Palmitate-TLR4 signaling regulates the histone demethylase,JMJD3, in macrophages and impairs diabetic wound healing

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4^−/−) or MyD88 (MyD88^−/−) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.     

Orthopädische Behandlung bei multiplen kartilaginären Exostosen

Multiple hereditary exostoses (MHE) is an autosomal dominant inherited genetic condition with an incidence of approximately 1:50,000. The routine resection of asymptomatic exostoses is unnecessary. Indications for surgery are pain, cosmetic complaints, vascular and neurological complications, abnormal growth and suspected malignancy. The spectrum ranges from resection of isolated exostoses through classical growth deviation measures up to neurological or even vascular surgical interventions. This article focuses on orthopedic surgery for the treatment of MHE. The main surgical procedures are illustrated by case studies.     

Coincidental diagnosis of tuberculous lymphadenitis: a case report

The aim of this case report was to present a case of multiple calcified tuberculous lymph nodes found on a panoramic radiograph coincidently diagnosed in an endodontic clinic. A detailed discussion on the differential diagnosis of similar such calcification found in the same region is also presented. A 14‐year‐old girl was referred to our department with the complaint of painless swelling in the left side of the lower jaw. Clinical and radiographical examinations were performed, leading to the initial diagnosis of chronic periapical abscess. The patient's medical history was re‐evaluated. Advanced imaging and excisional biopsy were performed in order to confirm the final diagnosis. Regarding the presenting signs and symptoms of bilateral carious mandibular molars, a periapical inflammatory process was considered in the provisional diagnosis. A thorough examination and investigations were suggestive of cervical tuberculous lymphadenitis (scrofula), and the patient underwent excision of the same. The clinician should consider the possibility of chronic granulomatous inflammatory lesions in the differential diagnosis of radiopaque lesions.     

Rabbit antithymocyte globulin (Thymoglobulin?) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients

Rabbit antithymocyte globulin-Genzyme™ is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme™ on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme™ during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme™ had almost undetectable levels of recent thymic emigrants (CD45RA⁺CD31⁺) of both conventional and regulatory CD4T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4⁺CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme™. In vitro, rabbit antithymocyte globulin-Genzyme™ induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius™. Rabbit antithymocyte globulin-Genzyme™ in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4⁺ T cells. The sustained depletion of conventional and regulatory CD4⁺T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme™ could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative.     

Primate neostriatal neurons containing tyrosine hydroxylase: immunohistochemical evidence

We have detected, in monkey caudate nucleus and putamen, neuronal cell bodies containing tyrosine hydroxylase-like immunoreactivity, as revealed by peroxidase-antiperoxidase immunohistochemistry. Many of these cells are distributed in an outer rim of 1-2 mm throughout the anterior-posterior extent of the neostriatum near its borders with the corona radiata; others are embedded in the adjacent white matter, especially near the ventral putamen and nucleus accumbens. Light and electron microscopy indicate that they are small (8-12 micron), bipolar cells with large nuclei. Such neostriatal neurons, containing tyrosine hydroxylase-like immunoreactivity, number in the tens of thousands.     

Weisheitszähne — Stationär behandlungsbedürftige Komplikationen

Background

In view of the conflicting guidelines issued by national and international scientific societies, debate about the indications for prophylactic extraction of wisdeom teeth is ongoing. This prospective study was therefore set up to explore the complications associated with wisdom teeth and requiring in-patient treatment.

Patients and Methods

From January /2003 to December 2003, 21 subjects were admitted for treatment of complications associated with wisdom teeth. The medical history was recorded for each of these patients, as were the cause and type of the complications. The parameter used to quantify the severity of any infections was the CRP, and the overall clinical complexity level of each case was assessed by the length of stay in hospital (and the duration of intensive care if this had been necessary). The characteristics of patients in the group with postoperative complications were compared to those of patients with complications attributable to pericoronitis. Moreover, complications in patients who had undergone prophylactic extraction of wisdom teeth that had not been causing any symptoms were compared with those in patients whose wisdom teeth had been extracted because of morbidity.

Results

Overall, 18 deep-space infections (15 abscesses, 2 inflammatory infiltrations, 1 case of phlegmonous cellulitis), 2 mandibular fractures and 1 lingual nerve injury were noted within 1 year. The complications resulted from surgical procedures in 15 of the 21 cases, while in 6 they had their origin in pericoronitis. Extensive surgery or intensive care was required only for patients with postoperative complications. The length of stay in hospital was significantly greater for patients with postoperative complications (p= 0.007, U-test). However, 9 of these 15 patients reported preoperative episodes of infection. Thus, more than two thirds of the complications could be traced back to wisdom teeth that were causing symptoms.

Conclusion

In our clinic’s catchment area, infectious complications were more frequent and more severe and required more intensive and longer treatment in hospital than complications arising from pericoronitis. However, complications of prophylactic extraction of wisdom teeth were decidedly less frequent than direct or indirect complications of extraction of symptomatic teeth. Thus, our data tend to support the concept of elective extraction of wisdom teeth with the aim of preventing serious infections.     

综合性ICU患者监护记录单临床应用的前瞻性研究

目的研究新时期综合ICU患者的临床监护记录单,以保证患者及护士使用过程的便利及安全。方法将我院ICU自2002年使用的“图标式ICU监护记录单”,在原表格的基础上根据综合ICU患者需要多系统监测的特点进行修订,主要以数字和符号表示形式形成新的护理记录表格,并采取对比的方法考证新旧两种表格的效用。结果两种表格各项指标比较：相同人数的护士分别填写两种不同表格所使用的时间分别是新表格平均（66±11）min,旧表格平均（97±10）min,每份表格的分数设为100分,护理质量检查小组检查的结果,新表格平均（97±2）分,旧表格平均（94±2）分,两组时间及分数比较差异有统计学意义（t=10．6263,4．0307;P〈0．01）;新旧表格使用合格率比较差异有统计学意义（90．12％比82．62％,x2=67．49,P〈0．01）。结论新的监护记录单更科学、更全面、简洁、更适合综合ICU不同种类的患者的记录要求,减轻护士工作量,减少记录时间,提高工作效率。     

Monocyte chemotactic protein expression during schistosome egg granuloma formation. Sequence of production, localization, contribution, and regulation.

The present study explored the role of murine monocyte chemotactic protein (MCP) in the T cell-mediated hypersensitive granulomatous response to Schistosoma mansoni eggs. The study examined the time course of local production, contribution to cellular infiltration, and the role of T cells in endogenous regulation. Synchronized pulmonary granulomas were induced under conditions of primary and secondary states of immunity. Primer-directed polymerase chain reaction analysis showed increased MCP mRNA expression in granulomatous lungs, mainly in the secondary response. Levels of MCP were measured by enzyme-linked immunosorbent assay in cultures of intact granulomas. Spontaneous MCP production was modest in primary granuloma cultures, reaching a maximum of 5.7 +/- 0.9 ng/ml by 16 days. In contrast, the secondary response showed augmented and accelerated production, achieving 13 +/- 2.0 ng/ml by 2 days. Immunohistochemical staining revealed the strongest MCP expression within microvascular adventitial cells or pericytes as well as in scattered mononuclear cells associated with granulomas. Staining was not detected in normal lungs. Passive immunization with anti-MCP-1 antibodies caused a 40% reduction in the secondary granuloma area but did not significantly affect the primary response. With adoptive cell transfer and T cell subset depletion, it was shown that Thy-1+ and CD5+ cells augmented, whereas CD8+ cells appeared to impair, MCP production. This provides direct evidence that MCP is involved in secondary Th2-mediated response to schistosome eggs and is subject to regulation by T cells.