Gendered experiences of health care.
To develop a method capable of bringing to light gender specific problems in the social interaction between providers and clients, and in so doing, contribute to improving quality of care for both sexes in five primary health care centers in Argentina. A qualitative study using semi-structured interviews. Texts were processed in a database and analyzed using a formal method of discourse called Semiotics of Statements. Male and female clients' ideas on perceived causes of illnesses and health care needs were compared, following which providers' perceptions on the same issues were then contrasted. Problems in quality of care were suggested when: (i) differences in perceptions and/or values between providers and either male or female clients were observed; and (ii) similarities in values revealed reinforcement of traditional gender roles. Public sector care provided to urban poor with hypertension and diabetes mellitus type 2 in five clinics in Avellaneda, Argentina. Participants were clients identified through community organizations (n = 27), and all physicians from these clinics (n = 10), 60% of nurses (n = 6) and 80% of receptionists (n = 4) were interviewed. Providers' views differed from women's in regard to: (i) the degree of individual responsibility (risky behavior) in disease causation; (ii) legitimacy of the reasons many women seek care; (iii) function of talk in the consultation; (iv) effects of chastisement; and (v) relevance of domestic violence. In addition, a series of shared values were identified that reinforce traditional gender roles, including situations detrimental to men's health. The method permitted identification of subjective issues relating to social interaction that could not have been accessed with other approaches, and that had practical implications for providers, as well as managers, policy-makers, educators and patient advocates.


Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer.
Although the association between diabetes mellitus (DM) and pancreatic cancer is well described, temporal patterns of changes in fasting blood glucose (FBG) and body mass index (BMI) before pancreatic cancer diagnosis are not known. We reviewed the medical records of pancreatic cancer cases seen at the Mayo Clinic from 15 January 1981 through to 9 July 2004 and selected those residing within 120 miles of Rochester, MN and who were seen at the Mayo Clinic within 30 days of the date of cancer diagnosis (index date). We identified approximately two matched controls per case residing locally and seen at Mayo in the year of their case index date. For the 736 cases and 1,875 controls with at least one outpatient FBG measurement, we abstracted all FBG values, and corresponding heights and weights up to 60 months before the index date and grouped them into 12-month intervals preceding the index. We compared FBG and BMI in each interval between cases and controls. Mean FBG values were similar between cases, compared with controls, in the intervals from months -60 to -48 (102 mg per 100 ml vs. 100 mg per 100 ml, P=0.34) and from months -48 to -36 (106 mg per 100 ml vs. 102 mg per 100 ml, P=0.09), but progressively increased in the intervals from months -36 to -24 (105 mg per 100 ml vs. 100 mg per 100 ml, P=0.01), from months -24 to -12 (114 mg per 100 ml vs. 102 mg per 100 ml, P=0.001), and from months -12 to +1 (123 mg per 100 ml vs. 102 mg per 100 ml, P<0.0001). Though mean BMI values were generally similar in cases and controls up to 12 months before index, they were significantly lower in cases vs. controls in the interval from months -12 to +1 (P<0.001). Pancreatic cancer is characterized by progressive hyperglycemia beginning up to 24 months before cancer diagnosis in the setting of decreasing BMI. Pancreatic cancer can potentially be diagnosed early if biomarkers are identified that can distinguish pancreatic cancer-induced DM from type II DM.


Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury.
Previous experimental and clinical studies have suggested that the behavioral and pathological outcomes of spinal cord injury (SCI) are affected by the individual's age at the time of injury. However, the underlying mechanism responsible for these differences remains elusive because it is difficult to match injuries of similar severities between young and adult animals due to differences in the sizes of their respective spinal cords. In this study, the spinal cord size-matched young (4-week-old) and adult (10-week-old) mice were compared to evaluate their locomotor functions and inflammatory cellular/molecular responses after standardized contusion SCI. During the acute phase of SCI, young mice showed better functional recovery and lower pro-inflammatory cytokines/chemokines compared to adult mice. Flow-cytometric analysis revealed that the time courses of leukocyte infiltration were comparable between both groups, while the number of infiltrating neutrophils significantly decreased from 6 h after SCI in young mice. By combining flow-cytometric isolation and gene expression analysis of each inflammatory cell fraction, we found that microglial cells immediately initiate the production of several cytokines in response to SCI, which serve as major sources of IL-6, TNFa, and CXCL1 in injured spinal cord. Interestingly, the secretion of pro-inflammatory cytokines/chemokines but not anti-inflammatory cytokines by microglia was significantly lower in young mice compared to that in adult mice at 3 h after SCI, which will be attributed to the attenuation of the subsequent neutrophil infiltration. These results highlight age-related differences in pro-inflammatory properties of microglial cells that contribute to the amplification of detrimental inflammatory responses after SCI.


The hallmarks of cancer: a long non-coding RNA point of view.
With the advent of next generation sequencing methods and progress in transcriptome analysis, it became obvious that the human genome contains much more than just protein-coding genes. In fact, up to 70% of our genome is transcribed into RNA that does not serve as templates for proteins. In this review, we focus on the emerging roles of these long non-coding RNAs (lncRNAs) in the field of tumor biology. Long ncRNAs were found to be deregulated in several human cancers and show tissue-specific expression. Functional studies revealed a broad spectrum of mechanisms applied by lncRNAs such as HOTAIR, MALAT1, ANRIL or lincRNA-p21 to fulfill their functions. Here, we link the cellular processes influenced by long ncRNAs to the hallmarks of cancer and therefore provide an ncRNA point-of-view on tumor biology. This should stimulate new research directions and therapeutic options considering long ncRNAs as novel prognostic markers and therapeutic targets.


Expression of SLP-2 gene and CCBE1 are associated with prognosis of rectal cancer.
This study aims to investigate the clinical significance of SLP-2 gene for patients with rectal cancer. To analyze the effect of CCBE1 (Collagen and calcium-binding EGF domain-containing protein 1) on rectal cancer tissue and lymph vessels of para-carcinoma tissue. A total of 50 samples of rectal cancer tissues were enrolled in the experimental group, confirmed by pathological examination. 50 samples of para-carcinoma normal tissues were collected as control group. Protein expression of SLP-2 and CCBE1 was examined with immunohistochemical staining. mRNA expression of SLP-2 was examined with RT-PCR. Lymphatic vessel density (LVD) was evaluated with LYVE-1 immunohistochemical staining. Correlation analysis was performed to assess the relationship between patient survival data and clinical pathological features of rectal cancer. Immunohistochemical staining showed that, compared with the control group, a positive expression rate of SLP-2 in the experimental group was significantly higher (68.0% vs. 24.0%, p<0.05), and mRNA of SLP-2 was also significantly increased (p<0.05). Compared with the control group, protein expression of CCBE1 in the experimental group was significantly higher (p<0.05). Moreover, the expression level of SLP-2 was remarkably associated with TNM classification and lymphatic metastasis. Further analysis demonstrated that a positive expression of CCBE1 was associated with lymphatic metastasis, LVD and Ducks classification, and had a negative correlation with survival rate. Increased expression of SLP-2 promoted the formation of lymph vessels and exacerbated lymphatic metastasis of rectal cancer via up-regulating CCBE1. As a risk factor related to lymphatic metastasis, CCBE1 could be a novel biomarker for diagnosis and prognosis of rectal cancer.


[Osteoarticular tuberculosis of the bones and joints in children: the present situation and prognosis].
In 1990-2005, a total of 855 children aged 4 months to 17 years were operated on for tuberculous lesions of bones and joints in a specialized department for surgery of childhood osteoarticular tuberculosis, Saint Petersburg Research Institute of Phthisiological Care. Changes in the course of the disease, its structure, and epidemiological features are analyzed. The lines to determine the urgency of the problem of osteoarticular tuberculosis in children within the next few years are given.


Comparison of Large Language Models in Answering Immuno-Oncology Questions: A Cross-Sectional Study.
The capability of large language models (LLMs) to understand and generate human-readable text has prompted the investigation of their potential as educational and management tools for cancer patients and healthcare providers. We conducted a cross-sectional study aimed at evaluating the ability of ChatGPT-4, ChatGPT-3.5, and Google Bard to answer questions related to four domains of immuno-oncology (Mechanisms, Indications, Toxicities, and Prognosis). We generated 60 open-ended questions (15 for each section). Questions were manually submitted to LLMs, and responses were collected on June 30th, 2023. Two reviewers evaluated the answers independently. ChatGPT-4 and ChatGPT-3.5 answered all questions, whereas Google Bard answered only 53.3% (p <0.0001). The number of questions with reproducible answers was higher for ChatGPT-4 (95%) and ChatGPT3.5 (88.3%) than for Google Bard (50%) (p <0.0001). In terms of accuracy, the number of answers deemed fully correct were 75.4%, 58.5%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (p = 0.03). Furthermore, the number of responses deemed highly relevant was 71.9%, 77.4%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (p = 0.04). Regarding readability, the number of highly readable was higher for ChatGPT-4 and ChatGPT-3.5 (98.1%) and (100%) compared to Google Bard (87.5%) (p = 0.02). ChatGPT-4 and ChatGPT-3.5 are potentially powerful tools in immuno-oncology, whereas Google Bard demonstrated relatively poorer performance. However, the risk of inaccuracy or incompleteness in the responses was evident in all three LLMs, highlighting the importance of expert-driven verification of the outputs returned by these technologies. Several studies have recently evaluated whether large language models may be feasible tools for providing educational and management information for cancer patients and healthcare providers. In this cross-sectional study, we assessed the ability of ChatGPT-4, ChatGPT-3.5, and Google Bard to answer questions related to immuno-oncology. ChatGPT-4 and ChatGPT-3.5 returned a higher proportion of responses, which were more accurate and comprehensive, than those returned by Google Bard, yielding highly reproducible and readable outputs. These data support ChatGPT-4 and ChatGPT-3.5 as powerful tools in providing information on immuno-oncology; however, accuracy remains a concern, with expert assessment of the output still indicated.


