Metabolic syndrome in type 1 diabetes mellitus. Does it have any impact on the course of pregnancy?

UNLABELLED: To determine whether the symptoms of metabolic syndrome (MS), if accompanied by oxidative stress (OS), in type 1 diabetes mellitus (DM) patients could affect the course of pregnancy and the perinatal outcome. Oxidized low density lipoproteins (ox-LDL) and total lipid peroxides (TLP) were studied in 98 pregnant women with type 1 DM in the I(st) and III(rd) trimesters. 24% of the participants met the criteria of MS. Vascular complications were significantly more frequent in the MS-group (41.9% vs. 17.4% in the non-MS group, p<0.05). No differences in the markers of OS between the MS and the non-MS groups were noted in either the I(st) or the III(rd) trimester. A significant gestational rise in Per-Ox was found in both groups. Chronic hypertension was associated with significant differences in ox-LDL levels in both the I(st) and III(rd) trimester. No differences in perinatal outcome, as measured by abnormal birth weight or poor neonatal status (Apgar score<6, umbilical venous and/or arterial pH<7.20), were found. CONCLUSIONS: 1) MS in type 1 DM is associated with some changes in markers of oxidative stress, but it poses no additional risk to the course of pregnancy and perinatal outcome in properly controlled and treated pregnant women with type 1 DM. 2) Maternal hypertension is the only component of MS in diabetic pregnancy that is associated with significant changes in markers of oxidative stress. 3) MS is significantly more frequent in diabetic pregnant women with co-existing vascular complications and obesity.

Concentration of chemokines in peripheral blood in first trimester of diabetic pregnancy.

BACKGROUND: Several types of regulators (i.e. chemokines and metalloproteinases) are considered to play a crucial role in pregnancy by local modulation of the immune system at the level of peripheral leukocytes. The aim of this study was to determine whether changes in chemokines (interferon-gamma-inducible protein (IP-10), monocyte chemotactic peptide-1(MCP-1), cytokines regulated upon activation normal T cell expressed and secreted (RANTES) and matrix metalloproteinase-9 (MMP-9)) concentrations in diabetic patients could affect the course of pregnancy. METHODS: The study group consisted of 65 diabetics in the first trimester of pregnancy. Some 47 pregnancies were successfully continued to delivery, 18 were terminated with spontaneous miscarriages. Twenty healthy women matched for gestational age served as a control group. RESULTS: Glycated haemoglobin (HbA1C), vascular complications and lipoproteins (cholesterol, HDL-cholesterol, low density lipoprotein (LDL)-cholesterol and triglicerides) concentrations in maternal blood did not influence the chemokines concentrations. Lower RANTES level and higher MMP-9 concentrations were found in diabetic women. MCP-1 and RANTES levels differed significantly between pregnancies with good and poor perinatal outcome. A logistic regression model revealed that not only duration of diabetes, age of patients, HbA1C and insulin requirements, but also MMP-9,RANTES, MCP-1 and LDL-cholesterol levels seem to be involved in first trimester metabolism. CONCLUSIONS: Our results suggest the possible role of chemokines in early pregnancy development, especially in well-controlled diabetic patients, when hyperglycaemia is unlikely to be the main reason for an unfavourable outcome. Our results show that MCP-1 and RANTES might serve as predictive factors for an unfavourable outcome in diabetic pregnancy, whereas MMP-9 seems to be a marker of immunological changes related to mild hyperglycaemia. However, the open question of how the modulation of chemokines concentrations might be applied to prevent miscarriage in diabetic patients remains.

In vivo effect of interferon-beta 1a on interleukin-12 and TGF-beta(1) cytokines in patients with relapsing-remitting multiple sclerosis.

We have studied in vivo effect of interferon-beta 1a (IFN-beta 1a) (6 MIU once weekly i.m.) on interleukin-12 (IL-12) and transforming growth factor-beta(1) (TGF-beta(1)) serum levels during 6 months of therapy in group of 20 patients with relapsing-remitting multiple sclerosis (MS). IL-12 and TGF-beta(1) concentrations were measured by enzyme linked immunoabsorbent assay (ELISA). There was a significant increase of IL-12 levels in MS patients in comparison with control group, suggesting a role of this cytokine in immunity of MS. We have also found a significant increase of TGF-beta(1) levels after 6 months of therapy with IFN-beta 1a, however, there was no in vivo effect of the therapy on IL-12 levels. The results suggest that IFN-beta 1a may exert its action through up- regulation and increase secretion of TGF-beta(1).

