Nonrandom Acts of Kindness: Parasympathetic and Subjective Empathic Responses to Sadness Predict Children's Prosociality.
How does empathic physiology unfold as a dynamic process, and which aspect of empathy predicts children's kindness? In response to empathy induction videos, 4- to 6-year-old children (N = 180) showed an average pattern of dynamic respiratory sinus arrhythmia (RSA) change characterized by early RSA suppression, followed by RSA recovery, and modest subsequent suppression during positive resolution of the empathic event. Children's capacity for this pattern of flexible RSA change was associated with their subjective empathic feelings, which were concurrently associated with more sympathetic and prosocial responses to others. Conversely, only children's dynamic RSA change longitudinally predicted prosocial behavior 2 years later. These findings have implications for understanding the dynamic and multifaceted nature of empathy, and its relation with prosocial development.


Comparing the use of Arabic decision aid to usual care. A multicenter randomized controlled trial for Arabic speaking metastatic colorectal cancer patients in Saudi Arabia.
To evaluate the effect of decision aids (DAs) for metastatic colorectal cancer (mCRC) patients in the Arabic language. A multi-centered randomized control trial was used to evaluate the effect of Arabic DA use with usual care for mCRC patients compared to usual care alone. Patients were recruited from 4 main oncology centers in Saudi Arabia: King Fahad Medical City, Riyadh; King Khalid University Hospital, Riyadh; King Saud Medical City, Riyadh; and King Fahd Specialist Hospital, Dammam, Saudi Arabia, between March 2016 and October 2018. The final follow up was in April 2019. The study measured patient understanding of prognosis, treatment options, and the level of the patient's anxiety. Ninety-two patients were included in the analysis; 51 in the intervention group. A small proportion of both (DA with usual care and usual care) understood that mCRC was incurable (8% and 5%) of the 2 groups, respectively. There was no significant difference between groups in anxiety level; however, a time effect both initially and after one month was significantly higher than at 6 month. The study shows that a higher level of patient's baseline understanding lowered anxiety levels over time. Decision aids group presented low levels of anxiety over time than those provided the usual care. We recommend using Arabic DA in the oncology centers dealing with mCRC patients, aiming to empower patients in decision making.


Assessing trauma care health systems in low- and middle-income countries, a protocol for a systematic literature review and narrative synthesis.
Trauma represents a major global health problem projected to increase in importance over the next decade. The majority of deaths occur in low- and middle-income countries (LMICs) where survival rates are lower than their high-income country (HIC) counterparts. Health system level changes in care for injured patients have been attributed to significant improvements in care quality and outcomes in HIC settings. There is a need for further research to assess trauma care health systems in LMICs to inform health system strengthening for the care of the injured. This study aims to conduct a narrative synthesis of a systematic search of the literature on the assessment of trauma care health systems in LMICs in order to inform the further development of trauma care health system assessment. The review will include primary quantitative, qualitative or mixed method studies and secondary literature reviews. No restriction will be placed on language or date. Reports and publications identified from the grey literature including from relevant national and international health organisations will be included. Articles will be screened by two independent reviewers with a third reviewer resolving any persisting disagreement. The search will reveal heterogenous studies not suitable for meta-analysis. A narrative synthesis of the identified papers will be conducted to identify key methodological ideas and paradigms used to assess trauma care health systems. The analysis will consider how the differing methodological approaches could be adopted to understand barriers and delays to seeking, reaching and receiving care within a "Three Delays" framework. An iterative approach will be adopted to categorise identified articles, with the results presented as both within and across study analysis. The results of the review will be disseminated through publication in a peer-reviewed academic journal. The study forms part of a PhD project. The results will inform the development of a trauma care health system assessment applicable to LMICs. As this is a review of secondary data, no formal ethical approval is required. PROSPERO CRD42018112990.


The heart of Ciona intestinalis: eicosanoid-generating capacity and the effects of precursor fatty acids and eicosanoids on heart rate.
Eicosanoids are a group of oxygenated fatty-acid derivatives formed from C20 polyunsaturated fatty acids including arachidonic and eicosapentaenoic acids. In mammals, these compounds have been shown to be key molecules in several physiological processes including regulation of the vascular system. This study determined whether eicosanoids or their precursors are involved in the regulation of heart rate in the sea squirt Ciona intestinalis. Eicosanoid generation by both heart and blood cells was measured. The major lipoxygenase products formed were both derivatives of eicosapentaenoic acid, namely 8- and 12-hydroxyeicosapentaenoic acids (8-HEPE and 12-HEPE). Smaller amounts of 8,15-dihydroxyeicosapentaenoic acid (8,15-diHEPE) were also formed. The cyclo-oxygenase product prostaglandin E was also found in small amounts in the heart. Isolated hearts were exposed either to these fatty acid precursors or to 8-HEPE, 12-HEPE or prostaglandin E3, and the effect on heart rate was recorded. Both eicosapentaenoic and arachidonic acids stimulated the heart rate at concentrations between 50 and 200 micromol l(-1). 12-HEPE (5 micromol l(-1)) and prostaglandin E3 (50 micromoll(-1)) caused a modest increase in heart rate, while 8-HEPE had no significant effects at any of the time periods studied (<or=180 min). Overall, the results show that arachidonic and eicosapentaenoic acids have limited effects on heart rate and only at concentrations unlikely to be routinely liberated in vivo. Similarly, the eicosanoids tested had a minor stimulatory activity on heart rate. The potential mechanisms for this stimulation are discussed. Overall, these results suggest that such compounds are of limited importance in regulating the heart and vascular system of sea squirts.


Mobile Health for All: Public-Private Partnerships Can Create a New Mental Health Landscape.
Research has already demonstrated that different mHealth approaches are feasible, acceptable, and clinically promising for people with mental health problems. With a robust evidence base just over the horizon, now is the time for policy makers, researchers, and the private sector to partner in preparation for the near future. The Lifeline Assistance Program is a useful model to draw from. Created in 1985 by the U.S. Federal Communications Commission (FCC), Lifeline is a nationwide program designed to help eligible low-income individuals obtain home phone and landline services so they can pursue employment, reach help in case of emergency, and access social services and healthcare. In 2005, recognizing the broad shift towards mobile technology and mobile-cellular infrastructure, the FCC expanded the program to include mobile phones and data plans. The FCC provides a base level of federal support, but individual states are responsible for regional implementation, including engagement of commercial mobile phone carriers. Given the high rates of disability and poverty among people with severe mental illness, many are eligible to benefit from Lifeline and research has shown that a large proportion does in fact use this program to obtain a mobile phone and data plan. In the singular area of mobile phone use, the gap between people with severe mental illness and the general population in the U.S. is vanishing. Strategic multi-partner programs will be able to grant access to mHealth for mental health programs to those who will not be able to afford them-arguably, the people who need them the most. Mobile technology manufacturing costs are dropping. Soon all mobile phones in the marketplace, including the more inexpensive devices that are made available through subsidy programs, will have "smart" capabilities (ie, internet connectivity and the capacity to host apps). Programs like Lifeline could be expanded to include mHealth resources that capitalize on "smart" functions, such as secure/encrypted clinical texting programs and mental health monitoring and illness-management apps. Mobile phone hardware and software development companies could be engaged to add mHealth programs as a standard component in the suite of tools that come installed on their mobile phones; thus, in addition to navigation apps, media players, and games, the new Android or iPhone could come with guided relaxation videos, medication reminder systems, and evidence-based self-monitoring and self-management tools. Telecommunication companies could be encouraged to offer mHealth options with their data plans. Operating system updates pushed out by the mobile carrier companies could come with optional mHealth applications for those who elect to download them. In the same manner in which the Lifeline Assistance Program has helped increase access to fundamental opportunities to so many low-income individuals, innovative multi-partner programs have the potential to put mHealth for mental health resources in the hands of millions in the years ahead.


Differentially expressed microRNAs in diapausing versus HCl-treated Bombyx embryos.
Differentially expressed microRNAs were detected to explore the molecular mechanisms of diapause termination. The total small RNA of diapause-destined silkworm eggs and HCl-treated eggs was extracted and then sequenced using HiSeq high-throughput method. 44 novel miRNAs were discovered. Compared to those in the diapause-destined eggs, 61 miRNAs showed significant changes in the acid-treated eggs, with 23 being up-regulated and 38 being down-regulated. The potential target genes of differentially expressed miRNAs were predicted by miRanda. Gene Ontology and KEGG pathway enrichment analysis of these potential target genes revealed that they were mainly located within cells and organelles, involved in cellular and metabolic processes, and participated in protein production, processing and transportation. Two differentially expressed genes, Bombyx mori SDH and Bmo-miR-2761-3p, were further analyzed with qRT-PCR. BmSDH was significantly up-regulated in the HCl-treated eggs, while Bmo-miR-2761-3p was down-regulated. These results suggested that these two genes were well coordinated in silkworm eggs. Dual luciferase reporter assay demonstrated that Bmo-miR-2761-3p inhibited the expression of BmSDH.


Plasmapheresis for Extrapontine Myelinolysis: A Case Series and a Literature Review.
Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are syndromes of osmotic demyelination attributed to the rapid correction of hyponatraemia. Isolated EPM is a rare clinical entity which poses a significant diagnostic challenge especially in the absence of a rapid rise in sodium. Typical MRI findings aid in the diagnosis. Treatment for established osmotic demyelination syndrome (ODS) is nonstandardized and the prognosis is considered poor. Therefore, different strategies including plasmapheresis (TPE), immunoglobulins (IVIG), and steroids have been used. We present our findings from a series of successfully treated patients at a high-volume tertiary care center in Sri Lanka, with an appraisal of available literature. A total of 21 patients with established ODS are analyzed here, including 5 cases of EPM managed by the authors over a 2-year period. Thirteen (40.2%) patients were treated with plasmapheresis alone, 6 (28.5%) received dual therapy (TPE + IVIG or steroids) and 2 (9.5%) received triple therapy (TPE + IVIG + steroids). There was complete or near complete response in 18 (85.7%) and complete response in 10 (47.6%) patients. We conclude that although the management of CPM/EPM is largely symptomatic, patients may show a significant response to immunomodulatory therapy. The marked improvement in motor, cognitive, and functional domains supports an immune basis for osmotic demyelination. Plasmapheresis, in particular, leads to favorable outcomes in ODS which is supported by previously published case reports. We propose its utility as standard treatment.


