Time has come to include Human Papillomavirus (HPV) testing in sperm donor banks.

HPV is well known as a potential cause of cervical cancer. Less well known is its link to temporal subfertility that is caused by binding of infectious virions to the spermatozoa's head which induces sperm-DNA damage and causes a reduction in clinical pregnancy rates in women receiving HPV positive semen. This impact on the global fertility burden remains greatly underestimated and underexplored. This risk of reduced fertility due to infectious HPV in sperm is especially important when donor sperm insemination is considered, since testing for the presence of HPV virions before use seems warranted. We tested 514 donor sperm samples from 3 different sperm banks for 18 different HPV types. Overall 3.9% (20/514) of tested donor sperm was positive for HPV, with different prevalence among the 3 different sperm banks (3.6% bank A, 3.1% bank B and 16.7% bank C). Also the HPV virion per spermatozoon ratio in donor samples was similar across the different sperm banks (95% CI 0,01 to 1,07 HPV virions/spermatozoon). When HPV positive donor sperm was used, no clinical pregnancies resulted, whereas when HPV negative donor sperm was used the clinical pregnancy rate was 14.6%. From both a cost/benefit and a safety point of view we recommend that donor sperm should always be tested for HPV before using it for insemination.

Morphometrical analysis of preantral follicular survival of VEGF-treated bovine ovarian cortex tissue following xenotransplantation in an immune deficient mouse model.

The increasing number of cancer survivors the past decades, has sparked the need for fertility preservation strategies. Due to predominantly ethical constraints, human research material is scarce. A bovine in vitro model is a valuable alternative. Therefore, the following objectives were defined: 1) to xeno-graft bovine ovarian cortex tissue in immune deficient mice as a study-model for female fertility preservation strategies; 2) to stereologically quantify vascularization in Vascular Endothelial Growth Factor (VEGF)-treated and non-treated tissue; 3) to study preantral follicular survival in situ, after xenotransplantation. Bovine ovarian tissue strips were incubated with or without VEGF prior to grafting into female, neutered BALB/c-nu mice (n=16). Non-transplanted cortical tissue was used as a control. At time zero (control), two (2 weeks) and four (4 weeks) weeks after transplantation, grafts were retrieved and assessed by von Willebrand Factor and caspase-3 immunostaining. Data were analyzed using a linear mixed model. In the VEGF+ grafts, 31% of the follicles were considered 'alive' 2 weeks after transplantation, compared to only 17% in the VEGF- grafts (P<0.05). However, no difference could be detected 4 weeks after transplantation (P=0.76) with less follicles being considered 'alive' after transplantation (22%), compared to the control (47.5%) (P<0.05). Finally, the vascular surface density was significantly less in the grafts, irrespective of the transplantation period or the use of VEGF. Although the transplantation process overall negatively influenced the number of viable follicles and vascular density, VEGF exposure prior to transplantation can favor follicle survival during a 2 weeks transplantation period.

Human Papillomavirus (HPV) virion induced cancer and subfertility, two sides of the same coin.

In the natural history of HPV infections, the HPV virions can induce two different pathways, namely the infec- tious virion producing pathway and the clonal transforming pathway. An overview is given of the burden that is associated with HPV infections that can both lead to cervical cancer and/or temporal subfertility. That HPV infections cause serious global health burden due to HPV-associated cancers is common knowledge, but that it is also responsible for a substantial part of idiopathic subfertility is greatly underestimated. The bulk of the detected HPV DNA whether in men or women is however infectious from origin. Because the dissociation between HPV viruses and HPV virions or infection and disease remains difficult for clinicians as well as for HPV detection, we propose a review of the different effects caused by the two different HPV virion induced pathways, and highlight the mechanisms that are responsible for causing transient subfertility and cancer.

In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes.

