Neutrophilic Infiltrates in Panniculitis: Comprehensive Review and Diagnostic Algorithm Proposal.

Neutrophilic infiltrates in panniculitis can be seen in different clinical-pathological entities. There are a "mostly neutrophilic inflammatory infiltrate" in some entities classically defined as neutrophilic panniculitis and already included in algorithms, such as enzymatic panniculitis, infective and factitial ones, erythema induratum, or subcutaneous Sweet syndrome, but there are also other panniculitis where neutrophils are frequently observed such as panniculitis associated with inflammatory bowel disease or rheumatoid arthritis, or drug-induced panniculitis associated with BRAF inhibitors, and finally, some panniculitis are better classified in other panniculitides groups but may present with neutrophil-rich variants, such as the neutrophil-rich subcutaneous fat necrosis of the newborn. We review the main clinical and histopathological features of most of these panniculitides and construct a diagnostic algorithm including these diseases.

Interstitial granulomatous dermatitis following tocilizumab, a paradoxical reaction?

Interstitial granulomatous dermatitis (IGD) is a rare dermatosis generally seen in the setting of rheumatic diseases, but also hematological disorders, internal malignances, infections, or drug induced. Herein, we report an exceptional case of an IGD with a clear chronological association with tocilizumab onset and cessation in a patient with adult-onset Still's disease. We review the granulomatous cutaneous reactions so far reported with this novel therapy: sarcoidosis, granuloma annulare, and IGD. Tocilizumab is a humanized anti-interleukin 6 receptor monoclonal antibody useful for the treatment of various systemic inflammatory disorders. Lately, it has found useful also for granulomatous diseases such as giant cell arteritis and even a promising response in IGD. Therefore, we believe our case adds the possibility of an IGD presenting as a paradoxical reaction.

Cutaneous Light Chain Deposition Disease: A Report of 2 Cases and Review of the Literature.

Light chain deposition disease (LCDD) is a rare systemic disorder with deposition of mostly monoclonal amorphous nonamyloid light chains in multiple organs. Renal involvement with rapidly progressing renal failure presents the dominant manifestation of LCDD. Approximately 20%-30% of patients show symptomatic cardiac or liver involvement. Cutaneous manifestations are extremely rare with only a few published cases. We report 2 additional cases of cutaneous LCDD without detectable systemic disease.

A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation­contraction coupling together with additional muscle alterations.

INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.

Theophylline is able to partially revert cachexia in tumour-bearing rats.

BACKGROUND AND AIMS: The aim of the present investigation was to examine the anti-wasting effects of theophylline (a methylxantine present in tea leaves) on a rat model of cancer cachexia. METHODS: The in vitro effects of the nutraceuticals on proteolysis were examined on muscle cell cultures submitted to hyperthermia. Individual muscle weights, muscle gene expression, body composition and cardiac function were measured in rats bearing the Yoshida AH-130 ascites hepatoma, following theophylline treatment. RESULTS: Theophylline treatment inhibited proteolysis in C2C12 cell line and resulted in an anti-proteolytic effect on muscle tissue (soleus and heart), which was associated with a decrease in circulating TNF-alpha levels and with a decreased proteolytic systems gene expression. Treatment with the nutraceutical also resulted in an improvement in body composition and cardiac function. CONCLUSION: Theophylline - alone or in combination with drugs - may be a candidate molecule for the treatment of cancer cachexia.

Nutraceutical inhibition of muscle proteolysis: a role of diallyl sulphide in the treatment of muscle wasting.

BACKGROUND & AIMS: The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss and atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism. The aim of the present investigation was to examine the anti-wasting effects of some nutraceuticals such as genistein, resveratrol, epigallocatechin gallate and diallyl sulphide (DAS). METHODS: The in vitro effects of these nutraceuticals on proteolysis were examined in muscle cell cultures submitted to hyperthermia. The in vivo effects of DAS were also tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). RESULTS: Although all the nutraceuticals tested inhibited muscle proteolysis, the most promising effects were related with DAS. In vivo administration of DAS only leads to a small improvement in tibialis muscle and heart weights; however, administration of DAS to healthy animals increased all muscle weights, this being associated with a decreased gene expression of proteolytic systems components. CONCLUSION: It may be suggested that DAS could be used to improve muscle mass during healthy conditions.

Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status.

In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω-3 fatty acids have been proposed as anti-inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto-Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of (14)C-triolein into adipose tissue was improved by the ω-3 administration. In vitro incubations of adipose tissue slices from EPA-treated rats showed an increase in (14)C-palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP-activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator-activated receptor-α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2-deoxy-D-[(14)C]glucose (2-DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear.

Patterns of gene expression in muscle and fat in tumor-bearing rats: effects of CRF2R agonist on cachexia.

The hypothesis we tested was that administering corticotropin-releasing factor receptor agonists preserves muscle mass during cancer that is related to changes in tissue gene expression. cDNA microarrays were used to compare mRNAs from muscle and adipose tissues of non-treated and agonist-treated tumor-bearing rats. In muscle of non-tumor-bearing agonist-treated animals we observed decreased expression of genes associated with fatty acid uptake and esterification. In tumor-bearing animals, CRF2R agonist administration produced decreased mRNA content of the atrogene lipin-1. In white adipose tissue, agonist treatment of non-tumor-bearing animals induced genes typically related to muscle structure and function. The fact that this treatment decreased expression of atrogenes could have clinical application. In addition, agonist treatment changed the gene pattern of adipose tissue to render it similar to that of skeletal muscle; thus, treatment with this agonist alters the gene pattern to what could be called "muscularization of white adipose tissue."

Interleukin-15 increases calcineurin expression in 3T3-L1 cells: possible involvement on in vivo adipocyte differentiation.

Different studies have revealed that the Ca2+-dependent serine/threonine phosphatase calcineurin is involved in the regulation of adipocyte differentiation. Calcineurin acts as a Ca2+-dependent molecular switch that negatively regulates the ability of 3T3-L1 cells to undergo adipocyte differentiation by preventing the expression of critical proadipogenic transcription factors. In this study we investigated the role of interleukin-15 (IL-15), a cytokine previously known to be involved in the control of fat accretion by adipose cells, in the differentiation of the 3T3-L1 preadipose cell line. We found that IL-15 is able to increase alpha-calcineurin mRNA content in white adipose tissue of rats chronically treated with the cytokine and also in the 3T3-L1 preadipose cell line. Moreover, IL-15 promoted a decrease in both leptin mRNA expression and lipid accumulation, as estimated by Red Oil O staining. Cotreatment with IL-15 and FK506 (a calcineurin inhibitor) resulted in no changes in lipid content compared with the non-treated group. These data suggest that IL-15 directly inhibits adipogenesis, possibly by upregulating alpha-calcineurin and preventing the induction of adipocyte differentiation.

PPARdelta mediates IL15 metabolic actions in myotubes: effects of hyperthermia.

C2C12 cells exposed to hyperthermia (41 degrees C) experienced an increase in both protein synthesis and degradation. The addition of IL15 under hyperthermic conditions resulted in an important increase in protein synthesis with no changes in protein degradation, except when cells overexpressed PPARdelta. The PPARdelta agonist GW501516 exerted similar effects on protein synthesis to IL15. Expression of a mutant dominant negative form of PPARdelta prevented the effect of the cytokine on protein synthesis, suggesting that this transcription factor is involved in the anabolic action of IL15. The present study also suggests that the effects of IL15 on lipid oxidation could be mediated by PPARdelta.

Both AP-1 and NF-kappaB seem to be involved in tumour growth in an experimental rat hepatoma.

Daily treatment of rats bearing Yoshida AH-130 ascites hepatoma with the nuclear factor kappa-B (NF-kappaB) and activator protein-1 (AP-1) double inhibitors SP100030 and SP100207 at a dose of 5 mg/kg and 10 mg/kg of body weight, respectively, resulted in a clear inhibition of tumour growth. The decrease was not related to an altered cell cycle distribution of the tumour cell population suggesting a merely necrotic effect. The results presented confirm that both transcription factors are involved in the growth of the experimental tumour system used, suggesting that both signaling cascades play a very important role in the signaling of tumour cell proliferation. This could, in future, allow for the development of new therapeutic strategies for cancer patients.