Immunostimulative Activity of Low Molecular Weight Chitosans in RAW264.7 Macrophages.
Chitosan and its derivatives such as low molecular weight chitosans (LMWCs) have been reported to exert many biological activities, such as antioxidant and antitumor effects. However, complex and molecular weight dependent effects of chitosan remain controversial and the mechanisms that mediate these complex effects are still poorly defined. This study was carried out to investigate the immunostimulative effect of different molecular weight chitosan in RAW264.7 macrophages. Our data suggested that two LMWCs (molecular weight of 3 kDa and 50 kDa) both possessed immunostimulative activity, which was dependent on dose and, at the higher doses, also on the molecular weight. LMWCs could significantly enhance the the pinocytic activity, and induce the production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon-γ (IFN-γ), nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in a molecular weight and concentration-dependent manner. LMWCs were further showed to promote the expression of the genes including iNOS, TNF-α. Taken together, our findings suggested that LMWCs elicited significantly immunomodulatory response through up-regulating mRNA expression of proinflammatory cytokines and activated RAW264.7 macrophage in a molecular weight- and concentration-dependent manner.


"If You Just Stay With Me and Wait…You'll Get an Idea of What I'm Saying": The Communicative Benefits of Time for Conversational Self-Repair for People With Aphasia.
This study investigated the communicative benefits of self-repair during conversation for persons with aphasia (PWAs). Self-repair of trouble sources is an interactional priority that emphasizes autonomy and competence. Of equal importance, conversationalists desire to minimize silences and work together to ensure forward movement (progressivity) of conversation. Simultaneously achieving progressivity and self-repair is challenging in aphasia, and PWAs and their partners often make trade-off decisions between these two activities. Conversation-level aphasia interventions usually focus on supportive techniques that promote participation while maintaining progressivity, effectively favoring progressivity over self-repair. This study evaluates the benefits of an alternative approach that shifts the emphasis to self-repair, thereby highlighting potential trade-off costs of routinely forgoing self-repair to achieve progressivity. Ten people with mild-to-moderate aphasia each held two conversations with two different partners. When trouble sources characterized by silent and/or filled pauses occurred, partners maintained a supportive and engaged stance, allowing PWAs time to self-repair. We analyzed language produced during these "edited turns" using three paradigms considering form, content, and use. The data yielded 311 edited turns. For form, on average, each edited turn resulted in 3.72 words; for content, most edited turns contained autobiographical information; for use, approximately 40% of edited turns introduced new information, and 40% added to the ongoing topic. The remainder were either ambiguous or comments such as, "I can't think of it." When given engaged support and time to self-repair, PWAs contributed meaningful personal information to conversations for approximately 80% of edited turns. Importantly, self-repair often resulted in self-expression that directed the conversation, which is a communicative role critical for empowering agency and identity. This research opens a dialogue about benefits and limitations of approaches that prioritize either progressivity or self-repair and how to balance the two to optimize therapeutic benefits for each individual. https://doi.org/10.23641/asha.19379738.


Whole genome analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Ghana.
Gonorrhoea is a major public health concern. With the global emergence and spread of resistance to last-line antibiotic treatment options, gonorrhoea threatens to be untreatable in the future. Therefore, this study performed whole genome characterization of Neisseria gonorrhoeae collected in Ghana to identify lineages of circulating strains as well as their phenotypic and genotypic antimicrobial resistance (AMR) profiles. Whole genome sequencing (WGS) was performed on 56 isolates using both the Oxford Nanopore MinION and Illumina MiSeq sequencing platforms. The Comprehensive Antimicrobial Resistance Database (CARD) and PUBMLST.org/neisseria databases were used to catalogue chromosomal and plasmid genes implicated in AMR. The core genome multi-locus sequence typing (cgMLST) approach was used for comparative genomics analysis. In vitro resistance measured by the E-test method revealed 100%, 91.0% and 85.7% resistance to tetracycline, penicillin and ciprofloxacin, respectively. A total of 22 sequence types (STs) were identified by multilocus sequence typing (MLST), with ST-14422 (n = 10), ST-1927 (n = 8) and ST-11210 (n = 7) being the most prevalent. Six novel STs were also identified (ST-15634, 15636-15639 and 15641). All isolates harboured chromosomal AMR determinants that confer resistance to beta-lactam antimicrobials and tetracycline. A single cefixime-resistant strain, that belongs to N. gonorrhoeae multiantigen sequence type (NG-MAST) ST1407, a type associated with widespread cephalosporin resistance was identified. Neisseria gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR), identified 29 unique sequence types, with ST-464 (n = 8) and the novel ST-3366 (n = 8) being the most prevalent. Notably, 20 of the 29 STs were novel, indicative of the unique nature of molecular AMR determinants in the Ghanaian strains. Plasmids were highly prevalent: pTetM and pblaTEM were found in 96% and 92% of isolates, respectively. The TEM-135 allele, which is an amino acid change away from producing a stable extended-spectrum β-lactamase that could result in complete cephalosporin resistance, was identified in 28.5% of the isolates. Using WGS, we characterized N. gonorrhoeae strains from Ghana, giving a snapshot of the current state of gonococcal AMR in the country and highlighting the need for constant genomic surveillance.


[Histochemical identification of preneoplastic hepatocellular lesions in the human liver].
The activity of gamma-glutamyltranspeptidase (GGT) as well as glycogen storage within hepatocytes from cirrhotic human liver were investigated by histochemical means. In 4 cases out of 9, many enzyme-altered, PAS positive dysplastic 'foci' were seen. Such lesions may be considered as possible precursors of hepatoma, as already reported in rat liver during chemical carcinogenesis. Among the preneoplastic liver markers, GGT positivity seems the most useful one to be added to the routine histological examination of liver biopsies.


Home-based transcranial direct current stimulation in dual active treatments for symptoms of depression and anxiety: A case series.
Transcranial direct current stimulation (tDCS) is a potential treatment strategy across some psychiatric conditions. However, there is high heterogeneity in tDCS efficacy as a stand-alone treatment. To increase its therapeutic potential, researchers have begun to explore the efficacy of combining tDCS with psychological and pharmacological interventions. The current case series details the effect of 6-10 weeks of self-administered tDCS paired with a behavioral therapy smartphone app (Flow™), on depressive and anxiety symptoms, in seven patients (26-51 years old; four female) presenting distinctive psychiatric disorders (major depression, dysthymia, illness anxiety disorder, obsessive-compulsive disorder, and anxiety disorders). tDCS protocol consisted of an acute phase of daily 30 min sessions, across 10 workdays (2 weeks Monday-to-Friday; Protocol 1) or 15 workdays (3 weeks Monday-to-Friday; Protocol 2). A maintenance phase followed, with twice-weekly sessions for 4 or 3 weeks, corresponding to 18 or 21 sessions in total (Protocol 1 or 2, respectively). The Flow tDCS device uses a 2 mA current intensity, targeting the bilateral dorsolateral prefrontal cortex. The Flow app offers virtually guided behavioral therapy courses to be completed during stimulation. We assessed depressive symptoms using MADRS-S and BDI-II, anxious symptoms using STAI-Trait, acceptability using ACCEPT-tDCS, and side effects using the Adverse Effects Questionnaire, at baseline and week 6 of treatment. Six patients underwent simultaneous cognitive-behavioral psychotherapy and two were on antidepressants and benzodiazepines. According to the Reliable Change Index (RCI), for depressive symptoms, we found clinically reliable improvement in five patients using MADRS-S (out of seven; RCI: -1.45, 80% CI; RCI: -2.17 to -4.82, 95% CI; percentage change: 37.9-66.7%) and in four patients using BDI-II (out of five; RCI: -3.61 to -6.70, 95% CI; percentage change: 57.1-100%). For anxiety symptoms, clinically reliable improvement was observed in five patients (out of six; RCI: -1.79, 90% CI; RCI: -2.55 to -8.64, 95% CI; percentage change: 12.3-46.4%). Stimulation was well-tolerated and accepted, with mild tingling sensation and scalp discomfort being the most common side effects. This case series highlights the applicability, acceptability, and promising results when combining home-based tDCS with psychotherapy and pharmacotherapy to manage depression and anxiety symptoms in clinical practice.


ANP32A modulates cell growth by regulating p38 and Akt activity in colorectal cancer.
Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) possesses multiple biochemical activities, has been found to be decreased or absent in malignant tumors. However, new findings have shown that it is expressed in greater amounts in advanced cancers than in early-stage tumors. The role and clinical significance of ANP32A in colorectal cancer (CRC) is still unknown. In the present study, the expression of ANP32A was assessed in 68 CRC patients by IHC, and then the correlation of its expression with clinicopathological factors was investigated using the Allred, Klein and immune response scoring system analysis. Western blot and real-time PCR analyses were used to assess ANP32A expression and the activity of Akt and p38 in cancer and normal tissues. These data indicated a significant association between ANP32A expression and the activity of Akt and p38, besides the tumor differentiation status in CRC patients. IHC and western blotting data revealed that ANP32A was overexpressed in CRC patients, and ANP32A levels were higher in poorly differentiated tumors. Protein and mRNA analysis revealed that with a high expression of ANP32A, the activation of Akt was enhanced, while the p-38 phosphorylation level was decreased in CRC tissues. MTT assay and functional studies revealed that knockdown of ANP32A inhibited cell growth and induced p38 phosphorylation and Akt dephosphorylation. The present study indicated that ANP32A promoted CRC proliferation by inhibition of p38 and activation of Akt signaling pathways and suggested that ANP32A may play a potential role in CRC diagnosis and therapy.


Cytoarchitecture of the periaqueductal gray matter in the cat: a quantitative Nissl study.
We studied the periaqueductal gray matter (PAG) in cresyl-violet-stained serial sections from 5 cats applying quantitative determinations. No significant variations were observed in the cytological aspects in the various sites examined (lateral, ventral and dorsal regions, and external and internal portions). The neuronal density was constant in the different regions, but showed a gradual and significant increase in the most external regions of the PAG. Our findings do not, therefore, confirm the existence in the PAG of subnuclei with a specific cytoarchitecture; this does not, however, rule out the possibility that there are specific regions for connections, histochemical properties or functions.


