Characterization of the thymus in Lrp4 myasthenia gravis: Four cases

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Most patients have pathogenic autoantibodies against the acetylcholine receptor (AChR). In the last years a novel subpopulation of MG patients has been described that harbors antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4), another postsynaptic neuromuscular antigen. In early-onset AChR MG (EOMG), the thymus plays an important role in immunopathogenesis, and early thymectomy is beneficial. It is still unknown if the thymus plays any role in Lrp4-MG. In this pilot study, we compared thymus samples from four patients with Lrp4-MG (one pre-treated with immunosuppressive drugs), four non-MG controls and five EOMG patients (not pretreated with immunosuppressive drugs). Immunohistochemistry of the Lrp4-MG thymi revealed normal architecture, with normal numbers and distribution of B-cells, lymphoid follicles and Hassall's corpuscles. Primary CD23⁺ lymphoid follicles were similarly infrequent in Lrp4-MG and control thymic sections. In none of the control or Lrp4-MG thymi did we find secondary follicles with CD10⁺ germinal centers. These were evident in 2 of the 5 EOMG thymi, where primary lymphoid follicles were also more frequent on average, thus showing considerable heterogeneity between patients. Even if characteristic pathological thymic changes were not observed in the Lrp4 subgroup, we cannot exclude a role for the thymus in Lrp4-MG pathogenesis, since one Lrp4-MG patient went into clinical remission after thymectomy alone (at one year follow-up) and one more improved after thymectomy in combination with immunosuppressive therapy.     

Towards equity in organised cancer screening: the case of cervical cancer screening in France

Background

The French national cancer institute (INCa) conducted a series of studies to assist decision-making in view of the implementation of organised cervical cancer screening that will be launched in 2018. The programme will concern all women aged 25–65 and targeted interventions will be developed for underscreened populations. This is an evolution from an equality-based approach to a step-by-step strategy of equity aiming to tackle health cancer inequalities that are avoidable and represents unfair differences. Here we present the work of the expert-group in ethics drafted by INCa to review the ethical issues prior to the programme implementation.

Discussion

We discuss the value of such a strategy and presents reflections with regard to issues of stigmatization, respect for individual freedom and autonomy. Indeed, the balance has to be found between the search for beneficence and the potential occurrence of perverse effects, which should be considered with particular attention.

Conclusion

Moving toward an equity-oriented policy under a strategy of proportionate universalism faces a number of challenges, thus an overview of ethics and social sciences must be an integral part of the process.

     

Impact of growth conditions on susceptibility of five microbial species to alkaline stress

The effects of different growth conditions on the susceptibility of five taxa to alkaline stress were investigated. Enterococcus faecalis ATCC 29212, Streptococcus sobrinus OMZ 176, Candida albicans ATCC 90028, Actinomyces naeslundii ATCC 12104, and Fusobacterium nucleatum ATCC 10953 were grown as planktonic cells, allowed to adhere to dentin for 24 hours, grown as monospecies or multispecies biofilms on dentin under anaerobic conditions with a serum-enriched nutrient supply at 37 degrees C for 5 days. In addition, suspended biofilm microorganisms and 5-day old planktonic multispecies cultures were used. Microbial recovery upon direct exposure to saturated calcium hydroxide solution (pH 12.5) for 10 and 100 minutes was compared with control exposure to physiologic saline. Planktonic microorganisms were most susceptible; only E. faecalis and C. albicans survived in saturated solution for 10 minutes, the latter also for 100 minutes. Dentin adhesion was the major factor in improving the resistance of E. faecalis and A. naeslundii to calcium hydroxide, whereas the multispecies context in a biofilm was the major factor in promoting resistance of S. sobrinus to the disinfectant. In contrast, the C. albicans response to calcium hydroxide was not influenced by the growth condition. Adherence to dentin and interspecies interactions in a biofilm appear to differentially affect the sensitivity of microbial species to calcium hydroxide.     

Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.     

Is melatonin ready to be used in preterm infants as a neuroprotectant?