The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome.

The CD5 lymphocyte surface receptor is a group B member of the ancient and highly conserved scavenger receptor cysteine-rich superfamily. CD5 is expressed on mature T and B1a cells, where it is known to modulate lymphocyte activation and/or differentiation processes. Recently, the interaction of a few group B SRCR members (CD6, Spalpha, and DMBT1) with conserved microbial structures has been reported. Protein binding assays presented herein indicate that the CD5 ectodomain binds to and aggregates fungal cells (Schizosaccharomyces pombe, Candida albicans, and Cryptococcus neoformans) but not to Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus) bacteria. Accordingly, the CD5 ectodomain binds to zymosan but not to purified bacterial cell wall constituents (LPS, lipotheicoic acid, or peptidoglycan), and such binding is specifically competed by beta-glucan but not by mannan. The K(d) of the rshCD5/(1-->3)-beta-d-glucan phosphate interaction is 3.7 +/- 0.2 nM as calculated from tryptophan fluorescence data analysis of free and bound rshCD5. Moreover, zymosan binds to membrane-bound CD5, and this induces both MAPK activation and cytokine release. In vivo validation of the fungal binding properties of the CD5 ectodomain is deduced from its protective effect in a mouse model of zymosan-induced septic shock-like syndrome. In conclusion, the present results indicate that the CD5 lymphocyte receptor may sense the presence of conserved fungal components [namely, (1-->3)-beta-d-glucans] and support the therapeutic potential of soluble CD5 forms in fungal sepsis.

Effects of IL-15 on rat brown adipose tissue: uncoupling proteins and PPARs.

OBJECTIVES: Interleukin-15 (IL-15) plays an important role in lipid metabolism as its administration to rats causes a marked depletion of white adipose tissue (WAT). This reduction in fat mass seems to be caused by and related to hipotriglyceridemia as a result of a lower hepatic lipogenesis and an increased fatty acid oxidation. We have previously observed that IL-15 treatment induces the expression of uncoupling proteins (UCPs) in muscle. The aim of this study was to investigate the effects of IL-15 on brown adipose tissue (BAT), and in particular on genes related to lipid metabolism in this tissue. METHODS AND PROCEDURES: Male Wistar rats were treated daily with IL-15 for 7 days. Adipose tissues were collected and the mRNA content of UCPs, peroxisome proliferator-activated receptors (PPARs) and several genes implicated in fatty acid transport and oxidation were evaluated on BAT. RESULTS: IL-15 treatment in rats causes a decrease in the mass of both WAT and BAT (35 and 24%, respectively). In BAT, an important upregulation of the mRNA content of thermogenic proteins (UCP1 and UCP3), lipid-related transcription factors (PPARdelta and PPARalpha) and other proteins implicated in membrane transport (fatty acid translocase (FAT) and fatty acid transport protein (FATP)), mitochondrial transport (carnitine palmitoyl transferase-I (CPT-I) and CPT-II) and consumption (acyl-CoA synthetase 4 (ACS4)) of fatty acids was observed as a consequence of the treatment. DISCUSSION: The changes observed in BAT suggest that IL-15 could be implicated in lipid consumption in this tissue by regulating lipid oxidation and probably thermogenesis, processes mediated by UCPs and PPARs.

Effects of the PPARgamma agonist GW1929 on muscle wasting in tumour-bearing mice.

Administration of the PPARgamma agonist GW1929 (10 mg/kg body weight) results in amelioration of muscle loss in tumour-bearing mice experimental cachexia. The effect of the agonist, which seems to be specific for white muscle extensor digitorum longus (EDL), is accompanied by an increase in the levels of the transcription factor MyoD and also the GLUT-4 glucose transporter. In addition, the effects of GW1929 on skeletal muscle are direct since incubation of isolated rat skeletal muscles in its presence results in a decreased rate of protein degradation. Collectively, the results presented suggest a potential clinical application - possibly in combination with other anabolic strategies - of GW1929 in restoring muscle waste during cancer cachexia.

Effects of CRF2R agonist on tumor growth and cachexia in mice implanted with Lewis lung carcinoma cells.

