Onychoscopy of non-infectious nail abnormalities in patients after allogeneic haematopoietic stem cell transplantation.

Nail abnormalities after allogeneic haematopoietic stem cell transplantation procedure (alloHSCT) are often reported. Usually, they are related to chronic graft-versus-host disease (cGvHD). So far, only clinical manifestations of selected nail abnormalities have been described, without the presentation of dermoscopic images. In this article, we present morphologic and dermoscopic manifestations of potential non-infectious nail abnormalities in patients after alloHSCT procedure based on reviewed literature and our own experience with dermoscopic iconography. In majority of studies published till now, nail changes are not connected to severity of other cGvHD symptoms; however, e.g. the presence of pterygium inversum unguis may be an indicator of lung dysfunction. As nail changes may be an early sign of cGvHD and always present in association with other manifestations, routine clinical assessment should include nails examination. Knowledge of possible presentation of nail involvement after alloHSCT may be valuable for treating physician.

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy.

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen-challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica.

Chronic kidney disease leads to hypoxia inducible factor-1alpha to hypoxia inducible factor-2alpha switch in the gastrocnemius muscle.

Hipoxia inducible factor-1 and HIF-2 are responsible for the adaptation of cell metabolism to hypoxia. Previously, a more severe capillary rarefaction was found in locomotor than in postural muscles of uremic animals. The aim of this study was to analyze the expression patterns of HIF and prolyl hydroxylases (PHDs) in functionally different skeletal muscles in uremic rats, an experimental model of chronic kidney disease (CKD). Rats were randomized to sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, expression of HIF-1α and -2α and PHD proteins was measured using WB in locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML). Serum concentrations of creatinine (Cr), hemoglobin (Hb), haptoglobin (Hp), MCP-1, AGEs, homocysteine (Hcy) were measured. HIF-1α increased in MG and ML for CKD1/2 versus CON. HIF-1α decreased in MG and increased in ML for CKD5/6 versus CON and CKD1/2. HIF-2α increased in MG for CKD5/6 and CKD1/2 versus CON. HIF-2α was not detected in ML in any group. PHD1 was not detected in MG in any group. PHD1 in ML was not detected in CON, but increased in CKD5/6 and CKD1/2. PHD2 decreased in MG but increased in ML for CKD5/6 versus CKD1/2 and CON. PHD3 did not differ between groups in MG, but in ML decreased in CKD5/6 versus CON and CKD1/2. There were significant differences for CKD5/6 and CKD1/2 versus CON in: Cr (1.2 ± 0.2; 0.7 ± 0.1 versus 0.8 ± 0.3 mg/dl), Hb (11.4 ± 3.1; 13.7 ± 0.7 versus 14.1 ± 1 g/dl), Hp (1.6 ± 0.6; 1.6 ± 0.6 versus 0.7 ± 0.4 mg/ml), AGEs (5.1 ± 0.6; 4.3 ± 1.2 versus 4.6 ± 0.9 AU), Hcy (7.2 ± 1.2; 5.1 ± 0.5 versus 4.9 ± 0.5 µM), MCP-1 (609 ± 255; 489 ± 265 versus 292 ± 113 pg/ml), respectively. CKD had a different effect on protein expression patterns of HIF-1α, -2α and PHDs depending on muscle type. A HIF-1α to HIF-2α switch in glycolytic MG in CKD5/6 might be a protective mechanism against tissue hypoxia and oxidative stress.

IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation.

A role for the IL-36 family of cytokines has been identified in the pathogenesis of psoriasis. Although significant mechanistic overlap can exist between psoriasis and inflammatory bowel disease (IBD), to date there have been no reports investigating the IL-36 family in gastrointestinal inflammation. Here we demonstrate that expression levels of IL-36α are specifically elevated in the colonic mucosa of ulcerative colitis patients. This elevated expression is mirrored in the inflamed colonic mucosa of mice, wherein IL-36 receptor deficiency confirmed this pathway as a mediator of mucosal inflammation. Il36r-/- mice exhibited reduced disease severity in an acute DSS-induced model of colitis in association with decreased innate inflammatory cell infiltration to the colon lamina propria. Consistent with these data, infection with the enteropathogenic bacteria Citrobacter rodentium, resulted in reduced innate inflammatory cell recruitment and increased bacterial colonization in the colons of il36r-/- mice. Il36r-/- mice also exhibited altered T helper cell responses in this model, with enhanced Th17 and reduced Th1 responses, demonstrating that IL-36R signaling also regulates intestinal mucosal T-cell responses. These data identify a novel role for IL-36 signaling in colonic inflammation and indicate that the IL-36R pathway may represent a novel target for therapeutic intervention in IBD.

GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future.

Glucagon-like peptide 1 (GLP-1) receptors expression has been found on many types of cancer cells. In case of benign insulinoma the density of those receptors is even higher than the density of somatostatin receptors. This article presents the results of clinical trials proving the utility of GLP-1 receptors imaging. Scintigraphy or positron emission tomography with the use of GLP-1 analogues labelled with appropriate radioisotopes (111In, 99mTc, 68Ga, 18F or 64Cu) seem to be superior compared with other available techniques in diagnosis of hardly detectable benign insulinoma. While surgery is the only effective therapy for insulinoma patients, therefore proper preoperative localization of the tumor allows sparing operation. Glucagon-like peptide 1 receptors might become also a target for imaging of other tumors such as gastrinoma, pheochromocytoma and medullary thyroid cancer (MTC), which also were shown to overexpress this type of receptors. However, studies with larger groups of patients are required to prove the clinical usefulness of this indication. Moreover GLP-1 receptor imaging seems to be a potential tool to evaluate pancreatic beta cell mass (BCM). It may be useful in the early diagnosis of beta cell loss in preclinical phases of diabetes. The panceratic beta cells imaging may influence the prophylaxis of diabetes and management of diabetic patients. Presented results of clinical trials prove that glucagon-like peptide 1 receptor imaging might become helpful diagnostic strategy particularly in case of patients with benign insulinoma tumors, but also patients with gastrinoma, pheochromocytoma, medullary thyroid cancer and diabetes.

Morphometric analysis of muscle fibre types in rat locomotor and postural skeletal muscles in different stages of chronic kidney disease.

Muscle weakness and progressive loss of skeletal muscle mass are serious complications of chronic kidney disease (CKD). The pathogenesis of this condition is still poorly understood. The study investigated fibre type distribution and diameter in functionally different skeletal muscles: locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML) together with an evaluation of metabolic disturbances and nutritional parameters of rats with different stages of CKD. Wistar rats were randomized to a sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, serum concentration haemoglobin (Hb), haptoglobin (Hp), MCP-1, advanced glycation end products (AGEs), and homocysteine (Hcy) were measured. Muscle specimens were stained for myofibrillary ATPase and NADH-diaphoreses activity according to Ziegan's method. There was a significant increase in the percentage of IID/X with a concomitant decrease of IIB fibres in ML in CKD1/2 vs. CON and CKD5/6. IIB fibre diameters in ML were smaller (53.4±7.3 vs. 58.1±8.1 and 59.8±11.2; p=0.08) for CKD5/6 vs. CKD1/2 and CON, respectively. There were significant differences for CKD5/6 and CKD1/2 vs. CON in: Hb (11.4±3.1; 13.7±0.7 and 14.1±1 g/dl), Hp (1.6±0.6; 1.6±0.6 and 0.7±0.4 mg/ml), AGEs (5.1±0.6; 4.3±1.2 and 4.6±0.9 AU), Hcy (7.2±1.2; 5.1±0.5 and 4.9±0.5 M), MCP-1 (609±255; 489±265 and 292±113 pg/ml), respectively. We concluded that early stages of CKD could induce the process of compensatory fast to slow fibre transformation, while in more advanced CKD this process may be blocked and atrophy of fast-twitch fibres may occur, predominantly in non-locomotor muscles. These disturbances can be secondary to CKD-related metabolic burden and inflammation.

Glucagon-Like Peptide-1 Receptor Imaging with [Lys (40) (Ahx-HYNIC- (99 m) Tc/EDDA)NH 2 ]-Exendin-4 for the Diagnosis of Recurrence or Dissemination of Medullary Thyroid Cancer: A Preliminary Report.

