Pressurized intra-peritoneal aerosol chemotherapy (PIPAC): increased intraperitoneal pressure does not affect distribution patterns but leads to deeper penetration depth of doxorubicin in a sheep model.

BACKGROUND: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is an innovative treatment against peritoneal carcinomatosis. Doxorubicin is a common intra-venous chemotherapy used for peritoneal carcinomatosis and for PIPAC. This study evaluated the impact of increased PIPAC intraperitoneal pressure on the distribution and cell penetration of doxorubicin in a sheep model. METHODS: Doxorubicin was aerosolized using PIPAC into the peritoneal cavity of 6 ewes (pre-alpes breed): N = 3 with 12 mmHg intraperitoneal pressure ("group 12") and N = 3 with 20 mmHg ("group 20"). Samples from peritoneum (N = 6), ovarian (N = 1), omentum (N = 1) and caecum (N = 1) were collected for each ewe. The number of doxorubicin positive cells was determined using the ratio between doxorubicine fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (µm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei over the total number of cell nuclei that were stained with DAPI. Penetration depth (µm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei. RESULTS: DOXO+ nuclei were identified in 87% of samples. All omental samples, directly localized in front of the nebulizer head, had 100% DOXO+ nuclei whereas very few nuclei were DOXO+ for caecum. Distribution patterns were not different between the two groups but penetration depth in ovary and caecum samples was significantly deeper in group 20. CONCLUSIONS: This study showed that applying a higher intra-peritoneal pressure during PIPAC treatment leads to a deeper penetration of doxorubicin in ovarian and caecum but does not affect distribution patterns.

Morphological hallmarks facilitating distinction of omental milky spots and lymph nodes: an exploratory study on their discriminative capacity.

BACKGROUND: Omental milky spots (OMSs) are the primary lymphoid structures of the greater omentum. However, the presence of lymph nodes (LNs) has occasionally been mentioned as well. Understanding which lymphoid structures are present is of significance, especially in gastric tumor metastasis; tumor deposits in omental LNs suggest local lymphatic spread, whereas tumor deposits in OMSs suggest peritoneal spread and hence extensive disease. Since LNs and OMSs share morphological characteristics and OMSs might be wrongly identified as LNs, reliable hallmarks facilitating easy discrimination are needed. MATERIALS AND METHOD: A series of microscopic morphological hallmarks unique to LNs were selected as potential candidates and were assessed for their discriminative capacity: 1) capsule, 2) trabeculae, 3) subcapsular sinus, 4) afferent lymphatic vessels, 5) distinct B- and T cell regions, and 6) a layered organization with, from the outside in a capsule, cortex, paracortex, and medulla. These hallmarks were visualized by multiple staining techniques. RESULTS: Hallmarks 1, 2 5 and 6 were shown to be the most efficient as these were consistent and discriminative. They were best visualized by Picrosirius red, smooth muscle actin and a B-cell / T-cell double staining. CONCLUSION: The presence of a capsule, trabeculae, distinct B- and T-cell regions and a layered organization represent consistent and reliable morphological features which allow to easily distinguish LNs from OMSs, especially when applied in combination.

Analytic comparison of talc in commercially available baby powder and in pelvic tissues resected from ovarian carcinoma patients.

OBJECTIVE: Measure the size and shape of talc particles in talcum powder and compare this data to the size and shape of talc particles found in surgically resected tissues from patients with ovarian carcinoma. METHODS: Using polarized light microscopy (PLM) and scanning electron microscopy (SEM), we measured the size and shape of talc particles in samples of talc-containing baby powder (TCBP) and surgically resected pelvic tissues (hysterectomies) from talc-exposed patients with ovarian carcinoma. RESULTS: The most frequent class of particles in TCBP can be unequivocally identified as talc, using both polarized light microscopy and scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX). The talc particles found in resected tissues from ovarian carcinoma patients are similar in size and shape to the most abundant morphological class of particles in TCBP. CONCLUSIONS: This finding, combined with previous epidemiological literature and tissue-based analytical studies, provides further evidence that the small, isodiametric particles that dominate TCBP can migrate from the perineum and become lodged in distal structures in the female reproductive tract, where they may lead to an increased risk of developing ovarian carcinoma.