Thalidomide therapy for myelofibrosis with myeloid metaplasia.
Thalidomide is a putative antiangiogenesis agent with activity in several hematologic malignancies. Forty-four patients who had myelofibrosis with myeloid metaplasia received treatment with thalidomide in a Phase II clinical trial at a dose of 200 mg daily with escalation by 200 mg weekly until the best tolerated dose (maximum, 800 mg) was reached. Seventeen of 41 evaluable patients (41%) who received treatment for at least 15 days had a response. A complete response (without reversal of bone marrow fibrosis) was achieved in 4 patients (10%), a partial response was achieved in 4 patients (10%), and hematologic improvements in anemia, thrombopenia, and/or splenomegaly were observed in 9 patients (21%). Improvements in anemia occurred in 7 of 35 patients (20%) with hemoglobin levels <10.0 g/dL, and improvements in thrombopenia occurred in 5 of 24 patients (21%) with platelet counts <100 x 10(9)/L. Five of 24 patients (21%) became transfusion-independent. Major or minor regression of splenomegaly was noted in 9 of 29 evaluable patients (31%), and complete regression was noted in 5 patients. Responders had a lower baseline median vascular endothelial growth factor levels (77.9 pg/mL vs. 97.7 pg/mL; P <.01) and higher median basis fibroblast growth factor levels (60.8 pg/mL vs. 37.4 pg/mL; P <.01) compared with nonresponders. Nine patients (22%) had deterioration that was attributed to thalidomide (resolved after withdrawal) with either progressive cytopenias or excessive proliferation. Two patients developed Grade 3 neutropenia with recovery and resumed therapy with dose reductions, and both later achieved a complete response. Dose-related toxicities included fatigue (50%), constipation (48%), rash or pruritus (37%), sedation (35%), peripheral edema (29%), tremors (23%), peripheral neuropathy (22%), and orthostasis (16%). Thalidomide warrants further evaluation in patients with MMM, particularly in combination regimens, along with the investigation of newer analogs.


Association of Early Patient-Physician Care Planning Discussions and End-of-Life Care Intensity in Advanced Cancer.
Early patient-physician care planning discussions may influence the intensity of end-of-life (EOL) care received by veterans with advanced cancer. The study objective was to evaluate the association between medical record documentation of patient-physician care planning discussions and intensity of EOL care among veterans with advanced cancer. This was a retrospective cohort study. Subjects were 665 veteran decedents diagnosed with stage IV colorectal, lung, or pancreatic cancer in 2008, and followed till death or the end of the study period in 2011. We estimated the effect of patient-physician care planning discussions documented within one month of metastatic diagnosis on the intensity of EOL care measured by receipt of acute care, intensive interventions, chemotherapy, and hospice care, using multivariate logistic regression models. Veterans in our study were predominantly male (97.1%), white (74.7%), with an average age at diagnosis of 66.4 years. Approximately 31% received some acute care, 9.3% received some intensive intervention, and 6.5% had a new chemotherapy regimen initiated in the last month of life. Approximately 41% of decedents received no hospice or were admitted within three days of death. Almost half (46.8%) had documentation of a care planning discussion within the first month after diagnosis and those who did were significantly less likely to receive acute care at EOL (OR: 0.67; p=0.025). Documented discussions were not significantly associated with intensive interventions, chemotherapy, or hospice care. Early care planning discussions are associated with lower rates of acute care use at the EOL in a system with already low rates of intensive EOL care.


DnaJ potentiates the interaction between DnaK and alpha-helical peptides.
Molecular chaperones bind selectively to nascent, unfolded, misfolded, or aggregated polypeptides, and are involved in protein folding, protein targeting to membranes, and protein renaturation after stress. The DnaK chaperone of Escherichia coli is known to interact preferentially with positively charged hydrophobic peptides in an extended conformation. Accordingly, we show in the present study that DnaK has a low affinity for alpha-helical peptides. In the presence of its co-chaperone DnaJ and ATP, however, DnaK interacts more efficiently with alpha-helical peptides. This suggests that DnaJ triggers a conformational change in DnaK which improves its interaction with these peptides. The ability of the DnaK/DnaJ/GrpE chaperone machine to interact with alpha-helical peptides (which represent the most frequent secondary structure in proteins) should be an important part of its role in protein folding and renaturation.


Evidence-Based Skin Care: A Systematic Literature Review and the Development of a Basic Skin Care Algorithm.
Patients in acute and long-term care settings receive daily routine skin care, including washing, bathing, and showering, often followed by application of lotions, creams, and/or ointments. These personal hygiene and skin care activities are integral parts of nursing practice, but little is known about their benefits or clinical efficacy. The aim of this article was to summarize the empirical evidence supporting basic skin care procedures and interventions and to develop a clinical algorithm for basic skin care. Electronic databases MEDLINE, EMBASE, and CINAHL were searched and afterward a forward search was conducted using Scopus and Web of Science. In order to evaluate a broad range of basic skin care interventions systematic reviews, intervention studies, and guidelines, consensus statements and best practice standards also were included in the analysis. One hundred twenty-one articles were read in full text; 41documents were included in this report about skin care for prevention of dry skin, prevention of incontinence-associated dermatitis and prevention of skin injuries. The methodological quality of the included publications was variable. Review results and expert input were used to create a clinical algorithm for basic skin care. A 2-step approach is proposed including general and special skin care. Interventions focus primarily on skin that is either too dry or too moist. The target groups for the algorithm are adult patients or residents with intact or preclinical damaged skin in care settings. The goal of the skin care algorithm is a first attempt to provide guidance for practitioners to improve basic skin care in clinical settings in order to maintain or increase skin health.


Impact of systemic venous congestion in heart failure.
Systemic venous congestion is one of the hallmarks of the syndrome of heart failure that results from activation of different deleterious neurohormonal pathways. Apart from contributing to patients' symptoms and hospital admissions, growing evidence suggests that congestion itself drives further heart failure progression. In addition, systemic venous congestion exerts detrimental effects on other organs (such as kidneys and liver) due to ineffective organ perfusion. Endothelial cell activation, altered ventricular geometry, and functional mitral insufficiency are among the proposed mechanisms. Diuretics and vasodilators remain the mainstay of treatment options, mostly because of poor understanding of the underlying cardiorenal mechanisms involved. Recently, ultrafiltration has emerged as an invasive treatment option in the setting of diuretic resistance. Congestion ideally should be prevented, often initially through water and salt restriction. Early detection, possibly with the help of novel implantable sensor technology, may allow for early detection and intervention long before overt congestion is established.


Morphometric and colorimetric analyses of human tumor cell line growth and drug sensitivity in soft agar culture.
Previous studies have demonstrated the suitability of image analysis of tetrazolium-stained colonies to assess growth and drug sensitivity of human tumor cells cultivated in soft agar culture. In the present study, the potential utility of colorimetric analysis to expedite experimental drug evaluations using human tumor cell lines was investigated. The same culture dishes were assessed by image analysis and by formazan colorimetry for purposes of comparing multiple methods of measuring growth as well as growth inhibition. Replicate cultures treated with 2-(p-iodonitrophenyl)-3-p-nitrophenyl-5-phenyltetrazolium chloride or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide exhibited nearly identical colony count and volume indices as well as excellent correlation in colorimetric end points. Colony-forming unit volume analysis versus colorimetric assessment of the same cultures following dimethyl sulfoxide extraction of protamine sulfate-rinsed, dried soft agar cultures exhibited excellent linear correlation for both growth (Pearson r ranging from 0.95 to 1.00) and drug sensitivity (Pearson r ranging from 0.90 to 0.99, and Spearman r ranging from 0.82 to 0.97) and similar drug sensitivity profiles. Results of the current investigation indicate that end points of soft agar culture remain stable for a period of at least 2 weeks following assay termination. In addition, a colorimetric detection range of 1.3-2.2 log units permits determinations of survival levels ranging from 100 to 5% of respective control levels. Colorimetric analysis is anticipated to expedite soft agar colony formation assay evaluations (a) by reducing the need to use the more rigorous and time-consuming image analysis procedures to measure activity in preliminary drug sensitivity assays and (b) by permitting the determination of effective concentration ranges of new experimental agents for subsequent, more detailed investigations.


Trends of cigarette smoking and smokeless tobacco use among US firefighters and law enforcement personnel, 1992-2019.
Previous studies indicate tobacco use was more prevalent among firefighters and law enforcement personnel than in the US adult population. Trends of smoking and smokeless tobacco (SLT) use among these first responders are unknown. We examined trends in current smoking and SLT use among US firefighters and law enforcement personnel and compared smoking and SLT use prevalence in firefighters and law enforcement personnel to US adults in non-first-responder occupations. Trends of smoking and SLT use prevalence among firefighters, law enforcement personnel, and adults in other occupations were assessed by fitting joinpoint regression models using the 1992-2019 Tobacco Use Supplement to the Current Population Survey (TUS-CPS). We used multivariable logistic regression models adjusted for demographics to examine associations between occupation and smoking and SLT use status using the 2018-2019 TUS-CPS data. Analyses were conducted in 2021. From 1992 to 2019, the smoking prevalence declined overall (all p's < 0.01). Though SLT use prevalence among adults in non-first-responder occupations declined (annual percentage change [APC] = -1.2%; 95% confidence interval [CI] = -1.7% to -0.7%), no changes were shown among firefighters and law enforcement personnel which suggests SLT use may be increasing among firefighters over time. In 2018-2019, firefighters (adjusted odds ratio [AOR] = 3.4; 95% CI = 1.7 to 6.8) and law enforcement personnel (AOR = 3.2; 95% CI = 2.1 to 4.7) were more likely than adults in non-first-responder occupations to use SLT. While smoking prevalence declined overall, SLT use is higher among firefighters and law enforcement personnel and may be increasing over time among firefighters. Research should examine reasons for SLT use by first responders. Comprehensive tobacco policies and SLT-specific cessation programs are needed for first responders.


