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The broad contemporary applications of silver nanoparticles (AgNPs) have been associated with various toxicities including reproductive toxicity. Taurine is well acknowledged for its potent pharmacological role in numerous disease models and chemically-mediated toxicity. We investigated the effect of taurine on AgNPs-induced reproductive toxicity in male rats. The animals were intraperitoneally injected with AgNPs (200 µg/kg) alone or co-administered with taurine at 50 and 100 mg/kg for 21 successive days. Exogenous taurine administration significantly abated AgNPs-induced oxidative injury by decreasing the levels of oxidative stress indices while boosting antioxidant enzymes activities and glutathione level in the hypothalamus, testes and epididymis of exposed animals. Taurine administration alleviated AgNPs-induced inflammatory response and caspase-3 activity, an apoptotic biomarker. Moreover, taurine significantly improved spermiogram, reproductive hormones and the marker enzymes of testicular function in AgNPs-treated animals. The ameliorative effect of taurine on pathological lesions induced by AgNPs in the exposed animals was substantiated by histopathological data. This study provides the first mechanistic evidence that taurine supplementation affords therapeutic effect against reproductive dysfunction associated with AgNPs exposure in male rats.

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Clostridium difficile (Clostridioides difficile) is a leading cause of nosocomial infections in hospitalized patients worldwide. Stool samples were collected from 112 inpatients admitted to different hospitals and were screened for C. difficile GDH + toxin A + B by immunoassay, and all positive samples by immunoassay were processed for molecular detection of C. difficile using the GeneXpert assay. C. difficile strains were detected in 12 (10.71%) out of 112 stool samples using the GDH + toxin A + B immunoassay method and toxigenic C. difficile was confirmed in 5 stool samples using the GeneXpert molecular assay. C. difficile strains were also detected in 7 (8.97%) out of 78 stool samples from intensive care unit patients, 3 (25%) out of 12 stool samples from internal medicine ward patients, 1 (11.11%) out of 9 stool samples from surgery ward patients, and 1 (10%) out of 10 stool samples from isolation ward patients using the GDH + toxin A + B immunoassay method and the toxigenic C. difficile strain was confirmed in 1, 2, 1, and 1 stool samples, respectively, using the GeneXpert molecular assay. Toxigenic C. difficile was confirmed in patients at 4 (51.14%) out of 7 hospitals. In the present study, we also analyzed the clinical information of patients with C. difficile-positive stool samples who were receiving one or more antibiotics during hospitalization. The binary toxin gene (cdt), the tcdC gene, and the C. difficile strain polymerase chain reaction (PCR) ribotype 027 were not detected using the GeneXpert molecular assay among 12 C. difficile-positive samples by immunoassay. This study should aid in the prevention of unnecessary empiric therapy and increase the understanding of the toxigenic C. difficile burden on the healthcare system in the southwestern province of Saudi Arabia.

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The adverse effect of silver nanoparticles (AgNPs) on the nervous system is an emerging concern of public interest globally. Taurine, an essential amino acid required for neurogenesis in the nervous system, is well-documented to possess antioxidant, anti-inflammatory, and antiapoptotic activities. Yet, there is no report in the literature on the effect of taurine on neurotoxicity related to AgNPs exposure. Here, we investigated the neurobehavioral and biochemical responses associated with coexposure to AgNPs (200 µg/kg body weight) and taurine (50 and 100 mg/kg body weight) in rats. Locomotor incompetence, motor deficits, and anxiogenic-like behavior induced by AgNPs were significantly alleviated by both doses of taurine. Taurine administration enhanced exploratory behavior typified by increased track plot densities with diminished heat maps intensity in AgNPs-treated rats. Biochemical data indicated that the reduction in cerebral and cerebellar acetylcholinesterase activity, antioxidant enzyme activities, and glutathione level by AgNPs treatment were markedly upturned by both doses of taurine. The significant abatement in cerebral and cerebellar oxidative stress indices namely reactive oxygen and nitrogen species, hydrogen peroxide, and lipid peroxidation was evident in rats cotreated with AgNPs and taurine. Further, taurine administration abated nitric oxide and tumor necrosis factor-alpha levels cum myeloperoxidase and caspase-3 activities in AgNPs-treated rats. Amelioration of AgNPs-induced neurotoxicity by taurine was confirmed by histochemical staining and histomorphometry. In conclusion, taurine via attenuation of oxido-inflammatory stress and caspase-3 activation protected against neurotoxicity induced by AgNPs in rats.

