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Background: Cutaneous leishmaniasis (CL) is a parasitic cutaneous infection caused by Leishmania parasite. The histopathology is usually granulomatous in nature., Aims: The aim of the present study is to elucidate the histology of CL and evaluate the presence and the frequency of panniculitis among the affected patients., Settings and Design: Case series interventional study., Materials and Methods: Thirty-five patients with CL were diagnosed clinically between December-2012 and May-2013. Diagnostic confirmation established by smears, culture, and polymerase chain reaction (PCR). The histopathological assessment was carried out to study the general pathology and to look for the presence of panniculitis., Statistical Analysis Used: Simple statistics utilized via SPSS version 16.0 (SPSS, Inc., Chicago, USA)., Results: Eighteen women and 17 men with CL were enrolled in the present work with a mean duration of their disease was 3 months. The results of the diagnostic tests were as follow: The smear was positive in 21 (60%) of cases, Leishman-Donovan (LD) bodies were seen in 7 (20%) patients, culture was positive in 24 (68%), and PCR was positive in 32 (91.4%) patients. The epidermal changes included acanthosis, pseudoepitheliomatous hyperplasia, ulceration, focal spongiosis, and interface dermatitis while the dermal changes were dependent on the spectrum of the disease, so in the ulcerative lesions there was lymphohistiocytic infiltration with foci of plasma cells and sometimes aggregate of LD bodies, whereas in the dry lesions the pathology is mainly of epithelioid granuloma. Panniculitis was seen in 16 (46%) cases as a diffuse lymphohistiocytic infiltration of both the septum and lobules of the subcutaneous layer of the skin., Conclusion: Panniculitis is an important feature of CL that must be differentiated from other diseases that can simulate CL such as chronic skin infections, Discoid lupus erythematosus, and cutaneous lymphoma.

Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice. The EP3(-/-) mice had increased macrophage infiltration, TNF-α, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with EP3(+/+) animals. Adipocytes isolated from EP3(+/+) or EP3(-/-) mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared with EP3(+/+). EP3(-/-) mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3(-/-) mice became hyperglycemic and hyperinsulinemic when compared with EP3(+/+) fed HFD, demonstrating a more severe insulin resistance phenotype in EP3(-/-). These results demonstrate that when fed a HFD, EP3(-/-) mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.

Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting primarily the joints but also other organs including skin. Panniculitis is an extremely rare manifestation of the disease manifesting mainly as reddish, ulcerative painful nodules and papules, usually in the legs. Histopathologically, it is characterised by liponecrobiosis, granulocytic and histiocytic infiltrates and vasculopathy. Herein, we describe a middle-aged woman with past medical history of hypertension and diabetes mellitus, and unremarkable family history, who presented with symmetrical polyarthritis, low grade fever and painful subcutaneous nodules in the abdomen. Her laboratory tests showed high acute phase reactants, positive rheumatoid factor and anti-Ro autoantibodies and negative anti-CCP. Surgical resection and histological examination of the nodules revealed neutrophilic lobular panniculitis associated with RA. She was treated with low doses of glucocorticosteroids and methotrexate. The latter was substituted with leflunomide due to toxicity. The patient had significant clinical and laboratory improvement.

Mesotherapy was first introduced in Europe for the treatment of localized pain. It is currently used mainly for aesthetical purposes and gradually getting widely used for body contouring, cellulite reduction, and skin rejuvenation. The reports concerning about mesotherapy is increasing in number in the literature. There are reported systemic and local side effects of mesotherapy. Panniculitis is a rare side effect of mesotherapy. In this article, we report a case of mesotherapy-induced panniculitis who responded to dapsone therapy.