[Lysogenic conversion caused by phage phi 80. III. The mapping of the conversion gene and additional characterization of the phenomenon].
The cor gene specifies lysogenic conversion caused by the lambdoid phage phi 80. The cor gene product inhibits tonA function in infected and lysogenic cells. The cells harboring pBR322 plasmid with the cloned cor gene of phi 80 became resistant to the phages T1 and phi 80 (TonA phenotype). The cor gene was mapped between 24 and 13 genes on the phi 80 phage genetic map. It is not essential for phage lytic growth. Its presence in lysogens leads up to accumulation of tonA mutants in a cell population.


Vasectomy by ligation and excision, with or without fascial interposition: a randomized controlled trial [ISRCTN77781689].
Randomized controlled trials comparing different vasectomy occlusion techniques are lacking. Thus, this multicenter randomized trial was conducted to compare the probability of the success of ligation and excision vasectomy with, versus without, fascial interposition (i.e. placing a layer of the vas sheath between two cut ends of the vas). The trial was conducted between December 1999 and June 2002 with a single planned interim analysis. Men requesting vasectomies at eight outpatient clinics in seven countries in North America, Latin America, and Asia were included in the study. The men were randomized to receive vasectomy with versus without fascial interposition. All surgeons performed the vasectomies using the no-scalpel approach to the vas. Participants had a semen analysis two weeks after vasectomy and then every four weeks up to 34 weeks. The primary outcome measure was time to azoospermia. Additional outcome measures were time to severe oligozoospermia (<100 000 sperm/mL) and vasectomy failure based on semen analyses. We halted recruitment after the planned interim analysis, when 841 men had been enrolled. Fascial interposition decreased time to azoospermia (hazard ratio [HR], 1.35; P < 0.0001) and time to severe oligozoospermia (HR, 1.32; P < 0.0001) and reduced failures based on semen analysis by about half, from 12.7% (95% confidence interval [CI], 9.7 to 16.3) to 5.9% (95% CI, 3.8 to 8.6) (P < 0.0001). Older men benefited less from fascial interposition than younger men in terms of the speed of achieving azoospermia. However, the number of vasectomy failures was reduced to a similar degree in all age groups. Slightly more adverse events occurred in the fascial interposition group, but the difference was not significant. These failure rates may appear high to practitioners in countries such as the USA, but they are similar to results from other careful studies of ligation and excision techniques. Fascial interposition significantly improves vasectomy success when ligation and excision is the method of vas occlusion. A limitation of this study is that the correlation between postvasectomy sperm concentrations and risk of pregnancy is not well quantified.


[The Na+-K+ pump and the thermogenesis of brown fatty tissue].
Mechanisms of participation of Na+K(+)-pump in regulation of the brown adipose tissue are discussed. It is settled that the increase in ATP hydrolysis by Na(+)-K(+)-ATPase is not a dominating factor of thermogenesis activation. It is assumed that the Na(+)-K(+)-pump, through the intracellular K+ concentration, serves a chain relating proliferation and thermogenesis of adipocytes.


Inhibitory prostanoid EP receptors in human non-pregnant myometrium.
Prostanoid EP receptor agonists relaxed cloprostenol-stimulated contraction of human non-pregnant myometrium in vitro with pEC50 values of (n = 4): prostaglandin E2, 7.8+/-0.2 > 1-OH prostaglandin E1, 7.2+/-0.3 > misoprostol, 6.6+/-0.1 > 16,16-dimethyl prostaglandin E2, 6.3+/-0.7 > butaprost, 5.7+/-0.3 > 11-deoxy prostaglandin E1, 5.5+/-0.2 = AH13205 ((+)-trans-2-[4-(1hydroxyhexyl)phenyl]-5-oxocyclopentaneheptano ic acid), 5.5+/-0.2. The EP4 receptor antagonist AH23848B ([1alpha(z), 2beta5alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morph olinyl)-3-oxo-cyclopentyl]-4-heptenoic acid) (29 microM) had no effect on concentration-effect curves to the EP receptor agonists. The mixed prostanoid receptor antagonist AH6809 (6-isopropoxy-9-oxaxanthene-2-carboxylic acid) competitively antagonised prostaglandin E2 with a pA2 of 5.6+/-0.2. AH6809 (42 microM) antagonised misoprostol, 11-deoxy prostaglandin E1, and the prostanoid DP receptor agonist BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin) with apparent pA2 values of 5.6+/-0.3, 5.1+/-0.9 and 5.9+/-0.4 (n = 4), respectively, but was ineffective against the IP receptor agonist cicaprost (n = 4). The prostanoid DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)h ydantoin) (50 nM) had no effect on responses to prostaglandin E2 or misoprostol. The presence of an AH6809-sensitive, AH23848B- and BW A868C-insensitive mechanism is consistent with the hypothesis that inhibitory EP receptor agonists cause relaxation of human non-pregnant myometrium by an EP2 receptor-mediated process.


Interaction of cationic peptides with lipoteichoic acid and gram-positive bacteria.
Compounds with antiendotoxin properties have been extensively studied for their potential as therapeutic agents for sepsis attributable to gram-negative bacteria. However, with the increasing incidence of gram-positive sepsis, there is interest in identifying compounds with a broad spectrum of action against both gram-positive and gram-negative bacteria. A series of synthetic alpha-helical cationic peptides related to bee melittin and silk moth cecropin have previously been shown to bind lipopolysaccharide (LPS) with high affinity, inhibit LPS-induced tumor necrosis factor alpha (TNF-alpha) production in vitro and in vivo, and kill gram-negative bacteria. In this study, we analyzed whether these peptides were active against gram-positive bacteria; whether they could bind to lipoteichoic acid (LTA), the major proinflammatory structure on gram-positive bacteria; and whether they could block the ability of LTA to promote the release of cytokines by the RAW 264.7 murine macrophage cell line. We found that the cationic peptides demonstrated moderate growth-inhibitory activity toward gram-positive bacteria. In addition, the peptides bound LTA with high affinity. This correlated with the ability of the peptides to block LTA-induced production of TNF and interleukin-6 by RAW 264.7 cells but did not correlate with their ability to kill the bacteria. The peptides also effectively inhibited LTA-induced TNF production in a whole human blood assay. The peptides were also able to partly block the ability of heat-killed Staphylococcus aureus, as well as soluble products of live S. aureus, to stimulate cytokine production by macrophages. Our results indicate that these cationic peptides may be useful to prevent sepsis and inflammation caused by both gram-negative and gram-positive bacteria.


Effect of motivational interviewing on smoking cessation in pregnant women.
This paper is a report of an evaluation of the effects of a motivational interviewing smoking cessation programme on smoking rates of pregnant women. Cigarette smoking during pregnancy is an important public health problem. Smoking cessation programmes provide women with an opportunity to learn how to protect their own health and that of their developing babies. An intervention study was conducted between December 2007 and June 2008. Thirty-eight pregnant and literate women who were smoking at least one cigarette each day and had not reached their 16th week of pregnancy applied to participate in the research at the prenatal unit of a public hospital. A total of eight home visits was made for each woman with 12- to 13-day intervals between visits; five visits were for intervention, with three follow-up visits at 1-month intervals. The intervention content was based on the transtheoretical model. The data were collected using an evaluation form, carbon monoxide level in expired air, cotinine measurements and a Self-efficacy Scale. A total of 39.5% of pregnant smokers gave up smoking; a further 44.7% reduced their smoking by 60% from their starting rate. The rate of passive smoking before the intervention (86.8%) decreased to 55.3%. The mean (sd) pre-intervention self-efficacy score was 61.36 (12.61), and it increased to 93.34 (27.04) after the intervention. The success of this programme shows the need for further development and application of similar programmes by nurses and midwives working in primary health care and antenatal settings.


Impaired secretion of rat mannose-binding protein resulting from mutations in the collagen-like domain.
Serum mannose-binding protein (MBP) or mannose-binding lectin initiates the lectin branch of the innate immune response by binding to the surface of potentially pathogenic microorganisms and initiating complement fixation through an N-terminal collagen-like domain. Mutations in this region of human MBP are associated with immunodeficiency resulting from a reduction in the ability of the mutant MBPs to fix complement as well as from reduced serum concentrations. Inefficient secretion of the mutant proteins, which is one possible cause of the reduced serum levels, has been investigated using a mammalian expression system in which each of the naturally occurring human mutations has been recreated in rat serum MBP. The mutations Gly25-->Asp and Gly28-->Glu disrupt the disulfide-bonding arrangement of the protein and cause at least a 5-fold increase in the half-time of secretion of MBP compared with wild-type rat serum MBP. A similar phenotype, including a 3-fold increase in the half-time of secretion, disruption of the disulfide bonding arrangement, and inefficient complement fixation, is observed when nearby glucosylgalactosyl hydroxylysine residues at positions 27 and 30 are replaced with arginine residues. The results suggest that defective secretion resulting from structural changes in the collagen-like domain is likely to be a contributory factor for MBP immunodeficiency.


Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models.
Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in patients with neuropathic pain syndromes such as postherpetic neuralgia, though its efficacy is controversial. After the publication of two randomized clinical trials in postherpetic neuralgia patients treated with similar intrathecal methylprednisolone acetate (MPA) dosing regimes with conflicting results; one showing significant pain reduction (Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;23: 1514-9), the other increased pain sensations (Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ: No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;38: 175-200), we decided additional research was warranted. Present study sought to determine effects of intrathecally delivered methylprednisolone on pain-like behaviour and pain-associated markers in three well established rodent pain models: (1) intraplantar carrageenan, (2) intraplantar formalin, and (3) ligation of L5/L6 spinal nerves (SNL model). Male rats with intrathecal catheters were examined for (1) tactile allodynia after unilateral hindpaw intraplantar carrageenan injection (2%), (2) flinching and subsequent long term tactile allodynia after unilateral hindpaw intraplantar formalin injection (2.5%) or (3) tactile allodynia after unilateral ligation of the L5 and L6 spinal nerves. Rats were treated with the maximum tolerable intrathecal dose of the soluble methylprednisolone sodium succinate (MP) or the particulate methylprednisolone acetate (MPA). Dorsal root ganglia and spinal cords were harvested for immunohistochemistry to assess markers of neuronal damage (ATF3) and glial activation (GFAP, Iba1). During dose finding, severe generalized allodynia was observed with high intrathecal doses of both MPA and MP in naive rats. MPA had no effect upon tactile allodynia after carrageenan. MP and MPA did not reverse tactile allodynia in the SNL model, and did not reduce flinching in the formalin model. MP and MPA prevented the delayed (7-day) tactile allodynia otherwise observed in the formalin-injected paw. Systemic MP or perineural MP or MPA did not reduce pain-like behaviour in the SNL model. No reduction of neuronal injury (ATF3) in the dorsal root ganglion or astrocyte activation (GFAP) in the spinal dorsal horn with intrathecal MP or MPA was observed. There was a decrease in microglial activation (Iba1) in the spinal dorsal horn with MPA after SNL. Severe generalized allodynia was observed after high intrathecal doses of MP and MPA in naive rats. No acute analgesic effects with intrathecal glucocorticoids were observed in three well established pain models. Only a late antiallodynic effect was present in the formalin model, 7 days after formalin injection and drug treatment. Our results do not support use of intrathecal methylprednisolone in the treatment of pain.


Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy.
This study evaluated the use of an artificial intelligence platform on mobile devices in measuring and increasing medication adherence in stroke patients on anticoagulation therapy. The introduction of direct oral anticoagulants, while reducing the need for monitoring, have also placed pressure on patients to self-manage. Suboptimal adherence goes undetected as routine laboratory tests are not reliable indicators of adherence, placing patients at increased risk of stroke and bleeding. A randomized, parallel-group, 12-week study was conducted in adults (n=28) with recently diagnosed ischemic stroke receiving any anticoagulation. Patients were randomized to daily monitoring by the artificial intelligence platform (intervention) or to no daily monitoring (control). The artificial intelligence application visually identified the patient, the medication, and the confirmed ingestion. Adherence was measured by pill counts and plasma sampling in both groups. For all patients (n=28), mean (SD) age was 57 years (13.2 years) and 53.6% were women. Mean (SD) cumulative adherence based on the artificial intelligence platform was 90.5% (7.5%). Plasma drug concentration levels indicated that adherence was 100% (15 of 15) and 50% (6 of 12) in the intervention and control groups, respectively. Patients, some with little experience using a smartphone, successfully used the technology and demonstrated a 50% improvement in adherence based on plasma drug concentration levels. For patients receiving direct oral anticoagulants, absolute improvement increased to 67%. Real-time monitoring has the potential to increase adherence and change behavior, particularly in patients on direct oral anticoagulant therapy. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02599259.


Recent advances in idiopathic bilateral vestibulopathy: a literature review.
Idiopathic bilateral vestibulopathy (IBV) is an acquired bilateral peripheral vestibular dysfunction of unknown etiology, with persistent unsteadiness but without sensorineural hearing loss (SNHL) other than age-related hearing loss (ARHL). The prevalence of IBV is unknown. The most common symptom is persistent unsteadiness, particularly in darkness and/or on uneven ground. The other main symptom is oscillopsia during head and body movements. IBV is neither associated with SNHL, except for ARHL, nor any other neurological dysfunction that causes balance disorders. The clinical time course of IBV can generally be divided into two main types: progressive type and sequential type. The progressive type involves gradually progressive persistent unsteadiness without episodes of vertigo. The sequential type involves recurrent vertigo attacks accompanied by persistent unsteadiness. Originally, IBV was found to exhibit bilateral dysfunction in the lateral semicircular canals (LSCCs) and the superior vestibular nerve (SVN) system. However, recently, with the development of more sophisticated vestibular function tests of the otolith organs and vertical semicircular canals, it has been revealed that IBV involves peripheral vestibular lesions other than those already identified in the LSCC and the SVN system. Furthermore, novel subtypes of IBV that do not involve bilateral dysfunction of the LSCC and/or the SVN system have been proposed. Therapeutically, exercise-based vestibular rehabilitation in adult bilateral vestibulopathy (BVP) patients has resulted in improved gaze and postural stability moderately. There are several technical approaches for the treatment of BVP such as vestibular implants, sensory substitution devices and noisy galvanic vestibular stimulation. Combined use of various vestibular function tests, including recently developed tests, revealed the diversity of lesion sites in IBV. Further studies are required to determine the therapeutic effects of the technical approaches on IBV.


Lineage divergence at the first TCR-dependent checkpoint: preferential γδ and impaired αβ T cell development in nonobese diabetic mice.
The first TCR-dependent checkpoint in the thymus determines αβ versus γδ T lineage fate and sets the stage for later T cell differentiation decisions. We had previously shown that early T cells in NOD mice that are unable to rearrange a TCR exhibit a defect in checkpoint enforcement at this stage. To determine if T cell progenitors from wild-type NOD mice also exhibit cell-autonomous defects in development, we investigated their differentiation in the Notch-ligand-presenting OP9-DL1 coculture system, as well as by analysis of T cell development in vivo. Cultured CD4 and CD8 double-negative cells from NOD mice exhibited major defects in the generation of CD4 and CD8 double-positive αβ T cells, whereas γδ T cell development from bipotent precursors was enhanced. Limiting dilution and single-cell experiments show that the divergent effects on αβ and γδ T cell development did not spring from biased lineage choice but from increased proliferation of γδ T cells and impaired accumulation of αβ T lineage double-positive cells. In vivo, NOD early T cell subsets in the thymus also show characteristics indicative of defective β-selection, and peripheral αβ T cells are poorly established in mixed bone marrow chimeras, contrasting with strong γδ T as well as B cell repopulation. Thus, NOD T cell precursors reveal divergent, lineage-specific differentiation abnormalities in vitro and in vivo from the first TCR-dependent developmental choice point, which may have consequences for subsequent lineage decisions and effector functions.


Spatial-temporal evolution of tuberculosis incidence rates in indigenous and non-indigenous people of Brazil, from 2011 to 2022.
To describe the space-time evolution of TB incidence rates (TI) in indigenous and non-indigenous people, according to the Federative Units (UF) of Brazil, from 2011 to 2022. Ecological, temporal, and spatial study on new tuberculosis cases in Brazil among indigenous and non-indigenous populations. Data from the Notifiable Diseases Information System (Sinan) were collected from 2011 to 2022 and stratified by Federal Unit, explored and statistically analyzed using R software version 4.2.3. The mean TI among indigenous populations in Brazil was 71.7 new cases per 100,000 inhabitants, while for non-indigenous populations it was 28.6/100,000 inhabitants. The regions of the country that presented the highest (mean) incidence among indigenous populations were: Central-West (102.8/100,000 inhabitants), Southeast (99.6/100,000 inhabitants), and North (79.9/100,000 inhabitants). For non-indigenous populations the highest incidence was in the North region (36.5/100,000 inhabitants), followed by the Southeast (31.3/100,000), and the Northeast (27,4/100,000 inhabitants). The analysis showed that the highest incidence of TB cases among indigenous populations occurred in the states of: SP, RO, RJ, MS, MT e PA. High incidence of the disease compared to the non-indigenous population show the need for a specific approach to address the health needs of these populations. Regional disparities in incidence indicate the need to address socioeconomic and infrastructure issues that affect the health of indigenous populations.


Acquired resistance of bluegill sunfish Lepomis macrochirus to glochidia larvae of the freshwater mussel Utterbackia imbecillis (Bivalvia: Unionidae) after multiple infections.
The effects of multiple infections on the host-parasite relationship between bluegill sunfish (Lepomis macrochirus) and parasitic glochidial larvae of the freshwater mussel Utterbackia imbecillis were examined. Naïve, young-of-the-year bluegills were infected with glochidia and placed in individual observation chambers. Each day, water was drained from each chamber and the numbers of dead glochidia, live glochidia, partially metamorphosed glochidia, and fully metamorphosed juvenile mussels were counted. The same fishes were infected a total of 4 times. After 2 infections, the fish began to exhibit evidence of acquired resistance to glochidia. During the third and fourth infections, this resistance was clearly evidenced by the marked increase in the percentage of dead and live glochidia shed during the first 5 days of the infection and by the significant decrease in the success of metamorphosis. The total number of glochidia that successfully attached to the fish decreased significantly during the fourth infection relative to the first. The number of larvae attached to the host fish was positively correlated with the size of the fish during the first infection but was negatively correlated during all subsequent infections. Variance to mean ratios indicated that larvae were aggregated among host fishes during the infections. This study has important implications in propagation and conservation efforts of this endangered group of organisms.


Ylide formal [4 + 1] annulation.
Over the past few decades, ylide chemistry has been significantly extended to an area beyond olefination and small ring formation, among which ylide [4 + 1] annulation has been extensively explored, and five-membered ring structures, such as dihydrofurans, isoxazolines, pyrrolines, indoles, dihydropyrazoles and cyclopentenones, can be readily constructed through this type of transformation. An overview of the recent advances in this field is presented herein. Ylide [4 + 1] annulations are reviewed by highlighting their product diversity, selectivity and applicability, and the mechanistic rationale is presented when possible.


Coping with Fear of and Exposure to Terrorism among Expatriates.
This paper examines existing research on the impact of terrorism on expatriate coping strategies. We consider pre-assignment fear of terrorism, in-country coping strategies, and anxiety and posttraumatic stress disorder (PTSD) associated with repatriation. The extant research is small but growing. Our model for expatriate coping at the pre-departure, in-country, and repatriation stages includes strategies specific to each stage. Preparation using proactive coping, systematic desensitization, problem and emotion focused coping, social support, and virtual reality explorations are recommended. Selecting expatriate candidates who are well-adjusted, emotionally intelligent, and possessing good coping skills is essential for successful assignments in terror-prone regions.