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Industry Revolution 4.0 pushes the industry to digitize all its operations. Cyberphysical Systems (CPSs), such as autonomous automobile systems and medical monitoring are examples of this revolution. However, as these systems are interconnected via the Internet, they become more vulnerable to cyber-attacks and in particular, stealthy attacks. Cyber attacks could affect the operations of CPS and cause physical damages before any indication. So, there is a need to design a secure control system to withstand in these circumstances. In this article, an event-triggering control scheme is designed for discrete time CPSs contain random delays in measurements and actuation signals and subject to simultaneous hybrid distributed denial of service (DDoS) and deception attacks. The cyber attacks are designed as Bernoulli distributed white sequences with conditional probabilities that are variable. Moreover, An event-triggering control scheme is proposed for decreasing the communication overhead in the system, such that the measurements' signals are sent when a selected triggering condition is met. An observer based control is designed to maintain the stability of the CPS under all possible scenarios of single or hybrid simultaneous attacks in the forward and or backward communication. Linear matrix inequalities are used to represent the overall control scheme. At the end, two illustrative examples are presented and discussed to show the effectiveness of the presented scheme.

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Several studies have documented the burden and risk factors associated with diarrhoea in low and middle-income countries (LMIC). To the best of our knowledge, the contextual and compositional factors associated with diarrhoea across LMIC were poorly operationalized, explored and understood in these studies. We investigated multilevel risk factors associated with diarrhoea among under-five children in LMIC. We analysed diarrhoea-related information of 796,150 under-five children (Level 1) nested within 63,378 neighbourhoods (Level 2) from 57 LMIC (Level 3) using the latest data from cross-sectional and nationally representative Demographic Health Survey conducted between 2010 and 2018. We used multivariable hierarchical Bayesian logistic regression models for data analysis. The overall prevalence of diarrhoea was 14.4% (95% confidence interval 14.2-14.7) ranging from 3.8% in Armenia to 31.4% in Yemen. The odds of diarrhoea was highest among male children, infants, having small birth weights, households in poorer wealth quintiles, children whose mothers had only primary education, and children who had no access to media. Children from neighbourhoods with high illiteracy [adjusted odds ratio (aOR) = 1.07, 95% credible interval (CrI) 1.04-1.10] rates were more likely to have diarrhoea. At the country-level, the odds of diarrhoea nearly doubled (aOR = 1.88, 95% CrI 1.23-2.83) and tripled (aOR = 2.66, 95% CrI 1.65-3.89) among children from countries with middle and lowest human development index respectively. Diarrhoea remains a major health challenge among under-five children in most LMIC. We identified diverse individual-level, community-level and national-level factors associated with the development of diarrhoea among under-five children in these countries and disentangled the associated contextual risk factors from the compositional risk factors. Our findings underscore the need to revitalize existing policies on child and maternal health and implement interventions to prevent diarrhoea at the individual-, community- and societal-levels. The current study showed how the drive to the attainment of SDGs 1, 2, 4, 6 and 10 will enhance the attainment of SDG 3.

