-gel digestion followed by tryptic peptide analysis by mass spectrometry. It was found that degassing the acrylamide solution to remove molecular oxygen prior to gel polymerization is a crucial process to protect the electrophoresed protein from reactive oxygen species generated during electrophoresis. However, significant artifactual protein oxidation remains that can only be eliminated entirely, if proteins are electrophoresed on an SDS gel photopolymerized with flavin as the photoinitiator and thioglycolate included in the cathode buffer as a reactive oxygen species scavenger. Using this combination of methodologies, cytochrome c isolated from adult rat heart mitochondria was purified and digested followed by mass spectrometric analysis, demonstrating the requisite high resolution of the polyacrylamide gel and the entire elimination of artifactual oxidation.


[Duration of meiotic prophase stages during oogenesis in the newt Triturus cristatus cristatus].
The duration of the early stages of meiotic prophase was determined in the oogenesis of T. cristatus cristatus by means of autoradiography. The oocytes were being investigated during 39 days from the moment of 3H-thymidine injection. It was shown that preleptotene lasts 1--2, leptotene ca. 4, zygotene 5 and pachytene 26 days. When studying the preparations obtained 1 day after the injection of 3H-thymidine, the silver grains were found to be localized over the nuclei at all stages of meiotic prophase; this suggests the amplification of rDNA which begins in leptotene-zygotene and ends in early diplotene.


Post-Covid-19 Syndrome: Improvements in Health-Related Quality of Life Following Psychology-Led Interdisciplinary Virtual Rehabilitation.
Coronavirus disease 2019 (COVID-19) is increasingly recognized as having significant long-term impact on physical and mental health. The Primary Care Wellbeing Service (PCWBS) in Bradford District Care NHS Foundation Trust (BDCFT) is a psychology-led specialist interdisciplinary team of health professionals specializing in persistent physical symptoms (PPS) and Chronic Fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME) with an emphasis on holistic integrated care. The PCWBS quickly recognized the risk of the long-term effects of COVID-19, particularly for social, health and care staff, and developed a 7-week virtual rehabilitation course which was piloted in October 2020. The "Recovering from COVID" course takes a whole system, biopsychosocial approach to understanding COVID-19 and post-viral fatigue (PVF) and is delivered by an interdisciplinary team consisting of a clinical psychologist, physiotherapist, occupational therapist, dietitian, speech and language therapist, assistant psychologist, and a personal support navigator with support from a team administrator. The course focuses on understanding PVF, sleep optimization, nutrition, swallowing, activity management, energy conservation, stress management, breathing optimization, managing setbacks, and signposting to appropriate resources and services. Since the pilot, PCWBS has delivered 7 courses to support over 200 people suffering from post-COVID-19 syndrome. One hundred and forty-nine individuals that enrolled on the "Recovering from COVID" course completed the EQ-5D-5L to assess Health-related quality of life (HRQoL) across 5 dimensions, including problems with mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Subsequently, 76 individuals completed these measures at the end of the rehabilitation course showing that patient ratings were significantly improved. In response to the NIHR recommendation for rapid evaluation of different service models for supporting people with post-COVID-19 syndrome, this data offers hope that rehabilitation is effective in reversing some of the problems faced by people living with the long-term effects of COVID-19.


Peering is not a formal indicator of subordination in bonobos (Pan paniscus).
It has been suggested that peering behavior in bonobos is a formal signal acknowledging social dominance status. We investigated whether peering meets the published criteria for a formal signal of subordination in five captive groups of bonobos. The degree of linearity in the set of peering relationships was significantly high in all study groups, and a linear rank order was found. However, unidirectionality was low, and there was little correspondence between the peering order and the agonistic dominance rank. Therefore, peering does not satisfy the criteria of a formal subordination indicator. We also studied the relation between peering and agonistic dominance rank, age, and sex. Animals directed peering significantly more often at high-ranking animals in four of the groups. We suggest that peering is indirectly related to dominance rank by the resource-holding potential of individuals. In contexts where dominant individuals can monopolize resources, peerers may direct their attention at those high-ranking animals. When resources are distributed more evenly, high-ranking animals may peer down the hierarchy. We speculate on the reasons why a formal dominance or subordination signal appears to be absent in bonobos.


Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma.
Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163-, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.


Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5-fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β-oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon-like peptide 1 receptor (GLP-1) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, peroxisome proliferator-activated receptor (PPAR-γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology-this is likely to be achieved with a combinatorial approach.


Olanzapine interactions with nicotine and mecamylamine in rats: effects on memory function.
Olanzapine is a widely used atypical antipsychotic drug. It is quite effective in reducing psychotic symptoms. However, the syndrome of schizophrenia encompasses more than psychosis. There is a pronounced cognitive impairment among other negative neurobehavioral symptoms. Classic antipsychotic drugs such as haloperidol do not alleviate cognitive impairment associated with schizophrenia and have been shown to exacerbate the dysfunction. The atypical antipsychotic drugs have a different profile of receptor actions and may have a different array of actions on cognitive function. The purpose of the current studies was to determine the effects of olanzapine on working memory function as measured by choice accuracy in the radial-arm maze. In determining the cognitive effects of any antipsychotic drug it is critical to determine its interactions with nicotinic manipulations since the great majority of people with schizophrenia smoke cigarettes and alterations in nicotinic receptors have been found in people with schizophrenia. Olanzapine caused a significant working memory impairment. Nicotine attenuated olanzapine-induced memory deficits. It may be the case that nicotinic co-treatment will be useful in addressing the cognitive impairment of schizophrenia.


Measuring perceived harmfulness of physical activities in patients with chronic low back pain: the Photograph Series of Daily Activities--short electronic version.
Cognitive-behavioral models of chronic low back pain (CLBP) predict that dysfunctional assumptions about the harmfulness of activities may maintain pain-related fear and disability levels. The Photograph Series of Daily Activities (PHODA) is an instrument to determine the perceived harmfulness of daily activities in patients with CLBP. This study examined the psychometric properties of a short electronic version of the PHODA (PHODA-SeV). The results show that the PHODA-SeV measures a single factor and has a high internal consistency. The test-retest reliability and stability of the PHODA-SeV over a 2-week time interval are good, with discrepancies between 2 measurements over 20 points suggesting true change. The construct validity is supported by the finding that both self-reported pain severity and fear of movement/(re)injury were uniquely related to the PHODA-SeV. Validity is further corroborated by the finding that patients who have received exposure in vivo, that aimed to systematically reduce the perceived harmfulness of activities, had significantly lower PHODA-SeV scores after treatment than patients receiving graded activity that did not address these assumptions. The findings support the PHODA-SeV as a valid and reliable measure of the perceived harmfulness of activities in patients with CLBP. Preliminary normative data of the PHODA-SeV are presented. This article describes a pictorial measurement tool (PHODA-SeV) for the assessment of the perceived harmfulness of activities in patients with chronic low back pain. The PHODA-SeV has good psychometric properties and can be used to elaborate on the contribution of beliefs about harmful consequences of activities to pain and disability.