Background: Limited data on adipose tissue zinc content in obesity exist. At the same time, the association between adipose tissue zinc content and metabolic parameters in dietary-induced obesity is poorly studied. Therefore, the primary objective of this study is to assess adipose tissue zinc content and its association  with morphometric parameters, adipokine spectrum, proinflammatory cytokines, and apolipoprotein profile in high fat fed Wistar rats., Methods: A total of 48 adult female Wistar rats were used in the present study. Rats were fed either control (10% of fat) or high fat diet (31.6% of fat). Adipose tissue zinc content was assessed using inductively coupled plasma mass spectrometry. Rats' serum was examined for adiponectin, leptin, insulin, interleukin-6, and tumor necrosis factor-α using enzyme-linked immunosorbent assay kits. Serum glucose and apolipoprotein spectrum were also evaluated., Results: High fat feeding resulted in a significant 34% decrease in adipose tissue zinc content in comparison to the control values. Fat pad zinc levels were significantly inversely associated with morphometric parameters, circulating leptin, insulin, tumor necrosis factor-α levels and HOMA-IR values. At the same time,      a significant correlation with apolipoprotein A1 concentration was observed., Conclusions: Generally, the obtained data indicate that (1) high fat feeding results in decreased adipose tissue zinc content; (2) adipose tissue zinc content is tightly associated with excessive adiposity, inflammation, insulin resistance and potentially atherogenic changes.

Scope: This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro., Methods and Results: C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures., Conclusion: Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The Ossabaw pig is emerging as an attractive model of human cardiometabolic disease because of its size and susceptibility to atherosclerosis, among other characteristics. The relationship between adipose tissue inflammation and metabolic dysfunction in this model was investigated here., Methods: Young female Ossabaw pigs were fed a Western-style high-fat diet (HFD) (n = 4) or control low-fat diet (LFD) (n = 4) for a period of 9 months and compared for cardiometabolic outcomes and adipose tissue inflammation., Results: The HFD-fed "OBESE" pigs were 2.5 times heavier (P < 0.001) than LFD-fed "LEAN" pigs and developed severe obesity. HFD feeding caused pronounced dyslipidemia, hypertension, and insulin resistance (systemic and adipose), as well as induction of inflammatory genes, impairments in vasomotor reactivity to insulin, and atherosclerosis in the coronary arteries. Remarkably, visceral, subcutaneous, and perivascular adipose tissue inflammation (via FACS analysis and RT-PCR) was not increased in OBESE pigs, nor were circulating inflammatory cytokines., Conclusions: These findings reveal a disconnect between adipose tissue inflammation and cardiometabolic dysfunction induced by Western diet feeding in the Ossabaw pig model., (© 2015 The Obesity Society.)

Catalpol, a bioactive component from the root of Rehmannia glutinosa, has been shown to possess hypoglycemic effects in type 2 diabetic animal models, however, the underlying mechanisms remain poorly understood. Here we investigated the effect of catalpol on high-fat diet (HFD)-induced insulin resistance and adipose tissue inflammation in mice. Oral administration of catalpol at 100 mg/kg for 4 weeks had no effect on body weight of HFD-induced obese mice, but it significantly improved fasting glucose and insulin levels, glucose tolerance and insulin tolerance. Moreover, macrophage infiltration into adipose tissue was markedly reduced by catalpol. Intriguingly, catalpol also significantly reduced mRNA expressions of M1 pro-inflammatory cytokines, but increased M2 anti-inflammatory gene expressions in adipose tissue. Concurrently, catalpol significantly suppressed the c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways in adipose tissue. Collectively, these results suggest that catalpol may ameliorate HFD-induced insulin resistance in mice by attenuating adipose tissue inflammation and suppressing the JNK and NF-κB pathways, and thus provide important new insights into the underlying mechanisms of the antidiabetic effect of catalpol., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis characterized by systemic features, due to histiocytic infiltration along with haemophagocytosis, which may also appear in bone marrow, spleen, lymph nodes, and liver. Haemophagocytic lymphohistiocytosis (HLH) is a group of autoinflammatory disorders, which include macrophage activation syndrome, sometimes observed in the course of systemic autoimmune diseases, such as juvenile chronic polyarthritis, systemic lupus erythematosus or vasculitis, and infection-associated haemophagocytic syndrome; if not promptly recognised and treated, HLH can be fatal. Visceral leishmaniasis (VL) is a systemic disease caused by different forms of Leishmania spp., an intracellular protozoa. VL is endemic in tropical countries such as in the Middle East and the Mediterranean. The typical clinical and laboratory features are fever, hepato-splenomegaly, hypergammaglobulinaemia and pancytopenia. The features of VL may mimic some haematologic diseases. We report a case of cytophagic histiocytic panniculitis and HLH, triggered by a previous visceral leishmania infection. Cyclosporine was quickly effective in this case, after failure of high-dose glucocorticoids, anakinra and etoposide.

