Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin

Dysplastic naevi (DN) are benign lesions with atypical features intermediate between that of common melanocytic naevi (CMN) and malignant melanoma (MM). Debate remains over whether DN represent progressive lesions from CMN. Through gene expression profiling and analysis of molecular gene signatures, our study revealed progressive increases in immune activation and regulation, along with pathways implicated in melanomagenesis, from CMN to DN to MM. Using criteria of 1.5‐fold change and false discovery rate ≤0.05, we found differential expression of 7186 probes (6370 unique genes) with the largest difference detected between DN and MM from the standpoint of genomic melanoma progression. Despite progressive increases in the T‐helper type 1 (Th1)‐inducing gene (IL‐12), RT‐PCR indicated impaired Th1 or cytotoxic T‐cell response (decreased IFN‐γ) in MM. Concordantly, our results indicated progressive increases in molecular markers associated with regulatory T cells, exhausted T cells and tolerogenic dendritic cells, including detection of increased expression of suppressor of cytokine signalling 3 (SOCS3) in dendritic cells associated with MM. All together, our findings suggest that the increased immunosuppressive microenvironment of melanoma may contribute to unhampered proliferation of neoplastic cells. In addition, the detection of increased markers associated with tolerogenic dendritic cells in MM suggests that targeting these suppressive immune cell types may represent an alternative avenue for future immunotherapy.     

JAK2‐positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature

We report the second case of cutaneous myelofibrosis with a documented JAK2 activating mutation involving the scalp of a 67‐year‐old woman with primary myelofibrosis in her marrow. In contrast to the previous case, the biopsy revealed extensive lesional collagen deposition and closely mimicked a fibrohistiocytic proliferation. Similar rare lesions occurring in the setting of myeloproliferative neoplasms have been called sclerosing extramedullary hematopoietic tumors. These entities appear histomorphologically and etiologically distinct from extramedullary hematopoiesis, and their diagnosis should prompt the workup for a myeloproliferative neoplasm in the absence of an antecedent diagnosis. The presence of the JAK2 mutation in our case confirmed that the lesions represented skin involvement by a neoplastic myeloid proliferation and not compensatory extramedullary hematopoiesis. Our patient died of disease several months following the appearance of her lesions, which is in keeping with other reports that suggest that cutaneous myelofibrosis may serve as an independent poor prognostic sign in otherwise advanced primary myelofibrosis. A review of the literature further emphasizes the importance of distinguishing this entity from mesenchymal neoplasms and acute myeloid leukemia involving the skin.     

Cellular inflammatory response to porcine collagen membranes

OBJECTIVES: The purpose of this study was to assess local inflammatory changes associated with the implantation of three different porcine collagen membranes having potential use in periodontal regeneration. METHODS: Materials were implanted subcutaneously into prepared sites along the dorsal skin surface of 60 female Wistar rats. Saline and turpentine were used as negative and positive controls, respectively. Animals were killed and biopsies obtained after 3 d, and at 1, 2, 4, 6, and 8 weeks after membrane implantation. A panel of six monoclonal antibodies was used to identify circulating monocytes (ED1), resident tissue macrophages (ED2), lymphoid macrophages (ED3), Ia-antigen expression (OX6), T-lymphocytes (OX19), and B-lymphocytes (OX33). Cells identified by each antibody were subjected to quantitative immunocytochemistry to compare any differences present among groups. Sera obtained 8 weeks after grafting were used in immunoblotting assays to detect the presence of systemic antiporcine antibodies. RESULTS: We found that the mononuclear cell subsets associated with implantation of porcine collagen membranes were similar to those obtained with saline administration. On the other hand, the use of turpentine resulted in an inflammatory infiltrate characterized by significantly higher numbers of all six monoclonal cell subsets at all time periods evaluated, compared to either saline or any of the membranes (P < 0.001). CONCLUSIONS: The collagen membranes do not appear to be associated with a significant local inflammatory response, nor a systemic immune response, and thus appear to be well tolerated, rendering them useful in periodontal regeneration.     

Consent requirements for research with human tissue: Swiss ethics committee members disagree

Background

In Switzerland, research with identifiable human tissue samples, and/or its accompanying data, must be approved by a research ethics committee (REC) before it can be allowed to take place. However, as the demand for such tissue has rapidly increased in recent years, and biobanks have been created to meet these needs, committees have had to deal with a growing number of such demands. Detailed instructions for evaluating every kind of tissue request are scarce. Committees charged with evaluating research protocols therefore sometimes face uncertainty in their decision-making.

Methods

We examine how a pool of Swiss REC members deal with a number of cases involving human tissue, in order to determine the standards they adhere to, and their understanding and implementation of existing laws and guidelines.

Results

There is considerable divergence in the approaches and decisions of Swiss REC members regarding human tissue sample requests, particularly concerning the issue of informed consent. Despite recent trends towards less strict consent requirements for biosample research, many of our respondents continue to employ demanding standards for researchers. The question of informed consent, and the circumstances in which it is required, continues to result in differences of opinion.

Conclusions

While room for local and cultural interpretation is essential to the workings of an REC, misunderstanding of existing guidelines, or an absence of regulation in sensitive areas, will only lead to suboptimal functioning of the REC itself. Our data suggests that there is uncertainty and disagreement on the question of consent for human tissue sample, which existing laws and guidelines may not fully clarify. Methods to address these uncertainties should be implemented in order to ensure efficient and harmonious review of research protocols.