Activation of the nigrostriatal dopaminergic pathway by injection of cholera enterotoxin into the substantia nigra.
Twenty-four hours after unilateral injection of cholera enterotoxin into the rat substantia nigra there is an increase, in the striatum on the injected side, of basal adenylate cyclase activity, 3,4-dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylacetic acid. Moreover, there is an increase of motor activity, and rats tend to circle contralateral to the side of the injection. Injection of cholera enterotoxin into brain nuclei may be a useful procedure for pharmacologically activating selected neuronal systems of brain and for studying the pharmacology of drugs that are suspected of interacting with these systems.


Attracting managed care. Eight tips for working with a managed care provider.
Managed care organizations won't work with a facility unless it offers what they need. These eight tips--and one case study--outline the key procedural changes and adjustments in attitude longterm care providers are making to accommodate managed care.


Booming markets for Moroccan argan oil appear to benefit some rural households while threatening the endemic argan forest.
Morocco's argan oil is now the most expensive edible oil in the world. High-value argan markets have sparked a bonanza of argan activity. Nongovernmental organizations, international and domestic development agencies, and argan oil cooperatives aggressively promote the win-win aim of simultaneously benefiting local people and the health of the argan forest. This paper tests some of these win-win claims. Analysis of a panel of detailed household data suggests that the boom has enabled some rural households to increase consumption, increase their goat herds (which bodes poorly for the argan forest), and send their girls to secondary school. The boom has predictably made households vigilant guardians of fruit on the tree, but it has not incited investments in longer term tree and forest health. We evaluate landscape-level impacts of these changes using commune-level data on educational enrollment and normalized difference vegetation index data over the period from 1981 to 2009. The results of the mesoanalysis of enrollment are consistent with the microanalysis: the argan boom seems to have improved educational outcomes, especially for girls. Our normalized difference vegetation index analysis, however, suggests that booming argan prices have not improved the forest and may have even induced degradation. We conclude by exploring the dynamic interactions between argan markets, local institutions, rural household welfare, and forest conservation and sustainability.


The development and classification accuracy of the life assessment questionnaire in the detection of pain-related malingering.
This paper describes three phases of the development and validation of the Life Assessment Questionnaire (LAQ), a multi-scale inventory for assessing potential malingering in adults reporting chronic pain. Study 1 involved scale construction and item analysis. Discriminant validity was investigated in Study 2 by comparing scores for the clinical reference group with participants instructed to simulate chronic pain. Study 3 examined the convergent validity of the LAQ with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Behavioral Assessment of Pain (BAP). Results revealed that the simulation groups scored significantly higher than the clinical reference group across all scales. Receiver operating characteristic analysis revealed sensitivity and specificity scores ranging from 0.44 to 0.57 and 0.88 to 0.93, respectively. Positive predictive power values ranged between 0.79 and 0.88. Strong convergent validity was found for the LAQ. These studies demonstrated the effectiveness of the LAQ in classifying individuals who feign pain complaints, supporting the utility of the LAQ for reaching conclusions about the presence of malingering.


CT and MR imaging findings of ocular adnexal mucosa-associated lymphoid tissue lymphoma associated with IgG4-related disease: multi-institutional case series.
To report CT and MR imaging findings of ocular adnexal mucosa-associated lymphoid tissue lymphoma associated with IgG4-related disease (IgG4-MALT lymphoma), a rare but clinically important complication of ocular adnexal IgG4-related disease. We retrospectively reviewed all cases of histologically confirmed ocular adnexal IgG4-related disease at three tertiary and one secondary referral centers, between February 2003 and December 2016. Seven cases of histopathologically diagnosed IgG4-MALT lymphoma were identified. CT and MR images were analyzed by consensus of two experienced head and neck radiologists. Lacrimal glands were the main site of involvement in all seven patients. The lesions typically showed well-demarcated margins, iso- to hyperattenuation on precontrast CT, T2 hypo- to isointensity, T1 isointensity, and homogenous internal architecture with homogenous enhancement pattern. Lesions were mostly hyperdense and isointense to normal extraocular muscles on postcontrast CT and MR images, respectively. Unlike in typical ocular adnexal IgG4-related disease, T2 isointensity and hyperattenuation on precontrast CT images were noted in some IgG4-MALT lymphoma cases. Although the findings may be nonspecific, the possibility of accompanying MALT lymphoma may need to be considered, when ocular adnexal lesions in patients clinically suspected of having IgG4-related disease are refractory to glucocorticoids and show T2 isointensity and hyperattenuation on precontrast CT for the optimal management of the patients. However, this is a case series of a very rare complication of ocular adnexal IgG4-related disease, and thus caution is warranted to generalize the conclusion.


Epworth sleepiness scale is associated with increased striatal dopamine uptake in Parkinson's disease: a cross-sectional study.
A cross-sectional study was designed to investigate the possible association between Epworth sleepiness scale (ESS) scores and striatal dopamine uptake in the early stages of Parkinson's disease (PD). Two groups of PD patients (n = 464) and healthy controls (HC) (n = 162) were enrolled in the current study from the Parkinson's progression markers initiative cohort ( https://www.ppmi-info.org ). All the subjects were evaluated for excessive daytime sleepiness (EDS) using the ESS. They also completed specific measures to be assessed for motor and non-motor symptoms, including cognitive, gait, autonomic, and olfactory dysfunction. Dopamine transporter (DaT) scans were used to identify dopamine transporter impairments. Spatial normalization for DaTscan imaging of participants was performed to reach consistent orientation. A significant correlation was found between ESS score and right putamen (P < 0.001; correlation coefficient = 0.186) and left putamen (P = 0.003; correlation coefficient = 0.139) dopamine uptake in PD patients. The same results were revealed after adjusted Pearson's correlation for the effects of handedness, age, gender, and education. No significant correlation was found between the ESS score and the amount of caudate nucleus dopamine uptake in PD patients. Moreover, there was a significant association between caudate nucleus dopamine uptake and ESS score in neither PD patients nor HCs. The results of our study suggest that increased dopaminergic function of putamen nuclei may be associated with ESS scores in the early stages of PD. Further studies are needed at different PD stages and evaluate PD progression as a possible confounder.


Brain shape regression components.
Identifying associations between the shape properties of brain regions, measured from magnetic resonance imaging (MRI), and numerical measures of neurodegenerative disease burden can clarify whether disease processes lead to distinctive spatial patterns of brain atrophy. However, prior methods for identifying such associations between shape and clinical variables either failed to summarize shape patterns into a concise set of summary measurements, or risked failing to discover such associations by extracting summary shape features blinded to the clinical variables. We present a method that overcomes these limitations by directly searching for a small set of linear shape features--shape regression components--that simultaneously account for a large amount of population shape variability and are highly correlated with a numerical clinical variable of interest. When applied to hippocampi of 299 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, the method identified correlations between hippocampal atrophy and markers of AD pathology and cogniton that were stronger than, and covered a more extended spatial region than, those identified by competing approaches.