Introduction. Epidemiological studies on medullary thyroid cancer (MTC) have shown that neither a change in stage at diagnosis nor improvement in survival has occurred during the past 30 years. In patients with detectable serum calcitonin and no clinically apparent disease, a careful search for local recurrence, and nodal or distant metastases, should be performed. Conventional imaging modalities will not show any disease until basal serum calcitonin is at least 150 pg/mL. The objective of the study was to present the first experience with labelled glucagon-like peptide-1 (GLP-1) analogue [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 in the visualisation of MTC in humans. Material and Method. Four patients aged 22-74 years (two with sporadic and two with MEN2 syndrome-related disseminated MTC) were enrolled in the study. In all patients, GLP-1 receptor imaging was performed. Results. High-quality images were obtained in all patients. All previously known MTC lesions have been confirmed in GLP-1 scintigraphy. Moreover, one additional liver lesion was detected in sporadic MTC male patient. Conclusions. GLP-1 receptor imaging with [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 is able to detect MTC lesions. GLP-1 scintigraphy can serve as a confirmatory test in MTC patients, in whom other imaging procedures are inconsistent.

Renal pericytes: multifunctional cells of the kidneys.

Pericytes have become a hot topic in renal biology. They play a critical physiological role in vessel development, maintenance and remodelling through active communication with their vascular partners-endothelial cells-and modulation of extracellular matrix proteins. Multiple functions for renal pericytes have been described; specialised perivascular populations participate in glomerular filtration, regulate medullary blood flow and contribute to kidney fibrosis by differentiation into collagen-generating myofibroblasts. Interestingly, the origin of renin-producing cells of the juxtaglomerular region is attributed to the perivascular cell lineage; we have observed the coincidence of renin and pericyte marker expression during human kidney development. Finally, pericytes have been shown to share features with mesenchymal stem cells, which places them as potential renal progenitor cell candidates. Since renal diseases are often associated with microvascular complications, renal pericytes may emerge as new targets for the treatment of kidney disease.

Long-term weight gain and metabolic syndrome, adiponectin and C-reactive protein in women aged 50-60 years.

PURPOSE: The aim of this study was to determine the impact of the weight change during 30-40 year follow-up on the prevalence of metabolic syndrome (MS) components, C-reactive protein (CRP) and adiponectin. MATERIAL AND METHODS: The study included 153 women. Blood pressure, anthropometric and laboratory measures were done at the age of 50-60 years. All women declared normal body weight at age 20. The MS was defined according to the International Diabetes Federation (IDF 2005). Women were divided into four groups according to weight gain: < 10 kg, 10-19 kg, 20-29 kg, > 30 kg. RESULTS: The highest values of waist circumference, BMI, WHR, CRP, glucose, HOMA index, insulin, triglycerides, blood pressure and the lowest concentrations of adiponectin and HDL-cholesterol were observed in the group with the highest weight gain (above 30 kg). Odds ratio for MS was tenfold higher in group with weight gain 10-19 kg and 20-29 kg and twenty fold higher in group with weight gain above 30 kg. In multiple regression analysis CRP was most significantly correlated with weight gain. CONCLUSIONS: Among biochemical parameters of metabolic syndrome CRP seems to be the most significantly related to weight gain. The risk of metabolic syndrome is significantly increased even when the weight gain is 10 kg in middle-aged women characterized by a normal BMI at the age of 20.

Potential role of chemerin in recruitment of plasmacytoid dendritic cells to diseased skin.

Interferon alpha-producing plasmacytoid dendritic cells (pDC) are crucial contributors to pro-inflammatory or tolerogenic immune responses and are important in autoimmune diseases such as psoriasis. pDC accumulate in the lesional skin of psoriasis patients, but are rarely found in the affected skin of patients with atopic dermatitis (AD). While homeostatic chemokine CXCL12 and inducible pro-inflammatory CXCR3 chemokine ligands may regulate pDC influx to psoriatic skin, the mechanism responsible for selective pDC recruitment in psoriasis vs. AD remains unknown. Circulating pDC from normal donors express a limited number of chemoattractant receptors, including CXCR3 and CMKLR1 (chemokine-like receptor 1). In this work, we demonstrate that circulating pDC from normal donors as well as psoriasis and AD patients express similar levels of CXCR3 and responded similarly in functional migration assays to CXCL10. We next found that blood pDC from normal, AD, and psoriasis patients express functional CMKLR1. In contrast to normal skin, however, lesional skin from psoriasis patients contains the active form of the CMKLR1 ligand chemerin. Furthermore, in affected skin from psoriatic patients the level of active chemerin was generally higher than in AD skin. Taken together, these results indicate that local generation of active chemerin may contribute to pDC recruitment to psoriatic skin.