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BACKGROUND: Diarrhoea poses serious health problems among under-five children (U5C) in Low-and Medium-Income Countries (LMIC) with a higher prevalence in rural areas. A gap exists in knowledge on factors driving rural-non-rural inequalities in diarrhoea development among U5C in LMIC. This study investigates the magnitude of rural-non-rural inequalities in diarrhoea and the roles of individual-level and neighbourhood-level factors in explaining these inequalities. METHODS: Data of 796,150 U5C, from 63,378 neighbourhoods across 57 LMIC from the most recent Demographic and Health Survey (2010-2018) was analysed. The outcome variable was the recent experience of diarrhoea while independent variables consist of the individual- and neighbourhood-level factors. Data were analysed using multivariable Fairlie decomposition at p < 0.05 in Stata Version 16 while visualization was implemented in R Statistical Package. RESULTS: Two-thirds (68.0%) of the children are from rural areas. The overall prevalence of diarrhoea was 14.2, 14.6% vs 13.4% among rural and non-rural children respectively (p < 0.001). From the analysis, the following 20 countries showed a statistically significant pro-rural inequalities with higher odds of diarrhoea in rural areas than in nonrural areas at 5% alpha level: Albania (OR = 1.769; p = 0.001), Benin (OR = 1.209; p = 0.002), Burundi (OR = 1.399; p < 0.001), Cambodia (OR = 1.201; p < 0.031), Cameroon (OR = 1.377; p < 0.001), Comoros (OR = 1.266; p = 0.029), Egypt (OR = 1.331; p < 0.001), Honduras (OR = 1.127; p = 0.027), India (OR = 1.059; p < 0.001), Indonesia (OR = 1.219; p < 0.001), Liberia (OR = 1.158; p = 0.017), Mali (OR = 1.240; p = 0.001), Myanmar (OR = 1.422; p = 0.004), Namibia (OR = 1.451; p < 0.001), Nigeria (OR = 1.492; p < 0.001), Rwanda (OR = 1.261; p = 0.010), South Africa (OR = 1.420; p = 0.002), Togo (OR = 1.729; p < 0.001), Uganda (OR = 1.214; p < 0.001), and Yemen (OR = 1.249; p < 0.001); and pro-non-rural inequalities in 9 countries. Variations exist in factors associated with pro-rural inequalities across the 20 countries. Overall main contributors to pro-rural inequality were neighbourhood socioeconomic status, household wealth status, media access, toilet types, maternal age and education. CONCLUSIONS: The gaps in the odds of diarrhoea among rural children than nonrural children were explained by individual-level and neighbourhood-level factors. Sustainable intervention measures that are tailored to country-specific needs could offer a better approach to closing rural-non-rural gaps in having diarrhoea among U5C in LMIC.

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OBJECTIVES: The aim of the study was to assess the magnitude of wealth inequalities in the development of diarrhoea among under-five children in low- and middle-income countries (LMICs) and to identify and quantify contextual and compositional factors' contribution to the inequalities. DESIGN: This is a cross-sectional study. METHODS: We used cross-sectional data from 57 Demographic and Health Surveys conducted between 2010 and 2018 in LMICs. Descriptive statistics were used to understand the gap in having diarrhoea between the children from poor and non-poor households and across the selected covariates using Fairlie decomposition techniques with multivariable binary logistic regressions at P = 0.05. RESULTS: Of the 57 countries, we found a statistically significant pro-poor odds ratio in only 29 countries, 7 countries showed pro-non-poor inequality and others showed no statistically significant inequality. Among the countries with statistically significant pro-poor inequality, the risk difference was largest in Cameroon (94.61/1000), whereas the largest pro-non-poor risk difference in diarrhoea was widest in Timor-Leste (-41.80/1000). Important factors responsible for pro-poor inequality varied across countries. The largest contributors to the pro-poor inequalities in having diarrhoea are maternal education, access to media, neighbourhood socio-economic status, place of residence, birth order and maternal age. CONCLUSION: Diarrhoea remains a major challenge in most LMICs, with a wide range of pro-poor inequalities. These disparities were explained by both compositional and contextual factors, which varied widely across the countries. Thus, multifaceted geographically specific economic alleviation intervention may prove to be a potent approach for addressing the poor and non-poor differentials in the risk of diarrhoea with policies tailored to country-specific risk factors. There is a need for further investigation of factors that drive pro-non-poor inequalities found in 9 of the LMICs.