Panniculitis associated with α1-antitrypsin deficiency (AATD) is well documented but rare. We report the first case, to our knowledge, of successful induction of clinical remission of AATD-related panniculitis following a single 120-mg/kg dose administration of plasma-purified α1-antitrypsin (AAT). A 23-year-old man with known PiZZ AATD presented to the hospital with a diffusely swollen and tender right upper limb. This was associated with subcutaneous induration, and a discrepancy of 5 cm in upper limb circumference at the mid arm was noted. There was no convincing precipitant for cellulitis or an infectious cause, and inflammatory markers were raised, with a C-reactive protein (CRP) level of 93.9 mg/L and erythrocyte sedimentation rate (ESR) of 71 mm/h. Doppler ultrasonography ruled out DVT. No antimicrobials or antiinflammatory medications were administered during or prior to admission. Biopsy specimens of the right upper limb revealed extensive panniculitis with neutrophils, foamy macrophages, and fat necrosis. A diagnosis of AATD-associated panniculitis was made. Following this, a single IV dose of 120 mg/kg of plasma-purified AAT was administered. By day 7 post AAT infusion, CRP level had normalized to 4.6 mg/L and ESR had dropped to 22 mm/h. Limb circumference discrepancy on day 7 was 1 cm. There was no tenderness to palpation or induration, and a clinical remission of panniculitis was observed. We report the first case, to our knowledge, of clinical remission following a single treatment with IV AAT at a dose of 120 mg/kg. This opens avenues to more timely and effective treatment of the more severe presentations of AAT-associated panniculitis.

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11β-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

A decrease in serum estrogen levels in menopause is closely associated with the development of visceral obesity and the onset of type 2 diabetes in women. In the present study, we demonstrated the therapeutic effects of the novel DPP4 inhibitor, teneligliptin, on the features of postmenopausal obesity in mice. In the control group, female C57BL/6 mice were sham-operated and maintained on a standard diet. In the postmenopausal obese group, ovariectomized (OVX) mice were maintained on a high-fat diet, and were referred to as OVX-HF. In the treated group, teneligliptin at 60 mg/kg per day was administrated to OVX-HF, and were referred to as Tene. After a 12-week food challenge, the metabolic phenotypes of these mice were analyzed. Body weight, fat accumulation, and glucose intolerance were greater in OVX-HF than in control, while these abnormalities were markedly improved without alterations in calorie intake in Tene. Teneligliptin effectively ameliorated the characteristics of metabolic abnormalities associated with postmenopausal obesity. Regarding chronic inflammation in visceral adipose tissue, the numbers of F4/80(+)CD11c(+)CD206(-) M1-macrophages in flow cytometry, crown-like structure formation in immunohistochemistry, and proinflammatory cytokine expression were significantly attenuated in Tene. Hepatic steatosis was also markedly improved. Furthermore, decreased energy consumption in the dark and light phases, reduced locomotor activity in the dark phase, and lowered core body temperature in OVX-HF were ameliorated in Tene. Since obesity and reduced energy metabolism are a common physiology of menopause, teneligliptin appears to be beneficial as a treatment for type 2 diabetes in postmenopausal obesity., (© 2015 Society for Endocrinology.)

Adipose tissue (AT) inflammation is an emerging factor contributing to cardiovascular disease. STAT4 is a transcription factor expressed in adipocytes and in immune cells and contributes to AT inflammation and insulin resistance in obesity. The objective of this study was to determine the effect of STAT4 deficiency on visceral and peri-aortic AT inflammation in a model of atherosclerosis without obesity. Stat4(-/-)Apoe(-/-) mice and Apoe(-/-) controls were kept either on chow or Western diet for 12 weeks. Visceral and peri-aortic AT were collected and analyzed for immune composition by flow cytometry and for cytokine/chemokine expression by real-time PCR. Stat4(-/-)Apoe(-/-) and Apoe(-/-) mice had similar body weight, plasma glucose, and lipids. Western diet significantly increased macrophage, CD4+, CD8+, and NK cells in peri-aortic and visceral fat in Apoe(-/-) mice. In contrast, in Stat4(-/-)Apoe(-/-) mice, a Western diet failed to increase the percentage of immune cells infiltrating the AT. Also, IL12p40, TNFa, CCL5, CXCL10, and CX3CL1 were significantly reduced in the peri-aortic fat in Stat4(-/-)Apoe(-/-) mice. Importantly, Stat4(-/-)Apoe(-/-) mice on a Western diet had significantly reduced plaque burden vs Apoe(-/-) controls. In conclusion, STAT4 deletion reduces inflammation in peri-vascular and visceral AT and this may contribute via direct or indirect effects to reduced atheroma formation., (© 2015 Society for Endocrinology.)