Coronary artery imaging in grown up congenital heart disease: complementary role of magnetic resonance and x-ray coronary angiography.
There is a high incidence of anomalous coronary arteries in subjects with congenital heart disease. These abnormalities can be responsible for myocardial ischemia and sudden death or be damaged during surgical intervention. It can be difficult to define the proximal course of anomalous coronary arteries with the use of conventional x-ray coronary angiography. Magnetic resonance coronary angiography (MRCA) has been shown to be useful in the assessment of the 3-dimensional relationship between the coronary arteries and the great vessels in subjects with normal cardiac morphology but has not been used in patients with congenital heart disease. Twenty-five adults with various congenital heart abnormalities were studied. X-ray coronary angiography and respiratory-gated MRCA were performed in all subjects. Coronary artery origin and proximal course were assessed for each imaging modality by separate, blinded investigators. Images were then compared, and a consensus diagnosis was reached. With the consensus readings for both magnetic resonance and x-ray coronary angiography, it was possible to identify the origin and course of the proximal coronary arteries in all 25 subjects: 16 with coronary anomalies and 9 with normal coronary arteries. Respiratory-gated MRCA had an accuracy of 92%, a sensitivity of 88%, and a specificity of 100% for the detection of abnormal coronary arteries. The MRCA results were more likely to agree with the consensus for definition of the proximal course of the coronary arteries (P<0.02). For the assessment of anomalous coronary artery anatomy in patients with congenital heart disease, the use of the combination of MRCA with x-ray coronary angiography improves the definition of the proximal coronary artery course. MRCA provides correct spatial relationships, whereas x-ray angiography provides a view of the entire coronary length and its peripheral run-off. Furthermore, respiratory-gated MRCA can be performed without breath holding and with only limited subject cooperation.


A3D 2.0 Update for the Prediction and Optimization of Protein Solubility.
Protein aggregation propensity is a property imprinted in protein sequences and structures, being associated with the onset of human diseases and limiting the implementation of protein-based biotherapies. Computational approaches stand as cost-effective alternatives for reducing protein aggregation and increasing protein solubility. AGGRESCAN 3D (A3D) is a structure-based predictor of aggregation that takes into account the conformational context of a protein, aiming to identify aggregation-prone regions exposed in protein surfaces. Here we inspect the updated 2.0 version of the algorithm, which extends the application of A3D to previously inaccessible proteins and incorporates new modules to assist protein redesign. Among these features, the new server includes stability calculations and the possibility to optimize protein solubility using an experimentally validated computational pipeline. Finally, we employ defined examples to navigate the A3D RESTful service, a routine to handle extensive protein collections. Altogether, this chapter is conceived to train and assist A3D non-experts in the study of aggregation-prone regions and protein solubility redesign.


A transforming ras gene in tumorigenic guinea pig cell lines initiated by diverse chemical carcinogens.
Fetal guinea pig cells were transformed by treatment with four different chemical carcinogens including nitroso compounds and polycyclic hydrocarbons. As a consequence of this treatment, oncogenes capable of transforming NIH/3T3 cells became activated in each of five independently established clonal guinea pig cell lines. Molecular characterization of representative NIH/3T3 transformants revealed that the same oncogene was present in each of the cell lines tested. Moreover, detection of this transforming gene paralleled the acquisition of tumorigenic properties by these neoplastic cells.


Effect of milking frequency and feeding level before and after dry off on dairy cattle behavior and udder characteristics.
The effects of 2 common dry-off management procedures, feed restriction [8 vs. 16 kg of dry matter (DM)/d] and reduced milking frequency (once, 1x vs. twice, 2x/d), on the behavior and udder characteristics of dairy cattle were assessed in late lactation and the early dry period. Milking cows 1x instead of 2x in the week before dry off reduced milk yield (7.0 vs. 8.9 +/- 0.95 kg/d for 1x and 2x, respectively), but had little effect on behavior before or after cessation of milking. In comparison, feed restriction reduced milk yield (6.9 vs. 9.1 +/- 0.95 kg/d for 8 and 16 kg of DM/d, respectively), udder firmness after dry off (7.3 vs. 8.0 +/- 0.24 g force for 8 and 16 kg of DM/d, respectively), milk leakage (2 d after dry off, 14% of cows offered 8 kg of DM/d were leaking milk compared with 42% cows offered 16 kg of DM/d), and the likelihood of Streptococcus uberis intramammary infection (nonclinical mastitis; 12.5 vs. 62.5% of groups with at least 1 cow with a new intramammary infection for 8 and 16 kg of DM/d, respectively). Despite these benefits, cows offered only 8 kg of DM/d spent less time eating (7.3 vs. 8.3 +/- 0.28 h/d for 8 and 16 kg DM/d, respectively), more time lying (8.8 vs. 7.3 +/- 0.24 h/d), and vocalized more before dry off than cows offered 16 kg of DM/d (0.8 vs. 0.2 +/- 0.15 calls/min for 8 and 16 kg of DM/d, respectively). These behavioral changes indicate that this level of feed restriction may cause hunger. Information is needed about alternative dry-off procedures that maintain the health benefits and comfort associated with lower milk yield before dry off but prevent hunger, such as feeding low quality diets ad libitum.


Aragonite crystalline biomatrices support astrocytic tissue formation in vitro and in vivo.
Astrocytes play a pivotal role in the development and function of the central nervous system by regulating synaptic activity and supporting and guiding growing axons. It is therefore a central therapeutic and scientific challenge to develop means to control astrocytic survival and growth. We cultured primary hippocampal astrocytes on a crystalline three-dimensional (3D) aragonite biomatrix prepared from the exoskeleton of the coral Porites lutea. Such culturing led to the formation of astrocytic tissue-like 3D structures in which the cells had a higher survival rate than astrocytes grown in conventional cell culture. Within the pore void areas, multiple layers of astrocytic processes formed concave sheet structures that had no physical contact with the surface. The astrocytes attached to the crystalline perpendicular edges of the crystalline template surface extended processes in 3D and expressed glial fibrillary acidic protein. The astrocytes also expressed gap junctions and developed partly synchronized cytosolic Ca2+ oscillations. Preliminary in vivo models showed that astrocytic networks were also developed when the matrices were implanted into cortical areas of postnatal rat brains. Hence, we suggest that the biomatrix is a biocompatible supportive scaffold for astrocytes and may be exploited in applications for neuronal tissue restoration in injured or diseased central nervous system.


Manipulating the reported age in earliest memories in a Dutch community sample.
Childhood amnesia in adults can be defined as the relative paucity of autobiographical memories from the first years of life. An earlier study by Wessel, Schweig and Huntjens demonstrated that 'how' we ask for an earliest memory may bias adults' estimations of when the earliest childhood memory actually happened. They suggested that snapshot memories (i.e., mental pictures) were less sensitive to an age manipulation than event memories (i.e. narratives). We aimed at replicating and extending these findings using a Dutch community sample stratified for age, gender and educational level. Participants (N = 619) were randomized into one of three experimental conditions. Prior to recalling their earliest memory, participants in the early and late conditions were presented with examples referring to memories from age 1-2 or 5-6, respectively. The example memories in the control group did not contain any age cues. Participants reported the estimated age in their earliest memory and their strategy for arriving at this estimate. They also rated their memory's phenomenology (e.g. vividness). Independent judges rated memory type (e.g., snapshot memories). Compared to the control group, participants in the early condition estimated the age in their memory to be significantly earlier. The difference between the late and control conditions was too small to be of interest. We did not observe a statistically significant interaction between memory type and condition. Snapshot memories were from a younger age than event memories and showed differences with respect to phenomenology (e.g., emotional intensity). The results of this community study replicate earlier findings that instructions including age cues influence estimates of age in earliest memories. Although snapshot and event memories seem to be qualitatively different, the idea that they respond differently to an age manipulation could not be corroborated.


The T4 molecule differentially regulating the activation of subpopulations of T4+ cells.
It has been demonstrated that the T4+2H4+ subset functioned as a suppressor inducer cell, whereas the reciprocal T4+2H4- subset provided help for B cell Ig production. In the present studies, a series of monoclonal antibodies to cell surface structures expressed on these subsets of cells were examined for their effects on the proliferative and immunoregulatory functions generated in AMLR. We demonstrated that anti-T4 antibody preferentially inhibited the proliferative response of the T4+2H4+ but not T4+2H4- cells against self-MHC antigens. In contrast, anti-T3 and anti-Ia antibodies inhibited the response of both subsets of cells. This subset preference of anti-T4 antibody was not attributable to either the isolation procedures used or a shift in the kinetics of proliferation to autologous self-MHC antigens. Moreover, both IL 2 production and the immunoregulatory function of the T4+2H4+ subset was profoundly inhibited by anti-T4 antibody, whereas the T4+2H4- subset was minimally influenced. In the absence of Ia molecules, T4+2H4+ but not T4+2H4- cell proliferation was inhibited with anti-T4 antibody. Together, these results suggest that the T4 molecule plays a distinct functional role in the differential triggering of subsets of T4+ cells.


The association between specific neuropsychiatric disturbances in people with Alzheimer's disease and dementia with Lewy bodies and carer distress.
Neuropsychiatric symptoms (NPSs) are identified as important care-recipient variables in terms of the impact on carer distress. The aim of this study was to determine whether specific neuropsychiatric disturbances in people with Alzheimer disease (AD) and dementia with Lewy bodies (DLB) differentially impact carer distress. This was a cross-sectional study of people diagnosed with AD and DLB and their primary carers. The Relatives' Stress Scale (RSS) was used to assess the level of reported distress in carers, and the Neuropsychiatric Inventory (NPI) was used to assess NPSs. The effect of NPSs on carer distress was analyzed using correlation analysis and partial least squares regression. This study included 159 participants diagnosed with AD (n = 97) and DLB (n = 62) and their primary carers (spouses and adult children). The majority of people diagnosed with dementia were women (64.2%), with a mean age of 75.9 years (SD, 7.4) and a mean Mini-Mental State Examination (MMSE) score of 23.5 (SD, 2.9). The main analysis identified apathy as the most important NPS contributing to carer distress. Compared with AD, the explained variance in the DLB group was higher (r2 = 37.3 vs r2 = 53.7). In addition, more NPSs were considered clinically important in the DLB group. The findings of this study identify apathy as the most important NPS contributing to carer distress among carers of people with AD and DLB. These findings help us identify the support needs of families dealing with dementia.


