Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells.

Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.

Olfactory Ensheathing Cells for Spinal Cord Injury: Sniffing Out the Issues.

Olfactory ensheathing cells (OECs) are glia reported to sustain the continuous axon extension and successful topographic targeting of the olfactory receptor neurons responsible for the sense of smell (olfaction). Due to this distinctive property, OECs have been trialed in human cell transplant therapies to assist in the repair of central nervous system injuries, particularly those of the spinal cord. Though many studies have reported neurological improvement, the therapy remains inconsistent and requires further improvement. Much of this variability stems from differing olfactory cell populations prior to transplantation into the injury site. While some studies have used purified cells, others have used unpurified transplants. Although both preparations have merits and faults, the latter increases the variability between transplants received by recipients. Without a robust purification procedure in OEC transplantation therapies, the full potential of OECs for spinal cord injury may not be realised.

Enhancing the Therapeutic Potential of Olfactory Ensheathing Cells in Spinal Cord Repair Using Neurotrophins.

Autologous olfactory ensheathing cell (OEC) transplantation is a promising therapy for spinal cord injury; however, the efficacy varies between trials in both animals and humans. The main reason for this variability is that the purity and phenotype of the transplanted cells differs between studies. OECs are susceptible to modulation with neurotrophic factors, and thus, neurotrophins can be used to manipulate the transplanted cells into an optimal, consistent phenotype. OEC transplantation can be divided into 3 phases: (1) cell preparation, (2) cell administration, and (3) continuous support to the transplanted cells in situ. The ideal behaviour of OECs differs between these 3 phases; in the cell preparation phase, rapid cell expansion is desirable to decrease the time between damage and transplantation. In the cell administration phase, OEC survival and integration at the injury site, in particular migration into the glial scar, are the most critical factors, along with OEC-mediated phagocytosis of cellular debris. Finally, continuous support needs to be provided to the transplantation site to promote survival of both transplanted cells and endogenous cells within injury site and to promote long-term integration of the transplanted cells and angiogenesis. In this review, we define the 3 phases of OEC transplantation into the injured spinal cord and the optimal cell behaviors required for each phase. Optimising functional outcomes of OEC transplantation can be achieved by modulation of cell behaviours with neurotrophins. We identify the key growth factors that exhibit the strongest potential for optimizing the OEC phenotype required for each phase.

Substitutional carbon doping of free-standing and Ru-supported BN sheets: a first-principles study.

The development of spatially homogeneous mixed structures with boron (B), nitrogen (N) and carbon (C) atoms arranged in a honeycomb lattice is highly desirable, as they open the possibility of creating stable two-dimensional materials with tunable band gaps. However, at least in the free-standing form, the mixed BCN system is energetically driven towards phase segregation to graphene and hexagonal BN. It is possible to overcome the segregation when BCN material is grown on a particular metal substrate, for example Ru(0 0 0 1), but the stabilization mechanism is still unknown. With the use of density-functional theory we study the energetics of BN/Ru slabs, with different types of configurations of C substitutional defects introduced to the h-BN overlayer. The results are compared to the energetics of free-standing BCN materials. We found that the substrate facilitates the C substitution process in the h-BN overlayer. Thus, more homogeneous BCN material can be grown, overcoming the segregation into graphene and h-BN. In addition, we investigate the electronic and transport gaps in free-standing BCN structures, and assess their mechanical properties and stability. The band gap in mixed BCN free-standing material depends on the concentration of the constituent elements and ranges from zero in pristine graphene to nearly 5 eV in free-standing h-BN. This makes BCN attractive for application in modern electronics.

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial.

BACKGROUND.: Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. METHODS.: Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h -1 ) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics ® software. Calculations of PTA and FTA were performed for common pathogens. RESULTS.: Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean ( sd ) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h -1 . Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. CONCLUSIONS.: Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. CLINICAL TRIAL REGISTRATION.: NCT02058979.

OC-07 - Decoding risk for thromboembolic events in lymphoma patients.