Wound healing disturbance is a common complication following surgery, but the underlying cause sometimes remains elusive. A 50-year-old Caucasian male developed an initially misunderstood severe wound healing disturbance following colon and abdominal wall surgery. An untreated alpha-1-antitrypsin (AAT) deficiency in the patient's medical history, known since 20 years and clinically apparent as a mild to moderate chronic obstructive pulmonary disease, was eventually found to be at its origin. Further clinical work-up showed AAT serum levels below 30% of the lower reference value; phenotype testing showed a ZZ phenotype and a biopsy taken from the wound area showed the characteristic, disease-related histological pattern of necrotising panniculitits. Augmentation therapy with plasma AAT was initiated and within a few weeks, rapid and adequate would healing was observed. AAT deficiency is an uncommon but clinically significant, possible cause of wound healing disturbances. An augmentation therapy ought to be considered in affected patients during the perioperative period., (© 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Obesity is associated with a systemic chronic low-grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity-related pro-inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low-grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high-fat diet may be a cause of low-grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity-associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria-mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high-fat diet-related systemic low-grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high-fat diet-induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues., (Copyright © 2014 John Wiley & Sons, Ltd.)

Fish oil improves obesity and its comorbidities, but its mechanisms of action remain unknown. We evaluate the effects of a diet rich in fish oil in white adipose tissue (WAT) inflammation pathways, renin-angiotensin system (RAS) and mitogen-activated protein kinases (MAPKs). To achieve our aims, four groups of male C57BL/6 mice were fed different diets: standard chow diet (SC; 10% energy from fat), SC+fish oil diet (SC-FO; 10% energy from fat), high-fat lard diet (HF-L; 50% energy from lard) and HF fish oil diet (HF-FO; 50% energy from fish oil). We evaluated body mass, epididymal fat pad mass, food intake and glucose tolerance. In WAT, we assessed adipocyte hypertrophy, monocyte chemotactic protein-1 immunofluorescence, and gene and protein expression of insulin signaling, inflammation, MAPKs, RAS, peroxisome proliferator-activated receptors (PPARs) and AMP-activated protein kinase (AMPK). In relation to the results, the HF-L group, as expected, showed elevated body mass and adiposity, glucose intolerance and hypertrophied adipocytes. In WAT, we found a defect in insulin signaling, infiltration of macrophages and inflammatory markers with the associated activation of MAPKs and local RAS. On the contrary, the HF-FO group did not present increased body mass, adiposity or glucose intolerance. In this group, insulin signaling, macrophage infiltration and inflammation were reduced in WAT in comparison with the HF-L group. We also observed decreases of MAPKs and local RAS and elevation of PPAR and AMPK. In summary, fish oil activates PPAR (the three isoforms) and AMPK, decreases WAT insulin resistance and inflammation, and inhibits MAPK and RAS pathways activation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study examined whether oral administration of an arginase inhibitor regulates adipose tissue macrophage infiltration and inflammation in mice with high fat diet (HFD)-induced obesity. Male C57BL/6 mice (n = 30) were randomly assigned to control (CTL, n = 10), HFD only (n = 10), and HFD with arginase inhibitor N(ω)-hydroxy-nor-l-arginine (HFD with nor-NOHA, n = 10) groups. Plasma and mRNA levels of cytokines in epididymal adipose tissues (EAT), macrophage infiltration into EAT, and macrophage phenotype polarization were measured in the animals after 12 weeks. Additionally, the effects of nor-NOHA on adipose tissue macrophage infiltration and mRNA expression of cytokines were measured in co-cultured 3T3-L1 adipocytes and RAW 264.7 macrophages. Macrophage infiltration into the adipocytes was significantly suppressed by nor-NOHA treatment in adipocyte/macrophage co-culture system and mice with HFD-induced obesity. Pro-inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), were significantly downregulated, and the anti-inflammatory cytokine IL-10 was significantly upregulated in nor-NOHA-treated co-cultured cells. In the mice with HFD-induced obesity, plasma and mRNA levels of MCP-1 significantly reduced after supplementation with nor-NOHA. In addition, oral supplement of nor-NOHA modified M1/M2 phenotype ratio in the EAT. Oral supplementation of an arginase inhibitor, nor-NOHA, altered M1/M2 macrophage phenotype and macrophage infiltration into HFD-induced obese adipose tissue, thereby improved adipose tissue inflammatory response. These results may indicate that arginase inhibition ameliorates obesity-induced adipose tissue inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Dermatomyositis-related panniculitis is a rare cutaneous manifestation of dermatomyositis. There are few reported cases in the medical literature. We present the case of a 60-year-old woman with a 2-year history of dermatomyositis and recent biopsy-confirmed panniculitis treated with prednisone, cyclophosphamide and i.v. immunoglobulin., (© 2014 The Australasian College of Dermatologists.)