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis.

For the better understanding of insulin resistance (IR), the molecular biomarkers in IR white adipocytes and its potential mechanism, we downloaded two mRNA expression profiles from Gene Expression Omnibus (GEO). The white adipocyte samples in two databases were collected from the human omental adipose tissue of IR obese (IRO) subjects and insulin-sensitive obese (ISO) subjects, respectively. We identified 86 differentially expressed genes (DEGs) between the IRO and ISO subjects using limma package in R software. Gene Set Enrichment Analysis (GSEA) provided evidence that the most gene sets enriched in kidney mesenchyme development in the ISO subjects, as compared with the IRO subjects. The Gene Ontology (GO) analysis indicated that the most significantly enriched in cellular response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the DEGs were most significantly enriched in cytokine-cytokine receptor interaction. Protein-Protein Interaction (PPI) network was performed with the STRING, and the top 10 hub genes were identified with the Cytohubba. CMap analysis found several small molecular compounds to reverse the altered DEGs, including dropropizine, aceclofenac, melatonin, and so on. Our outputs could empower the novel potential targets to treat omental white adipocyte insulin resistance, diabetes, and diabetes-related diseases.

Topical purified omental lipid formulations in the prevention of skin ulcers: a narrative review.

The omentum is a large peritoneal fold. Its main function is to protect abdominal organs, exerting a defensive action against infective agents. The tissue promotes repair after several types of injury. An extensive vascularisation is the key characteristic of this tissue and the omentum has the highest level of production and content of vascular endothelial growth factor (VEGF). A component of omentum is the lipid compound, which carries out important activities for the organism. Omentum is rich in neutral glycerides, phospholipids, glycolipids and gangliosides. Dermatological products containing purified omental lipids are commercially available and topical omental extracts have been useful in the softening, moisturising and smoothing of skin. Animal-derived omental lipids could be use in topical products with different textures (creams, fluids, emulsions and cleansers) and at different concentrations (10-25%) for the treatment of fragile skin or skin conditions causing risk of ulcer formation. This review summarises the pharmacological rationale of purified omental lipids in topical formulations for use in fragile skin conditions, the clinical efficacy data available in the scientific literature and the potential future perspectives. Efficacy of topical purified omental lipids have been demonstrated in numerous clinical controlled trials involving a total of 320 subjects. These studies demonstrated that this product helps prevent the formation of pressure ulcers (PU) in hospitalised high-risk subjects, improves wound healing process, normalises skin hydration in diabetic subjects with moderate-severe skin xerosis and improve the clinical evolution of diabetic foot. Therefore, purified omental lipid could be an effective tool for the management of fragile skin and the skin at high risk of PU formation.

Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients.

Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis. Consistently different biopotential values were detected in cancerous tissue versus non-cancerous tissue across all cases (p < 0.001). High tumour biopotential levels correlated with advanced tumour stage (p = 0.048) and tumour load, and negatively correlated with stroma. Within our EOC cohort and specifically the high-grade serous subtype, low biopotential levels associated with poorer progression-free survival (p = 0.0179, p = 0.0143 respectively). Changes in biopotential levels significantly correlated with common apoptosis related pathways. Lactate and glucose levels measured in paired tissues showed significantly higher lactate/glucose ratio in tissues with low biopotential (p < 0.01, n = 12). Our study proposes the feasibility of biopotential and metabolite monitoring as a biomarker modality profiling EOC to predict surgical and clinical outcomes.

Selected Case From the Arkadi M. Rywlin International Pathology Slide Club: Peritoneal Lipofuscinosis and Deciduosis in Pregnancy.