Biological markers to confirm diagnosis and monitor the therapy in multiple sclerosis patients.

In patients suspected of multiple sclerosis (MS), even in the case of MRI positive changes, cerebrospinal fluid (CSF) analysis is of great practical value. Until now, however, only IgG index, restricted oligoclonal IgG bands and the examination of IgG subclasses have been of practical value. The determination of other immunological markers is too expensive to be introduced into laboratory diagnostic standards in MS. However, the clinical trials should be monitored by a large set of markers of MS activity, including the estimation of anti MBP antibodies, presence of MBP material in the CSF and concentration of sVCAM-1, ICAM-1, PECAM-1 in CSF and serum.

[Surface CD2, CD4, CD8 markers and IL-2 and TNF-alpha cytokines in amyotrophic lateral sclerosis]. / Markery powierzchniowe CD2, CD4, CD8 oraz cytokiny: IL-2 i TNF-alpha w stwardnieniu bocznym zanikowym.

The cause of amyotrophic lateral sclerosis is still unknown. In the paper CD2, CD4 and CD8 markers on mononuclear cells as well as levels of TNF-alpha and IL-2 in sera from 15 patients with ALS were evaluated. There was a significant increase of TNF-alpha in sera of ALS patients in comparison with control group. This is the first such observation. It supports the concept that immune mechanisms may play a role in the pathogenesis of ALS.

[Chemokines MIP-1 and MCP-1 and patients with multiple sclerosis treated with interferon beta-1a]. / Chemokiny: MIP-1 alpha oraz MCP-1 u pacjentów ze stwardnieniem rozsianym leczonych interferonem beta-1a.

Chemokines: MCP-1 and MIP-1 alpha may play an important role in the pathogenesis of multiple sclerosis, influencing migration of lymphocytes to the CNS. One of possible mechanisms of interferon beta action may be an effect on chemokines. We measured MCP-1 and MIP-1 alpha chemokines in sera of 24 patients with MS treated with interferon beta-1a before and after 3 months of therapy and in 15 control patients. There was a significant increase of MIP-1 alpha concentration in sera of MS patients in comparison with control group. After 3 months of therapy with interferon beta-1a, MIP-1 alpha and MCP-1 levels did not differ from the values before therapy. Investigations will be continued after longer time of treatment with interferon beta.

[Immunological markers of disease activity in the course of 2-CDA treatment of multiple sclerosis]. / Immunologiczne markery aktywnosci choroby w przebiegu leczenia kladrybina stwardnienia rozsianego.

52 clinically definite multiple sclerosis (MS) patients were treated with subcutaneous injection of 5 mg 2-CDA in 5 consecutive days. The injection courses were repeated 6 times in one month interval. The MRI pattern and immunological markers were studied in serum and CSF before and after 6 months of treatment. The obtained results suggest that treatment with 2-CDA has not any significant effect on humoral immunological events in multiple sclerosis, what is in contrast to some normalization of cellular immunopathological processes.

[The effect of large dose prednisone therapy on immunological markers in multiple sclerosis]. / Wplyw leczenia stwardnienia rozsianego duzymi dawkami Encortonu na humoralne markery immunologiczne.

The effect of large-dose prednisone therapy (3960 mg over 56 days) on humoral immunological markers and MRI pattern was studied in 25 patients with clinically definite multiple sclerosis. There was a decrease in levels of some studied markers (TNF in CSF, MBP level, IgG index, kappa chains in urine and kappa/creatinine ratio) after the treatment, but the differences reached statistical significance in some groups only. The decrease of total lesion area in MRI was not statistically significant. The obtained results proved clearly, that the above mentioned immunological markers might be helpful for monitoring of therapy in MS patients.

[Urine free light chains kappa in multiple sclerosis]. / Wolne lancuchy kappa w moczu w stwardnieniu rozsianym.

The evaluation of free light chains kappa in urine was performed in 77 cases of multiple sclerosis, including 52 patients before and after treatment with 2 CDA and in 25 patients before and after therapy with high doses of prednisone. The high variations in the level of free kappa chains indicate a limited diagnostic value, and only for cases with very high level. We have found effect of 2 CDA therapy in chronic progressive MS group on free kappa light chain value. A significant effect of prednisone treatment was observed in early onset cases of multiple sclerosis and in cases with clinical improvement after therapy. In conclusion, the study suggests that urinary free light chains level may be considered as one of markers for monitoring of the effect of therapy on the activity of the immunological processes in multiple sclerosis.

