[Disseminated osteolytic lesions in a 28-year-old refugee]. / Disseminierte osteolytische Läsionen bei einem 28-jährigen Flüchtling.

A 28-year-old Syrian refugee presented with right-sided knee pain and progressive deterioration of the general condition over the past months. Laboratory diagnostics revealed severe hypercalcemia due to primary hyperparathyroidism, and computed tomography (CT) scanning demonstrated disseminated osteolytic lesions throughout the skeleton. Histologically, these lesions were characterized by multinuclear giant cells (defining these lesions as so-called brown tumors). Finally, surgical removal of a jugular mass allowed the histopathologic diagnosis of a sporadic parathyroid carcinoma. In the patient, this condition was associated with a mutation in the HPRT2 gene locus.

Short-Term Regulation of Lipocalin-2 but not RBP-4 During Oral Lipid Tolerance Test and Oral Glucose Tolerance Test.

The postprandial regulation of lipocalin-2 and retinol binding protein-4 (RBP-4) by oral uptake of lipids and carbohydrates in healthy individuals has not yet been investigated. The regulation of lipocalin-2 and RBP-4 in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100) was analyzed. One hundred healthy volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn after 0, 2, 4, and 6 h in OLTT and after 0, 1, and 2 h in OGTT. In order to dissect carbohydrate-induced from lipid-induced effects, a novel OLTT solution completely free of carbohydrates and protein was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of lipocalin-2 and RBP-4 were measured by enzyme-linked immunosorbent assay (ELISA). Whereas RBP-4 levels remained unchanged during OGTT, lipocalin-2 concentrations significantly decreased during OGTT. During OLTT, RBP-4 levels were not influenced, whereas lipocalin-2 levels decreased significantly and stepwise. Fasting concentrations of RBP-4 were negatively correlated with BMI and waist-hip ratio, whereas lipocalin-2 levels were positively associated with BMI and waist-hip ratio. Female users of hormonal contraception had higher RBP-4 levels than females not on contraceptives. There is no significant short-term regulation of RBP-4 by orally ingested lipids or carbohydrates. Lipocalin-2 is downregulated after lipid and carbohydrate ingestion and this kind of regulation was not predicted by age, sex, triglycerides, glucose, or insulin levels.

Serum progranulin concentrations are not responsive during oral lipid tolerance test and oral glucose tolerance test.

The postprandial regulation of progranulin by oral uptake of lipids and carbohydrates in healthy individuals has not yet been investigated. The regulation of progranulin in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100) was analyzed. One hundred healthy volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn at 0 hours (h) (fasting) and at 2, 4, and 6 h in OLTT or 1 and 2 h in OGTT. A novel OLTT solution completely free of carbohydrates and protein was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of progranulin were measured by enzyme-linked immunosorbent assay (ELISA). Circulating progranulin levels remained unchanged during OLTT and OGTT. Fasting progranulin levels ranged between 31.3±8.7 and 40.6±7.7 ng/ml and were not different in subgroups addressing BMI, gender, family history, smoking habits, and hormonal contraception. There was a reciprocal correlation of progranulin with HDL (negative) and LDL cholesterol levels (positive). In healthy adults, fasting and postprandial circulating progranulin levels are not different in BMI subgroups. Oral uptake of carbohydrates and lipids does not influence circulating progranulin levels in a short-term manner. A postprandial and short-term regulation of this adipokine is absent, at least in healthy subjects. There is a negative correlation of progranulin with HDL cholesterol, but a positive correlation with LDL cholesterol. This reciprocal association might be of physiological importance for an individual's atherosclerotic risk.

[Panniculitis of the thigh and lung emphysema in a 54-year-old patient]. / Pannikulitis des Oberschenkels und Lungenemphysem bei einem 54-jährigen Patienten.

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.

Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases.

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels.

[A 55-year-old man with abdominal pain and fever]. / 55-jähriger Patient mit abdominellen Schmerzen und Fieber.

