Lymphatic drainage map of the head and neck skin squamous cell carcinoma detected by sentinel lymph node biopsy.

OBJECTIVE: Squamous cell carcinoma of the skin often affects the scalp and neck region and has a potential for complex lymphatic metastases. The aim of this study was to examine the pattern of lymphatic drainage that would enable better insight and prediction of lymphatic metastasis of head and neck squamous cell carcinoma (HNSCC) in relation to the anatomical localization of the primary process. PATIENTS AND METHODS: A prospective analysis included 64 patients who underwent sentinel lymph node (SLN) biopsy. The biopsy was performed in patients with high-risk cutaneous head and neck squamous cell carcinoma between 2006 and 2010. RESULTS: SLNs in tumors of the forehead, temporal region, lateral cheek, and auricle were found in the cervical region at level II and parotid lymph nodes (p<0.001). In tumors of the nose, periorbital region, and postauricular tumors, SLNs were found in parotid lymph nodes (p<0.001), in tumors of the medial cheek in level I cervical lymph nodes and parotid lymph nodes (p=0.003). In tumors of the neck, SLNs were detected in the cervical region at level IV, whereas in tumors of the posterior scalp they were found in the occipital region (p<0.001). CONCLUSIONS: The results of SLN biopsy in high-risk cutaneous HNSCCs show the regularity of metastasis based on which a lymphatic drainage map can be constructed and thus potential metastatic sites depending on the primary tumor localization predicted.

Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP.

It was reported that novel O, O'-diethyl-(S, S)-ethylenediamine- N, N'-di-2-(3-cyclohexyl) propanoate dihydrochloride (DE-EDCP) displayed in vitro antiproliferative activity on several human and mouse cancer cell lines, which was comparable to that of the prototypical anticancer drug cisplatin. In order to reveal its toxicity profile, acute and repeated-dose toxicity studies were performed in Naval Medical Research Institute (NMRI) Han mice. The intravenous LD50 values of DE-EDCP were found to be 95.3 and 101.3 mg/kg body weight in female and male mice, respectively. In the subacute toxicity study, DE-EDCP was administered intravenously at the doses of 15, 25, and 40 mg/kg/day for a period of 28 days. There were no adverse effects on general condition, growth, feed and water consumption, and hematological parameters. There was a significant increase in urea and alanine aminotransferase in female mice and aspartate aminotransferase and alkaline phosphatase in both genders in 40 mg/kg/day dose-treated group. The histopathological changes confined to the liver and kidney, but in other organs were not found. Satellite group revealed that changes in the kidney and liver were less pronounced, suggesting their reversibility. Interactions with DNA could also be of importance for understanding DE-EDCP toxic side effects. Hyperchromic effect obtained with ultraviolet-visible, suggested electrostatic interactions between DE-EDCP and calf thymus DNA. The toxicity testing of DE-EDCP was conducted to predict human outcomes.

Measles and rubella elimination in the WHO Region for Europe: progress and challenges.

Globally measles remains one of the leading causes of death among young children even though a safe and cost-effective vaccine is available. The World Health Organization (WHO) European Region has seen a decline in measles and rubella cases in recent years. The recent outbreaks have primarily affected adolescents and young adults with no vaccination or an incomplete vaccination history. Eliminating measles and rubella is one of the top immunization priorities of the European Region as outlined in the European Vaccine Action Plan 2015-2020. Following the 2010 decision by the Member States in the Region to initiate the process of verifying elimination, the European Regional Verification Commission for Measles and Rubella Elimination (RVC) was established in 2011. The RVC meets every year to evaluate the status of measles and rubella elimination in the Region based on documentation submitted by each country's National Verification Committees. The verification process was however modified in late 2014 to assess the elimination status at the individual country level instead of at regional level. The WHO European Region has made substantial progress towards measles and rubella elimination over the past 5 years. The RVC's conclusion in 2016 that 70% and 66% of the 53 Member States in the Region had interrupted the endemic transmission of measles and rubella, respectively, by 2015 is a testament to this progress. Nevertheless, where measles and rubella remain endemic, challenges in vaccination service delivery and disease surveillance will need to be addressed through focused technical assistance from WHO and development partners.