Peritoneal lipofuscinosis is a very rarely recognized condition occurring during pregnancy characterized by brown pigmentation of the omentum and peritoneum, a decidual reaction and benign mesothelial cells. The iron negative pigment, which is likely to be confused with hemosiderin in the hematoxylin and eosin stain, is lipofuscin. The seminar case, apparently the third published, arose in a 37-year-old woman who presented in October 2015 at 24 weeks pregnancy with abdominal pain. Investigations revealed a ruptured left ovarian cyst and rising serum carcinoembryonic antige levels. At laparotomy, there was no free intraperitoneal blood but the omentum and uterine serosa were black. Histology showed lipofuscinosis and a decidual reaction. The patient delivered a normal baby in February 2016 and was clinically well after delivery. A left ovarian endometriotic cyst was removed in February 2017. The patient made a good recovery with no clinically apparent symptoms from the liposuscinosis. We postulate that the endometriotic cyst had ruptured and released blood into the peritoneal cavity in 2015. The iron from the red cells breakdown was then rapidly resorbed because of the pregnancy requirements for iron, leaving lipofuscin in peritoneal macrophages.

Biodistribution and Clearance of Stable Superparamagnetic Maghemite Iron Oxide Nanoparticles in Mice Following Intraperitoneal Administration.

Nanomedicine is an emerging field with great potential in disease theranostics. We generated sterically stabilized superparamagnetic iron oxide nanoparticles (s-SPIONs) with average core diameters of 10 and 25 nm and determined the in vivo biodistribution and clearance profiles. Healthy nude mice underwent an intraperitoneal injection of these s-SPIONs at a dose of 90 mg Fe/kg body weight. Tissue iron biodistribution was monitored by atomic absorption spectroscopy and Prussian blue staining. Histopathological examination was performed to assess tissue toxicity. The 10 nm s-SPIONs resulted in higher tissue-iron levels, whereas the 25 nm s-SPIONs peaked earlier and cleared faster. Increased iron levels were detected in all organs and body fluids tested except for the brain, with notable increases in the liver, spleen, and the omentum. The tissue-iron returned to control or near control levels within 7 days post-injection, except in the omentum, which had the largest and most variable accumulation of s-SPIONs. No obvious tissue changes were noted although an influx of macrophages was observed in several tissues suggesting their involvement in s-SPION sequestration and clearance. These results demonstrate that the s-SPIONs do not degrade or aggregate in vivo and intraperitoneal administration is well tolerated, with a broad and transient biodistribution. In an ovarian tumor model, s-SPIONs were shown to accumulate in the tumors, highlighting their potential use as a chemotherapy delivery agent.

ECM-based macroporous sponges release essential factors to support the growth of hematopoietic cells.

The success of hematopoietic stem cells (HSCs) transplantation is limited due to the low number of HSCs received from donors. In vivo, HSCs reside within a specialized niche inside the 3D porous spongy bone. The natural environment in the niche is composed of structural proteins, glycosaminoglycans (GAGs) and soluble factors that control cells fate. However, the designed scaffolds for in vitro culture do not fairly recapitulate this microenvironment and cannot efficiently control HSCs fate. Here we report on the development of new omental ECM-based 3D macroporous sponges for hematopoietic cell culture. The scaffolds' structure, porosity and stability were characterized and optimized. Analysis of the biochemical content revealed that they were composed of collagens and GAGs, including sulfated GAGs. This morphology and composition enabled growth factors interaction with the sulfated GAGs, as indicated by the high loading capacity and release profile of three different hematopoietic niche factors. Finally, the ability of the ECM-based scaffolds to efficiently support the growth of hematopoietic cells by releasing stem cell factor (SCF) was demonstrated.

Hepatic epithelioid hemangioendothelioma metastasized to the peritoneum, omentum and mesentery: a case report.

Epithelioid hemangioendothelioma (EHAE) is a malignant vascular tumor derived from endothelial cell often misdiagnosed as Hepatic carcinoma on the basis of radiological features. Till now etiology of this rare curiosity is unknown but it is related with use of oral contraceptives pills (OCP), liver trauma, exposure to vinyl chloride and hepatitis. We herein report on a case which failed to be diagnosed by cytopathology, computed tomography (CT) and magnetic resonance imaging (MRI). Patient was a 46 yr old man presented with abdominal distension for a month. Initial liver function test (LFT) was increased whereas renal function test (RFT) and alpha-fetoprotein (AFP) were normal. His abdominal ultrasound revealed multiple hypoechoic nodules and multiple liver calcifications. Subsequently laparoscopic omental biopsy and Ultrasound guided liver biopsy was done showing the neoplastic cells scattered in fibrous stroma. The immunohistochemistry for endothelial tumor cells stained positive for Vimentin (+++), CD10 (+++), CD34 (++), CD31 (+), Factor VIII antigen (focal) (+) and low proliferative activity for ki-67. Our case is very interesting in which patient admitted with nonspecific symptoms of abdominal pain and diagnosed to be a Malignant Hepatic EHAE metastasized to the peritoneum, omentum and mesentery. The patient was on thalidomide 50 mg/day and increased to 100 mg/day. 5-Flurouracil (FU) intraperitoneal chemotherapy and other symptomatic and supportive treatment was given to the patient. Our case highlights on the importance of immunohistopathological diagnosis, compare the radiological findings of this disease and discuss the treatment strategy with review of available literature.