A 55-year-old man was admitted for evaluation of chronic abdominal pain and fever. Computed tomography demonstrated a retroperitoneal inflammatory process involving the mesenteric root. Adipose tissue biopsy showed panniculitis mesenterica with granulomas. Further examinations confirmed the diagnosis of plasmocytoma type IgG kappa. Treatment with steroids (prednisolone), resulted in immediate improvement of pain and fever. Mesenteric panniculitis represents a paraneoplastic syndrome associated with non-Hodgkin lymphoma.

Wound healing responses at the gastrointestinal epithelium: a close look at novel regulatory factors and investigative approaches.

The gastrointestinal epithelium functions as an important physical barrier that separates the rich, diverse, and potentially immunogenic luminal content from the underlying mucosal immune system. In pathological situations such as inflammatory bowel disease, ischemic/hypoxic episodes and bacterial infection, insults to the intestinal epithelium threaten the integrity of the mucosal barrier and represent a huge challenge for the host. During episodes of epithelial injury and barrier breakdown, the host initiates a rapid wound healing response aimed at resealing the gap region and reestablishing homeostasis. This response named "restitution" involves migration of epithelial cells toward the injured regions, as well as epithelial cell proliferation until the gap is closed and the barrier function is reestablished. These biological processes are influenced by a variety of factors derived from the gastrointestinal microenvironment, including host epithelial and lamina propria cells, as well as the microbiota, and the dietary and non-dietary components present in the gastrointestinal lumen. In this manuscript, we will review both host signaling events and luminal factors that influence the wound healing response and have an impact on host homeostasis.

Unusual gastric mucosal infiltration by a medullary thyroid carcinoma: a case report.

BACKGROUND: Medullary thyroid carcinoma accounts for approximately 1 to 2 % of all thyroid carcinoma cases. The most common route of dissemination is to locoregional lymph nodes. Distant metastases commonly affect bones, lungs, and liver. We present a case of a white woman with a 25-year history of medullary thyroid carcinoma on multiple medications including tyrosine kinase inhibitor therapy for the last 11 months, who exhibited unusual diffuse infiltration of advanced stage medullary thyroid carcinoma to her gastric mucosa. CASE PRESENTATION: A 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of medullary thyroid carcinoma (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and repeated bilateral cervical lymph node dissection. Medical therapy included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 months ago when computed tomography scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases. Of note, she demonstrated macroscopically stable pulmonary and mediastinal lymph node metastases; however, her calcitonin serum levels dramatically increased. Computed tomography scanning revealed a single new intrahepatic lesion (4 mm) as well as multiple (>10) new supraclavicular lesions suggestive of medullary thyroid carcinoma progress. As proven by gastric biopsy and immunohistochemical evaluation, her epigastric pain was explained by a diffuse infiltration of her gastric mucosa by metastatic medullary thyroid carcinoma. Subsequently, she rapidly deteriorated and died. CONCLUSIONS: The current case report shows for the first time an unusual metastatic infiltration of the gastric mucosa by medullary thyroid carcinoma. When treating these patients, it is important to include this differential diagnosis during follow-up.

Short-term Regulation of Resistin in vivo by Oral Lipid Ingestion and in vitro by Fatty Acid Stimulation.