Background: Metabolic and transcriptomic differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments, particularly in the context of obesity, may play a role in colorectal carcinogenesis. We investigated the differential functions of their metabolic compositions., Objectives: Biochemical differences between adipose tissues (VAT compared with SAT) in patients with colorectal carcinoma (CRC) were investigated by using mass spectrometry metabolomics and gene expression profiling. Metabolite compositions were compared between VAT, SAT, and serum metabolites. The relation between patients' tumor stage and metabolic profiles was assessed., Design: Presurgery blood and paired VAT and SAT samples during tumor surgery were obtained from 59 CRC patients (tumor stages I-IV) of the ColoCare cohort. Gas chromatography time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were used to measure 1065 metabolites in adipose tissue (333 identified compounds) and 1810 metabolites in serum (467 identified compounds). Adipose tissue gene expression was measured by using Illumina's HumanHT-12 Expression BeadChips., Results: Compared with SAT, VAT displayed elevated markers of inflammatory lipid metabolism, free arachidonic acid, phospholipases (PLA2G10), and prostaglandin synthesis-related enzymes (PTGD/PTGS2S). Plasmalogen concentrations were lower in VAT than in SAT, which was supported by lower gene expression of FAR1, the rate-limiting enzyme for ether-lipid synthesis in VAT. Serum sphingomyelin concentrations were inversely correlated (P = 0.0001) with SAT adipose triglycerides. Logistic regression identified lipids in patients' adipose tissues, which were associated with CRC tumor stage., Conclusions: As one of the first studies, we comprehensively assessed differences in metabolic, lipidomic, and transcriptomic profiles between paired human VAT and SAT and their association with CRC tumor stage. We identified markers of inflammation in VAT, which supports prior evidence regarding the role of visceral adiposity and cancer., (© 2015 American Society for Nutrition.)

Objectives: Lymphocytic infiltrates in the subcutaneous adipose tissue, often accompanied by fat necrosis, are typically seen in benign panniculitis. Diagnostic considerations include subcutaneous panniculitis-like T-cell lymphoma and cutaneous γδ T-cell lymphoma, whereas a primary subcutaneous B-cell lymphoma in this setting has not been previously described., Methods: We report the case of a 72-year-old woman with multiple deep cutaneous nodules on the trunk and upper extremities., Results: During 3 years of clinical follow-up, new skin nodules developed, while existing lesions remained stable or regressed. No other organ involvement was detected. Sequential biopsy specimens of the subcutaneous lesions revealed patchy, predominantly septal, lymphocytic infiltrates associated with extensive hyaline fat necrosis. The histologic and immunophenotypic features were consistent with marginal zone lymphoma. Genotyping revealed an identical monoclonal immunoglobulin gene rearrangement across all biopsy specimens., Conclusions: This case represents, to our knowledge, the first reported case of primary subcutaneous B-cell lymphoma closely associated with panniculitis., (Copyright© by the American Society for Clinical Pathology.)