Persistent organic pollutants (POPs) and fibroids: results from the ENDO study.

To evaluate the association between persistent organic pollutants (POPs) and uterine fibroids, we used previously collected data from a cohort of women aged 18-44 years undergoing laparoscopy or laparotomy at 14 participating hospital surgical centers (n=473). POP concentrations were measured in omental fat and serum. Presence of fibroids was defined on the basis of a postoperative diagnosis (n=99). Odds ratios (OR) and 95% confidence interval (CI) for each POP by biologic medium were estimated using unconditional logistic regression adjusted for identified covariates. Concentrations were higher in omental fat than in serum for all POPs. Serum p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) was the only POP associated with fibroids (per 1-SD increase in log-transformed p,p'-DDE OR (95% CI): 1.37 (1.05-1.80)). In analyses excluding women diagnosed with endometriosis, a number of polychlorinated biphenyls (PCBs) measured in omental fat were associated with fibroids (PCB 99: 1.64 (1.08, 2.49); PCB 138: 1.64 (1.03, 2.59); PCB 146: 1.54 (1.01, 2.37); PCB 153: 1.88 (1.12, 3.13); PCB 196: 1.60 (1.02, 2.51); PCB 206: 1.52 (1.01, 2.29)). Although exploratory, our study suggests that PCBs may be associated with fibroids in the absence of other gynecologic disorders such as endometriosis, but the associations varied by biologic media with more POPs emerging when quantified in fat.

Expression and prognostic significance of the polymeric immunoglobulin receptor in epithelial ovarian cancer.

BACKGROUND: High expression of the polymeric immunoglobulin receptor (PIGR) has previously been associated with a favourable prognosis in a few cancer forms, but its expression and relationship with clinical outcome in epithelial ovarian cancer (EOC) has not yet been reported. The aim of this study was therefore to examine the clinicopathological correlates and prognostic significance of PIGR expression in EOC. METHODS: After an initial screening in the Human Protein Atlas portal, a validated antibody was selected for extended analysis of immunohistochemical PIGR expression in tissue microarrays with tumours from 154 incident cases of EOC from two pooled prospective population-based cohorts. Subsets of corresponding benign-appearing fallopian tubes (n = 38) and omental metastases (n = 33) were also analysed. Kaplan-Meier analysis and Cox regression analysis were applied to examine the impact of PIGR expression on overall survival (OS) and ovarian cancer-specific survival (OCSS). RESULTS: PIGR expression was significantly higher in fallopian tubes compared to primary tumours and metastases (p < 0.001) and lower in carcinoma of the serous subtype compared to other carcinomas (p < 0.001). PIGR expression was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = 0.002), positive progesterone receptor expression (p = 0.009) and negative or low Ki-67 expression (p = 0.003). Kaplan-Meier analysis revealed a significantly improved OS (p = 0.013) and OCSS (p = 0.009) for patients with tumours displaying high expression of PIGR. These associations were confirmed in unadjusted Cox regression analysis (HR = 0.48; 95% CI 0.26-0.87; p = 0.015 for OS and HR = 0.43, 95% CI 0.22-0.82; p = 0.011 for OCSS) but did not remain significant after adjustment for age, grade and clinical stage. CONCLUSIONS: This study provides a first demonstration of PIGR expression in human fallopian tubes, primary EOC tumours and metastases. High tumour-specific expression of PIGR was found to be associated with a favourable prognosis in unadjusted, but not in adjusted, analysis. These findings are novel and merit further investigation.