INTRODUCTION: There are few prediction tools for estimating the risk of thrombosis but they are based on studies performed on hospitalized medical patients without cancer or on hospitalized neutropenic cancer patients without special consideration to lymphoma patients. AIM: Aim of our study was to determine incidence of thromboembolic (TE) events in patients with non Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who were hospitalized to the lymphoma department in the Clinic of hematology, Clinical Center Serbia, Belgrade and Clinic of hematology, Clinical Center Kragujevac. Also, we assessed 2 predictive models (Padua and Khorana score) and create new model for the identification of lymphoma patients at risk for thromboembolism. MATERIALS AND METHODS: We reviewed all medical records of patients with with NHL, HL and CLL/SLL diagnosed and treated at two previously mentioned institution between January 2006 and December 2014. RESULTS: The study population included 1820 eligible lymphoma patients. Of all the patients included in the study, 99 (5.4%) developed at least one TE during a follow-up period of 3 months from the end of therapy. In the final multivariate analysis, the following variables were independently associated with risk of TE: previous VTE and/or arterial events, reduced mobility (ECOG 2-4), obesity (BMI >30 kg/m(2)), extranodal localization, mediastinum involvement, development of neutropenia during therapy and hemoglobin level less than 100g/L. Subsequently, we assigned points for the risk model based on the regression coefficients obtained from the final model and developed Thrombosis Lymphoma (ThroLy) score consisting of all significant variables from the multivariate analysis. The Throly score was arrived at by assigning 2 points for all parameters with an OR >5 in multivariate regression analyses (e.g., previous VTE and arterial events, mediastinum involvement, and BMI) and 1 point for rest all other significant variables. Finally, population were divided into 3 risk categories for TE based on the score from the risk model: low (score 0-1), intermediate (score 2-3) and high (score >3). High risk score had a positive predictive value (probability of TE in those designated high risk) of 65.2%. CONCLUSIONS: Significance of our investigation is development of score that help phisicians to recruit lymphoma patients at risk for development of thromboembolic complications. Also, we can say that our score is dynamic allowing us to change approach during different phase of therapy and is not limited to outpatient settings or with some complicated laboratory analysis.

Lenalidomide normalizes tumor vessels in colorectal cancer improving chemotherapy activity.

BACKGROUND: Angiogenesis inhibition is a promising approach for treating metastatic colorectal cancer (mCRC). Recent evidences support the seemingly counterintuitive ability of certain antiangiogenic drugs to promote normalization of residual tumor vessels with important clinical implications. Lenalidomide is an oral drug with immune-modulatory and anti-angiogenic activity against selected hematologic malignancies but as yet little is known regarding its effectiveness for solid tumors. The aim of this study was to determine whether lenalidomide can normalize colorectal cancer neo-vessels in vivo, thus reducing tumor hypoxia and improving the benefit of chemotherapy. METHODS: We set up a tumorgraft model with NOD/SCID mice implanted with a patient-derived colorectal cancer liver metastasis. The mice were treated with oral lenalidomide (50 mg/Kg/day for 28 days), intraperitoneal 5-fluorouracil (5FU) (20 mg/Kg twice weekly for 3 weeks), combination (combo) of lenalidomide and 5FU or irrelevant vehicle. We assessed tumor vessel density (CD146), pericyte coverage (NG2; alphaSMA), in vivo perfusion capability of residual vessels (lectin distribution essay), hypoxic areas (HP2-100 Hypoxyprobe) and antitumor activity in vivo and in vitro. RESULTS: Treatment with lenalidomide reduced tumor vessel density (p = 0.0001) and enhanced mature pericyte coverage of residual vessels (p = 0.002). Perfusion capability of tumor vessels was enhanced in mice treated with lenalidomide compared to controls (p = 0.004). Accordingly, lenalidomide reduced hypoxic tumor areas (p = 0.002) and enhanced the antitumor activity of 5FU in vivo. The combo treatment delayed tumor growth (p = 0.01) and significantly reduced the Ki67 index (p = 0.0002). Lenalidomide alone did not demonstrate antitumor activity compared to untreated controls in vivo or against 4 different mCRC cell lines in vitro. CONCLUSIONS: We provide the first evidence of tumor vessel normalization and hypoxia reduction induced by lenalidomide in mCRC in vivo. This effect, seemingly counterintuitive for an antiangiogenic compound, translates into indirect antitumor activity thus enhancing the therapeutic index of chemotherapy. Our findings suggest that further research should be carried out on synergism between lenalidomide and conventional therapies for treating solid tumors that might benefit from tumor vasculature normalization.

Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease.

Parkinson's disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinson's disease cases are idiopathic, of unknown origin. The aetiology of Parkinson's disease is not fully understood but increasing evidence implies a failure in fundamental cellular processes including mitochondrial dysfunction and increased oxidative stress. To dissect the cellular events underlying idiopathic Parkinson's disease, we use primary cell lines established from the olfactory mucosa of Parkinson's disease patients. Previous metabolic and transcriptomic analyses identified deficiencies in stress response pathways in patient-derived cell lines. The aim of this study was to investigate whether these deficiencies manifested as increased susceptibility, as measured by cell viability, to a range of extrinsic stressors. We identified that patient-derived cells are more sensitive to mitochondrial complex I inhibition and hydrogen peroxide induced oxidative stress, than controls. Exposure to low levels (50 nM) of rotenone led to increased apoptosis in patient-derived cells. We identified an endogenous deficit in mitochondrial complex I in patient-derived cells, but this did not directly correlate with rotenone-sensitivity. We further characterized the sensitivity to rotenone and identified that it was partly associated with heat shock protein 27 levels. Finally, transcriptomic analysis following rotenone exposure revealed that patient-derived cells express a diminished response to rotenone-induced stress compared with cells from healthy controls. Our cellular model of idiopathic Parkinson's disease displays a clear susceptibility phenotype to mitochondrial stress. The determination of molecular mechanisms underpinning this susceptibility may lead to the identification of biomarkers for either disease onset or progression.

Student learning styles in anatomy and physiology courses: Meeting the needs of nursing students.

Anatomy and Physiology is a core course in pre-registration nursing programs, yet many students have difficulty successfully negotiating the large volume of content and the complex concepts in these bioscience courses. Typically students perform poorly in these 'threshold' courses', despite multiple interventions to support student engagement. Investigation of the shortcomings in these courses, based on feedback from students indicated several key areas of difficulty in the course, especially focused around a relative lack of hands-on 'concrete' activities in laboratories and tutorials. To attempt to address this, academic and technical staff developed activities for students that promoted discussion and allowed students to interact easily and repetitively with content. Interactive tables and posters that needed to be labelled or 'filled-in' using pre-prepared Velcro dots, as well as pre-prepared flash cards to promote group work, were some examples of the activities used to enhance student experiences and promote hands-on learning. Over the academic year of 2013 these activities were introduced into the laboratory and tutorial classes for first year Bachelor of Nursing anatomy and physiology students. Staff and student participants positively rated implementation of these new activities on surveys, as they allowed them to explore the difficult aspects of anatomy and physiology, utilising various learning styles that may have been neglected in the past.

Orbital and ocular adnexal Mucosa-Associated Lymphoid Tissue (MALT) lymphomas: a single-center 10-year experience.

