Rationale Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered as a plausible therapy. Objective To evaluate the efficacy of the anti-fibrotic hormone relaxin (RLX) at suppressing AF in spontaneously hypertensive rats (SHR). Methods and Results Normotensive Wistar Kyoto (WKY) and SHR were treated for 2-weeks with vehicle (WKY+V and SHR+V), or RLX (0.4mg/kg/day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations (APDs), intracellular Ca2+-transients, restitution kinetics (RK) and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV) (p< 0.01 vs. WKY), steeper CV RKs, greater collagen deposition, higher levels of transcripts for TGFβ, metalloproteinase-2, metalloproteinase-9, collagen I/III and reduced connexin-43 phosphorylation (p< 0.05 vs. WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5), SHR+V (n=4/4) but not in WKY (n=0/5) and SHR+RLX (n=1/8, p<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV-RK, reduced APD90, increased CV (p<0.01) and reversed atrial hypertrophy (p<0.05). Independent of anti-fibrotic actions, RLX (0.1µM) increased Na+-current density, INa (~2-fold in 48-hours) in human cardiomyocytes derived from iPSCs (n=18/18, p<0.01). Conclusions RLX-treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis, and hypertrophy and modulating cardiac ionic currents.

Although tuberculous pleurisy (TP) presumably involves a hypersensitivity reaction, there is limited evidence indicating overreactive effector responses of γδ T cells and αβ T cells and their interrelation with Foxp3(+) Tregs in pleural and other compartments. We found that TP induced reciprocal representations of Foxp3(+) Tregs and Mtb phosphoantigen-specific Vγ2Vδ2 T cells in different anatomic compartments. Patients with TP exhibited appreciable numbers of "proliferating" Ki-67(+) Vγ2Vδ2 T cells in the airway where Foxp3(+) Tregs were not dominant, whereas striking increases in Foxp3(+) Tregs in the blood and pleural compartments coincided with low frequencies of Vγ2Vδ2 T cells. Interestingly, anti-tuberculosis chemotherapy control of Mtb infection in patients with TP reversed reciprocal representations of Foxp3(+) Tregs and proliferating Vγ2Vδ2 T cells. Surprisingly, despite high-level Foxp3(+) Tregs, TP appeared to drive overreactive responses of IFN-γ-producing Vγ2Vδ2, CD4(+)CD25(+), and CD8(+)CD25(+) T effector subpopulations, whereas IL-22-producing Vγ2Vδ2 T cells increased subtly. Th1 effector responses were sustained despite remarkable declines in Foxp3(+) Tregs at 1 mo after the treatment. Overreactive T effector responses of Mtb-reactive γδ T cells, αβ CD25(+)CD4(+), and CD25(+)CD8(+) T cell subpopulations appear to be immune features for TP. Increased Foxp3(+) Tregs might be responsive to overreactive TP but unable to influence T effector responses despite having an inverse relation with proliferating Vγ2Vδ2 T cells.

The use of confocal laser scanning microscopy (CLSM) may be an eligible alternative for confirmation of the diagnosis of hypopigmented macules. Our purpose was to evaluate CLSM features for non-invasive imaging of vitiligo, nevus depigmentosus and postinflammatory hypopigmentation in vivo. A total of 68 patients with a clinical diagnosis of the aforementioned diseases were included in this study. CLSM was performed on lesional and adjacent normal appearing skin for all patients. In the active and stable phases of vitiligo, CLSM demonstrated a complete loss of melanin in lesional skin in 14 of 25 patients (56.0%) and 16 of 20 patients (80.0%), respectively. In 11 of 25 (44.0%) patients, the amount of melanin in lesional skin decreased in the active phase of vitiligo, but it is noteworthy to know that the melanin was distributed homogeneously in the dermal papillary rings. In four of 20 patients (20.0%), the dermal papillary rings disappeared completely, but some refractile granules and dendrites could be seen in the stable phase of vitiligo, which may indicate the start of vitiligo repigmentation. Although, in 20 of 20 patients (100%) with nevus depigmentosus, the dermal papillary rings lost their integrity and the content of melanin decreased obviously, there must have been melanin in the dermal papillary rings during its development in all patients. Simultaneously, the melanin was distributed heterogeneously in the dermal papillary rings. The content of melanin and dermal papillary rings in postinflammatory hypopigmentation probably depend on the depth and site of the inflammation; moreover, melanophages were observed in postinflammatory hypopigmentation but did not exist in vitiligo and nevus depigmentosus. In addition, the content of melanin and dermal papillary rings in adjacent normal appearing skin showed changes in the active phase of vitiligo but showed no changes in any of the patients in the stable phases of vitiligo, nevus depigmentosus and postinflammatory hypopigmentation. Differences based on CLSM in the aforementioned diseases were the content of melanin and its distribution pattern. CLSM may be useful to discriminate vitiligo, postinflammatory hypopigmentation and nevus depigmentosus in a non-invasive fashion.