The state of measles and rubella in the WHO European Region, 2013.

Measles and rubella persist in the World Health Organization European Region despite long-standing and widespread use of vaccines against them. Our aim was to review the epidemiology of measles and rubella in relation to the goal of eliminating these diseases from the Region by 2015. We report on the number of measles and rubella cases by country in 2012 and present an analysis of preliminary measles and rubella surveillance data for 2013. We analysed data of these diseases for 2013 by age group, diagnosis confirmation (clinical, laboratory-confirmed and epidemiologically linked), and vaccination, hospitalization and importation status. We also report on measles-related deaths. For 2012, there were 26,785 [corrected] measles cases and 29,601 rubella cases reported in the Region. For 2013, these figures were 31,520 and 39,367 respectively. Most measles cases in 2013 (96%; n = 30,178) were reported by nine countries: Georgia (7830), Germany (1773), Italy (2216), the Netherlands (2499), Romania (1074), the Russian Federation (2174), Turkey (7404), Ukraine (3308) and the United Kingdom (1900). In 2013, most measles cases were among unvaccinated persons and over one in three patients were aged 20 years and older. For 2013, almost all rubella cases were reported by Poland (n = 38,585; 98%). High population immunity and high-quality surveillance are the cornerstones to eliminate measles and rubella. Without sustained political commitment and accelerated action by Member States and partners, the elimination of measles and rubella in the WHO European Region may not be achieved.

Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas-kidney transplantation with systemic venous insulin delivery.

BACKGROUND: In patients with type 1 diabetes mellitus (T1DM), insulin is usually replaced systemically (subcutaneously) and not via the physiological portal route. According to previous studies, the liver's capacity to store glycogen is reduced in T1DM patients, but it remains unclear whether this is due to hyperglycaemia, or whether the route of insulin supply could contribute to this phenomenon. T1DM patients after successful pancreas-kidney transplantation with systemic venous drainage (T1DM-PKT) represent a suitable human model to further investigate this question, because they are normoglycaemic, but their liver receives insulin from the pancreas transplant via the systemic route. MATERIALS AND METHODS: In nine T1DM-PKT, nine controls without diabetes (CON) and seven patients with T1DM (T1DM), liver glycogen content was measured at fasting and after two standardized meals employing (13) C-nuclear-magnetic-resonance-spectroscopy. Circulating glucose and glucoregulatory hormones were measured repeatedly throughout the study day. RESULTS: The mean and fasting concentrations of peripheral plasma glucose, insulin, glucagon and C-peptide were comparable between T1DM-PKT and CON, whereas T1DM were hyperglycaemic and hyperinsulinaemic (P < 0·05 vs T1DM-PKT and CON). Total liver glycogen content at fasting and after breakfast did not differ in the three groups. After lunch, T1DM-PKT and T1DM had a 14% and 21% lower total liver glycogen content than CON (P < 0·02). CONCLUSION: In spite of normalized glycaemic control, postprandial liver glycogen content was reduced in T1DM-PKT with systemic venous drainage. Thus, not even optimized systemic insulin substitution is able to resolve the defect in postprandial liver glycogen storage seen in T1DM patients.

[Progress in the elimination of measles and rubella in the WHO European Region]. / Fortschritte bei der Eliminierung von Masern und Röteln in der Europäischen Region der WHO.