BACKGROUND AND AIM: Dysbalance of pro- and anti-inflammatory adipokines is a hallmark of metabolic syndrome but their nutrition-dependent regulation in healthy individuals is poorly characterized. We investigated pro-inflammatory resistin and anti-inflammatory adiponectin regulation during oral lipid ingestion (OLI) in healthy adults. Response of resistin upon free fatty acid (FFA) stimulation was investigated in 3T3-L1 adipocytes. MATERIAL AND METHODS: 100 healthy volunteers underwent OLI. Venous blood was drawn after 0, 2, 4, and 6 hours (h). Subjects were characterized by anthropometric and standard laboratory parameters. Serum concentrations of adiponectin and resistin were measured by enzyme-linked immunosorbent assay (ELISA). Adipocytes were stimulated with FFA and concentrations of adipokines were measured by ELISA. RESULTS: Irrespective of BMI and gender, OLI led to a significant reduction of resistin serum levels in a stepwise manner whereas adiponectin concentrations remained unchanged. There were positive correlations of resistin with waist/hip ratio and visfatin levels, as was calculated by regression analysis. Resistin concentrations were significantly higher in smokers when compared to non-smokers. Adiponectin concentrations were higher in females and in users of hormonal contraception. Adiponectin levels showed a positive correlation with heart rate and HDL cholesterol and a negative correlation with age, waist/hip-ratio, BMI, diastolic/systolic blood pressure, visfatin levels and LDL/HDL-ratio. Resistin secretion was significantly induced by palmitic acid, linoleic acid and oleic acid in adipocytes. CONCLUSIONS: OLI is a physiological repressor of systemic resistin release whereas FFA upregulate resistin release in vitro from adipocytes.

Short-term and divergent regulation of FGF-19 and FGF-21 during oral lipid tolerance test but not oral glucose tolerance test.

CONTEXT: Regulation of FGF-19 and FGF-21 by oral uptake of lipids and carbohydrates in healthy individuals is poorly characterized. OBJECTIVE: We investigated the regulation of FGF-19 and FGF-21 in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100). DESIGN AND SETTING: 100 volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn at 0 h (fasting) and at 2, 4, and 6 h in OLTT or 1 and 2 h in OGTT. In order to dissect carbohydrate-induced from lipid-induced effects, a special OLTT solution was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of FGF-19 and FGF-21 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Mean FGF-19 levels ranged between 12 and 544 pg/ml with a fasting mean value of 105±81 pg/ml and 118±86 pg/ml in OLTT and OGTT. Mean FGF-21 levels ranged between 4 and 1 393 pg/ml with a fasting mean value of 160±204 pg/ml and 235±288 pg/ml in OLTT and OGTT. There was a significant, positive correlation between FGF-19 and FGF-21 in OLTT (p<0.001, r=0.5) and in OGTT (p=0.011, r=0.4). FGF-21 levels were positively correlated with waist circumference and waist hip-ratio in both cohorts. OGTT had no effect on FGF-19 and FGF-21. In contrast, FGF-19 levels were significantly induced and FGF-21 levels were significantly reduced during OLTT. CONCLUSIONS: OLTT is a physiological inductor of FGF-19 and a repressor of FGF-21 in healthy adults. There is a significant and positive correlation between FGF-19 and FGF-21. Dietary lipids specifically and differentially regulate FGF-19 and FGF-21 whereas dietary carbohydrates have no effect. The present data provide the clinical basis for the postulated negative feedback loop between dietary lipids and postprandial inhibition of hepatic lipogenesis.

Impact of toll-like-receptor-9 (TLR9) deficiency on visceral adipose tissue adipokine expression during chronic DSS-induced colitis in mice.

BACKGROUND: Studies postulate an involvement of adipokines in inflammatory gastrointestinal diseases. Leptin-deficient ob/ob mice as well as TLR9-deficient mice have a more moderate course of chronic DSS-induced colitis (DSS-CC) and adipocytes do express functional TLR9 molecules. MATERIAL AND METHODS: Adipokine mRNA expression in visceral adipose tissue of mice before and after the induction of DSS-CC was investigated. Experiments were performed in both TLR9(wt/wt) and TLR9(-/-) mice. In vitro, the effect of TLR9 blocking peptide on leptin and visfatin protein secretion was studied in 3T3-L1 adipocytes. RESULTS: Induction of DSS-CC led to an upregulation of leptin mRNA expression in TLR9(wt/wt) mice, while TLR9(-/-) animals showed a significant reduction of leptin expression even below baseline. While visfatin expression remained unchanged in TLR9(wt/wt) animals, TLR9(-/-) mice exhibited a significant induction during DSS-CC. CTRP-3 expression was reduced after colitis induction only in TLR9(-/-) animals. Of note, IL-6 expression levels remained unchanged, while CXCL1/KC and cyclophilin A expression was reduced in DSS-CC. Inhibition of TLR9 signaling by using TLR9 blocking peptide led to reduced leptin protein secretion into cell culture supernatants in 3T3-L1 adipocytes, while visfatin protein secretion was enhanced. CONCLUSIONS: DSS-CC leads to differential adipokine expression profiles in the visceral fat pad in TLR9(wt/wt) vs. TLR9(-/-) mice. In vitro, inhibition of TLR9 signaling induces visfatin secretion while inhibiting leptin secretion in adipocytes. Thus, visceral adipokines are regulated by intact TLR9 signaling pathway and a specific interplay between the leptin- and the TLR9-pathways might be of pathophysiological importance in chronic intestinal inflammation.