Postirradiation pseudosclerodermatous panniculitis presents as an erythematous indurated plaque, on a previously irradiated area. Histopathologically, thick and sclerotic septa and inflammatory infiltrate with foamy histiocytes and adiponecrosis are seen. To date, 12 cases have been reported worldwide. Hereby, we report the case of a 68-year-old woman who developed an indurated painful erythematous plaque on her right leg after radiotherapy for a soft tissue sarcoma, with a septal panniculitis and lobular adiponecrosis on histopathological examination. This is the 13th case reported and the second of extrathoracic location.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic tumor, with an estimated frequency of less than 1% of pancreatic malignancies. There are no prospective studies to guide diagnostic or therapeutic algorithms. We report the case of a 36 year-old woman, diagnosed of a pancreatic tumor with liver and peritoneal metastases that was initially managed as a neuroendocrine tumor with temozolomide and capecitabine. After two cycles a severely painful arthritis developed in her left ankle with panniculitis and extensive fat necrosis, and CT scan demonstrated progressive disease. Pathology of the primary was reassessed establishing the diagnosis of PACC. The patient started treatment with FOLFIRINOX regimen, achieving clinical benefit and disease stabilization. We also briefly reviewed the literature on this rare subtype of pancreatic tumor., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

This article reports a case of febrile, symmetrical and painful soft tissue swelling on both thighs in a 54-year-old otherwise healthy male patient. Histologically, necrotizing panniculitis of subcutaneous adipose tissue was described as a marker manifestation of a previously unknown alpha-1-antitrypsin (A1AT) deficiency with pulmonary emphysema and low plasma A1AT levels. The PiZZ homozygous form of A1AT could be diagnosed by gene sequencing. Complete remission of panniculitis could be achieved by A1AT replacement therapy.

Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT Arg1 and Tlr4 expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue.

Background: Obesity is associated with a mild chronic inflammatory response, which has been suggested to be pivotal in the development of cardiometabolic alterations of obesity. However, little is known about the involvement of acute inflammation., Objective: To evaluate whether circulating neutrophils, markers of acute inflammation, are associated (quantitatively and qualitatively) with adolescent obesity and whether leptin modulates these associations., Subjects and Methods: We assessed 528 adolescents (16.8 yr old, 47% females), without chronic/acute illness. We measured anthropometry and dual energy X-ray absorptiometry and calculated fat mass percentage (FM%). Fasting serum glucose, high-density lipoprotein (HDL)-cholesterol, and triglycerides were used with blood pressure and waist circumference to compute a metabolic z-score. Leukocyte and neutrophil counts were obtained, together with levels of serum leptin. In a subsample of 23 males, flow cytometry was used to assess degranulation (CD66b expression) of neutrophils., Results: Female sex and obesity were positively related to mean neutrophil counts (p < 0.05). When accounting for sex and weight status, leptin was associated with neutrophil counts (p < 0.05), partially explaining the association between obesity and neutrophil counts. Neutrophil counts were related to metabolic risk z-scores, controlling for fat mass. Participants with elevated FM% showed more neutrophil degranulation than controls (p < 0.05)., Conclusions: Participants with increased adiposity had higher circulating neutrophil counts, suggesting acute inflammation. Furthermore, the neutrophils showed more degranulation, indicating inflammation. Obesity-induced alteration of the adipose secretory pattern (i.e., changes in leptin levels) could be involved in acute inflammation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: The breakdown of previously inserted intravascular devices can lead to microemboli that can clinically mimic the symptoms of common disorders, such as senile purpura, and have subtle histologic findings. However, device failure can occur gradually and start months after placement. If not identified early, microemboli to noncutaneous sites can cause significant morbidity and mortality., Observations: A woman in her 70s presented 6 months after a complex aortic aneurysm repair with several large ecchymoses radiating from firm subcutaneous nodules on the buttocks, arms, and thighs. Skin biopsy specimens revealed extensive hemorrhage and a panniculitis with sparse, subtle, intra-arteriole, gray amorphous deposits that, on analysis by scanning electron microscopy with energy-dispersive radiography analysis and infrared spectrometry, were most consistent with a hydrophilic polymer. This type of hydrophilic polymer coats catheters and stents such as those used in aortic aneurysm repair., Conclusions and Relevance: This is an unusual case of microemboli from the polymer coating intra-arterial stents starting months after placement and causing a panniculitis. Prior observations show that polymers coating intravascular devices have the potential to break down gradually and long after the device's placement, but clinical consideration for delayed microembolization is underrecognized until catastrophic impairment or death.