Diversity of V delta-J delta gene rearrangement in peripheral blood lymphocytes and intrathecal IgG synthesis in multiple sclerosis.

The object of the study is a comparison of intrathecal IgG synthesis and gamma/delta TCR genes rearrangement in multiple sclerosis. The subgroup of 13 cases with intrathecal IgG synthesis and positive oligoclonal bands was compared with 8 cases with IgG index below 0.75 and with undetectable oligoclonal bands. TCR gene rearrangement was studied in peripheral blood lymphocytes by PCR analysis. In majority of cases of the first group the V delta-J delta junctional repertoire was restricted as evidenced by oligoclonal rearrangement. Monoclonal pattern of rearrangement was also established in some cases concerning V delta 1-J delta 1 and V delta 5-J delta 1. In all cases with one exception, demonstrating IgG index < 0.75 and with negative oligoclonal bands in CSF the oligo- or polyclonal pattern of V delta-J delta gene rearrangement was noticed. It is therefore suggested that subset T and B lymphocytes may undergo clonal expansion in MS as evidenced by restricted pattern of V delta-J delta rearrangement and intrathecal oligoclonal IgG synthesis, respectively. Oligoclonal expansion at certain B and T cells may occur due to stimulation by an antigen related to MS pathogen.

The early stage of multiple sclerosis in the light of molecular and immunological studies.

The studied material consisted of patients in the first and second year from the onset of multiple sclerosis. In majority of the studied 18 cases the junctional repertoire of TCR in blood lymphocytes of patients in early phase of MS was restricted demonstrating the mono- or oligoclonal character of rearrangement in the spectrum V delta 1-J delta 1, V delta 5-J delta 1 and V delta 3-J delta 1 in contrast to overwhelming polyclonal picture in the control group. In majority of the cases oligoclonal bands were detected and IgG index was above normal level indicating on intrathecal IgG synthesis. The comparison of humoral immunological markers in the early phase of MS with the control group revealed several higher values in patients, but only concerning TNF alpha level in serum, IgG in CSF and IgG index the differences were statistically significant. After treatment with Prednisone the decrease of all studied markers was established, but significant only of free kappa chains to creatinine ratio in urine. The obtained results indicate, that the early phase of MS is characterised by the profound shift of gamma/delta TCR receptors in direction of mono- or oligoclonal bands in CSF, what may be explained by the oligoclonal expansion of certain B and T cells due to stimulation by an antigen related to MS pathogen.

Gamma/delta T cell receptor genes rearrangement in the blood and brain of multiple sclerosis patients. A preliminary study.

The characterization of TCR gamma/delta gene diversity in peripheral blood lymphocytes and in cerebral white matter of MS patients was performed. In overwhelming majority of MS cases the V delta-J delta junctional repertoire was restricted as evidenced by oligoclonal rearrangements concerning V delta 1-J delta 1, V delta 2-J delta 1, V delta 3-J delta 1, V delta 5-J delta 1. The obtained results indicate, that the restricted pattern of TCR gene rearrangement may suggest oligoclonal expansion of certain clones of gamma/delta T cells that may be involved in recognition of putative autoantigen, significant in the etiopathogenesis of MS. The very striking positive correlation between monoclonal pattern of V delta-J delta rearrangement in peripheral blood and cerebral white matter of MS patients indicate that the gamma/delta T lymphocytes play significant role in MS pathogenesis.

Limited junctional diversity of V delta 5-J delta 1 rearrangement in multiple sclerosis patients.

T-cell receptor (TCR) delta gene repertoire, as assessed by V delta-J delta rearrangements, has been analyzed in nine multiple sclerosis (MS) cases and in 30 healthy individuals by seminested PCR technique. Among the V delta-J delta junctional diversities studied, the most striking result has been observed in V delta 5-J delta 1 rearrangement. The detection of repeated V delta 5-J delta 1 nucleotide sequences in all analyzed clones from seven out of nine patients studied proved the monoclonal nature of gamma delta T-cells with V delta 5-J delta 1 rearrangement. The clonal nature of this rearrangement proved by PAGE and sequencing analysis may suggest an antigen-driven expansion of gamma delta T cells and argues for a significant role of gamma delta T-cells with V delta 5-J delta 1 rearrangement in MS pathogenesis. However, it cannot be excluded that clonal expansion of these lymphocytes may represent secondary change to central nervous system damage.