[Performance of two new closed ostomy bags of unique design with two different types of cutaneous protectors].
The authors study the performance of two closed bags, Almarys Optima and Almaris Quiet, in ostomized patients in Spain. The behavior of both cutaneous protectors in the two bags is analyzed based on the characteristics of the ostomized patients; security, discretion and comfort levels have been evaluated. It has been evaluated if the characteristics of the ostomized patients influence in the valuation of these new bags. The study has been prospective, multicentric and single blinded. The authors concluded that the valuation of both bags is very positive as much by the users as by the sanitary professionals in charge to carry out the study, although the opportunity stands out to approach the use of one or another one of the bags based on the type of skin and of the physical activity made by the user.


Characteristics and Job Stressors Associated With Turnover and Turnover Intention Among Community Mental Health Providers.
This study aimed to examine the provider characteristics and job stressors that are related to turnover intention and actual turnover among community mental health providers. Secondary analyses were conducted with data collected from 186 community mental health providers from two agencies. Self-reported provider characteristics, job stressors, and turnover intention data were collected with the baseline survey, and actual turnover data were obtained from the agencies 12 months later. Bivariate analyses were conducted to examine factors associated with each turnover variable. Turnover intention and actual turnover were correlated, yet a distinct set of variables was associated with each outcome. Namely, job stressors were related to turnover intention, while provider characteristics were related to actual turnover. Given that both turnover intention and actual turnover have important implications for both providers and agencies, it is critical to consider differential factors associated with each.


Elemental analyses and determination of lead content in kohl (stone) by laser-induced breakdown spectroscopy.
Elemental analyses of kohl (stone) samples collected from three different parts of the world were performed using laser-induced breakdown spectroscopy (LIBS). The analyses indicated that lead (Pb), copper (Cu), silver (Ag), iron (Fe), calcium (Ca), aluminum (Al), silicon (Si), and sodium (Na) were present in all the kohl samples. In addition to these elements, the sample from Madina, Kingdom of Saudi Arabia (KSA), contained the elements tin (Sn), zirconium (Zr), and antimony (Sb). The sample from Mount Toor, Egypt, also contained Sn. Also, quantitative analysis for lead was carried out by the standard addition method using the LIBS technique. The result showed the presence of 14.12 ± 0.28% by weight of Pb in the sample from Madina, which compares well with the measurement done using atomic absorption spectroscopy (AAS) (13.31 ± 0.46%). The standard addition method used three calibration curves drawn for three emission lines of the LIBS spectra of Pb. The limits of detection (LoD) for these calibration curves varied from 0.27% to 1.16% by weight. The lead contents of the samples from Mount Toor and the local market of Bangladesh were also measured by the AAS technique, and the results were 14.61 ± 0.48% and 8.98 ± 0.35% by weight, respectively. The reason for determining only the lead content in kohl, which may be used as an eye cosmetic, is the adverse effect that lead has on health.


A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher.
Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog.


Effects of ultraviolet-B irradiance on intraspecific competition and facilitation of plants: self-thinning, size inequality, and phenotypic plasticity.
(1) The effects of facilitation on the structure and dynamics of plant populations have not been studied so widely as competition. The UV-B radiation, as a typical environmental factor causing stress, may result in direct stress and facilitation. (2) The effects of UV-B radiation on intraspecific competition and facilitation were investigated based on the following three predictions on self-thinning, size inequality, and phenotypic plasticity: i) Self-thinning is the reduction in density that results from the increase in the mean biomass of individuals in crowded populations, and is driven by competition. In this study, the mortality rate of the population is predicted to decrease from UV-B irradiance. ii) The size inequality of a population increases with competition intensity because larger individuals receive a disproportionate share of resources, thereby leaving limited resources for smaller individuals. The second hypothesis assumes that direct stress decreases the size inequality of the population. iii) Phenotypic plasticity is the ability to alter one's morphology in response to environmental changes. The third hypothesis assumes that certain morphological indices can change among the trade-offs between competition, facilitation, and stress. These predictions were tested by conducting a field pot experiment using mung beans, and were supported by the following results: (3) UV-B radiation increased the survival rate of the population at the end of self-thinning. However, this result was mainly due to direct stress rather than facilitation. (4) Just as competitor, facilitation was also asymmetric. It increased the size inequality of populations during self-thinning, whereas stress decreased the size inequality. (5) Direct stress and facilitation influence plants differently on various scales. Stress inhibited plant growth, whereas facilitation showed the opposite on an individual scale. Stress increased survival rate, whereas facilitation increased individual variability on the population scale. (6) Trade-offs between competitions, facilitation, and direct stress varied in different growing stages.


Semi-quantitative measurement of Plasmodium falciparum antigen PfHRP2 in blood and plasma.
Plasmodium falciparum histidine rich protein 2 (PfHRP2) antigen was measured semi-quantitatively in whole blood, plasma, and supernatants and red blood cells of cultures in vitro using the dipstick ParaSight-F test and also by a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA). In vitro, PfHRP2 was secreted mainly during the second half of the asexual cycle with a marked rise during schizont development and rupture. The total PfHRP2 secreted before schizogony corresponded to approximately 4% of that contained in the red blood cells. In samples from 55 patients with acute falciparum malaria, the level of detection by ELISA corresponded to parasitaemias of 100/microL for whole blood and 1600/microL for separated plasma. Whole blood PfHRP2 levels were correlated significantly with admission parasitaemia (r = 0.76, P < 0.0001) and the stage of parasite development (r = 0.43, P < 0.01). Although whole blood PfHRP2 concentrations were higher in severe malaria, plasma concentrations of PfHRP2 were considerably higher in severe malaria (median titre 1:320, range zero to 1:1280) than in uncomplicated malaria (median titre 1:5, range zero to 1:80; P < 0.0001). The ratio of whole blood to plasma PfHRP2 was lower in severe than in uncomplicated malaria (median 4, range 0.25 to 256, versus 64, range 4 to 1280; P < 0.0001). With plasma samples the intensity of colour change on the dipstick correlated well with more precise measurement of optical density in the ELISA (r = 0.88, P < 0.0001). These results suggest that measurement of PfHRP2 in plasma could provide an alternative approach to the assessment of the parasite biomass, and thus prognosis, in severe malaria, and that this could be done simply by using the currently available dipsticks.


Synesthesia: a new approach to understanding the development of perception.
In this article, the authors introduce a new theoretical framework for understanding intersensory development. Their approach is based upon insights gained from adults who experience synesthesia, in whom sensory stimuli induce extra cross-modal or intramodal percepts. Synesthesia appears to represent one way that typical developmental mechanisms can play out by magnifying connections present in early life that are pruned and/or inhibited during development but persist in muted form in all adults. As such, the study of synesthesia provides valuable insights into the nature of intersensory development. The authors review evidence on the perceptual reality and neural basis of synesthesia, then summarize developmental models and evidence that its underlying mechanisms are universal in adults. They illustrate how evidence for consistent sensory associations in adults leads to predictions about toddlers' perception and present 3 bodies of work that have confirmed those hypotheses. They end by describing novel hypotheses about intersensory development that arise from this framework. Such intersensory associations appear to reflect intrinsic sensory cortical organization that influences the development of perception and of language and that may constrain the learning of environmentally based associations.


Analysis of suicidality in pooled data from 2 double-blind, placebo-controlled aripiprazole adjunctive therapy trials in major depressive disorder.
To assess the impact of adjunctive aripiprazole versus adjunctive placebo treatment on suicidality in patients with major depressive disorder. Data were pooled from 2 identical aripiprazole augmentation studies. Patients with DSM-IV-TR-diagnosed major depressive disorder with an inadequate response to 8 weeks of prospective antidepressant treatment were randomly assigned to adjunctive placebo or adjunctive aripiprazole (2-20 mg/d) treatment for 6 weeks. Adverse events related to suicidality were identified in the adverse event database using the Medical Dictionary for Regulatory Activities-preferred term. Treatment-emergent suicidal ideation was defined using item 10 (suicidality) of the Montgomery-Åsberg Depression Rating Scale (MADRS) and item 18 (suicidality) of the Inventory of Depressive Symptomatology (IDS). In total, 737 patients were included in the safety database (aripiprazole n = 371; placebo n = 366). No suicides were reported. There were no treatment-emergent, suicide-related adverse events in the aripiprazole group; 2 patients in the placebo group had ≥ 1 adverse event related to suicide (both suicidal ideation). More placebo than aripiprazole patients > 25 years old experienced a 2-point (P < .01) or 1-point (P < .05) worsening of MADRS item 10 scores. For this age group, 2-point improvement in MADRS item 10 scores and 1-point improvement of IDS item 18 scores were significantly more common in aripiprazole patients than placebo patients (both P < .05). This post hoc analysis demonstrated that adjunctive aripiprazole treatment in patients with depression with a history of an inadequate response to antidepressant medication is associated with a decreased rate of suicidality in a group of subjects not at significant risk. Prospective trials directly assessing suicidality are needed to further understand the benefits of an adjunctive antipsychotic in an at-risk population. clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.


Revision of Coprosma (Rubiaceae, tribe Anthospermeae) in the Marquesas Islands.
During the preparation of the Vascular Flora of the Marquesas Islands three new species of Coprosma (Rubiaceae, tribe Anthospermeae) have come to light and are described herein: Coprosma fatuhivaensis W. L. Wagner & Lorence, Coprosma meyeri W. L. Wagner & Lorence, and Coprosma temetiuensis W. L. Wagner & Lorence. Descriptions, illustrations, conservation status, and specimen citations are provided. Amended descriptions of three previously described Marquesan Coprosma species are also provided as well as a key to the species, four of which fall into the Critically Endangered (CR) and two into the Endangered (EN) category. With the description of these the new species, Coprosma becomes the sixth largest lineage in the Marquesas Islands with six species after Psychotria (one lineage which has 9 spp.), Cyrtandra (8 spp.), Bidens (8 spp.), Melicope (7 spp.), and Ixora (7 spp.).