Diffuse large B-cell lymphoma of the uterus suspected of having transformed from a marginal zone B-cell lymphoma harboring trisomy 18: a case report and review of the literature.

The patient was a 72-year-old female with the chief complaint of abdominal fullness. A giant primary myoma of the uterine cervix was suspected, and total hysterectomy was performed. Based on a postoperative histopathological examination of the tumor a diagnosis of diffuse large B-cell lymphoma (DLBCL) was made in the uterus and a mass in the greater omentum was diagnosed as a marginal zone B-cell lymphoma (MZBCL). No flow-cytometry studies or chromosome or gene examinations were performed on a fresh specimen. The results of an examination of a paraffin block histopathology specimen by fluorescence in-situ hybridization (FISH) showed no mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) (18q21.1), B-cell lymphoma 2 (BCL2) (18q21.3), or BCL6 (3q27) split signals in either the uterus or the greater omentum, however, trisomy 18 was detected in approximately 50%-70% of the tumor cells in both the uterus and the greater omentum. Trisomy 18 was present in around 15-33% of the DLBCL cells and MZBCL cells. These findings suggested a strong possibility that the tumor cells in the uterus and greater omentum were the same clone and that transformation from MZBCL to DLBCL had occurred. Since DLBCLs that result from a transformation usually have a worse outcome than de novo DLBCLs, even when a DLBCL seems to have originated in the uterus the surrounding tissue should always be examined, and caution should be exercised in regard to transformation from a low-grade B-cell lymphoma to a DLBCL.

Decellularized omentum as novel biologic scaffold for reconstructive surgery and regenerative medicine.

Homologous tissues, such as adipose tissue, may be an interesting source of acellular scaffolds, maintaining a complex physiological three-dimensional (3D) structure, to be recellularized with autologous cells. The aim of the present work is to evaluate the possibility of obtaining homologous acellular scaffolds from decellularization of the omentum, which is known to have a complex vascular network. Adult rat and human omenta were treated with an adapted decellularization protocol involving mechanical rupture (freeze-thaw cycles), enzymatic digestion (trypsin, lipase, deoxyribonuclease, ribonuclease) and lipid extraction (2-propanol). Histological staining confirmed the effectiveness of decellularization, resulting in cell-free scaffolds with no residual cells in the matrix. The complex 3D networks of collagen (azan-Mallory), elastic fibers (Van Gieson), reticular fibers and glycosaminoglycans (PAS) were maintained, whereas Oil Red and Sudan stains showed the loss of lipids in the decellularized tissue. The vascular structures in the tissue were still visible, with preservation of collagen and elastic wall components and loss of endothelial (anti-CD31 and -CD34 immunohistochemistry) and smooth muscle (anti-alpha smooth muscle actin) cells. Fat-rich and well vascularized omental tissue may be decellularized to obtain complex 3D scaffolds preserving tissue architecture potentially suitable for recellularization. Further analyses are necessary to verify the possibility of recolonization of the scaffold by adipose-derived stem cells in vitro and then in vivo after re-implantation, as already known for homologus implants in regenerative processes.

Giant solitary fibrous tumor arising from greater omentum.

Extrathoracic solitary fibrous tumors (SFTs) have been described at almost every anatomic location of human body, but reports of SFT in the abdominal cavity are rare. We herein present a rare case of SFT originating from greater omentum. Computed tomography revealed a 15.8 cm × 21.0 cm solid mass located at superior aspect of stomach. Open laparotomy confirmed its mesenchymal origin. Microscopically, its tissue was composed of non-organized and spindle-shaped cells exhibiting atypical nuclei, which were divided up by branching vessel and collagen bundles. Immunohistochemical staining showed that this tumor was negative for CD117, CD99, CD68, cytokeratin, calretinin, desmin, epithelial membrane antigen, F8 and S-100, but positive for CD34, bcl-2, α-smooth muscle actin and vimentin. The patient presented no evidence of recurrence during follow-up. SFT arising from abdominal cavity can be diagnosed by histological findings and immunohistochemical markers, especially for CD34 and bcl-2 positive cases.

Biomarker expression in pelvic high-grade serous carcinoma: comparison of ovarian and omental sites.