Substantial progress has been made in the World Health Organization (WHO) European Region toward reaching the goal of measles and rubella elimination. We analyzed the surveillance data of 2012 on measles and rubella for age-group, diagnosis confirmation status (clinical, laboratory-confirmed and epidemiologically linked), vaccination status, and measles-related deaths. For 2012, there were 23,871 measles cases and 29,361 rubella cases reported in the region, mostly among unvaccinated persons. Almost one in three patients with measles and one in five patients with rubella were aged 20 years and older. In a few countries, widespread outbreaks or indigenous transmission of measles persisted in 2012. While most countries in the region have controlled rubella, a small number still reported a high incidence and several outbreaks. Therefore, more efforts are required to achieve the goal of eliminating measles and rubella in the WHO European Region by 2015, particularly in high-incidence countries. The WHO measles and rubella elimination plan stipulates that all countries should achieve and maintain the required high vaccination coverage while conducting high-quality surveillance.

IL-10 production by CD4+ effector T cells: a mechanism for self-regulation.

The development of Th1 lymphocytes is essential for cell-mediated immunity and resistance against intracellular pathogens. However, if left unregulated, the same response can cause serious damage to host tissues and lead to mortality. A number of different paracrine regulatory mechanisms involving distinct myeloid and lymphoid subpopulations have been implicated in controlling excessive secretion of inflammatory cytokines by Th1 cells. Much of this work has focused on interleukin (IL)-10, a cytokine with broad anti-inflammatory properties, one of which is to counteract the function of Th1 lymphocytes. While studying the role of IL-10 in regulating immunopathology during infection with the intracellular parasite Toxoplasma gondii, we discovered that the host-protective IL-10 derives in an autocrine manner from conventional interferon-gamma (IFN-gamma)-producing T-bet(+) Foxp3(neg) Th1 cells. In the following review, we will discuss these findings that support the general concept that production of IL-10 is an important self-regulatory function of CD4(+) T lymphocytes.

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia.

Retroviral expression of leukemogenic oncogenes in the murine hematopoietic system is essential but not sufficient to induce acute leukemia. Proviral integration-mediated elevated expression of the meningioma 1 (MN1) oncogene suggested MN1 acting as cooperating event in mixed-lineage leukemia 1 (MLL) and eleven nineteen leukemia (ENL)-induced murine leukemia. Indeed, co-expression of MN1 with MLL-ENL enhanced transformation in vivo, and resulted in a significantly reduced latency for induction of an aggressive acute leukemia when compared with MN1 or MLL-ENL alone. In addition, co-expression of MN1 increased the granulocyte macrophage progenitor cell population with leukemia-initiating properties as shown in secondary transplantation experiments. Gene expression profiling experiments identified putative downstream MN1 targets, of which FMS-like tyrosine kinase 3 (FLT3) and CD34 were upregulated in both MN1-overexpressing murine leukemias and in pediatric acute leukemias with high MN1 levels. Interestingly, small interfering RNA (siRNA)-mediated MN1 knockdown resulted in cell cycle arrest and impaired clonogenic growth of human leukemia cell lines with high MN1 levels. Our work shows for the first time that high MN1 levels are important for the growth of leukemic cells, and that increased MN1 expression can synergize with MLL-ENL and probably other transforming fusion genes in leukemia induction through a distinct gene expression program that is able to expand the leukemia-initiating cell population.

Ethical considerations in the collection of genetic data from critically ill patients: what do published studies reveal about potential directions for empirical ethics research?

Critical illness trials involving genetic data collection are increasingly commonplace and pose challenges not encountered in less acute settings, related in part to the precipitous, severe and incapacitating nature of the diseases involved. We performed a systematic literature review to understand the nature of such studies conducted to date, and to consider, from an ethical perspective, potential barriers to future investigations. We identified 79 trials enrolling 24 499 subjects. Median (interquartile range) number of participants per study was 263 (116.75-430.75). Of these individuals, 16 269 (66.4%) were Caucasian, 1327 (5.4%) were African American, 1707 (7.0%) were Asian Pacific Islanders and 139 (0.6%) were Latino. For 5020 participants (20.5%), ethnicity was not reported. Forty-eight studies (60.8%) recruited subjects from single centers and all studies examined a relatively small number of genetic markers. Technological advances have rendered it feasible to conduct clinical studies using high-density genome-wide scanning. It will be necessary for future critical illness trials using these approaches to be of greater scope and complexity than those so far reported. Empirical research into issues related to greater ethnic inclusivity, accuracy of substituted judgment and specimen stewardship may be essential for enabling the conduct of such trials.