[Limited value of colloidal tests in CSF in the diagnosis of multiple sclerosis]. / Ograniczona wartosc odczynów koloidowych plynu mzgowordzeniowego w diagnostyce neurologiczenej na przykladzie stwardnienia rozsianego.

In 136 clinically definite MS cases the comparison was performed of intrathecal IgG production and detection of oligoclonal bands, evaluated by immunological methods with results of colloidal tests. The obtained results show, that the left side precipitation in colloidal tests indicates the presence of intrathecal IgG production, what was a definite value in the diagnosis of MS. However, the value of colloidal tests is very much limited by several times lower sensitivity of colloidal tests in detection of intrathecal IgG production in comparisons with the evaluation of intrathecal production and detection of oligoclonal bands by the immunological methods.

The effect of large-dose prednisone therapy on IgG subclasses in multiple sclerosis.

The effect of large-dose prednisone therapy (3960 mg over 56 days) on IgG subclasses in the cerebrospinal fluid and sera, as well as on their intrathecal synthesis, was studied in 15 patients with clinically definite multiple sclerosis. The concentration of IgG subclasses was measured using ELISA with monoclonal antibodies against human IgG subclasses, secondary biotinylated antibody and avidin-biotin-peroxidase complex. There was a decrease of IgG1, IgG3 and IgG4 in the CSF of MS patients after the treatment, but the differences did not reach statistical significance. The IgG index was decreased about 34% (p < 0.01) after the therapy. This was mainly due to diminished synthesis of IgG1 and IgG3. The significance of IgG subclasses in the pathogenesis of MS is discussed.

[Determination of IgG subclass antibodies to the basic myelin protein in patients with multiple sclerosis]. / Badania nad okresleniem podklas IgG przeciwcial przeciwko bialku zasadowemu mieliny u pacjentów ze stwardnieniem rozsianym.

The aim of the study was to determine IgG subclasses of MBP antibodies in patients with multiple sclerosis. The enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies against human IgG subclasses was applied. Anti-MBP antibodies were found in the CSF of 16% and in the sera of 20% patients with MS. MBP antibodies belonged to IgG1, IgG2 and IgG3 subclasses (in the CSF) and to IgG1 and IgG3 subclasses (in the sera). The role of MBP antibodies in context of their IgG subclasses distribution is discussed.

[The immunologic reaction in patients with ischemic stroke]. / Odpowiedz immunologiczna w udarach niedokrwiennych mózgu.

The humoral and cell mediated immunity was studied in 75 cases of completed ischaemic stroke. The results demonstrated only in few cases intrathecal IgG production and presence of oligoclonal IgG bands. A significant relative drop of cell count with CD3 reactivity and increase of cells with reactivity Anti-HLADR and CD11 was observed in peripheral blood. The results demonstrate that in the course of ischaemic stroke various immunological reactions may occur in particular cases. However, there exist no evidence that repeated stroke leads to immunization of the patient.

[The effect of azathioprine treatment on IgG subclasses in multiple sclerosis]. / Wplyw leczenia azatiopryna na podklasy IgG w stwardnieniu rozsianym.

IgG and its subclasses: IgG1, IgG2, IgG3 and IgG4 were determined in the CSF and sera from 20 patients with multiple sclerosis before and after treatment with azathioprine. The effect of the treatment on IgG and IgG subclasses intrathecal synthesis was studied as well. There was a decrease in IgG level in the CSF of MS patients after the treatment with azathioprine. This was mainly due to the decrease of IgG1 and IgG2 subclasses levels. There was no evidence of the influence of azathioprine treatment on IgG and its subclasses levels in MS sera as well as on IgG and IgG subclasses intrathecal synthesis.

[Trials of monosialoganglioside (Sygen) treatment in ischemic stroke]. / Próby leczenia monosialogangliozydem (Sygenem) chorych z niedokrwiennym udarem mózgu.

65 patients with ischaemic stroke were treated for 6 weeks by intramuscular injections of Sygen--monosialoganglioside 40 mg daily. The results were double-blinded and compared with those in placebo group (Vitamin PP). The results evaluated by Mathew scale did not show any significant differences between both groups. However in the Sygen group we have noticed more patients with very good therapeutic results (almost complete recovery of functions). Immunological studies have not revealed any reaction, which may be considered as a result of allergogenic action of monosialoganglioside.