Phase II diaziquone-based chemotherapy trials in patients with anaplastic supratentorial astrocytic neoplasms.
We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.


Metagenomic analysis identified microbiome alterations and pathological association between intestinal microbiota and polycystic ovary syndrome.
To identify different microbial species in women with polycystic ovary syndrome (PCOS) and reveal a possible relationship between gut dysbiosis and pathological changes. Cross-sectional study. Academic institution. Reproductive-aged women with PCOS (n = 14) and controls (n = 14) from the Centre for Reproductive Medicine. Shotgun metagenomic sequencing on fecal samples from patients, and clinical parameters (including body mass index, endocrine hormone levels, and glycemia level) gathered for correlation analysis. Identification of different gut microbial strains and relativity between microbiota and clinical parameters. We found several microbial strains were statistically significantly more abundant in the PCOS group, including Parabacteroides merdae, Bacteroides fragilis, and strains of Escherichia and Shigella, whereas Faecalibacterium prausnitzii was enriched in the control group. Metagenomic species (MGS) analysis revealed that the microbes of the PCOS group were negatively correlated with those of the control group. Of note, we observed a positive correlation between MGS relevant to PCOS and endocrine disorders, including body mass index and elevated levels of serum testosterone, luteinizing hormone, and antimüllerian hormone. Functional alterations, reflected by Kyoto Encyclopedia of Genes and Genomes orthologues, could imply potential mechanisms of microbial involvement in the developmental progress of PCOS. Our findings suggest an intimate association and potential mechanisms linking microbial dysbiosis and the pathophysiologic changes of PCOS. We address the importance of monitoring and modulating microbial composition and functional shifts in future clinical practice.


Search strategies of ants in landmark-rich habitats.
Search is an important tool in an ant's navigational toolbox to relocate food sources and find the inconspicuous nest entrance. In habitats where landmark information is sparse, homing ants travel their entire home vector before searching systematically with ever increasing loops. Search strategies have not been previously investigated in ants that inhabit landmark-rich habitats where they typically establish stereotypical routes. Here we examine the search strategy in one such ant, Melophorus bagoti, by confining their foraging in one-dimensional channels to determine if their search pattern changes with experience, location of distant cues and altered distance on the homebound journey. Irrespective of conditions, we found ants exhibit a progressive search that drifted towards the fictive nest and beyond. Segments moving away from the start of the homeward journey were longer than segments heading back towards the start. The right tail distribution of segment lengths was well fitted by a power function, but slopes less than -3 on a log-log plot indicate that the process cannot be characterized as Lévy searches that have optimal slopes near -2. A double exponential function fits the distribution of segment lengths better, supporting another theoretically optimal search pattern, the composite Brownian walk.


WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors.
About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF(V600E/K)) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFi-resistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.


Quantum double pendulum: study of an autonomous classically chaotic quantum system.
A numerical study of the quantum double pendulum is conducted. A suitable quantum scaling is found which allows us to have as the only parameters the ratios of the lengths and masses of the two pendula and a (quantum) gravity parameter containing Planck's constant. Comparison with classical and semiclassical results is used to understand the behavior of the energy curves of the levels, to define regimes in terms of the gravity parameter, and to classify the (resonant) interactions among levels by connecting them to various classical phase space structures (resonance islands).


Minimal interruption of cardiopulmonary resuscitation for a single shock as mandated by automated external defibrillations does not compromise outcomes in a porcine model of cardiac arrest and resuscitation.
Current automated external defibrillations require interruptions in chest compressions to avoid artifacts during electrocardiographic analyses and to minimize the risk of accidental delivery of an electric shock to the rescuer. The earlier three-shock algorithm, with prolonged interruptions of chest compressions, compromised outcomes and increased severity of postresuscitation myocardial dysfunction. In the present study, we investigated the effect of timing of minimal automated external defibrillation-mandated interruptions of chest compressions on cardiopulmonary resuscitation outcomes, using a single-shock algorithm. We hypothesized that an 8-sec interruption of chest compressions for a single shock, as mandated by automated external defibrillations, would not impair initial resuscitation and outcomes of cardiopulmonary resuscitation. Randomized prospective animal study. University affiliated research laboratory. Domestic pigs. In 24 domestic male pigs weighing 41 +/- 2 kg, ventricular fibrillation was induced by left anterior descending coronary artery occlusion and untreated for 7 min. Cardiopulmonary resuscitation, including chest compressions and ventilation with oxygen, was then performed for an interval of 2 min before attempted defibrillation. Animals were randomized into three groups: A) interruption immediately before defibrillation; B) interruption after 1 min of cardiopulmonary resuscitation; or C) no interruption. Chest compressions were delivered with the aid of a mechanical chest compressor at a rate of 100 compressions/min and compression/ventilation ratio of 30:2. Defibrillation was attempted with a single biphasic 150-J shock. Each animal was successfully resuscitated and survived for >72 hr. No differences in the number of shocks before return of spontaneous circulation, frequency of recurrent ventricular fibrillation, duration of cardiopulmonary resuscitation, and severity of postresuscitation myocardial dysfunction were observed. In this experimental model of cardiac arrest and cardiopulmonary resuscitation, minimal automated external defibrillation-mandated interruption of chest compressions for a single-shock algorithm did not have adverse effects on postresuscitation myocardial or neurologic function. All animals, whether subjected to cardiopulmonary resuscitation interruptions or not, survived.


Desulfosporosinus meridiei sp. nov., a spore-forming sulfate-reducing bacterium isolated from gasolene-contaminated groundwater.
Eight strains of spore-forming, sulfate-reducing bacteria, isolated from groundwater contaminated with motor fuel [mostly benzene, toluene ethylbenzene and xylene (BTEX) compounds] in sandy soil near Perth, Australia, were closely related to Desulfosporosinus (previously Desulfotomaculum) orientis DSM 765T (95.3-97.3% 16S rDNA sequence similarity). Whole-cell fatty acids were dominated by even-carbon, straight-chain saturated and mono-unsaturated fatty acids, in particular 16:0, 16:1cis9, 14:0 and 18:1cis11. The strains grew at temperatures between 4 and 42 degrees C and in medium containing up to 4% NaCl. The eight strains clustered into two main groups based on phylogeny, randomly amplified polymorphic DNA (RAPD)-PCR patterns and nutritional characteristics. Representatives of the two groups, strain S5 (group A) and strain S10T (group B) had 81% DNA-DNA homology with each other and therefore should be accommodated in the same species. Strain S10T had less than 38% homology with Desulfosporosinus orientis DSM 765T, the most closely phylogenetically related type strain available. The new strains were distinguished from Desulfosporosinus orientis DSM 765T by different banding patterns in a RAPD-PCR, and phenotypically by their inability to utilize fumarate as a carbon and energy source with sulfate as the electron acceptor and by their lower tolerance to NaCl. The DNA G+C contents were 46.8 and 46.9 mol% for strains S5 and S10T, respectively (Desulfosporosinus orientis DSM 765T 45.9 mol%). It is proposed that these new strains be placed in a new species of the genus Desulfosporosinus. The name Desulfosporosinus meridiei is proposed, with strain S10T as the type strain (= DSM 13257T = NCIMB 13706T).