We describe a rare case of a patient with pancreatic adenocarcinoma who presented initially with a rash on her lower legs. Skin biopsy showed lobular panniculitis and characteristic "ghost" adipocytes consistent with pancreatitic panniculitis. This clinical case is an interesting example where a seemingly innocuous skin condition heralds an underlying malignant disease process.

Background: Painful cutaneous injection site reactions may hamper treatment with interferon β (IFN-β) and glatiramer acetate (GA) in multiple sclerosis (MS) patients., Objective: To maintain therapy adherence, efficient therapeutic modalities for these subcutaneous inflammatory lesions are urgently needed. We tested the application of local extracorporeal shock wave therapy (ESWT)., Methods: We applied 5 sessions of ESWT to 8 patients suffering from MS who had developed painful panniculitis at the injection sites of either IFN-β or GA. Clinical outcomes, i.e. pain reduction and regression of induration, were assessed 3 and 6 months after completion of the ESWT using a visual analogue score., Results: All patients showed both significant pain reduction and reduction of the skin induration in the treated lesions, while in untreated control lesions there was no improvement., Conclusion: ESWT proved to be a non-invasive, safe and efficient physical treatment modality for injection-induced painful cutaneous side effects of disease-modifying drugs in MS., (© 2014 S. Karger AG, Basel.)

A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress.

Alkaptonuria, with its sequel, ochronosis, is a rare disease, with an incidence of 1:125,000 to 1:1 million worldwide. Reported cases of ochronotic arthropathy and other orthopedic manifestations are mostly limited to a single family tree, and few cases have been reported. This study highlights 9 previously unreported patients with sporadic presentation and varied orthopedic manifestations of alkaptonuria. Patient age ranged from 34 to 50 years. One patient who had severe arthropathy of the right hip joint along with subcutaneous nodules over both knees and Achilles tendons underwent total hip replacement. Another patient had intramedullary calcification of the femur. An additional patient had associated caries of the spine at L3, L4, and L5, with resolution of symptoms after antitubercular chemotherapy. Another patient had associated features of hyperthyroidism, which was an incidental finding. A further patient had nonunion fracture of the neck of the femur and underwent total hip replacement. The remaining 4 patients had typical features of low backache and arthritis of the large joints. The parents were nonconsanguineous, and only 2 patients had affected siblings. The remaining 7 patients had sporadic nonfamilial presentation. Diagnosis was established by typical clinical and radiologic findings and biochemical analysis. At 2 years of follow-up, both patients who underwent total hip replacement were normal, with no radiologic signs of loosening or lysis. Clinicians need a high index of suspicion and awareness to make the diagnosis of ochronosis. The current study is unique because of presentation with subcutaneous nodules in 1 patient and associated caries of the spine in another patient., (Copyright 2014, SLACK Incorporated.)

The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D-NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D-NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue.

Context: Neutrophilic panniculitis encompasses an etiologically and morphologically heterogeneous group of disorders. Correct histopathologic diagnosis is important in identifying certain systemic diseases and guiding appropriate treatment., Objective: To review the clinical and histopathologic features of different types of neutrophilic panniculitis, and to provide a diagnostic algorithm for these disorders., Data Sources: A review of the literature with emphasis on the distinguishing features of different entities was performed., Conclusions: Evaluation for neutrophilic panniculitis entails paying close attention to the pattern of inflammation, the type of fat necrosis present, any evidence of vascular damage, and other relevant histopathologic features. An algorithmic approach integrating all histopathologic, clinical, and laboratory findings is required for correct diagnosis.

Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepatic PPARα mRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.