Particle size analysis: 90Y and 99mTc-labelled colloids.

Colloidal particle size is an important characteristic to consider when choosing a radiopharmaceutical for diagnosis and therapeutic purposes in nuclear medicine. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) were used to determine the particle-size distribution of (90)Y- and (99m)Tc-labelled antimony trisulfide (Sb(2)S(3)) and tin colloids (Sn-colloid). (90)Y-Sb(2)S(3) and (99m)Tc-Sb(2)S(3) were found to have a diameter of 28.92 +/- 0.14 and 35.61 +/- 0.11 nm, respectively, by PCS. By TEM, (90)Y-Sb(2)S(3) particles were measured to be 14.33 +/- 0.09 nm. (90)Y-labelled Sn colloid were found to exist with a d(v(max1)) of 805 nm and a d(v(max2)) of 2590 nm, by PCS, whereas (99m)Tc-Sn colloid was shown to have more than 80% of radioactive particles of approximately 910 nm by PCS. For (90)Y-labelled Sb(2)S(3) and Sn colloid, a comparison of TEM and PCS indicates that these techniques found significantly different mean diameters. TEM has an excellent resolution necessary for radiocolloid particle-sizing analysis, and it is a desirable size-measuring technique because it is more reliable than PCS.

The frozen shoulder syndrome. Description of a new technique and five case reports using the subscapular nerve block and subscapularis trigger point infiltration.

BACKGROUND AND OBJECTIVES: A frozen shoulder is considered by some authors to be a common stage of many disorders affecting the shoulder, while others regard it as an independent idiopatic condition. A consistent finding is that subscapularis muscle trigger points play a key role in the development of the frozen shoulder syndrome. Apart from the conventional treatment, a selective subscapularis fossa nerve block combined with subscapularis trigger points infiltration, may be an effective treatment in preventing chronic pain. METHODS: In this manuscript the posterior injection technique of the subscapularis fossa nerve block is described. RESULTS: Five patients with typical symptoms of frozen shoulder, who did not respond to conventional treatment, but obtained pain relief after a combination of a subscapularis nerve block with the infiltration of trigger points, are presented. CONCLUSION: The results of this block in various painful situations of the shoulder region suggest the importance of subscapularis muscle in the etiology of the frozen shoulder. Using this technique, we could demonstrate that a subscapular nerve block and subscapularis trigger points infiltration have both a diagnostic and therapeutic value for the treatment of the frozen shoulder.

Two clusters of human infection with influenza A/H5N1 virus in the Republic of Azerbaijan, February-March 2006.

Following the appearance of influenza A/H5 virus infection in several wild and domestic bird species in the Republic of Azerbaijan in February 2006, two clusters of potential human avian influenza due to A/H5N1 (HAI) cases were detected and reported by the Ministry of Health (MoH) to the World Health Organization (WHO) Regional Office for Europe during the first two weeks of March 2006. On 15 March 2006, WHO led an international team, including infection control, clinical management, epidemiology, laboratory, and communications experts, to support the MoH in investigation and response activities. As a result of active surveillance, 22 individuals, including six deaths, were evaluated for HAI and associated risk infections in six districts. The investigations revealed eight cases with influenza A/H5N1 virus infection confirmed by a WHO Collaborating Centre for Influenza and one probable case for which samples were not available. The cases were in two unrelated clusters in Salyan (seven laboratory confirmed cases, including four deaths) and Tarter districts (one confirmed case and one probable case, both fatal). Close contact with and de-feathering of infected wild swans was considered to be the most plausible source of exposure to influenza A/H5N1 virus in the Salyan cluster, although difficulties in eliciting information were encountered during the investigation, because of the illegality of some of the activities that might have led to the exposures (hunting and trading in wild birds and their products). These cases constitute the first outbreak worldwide where wild birds were the most likely source of influenza A/H5N1 virus infection in humans. The rapid mobilisation of resources to contain the spread of influenza A/H5 in the two districts was achieved through collaboration between the MoH, WHO and its international partners. Control activities were supported by the establishment of a field laboratory with real-time polymerase chain reaction (RT-PCR) capacity to detect influenza A/H5 virus. Daily door-to-door surveillance undertaken in the two affected districts made it unlikely that human cases of influenza A/H5N1 virus infection remained undetected.

Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in vitro by anticancer drugs.

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.

Two clusters of human infection with influenza A/H5N1 virus in the Republic of Azerbaijan, February-March 2006.

Following the appearance of influenza A/H5 virus infection in several wild and domestic bird species in the Republic of Azerbaijan in February 2006, two clusters of potential human avian influenza due to A/H5N1 (HAI) cases were detected and reported by the Ministry of Health (MoH) to the World Health Organization (WHO) Regional Office for Europe during the first two weeks of March 2006. On 15 March 2006, WHO led an international team, including infection control, clinical management, epidemiology, laboratory, and communications experts, to support the MoH in investigation and response activities. As a result of active surveillance, 22 individuals, including six deaths, were evaluated for HAI and associated risk infections in six districts. The investigations revealed eight cases with influenza A/H5N1 virus infection confirmed by a WHO Collaborating Centre for Influenza and one probable case for which samples were not available. The cases were in two unrelated clusters in Salyan (seven laboratory confirmed cases, including four deaths) and Tarter districts (one confirmed case and one probable case, both fatal). Close contact with and de-feathering of infected wild swans was considered to be the most plausible source of exposure to influenza A/H5N1 virus in the Salyan cluster, although difficulties in eliciting information were encountered during the investigation, because of the illegality of some of the activities that might have led to the exposures (hunting and trading in wild birds and their products). These cases constitute the first outbreak worldwide where wild birds were the most likely source of influenza A/H5N1 virus infection in humans. The rapid mobilisation of resources to contain the spread of influenza A/H5 in the two districts was achieved through collaboration between the MoH, WHO and its international partners. Control activities were supported by the establishment of a field laboratory with real-time polymerase chain reaction (RT-PCR) capacity to detect influenza A/H5 virus. Daily door-to-door surveillance undertaken in the two affected districts made it unlikely that human cases of influenza A/H5N1 virus infection remained undetected.

Strengthening early warning function of surveillance in the Republic of Serbia: lessons learned after a year of implementation.

The Republic of Serbia, with WHO support, has implemented an early warning system (ALERT) for priority communicable diseases, to complement the routine surveillance system which notifies individual confirmed cases. The results of its evaluation, conducted one year after implementation is presented here. ALERT relies on notification of 11 syndromes by primary care facilities. Data is analysed weekly at district level and transmitted to national epidemiologists. ALERT is perceived to be a simple and flexible tool. Acceptability is higher at national level than at district level. Some districts perceive ALERT as a parallel system poorly connected to control measures. Sensitivity of ALERT in detecting cases of meningitis is 93%, and 37% for cases of hepatitis. Retrospective analysis of ALERT data identified 9 outbreaks, 5 of which had been recognized by epidemiologists. ALERT was the timeliest system for detecting 4 outbreaks identified by both systems. ALERT was useful for triggering timely investigation and control of outbreaks of hantavirus and salmonellosis and for detecting the start of the influenza season. However, ALERT did not detect clusters of brucellosis and tularaemia targeted by the unexplained fever syndrome. This evaluation underlined the need for a global review of surveillance activities when implementing new components such as ALERT. While control measures based on notification of individual confirmed cases are well understood and implemented, the investigation and verification process that should result from an increase in ALERT syndromes is not fully understood. Field epidemiology training programmes, such as the EPIET programme, are best suited to bring about this change of perspective.

Strengthening early warning function of surveillance in the Republic of Serbia: lessons learned after a year of implementation.