[Circulating immune complexes and apolipoproteins in ischemic heart disease].
Levels of circulating immune complexes (CIC) and apolipoproteins (apo-A and apo-B) were compared and correlated with the severity of atherosclerotic affection of heart vessels in coronary patients with coronarographically-verified coronary arterial atherosclerosis. An inverse correlation between blood CIC and apo-A levels, and a direct correlation between the CIC level and the apo-B/apo-A index were demonstrated. The variation of CIC levels in patients with atherosclerotic lesions of varying severity corresponded to that of the apo-B/apo-A index. The correlation of these parameters was particularly significant in coronary patients with 2 coronary vessels affected.


Adropin is a brain membrane-bound protein regulating physical activity via the NB-3/Notch signaling pathway in mice.
Adropin is a highly conserved polypeptide that has been suggested to act as an endocrine factor that plays important roles in metabolic regulation, insulin sensitivity, and endothelial functions. However, in this study, we provide evidence demonstrating that adropin is a plasma membrane protein expressed abundantly in the brain. Using a yeast two-hybrid screening approach, we identified NB-3/Contactin 6, a brain-specific, non-canonical, membrane-tethered Notch1 ligand, as an interaction partner of adropin. Furthermore, this interaction promotes NB3-induced activation of Notch signaling and the expression of Notch target genes. We also generated and characterized adropin knockout mice to explore the role of adropin in vivo. Adropin knockout mice exhibited decreased locomotor activity and impaired motor coordination coupled with defective synapse formation, a phenotype similar to NB-3 knockout mice. Taken together, our data suggest that adropin is a membrane-bound protein that interacts with the brain-specific Notch1 ligand NB3. It regulates physical activity and motor coordination via the NB-3/Notch signaling pathway and plays an important role in cerebellum development in mice.


Selective trapping of multiple particles by volume speckle field.
We suggest a new approach for selective trapping of light absorbing particles in gases by multiple optical bottle-beam-like traps created by volume speckle field. We demonstrate stable simultaneous confinement of a few thousand micro-particles in air with a single lowpower laser beam. The size distribution of trapped particles exhibits a narrow peak near the average size of an optical speckle. Thus, the speckleformed traps act as a sieve with the holes selecting particles of a similar size.


Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities.
Seventy-nine acute myeloid leukemias (AML) and myelodysplastic syndromes without cytogenetic evidence of 12p aberrations were investigated by fluorescence in situ hybridization with probes for ETV6 and CDKN1B (previously called TEL and KIP1, respectively) to ascertain whether abnormalities of these genes are frequently undetected by standard chromosome banding analyses and, if so, whether they are associated with specific karyotypic patterns and morphologic features. One of sixty cytogenetically aberrant myeloid malignancies, an AML with a complex karyotype including del(5q) and del(20q), showed a hemizygous interstitial deletion of the ETV6 and CDKN1B loci. No concomitant rearrangement of the other ETV6 allele was detected. Two of nineteen cytogenetically normal AML displayed a hemizygous interstitial deletion involving CDKN1B, but not ETV6. Thus, cryptic deletions of these genes seem to be rare in cytogenetically abnormal myeloid malignancies without 12p aberrations (2%), whereas they may be more frequent in karyotypically normal AML (10%). Furthermore, the present findings show that the deletions may be narrow, not including the ETV6 gene, and indirectly suggest that CDKN1B, or a closely located genomic segment, is the target of 12p deletions.


Endovascular treatment of popliteal artery segments P1 and P2 in patients with critical limb ischemia: initial experience using a helical nitinol stent with increased radial force.
To evaluate efficacy, safety, and midterm patency of a helical, self-expanding nitinol stent after failed percutaneous transluminal angioplasty (PTA) of popliteal artery segments P1 and P2 in patients with chronic critical limb ischemia (CLI) or lifestyle-limiting claudication. Between February 2009 and March 2011, 40 patients (23 men; mean age 77±10 years) classified as Rutherford category 3 (n = 10) or 4/5 (n = 30) underwent PTA of the proximal and mid popliteal artery followed by implantation of a SUPERA stent for elastic recoil, residual stenosis, or flow-limiting dissection. All patients had an elevated operative risk. Before and after the procedure and during the 12-month follow-up, a clinical investigation, ankle-brachial-index (ABI) measurement, and color-coded duplex sonography and/or digital subtraction angiography were performed. Primary endpoints were limb salvage and anatomical patency at 12 months. Stent implantation was successful in all patients. The major complication rate was 7.5% (an access-site pseudoaneurysm, 2 retroperitoneal hematomas, and 1 death from retroperitoneal bleeding). Mean follow-up was 15.9 months (range 0.5-27.9). The mean baseline ABI of 0.37 significantly increased to 0.91 at 12 months (p<0.01). Three (7.5%) patients underwent bypass surgery owing to lack of clinical improvement (<0.10 improvement in ABI). Primary and secondary patency rates at 12 months in the 34 patients eligible for follow-up were 68.4% and 79.8%, respectively. The major amputation rate was 5% at 1 year. Five (12.5%) in-stent stenoses and 1 of 2 (5.0%) in-stent occlusions were successfully recanalized (the second occlusion was asymptomatic). Implantation of this helical stent into segments of the popliteal artery at the knee joint in CLI patients is a safe and clinically effective bailout method with acceptable intermediate patency.


Complement and the atypical hemolytic uremic syndrome in children.
Over the past decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the regulation of the complement alternative pathway. Among approximately 200 children with the disease, reported in the literature, 50% had mutations of the complement regulatory proteins factor H, membrane cofactor protein (MCP) or factor I. Mutations in factor B and C3 have also been reported recently. In addition, 10% of children have factor H dysfunction due to anti-factor H antibodies. Early age at onset appears as characteristic of factor H and factor I mutated patients, while MCP-associated HUS is not observed before age 1 year. Low C3 level may occur in patients with factor H and factor I mutation, while C3 level is generally normal in MCP-mutated patients. Normal plasma factor H and factor I levels do not preclude the presence of a mutation in these genes. The worst prognosis is for factor H-mutated patients, as 60% die or reach end-stage renal disease (ESRD) within the first year after onset of the disease. Patients with mutations in MCP have a relapsing course, but no patient has ever reached ESRD in the first year of the disease. Half of the patients with factor I mutations have a rapid evolution to ESRD, but half recover. Early intensive plasmatherapy appears to have a beneficial effect, except in MCP-mutated patients. There is a high risk of graft loss for HUS recurrence or thrombosis in all groups except the MCP-mutated group. Recent success of liver-kidney transplantation combined with plasmatherapy opens this option for patients with mutations of factors synthesized in the liver. New therapies such as factor H concentrate or complement inhibitors offer hope for the future.