Antibacterial Susceptibilities of Escherichia coli from Community-Acquired Urinary Tract Infections in the Faroe Islands, Associations with Antibacterial Sales, and Comparison with Iceland and Denmark.
Currently, data on Escherichia coli antibacterial susceptibilities in the Faroe Islands are lacking. The aim was to investigate the antibacterial susceptibilities of E. coli from patients with community-acquired urinary tract infections in the Faroe Islands, correlate with antibacterial sales, and compare with Iceland and Denmark. From 2009 to 2010 and in 2012, 12 general practitioners from the Faroe Islands were recruited to provide urine samples from patients. Antibacterial susceptibilities were determined by disc diffusion testing according to the Clinical and Laboratory Standards Institute methods and criteria. Logistic regression (quasibinomial) of the antibacterial resistance proportions versus mean sales during the period of 2008-2011 was used to determine association. Nonsusceptibility to at least 1 of the 14 antibacterial drugs investigated was found in 54% of the E. coli isolates and was most common to ampicillin (46%), followed by sulfamethoxazole (39%), trimethoprim (27%), trimethoprim/sulfamethoxazole (27%), and <10% to the remaining 10 antibiotics. The resistance prevalence did not change significantly with time. From logistic regression modeling, we find significant associations between antibacterial mean sales and antibacterial resistances. For the resistances in the Faroe Islands compared with data from Denmark and Iceland, we infer two groups of resistances indicating different responses-one steep and one gradual-to antibacterial sales. For these two groups, we find β1 = 4.77 (Std. Error = 0.624, p-value = 0.002) and β1 = 0.26 (Std. Error = 0.020, p-value = 4e-7) for the steep and gradual groups, respectively. This knowledge can potentially be used to predict and control the future increase in E. coli resistance with antibacterial sales.


Drowning deaths in Mthatha area of South Africa.
Deaths by drowning are a serious public health problem worldwide. They are under-investigated and hence under-estimated. Drowning is an important and preventable cause of death. This paper aims to estimate the deaths by drowning in Mthatha area of South Africa. Records of the medico-legal autopsies in Umtata General Hospital (UGH) were reviewed from 1993 to 2004. All cases of unnatural death are brought by the police to UGH mortuary. Three hundred and forty-three cases of death as a result of drowning were recorded over a period of 12 years (1993-2004). There was an increased trend of drowning from 2.7 per 100, 000 in 1993 to 12 per 100,000 in 2004. Males outnumbered females by 2.6:1. The incidence of drowning declines as age advances. The highest number (96) of victims was under ten years of age. Deaths due to drowning are increasing especially among male children and young adults.


Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs.
Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine-cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds.


Detection of Epstein-Barr virus in Hodgkin's disease occurring in an Oriental population.
Like Burkitt's lymphoma, the strength of association of Epstein-Barr virus (EBV) with Hodgkin's disease occurring in different populations and clinical settings is highly variable, being 30% to 50% in Western countries, nearly 100% in Third World countries like Peru and Honduras, and nearly 100% in patients seropositive for human immunodeficiency virus. Data on the Oriental populations are very limited. Therefore, the current study was performed on the Chinese population of Hong Kong, where the incidence of Hodgkin's disease is low and EBV seroconversion occurs early in life. Twenty-three consecutive samples of Hodgkin's disease collected from 18 male and five female patients over a 12-year period were studied. The first age peak occurred in the second decade of life, and the second peak in the seventh decade. Using the sensitive and specific EBV-encoded RNAs (EBERs) in situ localization technique, positive labeling of the Reed-Sternberg cells and their variants was detected in five of five samples (100%) of mixed cellularity, nine of 16 samples (56%) of nodular sclerosing, one of one sample (100%) of lymphocyte depleted, and none of one sample (0%) of nodular lymphocyte predominant Hodgkin's disease. Further analysis of the data by age group yielded the following results: four of five (80%) for age younger than 15 years, three of nine (33%) for age 15 to 49, and eight of nine (89%) for age 50 or higher, confirming the reported strong association of EBV with Hodgkin's disease at the extremes of life. The overall positivity rate was 65%, which was intermediate between that reported in the Western populations and that in the Third World countries. These findings can be explained by the epidemiological pattern of Hodgkin's disease in Hong Kong, in which the first age peak is left-shifted to a younger age compared with that of Western populations (but not as early as that observed in Third World countries), moving the peak toward an age bracket in which Hodgkin's disease shows stronger association with EBV.


Supporting culturally and linguistically diverse students during clinical placement: strategies from both sides of the table.
Increasing proportions of Culturally and Linguistically Diverse (CALD) students within health professional courses at universities creates challenges in delivering inclusive training and education. Clinical placements are a core component of most health care degrees as they allow for applied learning opportunities. A research gap has been identified in regard to understanding challenges and strategies for CALD students in health professional placements. A key stakeholder approach was used to examine barriers and enablers experienced by CALD students in clinical placement. Semi-structured focus groups with healthcare students (n = 13) and clinical placement supervisors (n = 12) were employed. The focus groups were analysed using open coding and thematic analysis. Three main barrier areas were identified: placement planning and preparation; teaching, assessment and feedback; and cultural and language issues. Potential solutions included addressing placement planning and preparation barriers, appropriate student placement preparation, pre-placement identification of higher risk CALD students, and diversity training for supervisors. For the barrier of teaching, assessment & feedback, addressing strategies were to: adapt student caseloads, encourage regular casual supervisor-student conversations, develop supportive placement delivery modes and structures, set expectations early, model the constructive feedback process, use visual aids, and tailor the learning environment to individual student needs. The enablers for cultural & language issues were to: build language and practical approaches for communication, raise awareness of the healthcare system (how it interacts with healthcare professions and how patients access it), and initiate mentoring programs. The findings suggest that teaching and learning strategies should be student-centred, aiming to promote awareness of difference and its impacts then develop appropriate responses by both student and teacher. Universities and partnering agencies, such as clinical training providers, need to provide an inclusive learning environment for students from multiple cultural backgrounds.


The Role of Meteorin-Like Peptide and Asprosin in Colon Carcinoma.
Colon cancer is one of the most frequent gastrointestinal system cancers on a global scale. Common colonoscopy tests have reduced the incidence of colorectal cancer (CRC). Although nutrition, microorganisms, and their metabolites are related to colon cancer, the exact mechanism of CRC is still not clear. For this reason, it is of great importance to elucidate the molecular mechanisms of colon oncogenesis. This study was conducted retrospectively with samples obtained from the laboratory of Firat University Faculty of Medicine, Department of Pathology. A total of 30 patient samples were used. The control group consisted of healthy colon tissues from the same patients, and the other group consisted of colon carcinoma tissues from the same patients. Tissue samples of both groups were evaluated immunohistochemically with meteorin-like (METRNL) peptide and Asprosin. The immunoreactivity of METRNL was found to be lower in colon carcinoma tissues than in healthy colon tissues (0.2 ± 0.06 and 0.08 ± 0.03, respectively). Asprosin immunoreactivity was found to be higher in colon carcinoma tissues than in healthy colon tissues (0.4 ± 0.07 and 1.08 ± 0.15, respectively). As a result of this study, it was observed that there was a significant difference between healthy colon tissue and colon carcinoma tissue in terms of METRNL and Asprosin expression. Both proteins might be involved in the molecular mechanism of colon carcinoma. This situation is important in terms of diagnosis.


Imaged-based high-throughput screening for anti-angiogenic drug discovery.
Recent developments in high-content screening (HCS) technologies make it an attractive alternative for anti-angiogenic drug discovery. HCS integrates high-throughput methodologies with automated multicolor fluorescence microscopy to collect quantitative morphological and molecular data from complex biological systems. Organotypic systems based on primary vascular cells model many facets of angiogenesis. The adaptation of these complex in vitro assay systems to high-throughput HCS formats with automated image acquisition enables large-scale chemical library screening campaigns. These HCS principles can be extended further to allow small molecule compounds in in vivo model organisms such as zebrafish. In this review we discuss the latest developments within automated image-based high-throughput screening of chemical libraries for anti-angiogenic compounds.


Reliability indexes of automated perimetric tests.
The "reliability" of a subject's automated perimetric test result is generally assessed by three measures: fixation loss and false-positive and false-negative rates. These reliability criteria were examined for 76 glaucomatous and 248 normal subjects who underwent visual field testing (C-30-2 program; Humphrey Visual Field Analyzer, Allergan Humphrey, San Leandro, Calif). Of the examination results, 45% in glaucomatous subjects and 30% in normal controls were considered unreliable with the use of the manufacturer's reliability criteria. Most test results were unreliable because they failed to meet the criterion for fixation loss. The greater rejection rate among glaucomatous subjects was entirely due to their higher rate of false-negative responses. Factors such as age, pupil diameter, and visual acuity did not explain the difference between the false-negative rates of glaucomatous patients and normal subjects.


[Association of hepatic adenomatosis and hepatoportal sclerosis in a woman with incontinentia pigmenti].
We report the case of the association of three uncommon diseases in a young woman: incontinentia pigmenti, portal hypertension due to hepatoportal sclerosis, and liver adenomatosis. Incontinentia pigmenti is a hereditary genodermatosis with pigmentary cutaneous lesions and dysmorphic malformations. In our patient, among liver abnormalities, there were blood biochemical alterations, portal hypertension, and initially neo hepatic nodular lesions. Histological examination of the surgical liver specimen showed several adenomas and fibrosis of the portal tracts with portal vascular changes. The etiopathogenic nature of the adenomatosis and hepatoportal sclerosis is unclear. As a general rule, hepatic adenomatosis is associated with normal liver. We hypothesize that the adenomas could be secondary to changes in hepatic vascularisation.


High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience.
There are multiple sclerosis patients who suffer from an aggressive course of the disease with severe relapses and rapid accumulation of disability despite adequate treatment. In such cases high-dose immunoablation with autologous haematopoietic stem cell transplantation (ASCT) may be considered. Our objective was to report our experience with 26 multiple sclerosis patients treated with ASCT within the years 1998-2008. Twenty-six patients (Expanded Disability Status Scale 2.5-7.5 (median 6.0), multiple sclerosis duration 2-19 years (median 7)) with aggressive multiple sclerosis underwent autologous haematopoietic stem cell transplantation. Stem cells were mobilized by high-dose cyclophosphamide and granulocyte colony-stimulating factor, BEAM (carmustine, etoposide, cytarabine, melphalan) was used for immunoablation. Patients were evaluated at baseline and every six months post ASCT for adverse events and clinical outcome. Follow-up period was 11-132 months (median 66). Progression-free survival was calculated using the Kaplan- Meier method. At 3 and 6 years of follow-up 70.8% and 29.2% of patients respectively were free of progression. Patients with relapsing multiple sclerosis course, disease duration <5 years and age <35 years had a more favourable outcome. There was no death within 100 days after ASCT. We conclude that ASCT represents a viable and effective treatment option for aggressive multiple sclerosis.