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Background: The rising digitisation and proliferation of data sources and repositories cannot be ignored. This trend expands opportunities to integrate and share population health data. Such platforms have many benefits, including the potential to efficiently translate information arising from such data to evidence needed to address complex global health challenges. There are pockets of quality data on the continent that may benefit from greater integration. Integration of data sources is however under-explored in Africa. The aim of this article is to identify the requirements and provide practical recommendations for developing a multi-consortia public and population health data-sharing framework for Africa. Methods: We conducted a narrative review of global best practices and policies on data sharing and its optimisation. We searched eight databases for publications and undertook an iterative snowballing search of articles cited in the identified publications. The Leximancer software © enabled content analysis and selection of a sample of the most relevant articles for detailed review. Themes were developed through immersion in the extracts of selected articles using inductive thematic analysis. We also performed interviews with public and population health stakeholders in Africa to gather their experiences, perceptions, and expectations of data sharing. Results: Our findings described global stakeholder experiences on research data sharing. We identified some challenges and measures to harness available resources and incentivise data sharing.  We further highlight progress made by the different groups in Africa and identified the infrastructural requirements and considerations when implementing data sharing platforms. Furthermore, the review suggests key reforms required, particularly in the areas of consenting, privacy protection, data ownership, governance, and data access. Conclusions: The findings underscore the critical role of inclusion, social justice, public good, data security, accountability, legislation, reciprocity, and mutual respect in developing a responsive, ethical, durable, and integrated research data sharing ecosystem.

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What explains the underlying causes of rural-urban differentials in severe acute malnutrition (SAM) among under-five children is poorly exploited, operationalized, studied and understood in low- and middle-income countries (LMIC). We decomposed the rural-urban inequalities in the associated factors of SAM while controlling for individual, household, and neighbourhood factors using datasets from successive demographic and health survey conducted between 2010 and 2018 in 51 LMIC. The data consisted of 532,680 under-five children nested within 55,823 neighbourhoods across the 51 countries. We applied the Blinder-Oaxaca decomposition technique to quantify the contribution of various associated factors to the observed rural-urban disparities in SAM. In all, 69% of the children lived in rural areas, ranging from 16% in Gabon to 81% in Chad. The overall prevalence of SAM among rural children was 4.8% compared with 4.2% among urban children. SAM prevalence in rural areas was highest in Timor-Leste (11.1%) while the highest urban prevalence was in Honduras (8.5%). Nine countries had statistically significant pro-rural (significantly higher odds of SAM in rural areas) inequality while only Tajikistan and Malawi showed statistically significant pro-urban inequality (p < 0.05). Overall, neighbourhood socioeconomic status, wealth index, toilet types and sources of drinking water were the most significant contributors to pro-rural inequalities. Other contributors to the pro-rural inequalities are birth weight, maternal age and maternal education. Pro-urban inequalities were mostly affected by neighbourhood socioeconomic status and wealth index. Having SAM among under-five children was explained by the individual-, household- and neighbourhood-level factors. However, we found variations in the contributions of these factors. The rural-urban dichotomy in the prevalence of SAM was generally significant with higher odds found in the rural areas. Our findings suggest the need for urgent intervention on child nutrition in the rural areas of most LMIC.

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OBJECTIVE: According to the World Health Organization, the increasing antibiotic resistance of pathogens is one of the most important threats to human health. Prevalence of a carbapenem-resistance gene (KPC), vancomycin-resistance genes (van A/B) and a methicillin-resistance gene (mecA) in hospital and municipal sewages will be potential threat to public health. RESULTS: Vancomycin-resistance genes were detected in the sewage of community tank-II, sewage tank of the tertiary and general hospital. Carbapenem-resistance gene was detected in sewage of community tank-II and sewage from tertiary hospital. Methicillin-resistance gene was detected in sewage of community tank-II, sewage from a fish market sewage tank and sewage from an animal slaughter house sewage tank. The detection of a KPC, van A/B and a mecA in sewages will help further the process to take the appropriate measures to prevent the spread of such bacteria in the environment.