Irrigation protocol among endodontic faculty and post-graduate students in dental colleges of India: A survey.
Irrigation protocol is the most critical step during the disinfection of an infected root canal system. The purpose of this study was to determine the root canal irrigation trends being practiced among the endodontic teaching faculty and post-graduate students in the dental colleges present in India. A postal invitation to participate in this national survey was sent to the Department of Conservative Dentistry and Endodontic of 294 Dental Colleges present in India. A total of 2389 forms were successfully delivered out of which 794 duly filled forms were received back. Survey participants were asked about their irrigant selection, irrigant concentration, smear layer removal protocol, and use of adjuncts during irrigation. This survey elicited a positive response rate of 33.23%. Our data indicated that 92.8% of respondents use sodium hypochlorite (NaOCl) as the primary endodontic irrigant, with 26 gauge needle being most preferred for syringe irrigation, with 49.3% of them using it at a concentration of 2.6-4.0%. 68% of our respondents aim to remove the smear layer during the endodontic treatment while 47% reported using ultrasonic activation as an adjunct during their irrigation protocol. The findings of this survey are that the majority of teaching institutions in India are employing NaOCl (2.6-4.0%) as the primary endodontic irrigant. The concept of smear layer removal is high (68%), and there is a general trend (78%) to modify the irrigation protocol according to the status of the pulp, status of the periapex and in retreatment cases.


Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection.
Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.


Virus-neutralizing antibodies to hepatitis B virus: the nature of an immunogenic epitope on the S gene peptide.
Using a murine monoclonal antibody (RF-HBs-1) which has been shown to be capable of neutralizing both ad and ay subtypes of hepatitis B virus (HBV), we have devised a competitive inhibition assay to measure the presence of virus-neutralizing antibodies in the sera of patients who have recovered from acute type B hepatitis. The majority of patients have this antibody in their serum. We also show that this antibody inhibits the binding of polymerized human serum albumin (pHSA) to the pHSA receptor site of the HBV particle, which has been proposed as an important site for the entry of HBV into liver cells. We have demonstrated that the epitope recognized by this antibody is dependent on the linkage of 24,000 and 28,000 mol. wt. polypeptides via a disulphide bond. This conformational determinant in the coat of the virus which is part of or near to the pHSA binding site is important in evoking a virus-neutralizing response.


Dipalmitoylphosphatidic acid inhibits tumor growth in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis, accounting for approximately 12-24% of breast cancer cases. Accumulating evidence has indicated that there is no effective targeted therapy available for TNBC. Dipalmitoylphosphatidic acid (DPPA) is a bioactive phospholipid. However, the function of DPPA in the growth of TNBC has not yet been studied. In this study, we employed TNBC cells and a subcutaneous tumor model to elucidate the possible effect of DPPA on tumor growth in TNBC. We showed that DPPA significantly inhibited tumor growth in the mouse subcutaneous tumor model and suppressed cell proliferation and angiogenesis in TNBC tumor tissues. This inhibition was mediated partly by suppressing the expression of cyclin B1 (CCNB1), which directly promoted the accumulation of cells in the G2 phase and arrested cell cycle progression in human TNBC. In addition, the inhibition of tumor growth by DPPA may also be mediated by the suppression of tumor angiogenesis in TNBC. This work provides initial evidence that DPPA might be vital as an anti-tumor drug to treat TNBC.


Comparing the processes: accreditation and recognition.
Diabetes education programs are developed to serve the diabetes community by offering quality education that meets a set of standards and is then eligible for third-party insurance reimbursement. Three organizations are authorized by the U.S. Centers for Medicare and Medicaid Services to determine whether diabetes education programs meet required standards. Each of the three relies on the 2007 edition of the National Standards for Diabetes Self-Management Education. This article summarizes similarities among and unique qualities of each of the organization's approaches to assuring quality.


Perturbation of Conformational Dynamics of ASCUT-1 from Ascaris lumbricoides by Temperature and Sodium Dodecyl Sulfate.
ASCUT-1 is a protein found in cuticlin, the insoluble residue of the cuticles of the nematode Ascaris lumbricoides. It contains the CUT-1-like domain which is shared by members of a novel family of components of extracellular matrices. The monomeric form of ASCUT-1 contains a single tryptophan residue. An understanding of the structure-function relationship of the protein under different chemical-physical conditions is of fundamental importance for an understanding of its structure and function in cuticles. In this paper we report the effect of the temperature and sodium dodecyl sulfate on the structural stability of this protein. The structure of the protein was studied in the temperature range 25-85°C in the absence and in the presence of sodium dodecyl sulfate by frequency-domain measurements of the intrinsic fluorescence intensity and anisotropy decays. The time-resolved fluorescence data in the absence of SDS indicated that the tryptophanyl emission decays were well described by a bimodal lifetime distribution, and that the temperature increases resulted in the sharpening and in the shortening of the tryptophanyl lifetime distribution. In the presence of SDS an unimodal fluorescence lifetime distribution as well as a marked decrease in the anisotropy decay values were observed.


HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.
Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.


Heat Transfer Enhancement in Tree-Structured Polymer Linked Gold Nanoparticle Networks.
Human brains use a tree-like neuron network for information processing at high efficiency and low energy consumption. Tree-like structures have also been engineered to enhance mass and heat transfer in various applications. In this work, we reveal the heat transfer mechanism in tree-structured polymer linked gold nanoparticle (AuNP) networks using atomistic simulations. We report both upward and downward heat fluxes between root and leaf nodes in tree-structured polyethylene (PE) and poly(p-phenylene) (PPP) linked AuNP networks at tree levels from 1 to 5. We found that the heat conductance increases with an increasing polymer tree level. The heat transfer enhancement is due to the resulting increase in the low-frequency vibrational modes. This and other thermal properties are affected by the location of the AuNPs in the tree. Moreover, complex tree structures with at least five levels were found to be robust in the sense that disabling half of the leaves did not change the overall heat conductance.


Homopolar dihydrogen bonding in main group hydrides: discovery, consequences, and applications.
This perspective describes the recent discovery and investigation of homopolar dihydrogen bonding, and focuses on the identification and characterisation of hydride-hydride interactions in compounds of the main group elements. A highlight of this programme has been an appreciation of the important role played by this interaction in the structural and thermochemical properties of these materials, and in the mechanisms through which they release hydrogen. A fuller understanding of this new class of H∙∙∙H interactions has also allowed us to explore their role in the supramolecular chemistry of hydrogen-rich compounds.


Measuring cerebrovascular reactivity: what stimulus to use?
Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.