Disaster Health Literacy of Middle-aged Women.
As disasters have been increasing in recent years, disaster health literacy is gaining more important for a population such as middle-age women. This is because they face developmental crises (menopause) and situational crisis (disaster). Due to the growing elderly population, it is imperative to seriously consider the issue of aging women's healthcare, and their educational needs relative to emergencies and disasters. The purpose of study was to clarify the importance of disaster health literacy for middle-age women. This study is a review of the literature using PubMed, ScienceDirect, Web of Science, Google Scholar, SCOPUS, OVID, ProQuest, Springer, and Wiley. Data was collected with keywords related to the research topic ("Women's health" OR "Geriatric health") AND ("Health literacy" OR "Disaster health literacy" OR "Disaster prevention literacy" OR "Risk knowledge" OR "Knowledge management") AND ("Disasters" OR "Risk" OR "Crises") in combination with the Boolean-operators OR and AND. We reviewed full text English-language articles published November 2011 November 2017. Additional references were identified from reference lists in targeted publications, review articles and books. This review demonstrated that disaster health literacy is critical for elderly women, because they may suffer from physical and psychological problems triggered by developmental crises such as menopause and situational crises such as disasters. Disaster literacy could enable them to improve resiliency and reduce disaster risk. Education has vital role in health promotion of middle-age women. Policymakers and health managers should be aware of the challenges of elderly women as a vulnerable group in disasters and develop plans to incorporate disaster health literacy for preparedness and prevention in educating this group.


Protective effects of Danggui Buxue Tang on renal function, renal glomerular mesangium and heparanase expression in rats with streptozotocin-induced diabetes mellitus.
Danggui Buxue Tang (DBT) is a simple combination of Radix Astragali and Radix Angelica sinensis (5:1), with a variety pharmacological activities. In the present study, a single intravenous injection of 30 mg/kg streptozotocin and subsequent six weeks of high glucose diet in Sprague Dawley rats were used to induce diabetic nephropathy. Rats with diabetes mellitus showed increased levels of fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG), and type IV collagen (all P<0.05). DBT treatment significantly decreased the levels of FBG, BUN, Scr, serum and urine β2-MG, and type IV collagen. Furthermore, DBT treatment significantly and dose-dependently restored the ultrastructural injury, and reduced the expression of heparanase, compared with the vehicle (P<0.05). Therefore, DBT may be a novel therapeutic approach for the prevention and treatment of diabetic nephrology.


High-Efficiency White Organic Light-Emitting Diodes Integrating Gradient Exciplex Allocation System and Novel D-Spiro-A Materials.
How to maintain high power efficiency (PE) and color stability under operating brightness is critical for the white organic light-emitting diodes (WOLEDs). To this end, two novel spiro-type materials STPy3 and STPy4 were designed. These materials could act as a single host and achieve a remarkable external quantum efficiency of 27.5% at 1000 cd m-2; to further optimize the PEs of OLEDs, STPy3/4 and PO-T2T were used as co-host-induced exciplexes, which enhanced the PE of green OLED to over 148.0 lm W-1. Unfortunately, the lower triplet energy level of exciplexes than blue emitters implied it is commonly unsuitable to fabricate WOLEDs. Herein, a new allocation of gradient exciplex (AGE) strategy was developed in which the formed excitons could be rationally allocated in a consequently doped nonuniform profile. The AGE incorporated the advantages of the exciplex with an ultralow turn-on voltage of 2.3 V and efficiency stability of spiro materials. The PE at 1000 cd m-2 was enhanced to 72.7 lm W-1, representing the first exciplex WOLED with the performance exceeding that of conventional fluorescent tubes.


Potential Risks to Hearing Functions of Service Members From Exposure to Jet Fuels.
Purpose Several military occupations, particularly those within the U.S. Air Force, require working with or around jet fuels. Jet fuels contain components that are known to affect central nervous function, yet effects of these fuels on auditory function, specifically auditory processing of sound, are not well understood at this time. Animal studies have demonstrated that exposure to jet fuels prior to noise exposure can exacerbate the noise exposure's effects, and service members exposed to jet fuels are at risk of noise exposure within their work environments. The purpose of this article was to give a brief synopsis of the evidence on the ototoxic effects due to jet fuel exposure to aid audiologists in their decision making when providing care for populations who are occupationally exposed to fuels or while during military service. Conclusions Exposure to jet fuels impacts central nervous function and, in combination with noise exposure, may have detrimental auditory effects that research has yet to fully explain. Additional longitudinal research is needed to explain the relationships, which have clinical implications for service members and others exposed to jet fuels. In the meantime, audiologists can gain useful information by screening for chemical exposures when obtaining patient case histories. If jet fuel exposure is suspected, the Lifetime Exposure to Noise and Solvents Questionnaire can be used to estimate a noise exposure ranking and identify other potentiating agents such as jet fuel and industrial chemicals. A history of jet fuel exposure should inform the selection of hearing tests in the audiometric evaluation and when devising the treatment plan.


Beating heart mitral valve surgery: results in 120 consecutive patients considered unsuitable for conventional mitral valve surgery.
The purpose of the study was to test whether a beating heart mitral valve operation was a valuable option in a heterogeneous group of patients considered very high risk for conventional mitral valve surgery. We conducted a retrospective, single-centre, observational cohort study of 120 patients (mean age 63.7 ± 12.1 years, range 25.3-88.8 years; mean logistic EuroSCORE 26.1 ± 20.6%, range 1.5-84.3%) undergoing beating heart mitral valve operations using normothermic cardiopulmonary bypass without aortic cross-clamping and without cardioplegia between September 2002 and April 2014. Preoperatively, 14 (11.7%) patients were in cardiogenic shock, 16 (13%) on a ventilator, 33 (27.5%) receiving inotropic support, 12 (10%) on dialysis and 1 on extracorporeal membrane oxygenation. Sixty-five (54%) patients had had at least 1 (range 1-6) previous heart operation. The mean follow-up period was 920 ± 973 days. A mitral valve procedure was performed alone in 75 (62.5%) patients and combined with additional cardiac procedures in 45 (37.5%). Fifty-eight (49%) patients had emergency or urgent procedures and 62 (51%), elective procedures. The mean cardiopulmonary bypass time was 103 ± 39 min (median 94 min, range 45-252, interquartile range 75-121.5 min). There were no conversions to conventional procedures and no intraoperative deaths. The 30-day mortality rate for patients without cardiogenic shock was 7.5% (8 deaths among 106 patients). Among 14 (11.7%) patients who underwent an operation in cardiogenic shock, 4 died during the first 30 days (30-day mortality rate = 28.6%, Fisher's exact test P = 0.338 versus patients without shock). The lowest 30-day mortality rate was in patients operated on with the beating heart because of a porcelain aorta (n = 8 patients, 30-day mortality rate = 0%). Patients considered unsuitable for a conventional mitral valve operation had favourable postoperative outcomes if the operation was performed on the beating heart.


Genetics of Chronic Lymphocytic Leukemia.
During the past 10 years, relevant advances have been made in the understanding of the pathogenesis of chronic lymphocytic leukemia via the integrated analysis of its genome and related epigenome, and transcriptome. These analyses also had an impact on our understanding of the initiation, as well as of the evolution of chronic lymphocytic leukemia, including resistance to chemotherapy and sensitivity and resistance to novel targeted therapies. This chapter will review the current state of the art in this field, with emphasis on the genetic heterogeneity of the disease and the biological pathways that are altered by the genetic lesions.


Effects of histamine receptor stimulation on diseased gallbladder and cystic duct.
The effects of histamine receptor stimulation on the motility of diseased human gallbladder and cystic duct were studied on tissue strips in vitro. Histamine produced concentration-dependent contractions in normal tissues and in tissues from each disease group, but the sensitivity of the strips to histamine as measured by the median effective dose was dependent upon the grade of disease: normal, 90.0 microM; mild chronic cholecystitis, 32.4 microM; advanced chronic cholecystitis, 12.5 microM; and acute cholecystitis, 3.0 microM. There were no differences in histamine sensitivity among different regions (body, neck, and cystic duct) of the biliary system. Studies with receptor-selective agonists and antagonists indicated that the contractile effects were mediated via histamine H1 receptors. Histamine H2 receptor agonists caused only small relaxant responses in about 30% of strips from gallbladder body, but were without effect in gallbladder neck and cystic duct. We conclude that the effects of histamine on the motility of diseased human gallbladder may depend upon the severity of the cholecystitis.


Plasma lipid alterations in patients with chronic renal disease.
Hyperlipidemia is common in patients with renal disease. This fact may be of great clinical relevance in view of the overwhelming evidence associating disturbed lipid metabolism and atherogenesis. Thus, hyperlipidemia may predispose to vascular disease in patients with chronic renal disorders and premature atherosclerosis could be an important risk in renal disease and a major factor limiting survival of patients on long-term maintenance hemodialysis. The aim of the present review is to present a brief but clinically relevant description of lipoprotein physiology and then to survey the now considerable literature concerned with lipoprotein and thus lipid abnormalities in patients with renal disease. A particular emphasis is placed on the role of the plasma lipoproteins in forming an integrated and controlled pathway for lipid metabolism, and how altered regulatory control within the pathway may be associated with pathogenic mechanisms. Finally, the evidence for accelerated development of vascular disease associated with these lipid abnormalities is briefly considered.


Output-only parameter identification of a colored-noise-driven Van-der-Pol oscillator: Thermoacoustic instabilities as an example.
The problem of output-only parameter identification for nonlinear oscillators forced by colored noise is considered. In this context, it is often assumed that the forcing noise is white, since its actual spectral content is unknown. The impact of this white-noise forcing assumption upon parameter identification is quantitatively analyzed. First, a Van-der-Pol oscillator forced by an Ornstein-Uhlenbeck process is considered. Second, the practical case of thermoacoustic limit cycles in combustion chambers with turbulence-induced forcing is investigated. It is shown that in both cases, the system parameters are accurately identified if time signals are appropriately band-pass-filtered around the oscillator eigenfrequency.