The prevention of neurological disabilities following preterm birth remains a major public health challenge and efforts are still needed to test the neuroprotective properties of candidate molecules. Melatonin serves as a neuroprotectant in adult models of cerebral ischemia through its potent antioxidant and anti‐inflammatory effects. An increasing number of preclinical studies have consistently demonstrated that melatonin protects the damaged developing brain by preventing abnormal myelination and an inflammatory glial reaction, a major cause of white matter injury. The main questions asked in this review are whether preclinical data on the neuroprotective properties of melatonin are sufficient to translate this concept into the clinical setting, and whether melatonin can reduce white matter damage in preterm infants. This review provides support for our view that melatonin is now ready to be tested in human preterm neonates, and discusses ongoing and planned clinical trials.     

Breast-specific gamma imaging is a cost effective and efficacious imaging modality when compared with MRI

Background

Both MRI and breast-specific gamma imaging are tools for surgical planning in newly diagnosed breast cancer. Breast-specific gamma imaging (BSGI) is used less frequently although it is of similar utility and lower cost. We compared the diagnostic and cost efficacy of BSGI with MRI.

Methods

Retrospective review of 1,480 BSGIs was performed in a community breast health center, 539 had a new diagnosis of cancer, 75 patients having both MRI and BSGI performed within 2 months of each other. Institutional charges for BSGI ($850) and MRI ($3,381) were noted.

Results

BSGI had a sensitivity of 92%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 90%. This compared favorably with MRI that had sensitivity of 89%, specificity 54%, positive predictive value 67%, and negative predictive value 83%. The accuracy of BSGI was higher at 82% vs MRI at 72%. Total cost of MRI imaging was $253,575 vs BSGI at $63,750.

Conclusions

BSGI is a cost-effective and accurate imaging study for further evaluation of dense breast tissue and new diagnosis of cancer.     

Sustained neural activity to gaze and emotion perception in dynamic social scenes

To understand social interactions, we must decode dynamic social cues from seen faces. Here, we used magnetoencephalography (MEG) to study the neural responses underlying the perception of emotional expressions and gaze direction changes as depicted in an interaction between two agents. Subjects viewed displays of paired faces that first established a social scenario of gazing at each other (mutual attention) or gazing laterally together (deviated group attention) and then dynamically displayed either an angry or happy facial expression. The initial gaze change elicited a significantly larger M170 under the deviated than the mutual attention scenario. At around 400 ms after the dynamic emotion onset, responses at posterior MEG sensors differentiated between emotions, and between 1000 and 2200 ms, left posterior sensors were additionally modulated by social scenario. Moreover, activity on right anterior sensors showed both an early and prolonged interaction between emotion and social scenario. These results suggest that activity in right anterior sensors reflects an early integration of emotion and social attention, while posterior activity first differentiated between emotions only, supporting the view of a dual route for emotion processing. Altogether, our data demonstrate that both transient and sustained neurophysiological responses underlie social processing when observing interactions between others.     

In vivo assessment of skin electroporation using square wave pulses.

The application of short-duration high-voltage pulses to the skin has been shown to enhance transdermal drug delivery by several orders of magnitude and to transiently permeabilize cells in tissue. Both exponentially decaying (ED) pulses and square wave (SW) pulses have been applied. The latter have also been used for electrochemotherapy. To date, their effect on skin integrity has not been analyzed. The scope of this work was (i) to investigate the effect induced by SW pulses on the stratum corneum and the skin, (ii) to evaluate the safety issue associated with electroporation, (iii) to contribute to the understanding of drug transport. Biophysical techniques (transepidermal water loss, chromametry, impedance and laser Doppler velocimetry or imaging measurement) and histological methods were combined to provide a global picture of the effects. Ten SW pulses applied to the skin induced a mild impairment of the skin barrier function and a dramatic decrease in skin resistance. These changes were reversible. A transient decrease (<5 min) in blood flow was observed. Neither inflammation, nor necroses were observed. These studies confirm the tolerance of the skin to square wave pulses in vivo.