A template and catalyst-free metal-etching-oxidation method to synthesize aligned oxide nanowire arrays: NiO as an example.
Although NiO is one of the canonical functional binary oxides, there has been no report so far on the effective fabrication of aligned single crystalline NiO nanowire arrays. Here we report a novel vapor-based metal-etching-oxidation method to synthesize high-quality NiO nanowire arrays with good vertical alignment and morphology control. In this method, Ni foils are used as both the substrates and the nickel source; NiCl(2) powder serves as the additional Ni source and provides Cl(2) to initiate mild etching. No template is deliberately employed; instead a nanograined NiO scale formed on the NiO foil guides the vapor infiltration and assists the self-assembled growth of NiO nanowires via a novel process comprising simultaneous Cl(2) etching and gentle oxidation. Furthermore, using CoO nanowires and Co-doped NiO as examples, we show that this general method can be employed to produce nanowires of other oxides as well as the doped counterparts.


Effect of diode laser irradiation on the bond strength of polymerized non-simplified adhesive systems after 12 months of water storage.
The aim of this in vitro study was to evaluate the bonding strength of non-simplified dentin bonding systems (DBS) to dentin irradiated with a diode laser (970 nm) immediately and after 12 months of water storage following either primer or bond application. The experimental design included three different factors: DBS type [AdperTM Scotchbond Multipurpose (MP) and Clearfil™ SE Bond (CSE)], irradiation [without irradiation - control (C), irradiation after primer application (AP), and irradiation after bond application (AB)], and time [initial (I) and after 12 months of water storage (12 m)]. Sixty sound human third molars (n = 10) were obtained, and their flat occlusal dentin areas were prepared and standardized. Laser irradiation was performed in the contact mode perpendicular to the dental surface over an automatically selected scanning area at a pulse energy of 0.8 W, frequency of 10 Hz, and energy density of 66.67 J/cm2. After 7 days of treatment, the specimens were cut, and half of them were subjected to microtensile testing (500 N/0.05 mm/min), whereas the remaining sticks were examined after 12 months of water storage. The obtained data were analyzed by three-way analysis of variance (ANOVA) followed by a Tukey test (p<0.05). The observed fracture modes were investigated using a portable digital microscope with a magnification of 40x. Among the utilized DBS, MP generally exhibited higher bond strengths, but did not always differ from CSE under similar conditions. The irradiation factor was statistically significant only for the MP/AB groups. After 12 months of storage, all groups demonstrated a significant reduction in the bond strength, whereas the results of fracture analysis showed a predominance of the adhesive type. The laser treatment of non-simplified DBS was not able to stabilize their bonding characteristics after 12 months.


Neurotoxic morphological changes induced in the medial prefrontal cortex of rats behaviorally sensitized to methamphetamine.
The present study examined whether the development in rats of behavioral sensitization to methamphetamine (MAP) is related to the development of neurotoxic morphological changes presumably induced in the medial prefrontal cortex (MFC). Male rats were intraperitonieally injected with MAP (5 mg/kg) once a day for 12 days (day 1-day 12), and then the drug was withdrawn for 7-42 days (WD7-WD42). The MAP- treatment caused hypersensitivity of a successive head-movement stereotypy, which reached a basic plateau level on day 4, and rose successively to a higher level by day 12. Morphological changes were histochemically and morphometrically examined in the MFC. In the strata covering layers II and III, the densities of tyrosine hydroxylase (TH)-immunoreactive axons decreased on a daily basis to 50% of the control on day 4 and then to 40% on days 6 and 12. The densities of dopamine-,beta-hydroxylase (DBH)-immunoreactive axons did not change during the injection period. A few TUNEL-positive cells were observed in a unit area (0.25 mm2) covering layers II-V on day 6 and they increased to 19 and 16 on day 12 and WD7, respectively. These observations demonstrate a role for the neurotoxic changes in the MFC in the processes of behavioral sensitization of a stereotypy to a low dose of MAP.


Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase.
Phosphatidylglycerol (PG) is an important membrane polyglycerolphospholipid required for the activity of a variety of enzymes and is a precursor for synthesis of cardiolipin and bis(monoacylglycerol) phosphate. PG is subjected to remodeling subsequent to its de novo biosynthesis to incorporate appropriate acyl content for its biological functions and to prevent the harmful effect of lysophosphatidylglycerol (LPG) accumulation. The enzymes involved in the remodeling process have not yet been identified. We report here the identification and characterization of a human gene encoding an acyl-CoA: lysophosphatidylglycerol acyltransferase (LPGAT1). Expression of the LPGAT1 cDNA in Sf9 insect and COS-7 cells led to a significant increase in LPG acyltransferase activity. In contrast, no significant acyltransferase activities were detected against glycerol 3-phosphate or a variety of lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylserine. The recombinant human LPGAT1 enzyme recognized various acyl-CoAs and LPGs as substrates but demonstrated clear preference to long chain saturated fatty acyl-CoAs and oleoyl-CoA as acyl donors, which is consistent with the lipid composition of endogenous PGs identified from different tissues. Kinetic analyses of LPGAT1 expressed in COS-7 cells showed that oleoyl-LPG was preferred over palmitoyl-LPG as an acyl receptor, whereas oleoyl-CoA was preferred over lauroyl-CoA as an acyl donor. Consistent with its proposed microsomal origin, LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. Northern blot analysis indicated that the human LPGAT1 was widely distributed, suggesting a dynamic functional role of the enzyme in different tissues.


Childhood immunisation.
Primary care practitioners play an important role in administering and advocating childhood vaccination to protect our children against infectious diseases and to ensure herd immunity in our population. Primary care practitioners may encounter children who present out-of-schedule, as well as children who come for vaccination with intercurrent illnesses, egg or other allergies, or are on long-term medications. This article describes the approach to these issues and present useful resources and references that primary care practitioners can access.


Manifestations of relapsing Epstein-Barr virus illness.
The Epstein-Barr Virus is well known for its pattern of communicability and features of clinical disease. It is a member of the herpes virus family and may establish a latency state in infected individuals. Characteristics of latency and reactivation have been well defined for both herpes and varicella. The Epstein-Barr Virus has been shown to establish a latency state within B lymphocytes, salivary gland epithelium, and oropharyngeal epithelial cells. Reactivation of the virus from these sites could produce relapse of EBV illness. Characteristics of relapse are described in this report.


Control of Calcium Phosphate Nucleation and Transformation through Interactions of Enamelin and Amelogenin Exhibits the "Goldilocks Effect".
Although amelogenin comprises the vast majority of the matrix that templates calcium phosphate nucleation during enamel formation, other proteins, particularly enamelin, are also known to play an important role in the formation of enamel's intricate architecture. However, there is little understanding of the interplay between amelogenin and enamelin in controlling processes of mineral nucleation and growth. Here, we used an in vitro model to investigate the impact of enamelin interaction with amelogenin on calcium phosphate nucleation for a range of enamelin-to-amelogenin ratios. We found that amelogenin alone is a weak promoter of nucleation, but addition of enamelin enhanced nucleation rates in a highly nonlinear, nonmonotonic manner reaching a sharp maximum at a ratio of 1:50 enamelin/amelogenin. We provide a phenomenological model to explain this effect that assumes only isolated enamelin proteins can act as sites of enhanced nucleation, while enamelin oligomers cannot. Even when interaction is random, the model reproduces the observed behavior, suggesting a simple means to tightly control the timing and extent of nucleation and phase transformation by amelogenin and enamelin.