Rebuilding Body-Brain Interaction from the Vagal Network in Spinal Cord Injuries.
Spinal cord injuries (SCIs) exert devastating effects on body awareness, leading to the disruption of the transmission of sensory and motor inputs. Researchers have attempted to improve perceived body awareness post-SCI by intervening at the multisensory level, with the integration of somatic sensory and motor signals. However, the contributions of interoceptive-visceral inputs, particularly the potential interaction of motor and interoceptive signals, remain largely unaddressed. The present perspective aims to shed light on the use of interoceptive signals as a significant resource for patients with SCI to experience a complete sense of body awareness. First, we describe interoceptive signals as a significant obstacle preventing such patients from experiencing body awareness. Second, we discuss the multi-level mechanisms associated with the homeostatic stability of the body, which creates a unified, coherent experience of one's self and one's body, including real-time updates. Body awareness can be enhanced by targeting the vagus nerve function by, for example, applying transcutaneous vagus nerve stimulation. This perspective offers a potentially useful insight for researchers and healthcare professionals, allowing them to be better equipped in SCI therapy. This will lead to improved sensory motor and interoceptive signals, a decreased likelihood of developing deafferentation pain, and the successful implementation of modern robotic technologies.


Occupational asthma due to methyl methacrylate and cyanoacrylates.
Five patients had asthma provoked by cyanoacrylates and one by methyl methacrylate, possibly because of the development of a specific hypersensitivity response. Acrylates have wide domestic as well as industrial uses, and inhalation of vapour emitted during their use can cause asthma.


Circular RNA ZFR accelerates non-small cell lung cancer progression by acting as a miR-101-3p sponge to enhance CUL4B expression.
Non-small-cell lung carcinoma (NSCLC) is the most common type of lung cancer. Circular RNA ZFR (circZFR) is an identified circular RNA (circRNA) that is correlated with cancer progression. However, the role of circZFR in NSCLC remains unknown. In the present study, we aimed to investigate the function of circZFR in NSCLC and the underlying mechanism. The expression patterns of circZFR were determined using qRT-PCR in NSCLC samples and cell lines. The subcellular distribution of circZFR in NSCLC cells was analyzed by fluorescence in situ hybridization (FISH). Cell proliferation was examined utilizing the CCK-8 assay. Cell migration and invasion were evaluated using the Transwell assay. We used the bioinformatics software TargetScan and miRanda to predict circRNA-miRNA and miRNA-mRNA interactions. Our results showed that circZFR expressions were significantly upregulated in NSCLC tissues and cell lines. Knockdown of circZFR significantly inhibited the cell proliferation, migration and invasion of NSCLC cells in vitro. Furthermore, we demonstrated that circZFR acted as a sponge to absorb microRNA-101-3p (miR-101-3p) and promoted cullin 4B (CUL4B) expression. Collectively, our results demonstrated that circZFR exhibited a carcinogenic role by sponging miR-101-3p and regulating CUL4B expression in NSCLC. These findings provided evidence for understanding the role of circZFR in NSCLC tumourigenesis.


A review of the effectiveness of operational curtailment for reducing bat fatalities at terrestrial wind farms in North America.
Curtailment of turbine operations during low wind conditions has become an operational minimization tactic to reduce bat mortality at terrestrial wind energy facilities. Site-specific studies have demonstrated that bat activity is higher during lower wind speeds and that operational curtailment can effectively reduce fatalities. However, the exact nature of the relationship between curtailment cut-in speed and bat fatality reduction remains unclear. To evaluate the efficacy of differing curtailment regimes in reducing bat fatalities, we examined data from turbine curtailment experiments in the United States and Canada in a meta-analysis framework. We used multiple statistical models to explore possible linear and non-linear relationships between turbine cut-in speed and bat fatality. Because the overall sample size for this meta-analysis was small (n = 36 control-treatment studies from 17 wind farms), we conducted a power analysis to assess the number of control-treatment curtailment studies needed to understand the relationship between fatality reduction and change in cut-in speed. We also identified the characteristics of individual curtailment field studies that may influence their power to detect fatality reductions, and in turn, contribute to future meta-analyses. We found strong evidence that implementing turbine curtailment reduces fatality rates of bats at wind farms; the estimated fatality ratio across all studies was 0.37 (p < 0.001), or a 63% decrease in fatalities. However, the nature of the relationship between the magnitude of treatment and reduction in fatalities was more difficult to assess. Models that represented the response ratio as a continuous variable (e.g., with a linear relationship between the change in cut-in speed and fatalities) and a categorical variable (to allow for possible non-linearity in this relationship) both had substantial support when compared using AICc. The linear model represented the best fit, likely due to model simplicity, but the non-linear model was the most likely without accounting for parsimony and suggested fatality rates decreased when the difference in curtailment cut-in speeds was 2m/s or larger. The power analyses showed that the power to detect effects in the meta-analysis was low if fatality reductions were less than 50%, which suggests that smaller increases in cut-in speed (i.e., between different treatment categories) may not be easily detectable with the current dataset. While curtailment is an effective operational mitigation measure overall, additional well-designed curtailment studies are needed to determine precisely whether higher cut-in speeds can further reduce bat fatalities.


Exploring "patient-centered" hospitals: a systematic review to understand change.
The healthcare scenario in developed countries is changing deeply: patients, who are frequently affected by multi-pathological chronic conditions, have risen their expectations. Simultaneously, there exist dramatic financial pressures which require healthcare organizations to provide more and better services with equal (or decreasing) resources. In response to these challenges, hospitals are facing radical transformations by bridging, redesigning and engaging their organization and staff. This study has the ambitious aim to shed light and clearly label the trends of change hospitals are enhancing in developed economies, in order to fully understand the presence of common trends and which organizational models and features are inspiring the most innovative organizations. The purpose is to make stock of what is known in the field of hospital organization about how hospitals are changing, as well as of how such change may be implemented effectively through managerial tools. To do so the methodology adopted integrates a systematic literature review to a wider engaged research approach. Evidence suggests that the three main pillars of change of the system are given by the progressive patient care model, the patient-centered approach and the lean approach. However, there emerge a number of gaps in what is known about how to exploit drivers of change and their effects. This study confirms that efforts in literature are concentrated in analyzing circumscribed experiences in the implementation of new models and approaches, failing therefore to extend the analysis at the organizational and inter-organizational level in order to legitimately draw consequences to be generalized. There seem to be a number of "gaps" in what is known about how to exploit drivers of change and their effects, suggesting that the research approach privileged till now fails in providing a clear guidance to policy makers and to organizations' management on how to concretely and effectively implement new organizational models.


MTFR2, A Potential Biomarker for Prognosis and Immune Infiltrates, Promotes Progression of Gastric Cancer Based on Bioinformatics Analysis and Experiments.
Background: Mitochondrial fission regulator 2 (MTFR2) which can promote mitochondrial fission, has recently been reported to be involved in tumorigenesis. However, little is known about its expression levels and function in gastric cancer (GC). This study aims to clarify the role of MTFR2 in GC. Methods:We firstly determined the expression level and prognostic value of MTFR2 in GC by integrated bioinformatics (Oncomine, GEPIA, Kaplan-Meier Plotter database) and experimental approaches (RT-qPCR, western blot, immunohistochemistry). After constructing stable down-regulated GC cells, the biological functions of MTFR2 in vitro and in vivo were studied through cell clone formation, wound healing, transwell and tumor formation experiments.To understand the reason for the high expression of MTFR2 in GC, copy number alternation, promoter methylation and mutation of MTFR2 were detected by UALCAN and cBioPortal. TargetScanHuman and PROMO databases were also used to explore the miRNAs and transcription factors of MTFR2, and the regulatory network was visualized by Cytoscape. LinkedOmics was used to detect the co-expression profile, and then these co-expressed genes were used for gene oncology function and pathway enrichment analysis to deepen the understanding of MTFR2 mechanism. The protein interaction network of MTFR2 was constructed by the GeneMANIA platform. Docking study of the binding mode was conducted by H DOCK webserver, and PYMOL is used for visualization, and analysis. TIMER database was used to explore the correlation between MTFR2 expression level and immune cells infiltration and gene markers of tumor infiltrating immune cells. Results: We demonstrated that MTFR2 was up-regulated in GC, and its overexpression led to poorer prognosis. MTFR2 downregulation inhibited the proliferation, migration, and invasion of GC cells in vitro and in vivo. By bioinformatics analysis, we identified the possible factors in MTFR2 overexpression. Moreover, function and pathway enrichment analyses found that MTFR2 was involved in chromosome segregation, catalytic activity, cell cycle, and ribonucleic acid transport. A MTFR2-protein interaction network revealed a potential direct protein interaction between MTFR2 and protein kinase adenosine-monophosphate-activated catalytic subunit alpha 1 (PRKAA1), and their potential binding site was predicted in a molecular docking model. In addition, we also found that MTFR2 may be correlated with immune infiltration in GC. Conclusions: Our study has effectively revealed the expression, prognostic value, potential functional networks, protein interactions and immune infiltration of MTFR2 in GC. Altogether, our data identify the possible underlying mechanisms of MTFR2 and suggest that MTFR2 may be a prognostic biomarker and therapeutic target in GC.