Show, give, and point gestures across infancy differentially predict language development.
It is well established that deictic gestures, especially pointing, play an important role in children's language development. However, recent evidence suggests that other types of deictic gestures, specifically show and give gestures, emerge before pointing and are associated with later pointing. In the present study, we examined the development of show, give, and point gestures in a sample of 47 infants followed longitudinally from 10 to 16 months of age and asked whether there are certain ages during which different gestures are more or less predictive of language skills at 18 months. We also explored whether parents' responses vary as a function of child gesture types. Child gestures and parent responses were reliably coded from videotaped sessions of parent-child interactions. Language skills were measured at 18 months using standardized (Mullen Scales of Early Learning) and parent report (MacArthur-Bates Communicative Development Inventory) measures. We found that at 10 months, show+give gestures were a better predictor of 18-month language skills than pointing gestures were, yet at 14 months, pointing gestures were a better predictor of 18-month language skills than show+give gestures. By 16 months, children's use of speech in the interaction, not gesture, best predicted 18-month language skills. Parents responded to a higher proportion of shows+gives than to points at 10 months. These results demonstrate that different types of deictic gestures provide a window into language development at different points across infancy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Consensus over directed static networks with arbitrary finite communication delays.
We study the consensus problem in directed static networks with arbitrary finite communication delays and consider both linear and nonlinear coupling. For the considered networked system, only locally delayed information is available for each node and also the information flow is directed. We find that consensus can be realized whatever the communications delays are. In fact, we do not even need to know the explicit values of the communication delays. One well-informed leader is proved to be enough for the regulation of all nodes' final states, even when the external signal is very weak. Numerical simulations for opinion formation in small-world and scale-free networks are given to demonstrate the potentials of our analytic results.


Presence of caprine arthritis-encephalitis virus (CAEV) infected cells in flushing media following oviductal-stage embryo collection.
To improve the knowledge on the risk of transmission of the caprine arthritis-encephalitis virus (CAEV) during embryo manipulations, we conducted a double-nested polymerase chain reaction (PCR) for CAEV proviral-DNA on flushing media recovered from the oviducts 48 h after the beginning of estrus and on blood from 89 donor does. Sixty-four does had negative blood and flushing media by PCR. Among the 25 CAEV infected goats (blood PCR positive), 11 were PCR flushing media positive (P < 0.01). Cell lysate from flushing media samples that were PCR positive were serially diluted 10 times at 1:100. Starting with the second 1:100 dilution all the cell lysate samples were PCR negative. The mean number of embryos recovered was not significantly different between goats with flushing media PCR positive and goats with flushing media PCR negative (6.0 +/- 5.4 versus 7.8 +/- 4.4, respectively; mean +/- S.D.) nor between goats with blood PCR positive and goats with blood PCR negative (7.0 +/- 5.0 versus 5.9 +/- 5.3; mean +/- S.D.). The presence of CAEV infected cells in oviductal flushing media from infected donor does was indicated for the first time during this study. The absence of flushing media PCR positive for goat blood PCR negative seemed to allow the use of the blood PCR test to confidently predict the absence of CAEV provirus in the oviductal fluid.


Mitochondrial function in intact skeletal muscle fibres of creatine kinase deficient mice.
Creatine kinase (CK) has a central role in skeletal muscle, acting as a fast energy buffer and shuttle between sites of energy production (mitochondria) and consumption (cross-bridges and ion pumps). Unexpectedly, isolated fast-twitch skeletal muscle cells of mice deficient in both cytosolic and mitochondrial CK (CK-/-) are highly fatigue resistant during stimulation protocols that stress aerobic metabolism. We have now studied different aspects of mitochondrial function in CK-/- skeletal muscle. Intact, single fibres of flexor digitorum brevis (FDB) muscles were fatigued by repeated tetanic stimulation (70 Hz, 350 ms duration, duty cycle 0.14). Under control conditions, CK-/- FDB fibres were more fatigue resistant than wild-type fibres. However, after mitochondrial inhibition with cyanide, force declined markedly faster in CK-/- fibres than in wild-type fibres. The rapid force decline in CK-/- fibres was not due to decreased myoplasmic [Ca2+] during tetani (measured with indo-1), which in these fibres remained virtually constant during fatigue in the presence of cyanide. Intact, single fibres of highly oxidative soleus muscles were fatigued by repeated tetani (50 Hz, 500 ms duration, duty cycle 0.5). All CK-/- soleus fibres tested (n = 9) produced > 40 % force at the end of the fatiguing stimulation period (500 tetani), whereas force fell to < 40 % before 500 tetani in two of three wild-type fibres. Mitochondrial [Ca2+] (measured with rhod-2 and confocal microscopy) increased during repeated tetanic stimulation in CK-/- but not in wild-type FDB fibres. In conclusion, mitochondria and energy shuttling operate effectively in CK-/- fibres and this is associated with an increase in mitochondrial [Ca2+].


'It's becoming harder to survive month to month'.
In the RCN's latest submission to the NHS Pay Review Body, the college called on the panel to recommend a pay award above the government's 1% pay cap 'in recognition of the many problems facing the nursing workforce'.


Continuous-wave coherent ultraviolet source at 326 nm based on frequency trippling of fiber amplifiers.
We have demonstrated a tunable single frequency source of continuous-wave (CW) coherent ultraviolet (UV) radiation at lambda (3omega) = 326 nm. Laser light of a tunable diode laser at lambda(omega) = 977 nm was split and injected into two independent fiber amplifiers yielding 1 W and 0.4 W, respectively. The 1 W branch was resonantly frequency doubled, resulting in 120 mW of useful power at lambda(2omega) = 488 nm. The third harmonic was generated by summation of the second branch of lambda(omega) and lambda(2omega) which were enhanced by a doubly resonant cavity. This light source has TEM(00) character and can be continuously tuned over more than 18 GHz. It is of interest for efficient laser cooling of In and potentially other applications.


Diabetic Peripheral Neuropathy and its Determinants among Patients Attending a Tertiary Health Care Centre in Mangalore, India.
The burden of diabetes mellitus (DM) is on the rise especially in developing countries like India. Due to its chronic nature DM tends to cause many debilitating complications and diabetic peripheral neuropathy (DPN) is one of them. The aim of this study is to determine the prevalence of DPN among patients attending a tertiary care hospital and to identify the determinants associated with it. A cross sectional study was conducted in Government Wenlock Hospital, Mangalore (India), during January-February 2014. A total of 208 patients with >5 year duration of DM were asked to respond to the patient history version of Michigan Neuropathy Screening Instrument (MNSI) and examinations were conducted after obtaining consent from them. The statistical analysis was done in terms of descriptive statistics and association between variables was tested using logistic regression test. The prevalence of DPN using the MNSI history version and MNSI examination were found to be 18.3% and 32.2% respectively. The major determinants associated with DPN were found to be male gender (OR: 2.7, CI: 1.4-5.1, P=0.001), smoking (OR: 5.8, CI: 1.9-17.3, P=0.001) and age >40 years (OR: 2.7, CI: 1.2-5.8, P=0.011). The burden of undetected DPN was found to be higher among diabetics, with an especially higher prevalence among males, smokers and those with long standing diabetes mellitus. Interventions in the form of early detection through routine screening, smoking cessation and regular follow up examinations would go a long way in reducing the burden of disability among diabetics and improve their quality of life significantly. Significance for public healthThe findings of the current research hold importance since diabetes is one of the leading causes of morbidity and mortality across the world. Due to its chronic nature and effects of hyperglycaemia, diabetes tends to be associated with many comorbidities, like peripheral neuropathy, nephropathy, retinopathy etc. The presence of diabetic peripheral neuropathy leads to a reduced quality of life among diabetic patients due to the trauma and consequent gangrenes andamputation. The concept of secondary prevention can be applied to the prevention of diabetic peripheral neuropathy using easy to apply screening tools and thus help in early diagnosis and treatment to reduce the burden of this debilitating illness.


Calcium in chronic kidney disease: recommended intake and serum targets.
Abnormal mineral metabolism has the potential to significantly increase mortality in patients with chronic kidney disease, especially by the time renal replacement therapy is required. While excess phosphorus and hyperphosphatemia have long been identified as risks for increased morbidity and mortality, the roles of calcium load and serum calcium levels have been less clear. Calcium-based recommendations in the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease were labeled as expert opinion. The rationale behind the opinion-based recommendations is reviewed along with additional supportive information that has become available since the bone and mineral guidelines were published.


Dissociation between LH-induced aerobic glycolysis and oocyte maturation in cultured Graafian follicles of the rat.
Luteinizing hormone (NIH-LH-S18; 5 mug/ml) stimulated aerobic glycolysis in cultured Graafian follicles explanted from pro-oestrous rats before the preovulatory gonadotrophin surge: lactate accumulation in the medium was 70% above control levels during 6 h incubations. Iodoacetate (2.5 x 10(-5) M) prevented this effect, without impairing the ability of LH to induce resumption of oocytic meiosis. Enrichment of the medium with pyruvate (3.3 x 10(-4) M) or lactate (2.5 x 10(-2) M) did not in itself cause ovum maturation. The results do not support the hypothesis that termination of meiotic arrest by LH is due to stimulation of glycolytic activity in the follicle cells, resulting in increased availability of an energy source readily urilizable by the oocyte.


Photoswitchable and dye-doped bubble domain texture of cholesteric liquid crystals.
We demonstrate control of the transmittance of the naturally formed bubble domain (BD) texture of cholesteric liquid crystals (CLC) with negative dielectric anisotropy confined into a cell with homeotropic surface anchoring. By using a photosensitive chiral dopant with variable helical twisting power under light irradiation, control of packing density of bubbles, spatial patterning, and all optical switching between bistable states with different optical densities is achieved. By introducing dichroic dye into the CLC mixture, a bistable and switchable by applied electric field guest-host system is obtained. The light dimming properties of dye-doped BD CLC systems may lead to development of a wide range of applications.


Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2.
The most frequent disorder of glycosylation is due to mutations in the gene encoding phosphomannomutase2 (PMM2-CDG). For this disease, which is autosomal and recessive, there is no cure at present. Most patients are composite heterozygous and carry one allele encoding an inactive mutant, R141H, and one encoding a hypomorphic mutant. Phosphomannomutase2 is a dimer. We reproduced composite heterozygosity in vitro by mixing R141H either with the wild type protein or the most common hypomorphic mutant F119L and compared the quaternary structure, the activity and the stability of the heterodimeric enzymes. We demonstrated that the activity of R141H/F119L heterodimers in vitro, which reproduces the protein found in patients, has the same activity of wild type/R141H, which reproduces the protein found in healthy carriers. On the other hand the stability of R141H/F119L appears to be reduced both in vitro and in vivo. These findings suggest that a therapy designed to enhance protein stability such as those based on pharmacological chaperones or modulation of proteostasis could be beneficial for PMM2-CDG patients carrying R141H/F119L genotype as well as for other genotypes where protein stability rather than specific activity is affected by mutations.


Human papillomavirus detection for cervical cancer prevention with polymerase chain reaction in self-collected samples.
We studied the usefulness of self-sampling in cervical cancer prevention. A cross-sectional study was undertaken at screening services in Recife (Brazil); 253 women aged 16 to 88 years were included. Participants were randomly selected from a high-risk population for cervical neoplasia. All participants collected a self-sample with a cotton-tipped swab by rotating it against the vaginal epithelium and, possibly, the cervix. Physician-collected samples from the ectocervix and endocervix, respectively, with an Ayre's spatula and a Cytobrush endocervical brush (Medscand) were followed by thorough colposcopy. Human papillomaviruses were detected by consensus polymerase chain reaction and typed by restriction fragment length polymorphism. The difference among human papillomavirus results in samples that were self-collected versus physician collected was significant (P <.03). The agreements were poor among patients with cervical intraepithelial neoplasia (CIN) grade 3 (kappa <0.29) and cervical cancer (kappa < 0.10). Self-sampling missed 50% more cancers than did physician sampling (P =.04). Self-sampling with a cotton-tipped swab for human papillomavirus detection is not a safe method for the collection of samples that are aimed at primary cervical cancer screening.


Cytotoxic effects of tetracycline analogues (doxycycline, minocycline and COL-3) in acute myeloid leukemia HL-60 cells.
Tetracycline analogues (TCNAs) have been shown to inhibit matrix metalloproteinases and to induce apoptosis in several cancer cell types. In the present study, the cytotoxic effects of TCNAs doxycycline (DOXY), minocycline (MINO) and chemically modified tetracycline-3 (COL-3) were investigated in the human acute myeloid leukemia HL-60 cell line. Cells were incubated with TCNAs in final concentrations of 0.5-100 µg/ml for 24 h. Viability of the leukemic cells was inhibited in a concentration-dependent manner using resazurin assay. The estimated IC50s were 9.2 µg/ml for DOXY, 9.9 µg/ml for MINO and 1.3 µg/ml for COL-3. All three TCNAs induced potent cytotoxic effects and cell death. Apoptosis, which was assessed by morphological changes and annexin V positivity, was concentration- and time-dependent following incubation with any one of the drugs. TCNAs induced DNA double strand breaks soon after treatment commenced as detected by γH2AX and western blot. The loss of mitochondrial membrane potential (Δψm), caspase activation and cleavage of PARP and Bcl-2 were observed; however, the sequence of events differed among the drugs. Pancaspase inhibitor Z-VAD-FMK improved survival of TCNAs-treated cells and decreased TCNAs-induced apoptosis. In summary, we demonstrated that TCNAs had a cytotoxic effect on the HL-60 leukemic cell line. Apoptosis was induced via mitochondria-mediated and caspase-dependent pathways in HL-60 cells by all three TCNAs. COL-3 exerted the strongest anti-proliferative and pro-apoptotic effects in concentrations that have been achieved in human plasma in reported clinical trials. These results indicate that there is a therapeutic potential of TCNAs in leukemia.


Treatment of cultured myotubes with the proteasome inhibitor beta-lactone increases the expression of the transcription factor C/EBPbeta.
The role of the proteasome in the regulation of cellular levels of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) is poorly understood. We tested the hypothesis that C/EBPbeta levels in cultured myotubes are regulated, at least in part, by proteasome activity. Treatment of cultured L6 myotubes, a rat skeletal muscle cell line, with the specific proteasome inhibitor beta-lactone resulted in increased nuclear levels of C/EBPbeta as determined by Western blotting and immunofluorescent detection. This effect of beta-lactone reflected inhibited degradation of C/EBPbeta. Surprisingly, the increased C/EBPbeta levels in beta-lactone-treated myotubes did not result in increased DNA-binding activity. In additional experiments, treatment of the myotubes with beta-lactone resulted in increased nuclear levels of growth arrest DNA damage/C/EBP homologous protein (Gadd153/CHOP), a dominant-negative member of the C/EBP family that can form heterodimers with other members of the C/EBP family and block DNA binding. Coimmunoprecipitation and immunofluorescent detection provided evidence that C/EBPbeta and Gadd153/CHOP interacted and colocalized in the nuclei of the beta-lactone-treated myotubes. When Gadd153/CHOP expression was downregulated by transfection of myotubes with siRNA targeting Gadd153/CHOP, C/EBPbeta DNA-binding activity was restored in beta-lactone-treated myotubes. The results suggest that C/EBPbeta is degraded by a proteasome-dependent mechanism in skeletal muscle cells and that Gadd153/CHOP can interact with C/EBPbeta and block its DNA-binding activity. The observations are important because they increase the understanding of the complex regulation of the expression and activity of C/EBPbeta in skeletal muscle.


[Analysis of tendon injuries accompanying distal radius fractures using volar locking plates].
We examined 6 cases of tendon injuries that accompanied distal radius fractures using volar locking plate between April 2006 and March 2012. Male: one case, female: five cases, average age 57.0 (33~70) years old. The fracture type was A2 in one case, A3 in four cases, and C2 in one case by AO classification. The average period for operation waiting was 2.7 days. We analyzed the time of occurrence of tendon rupture (extensor pollicis longus (EPL)・flexor pollicis longus (FPL)), the existence or not of screw prominence and dorsal roof fragment, and the positioning of the plate setting. The tendon ruptures were EPL in four cases, and FPL in two cases. The average period of rupture occurrence was 86.8 (1~182) days. In four EPL tendon ruptures we recognized one marked screw prominence (16.7%), and two dorsal roof fragments (50%), both showing widespread displacement. Moreover, we recognized the malposition of the plate setting in the two cases of FPL tendon rupture (100%). The incidence of tendon ruptures accompanying distal radius fractures using volar locking plates was not low at all, therefore we should more pay attention to the prevention of this occurrence.


Combined vitrectomy and glaucoma drainage device implantation surgical approach for complex pediatric glaucomas.
To evaluate efficacy of combined vitrectomy with posteriorly placed glaucoma drainage device (GDD) in lowering intraocular pressure (IOP) in children. The medical records of children who underwent vitrectomy with posteriorly placed GDD were reviewed retrospectively. Patients with a minimum of 6 months' follow-up were included. The first eye operated on for each patient was analyzed. Success was defined as IOP of 5-20 mm Hg and no additional IOP-lowering surgery or visually devastating complications. A total of 20 patients were included, with the following etiologies: primary infantile-onset glaucoma, 5 (25%); traumatic glaucoma, 3 (15%); Peters anomaly, 3 (15%); microphthalmia, 5 (25%); glaucoma following cataract surgery, 2 (10%); microspherophakia, 1 (5%); and retinopathy of prematurity, 1 (5%). Eyes with corneal opacification (8 [40%]) underwent endoscopic vitrectomy (5 [25%]), concurrent penetrating keratoplasty (3 [15%]) and/or keratoprosthesis surgery (1 [5%]). Mean follow-up was 1.9 ± 1.1 years (range, 6.5-49.2 months). Vision remained stable or improved in 17 eyes (85%). Mean IOP decreased from 27.2 ± 10.1 mm Hg to 14.5 ± 6.8 mm Hg (P < 0.0001) at last follow-up or at failure. Kaplan-Meier curves showed 12- and 24-month rate of IOP control of 69% and 62%, respectively. The number of glaucoma medications decreased from a mean of 2.3 ± 1.4 to 1.3 ± 1.2 (P < 0.015) at last follow-up or at failure. Overall success rate was 65%. Complications included hypotony (3 [15%]), vitreous hemorrhage (1 [5%]), and retinal detachment (1 [5%]). Two eyes (10%) required surgery for hypotony; 4 eyes (20%) underwent additional glaucoma surgery. Combined surgical approach with vitrectomy and posteriorly placed GDD decreased IOP in complex pediatric glaucomas. Further, endoscope-assisted vitrectomy is useful in cases with corneal opacification. Complication rates of this combined procedure appear to be comparable to traditional anterior chamber approach.


MiR-155 targets PTCH1 to mediate endothelial progenitor cell dysfunction caused by high glucose.
Endothelial progenitor cells (EPCs) are involved in diabetes-associated complications, including diabetic foot ulcer (DFU). Recent reports showed that miR-155 downregulation promotes wound healing in diabetic rats and ameliorates endothelial injury induced by high glucose, but its role in DFU is unknown. We found that miR-155 was overexpressed in EPCs from patients with DFU and in high glucose-induced EPCs from healthy people. Reductions in cell viability, migration, tube formation and nitric oxide production, as well as increases in lactated hydrogenase, cell apoptosis, and reactive oxygen species induced by high glucose, were enhanced by miR-155 overexpression and restrained by miR-155 inhibition. Additionally, dual-luciferase reporter assay demonstrated that miR-155 directly targeted the 3' untranslated region of patched-1 (PTCH1), a receptor of the sonic hedgehog signaling pathway, and downregulated the mRNA and protein expression of PTCH1. qRT-PCR and Western blot results revealed that the PTCH1 was downregulated in EPCs treated with high glucose. Silencing PTCH1 by PTCH1 siRNA alleviated the protective effect of anti-miR-155 on high glucose-induced EPC dysfunction. Our results indicate that miR-155 worsened high glucose-induced EPC function by downregulating PTCH1. These findings suggest that miR-155 may be a potential therapeutic target for DFU.