The Republic of Serbia, with WHO support, has implemented an early warning system (ALERT) for priority communicable diseases, to complement the routine surveillance system which notifies individual confirmed cases. The results of its evaluation, conducted one year after implementation is presented here. ALERT relies on notification of 11 syndromes by primary care facilities. Data is analysed weekly at district level and transmitted to national epidemiologists. ALERT is perceived to be a simple and flexible tool. Acceptability is higher at national level than at district level. Some districts perceive ALERT as a parallel system poorly connected to control measures. Sensitivity of ALERT in detecting cases of meningitis is 93%, and 37% for cases of hepatitis. Retrospective analysis of ALERT data identified 9 outbreaks, 5 of which had been recognized by epidemiologists. ALERT was the timeliest system for detecting 4 outbreaks identified by both systems. ALERT was useful for triggering timely investigation and control of outbreaks of hantavirus and salmonellosis and for detecting the start of the influenza season. However, ALERT did not detect clusters of brucellosis and tularaemia targeted by the unexplained fever syndrome. This evaluation underlined the need for a global review of surveillance activities when implementing new components such as ALERT. While control measures based on notification of individual confirmed cases are well understood and implemented, the investigation and verification process that should result from an increase in ALERT syndromes is not fully understood. Field epidemiology training programmes, such as the EPIET programme, are best suited to bring about this change of perspective.

T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells.

Differentiation of naive CD4(+) T cells into IFN-gamma-producing T helper 1 (T(H)1) cells is pivotal for protective immune responses against intracellular pathogens. T-bet, a recently discovered member of the T-box transcription factor family, has been reported to play a critical role in this process, promoting IFN-gamma production. Although terminal T(H)1 differentiation occurs over days, we now show that challenge of mice with a prototypical T(H)1-inducing stimulus, Toxoplasma gondii soluble extract, rapidly induced IFN-gamma and T-bet; T-bet induction was substantially lower in IFN-gamma-deficient mice. Naive T cells expressed little T-bet, but this transcription factor was induced markedly by the combination of IFN-gamma and cognate antigen. Human myeloid antigen-presenting cells showed T-bet induction after IFN-gamma stimulation alone, and this induction was antagonized by IL-4 and granulocyte/macrophage colony-stimulating factor. Although T-bet was induced rapidly and directly by IFN-gamma, it was not induced by IFN-alpha, lipopolysaccharide, or IL-1, indicating that this action of IFN-gamma was specific. Moreover, T-bet induction was dependent on Stat1 but not Stat4. These data argue for a model in which IFN-gamma gene regulation involves an autocrine loop, whereby the cytokine regulates a transcription factor that promotes its own production. These findings substantially alter the current view of T-bet in IFN-gamma regulation and promotion of cell-mediated immune responses.

Mice infected with Schistosoma mansoni develop a novel non-T-lymphocyte suppressor population which inhibits virus-specific CTL induction via a soluble factor.

We previously observed that Schistosoma mansoni-infected mice were deficient in their ability to mount a CTL response to unrelated viral antigens and to clear a vaccinia viral infection. Here, we explore the mechanism of that deficiency. Mixing experiments showed that splenocytes from S. mansoni-infected mice actively suppress stimulation in vitro of both viral-peptide specific CTL in spleen cells from virus-infected mice, and allospecific CTL. The mechanism of suppression involves at least in part a soluble factor, in that it can occur across a 0.4-microm membrane which prohibits direct cell contact. However, the inhibition is not alleviated by blocking with antibodies to IL-4, IL-10 or TGF-beta. Fractionation of the splenocyte population from S. mansoni-infected mice shows that the suppression is mediated by a non-B, non-T cell that expresses CD16 and Mac-1, but not FcepsilonR or NK1.1. This represents a novel suppressor population that is distinct from the FcepsilonRI(+) populations of non-B, non-T cells in the spleens of S. mansoni-infected mice that provide a major source of IL-4 in these animals. Similar cells in schistosome-infected humans could affect susceptibility to other infections or responsiveness to vaccines.