Orbital and ocular andexal Mucosa-Associated Lymphoid Tissue Lymphoma (MALT) or ocular adnexal MALT lymphoma (OAML) is the most common of all eye non-Hodgkin lymphomas. Autoimmune inflammatory disorders and chronic infections are important etiological factors and CD5 and CD43 (sialophorin) tumor markers are significant negative prognostic factors. Disease signs and symptoms can occur a long time before diagnosis. Varieties of treatment options are available. The aim of this retrospective analysis was to compare the efficiency of different treatment options and to investigate disease outcome. Twenty OAML patients, diagnosed in the Clinic of Hematology, Clinical Centre of Serbia, between 2003 and 2013, were enrolled. In most cases, OAML developed in the eighth decade with greater incidence in the male population. Median age was 67.5 years. The median period between the appearance of local signs and symptoms and diagnosis was 7 months. The dominant sign at presentation was swelling of involved tissue (40%). The most common was orbital involvement (55%). All patients had localized disease. Observed laboratory parameters on presentation showed low disease activity. Sialophorin prognostic significance was not registered. Our patients were initially treated differently but there was no significant difference in progression-free survival (PFS) due to initial treatment option (p = 0.2957). Median PFS was 22 months (3-89), and 5-year PFS was 60%. Median overall survival (OS) was 43 months (1-105) and 5-year OS 95%. Eight patients (40%) relapsed and one patient died due to non-hematological complications. In our experience, most modern induction treatment options appear to result in the same, favorable outcome.

Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland?

PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice.

Water quality as an indicator of hydrogeological conditions: a case study of the Belgrade Groundwater Source (Sava/Danube confluence area).

The City of Belgrade receives most of its drinking water supply from the alluvial aquifer of the Sava River. The wells are radial, placed in the lower part of the aquifer, so they partly run below the Sava riverbed. However, the groundwater quality of the wells in one part of the source (near the confluence of the Sava and Danube rivers) is found to differ somewhat from the groundwater quality of the other wells. The finding gave rise to additional investigations. The results revealed the existence of a deeper, limestone aquifer which is isolated from upper alluvial sediments by a thick layer of clay in most of the terrain. The naturally potential hydraulic contact of the two aquifers was additionally maintained by well operation in this part of the source. According to multiple analyses of groundwater flow using a hydrodynamic mathematical model, a hydrogeological and hydraulic system of groundwater flow was defined. Although the wells are situated adjacent to the river, and some well laterals are below the riverbed, most of the groundwater that flows to the wells is partly from the wider zone of the alluvial aquifer, and partly from the deeper aquifer. The initial results of hydrochemical investigations also showed an unexpected, inverse oxic character of the groundwater in these two aquifers.

Non-adiabatic simulations of current-related structural transformations in metallic nanodevices.

One of the less explored aspects of molecular electronics is the effect of current on the mechanical stability of the conducting molecule: charge flow can alter both the geometry and electronic properties of the device, modifying the conductance and giving rise to nonlinear conduction characteristics or conductance switching. We performed a fundamental study on the correlation between the geometry and evolving electronic structure of small Au clusters that were embedded in finite Au wires and subjected to periodic transient currents. Both the current-carrying electronic states and the local electronic structure of the model system were described away from the ground state within a time-dependent Ehrenfest formalism. Non-adiabatic molecular dynamics simulations revealed that clusters undergo structural transformations between several representative geometries that coincide with patterns in cluster charging. The shape changes were enabled by the fluctuations in cluster band filling associated with the current and assisted by current-related forces. Metastable configurations of stable clusters were linked to events of charge trapping on the cluster.

Genetic map construction and QTL mapping of resistance to blackleg (Leptosphaeria maculans) disease in Australian canola (Brassica napus L.) cultivars.

Genetic map construction and identification of quantitative trait loci (QTLs) for blackleg resistance were performed for four mapping populations derived from five different canola source cultivars. Three of the populations were generated from crosses between single genotypes from the blackleg-resistant cultivars Caiman, Camberra and (AV)Sapphire and the blackleg-susceptible cultivar Westar(10). The fourth population was derived from a cross between genotypes from two blackleg resistant varieties (Rainbow and (AV)Sapphire). Different types of DNA-based markers were designed and characterised from a collection of 20,000 EST sequences generated from multiple Brassica species, including a new set of 445 EST-SSR markers of high value to the international community. Multiple molecular genetic marker systems were used to construct linkage maps with locus numbers varying between 219 and 468, and coverage ranging from 1173 to 1800 cM. The proportion of polymorphic markers assigned to map locations varied from 70 to 89% across the four populations. Publicly available simple sequence repeat markers were used to assign linkage groups to reference nomenclature, and a sub-set of mapped markers were also screened on the Tapidor x Ningyou (T x N) reference population to assist this process. QTL analysis was performed based on percentage survival at low and high disease pressure sites. Multiple QTLs were identified across the four mapping populations, accounting for 13-33% of phenotypic variance (V (p)). QTL-linked marker data are suitable for implementation in breeding for disease resistance in Australian canola cultivars. However, the likelihood of shifts in pathogen race structure across different geographical locations may have implications for the long-term durability of such associations.