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OBJECTIVE: The present research was undertaken to study the accuracy and reliability of the foramen magnum (FM) and some cranial measurements in gender classification through the use of reconstructed helical CT images. METHODS: 88 patients (43 males and 45 females; age range, 20-49 years) were selected for this study. FM sagittal diameter, transverse diameter, area and circumference were measured and data were subjected to discriminant analysis for gender using multiple regression analysis. RESULTS: FM circumference and area were the best discriminant parameters that could be used to study sexual dimorphism with an overall accuracy of 67% and 69.3%, respectively. By using multivariate analysis, 90.7% of FM dimensions of males and 73.3% of FM dimensions of females were sexed correctly. CONCLUSION: It can be concluded that the reconstructed CT image can provide valuable measurements for the FM and could be used for sexing when other methods are inconclusive.

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BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory condition that typically causes a symmetrical chronic arthritis. Timely use of disease-modifying antirheumatic drugs (DMARDs) is an essential aspect of disease management, but many patients may not respond even when conventional agents are used optimally. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of adalimumab (ADA), etanercept (ETN), infliximab (IFX), rituximab (RTX) and abatacept (ABT) when used in patients with RA who have tried conventional agents and have failed to improve after trying a first tumour necrosis factor (TNF) inhibitor. DATA SOURCES: A systematic review of primary studies was undertaken. Databases searched included the Cochrane Library, MEDLINE (Ovid) and EMBASE up to July 2009. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. The quality of included studies was assessed independently by two reviewers, with any disagreements resolved by discussion and consultation with a third reviewer if necessary. RESULTS: Thirty-five studies were included in the systematic review: five randomised controlled trials (RCTs), one comparative study, one controlled study and 28 uncontrolled studies. One RCT (REFLEX) demonstrated the effectiveness of RTX. At 6 months significantly more patients treated with RTX achieved American College of Rheumatology (ACR) 20 [relative risk (RR) = 2.85, 95% confidence interval (CI) 2.08 to 3.91] and ACR70 (RR = 12.14, 95% CI 2.96 to 49.86) compared with those treated with the placebo. Differences between groups in favour of RTX were observed at 6 months for mean change from baseline in Disease Activity Score 28 (DAS28) (mean difference -1.50, 95% CI -1.74 to -1.26) and mean change from baseline in Health Assessment Questionnaire (HAQ) score (mean difference -0.30, 95% CI -0.40 to -0.20). One RCT (ATTAIN) demonstrated the effectiveness of ABT. At 6 months significantly more patients treated with ABT achieved ACR20 (RR = 2.56, 95% CI 1.77 to 3.69) and ACR70 (RR = 6.70, 95% CI 1.62 to 27.80) compared with those treated with placebo. Significant differences between groups in favour of ABT were observed at 6 months for mean change from baseline in DAS28 score (mean difference -1.27, 95% CI -1.62 to -0.93) and mean change from baseline in HAQ score (mean difference -0.34). Twenty-eight uncontrolled studies observed improvement of effectiveness compared with before switching, in patients who switched to ADA, ETN or IFX after discontinued previous TNF inhibitor(s). Four studies were included in the systematic review of cost-effectiveness. Independent economic evaluation undertaken by the assessment group showed that compared with DMARDs, the incremental cost-effectiveness ratios (ICERs) were £34,300 [per quality-adjusted life-year (QALY)] for ADA, £38,800 for ETN, £36,200 for IFX, £21,200 for RTX and £38,600 for ABT. RTX dominates the TNF inhibitors and the ICER for ABT compared with RTX is over £100,000 (per QALY). LIMITATIONS: Paucity of evidence from RCTs for assessing the clinical effectiveness of TNF inhibitors and an absence of head-to-head trials comparing the five technologies. CONCLUSIONS: Evidence from RCTs suggests that RTX and ABT are more effective than supportive care. Data from observational studies suggest that the use of an alternative TNF inhibitor in patients who exhibit an inadequate response to a first TNF inhibitor may offer some benefit, but there remain uncertainties with regard to the magnitude of treatment effects and their cost-effectiveness. Future research should include head-to-head trials comparing the clinical effectiveness and cost-effectiveness of the technologies against each other and emerging biologics. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute for Health Research.