OBJECTIVE: Depression is accompanied by activation of immuno-inflammatory and oxidative and nitrosative stress (IO&NS) pathways, and increased IgM/IgA responses to lipopolysaccharide (LPS) of gram-negative commensal bacteria. The latter suggests that bacterial translocation has caused IgM/IgA responses directed against LPS. Bacterial translocation may drive IO&NS responses. METHOD: To examine the associations between IgM/IgA responses to LPS and IO&NS measurements, including plasma/serum interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin, lysozyme, oxidized LDL (oxLDL) antibodies, peroxides, and IgM (auto)immune responses against malondialdehyde (MDA), azelaic acid, phophatidyl inositol (Pi), NO-tryptophan and NO-tyrosine in depressed patients and controls. RESULTS: We found significant positive associations between IgM/IgA responses to LPS and oxLDL antibodies, IgM responses against MDA, azelaic acid, Pi, NO-tryptophan, and NO-tyrosine. The IgA responses to LPS were correlated with lysozyme. There were no significant positive correlations between the IgM/IgA responses to LPS and IL-1 and neopterin. CONCLUSION: The findings show that in depression there is an association between increased bacterial translocation and lysozyme production, an antibacterial compound, O&NS processes, and autoimmune responses directed against O&NS generated neoantigenic determinants. It is suggested that bacterial translocation may drive IO&NS pathways in depression and thus play a role in its pathophysiology.

Unravelling the needs of singly in vitro-produced bovine embryos: from cumulus cell co-culture to semi-defined, oil-free culture conditions.

Producing bovine in vitro embryos individually is a challenge as it generally leads to impaired embryo development. Earlier research optimised a single embryo in vitro production (IVP) protocol using serum, cumulus cells and oil during culture. As some of these factors are undesirable in certain circumstances, the present study investigated their necessity and possible interactions, and defined their role during single-embryo culture. Although the cumulus cell monolayer produced progesterone, it appeared not to be a key factor in supporting single-embryo development. Because in vitro culture in large medium volumes was shown to impair single-embryo development, two new oil-free culture protocols were tested. Using a 30-µL droplet of medium in 96-well plates with a small surface area resulted in comparable blastocyst rates to those obtained under oil. When serum was used, co-culture with cumulus cells seems necessary, leading to consistently high blastocyst rates. Finally, a serum-free, oil-free culture system using insulin, transferrin, selenium and BSA resulted in embryos with similar total cell numbers and apoptotic cell ratios, but blastocyst rates did not equal those obtained with serum and co-culture. This research additionally stresses the fact that specific interaction mechanisms between somatic cells and a developing in vitro embryo are far from unravelled.

Combination of serum markers related to several mechanisms in Alzheimer's disease.

Alzheimer's disease (AD) probably involves several pathobiochemical mechanisms and this may be reflected by changes in different serum components. The present study investigated whether the combined analysis of serum molecules related to different mechanisms improves the discrimination of AD patients from healthy controls. Serum of patients with AD was analyzed for a broad spectrum of marker molecules, including 11 inflammatory proteins, 12 sterol intermediates and phytosterols, 2 brain-specific proteins and 4 constituents involved in homocysteine homeostasis. The serum molecule concentrations were combined in a logistic regression model, using a forward stepwise inclusion mode. The results showed that the combination of interleukin-6 (IL-6) receptor, protein alpha1 fraction, cysteine and cholesterol concentrations improved the discrimination between AD patients and healthy controls compared to the single markers. In conclusion, the results of this study have shown that the complex pathology in AD is reflected in a pattern of altered serum concentrations of several marker molecules related to several pathobiochemical mechanisms.

Interleukin (IL)-6, IL-8 and IL-10 in serum and CSF of Trypanosoma brucei gambiense sleeping sickness patients before and after treatment.

Serum and cerebrospinal fluid (CSF) concentrations of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-alpha and interferon-gamma were determined in 46 Trypanosoma brucei gambiense sleeping sickness patients in DR Congo, before and after treatment. According to their CSF cell number before treatment, patients were classified as early-stage (0-5 cells/microL), intermediate-stage (6-20 cells/microL) or late-stage patients (> 20 cells/microL). In serum, slightly higher IL-8 concentrations were found in early-stage patients compared to intermediate- or late-stage patients. These high IL-8 levels dropped after treatment. Higher IL-10 concentrations were detected in serum of patients in intermediate or late stage compared to early-stage patients. In both intermediate- and late-stage groups, serum IL-10 decreased after treatment. In CSF, elevated concentrations of IL-6, IL-8 and especially of IL-10 were observed in late-stage T. b. gambiense patients. After treatment, these concentrations dropped to levels similar to those of the other patients. Tumour necrosis factor-alpha was detected only in a few serum and CSF samples, which were scattered over the different patient groups. Interferon-gamma was detected in serum of 5 patients and remained undetectable in CSF.