     

A European multicentre, placebo-controlled supplementation study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: analysis of serum responses

Increased levels of oxidative stress have been implicated in tissue damage and the development of chronic diseases, and dietary antioxidants may reduce the risk of oxidative tissue damage. As part of a European multicentre project, several studies were undertaken with the aim of testing whether the consumption of foods rich in carotenoids reduces oxidative damage to human tissue components. We describe here the serum response of carotenoids and tocopherols upon supplementation with carotenoids from natural extracts (alpha-carotene+beta-carotene, lutein or lycopene; 15 mg/day) and/or with alpha-tocopherol (100 mg/day) in a multicentre, placebo-controlled intervention study in 400 healthy male and female volunteers, aged 25-45 years, from five European regions (France, Northern Ireland, Republic of Ireland, The Netherlands and Spain). Supplementation with alpha-tocopherol increased serum alpha-tocopherol levels, while producing a marked decrease in serum gamma-tocopherol. Supplementation with alpha- + beta-carotene (carotene-rich palm oil) resulted in 14-fold and 5-fold increases respectively in serum levels of these carotenoids. Supplementation with lutein (from marigold extracts) elevated serum lutein (approx. 5-fold), zeaxanthin (approx. doubled) and ketocarotenoids (although these were not present in the supplement), whereas lycopene supplementation (from tomato paste) resulted in a 2-fold increase in serum lycopene. The isomer distributions of beta-carotene and lycopene in serum remained constant regardless of the isomer composition in the capsules. In Spanish volunteers, additional data showed that the serum response to carotenoid supplementation reached a plateau after 4 weeks, and no significant side effects (except carotenodermia) or changes in biochemical or haematological indices were observed throughout the study. This part of the study describes dose-time responses, isomer distribution, subject variability and side effects during supplementation with the major dietary carotenoids in healthy subjects.     

Family member presence during resuscitation in the emergency department: An Australian perspective

Objective: The practice of family member presence during resuscitation in the ED has attracted widespread attention over the last few decades. Despite the recommendations of international organizations, clinical staff remain reluctant to engage in this practice in many EDs. This paper separates the evidence from opinion to determine the current state of knowledge about this practice. Methods: A search strategy was developed and used to locate research based publications, which were subsequently reviewed for the strength of evidence providing the basis for recommendations. Results: The literature was examined to reveal what patients and their family members want; the outcomes of family presence during resuscitation for patients and their family members; staff views and practices regarding family presence during resuscitation. Findings suggest that providing the opportunity to be with their critically ill family member is both important to and beneficial for families, however, disparity in staff views has been identified as a major obstacle to family presence during resuscitation. Examination of published guidelines and staff practices described in the literature revealed consistent elements. Conclusion: Although critics point to the lack of rigour in this body of literature, the current state of knowledge suggests merit in pursuing future research to examine and measure effects of family member presence during resuscitation on patients, family members and healthcare providers.     

A functional MRI study of visual oddball: evidence for frontoparietal dysfunction in subjects at risk for alcoholism

Attending to rare stimuli interspersed among repetitive frequent stimuli produces a positive scalp potential at 300 to 600 ms after the target stimulus onset; this potential is known as the P300 wave. Although there is clear evidence of low visual P300 in subjects at high risk (HR) for developing alcoholism, the functional neuroanatomical correlates have not been studied. Functional and high-resolution anatomical magnetic resonance images were collected during the performance of a visual oddball task, from six control (low risk-LR) subjects with high P300s and eight HR subjects with low P300s. All the HR subjects were offspring of male alcoholics. The data were analyzed using a randomization-based statistical method that accounts for multiple comparisons, requires no assumptions about the noise structure of the data, and does not require spatial or temporal smoothing. Target counts showed that all subjects performed the task comparably. Analysis of the functional magnetic resonance imaging (fMRI) data revealed two areas with significantly lower activation in the HR group when compared to the LR group: the bilateral inferior parietal lobule (BA 40), and the bilateral inferior frontal gyrus (BA 44). Inferior parietal lobule showed significantly lower activation in the HR group in contrast to the LR group, and inferior frontal gyrus was not activated in the HR group but was only activated in the LR group. This finding indicates that a dysfunctional frontoparietal circuit may underlie the low P300 responses seen in HR subjects. This perhaps implies a deficiency in the rehearsal component of the working memory system.     

Evolution of Ebola Virus Disease from Exotic Infection to Global Health Priority,Liberia, Mid-2014

Over the span of a few weeks during July and August 2014, events in West Africa changed perceptions of Ebola virus disease (EVD) from an exotic tropical disease to a priority for global health security. We describe observations during that time of a field team from the Centers for Disease Control and Prevention and personnel of the Liberian Ministry of Health and Social Welfare. We outline the early epidemiology of EVD within Liberia, including the practical limitations on surveillance and the effect on the country’s health care system, such as infections among health care workers. During this time, priorities included strengthening EVD surveillance; establishing safe settings for EVD patient care (and considering alternative isolation and care models when Ebola Treatment Units were overwhelmed); improving infection control practices; establishing an incident management system; and working with Liberian airport authorities to implement EVD screening of departing passengers.