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This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA) that have not responded adequately to treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 response rates and quality of life measures after 3 months and 6 months of treatment. The ERG examined the submission's search strategies and considered they appeared comprehensive and that it was unlikely that relevant studies would have been missed. Only English language studies were considered in the submission and non-English language studies relevant to the decision problem may possibly have been ignored. The ERG analysed the first submitted economic model so as to itemise in detail clarification points that were brought to the attention of the manufacturer. In response the manufacturer submitted a modified cost-effectiveness analysis. The ERG undertook further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; and ignored the potential influence of differences between bDMARDs with regard to adverse events and their related costs and health impacts. The NICE guidance issued in October 2009 states that: the Committee is minded not to recommend certolizumab pegol as a treatment option for people with RA; and the Committee recommends that NICE asks the manufacturer of CZP for more information on the clinical effectiveness and cost-effectiveness of CZP for the treatment of people with RA. On receipt of this information and details of a patient access scheme NICE issued final guidance recommending CZP, under certain criteria, as a treatment option for people with RA.

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BACKGROUND: Lead, an example of heavy metals, has, for decades, being known for its adverse effects on various body organs and systems such that their functions are compromised. AIM: In the present study, the ability of lead to adversely affect the male reproductive system was investigated and tomato (Lycopersicon esculentum: Source of antioxidants) paste (TP) was administered orally to prevent the adverse effects of Pb. MATERIALS AND METHODS: Fifteen Sprague Dawley rats, randomised into three groups (n = 5), were used for this study. Animals in Group A served as the control and were drinking distilled water. Animals in Groups B and C were drinking 1% Pb (II) acetate (LA). Group C animals were, in addition to drinking LA, treated with 1.5 ml of TP/day. All treatments were for 8 weeks. STATISTICAL ANALYSIS USED: A Mann-Whitney U-test was used to analyse the results obtained. RESULTS: The obtained results showed that Pb caused a significant reduction in the testicular weight, sperm count, life-death ratio, sperm motility, normal sperm morphology, and plasma and tissue superoxide dismutase and catalase activity, but a significant increase in plasma and tissue malondialdehyde concentration. But, Pb did not cause any significant change in the serum testosterone level. TP, however, significantly reduced these adverse effects of Pb. CONCLUSION: These findings lead to the conclusion that TP significantly lowered the adverse effects of Pb exposure on the kidney as well as Pb-induced oxidative stress.

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Recently, BMI-1 was identified as a protein downregulating p16ink4a and mandatory for the continued existence of several stem cell compartments like hematopoietic and neural stem cells. In this study we investigated BMI-1 expression as a potential stem cell marker of the gastrointestinal tract. We found weak expression in the isthmus region of the stomach, and moderate expression in crypts of the intestines, whereas intestinal surface epithelial cells were weakly positive or negative for BMI-1. In addition, a variety of highly differentiated cells such as parietal cells, neuroendocrine cells of the pylorus, Paneth cells and a subset of goblet cells were moderately to strongly positive for BMI-1. Furthermore, we detected strong expression in gastrointestinal neoplasias. This expression pattern indicates a correlation of BMI-1 expression with gastrointestinal stem cells as well as numerous specialized cell types and points to a role of this protein in cellular differentiation in addition to that of stem cell maintenance. Besides, our results imply a role for BMI-1 in the tumorigenesis of gastrointestinal cancer.