The unique case of adrenocortical malignant and functioning oncocytic tumour.

UNLABELLED: Adrenocortical oncocytoma is extremely rarely found. Only a little more than thirty cases of adrenal oncocytoma, mainly nonfunctioning and benign, have been reported in the literature. Adrenal mass 150 x 160 x 172 mm in size and enlarged periarterial lymph nodes were found in CT examination performed in 51-year-old male. Main complaints: weight loss, general asthenia and abdominal pain. PHYSICAL EXAMINATION: elevated blood pressure (180/120 mmHg), no features typical of Cushing's syndrome. Abnormal laboratory findings: oral glucose tolerance test revealed diabetes, elevated serum dehydroepiandrosterone-sulfate (1101.9 microg/dl; normal, 59-452), elevated serum cortisol following overnight 1 mg dexamethasone test (5.1 microg/dl; normal, <1.8), increased urinary excretion of 17- hydroxycorticosteroids (18.1 mg/24 h; normal, 2.0-7.0) with pathological response to high-dose dexamethason test (16.6 mg/24). On laparotomy, the lesion was considered unresectable because of evident - confirmed by intraoperative ultrasound - tumour infiltration of the inferior caval vein. The large biopsy specimen was obtained for histological examination in which tumour fulfilled criteria proposed by Bisceglia et al. for adrenocortical oncocytic borderline tumour. On immunohistochemistry, the lesion showed cytoplasmic reaction for cytokeratin, vimentin and synaptophysin. The presented case appears to be the first malignant and functioning adrenocortical oncocytic tumour reported and confirms the complexity of its biology.

SB-253514 and analogues; novel inhibitors of lipoprotein-associated phospholipase A2 produced by Pseudomonas fluorescens DSM 11579. I. Fermentation of producing strain, isolation and biological activity.

Two new classes of inhibitors of LpPLA2 have been identified in fermentations of Pseudomonas fluorescens. The two structurally isomeric series differ in the geometry of closure of the bicyclic carbamate and comprise a range of compounds varying only in length of their lipophilic sidechain. The most abundant species were extracted from the cells and purified by silica and C18 chromatography. Members of the more stable class were shown to be potent and selective competitive inhibitors of LpPLA2.

SB-219383, a novel tyrosyl tRNA synthetase inhibitor from a Micromonospora sp. I. Fermentation, isolation and properties.

A novel, potent and selective inhibitor of bacterial tyrosyl tRNA synthetase, designated SB-219383 has been isolated from Micromonospora sp. NCIMB 40684. The fermentation, isolation and some properties are described, whilst the structure determination is described in the succeeding paper). SB-219383 showed competitive, inhibitory activity against a Staphylococcus tyrosyl tRNA synthetase, with an IC50 of <1 nM, and exhibited weak in vitro activity against some Streptococcus sp.

SB-203207 and SB-203208, two novel isoleucyl tRNA synthetase inhibitors from a Streptomyces sp. I. Fermentation, isolation and properties.

Two novel inhibitors of isoleucyl tRNA synthetase designated SB-203207 and SB-203208 have been detected in the culture of a new Streptomyces species. The fermentation, isolation and some properties of the inhibitors are described.

A potent seryl tRNA synthetase inhibitor SB-217452 isolated from a Streptomyces species.

A potent inhibitor of seryl tRNA synthetase, designated SB-217452 has been isolated from Streptomyces sp. ATCC 700974. The fermentation, isolation, structure elucidation and some properties are described. SB-217452 showed inhibitory activity against both Staphylococcus aureus and rat seryl tRNA synthetases, with similar IC50 values of approximately 8 nM. The inhibitor is the serine linked nucleoside moiety of the antibiotic albomycin delta2. In contrast to albomycin delta2, SB-217452 showed only very weak antibacterial activity against a limited range of microorganisms. The compound has not been previously reported as a naturally occurring metabolite. In addition to SB-217452, albomycin delta2 Fe3+ complex and the novel Al3+ complex were isolated from the fermentation. These complexes had no seryl tRNA synthetase inhibitory activity.