Platelet alpha2-adrenoceptor density in humans: relationships to stress-induced anxiety, psychasthenic constitution, gender and stress-induced changes in the inflammatory response system.

BACKGROUND: This study examined the effects of psychological stress on platelet alpha2-adrenergic receptor (alpha2-AR) binding sites in relation to stress-induced anxiety and changes in the inflammatory response system (IRS). METHODS: The maximum number of binding sites (Bmax) and their affinity (Kd) for [3H]rauwolscine, a selective alpha2-AR antagonist, and the stimulated production of tumor necrosis factor-alpha (TNFalpha), the Th1-like cytokine, interferon-gamma (IFNgamma), and the Th2-like cytokines, interleukin-10 (IL-10) and IL-5, were measured in 35 university students a few weeks before (baseline) as well as on the day before a difficult, oral examination (stress condition). The State-Trait-Anxiety Inventory (STAI) was recorded during both conditions. The Minnesota Multiphase Personality Inventory (MMPI-2) was used to assess psychasthenia (Scale 7). RESULTS: Academic examination stress induced a significant increase in alpha2-AR density in students whose STAI scores increased in the stress period, in female students and in students who scored higher on psychasthenia. There were significant and positive correlations between stress-induced anxiety and changes in alpha2-AR density. Stress-induced anxiety was accompanied by a pro-inflammatory and Th1-like response, i.e. increased IFNgamma and TNFalpha production. The stress-induced changes in platelet alpha2-AR density were significantly and positively related to the production of TNFalpha, IL-10 and IL-5 and negatively to that of IFNgamma. CONCLUSIONS: Subchronic psychological stress in humans induces increased alpha2-AR density, which is related to stress-induced anxiety, an anxiety-prone constitution and female sex. Increased alpha2-AR density is accompanied by a Th2-like response and increased TNFalpha production. The results suggest that: (i) alpha2-AR density is sensitive to graded differences in stress-induced anxiety; and (ii) psychological stress is accompanied by intertwined responses in the catecholaminergic system, such as alpha2-ARs, and the IRS, such as Th1/Th2-like functions and the production of TNFalpha.

Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy.

The relationship between immune activation and the development of early depressive symptoms were studied in 33 cancer patients undergoing cytokine therapy. Patients were treated either with subcutaneous IL-2 administered alone (n=13) or in association with IFN-alpha (n=5), or with IFN-alpha alone administered subcutaneously at low doses (n=5) or intravenously at high doses (n=10). The intensity of depressive symptoms was assessed during a clinical interview carried out before the start of cytokine therapy and five days later using the Montgomery and Asberg Depression Rating Scale (MADRS). On the same days, blood samples were collected for each patient to measure serum concentrations of cytokines (IL-6, IL-10, IL-1ra) and cytokine-receptors (sIL-2R, LIF-R). Results showed that patients treated with IL-2 or IL-2+IFN-alpha displayed concomitant mood symptoms and increased serum cytokine levels during treatment. In these patients, the intensity of depressive symptoms at endpoint was positively correlated with the increases measured in serum levels of IL-10 between baseline and endpoint. IL-10 is an anti-inflammatory cytokine that is produced in response to the production of pro-inflammatory cytokines, and thereby reflects an inflammatory response. These results support the hypothesis of close relationship between depressive symptoms and the activation of the cytokine network.

Insertion or deletion of the Cheo box modifies radiation inducibility of Clostridium promoters.

Radiation-inducible promoters are being used in many viral vector systems to obtain spatial and temporal control of gene expression. It was previously proven that radiation-induced gene expression can also be obtained in a bacterial vector system using anaerobic apathogenic clostridia. The effect of radiation inducibility was detected using mouse tumor necrosis factor alpha (mTNF-alpha) as a model protein under regulation of the radiation-inducible recA promoter. In this report, experiments are described in which this recA promoter was modified in order to increase radiation responsiveness. Incorporation of an extra Cheo box in the recA promoter region resulted in an increase in mTNF-alpha secretion from 44% for the wild-type promoter to 412% for the promoter with an extra Cheo box after a single irradiation dose of 2 Gy. Deletion of the Cheo box in the promoter region eliminated radiation inducibility. These results prove that the Cheo box in the recA promoter is indeed the radiation-responsive element. We also tested whether we could induce the constitutive endo-beta-1,4-glucanase promoter (eglA) via ionizing irradiation by introducing a Cheo box in the promoter region. While the use of the constitutive promoter did not lead to an increase in mTNF-alpha secretion after irradiation, the introduction of a Cheo box resulted in a 242% increase in mTNF-alpha secretion. Reverse transcriptase PCR of RNA samples isolated from irradiated and nonirradiated bacterial cultures demonstrated that the increase in secretion was the result of enhanced transcription of the mTNF-alpha gene.

