A pilot methodology study for the photographic assessment of post‐inflammatory hyperpigmentation in patients treated with tretinoin

Background Post‐inflammatory hyperpigmentation (PIH) is a common occurrence in patients with acne vulgaris, particularly in those with skin of colour. Aims A previous study has demonstrated the benefit of tretinoin (retinoic acid) in the treatment of PIH; however, there is currently no standard protocol to evaluate change in PIH following treatment. Based on these findings, we performed a pilot, exploratory, blinded, intraindividual‐controlled methodology study that consisted of a photographic assessment protocol with facial mapping. Materials and methods The study was based on a secondary analysis of a phase 4, community‐based trial of 544 acne patients who were treated with tretinoin gel microsphere 0.04% or 0.1%. Only patients with Fitzpatrick types III–V (skin of colour) were included in the study; subjects with Fitzpatrick skin type VI were excluded because the photographic assessment did not allow for proper evaluation. Results Despite the small number of subjects evaluated (n = 25), the results revealed consistent assessment of improvement in PIH between two independent graders (weighted κ = 0.84). Conclusion Further study with a larger population is recommended to validate the accuracy of this method.     

Spinal decompression and vertebroplasty in Paget's disease of the spine

Paget's disease is an osteometabolic disorder affecting in particular long bones. The spine is the second most commonly involved site in Paget's disease. This pathology can cause low back pain, spinal stenosis, myeloradiculopathy, and vertebral collapse. Medical therapy is the first choice for the treatment of Paget's disease of the spine; in case of failure, surgery remains a valid option. In the present article, we report a case of a patient with leg disability due to myelopathy caused by spinal Paget's disease treated with spinal decompression and vertebroplasty. To our knowledge, this is the first case report in which these procedures have been performed together in the same operation to treat spinal pathologies due to Paget's disease.     

Soluble suppression of tumorigenicity-2 predicts pneumonia in patients with inhalation injury: Results of a pilot study

IntroductionSeveral mechanisms play a role in the development of pneumonia after inhalation injury. Our aim was to analyze whether higher concentrations of inflammatory markers or of biomarkers of epithelial injury are associated with a higher incidence of pneumonia in patients with inhalation injury.Material and methodsSecondary analysis of a single-center prospective observational cohort pilot study, performed over a two-year period (2015–2017) at the Burns Unit of the Plastic and Reconstructive Surgery Department of Vall d’Hebron University Hospital. All patients aged 18 with suspected inhalation injury undergoing admission to the Burns Unit were included. Plasma biomarkers of the lung epithelium (RAGE and SP-D), inflammation markers (IL6, IL8), and IL33, as well as soluble suppression of tumorigenicity-2 (sST2) levels, were measured within the first 24 h of admission.ResultsTwenty-four patients with inhalation injury were included. Eight (33.3%) developed pneumonia after a median of 7 (4–8) days of hospital stay. Patients with pneumonia presented higher plasma concentrations of sST2 (2853 [2356–3351] ng/mL vs 1352 [865–1839] ng/mL; p < 0.001), IL33 (1.95 [1.31–2.59] pg/mL vs 1.26 [1.07–1.45] pg/mL; p = 0.002) and IL8 (325.7 [221.6–430.0] pg/mL vs 174.1 [95.2–253.0] pg/mL; p = 0.017) on day 1 of inclusion. Plasma sST2 concentration in the first 24 h demonstrated excellent diagnostic accuracy for predicting the occurrence of pneumonia in patients with smoke inhalation (AUROC 0.929 [95%CI 0.818–1.000]). A cutoff point of ≥2825 ng/mL for sST2 had a sensitivity of 75% and a specificity of 100%. The risk ratio of pneumonia in patients with sST2 ≥ 2825 ng/mL was 7.14 ([95% CI 1.56–32.61]; p = 0.016).ConclusionsPlasma sST2 in the first 24 h of admission predicts the occurrence of pneumonia in patients with inhalation injury.     

Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice

Chemerin is an adipokine that regulates adipogenesis and metabolic functions of mature adipocytes mainly through the activation of chemokine‐like receptor 1 (CMKLR1). Elevated levels of chemerin have been found in individuals with obesity, type 2 diabetes, and osteoporosis. This adipokine was identified as an inflammatory and metabolic syndrome marker. Considering that the association between metabolic syndrome and bone health remains unclear, the present study aimed to clarify the role of chemerin in the pathophysiology of bone loss induced by dyslipidemia, particularly modulating osteoclastogenesis. In vitro analyses showed a downregulation of CMKLR1 at the early stage of differentiation and a gradual increase at late stages. Strikingly, chemerin did not modify osteoclast differentiation markers or osteoclast formation; however, it increased the actin‐ring formation and bone resorption activity in mature osteoclasts. The increased bone resorption activity induced by chemerin was effectively inhibited by CMKLR1 antagonist (CCX832). Chemerin boosting mature osteoclast activity involves ERK5 phosphorylation. Moreover, two models of dyslipidemia (high‐fat diet [HFD]‐treated C57/BL6 and db/db mice) exhibited significantly increased level of chemerin in the serum and gingival tissue. Morphometric analysis showed that HFD‐treated and db/db mice exhibited increased alveolar bone loss compared to respective control mice, which was associated with an up‐regulation of chemerin, CMKLR1 and cathepsin K mRNA expression in the gingival tissue. The treatment of db/db mice with CCX832 effectively inhibited bone loss. Antagonism of chemerin receptor also inhibited the expression of cathepsin K in the gingival tissue. Our results show that chemerin not only increases osteoclasts activity in vitro, but also that increased level of chemerin in dyslipidemic mice plays a critical role in bone homeostasis. © 2016 American Society for Bone and Mineral Research.     

Renal and hematologic side effects of long‐term intravenous immunoglobulin therapy in patients with neurologic disorders

Introduction: For patients receiving intravenous immunoglobulin (IVIg), renal and hemolytic side effects are well recognized. However, there are very few data on the effects of chronic IVIg therapy. Methods: We retrospectively analyzed laboratory data on 166 patients who received IVIg for 12 months with a dose range of 0.441–2.58 g/kg/month, measuring changes in hematocrit and glomerular filtration (GFR) rates at 6 and 12 months. Results: Of the 2,232 infusions, there were no incidents of clinical hemolysis. However, after 12 months of treatment, 21% of patients had a ≥3‐g/dl decline in hematocrit and 10% had a ≥20% decline in GFR. Discussion: No clinically significant hemolysis was observed in patients receiving chronic IVIg therapy. However, a significant number of patients had a decline in hematocrit and/or GFR while on therapy. This emphasizes the need for observation of hematologic and renal function in patients treated with chronic IVIg. Muscle Nerve 56 : 1173–1176, 2017     

On age differences in prefrontal function: The importance of emotional/cognitive integration

Evidence of prefrontal cortex decline among healthy older adults has been widely reported, although many questions remain regarding the functional heterogeneity of the prefrontal lobes and the uniformity (or lack thereof) with which discrete regions decline with age. MacPherson, Phillips, and Della Sala (2002) previously reported age differences in tasks associated with dorsolateral prefrontal cortex (DLPFC) function (executive control), but not for tasks associated with ventromedial prefrontal cortex (VMPFC) function (emotional/cognitive integration). The present study, conducted using 39 younger adults and 39 older adults, replicates the MacPherson et al. findings regarding DLPFC functioning. However, and perhaps due to the use of more sensitive tasks, we also find age differences in tasks associated with VMPFC function. Specifically, both univariate and multivariate analyses indicated older adults showed deficits across the DLPFC and VMPFC tasks. Exploratory factor analysis of the task performance scores indicated four underlying dimensions, two related to DLPFC functioning and two related to VMPFC functioning. A set of structural equation models specifying age effects on the four task performance factors was tested, in order to contrast models of process-specific vs. common age effects. Our results suggest that older adults show deficits in emotional/cognitive integration as well as in executive function, and that those effects do include process-specific age deficits.     