Estradiol Fluctuation, Sensitivity to Stress, and Depressive Symptoms in the Menopause Transition: A Pilot Study.
The menopause transition is associated with an increased risk of depressed mood. Preliminary evidence suggests that increased sensitivity to psychosocial stress, triggered by exaggerated perimenopausal estradiol fluctuation, may play a role. However, accurately quantifying estradiol fluctuation while minimizing participant burden has posed a methodological challenge in the field. The current pilot project aimed to test the feasibility of capturing perimenopausal estradiol fluctuation via 12 weekly measurements of estrone-3-glucuronide (E1G), a urinary metabolite of estradiol, using participant-collected urine samples in 15 euthymic perimenopausal women ages 45-55 years. Furthermore, it aimed to correlate E1G fluctuation (standard deviation across the 12 E1G measurements) with weekly mood and cardiovascular, salivary cortisol, and subjective emotional responses to the Trier Social Stress Test (TSST) at weeks 4, 8, and 12. Protocol acceptability and adherence was high; furthermore, E1G fluctuation was positively associated with anhedonic depressive symptoms and weekly negative affect. E1G fluctuation was also associated with increased heart rate throughout the TSST as well as higher levels of rejection, anger, and sadness. E1G fluctuation was not significantly associated with TSST blood pressure or cortisol levels. This study suggests a feasible method of assessing estradiol fluctuation in the menopause transition and provides support for the hypothesis that perimenopausal estradiol fluctuation increases sensitivity to psychosocial stress and vulnerability to depressed mood.


Immunological studies on cathepsins B and H from rat liver.
The immunological properties of thiol proteinases from rat liver, cathepsin B, H, and L, were examined. Rabbit antisera were prepared against cathepsins B and H from rat liver. Anti-cathepsin B and H ser quantitatively precipitated only the corresponding enzyme protein. On immunodiffusion analysis, anti-cathepsin B serum reacted with cathepsin B, but not with cathepsin H, indicating that the three thiol proteinases are distinct. Immunoelectrophoresis using a mixture of anti-cathepsin B and anti-cathepsin H showed that the precipitin line with cathepsin B moved faster to the anode than with cathepsin H. Immunological diffusion with antisera indicated that rat liver cathepsin B and H were immunologically identical with cathepsins B and H from rat kidney, lung, spleen, brain, and heart, but different from cathepsin B or H from human or rabbit liver.


Impact of COVID-19 on Spanish mortality rates in 2020 by age and sex.
Previous studies have used different biometric indicators to measure the effect of Covid-19 on population mortality such as the number of deaths or the decrease of life expectancy showing a dependence of mortality on age and sex. According to them, the impact of the pandemic was greater on women than in men and that the older the population, the greater the number of deaths caused by Covid-19. We apply graduation techniques and non-parametric methods to estimate mortality rates allowing us to obtain an age-by-age picture of changes in mortality rates from 2018-2019 to 2020. Graduation techniques have detected a significant U-shaped reduction in infant mortality rates although with an anomalous peak in girls aged 10-12. Likewise, we have observed a notable increase in mortality rates of the female population between 28 and 40 years of age. The increase of mortality rates after the age of 70 years was similar for both men and women with a slight decline after the age of 80. The use of graduation techniques and the focus on age-by-age changes in mortality rates showed a complex behaviour in some tranches of the mortality curve that might otherwise have gone unnoticed.


Localization of androgen-binding protein in proliferating Sertoli cells in culture.
The peroxidase and immunofluorescent localization patterns of androgen-binding protein (ABP), a biological marker of Sertoli cell function, have been examined in cultured Sertoli cells isolated from 20- to 22-day-old rats. ABP immunoreactivity in the form of cytoplasmic granules of variable diameter was observed in Sertoli cells with characteristic lipid droplets and a colony-forming, epithelial-like growth pattern. Incubation of cultures with [3H]thymidine demonstrated that Sertoli cells continue to produce ABP while retaining their capability for synthesizing DNA and undergoing mitosis. A variable number of cultured Sertoli cells became morphologically transformed after exposure to follitropin (follicle-stimulating hormone) and pharmacological agents acting on cyclic nucleotide metabolism. The induced change in Sertoli cell shape coincided with a disappearance of ABP-containing granules from the cytoplasm. These observations demonstrate that localization of ABP by immunological techniques is a valuable tool for the characterization of structural and functional properties of Sertoli cell in culture.


Napping reduces emotional attention bias during early childhood.
Sleep loss alters processing of emotional stimuli in preschool-aged children. However, the mechanism by which sleep modifies emotional processing in early childhood is unknown. We tested the hypothesis that a nap, compared to an equivalent time spent awake, reduces biases in attention allocation to affective information. Children (n = 43; M = 55.40 months, SD = 8.05 months) completed a Dot Probe task, which provides a measure of attention biases to emotional stimuli, following a mid-day nap and an equivalent interval spent awake. No emotional attention biases emerged when children napped. However, when nap-deprived, children exhibited biases towards negative and positive stimuli. This emotional bias after wake was greater in children who napped habitually. Gender differences also emerged such that females were more attentive to positive emotional stimuli whereas males showed heightened attention to negative emotional stimuli, regardless of having napped or not. Moreover, greater slow wave activity (SWA) during the nap was associated with faster responding, which suggests that SWA may promote efficiency of attention allocation. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=JIoZ8mzxQgg.


[Imaging procedures in systemic connective tissue diseases (collagenoses)].
Systemic lupus erythematosus (SLE) and progressive systemic sclerosis (PSS) represent the most frequent manifestations of systemic connective tissue diseases (collagen diseases). Radiological examinations are employed to estimate the extension and degree of the pathological process. In addition, progression of the disease can be verified. In both of the above collagen diseases, specific radiological findings can be observed that permit them to be differentiated from other entities. An algorithm for the adequate radiological work-up of collagen diseases is presented.


[Skin manifestations in HIV infection].
In HIV-infections, skin manifestations are manifold and are conditioned mainly by the immunodeficiency. Kaposi's sarcoma, oral hairy leucoplakia and candidiasis of the esophagus are of diagnostic significance as same as a severe course of opportunistic infections e.g. herpes simplex, herpes zooster, cryptococcosis, dermatomycoses, verrucae vulgares, condylomata acuminata and others. Sometimes skin manifestations are the first perceivable sign of an HIV-infection.


Mitomycin C as an alternative to irradiation to inhibit the feeder layer growth in long-term culture assays.
Mitomycin C (MMC), an antitumoral antibiotic, has been described inhibiting the proliferation of different cell types in vitro. Since irradiation is commonly used to stop the cell growth of adherent cells in several experimental models, we aimed to define the optimal dose and incubation time of MMC capable of inhibiting the growth of murine fibroblasts, used as an adherent feeder layer in long-term hematopoietic culture assay. M2 10B4 (both parental and engineered to produce human IL-3 and G-CSF) and Sl/Sl (engineered to produce human IL-3 and steel factor) murine fibroblast cell-lines, frequently used in LTC-IC assay, were incubated with increasing doses of MMC for either a short (3 h) or a long (16 h) period. The efficiency of MMC in stopping the cell growth was evaluated for 5 days following MMC removal. The effects of MMC treatment on human hematopoietic cells were studied using both LTC-IC and limiting dilution (CAFC) assays. The growth of M2 10B4 cells was stopped at 3 and 16 h in the presence of 20 microg/mL and 2 microg/mL of MMC, respectively while Sl/Sl fibroblasts required a lower dose of drug (2 and 0.2 microg/mL, respectively). No significant difference was found between the number of LTC-IC or CAFC obtained from cultures containing irradiated or MMC-treated feeder cells. MMC inhibits the growth of murine fibroblasts used as adherent feeder cells in long-term culture assays, without interfering with the subsequent growth of co-cultured hemopoietic cells. Different cell types might present a different sensitivity to MMC and therefore a dose-response curve to MMC has to be obtained for each cell type of interest.


Economic evaluation of fulvestrant 500 mg versus generic nonsteroidal aromatase inhibitors in patients with advanced breast cancer in the United Kingdom.
The goal of this study was to examine the cost-effectiveness of fulvestrant 500 mg for the treatment of first progression or recurrence of advanced breast cancer in postmenopausal patients compared with generic nonsteroidal aromatase inhibitors (anastrozole and letrozole) in the United Kingdom. A cost-utility model based on a time-in-state approach was used. Clinical effectiveness estimates used in the model were derived from a network meta-analysis for overall survival and serious adverse events. Overall survival was extrapolated by using a Weibull distribution, and progression-free survival (PFS) estimates were derived from a simultaneous network meta-analysis and extrapolation of PFS curves by using the log-normal distribution. Data on resource use, costs, and utilities were based on various sources, including expert opinion and published data. To explore uncertainty, 1-way and probability sensitivity analyses were conducted. The study was conducted from the perspective of the UK National Health Service, and costs are reported in 2010/2011 British pounds. The base case incremental cost-effectiveness ratio (ICER) for fulvestrant 500 mg versus letrozole was £34,528, with incremental costs of £14,383 and an incremental quality-adjusted life-year (QALY) of 0.417. Extended dominance occurred for anastrozole because the ICER for anastrozole versus letrozole was higher than the ICER for fulvestrant 500 mg versus anastrozole. Based on the probability sensitivity analyses, the probability that fulvestrant 500 mg was the most cost-effective treatment option was 3%, 20%, and 53% at a willingness-to-pay threshold of £20,000, £30,000, and £40,000 per QALY, respectively. According to the 1-way sensitivity analyses, the PFS estimates were the key drivers of the model results. Although fulvestrant 500 mg was found not to be a cost-effective option at a standard UK threshold of £20,000 to £30,000 per QALY, it may be relevant to apply a higher threshold due to the poor prognosis of patients with advanced breast cancer and the limited number of hormonal treatment options available for this stage of treatment. Certain subgroups may also benefit from fulvestrant as a treatment option; however, limited data are currently available to identify these subgroups.