Neoadjuvant therapy has an emerging role in the treatment of high-stage ovarian carcinoma. Some ovarian carcinoma subtypes do not respond well to standard chemotherapy, making accurate subtype diagnosis before starting therapy important. This diagnosis is frequently based on omental biopsy specimens. In particular, with very small biopsies, immunostaining for diagnostic biomarkers may be needed. To assess intratumoral heterogeneity of biomarker expression in pelvic high-grade serous carcinoma, we compared the expression of a set of 10 biomarkers between ovarian and omental sites. Tissue microarrays were constructed from 123 high-grade serous carcinomas with paired ovarian and omental tumor samples. These samples were stained with biomarkers that have been used in ovarian carcinoma subtype diagnosis (WT1, TP53/p53, MUC16/CA125, CDKN2A/p16), and with biomarkers of the tumor microenvironment (CD8, CD163, SPARC, PDGFRB), cell adhesion (CDH1/E-Cadherin), and proliferation (Ki67) as well. Expression frequencies in samples from the 2 sites were compared, as was concordance at the 2 sites for individual tumors. The 2 markers of desmoplastic stromal response (PDGFRB, SPARC) were more frequently expressed in the omentum compared with the ovary (P<0.001; McNemar test). The other 8 markers did not show a significant difference in the frequency of expression between sites. Within individual cases, some markers such as Ki67 and CDKN2A showed variability, indicating that these markers are affected by intratumoral heterogeneity. The intratumoral variability for MUC16, TP53, and WT1 was modest. Commonly used diagnostic markers, such as TP53 and WT1, show little variability between ovarian and omental sites, suggesting that they can be successfully used in small biopsy specimens from extraovarian sites. In contrast, markers of host stromal response do vary between sites, suggesting a biologic difference of the microenvironment at different sites that should be taken into account when tissue-based research is carried out.

The omentum is a site of stromal cell-derived factor 1alpha production and reservoir for CXC chemokine receptor 4-positive cell recruitment.

BACKGROUND: The mechanism of the omental response to injury remains poorly defined. This study investigates the omental reaction to a foreign body, examining the role of a chemokine ligand/receptor pair known to play a crucial role in angiogenesis and wound healing. METHODS: A ventral hernia, surgically created in the abdominal wall of 6 swine, was repaired with silicone sheeting to activate the omentum. Omental thickness was determined by ultrasonography. Serial stromal cell-derived factor 1alpha (SDF-1alpha) concentrations were measured in blood, wound, and peritoneal fluids by enzyme-linked immunosorbent assay. RESULTS: During the 14-day study period, serial ultrasonography showed a 20-fold increase in omental thickness, and enzyme-linked immunosorbent assay revealed a 4-fold increase in SDF-1alpha concentration in local wound fluid. Omental vessel count and vascular surface area were 8- to 10-fold higher in reactive omentum. Immunohistochemistry showed nearly complete replacement of control omental fat with CXC chemokine receptor 4 (CXCR4)-positive cells by day 14. CONCLUSIONS: Activated omentum, important in the SDF-1alpha/CXCR4 axis, may serve as an intraperitoneal reservoir for recruitment of circulating bone marrow-derived cells vital to healing.

Contribution of genetic and metabolic syndrome to omental adipose tissue PAI-1 gene mRNA and plasma levels in obesity.