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Background Studies have investigated whether patients with lichen planus are at a high risk of metabolic syndrome; however, currently, no conclusive data are available in this regard. Objective This meta-analysis was performed to analyze the published literature investigating the association between metabolic syndrome and lichen planus. Method Two reviewers independently searched 4 databases (PubMed, Embase, the Cochrane Library and Web of Science) for observational studies assessing the prevalence of metabolic syndrome in patients with lichen planus. Review Manager 5.3 software was used to statistically analyze the data. Results 200 relevant articles were searched. After a further reading, 12 studies with 1422 participants (715 with LP and 707 controls) fulfilled the eligibility criteria. Overall, the pooled odds ratio based on random effects analysis was 2.81 (95% confidence interval: 1.79-4.41, P<0.00001). This meta-analysis shows that compared with the general population, patients with lichen planus are more likely to develop metabolic syndrome. Subgroup analysis of prevalence of metabolic syndrome showed higher odds ratio in studies using International Diabetes Federation diagnostic criteria (odds ratio 4.65) and the Harmonized criteria (odds ratio 26.62) than studies using National Cholesterol Education Program Adult Treatment Panel III criteria (odds ratio 1.75), and thus might be more appropriate for diagnosing metabolic syndrome.

Background Hyperphosphatemia, hypocalcemia, and elevation of parathyroid hormone (PTH) are typical abnormalities of uremic patients with Secondary hyperparathyroidism (SHPT). However, metabolic imbalance associated with SHPT is not well understood. Methods A total of 15 SHPT patients with an intact parathyroid hormone (iPTH) level > 600 pg/mL were set as preoperative (PR) group, 15 age‐ and gender‐matched controls who had undergone parathyroidectomy plus forearm transplantation because of hyperparathyroidism and achieved an iPTH level <150 pg/mL were set as postoperative (PO) group. Metabolite profiling of these 30 uremic patients and five healthy controls (HC) was performed using ultra performance liquid chromatography‐mass spectrometry. Results Five differential metabolites, including allyl isothiocyanate, L‐phenylalanine, D‐Aspartic acid, indoleacetaldehyde, and D‐galactose correlated with PTH were identified in this study. Taking them as a biomarker signature, PR group can be distinguished from HC group with an area under the curve (AUC) of 0.947 (95% CI, 0.76‐1) and PO group with an AUC of 0.6 (95% CI, 0.38‐0.807). Conclusions The serum metabolome correlated with PTH is successfully demonstrated for a better understanding of the pathogenesis of SHPT.

Background In clinical settings, atypical facial hyperpigmentation such as nevus of Ota, acquired bilateral nevus of Ota‐like macules (ABNOM), melasma, and café‐au‐lait spots are often missed and misdiagnosed. Summarizing in vivo reflectance confocal microscopy (RCM) features of the hyperpigmentation is helpful in the diagnosis of ambiguous lesions. Methods We recruited 196 patients referred for unequivocal facial hyperpigmentation, including 55 patients with nevus of Ota, 45 patients with ABNOM, 62 patients with melasma, and 34 patients with café‐au‐lait spots. The RCM images were evaluated at the epidermis, the dermis‐epidermis junction (DEJ), and the upper papillary dermis from both hyperpigmented patches and normal skin. Results In the superficial and middle dermis, 41 of 55 patients (74.5%) with nevus of Ota were characterized by a cord‐like or lumpy structure between the collagen fibers. And there was no melanin deposition detected in the dermis in 14 of 55 (25.5%) patients. In ABNOM, 37 of 45 (82.2%) patients were characterized by a cord‐like or lumpy structure in the superficial dermis and 8 of 45 patients (17.8%) was no melanin deposition detected in the dermis. The epidermis was no difference between nevus of Ota, ABNOM, and the normal skin. Melasma was detected increased cobblestone pattern in the epidermis of all patients, branching architecture in 21 of 62 patients (33.9%), and focally aggregated round to triangular cells in the upper dermis of 18 of 62 patients (29.0%). In all patients with afé‐au‐lait spots, increased cobblestone pattern in the epidermis and regular and increased density of ringed pattern in the DEJ were visualized. Conclusions Our findings indicate that RCM may be useful in the auxiliary diagnosis of nevus of Ota, ABNOM, melasma, and café‐au‐lait spots.

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