Priming of human neutrophils with N-formyl-methionyl-leucyl- phenylalanine by a calcium-independent, pertussis toxin-insensitive pathway

Resting neutrophils may be "primed" to augmented effector function, eg, superoxide (O2-) production in the respiratory burst, upon a second stimulation with a variety of soluble agonists including formylated methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA). At priming concentrations of FMLP (5 x 10(-9) mol/L) that did not initiate O2- generation, two metabolic activities were noted: (1) approximately a threefold increase in the baseline intracellular calcium (Ca++i) level, that was not dependent on extracellular Ca++, and (2) a rapid rise in intracellular pH that was blocked by 5-(N,N- dimethyl) amiloride (DA), that had no effect on the Ca++i response to priming. Furthermore, there were no significant increases in inositol metabolites in cells primed and stimulated with FMLP compared with cells receiving the stimulating dose of FMLP alone and pretreatment with pertussis toxin (PT) (before the addition of the priming -5 x 10(- 9) mol/L dose of FMLP), whereas abolishing the response to FMLP during the second stage of stimulation, had (1) no effect on FMLP-primed cells subsequently stimulated with PMA, and (2) only partially ablated the rise in Ca++i initiated with FMLP. That FMLP priming involved distinctive processes to those of the well characterized FMLP-coupled Ca++-dependent activation cascade was shown by the full priming effect attained in a Ca++-free buffer, which did not sustain an O2- response to a second-stage FMLP stimulation, but sustained a primed response to PMA. These data demonstrate that FMLP primes human neutrophils by a Ca++-independent and PT-insensitive pathway, offering a functional model for studying heterogeneous FMLP receptor-coupled reactions.     

Association of granulocyte-macrophage colony-stimulating factor with the crystalloid granules of human eosinophils

We have previously shown that normal-density human peripheral blood eosinophils transcribe and translate mRNA for granulocyte-macrophage colony-stimulating factor (GM-CSF) and that the intracellular distribution was granular as assessed by light microscopy immunocytochemistry. The present study was conducted to confirm this apparent association between GM-CSF and the crystalloid granule using a subcellular fractionation method for human eosinophils and immunogold electron microscopy (EM). Highly purified (> 99%, by negative selection using anti-CD16 immunomagnetic microbeads) human peripheral blood eosinophils were obtained from four asthmatic subjects (not taking systemic medication), homogenized and density fractionated (5 x 10(7) cells/subject) on linear Nycodenz gradients. Twenty-four fractions were collected from each cell preparation and analyzed for marker enzyme activities as well as total protein. Dot blot analysis with specific monoclonal antibodies (MoAbs) was used to detect the eosinophil granule proteins major basic protein (MBP) and eosinophil cationic protein (ECP). An anti-CD9 MoAb was used as an eosinophil plasma membrane marker. Lactate dehydrogenase (LDH) was used as a cytosolic marker. Immunoreactivity for GM-CSF was detected by a specific enzyme-linked immunosorbent assay using a polyclonal antihuman GM-CSF antibody and confirmed by dot blot. GM-CSF coeluted with the cellular fractions containing granule markers (MBP, ECP, eosinophil peroxidase, hexosaminidase, and arylsulphatase), but not those containing cytoplasm (LDH+) or membrane (CD9+) markers. EM examination of pooled fractions associated with the peak of GM-CSF immunoreactivity confirmed that they contained crystalloid and small granules, but not plasma membrane. In addition, quantification, using immunogold labeling with an anti/GM-CSF MoAb, indicated preferential localization of gold particles over the eosinophil granule cores of intact cells. Thus, our results indicate that GM-CSF resides as a granule-associated, stored mediator in unstimulated human eosinophils.