Previous studies have demonstrated an effect of corticotropin-releasing factor 2 receptor (CRF2R) agonists in the maintenance of skeletal muscle mass. The aim of this study was to evaluate the effects of a CRF2R agonist in preserving skeletal muscle in a mouse cachexia model. Implantation of a fast-growing tumor to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. We found that administration of a CRF2R agonist (PG-873637) at 100 microg/kg/day by means of osmotic minipumps to tumor-bearing mice resulted in beneficial effects on muscle weight loss. Thus, muscle loss was partially reversed by the CRF2R agonist at different stages of tumor growth (at day 14 after tumor inoculation: 12% in tibialis posterior; 9% in gastrocnemius; and 48% in soleus). Moreover, the CRF2R agonist significantly reduced both the number of metastases and their mass (at day 19 after tumor inoculation: 66% and 61%, respectively). These data suggest a potentially beneficial effect of the CRF2R agonist in preserving skeletal muscle during cancer cachexia and open a line of research for the development of new therapeutic approaches for the treatment of muscle wasting associated with cancer.

Apoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients.

BACKGROUND & AIMS: Previous studies of our research group have shown that apoptosis is present in skeletal muscle of tumour-bearing animals subject to cachexia. For this reason we decided to investigate the apoptosis in skeletal muscle of cancer patients. METHODS AND RESULTS: In the present study, muscle biopsies from weight-losing patients with upper gastro-intestinal cancer showed a significant increase in muscle DNA fragmentation (three-fold), as compared with control subjects. The increase in DNA laddering was associated with an increase in poly(ADP-ribose) polymerase (PARP) cleavage (four-fold) as measured by western blotting. These two events indicate the presence of muscle apoptosis. These changes were associated with a decrease in MyoD protein content, suggesting important alterations in skeletal muscle physiology. CONCLUSIONS: The results presented therefore confirm that apoptosis is also present in human subjects undergoing cancer cachexia.

Are peroxisome proliferator-activated receptors involved in skeletal muscle wasting during experimental cancer cachexia? Role of beta2-adrenergic agonists.

Implantation of the Yoshida AH-130 ascites hepatoma to rats resulted in a decrease in muscle weight 7 days after the inoculation of the tumor. These changes were associated with increases in the mRNA content for both peroxisome proliferator-activated receptor (PPAR) gamma and PPAR delta in skeletal muscle. The increase in gene expression for these transcription factors was related to increases in the expression of several genes involved in fatty acid transport, activation, and oxidation. Tumor burden also resulted in increases in PPAR gamma coactivator-1 alpha gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolic shift occurs in skeletal muscle of tumor-bearing rats toward a more oxidative phenotype. Formoterol treatment to tumor-bearing rats resulted in an amelioration of all the changes observed as a result of tumor burden. Administration of this beta(2)-adrenergic agonist also resulted in a decrease in mRNA content of muscle PPAR alpha, PPAR delta, and PPAR gamma, as well as in mRNA levels of many of the genes involved in both lipid and mitochondrial metabolism. All these results suggest an involvement of the different PPARs as transcription factors related with muscle wasting and also indicate that a possible mode of action of the anticachectic compound formoterol may involve a normalization of the levels of these transcription factors.

Targets in clinical oncology: the metabolic environment of the patient.

Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. Lean body mass depletion is one of the main features of cachexia and it involves not only skeletal muscle but also affects cardiac protein. The cachectic state is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Unfortunately, at the clinical level, cachexia is not treated until the patient suffers from a considerable weight loss and wasting. Therefore, it is of great interest to analyze possible early markers of the syndrome. In the present review both metabolic and hormonal markers are described. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from fully understanding the underlying basis for this syndrome. The suggested mediators (associated with both depletion of fat stores and muscular tissue) can be divided into two categories: of tumour origin (produced and released by the neoplasm) and humoural factors (mainly cytokines). One of the aims of the present review is to summarize and evaluate the different catabolic mediators (both humoural and tumoural) involved in cancer cachexia, since they may represent targets for clinical investigations. Additionally, an overview of the main therapeutic approaches for the treatment of the cachectic syndrome is presented.