Early effects of gamma rays and protons on human melanoma cell viability and morphology.

The effects of irradiation with gamma rays and protons on HTB140 human melanoma cell morphology and viability were analyzed. Exponentially growing cells were irradiated close to the Bragg peak maximum of the 62-MeV proton beam, as well as with (60)Co gamma rays, with doses ranging from 8 to 24 Gy. The overall cell morphology was unchanged 6 and 48 h after gamma irradiation, also showing a relatively weak cell-inactivation level. After exposure to proton beam, considerable changes in cell morphology followed by stronger cell inactivation were achieved. Proliferation capacity of irradiated cells significantly decreased in both experimental set-ups. Higher ionization level of protons with respect to gamma rays, representing the main physical difference between these two types of radiation, was also revealed on the cell membrane level through larger pro-apoptotic capacity of protons.

Characterisation of MCP-600D and MCP-700D thermoluminescence detectors and their applicability for photoneutron detection.

This paper presents the characteristics of two high-sensitive LiF:Mg,Cu,P thermoluminescence detectors (TLDs) named MCP-600D and MCP-700D [thermoluminescence detector (TLD) Poland]. Furthermore, the applicability of both detectors used as a paired system for photoneutron detection in a high-energy photon field at a linear accelerator is shown. For MCP-600D and MCP-700D, the batch homogeneity is within 22 and 14%, respectively (2 SD). Correction for the individual response of each TLD leads to a reproducibility of 5 and 4%, respectively Both TLD types reveal a linear detector response to dose up to 4 Gy. The energy dependence for both is within 2% for 4 and 6 MV photons. For a 15 MV photon beam, the MCP-600D shows a higher response (10%); compared with the MCP-700D (2%). The MCP-600D is capable of detecting extra doses due to photoneutrons in a 15 MV photon exposure; however, the signal for an open field of the used linear accelerator is in the order of the reproducibility. Using a kind of albedo technique allows detection of photoneutrons in the open photon field anyhow. The neutron detection limit is 10 microGy neutron dose per 1 Gy photon dose. Reproducibility of the TLDs, however, requires more than 10 detectors to determine results with an uncertainty of <5%.

Triple-way therapeutic approach for paraganglioma-dependent erythrocytosis: drugs and surgery plus "multi-manner" apheresis.

Paragangliomas are tumors arising from the extra-adrenal paragangliar neural crest cells. The sympathoadrenal neuroendocrine system consists of extra-adrenal paragangliar cellular layer along the paravertebral and para-aortic axis, and the adrenal medullae. Paraganglioma should be included in the differential diagnosis of secondary erythrocytosis due to its possible ectopic erythropoietin (EPO) secretion. Thus, in this report we present a 24-year-old female patient with onset of unregulated ectopic EPO secretion, and consecutive erythrocytosis followed by hypertension, secondary to paraganglioma of multifocal retroperitoneal localization. Clinical, laboratory, and radiological investigations confirmed both an elevated EPO level and the presence of multiple paraganglioma. This paraneoplastic-mediated medical condition with high risk of cellular hyperviscosity syndrome (CHVS) requires prompt diagnosis and rapid therapeutic interventions. Initially, simple phlebotomy procedures were used; following that, tumors were surgically removed. In the course of the disease, this tumor relapsed, and urgent apheresis, as a treatment of life-threatening state, was used. The therapy performed resulted in a rapid blood viscosity depletion and a significant (P < 0.01) serum EPO reduction, as well as the general clinical benefit. Therefore, we conclude that the use of our own "multi-manner" apheresis (erythrocythapheresis plus plasma exchange), for long-time interval (until further causative therapy), effectively cross-bridged the possible hazards of EPO-dependent CHVS.

Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance.

The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three "hot spots" at 400x magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF-positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three "hot spots". There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (> or = 15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma.

Immunophenotypic profile and clinical characteristics in patients with advanced stage mantle cell lymphoma.

The objective of this study was to evaluate immunophenotypic profile along with clinical follow-up in patients with advanced stage mantle cell lymphoma (MCL), and their possible influence on overall survival (OS). Bone marrow (BM) cell and/or peripheral blood mononuclear cell flow cytometric analyses of the following antigens were performed: HLA-DR, CD19, CD20, CD22, CD23, CD25, CD10, SmIg, kappa, lambda, CD79b, CD38, FMC7, CD3, CD2, and CD5. There were 14 patients in IV CS, and 26 patients in CS V. All patients were treated with CHOP. Immunological markers showed a typical phenotype (CD5+ CD23-, Cyclin D1) in all cases. Pathohistological type of BM infiltration was predominantly diffuse (72.5%), and in remainder of patients, nodular. Comparison of patients with leukemic phase of MCL with CSIV (BM), has shown significantly higher expression of CD19, CD20, and CD23, followed by permanently negative expression of CD23. Patients with blastic variant of MCL had higher expression of CD23, compared to typical MCL (P < 0.001). Median OS was 20 months, and there were no significant OS-differences between CS IV and leukemic phase patients. Survival analyses showed that negative prognostic influence had high IPI (P < 0.01), presence of extranodal localization (P < 0.01), and diffuse type of BM involvement (P < 0.01). Using Cox regression according to OS, IPI had independent prognostic value (P < 0.001). Our results demonstrated that in the advanced MCL patients the most powerful prognostic factor was IPI, while extranodal localization and type of BM infiltration were of a limited value.

Elevated serum dipeptidyl peptidase IV activity in patients with chronic tonsillitis.

BACKGROUND: Palatine tonsils represent the first place of contact for a variety of antigenic substances present in air and food. Upon antigen stimulation, the interactions between T and B lymphocytes in the tonsil are known to depend on the expression of different co-stimulatory molecules, including proteolytic ectoenzymes. Dipeptidyl peptidase IV (DPP IV) and aminopeptidase N (APN), as T lymphocyte co-stimulatory molecules, participate in the regulation of the immune response during inflammation. METHODS: In this study, the serum and lymphocyte enzymatic activity of DPP IV and APN was investigated in 32 patients, 13 with recurrent tonsillitis (RT) and 19 with tonsillar hypertrophy (TH), before and one month after tonsillectomy. The enzymatic activity of DPP IV and APN in tonsillar lymphocytes and serum was determined kinetically at 37 degrees C using Gly-Pro-p-nitroanilide (for DPP IV) and Ala-p-nitroanilide (for APN) as chromogenic substrates. RESULTS: Significantly higher serum DPP IV and APN activities (P<0.001) were found in TH patients compared with those with RT before tonsillectomy. DPP IV activity in TH patients was also elevated compared with the control of the same age (P<0.001), whereas the activity of APN was the same as the control group. The activity of both enzymes was the same as of controls after tonsillectomy. In addition, the results show that DPP IV and APN activities in serum decrease significantly with age. Tonsillar lymphocytes demonstrated a wide range of DPP IV and APN activities without significant differences between the investigated groups. CONCLUSION: An increased serum DPP IV activity was observed in TH patients compared with both RT patients and controls before tonsillectomy. After tonsillectomy, all activities were similar. The results suggest that serum DPP IV activity may have potential as a diagnostic marker for patients with TH.