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Human herpesvirus type 8 (HHV-8) has been identified as the most likely candidate to be involved in the development of Kaposi's Sarcoma (KS). HHV-8 has been associated with all forms of KS, primary effusion lymphoma, and multicentric Castleman's disease and detected in various non-neoplastic cells. Its presence in cells of the different hemopoietic lineages has not yet been investigated in a comprehensive and systematic manner. In this study we searched for the presence of HHV-8 in different subpopulations of peripheral blood mononuclear cells (PBMC) from patients with classic and AIDS-associated KS, as well as from HIV-1 sero-positive and sero-negative persons without KS. Thirty-four samples of PBMC were isolated from 30 patients. Subpopulations were isolated with immunomagnetic beads. Polymerase chain reaction for HHV-8 DNA was performed on PBMC and subpopulations with a primer pair selected from ORF26 of the viral genome. Polymerase chain reaction products were subsequently Southern blotted and hybridized. In patients with KS, HHV-8 DNA was detected in nine of 11 (81%) CD19+ cells, four of 11 (36%) CD2+ cells, three of 11 (27%) CD14+ cells, and nine of 11 (81%) of the remaining depleted cell populations (DP) that contain CD34 positive cells. In a subsequent set of experiments HHV-8 DNA was detected in 10 of 12 (83%) CD34 positive cell fractions. All cell subpopulations from the non-KS group were HHV-8 negative, with the exception of one positive B cell sample obtained from an HIV-infected patient. Our data demonstrate that in peripheral blood HHV-8 is detectable not only in CD19+ cells, as previously reported, but also in other cells, including T cells, monocytes, and cells devoid of specific lineage markers. We also show for the first time that CD34+ cells in peripheral blood of KS patients are a predominant HHV-8-harboring population, suggesting that they represent an additional important reservoir for this virus in vivo.

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We used a new combined chemo- (COP/ABVD), radiation and interferon-alpha (10 x 10(6) IU s.c. 3x per week/12 months) therapy regimen to treat severe multicentric Castleman's disease (CD) complicated by relapsing Behcet's disease (BD) manifestations. More than 16 years after diagnosis of CD the patient remains in very good clinical condition, with remission of all CD and BD manifestations 13 months after discontinuation of the interferon-alpha treatment. In addition, our clinicopathological, immunohistological and virological data suggest a pathogenetic link between CD and BD via activation of pre-existing BD-specific plasma cells due to CD-related HHV8-induced overexpression of interleukin-6.

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As the parapharyngeal space is difficult to examine clinically, the radiographic distinction between deep lobe parotid masses and extraparotid tumors is essential in determining the surgical approach. We describe the case of a 53-year-old woman who presented with facial pain consequent to metastatic papillary thyroid carcinoma of the parapharyngeal space. A highly unusual pattern of calcification was present in the mass as observed by panoramic radiography and computed tomography. Parapharyngeal metastasis as the presenting feature of occult thyroid carcinoma has only been described four times previously in the medical literature.

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Vascular endothellal growth factor (VEGF) increases vascular permeability and acts as a mitogen for endothelial cells in vivo and in vitro. We and others recently demonstrated that cultured human keratinocytes constitutively secrete VEGF. In the present study, we examined the expression of this growth factor in various epithelial skin tumors and in normal skin. Using in situ hybridization, we detected strong VEGF mRNA expression in all of 10 squamous cell carcinomas, 13 common warts, 11 seborrheic keratoses, and in 7 of 8 keratoacanthomas studied. By contrast, we found no VEGF mRNA in 9 of 14 basal cell carcinomas. VEGF mRNA was readily detectable within the epidermis adjacent to the tumors as well as in tumor cells and in the epidermis of normal human skin. Northern hybridization of RNA derived from normal human epidermis identified VEGF transcripts of 3.7 and 1.8 kb, and reverse transcriptase polymerase chain reaction confirmed that epidermal cells, like keratinocytes in vitro, express the three major splice forms of VEGF. Immunohistochemical staining with monoclonal antibodies confirmed that expression of VEGF mRNA was accompanied by the presence of VEGF protein. Our data demonstrate that VEGF production by tumor cells in situ does not distinguish malignant from benign epithelial tumors of the skin because it is present in both. The constitutive expression of VEGF by normal keratinocytes in situ suggests that this angiotropic cytokine is important for the regulation of vessel function under physiologic conditions.

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