Correlation of autoantibodies against BP180/BP230 in response to topical corticosteroids in patients with bullous pemphigoid.
Topical steroids are effective in treating bullous pemphigoid (BP). Autoantibodies against BP180 are related to disease activity, but correlation of these autoantibodies with response to topical steroid therapy has not yet been clearly evaluated. We investigate the usefulness of close and early monitoring of autoantibodies against BP180 and BP230 for assessment of response to therapy and early detection of therapeutic failure in BP patients treated topically. In eight BP patients under treatment with topical or systemic steroid therapy we retrospectively evaluated clinical course and autoantibodies against BP180 and BP230 as well as indirect immunofluorescence titres (IIF). Data were included at diagnosis, during hospitalization and follow-ups. Autoantibodies against BP180 parallel disease activity in all topically and as well as systemically treated patients. Autoantibodies against BP230 correlated in five out of eight patients. Autoantibodies directed against BP180 and, to a lesser degree, against BP230 correlate with the clinical course of topically treated BP patients. Monitoring autoantibodies against BP180 is a useful tool to evaluate the efficacy of topical therapy in BP.


Route learning impairment associated with encephalomalasia secondary to traumatic brain injury: a case report.
Topographical disorientation is marked by difficulty finding one's way in familiar or new environments. The present case study reports findings from a 30-year-old male with encephalomalasia of the left parahippocampal region secondary to brain trauma with subsequent difficulty in learning of new routes. His navigation in premorbidly known (familiar) surroundings was intact. Magnetic resonance images revealed left parahippocampal and bilateral occipital encephalomalasia. Neuropsychological screening showed impairment in structuring a representation of the spatial relationships among landmarks with relatively preserved ability to learn visual and verbal information of these landmarks. Decreased visual perception and inappropriate visual inputs due to cervical dystonia and right homonymous hemianopsia also appear to play a role in his disability. The current knowledge about the neuronal systems involved in visual cognition and topographical orientation also are addressed in this report.


Are the acute effects of particulate matter on mortality in the National Morbidity, Mortality, and Air Pollution Study the result of inadequate control for weather and season? A sensitivity analysis using flexible distributed lag models.
Time-series studies have linked daily variations in nonaccidental deaths with daily variations in ambient particulate matter air pollution, while controlling for qualitatively larger influences of weather and season. Although time-series analyses typically include nonlinear terms for weather and season, questions remain as to whether models to date have completely controlled for these important predictors. In this paper, the authors use two flexible versions of distributed lag models to control extensively for the confounding effects of weather and season. One version builds on the current approach to controlling for weather, while the other version offers a new approach. The authors conduct a comprehensive sensitivity analysis of the particulate matter-mortality relation by applying these methods to the recently updated National Morbidity, Mortality, and Air Pollution Study database that comprises air pollution, weather, and mortality time series from 1987 to 2000 for 100 US cities. They combine city-specific estimates of the short-term effects of particulate matter on mortality using a Bayesian hierarchical model. They conclude that, within the broad classes of models considered, national average estimates of particulate matter relative risk are consistent with previous estimates from this study and are robust to model specification for weather and seasonal confounding.


Perylene and coronene derivatives binding to G-rich promoter oncogene sequences efficiently reduce their expression in cancer cells.
A novel approach to cancer therapeutics is emerging in the field of G-quadruplex (G4) ligands, small molecules designed to stabilize four-stranded structures that can form at telomeres as well as in other genomic sequences, including oncogene promoter sequences, 5'-UTR regions and introns. In this study, we investigated the binding activity of perylene and coronene derivatives PPL3C, CORON and EMICORON to G4 structures formed within the promoter regions of two important cancer-related genes, c-MYC and BCL-2, and their biochemical effects on gene and protein expression. In order to fully characterize the ability of the selected ligands to bind and stabilize the G4 structures originated by the c-MYC and BCL-2 promoter sequences, we performed electrospray ionization mass spectrometry (ESI-MS), Fluorescence Resonance Energy Transfer (FRET) measurements, Circular Dichroism (CD) spectra and polymerase stop assay. Altogether our results showed that the ligands had a high capacity in binding and stabilizing the G4 structures within the c-MYC and BCL-2 promoter sequences in vitro. Notably, when we evaluated by quantitative real-time PCR and western blotting analysis, the effects of treatment with the different G4 ligands on c-MYC and BCL2 expression in a human melanoma cell line, EMICORON appeared the most effective compound in reducing the mRNA and protein levels of both genes. These results encourage to consider EMICORON as a promising example of multimodal class of an antineoplastic drug, affecting different tumor crucial pathways simultaneously: telomere maintenance (as previously described), cell proliferation and apoptosis via down-regulation of both c-MYC and BCL-2 (this paper).


Discontinuation of hypnotics during cognitive behavioural therapy for insomnia.
In practical sleep medicine, therapists face the question of whether or not to discontinue the ongoing use of hypnotics in patients, as well as the possible effects of discontinuation. The aim of this study was to evaluate the effects of discontinuing third-generation hypnotics on the results of cognitive-behavioural therapy (CBT) for primary insomnia in patients after long-term abuse. Twenty-eight outpatients were treated by CBT for 8 weeks. The treatment outcome was estimated by means of differences among subjective clinical scales and polysomnography variables assessed before and after the treatment period. The therapeutic effect in a subgroup of 15 patients who had previously received hypnotics and were successively withdrawn during weeks 2-6 was compared to the effect achieved in patients who had not used hypnotics before CBT. There were no significant differences in baseline subjective and objective sleep characteristics between the hypnotic abusers and non-abusers. According to clinical scales and most polysomnographic measures, CBT was highly effective in both groups of subjects; it produced the greatest changes in total sleep time, REM sleep and sleep efficiency. Unexpectedly, discontinuation of hypnotics, as a factor in the analysis, was followed by an additional improvement of sleep efficiency and wake after sleep onset parameters. Our study confirmed the efficacy of CBT in both hypnotic-abusing and non-abusing patients with chronic insomnia. The results of this study suggest that tapered withdrawal of third-generation hypnotics during CBT therapy for chronic insomnia could be associated with improvement rather than worsening of sleep continuity.