Radio-responsive recA promoter significantly increases TNFalpha production in recombinant clostridia after 2 Gy irradiation.

One of the major problems with gene therapy today is the lack of tumour specificity. The use of anaerobic apathogenic clostridia as a gene transfer system can target anoxic areas within the tumour. These bacteria can be genetically modified to express therapeutic proteins such as TNFalpha locally in the tumour. As shown in our results, ionising irradiation can be used in clostridia to activate genes encoding cytotoxic agents under control of a radiation-inducible promoter. A 44% significant increase (P < 0.05) in TNFalpha secretion was seen 3.5 h after a single dose of 2 Gy. A second dose of 2 Gy was also capable of repeating gene activation and gave a significant increase of TNFalpha production of 42% (P < 0.05). These results provide evidence that spatial and temporal control of gene expression can be achieved using a radio-inducible promoter. Repetitive gene activation was feasible with a second dose of 2 Gy, indicating that fractionated radiotherapy could lead to repeated gene induction resulting in prolonged and enhanced protein expression. Gene targeting by ionising radiation could thus provide a new means of increasing the therapeutic ratio in cancer treatment.

Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression.

BACKGROUND: There is now evidence that the availability of plasma tryptophan is decreased during pregnancy and the puerperium and also in patients with major depression and inflammation. The aims of the present study were to examine: (i) the effects of pregnancy and delivery on plasma tryptophan and the amino acids known to compete for the same cerebral uptake mechanism (CAAs), valine, leucine, tyrosine, phenylalanine and isoleucine; (ii) the relationships between the availability of plasma tryptophan and postpartum depression or anxiety; and (iii) the relationships between the availability of plasma tryptophan to the brain and inflammatory markers, such as serum interleukin-6 (IL-6), interleukin-1 receptor-antagonist (IL-1RA) and the leukaemia inhibitory factor receptor (LIF-R). METHODS: The above variables were measured in 13 healthy non-pregnant and in 98 pregnant women 3 to 6 days before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the state version of Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). RESULTS: Plasma tryptophan and the tryptophan/CAA ratio were significantly lower at the end of term and after delivery than in the plasma of non-pregnant, healthy women. The tryptophan/CAA ratio was significantly lower in the early puerperium than at the end of term. There were no significant relationships between the availability of plasma tryptophan and either post-partum depression or changes in the STAI or ZDS scores in the early puerperium. The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R. CONCLUSIONS: The results show that the reduction in the availability of plasma tryptophan from the end of term to the early puerperium is related to immune activation; and that the lowered availability of plasma tryptophan is not related either to depressive or anxiety symptoms in the early puerperium or to post-partum depression ensuing some months later.

Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis.

There is now evidence that major depression is accompanied by activation of the inflammatory response system (IRS) as indicated by an increased production of pro-inflammatory cytokines. There is circumstantial evidence implicating pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha) in the pathogenesis of multiple sclerosis (MS). The aims of the present study were to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-8, TNFalpha, IL-2 receptor (IL-2R) and CC16 (uteroglobulin), an endogenous anti-cytokine, in depressed and MS patients compared to normal controls, and (ii) the effects of treatment with antidepressants on the above IRS variables in depressed patients. Serum TNFalpha was significantly higher in depressed and MS patients than in normal controls. Serum IL-8 was significantly higher in depressed patients than in patients with MS. Serum CC16 was significantly higher in patients with MS than in normal controls and depressed patients. Nonresponders to treatment with antidepressants had significantly higher serum IL-2R and lower serum CC16 concentrations than responders to treatment. The results show that (i) depression is accompanied by activation of the IRS and that this activation is more pronounced in depression than in MS, and (ii) IRS activation in depressed patients is related to a nonresponse to treatment with antidepressants.

The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system.