Inflammation of adipose tissue triggers the metabolic syndrome, atherosclerosis and CHD. In the present study, we investigated whether the milk casein-derived tripeptide valine-proline-proline (VPP) has an anti-inflammatory effect on the adipose tissue of high-fat diet (HFD)-fed mice. Male C57BL/6J mice (7 weeks of age) were fed ad libitum with either a HFD and plain tap water (HFD group) or a HFD and water containing 0·3 mg VPP/ml (HFD+VPP group) for 10 weeks. The results showed that the expression level of CD18 in the peripheral blood monocytes of the HFD+VPP group was significantly decreased compared with the level observed in those of the HFD group. Activated monocytes and pro-inflammatory macrophages were accumulated in the stromal vascular fractions of the adipose tissue from HFD-fed mice, which were significantly decreased in those supplemented with VPP. The formation of crown-like structures rich in pro-inflammatory macrophages was also significantly reduced in the adipose tissue of mice administered with VPP. Real-time PCR analysis revealed that the expression of monocyte chemoattractant protein-1 and that of the pro-inflammatory cytokine IL-6 in adipose tissue tend to be lower in the HFD+VPP group than in the HFD group. These observations indicate that oral administration of VPP exerts an anti-inflammatory effect on the adipose tissue of HFD-fed mice, which may eventually lead to the primary prevention of chronic inflammation-related diseases.

Introduction: Use of endermology (Endermologie®), which consists of a deep mechanical massage, in patients with multiple sclerosis receiving glatiramer acetate suggested improvements in injection-site indurations and panniculitis/lipoatrophy in our previous pilot experience. We aimed to assess the effect of endermology in a larger population of patients with multiple sclerosis receiving glatiramer acetate in clinical practice., Methods: This was the extension phase of our pilot experience, carried out in patients with relapsing-remitting multiple sclerosis (RRMS) and indurations and/or panniculitis/lipoatrophy associated with long-term glatiramer acetate administration. Patients underwent endermology sessions twice per week, for 6 weeks, according to clinical practice., Results: Seventy evaluable patients were included (mean age, 42.7±9.3 years; female, 95.7%; mean multiple sclerosis duration, 9.2±8.6 years; mean glatiramer acetate duration, 46.7±29.9 months). Fifty (71.4%) patients showed indurations and 58 (82.9%) panniculitis/lipoatrophy. After 12 endermology sessions, the number of patients with indurations significantly decreased (71.4% vs. 28.6%; p<0.001), as did the number of their indurations (4.2±3.6 vs. 3.7±3.4; p<0.001). Although the number of patients with panniculitis/lipoatrophy did not significantly decrease, there was a significant reduction in the number of areas of panniculitis/lipoatrophy (4.3±2.6 vs. 3.9±2.2; p<0.05). Forty-nine (98.0%) patients with indurations and 57 (98.3%) patients with panniculitis/lipoatrophy felt satisfied/very satisfied with treatment and considered endermology useful/very useful. Endermology was well tolerated, as some pain was reported in eight (11.4%) patients, discomfort in three (4.3%) patients, and local blotch/swelling and transient bruise in one (1.4%) patient each. Endermology enabled glatiramer acetate tolerance to be enhanced in 42 (60.0%) patients., Conclusion: This project represents the largest experience available supporting the benefit of endermology in the reduction/disappearance of indurations and improvement in panniculitis/lipoatrophy in patients with RRMS receiving long-term glatiramer acetate treatment. Moreover, these benefits also contributed to enhancing glatiramer acetate tolerance.

Patients with α₁-antitrypsin (AAT) deficiency may develop cutaneous manifestations of the disorder that histologically appear as panniculitis. Algorithms consistently emphasize measuring AAT levels when both clinical and histological features of deficiency are present; however, the patient's medical history and a physical examination alone can be extremely helpful in guiding the physician to the diagnosis of AAT deficiency. We describe a patient who presented with the classic clinical findings of AAT deficiency-associated panniculitis with surprising absence of panniculitis on repeated deep incisional biopsies. We propose a triad of classic findings that should alert the clinician to check the patient's serum AAT levels, even in the absence of panniculitis on histologic evaluation. Consideration of this clinical triad may prevent delays in the diagnosis of AAT deficiency, as early lesions may not yet demonstrate subcutaneous fat involvement.

Subcutaneous fat necrosis of the newborn (SCFN) is a rare, benign, and self-limiting panniculitis of neonates that presents in the first few weeks of life and is most commonly associated with birth asphyxia and meconium aspiration. There have been few case reports of SCFN following therapeutic hypothermia. With the increasing use of therapeutic whole-body hypothermia, SCFN may become more prevalent. The differential diagnosis of SCFN can be broad, and clinicopathologic correlation is essential to make the correct and timely diagnosis. Clinicians should be aware of this rare disease and its potential serious complication hypercalcemia.