Rapid completion of mitosis and cytokinesis in PtK cells following release from nocodazole arrest.
Mitotic PtK1 cells were arrested at nuclear envelope breakdown with the rapidly reversible microtubule inhibitor nocodazole. Addition of 1 microgram/ml nocodazole for 20 min resulted in complete blockage of spindle microtubule assembly but permitted other mitotic events to proceed such as chromosome condensation and cell rounding, typical of a c-mitosis. Upon release from nocodazole, mitosis and cytokinesis were completed approximately 35% faster than in a normal mitosis. The duration of each mitotic stage was compared in untreated and treated and released cells. Metaphase and cytokinesis were dramatically shortened while anaphase was unaffected. Cells treated for shorter periods of time with nocodazole and then released also reduced the length of time to complete mitosis and cytokinesis. The reduction in duration of these events was equivalent to the period of interruption of the mitotic cycle by nocodazole. With respect to the cell division cycle, PtK1 cells display a timing mechanism which is independent of the presence of microtubules.


Homo- and heteroleptic trimethoxy terpyridine-Cu(ii) complexes: synthesis, characterization, DNA/BSA binding, DNA cleavage and cytotoxicity studies.
In the current study, four novel mononuclear Cu(ii) complexes with terpyridine (L) and different co-ligands (phen, bipy, and imd) were synthesized and characterized in detail, where L is 4'-(3,4,5-trimethoxyphenyl)-2,2':6',2''-terpyridine. The identity and purity of all complexes were determined by elemental analysis, spectroscopic techniques (UV-vis, FTIR, ESI-MS, and EPR) and CV, including single crystal X-ray determination of three complexes ([Cu(L)(phen)](ClO4)2 (C-I), [Cu(L)2](ClO4)2 (C-II) and [Cu(L)(imd)(ClO4)](ClO4) (C-IV). DNA binding studies were performed using fluorescence assay and the binding constants were calculated using the Stern-Volmer equation and the modified Stern-Volmer equation. The magnitude of Kapp of all complexes was 105 M-1, indicating moderate intercalative binding between CT-DNA and the complexes. Agarose gel electrophoresis clearly reflected their ability to cleave a double stranded pET-28b plasmid in the presence of an external reducing agent (3-mercapto propionic acid). Steady-state fluorescence quenching was performed to understand their interactions with BSA. The studies suggested a mixed quenching mechanism with an initial static process. Furthermore, the antiproliferative activity of the complexes was evaluated against lung cancer A549 cells and primary mice splenocytes. Interestingly, the complexes show 25-200 fold greater toxicity towards the A549 cells than primary splenocytes, indicating their selectivity towards the former. The good binding behavior of all four complexes towards DNA and BSA and their cytotoxicity render these compounds promising potent anticancer drugs.


"I don't like to be seen by a male provider": health workers' strike, economic, and sociocultural reasons for home birth in settings with free maternal healthcare in Nigeria.
Ending maternal mortality has been a significant global health priority for decades. Many sub-Saharan African countries introduced user fee removal policies to attain this goal and ensure universal access to health facility delivery. However, many women in Nigeria continue to deliver at home. We examined the reasons for home birth in settings with free maternal healthcare in Southwestern and North Central Nigeria. We adopted a fully mixed, sequential, equal-status design. For the quantitative study, we drew data from 211 women who reported giving birth at home from a survey of 1227 women of reproductive age who gave birth in the 5 y before the survey. The qualitative study involved six focus group discussions and 68 in-depth interviews. Data generated through the interviews were coded and subjected to inductive thematic analysis, while descriptive statistics were used to analyse the quantitative data. Women faced several barriers that limited their use of skilled birth attendants. These barriers operate at multiple levels and could be grouped as economic, sociocultural and health facility-related factors. Despite the user fee removal policy, lack of transportation, birth unpreparedness and lack of money pushed women to give birth at home. Also, sociocultural reasons such as hospital delivery not being deemed necessary in the community, women not wanting to be seen by male health workers, husbands not motivated and husbands' disapproval hindered the use of health facilities for childbirth. This study has demonstrated that free healthcare does not guarantee universal access to healthcare. Interventions, especially in the Nasarawa state of Nigeria, should focus on the education of mothers on the importance of health facility-based delivery and birth preparedness.


Watermelon consumption improves inflammation and antioxidant capacity in rats fed an atherogenic diet.
Cardiovascular disease (CVD) is the leading cause of death in the United States. Watermelon, rich in antioxidants and other bioactive components, may be a viable method to improve CVD risk factors through reduced oxidative stress. The purpose of the study was to determine the effects of watermelon powder consumption on lipid profiles, antioxidant capacity, and inflammation in dextran sodium sulfate (DSS)-treated rats fed an atherogenic diet. We hypothesized that watermelon would increase antioxidant capacity and reduce blood lipids and inflammation through modulation of related gene expression. Forty male-weanling (21 days old) Sprague-Dawley rats were divided into 4 groups (10 per group, total N = 40) in a 2 diets (control or 0.33% watermelon) × 2 treatments (with or without DSS) factorial design using an atherogenic diet. Watermelon-fed groups exhibited significantly lower serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol (P< .05). C-reactive protein levels were significantly lower in watermelon-fed rats than the control (P= .001). In addition, oxidative stress as measured by thiobarbituric acid reactive substances was significantly lower in watermelon groups (P= .001). Total antioxidant capacity, superoxide dismutase, and catalase activities were greater in watermelon groups (P< .05). Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase were significantly lower in DSS-treated rats when watermelon was consumed (P< .05). Fatty acid synthase, 3-hydroxy-3methyl-glutaryl-CoA reductase, sterol regulatory element-binding protein 1, sterol regulatory element-binding protein 2, and cyclooxygenase-2 gene expression was significantly downregulated in the watermelon group without DSS (P< .05). These findings indicate that watermelon improves risk factors for CVD in rats through better lipid profiles, lower inflammation, and greater antioxidant capacity by altering gene expression for lipid metabolism.


Genetically predicted cortisol levels and risk of venous thromboembolism.
In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780). This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.


A Web-based graphical user interface for evidence-based decision making for health care allocations in rural areas.
The creation of successful health policy and location of resources increasingly relies on evidence-based decision-making. The development of intuitive, accessible tools to analyse, display and disseminate spatial data potentially provides the basis for sound policy and resource allocation decisions. As health services are rationalized, the development of tools such graphical user interfaces (GUIs) is especially valuable at they assist decision makers in allocating resources such that the maximum number of people are served. GIS can used to develop GUIs that enable spatial decision making. We have created a Web-based GUI (wGUI) to assist health policy makers and administrators in the Canadian province of British Columbia make well-informed decisions about the location and allocation of time-sensitive service capacities in rural regions of the province. This tool integrates datasets for existing hospitals and services, regional populations and road networks to allow users to ascertain the percentage of population in any given service catchment who are served by a specific health service, or baskets of linked services. The wGUI allows policy makers to map trauma and obstetric services against rural populations within pre-specified travel distances, illustrating service capacity by region. The wGUI can be used by health policy makers and administrators with little or no formal GIS training to visualize multiple health resource allocation scenarios. The GUI is poised to become a critical decision-making tool especially as evidence is increasingly required for distribution of health services.