BACKGROUND: Plasminogen activator inhibitor type-1 (PAI-1) has already been associated with atherosclerosis; myocardial infarction; and cardiovascular disease risk factors such as obesity, insulin resistance, and dyslipidemia. However, factors regulating PAI-1 adipose tissue (AT) gene expression and plasma levels are not yet well defined. AIM: This study aims to assess the contribution of PAI-1 omental AT mRNA levels and genetic and metabolic factors to variation in plasma PAI-1 concentrations. METHODS: Ninety-one non-diabetic premenopausal severely obese women (body mass index, BMI >35 kg/m(2)) undergoing bariatric surgery were phenotyped (fasting plasma glucose, lipid-lipoprotein, and PAI-1 levels) and genotyped for four PAI-1 polymorphisms. Omental AT PAI-1 mRNA levels were determined using real-time polymerase chain reaction. Stepwise regression analysis was used to identify independent PAI-1 AT mRNA and plasma level predictors. RESULTS: Among the variables included to the stepwise regression analysis, plasma high-density lipoprotein (HDL)-cholesterol (r = 0.38; p = 0.0004) and total cholesterol (r = 0.16; p = 0.0541) levels were the only two (out of 12) independent variables retained as predictive of PAI-1 omental AT mRNA levels, whereas BMI (r = 0.35; p = 0.0039), plasma HDL-cholesterol concentrations (r = -0.31; p = 0.0375), PAI-1 omental AT mRNA levels (r = 0.19; p = 0.0532) and PAI-1-844G/A (p = 0.0023), and rs6092 (p.A15T; p = 0.0358) polymorphisms contributed independently to plasma PAI-1 concentrations. Taken together, these variables explained 17.8% and 31.0% of the variability in PAI-1 AT mRNA and plasma levels, respectively. CONCLUSION: These results suggest that PAI-1 polymorphisms contribute significantly to PAI-1 plasma levels but do not support the notion that omental AT is one of its major source.

Osteopontin involvement in granuloma formation and in the severity of Paracoccidioides brasiliensis infection.

The participation of osteopontin (OPN) in Paracoccidioides brasiliensis infected mice, its association to granulomatogenesis, severity of infection, pattern of lesions, nitric oxide (NO) levels and fungal load were evaluated in this investigation. Immunohistochemistry analysis showed marked OPN staining in extracellular matrix and in macrophages and multinucleated giant cells at the center of lesions, suggesting a possible role of OPN in the distribution of these cells within the granulomas. At 15 days post-infection with a virulent P. brasiliensis isolate, OPN+ cells were more numerous and intensely immunostained in the loose granulomas of susceptible mice than in those of resistant mice. In addition, high fungal loads and low NO levels were observed in susceptible mice. At 120 days after infection, resistant mice had increased total OPN levels (ELISA) and OPN positivity in compact granulomas, higher NO levels and lower fungal loads than susceptible mice. Residual lesions associated with low OPN levels, high NO and control of fungal dissemination were observed in both mouse strains at 120 days post-infection with the slightly virulent fungal isolate. Therefore, OPN could be associated with higher severity of the disease in an early phase of infection and with a degree of control of the progressive infection.

Proteomic biomarkers for the diagnosis and risk stratification of polycystic ovary syndrome: a systematic review.

BACKGROUND: The exact causes of polycystic ovary syndrome (PCOS) are uncertain, and treatment could be improved. Discovery-based approaches like 'proteomics' may result in faster insights into the causes of PCOS and improved treatment. OBJECTIVES: To identify the number and nature of proteomic biomarkers found in PCOS so far and to identify their diagnostic and therapeutic potential. SEARCH STRATEGY: All published studies on proteomic biomarkers in women with PCOS identified through the MEDLINE (1966-2008), EMBASE (1980-2008) and the ISI web of knowledge (v4.2) databases. SELECTION CRITERIA: The terms 'polycystic ovary syndrome' and 'proteomic', 'proteomics', 'proteomic biomarker' or 'proteomics biomarker' without any limits/restrictions were used. DATA COLLECTION AND ANALYSIS: Original data were abstracted where available and summarised on a separate Microsoft Excel (2007) database for analysis. MAIN RESULTS: Seventeen articles were identified, of which 6 original papers and 1 review article contained original data. Tissues investigated included serum, omental biopsies, ovarian biopsies, follicular fluid and T lymphocytes. Sample sizes ranged from 3 to 30 women. One hundred and forty-eight biomarkers were identified. The biomarkers were involved in many pathways, for example the regulation of fibrinolysis and thrombosis, insulin resistance, immunity/inflammation and the antioxidant pathway. Eleven groups of biomarkers appeared to be independently validated. The individual sensitivities for the diagnosis of PCOS were reported for 11 named biomarkers and ranged from 57 to 100%. AUTHOR'S CONCLUSIONS: Proteomic biomarker discovery in PCOS offers great potential. Current challenges include reproducibility and data analysis. The establishment of a PCOS-specific biomarker data bank and international consensus on the framework of systematic reviews in this field are required.