BACKGROUND: There is now evidence that some patients with major depression show an activation of the inflammatory response system (IRS). This study was carried out to examine whether major depression may induce sensitization with increased IRS responses to the stress of child birth. METHODS: Serum concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R), sgp130 (the IL-6 signal transducing protein) and the sIL-1R antagonist (sIL-1RA) were determined in 16 and 50 women with and without a lifetime history of major depression, respectively. Blood was collected 3-6 days before delivery and 1 and 3 days after delivery. On each occasion the women completed the Zung Depression Rating Scale (ZDS). RESULTS: Serum IL-6, sIL-6R, sIL-1RA were significantly higher 1 and 3 days after delivery than before. Women who had suffered from a lifetime history of major depression had greater increases in serum IL-6 and sIL-1RA in the early puerperium than women without a lifetime history. Women who had suffered from a lifetime history of major depression had significantly higher IL-6, and sIL-1RA concentrations 1 and 3 days after delivery than women with a negative life-time history. CONCLUSIONS: The responses of IL-6 and sIL-1RA following delivery are amplified in women who previously suffered from major depression. The results suggest that major depression is accompanied by a sensitization of the IRS.

Improvement of Clostridium tumour targeting vectors evaluated in rat rhabdomyosarcomas.

Previous studies have demonstrated the feasibility of using apathogenic clostridia as a promising strategy for hypoxia-specific tumour targeting. The present study shows that the use of the vascular targeting compound combretastatin A-4 phosphate could significantly (P<0.001) increase the number of Clostridium vegetative cells in rat rhabdomyosarcomas with sizes between 0.2 cm(2) and 3 cm(2). Furthermore, this study showed that administration of metronidazole for a 9-day period was sufficient to eliminate systemically administered Clostridium from the tumour. Moreover, previous Clostridium spore administration did not effect tumour colonisation, regardless of the immune response status of the host.

Immunological differences between patients with major depression and somatization syndrome.

There is some evidence that major depression is accompanied by activation of the inflammatory response system (IRS). There is also evidence that proinflammatory cytokines and induction of IRS activation are associated with sickness behavior in experimental animals. However, no research has examined the IRS in somatization disorder. The aim of this study was to examine possible immunological differences between major depression, somatization and healthy controls. We measured the following IRS variables in patients with major depression (n=36), somatization syndrome (SSI-8; n=37), major depression and somatization (n=40) and healthy controls (n=37): interleukin-6 (IL-6); interleukin-1-receptor-antagonist (IL-1RA); plasma soluble interleukin-6 receptor (IL-6R); soluble suppressor/cytotoxic antigen (CD8); leukemia inhibitory factor (LIF-R); and Clara cell protein (CC16), an endogenous anticytokine. Serum CD8 concentrations were significantly increased in patients with major depression compared with concentrations in patients with somatization syndrome, whereas concentrations in normal controls were intermediate between those of the two groups of patients. Serum CC16 was significantly lower in major depression than in healthy controls. The highest CC16 scores were found in patients with somatization syndrome. Somatizing patients have significantly lower serum IL-6 values than normal controls and depressed patients. The present results indicate (1) an activation of the IRS in depression with signs of T-cell activation (increased CD8), monocytic activation (IL-1RA) and a lowered anti-inflammatory capacity of the serum (lower CC16) and (2) an immune alteration in somatizing syndrome, such as monocytic activation (increased IL-1RA) and indicators of lowered T-lymphocytic activity (lowered CD8 and IL-6). These results suggest different immune alterations in somatization syndrome and depression.

Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy.