Plastic surgical techniques in the fifteenth century by Serafeddin Sabuncuoğlu.
Serafeddin Sabuncuoğlu (A.D. 1385-1468) is the author of the first illustrated surgical textbook in the Turkish-Islamic literature, namely, Cerrahiyet-ül Haniyye (Imperial Surgery). A pioneer in all fields of surgery. Sabuncuoğlu developed numerous original techniques. He was a keen observer and inventor and a prolific writer who combined his fortune with knowledge of his era. He described a mass reduction procedure for the management of gynecomastia, probably one of the first attempts at reduction mammaplasty. He gave detailed descriptions of different eyelid pathologies and their surgical managements. The aim of this study is to investigate the contributions of this remarkable pioneer to the field of plastic surgery.


What determines auditory distraction? On the roles of local auditory changes and expectation violations.
Both the acoustic variability of a distractor sequence and the degree to which it violates expectations are important determinants of auditory distraction. In four experiments we examined the relative contribution of local auditory changes on the one hand and expectation violations on the other hand in the disruption of serial recall by irrelevant sound. We present evidence for a greater disruption by auditory sequences ending in unexpected steady state distractor repetitions compared to auditory sequences with expected changing state endings even though the former contained fewer local changes. This effect was demonstrated with piano melodies (Experiment 1) and speech distractors (Experiment 2). Furthermore, it was replicated when the expectation violation occurred after the encoding of the target items (Experiment 3), indicating that the items' maintenance in short-term memory was disrupted by attentional capture and not their encoding. This seems to be primarily due to the violation of a model of the specific auditory distractor sequences because the effect vanishes and even reverses when the experiment provides no opportunity to build up a specific neural model about the distractor sequence (Experiment 4). Nevertheless, the violation of abstract long-term knowledge about auditory regularities seems to cause a small and transient capture effect: Disruption decreased markedly over the course of the experiments indicating that participants habituated to the unexpected distractor repetitions across trials. The overall pattern of results adds to the growing literature that the degree to which auditory distractors violate situation-specific expectations is a more important determinant of auditory distraction than the degree to which a distractor sequence contains local auditory changes.


Antibacterial peptides of bovine lactoferrin: purification and characterization.
Three peptides with antibacterial activity toward enterotoxigenic Escherichia coli have been purified from a pepsin digest of bovine lactoferrin. All peptides were cationic and originated from the N-terminus of the molecule in a region where a bactericidal peptide, lactoferricin B, had been previously identified. The most potent peptide, peptide I, was almost identical to lactoferricin B; the sequence corresponded to residues 17 to 42, and the molecular mass was 3195 as determined by mass spectrometry. A second, less active peptide, peptide II, consisted of two sequences, residues 1 to 16 and 43 to 48 (molecular mass of 2673), linked by a single disulfide bond. The third peptide, peptide III, also a disulfide-linked heterodimer, corresponded to residues 1 to 48 (molecular mass of 5851), cleaved between residues 42 and 43. Peptides I and II displayed antibacterial activity toward a number of pathogenic and food spoilage microorganisms, and peptide I inhibited the growth of Listeria monocytogenes at concentrations as low as 2 microM. Bacterial growth curves showed that bactericidal effects of peptides I and II were observable within 30 min of exposure. The results confirmed and extended those of earlier studies suggesting that the bactericidal domain of lactoferrin was localized in the N-terminus and did not involve iron-binding sites.


Insulin-like growth factor binding protein-1 induces decidualization of human endometrial stromal cells via alpha5beta1 integrin.
Progesterone is known to induce decidualization of human endometrial stromal cells in vitro. Decidualized stromal cells produce insulin-like growth factor binding protein-1 (IGFBP-1) as well as prolactin (PRL). In this study, we tested the possibility that IGFBP-1 directly stimulates endometrial stromal cell decidualization. Endometrial stromal cells were obtained from normal menstruating patients with uterine myoma at hysterectomy. Stromal cells were cultured for up to 4 weeks with estradiol (E(2)) and/or medroxy progesterone acetate (MPA) in the presence or the absence of IGFBP-1 and, LR(3)-IGF-I (an IGF-I analogue) that binds to the IGF-I receptor but has reduced affinity for IGFBPs. Decidualization of endometrial stromal cells was evaluated by morphological changes and PRL release into culture media. The binding of IGFBP-1 to endometrial cells was analysed using a biosensor. MPA and E(2) induced decidualization of stromal cells, while LR(3)-IGF-I inhibited decidualization by MPA and E(2) as well as PRL and IGFBP-1 secretion into medium. IGFBP-1 induced decidualization of stromal cells in the absence of MPA and E(2) in the medium. IGFBP-1-induced decidualization was not inhibited by the addition of LR(3)IGF-1 but was inhibited by the addition of an RGD peptide, however, the RGD peptide had no effect on decidualization when added alone. The binding analysis showed that IGFBP-1 bound to the surface of endometrial stromal cells and an anti-alpha5beta1 integrin antibody inhibited its binding. These results suggest that IGFBP-1 produced by endometrium can mediate progesterone-induced decidualization possibly by interacting with alpha5beta1 integrin on the surface of endometrial stromal cells.


Seasonal activity of the common European tick, Ixodes ricinus (Linnaeus, 1758), in the forested areas of the city of Olsztyn and its surroundings.
Common European ticks, Ixodes ricinus, have been found in forest areas situated within the boundaries of big cities, and in areas changed by anthropogenic pressure. Monitoring I. ricinus, in the areas used by the public for recreation and leisure, makes it possible to assess the risk of infection with the diseases they transmit. The objective of this study was the comparison of the seasonal activity of ticks, I. ricinus, in the afforested areas of the city of Olsztyn and its surroundings. This survey was conducted at sites located in the afforested areas of Olsztyn and within the Warmiński Forest situated about 15 km from Olsztyn. Ticks, I. ricinus, were caught every 10-14 days from April to October 2001 by the commonly applied method of flagging. During each catch, the temperature (T) and relative humidity (%RH) was measured with a thermohygrometer, 1 m above the duff level. The tick population density at the Warmiński Forest site was higher than that at the sites within the city limits (116.8 and 20.5 ticks per 100 m2, respectively). Two peaks of tick activity were recorded in this area--the spring peak in June and the autumn peak (much lower) in September. The activity of ticks in the afforested area within the city limits was much lower--only one (spring) peak occurred, which at most sites was observed in June. At all sites, included in the study, the peak activity of ticks was observed in April. The study suggests that the afforested areas outside the city are more dangerous to people than the area within the city because of the large number of ticks there.


Night-time metabolic changes in normal subjects in the absence of the dawn phenomenon.
Metabolic changes have been followed overnight in 10 normal subjects. Blood glucose and serum C-peptide concentrations were constant from 0100 to 0800 h, as was serum insulin. Plasma NEFA, and blood glycerol and 3-hydroxybutyrate concentrations fell steadily after 0200 h however, suggesting a decreasing rate of lipolysis, fatty acid oxidation, and ketogenesis. The changes in NEFA concentrations were consistent with small rises in blood pyruvate and alanine concentrations. While it is unclear how glucose homeostasis is maintained when major changes are occurring in turnover of other metabolic intermediates, the results suggest potential mechanisms for an overnight disturbance of glucose metabolism in stressed or insulin deficient man.


Improving the design and analysis of high-throughput screening technology comparison experiments using statistical modeling.
Contemporary small-molecule drug discovery frequently involves the screening of large compound files as a core activity. Subsequently cost, speed, and safety become critical issues. In order to meet this need, numerous technologies have been developed to allow mix and measure approaches, facilitate miniaturization, and to increase speed and to minimize the use of potentially hazardous reagents such as radioactive materials. However, despite the on-paper advantages of these new technologies, risks can remain undefined. For example, the question of whether the novel method will facilitate identification of active chemical series in a way that is comparable with conventional methods arises. In order to address this question, we have taken the approach of carrying out experiments to directly compare the output of high-throughput screens using a given novel approach and a traditional method. The concordance between the screening methods can then be determined via comparison of the numbers and structures of the active molecules identified. This article describes the approach taken in our laboratory to minimize variability in such experiments and shows data that exemplifies the general result of lower than expected concordance. Statistical modeling was subsequently used to facilitate this interpretation. The model used beta-distribution function to generate a real-activity frequency relationship with added normal random error and occasional outliers to represent assay variability. Hence, the effect of assay parameters such as the threshold, the number of real actives, and the number of outliers and the standard deviation could readily be explored. The model was found to describe the data reasonably and moreover was found to be of great utility when it came to planning further optimal experiments. A key conclusion from the model was that concordance between screening methods could appear poor even when one approach is compared with itself. This occurs simply because the result is a function of assay threshold, standard deviation and the true compound % activity. In response to this finding we have adopted alternative experimental designs that more reliably measure the concordance between screening methods.


Older adults with a higher frailty index tend to have electrolyte imbalances.
Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor. We hypothesized that frail older adults would tend to have electrolyte imbalances because they should have many stressors together with fragile physiological systems. In this study, we aimed to determine whether older adults with higher Frailty Index scores have electrolyte imbalances and to establish which domains of the Frailty Index are correlated with electrolyte imbalances. A cross-sectional study. A total of 4204 older adults aged 70 years or over who visited the Japanese National Center for Geriatrics and Gerontology. We calculated the 50-item Frailty Index with the following domains: comorbidities, cognitive function and mood, basic and instrumental activities of daily living, physical function, nutrition, and fall risks from physical weakness and comorbidities. Participants were categorized into four groups: a non-frail group (Frailty Index ≤0.2), mildly frail group (0.20 < Frailty Index ≤0.3), moderately frail group (0.3 < Frailty Index ≤0.4), and severely frail group (0.4 < Frailty Index). Their serum sodium, potassium, calcium, and phosphorus concentrations were measured. A multiple regression model was used to explore the relationship of electrolyte imbalances with the Frailty Index and to determine which frailty domains are correlated with electrolyte imbalances. Compared with the non-frail group, the mildly and moderately frail groups tended to have hypernatremia and hypophosphatemia, whereas the severely frail group tended to have dysnatremia, hypokalemia, and hypophosphatemia. The estimated odds ratios increased by 15%-52% for each electrolyte imbalance as the Frailty Index increased by 0.1. The Frailty Index domains of cognitive function, activities of daily living, and nutrition were correlated with more than three kinds of electrolyte imbalances, the domains of physical function and fall risks from physical weakness were correlated with three kinds of electrolyte imbalances, and the domains of comorbidities and fall risks from comorbidities were correlated with two kinds of electrolyte imbalances. Older adults with higher Frailty Index scores tend to have electrolyte imbalances.