Plasmacytic cutaneous pathology: A review

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B‐lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.     

Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid

Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (>1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphylococcal therapeutic strategies.     

Percutaneous bone-anchored hearing aid

Patients born with severe dysmorphology involving the ears usually have hearing derangements as well as other areas of the craniofacial skeleton affected. To correct the functional problem, the usual and customary treatment is augmentation of the hearing with a bone conducting hearing device. The patients have to wear these devices with an external band. The new advances in osseointegrated implant allowed us today to utilize the same technology in the patient with the application of a bone anchored hearing device. The advantages are related to the obviation of the need to use a hearing band across the head, that most children object to, and the new device is much smaller than the large and cumbersome banded device. There is also an added advantage in the improvement of the hearing as the units are anchored internally in the bone. The device utilizes digital technology and can be calibrated easily. The patient can apply the device in the morning by a simple application click. The disadvantage to the patient is that the area requires consistent maintenance and care, however, this operation can be done very easily. A sleeper osseointegrated unit is kept as a spare that can be utilized if any osseo-integrated functional problem appears. The functional changes in the hearing and the audiological improvements are well documented.     

OPTN/SRTR 2018 Annual Data Report: Intestine

Despite medical and surgical advances in treatment of intestinal failure, intestine transplant still plays an important role. However, the number of new patients added to the intestine transplant waiting list has decreased over the past decade, reaching a low of 135 in 2018. The number of intestine donors also decreased, reaching a low of 106 in 2018, and the number of intestine transplants performed declined to its lowest level, 104, of which 59% were intestine‐liver transplants. Graft failure has plateaued over the past decade. Patient survival for transplants in 2011‐2013 varied by age and transplant type. Patient survival was lowest for adult intestine‐liver recipients (1‐and 5‐year survival 66.7% and 49.1%, respectively) and highest for pediatric intestine recipients (1‐and 5‐year survival 89.1% and 76.4%, respectively).     

The β2-adrenoceptor agonist clenbuterol reduces the neuroinflammatory response,neutrophil infiltration and apoptosis following intra-striatal IL-1β administration to rats

Objectives: Clenbuterol is a brain penetrant β₂-adrenoceptor agonist with anti-inflammatory and putative neuroprotective properties. In the present investigation, the effect of clenbuterol was assessed in a rat model of acute brain injury induced by intra-striatal administration of the pro-inflammatory cytokine IL-1β.

Methods: Clenbuterol (0.5?mg/kg; i.p.) was administered one hour prior to stereotactically delivered IL-1β (100?ng) into the striatum. Four hours postinjection, rats were anesthetized, blood samples were collected for circulating cytokine and chemokine analysis, and the ipsilateral striatum and liver tissue were harvested for mRNA expression analysis of target genes.

Results: Intrastriatal IL-1β provoked an inflammatory response with increased expression of IL-1β and the pro-inflammatory cytokine TNF-α. TNF-α expression was also increased in the liver and circulating concentrations of the chemokine cytokine-induced neutrophil chemoattractant 1 (CINC-1) were raised in response to intrastriatal IL-1β administration. The striatal response was accompanied by NFκB activation and 24?hours postinjection, increased immunoreactivity of the neutrophil marker MBS-2, indicative of cell infiltration and increased TUNEL staining, a cell marker of apoptosis. Treatment with clenbuterol attenuated all IL-1β-induced changes in the striatum including MBS-2 immunoreactivity and TUNEL?+?staining. Clenbuterol also attenuated IL-1β-induced expression of TNF-α in the liver and the increase in circulating CINC-1 concentrations.

Conclusions: The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1β–induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.     

Beyond Food Promotion: A Systematic Review on the Influence of the Food Industry on Obesity-Related Dietary Behaviour among Children

An increased consumption of energy-dense, nutrient-poor food and beverages as a result of a changing obesogenic environment contributes substantially to the increasing prevalence of childhood overweight and obesity. This paper reviews the nature and extent of food industry influences which expose children to commercial influences and thus might affect unhealthy dietary behaviour and finally contributes to obesity. A systematic search of nine electronic databases (including PubMed, PsycINFO, EconLit) and reference lists of original studies and reviews using key search terms identified 1900 articles. Of these only thirty-six articles met the inclusion and quality criteria. A narrative synthesis of the reviewed studies revealed six key obesogenic environments by which the food industry possibly influences obesity-related dietary behaviours in young children. These were schools, retailers, mass media “television”, mass media “internet”, home and promotional campaigns. Identifying these obesogenic environments is critical for monitoring and controlling the food industry, the development of effective environmental-level interventions to prevent childhood overweight and obesity and to identify knowledge gaps to be addressed in future research to support informed decisions of policy makers.     

The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis

Background

The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs. As the CXCL8-based decoy PA401 displays no chemotactic activity, yet demonstrates glycan binding affinity, the aim of this study was to investigate the anti-inflammatory effect of PA401 on CXCL8 levels, and activity, in CF airway samples in vitro.

Methods

Bronchoalveolar lavage fluid (BALF) was collected from patients with CF homozygous for the ΔF508 mutation (n = 13). CXCL8 in CF BALF pre and post exposure to PA401 was quantified by ELISA. Western blot analysis was used to determine PA401 degradation in CF BALF. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post exposure to PA401 by use of a Boyden chamber-based motility assay.

Results

Exposure of CF BALF to increasing concentrations of PA401 (50–1000 pg/ml) over a time course of 2–12 h in vitro, significantly reduced the level of detectable CXCL8 (P < 0.05). Interestingly, PA401 engendered release of CXCL8 from GAGs exposing the chemokine susceptible to proteolysis. Subsequently, a loss of PA401 was observed (P < 0.05) due to proteolytic degradation by elastase like proteases. A 25% decrease in neutrophil chemotactic efficiency towards CF BALF samples incubated with PA401 was also observed (P < 0.05).

Conclusion

PA401 can disrupt CXCL8:GAG complexes, rendering the chemokine susceptible to proteolytic degradation. Clinical application of a CXCL8 decoy, such as PA401, may serve to decrease the inflammatory burden in the CF lung in vivo.     

Synthesis,characterization, and monoamine transporter activity of the new psychoactive substance 3′,4′‐methylenedioxy‐4‐methylaminorex (MDMAR)

The recent occurrence of deaths associated with the psychostimulant cis‐4,4′‐dimethylaminorex (4,4′‐DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4‐methylenedioxy‐4‐methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis‐ and trans‐MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis‐isomer (90%). Exposure of the cis‐isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans‐isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non‐selective monoamine releasing agent (+)‐3,4‐methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis‐ and trans‐4,4′‐DMAR, were assessed under identical conditions. cis‐MDMAR, trans‐MDMAR, cis‐4,4′‐DMAR and trans‐4,4′‐DMAR were more potent than MDMA in their ability to function as efficacious substrate‐type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis‐4,4′‐DMAR, cis‐MDMAR and trans‐MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans‐4,4′‐DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring‐substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side‐effects after high dose exposure. Copyright © 2014 John Wiley & Sons, Ltd.