Short-term regulation of Visfatin release in vivo by oral lipid ingestion and in vitro by fatty acid stimulation.

Visfatin represents a new adipokine secreted by visceral adipose tissue and possibly regulating insulin sensitivity. Data on the regulation of visfatin are sparse and contradictory. Our study investigates the regulation of serum visfatin concentrations in healthy and non-diabetic subjects in response to the ingestion of a newly developed oral lipid solution (OLI) in vivo. Furthermore, the effects of a broad spectrum of fatty acids on adipocytic visfatin release were investigated in vitro.100 (42 male and 58 female) healthy volunteers were included in the study. Anthropometric and laboratory parameters (lipoproteins, glucose, insulin, C-peptide) were measured after an overnight fast at 0 h and 2 h, 4 h, and 6 h after OLI. 3T3-L1 preadipocytes were differentiated into mature adipocytes and stimulated with increasing doses of 10 different fatty acids, and the release of visfatin into the supernatants was measured by ELISA.Serum triglycerides significantly rose after OLI. This was accompanied by a significant decrease of glucose, insulin and C-peptide. Serum visfatin levels significantly decreased after OLI. Fasting visfatin levels were negatively correlated with fasting glucose levels. Of the 5 saturated fatty acids tested, only palmitic acid exerted significant effects by strongly downregulating visfatin release by about 66%. The mono-unsaturated fatty acids palmitoleic acid and oleic acid exerted opposite effects decreasing/increasing visfatin release, respectively. Both of the poly-unsaturated fatty acids linoleic acid and arachidonic acid decreased visfatin release.Oral lipid ingestion is a physiological regulator of systemic visfatin release. Fatty acids differentially regulate visfatin release in vitro.

Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection.

Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-kappaB. Although it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1-1%) on the development of colitis, immune activation, and in vivo NF-kappaB activity in germ-free IL-10(-/-) or IL-10(-/-);NF-kappaB(EGFP) mice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN-gamma and IL-12/23p40 mRNA expression followed similar pattern ( approximately 50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-gamma by colonic explants and mesenteric lymph node cells was elevated in IL-10(-/-) mice and was not decreased by dietary curcumin. Surprisingly, activation of NF-kappaB in IL-10(-/-) mice (phospho-NF-kappaBp65) or in IL-10(-/-);NF-kappaB(EGFP) mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-kappaB activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10(-/-) mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-kappaB activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.

["Tingling feet," forgetfulness, and progressive personality changes in a 63-year-old patient]. / "Fusskribbeln", Vergesslichkeit und progrediente Wesensveränderung bei einer 63-jährigen Patientin.

A 63-year-old female was admitted to the hospital with leg and forearm paresthesias. We found progressive ataxia, dementia, and psychosocial deterioration. The clinical symptoms, the neurologic and psychiatric abnormalities together with the inflammatory cerebrospinal fluid alteration and the cerebral magnetic resonance imaging changes suggested a paraneoplastic etiology. It was confirmed by paraneoplastic antineuronal antibodies in the patient's serum and the histological diagnosis of a small cell bronchial carcinoma. The prognosis of patients with paraneoplastic symptoms is the better the earlier a diagnosis is established and antitumor therapy is initiated.