There is some evidence that treatment with interleukin-2 (IL-2) and interferon-alpha (IFNalpha) frequently induces depressive symptoms and activation of the inflammatory response system (IRS). There is evidence that major depression is accompanied by lowered serum activity of dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5), a membrane-bound serine protease which catalyses the cleavage of some cytokines and neuro-active peptides and which modulates T cell activation and the production of cytokines, such as IL-2. This study was carried out to examine the effects of immunochemotherapy with IL-2 and IFNalpha, alone and together, in cancer patients on serum DPP IV activity in relation to changes in depressive symptoms and the IRS. The Montgomery and Asberg Rating Scale (MADRS), serum DPP IV activity, and the serum IL-6, and IL-2 receptor (IL-2R) concentrations were measured in 26 patients with metastatic cancers before and three and five days after treatment with IL-2 and IFNalpha, alone or together. Treatment with IL-2 with or without IFNalpha significantly suppressed serum DPP IV activity. The MADRS scores were significantly elevated by treatment with IL-2 with or without IFNalpha, but not IFNalpha alone. The immunochemotherapy-induced decreases in serum DPP IV were significantly and inversely correlated with the increases in the MADRS. Treatment with IL-2 alone or combined with IFNalpha also elevated serum IL-6 and IL-2R. There were significant and inverse correlations between the immuchemotherapy-induced decreases in serum DPP IV and the elevations in serum IL-6 or IL-2R. In conclusion, treatment with IL-2/IFNalpha decreases serum DPP IV activity within 3-5 days and the immunochemotherapy-induced decreases in serum DPP IV activity are significantly and inversely related to treatment-induced increases in severity of depression and signs of activation of the IRS.

The effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products.

There are some reports that catecholamines may modulate the production of monocytic cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha). The present study was carried out in order to examine the effects of noradrenaline (10(-5), 10(-6) and 10(-7) M), clonidine (10(-5), 10(-6) and 10(-7) M), an alpha2-adrenoceptor agonist, and yohimbine (10(-5), 10(-6) and 10(-7) M), an alpha 2-adrenoceptor antagonist, on the production of IL-6, the IL-1 receptor antagonist (IL-1RA) and TNF alpha by stimulated whole blood of normal humans. We measured the in vitro production of IL-6, TNF alpha and IL-1RA by stimulated (phytohemagglutinin+lipopolysaccharide), diluted whole blood of 16 normal volunteers. The results show that noradrenaline, 10(-5) M, significantly suppressed the production of IL-6; noradrenaline, 10(-5) and 10(-6) M, significantly suppressed the production of IL-1RA and TNF alpha; clonidine, 10(-5) M, significantly suppressed the production of TNF alpha; and yohimbine, 10(-5) and 10(-6) M, significantly suppressed the production of IL-1RA. It is concluded that (1) noradrenaline has significant negative immunoregulatory effects in humans through suppression of the production of (monocytic) proinflammatory cytokines, e.g. IL-6 and TNF alpha, and (2) the suppression of the production of TNF alpha may be related to alpha(2)-adrenoceptor-related mechanisms.

Plasma levels of interleukin-6, interleukin-10, and interleukin-1 receptor antagonist in depression: comparison between the acute state and after remission.

There is now some evidence that major depression is accompanied by an immune response with an increased production of pro-inflammatory cytokines. The aim of the present study was to examine serum level of cytokines: interleukin-6 (IL-6), which is considered pro-inflammatory one and anti-inflammatory cytokines: interleukin 10 (IL-10), and interleukin-1 receptor antagonist (IL-1Ra) in acute clinical state of depression and after 6-week antidepressant treatment. Serum IL-6, IL-10, IL-1Ra levels were higher in the subjects with major depression than in normal controls although these results were not statistically significant. The mean score according to the Hamilton Depression Rating Scale (HDRS) in the patients significantly decreased during the 6 weeks of the study, demonstrating an overall improvement. Successful antidepressant treatment had no significant effect on serum level of this cytokines.

Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides.

Dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) is a serine type protease with an important modulatory activity on a number of chemokines, neuropeptides and peptide hormones. It is also known as CD26 or adenosine deaminase (ADA; EC 3.5.4.4) binding protein. DPPIV has been demonstrated on the plasmamembranes of T cells and activated natural killer or B cells as well as on a number of endothelial and differentiated epithelial cells. A soluble form of CD26/DPPIV has been described in serum. Over the past few years, several related enzymes with similar dipeptidyl peptidase activity have been discovered, raising questions on the molecular origin(s) of serum dipeptidyl peptidase activity. Among them attractin, the human orthologue of the mouse mahogany protein, was postulated to be responsible for the majority of the DPPIV-like activity in serum. Using ADA-affinity chromatography, it is shown here that 95% of the serum dipeptidyl peptidase activity is associated with a protein with ADA-binding properties. The natural protein was purified in milligram quantities, allowing molecular characterization (N-terminal sequence, glycosylation type, CD-spectrum, pH and thermal stability) and comparison with CD26/DPPIV from other sources. The purified serum enzyme was confirmed as CD26.