Pitfalls and artefacts using contrast enhanced ultrasound.
Ultrasound is the method of choice in the detection and characterization of diffuse and focal organic diseases. For B-mode and colour (power) Doppler ultrasound, besides manual skills, (hands-on) a technical knowledge about ultrasound images is of the upmost importance for the investigator. Contrast enhanced ultrasound (CEUS) has become an important diagnostic tool for hepatic, renal, pancreatic indications and several others due to: (a) an increasing rate of studies resulting in sufficient evidence especially in hepatic indications, (b) a rate of adverse events close to zero (1:10,000 in comparison to iodinated contrast agents from 1-12:100) enabling the application of CEUS in patients with severe renal insufficiency or thyroid gland autonomy, and (c) a reasonable price (depends on the country and influence of the health-care system [reimbursement]) and the dosage used. Mini-doses from 0.1 to 0.4 mL are used depending on the contrast agent and applied indication. Therefore a well founded knowledge concerning the technical aspects of CEUS is important for the investigator to avoid misinterpretation especially when artefacts specific for CEUS occur. Special literature is rare. In the presented article we present pitfalls concerning CEUS. The following aspects are considered and illustrated by images: (i) acoustic power (mechanical index) and other aspects resulting in micro bubble destruction, (ii) the possibility of false positive contrast signals in non-vascularized areas, (iii) attenuation caused by too high contrast agent dose, (iv) influence of the frame rate on the spatial resolution, (v) dealing with deep located lesions, (vi) differences in focus positioning in detection and characterization studies, (vii) advantages and disadvantages of replenishment studies, (viii) reliability of contrast enhanced spectral Doppler measurements.


Panniculitis in children.
This paper will give a comprehensive view of the most frequent panniculitides seen in childhood, with emphasis on the types exclusively found in infancy, and for all other types of panniculitides also found in adults. Aim of this paper is also to analyze the clinical differences between panniculitis in childhood and in adulthood, and to give reliable histopathologic criteria for a specific diagnosis. A review of the literature is here integrated by authors' personal contribution. Panniculitides in children is a heterogeneous group of diseases, as well as in adult life, characterized by inflammation of the subcutaneous fat. Only very few types of panniculitis are exclusively found in childhood, such as Sclerema neonatorum and subcutaneous fat necrosis of the newborn, while the vast majority of the other types may be found both in paediatric age and in adults. Furthermore, this paper will consider in detail panniculitis according to their frequency, such as Erythema nodosum, Lupus panniculitis, Cold panniculitis, panniculitis in Behçet disease, and poststeroid panniculitis. It will also describe rare forms of panniculitis, such as Eosinophilic panniculitis (a pathological entity debated by many authors), Subcutaneous panniculitis T-cell lymphoma, and the different forms of the so call "Lipophagic panniculitis", encompassing respectively the febrile relapsing panniculitis of Weber-Christian disease and the non-relapsing form of Rothmann-Makai disease. For each type of panniculitis considered concise information will be given about epidemiology, etiology, clinical findings, laboratory data, prognosis and therapy, while histopathologic findings will be described in detail.


Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.


Exposure to cigarette smoke precipitates simple hepatosteatosis to NASH in high-fat diet fed mice by inducing oxidative stress.
Consumption of diet rich in fat and cigarette smoking (CS) are independent risk factors of non-alcoholic steatohepatitis (NASH), and they often occur together in some populations. The present study investigated the mechanisms of high-fat diet (HFD) and CS, individually and in combination, on the pathogenesis of NASH in mice. C57BL/6 male mice were subjected to either a low-fat chow (CH) or HFD with or without mainstream CS-exposure (4 cigarettes/day, 5 days/ week for 14 weeks). HFD alone caused hepatosteatosis (2.5-fold increase in TG content) and a significant increase in 3-nitrotyrisine (by ∼40-fold) but without an indication of liver injury, inflammation or fibrosis. CS alone in CH-fed mice increased in Tnfα expression and macrophage infiltration by 2-fold and relatively less increase in 3-nitrotyrosine (18-fold). Combination of HFD and CS precipitated hepatosteatosis to NASH reflected by exacerbated makers of liver inflammation and fibrosis which were associated with much severe liver oxidative stress (90-fold increase in 3-nitrotyrisine along with 6-fold increase in carbonylated proteins and 56% increase in lipid oxidations). Further studies were performed to administer the antioxidant tempol to CS exposed HFD mice and the results showed that the inhibition of liver oxidative stress prevented inflammatory and fibrotic changes in liver despite persisting hepatosteatosis. Our findings suggest that oxidative stress is a key mechanism underlying CS-promoted progression of simple hepatosteatosis to NASH. Targeting hepatic oxidative stress may be a viable strategy in halting the progression of metabolic associated fatty liver disease.


The Surveillance After Extremity Tumor Surgery (SAFETY) trial: protocol for a pilot study to determine the feasibility of a multi-centre randomised controlled trial.
Following the treatment of patients with soft tissue sarcomas (STS) that are not metastatic at presentation, the high risk for local and systemic disease recurrence necessitates post-treatment surveillance. Systemic recurrence is most often detected in the lungs. The most appropriate surveillance frequency and modality remain unknown and, as such, clinical practice is highly varied. We plan to assess the feasibility of conducting a multi-centre randomised controlled trial (RCT) that will evaluate the effect on overall 5-year survival of two different surveillance frequencies and imaging modalities in patients with STS who undergo surgical excision with curative intent. The Surveillance After Extremity Tumor Surgery trial will be a multi-centre 2×2 factorial RCT. Patients with non-metastatic primary Grade II or III STS treated with excision will be allocated to one of four treatment arms1: chest radiograph (CXR) every 3 months for 2 years2; CXR every 6 months for 2 years3; chest CT every 3 months for 2 years or4 chest CT every 6 months for 2 years. The primary outcome of the pilot study is the feasibility of a definitive RCT based on a combination of feasibility endpoints. Secondary outcomes for the pilot study include the primary outcome of the definitive trial (overall survival), patient-reported outcomes on anxiety, satisfaction and quality of life, local recurrence-free survival, metastasis-free survival, treatment-related complications and net healthcare costs related to surveillance. This trial received provisional ethics approval from the McMaster/Hamilton Health Sciences Research Ethics Board on 7 August 2019 (Project number 7562). Final ethics approval will be obtained prior to commencing patient recruitment. Once feasibility has been established and the definitive protocol is finalised, the study will transition to the definitive study. NCT03944798; Pre-results.


The Relationship between Age at Initiation of Regular Drinking of Alcohol and Viral Suppression Status, and Depression Symptoms Among People Living with HIV in South-Western Uganda.
Alcohol use is an important factor in achieving and maintaining viral suppression and optimal mental health among persons with HIV (PWH), however, the effect of age at first regular drinking on viral suppression and depression remains poorly understood. Here, using secondary data from the Alcohol Drinkers' Exposure to Preventive Therapy for Tuberculosis (ADEPT-T) study, we used logistic regression analyses to explore whether there is an association between age at first regular drinking and viral suppression (< 40 copies/ml), or presence of depressive symptoms (Center for Epidemiologic Studies Depression, CES-D ≥ 16) among 262 PWH. The median age at first regular drinking was 20.5 years (IQR: 10), with high proportions starting under age 12 (12.2%) and as teens (13.4%). The majority had an undetectable viral load (91.7%) and 11% had symptoms of probable depression. We found no significant association between age at first regular drinking and viral suppression (i.e., child (aOR = 0.76 95%CI: 0.18, 3.26), adolescent (aOR = 0.74 95%CI: 0.18, 2.97) and young adult (aOR = 1.27 95%CI: 0.40, 3.97)) nor with depressive symptoms (i.e., child (aOR = 0.72 95%CI: 0.19, 2.83), adolescent (aOR = 0.59 95%CI: 0.14, 2.50) and young adult (aOR = 0.57 95%CI: 0.22, 1.53)). Age at first regular drinking among PWH did not appear to be associated with either viral suppression or the presence of depressive symptoms, suggesting interventions may best be focused on the harmful effects of current alcohol use.


Safety and feasibility of intra-arterial delivery of teniposide to high grade gliomas after blood-brain barrier disruption: a case series.
This case series describes the safety and efficacy of superselective intra-arterial (IA) cerebral infusion of teniposide for the treatment of patients with glioma, to provide new ideas and methods for the treatment of high grade gliomas. 12 patients with glioma who were previously treated with standard therapy were treated with superselective IA cerebral infusion of teniposide. Patients received at least two cycles of treatment (one cycle: 150 mg/time, used for 1 day, repeated at 28 day intervals) after blood-brain barrier disruption. Patients received individualized treatment on the tumor location. The ophthalmic artery was bypassed during the super-selective arterial infusion. No significant differences in biochemical indexes and Karnofsky performance status (KPS) score were observed before and after treatment, and no evident adverse events occurred (P>0.05). In a recent response evaluation (August 2023), two (8%) patients presented with a complete response (16.7%), four had a partial response (33.3%), four had stable disease (33.3%), and two showed progressive disease (16.7%). The overall response rate and disease control rate were 50.0% and 83.3%, respectively. In addition, we described the detailed course of treatment in two patients. Case No 1 (recurrent tumor) and case No 2 (primary tumor) received six and three cycles of teniposide infusion, respectively. After treatment, the tumors of the patients were significantly reduced without evident adverse effects. This small series suggests that superselective IA cerebral infusion of teniposide may be a safe and effective therapy in the multimodal treatment of malignant glioma and warrants further study in larger prospective investigations.


Tegumental ultrastructure of the juvenile and adult Himasthla alincia (Digenea: Echinostomatidae).
The tegumental ultrastructure of juvenile and adult Himasthla alincia (Digenea: Echinostomatidae) was observed by scanning electron microscopy. One-, 5- (juveniles) and 20-day-old worms (adults) were harvested from chicks experimentally fed metacercariae from a bivalve, Mactra veneriformis. The juvenile worms were elongated and curved ventrally. The head crown bore 31 collar spines, arranged in a single row. The lip of the oral sucker had 12 paired, and 3 single type I sensory papillae, and the ventral sucker had about 25 type II sensory papillae. The anterolateral surface between the two suckers was densely packed with tegumental spines with 4-7 pointed tips. The adult worms were more elongated and filamentous, and had severe transverse folds over the whole body surface. On the head crown and two suckers, type I and II sensory papillae were more densely distributed than in the juvenile worms. Retractile brush-like spines, with 8-10 digits, were seen on the anterolateral surface, whereas claw-shaped spines, with 2-5 digits, were sparsely distributed posteriorly to the ventral sucker. The cirrus characteristically protruded out, and was armed with small spines distally. The surface ultrastructure of H. alincia was shown to be unique among echinostomes, especially in the digitation of its tegumental spines, the distribution of sensory papillae and by severe folds of the tegument.