Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.     

Magnetic resonance imaging of brain abnormalities in patients with the Nijmegen breakage syndrome

The results of brain MRI are presented in 22 patients with documented Nijmegen breakage syndrome (NBS), aged from 1 and 9/12 to 20 years. T1-, PD or FLAIR and T2-weighted SE/TSE images in three planes were obtained. Twenty-one patients showed microcephaly. Decreased size of frontal lobes and narrow frontal horns of the lateral ventricles was observed in all cases. In 6 patients agenesis of the posterior part of the corpus callosum was found as well as colpocephaly and temporal horn dilatation. In 2 patients callosal hypoplasia was accompanied by other anomalies: abnormal cerebrospinal fluid spaces. Sinusitis was present in all patients as a result of primary immunodeficiency. As in ataxia teleangiectasia and other breakage syndromes, NBS patients show inherited malignancy susceptibility and hypersensitivity to X and gamma radiation. Because of that computed tomography is contraindicated in these patients and MRI should be the method of choice in diagnostic imaging.     

Natural mechanisms protecting against cancer

Carcinogenesis is a multistage process. At each step of this process, there are natural mechanisms protecting against development of cancer. The majority of cancers in humans is induced by carcinogenic factors present in our environment including our food. However, some natural substances present in our diet or synthesized in our cells are able to block, trap or decompose reactive oxygen species (ROS) participating in carcinogenesis. Carcinogens can also be removed from our cells. If DNA damage occurs, it is repaired in most of the cases. Unrepaired DNA alterations can be fixed as mutations in proliferating cells only and mutations of very few strategic genes can induce tumor formation, the most relevant are those activating proto-oncogenes and inactivating tumor suppressor genes. A series of mutations and/or epigenetic changes is required to drive transformation of a normal cell into malignant tumor. The apparently unrestricted growth has to be accompanied by a mechanism preserving telomeres which otherwise shorten with succeeding cell divisions leading to growth arrest. Tumor can not develop beyond the size of 1–2 mm in diameter without the induction of angiogenesis which is regulated by natural inhibitors. To invade the surrounding tissues epithelial tumor cells have to lose some adhesion molecules keeping them attached to each other and to produce enzymes able to dissolve the elements of the basement membrane. On the other hand, acquisition of other adhesion molecules enables interaction of circulating tumor cells with endothelial cells facilitating extravasation and metastasis. One of the last barriers protecting against cancer is the activity of the immune system. Both innate and adaptive immunity participates in anti-tumor effects including the activity of natural killer (NK) cells, natural killer T cells, macrophages, neutrophils and eosinophils, complement, various cytokines, specific antibodies, and specific T cytotoxic cells. Upon activation neutrophils and macrophages are able to kill tumor cells but they can also release ROS, angiogenic and immunosuppressive substances. Many cytokines belonging to different families display anti-tumor activity but their role in natural anti-tumor defense remains largely to be established.     

The striopallidal pathway is involved in antiparkinsonian-like effects of the blockade of group I metabotropic glutamate receptors in rats

The aim of the study was to examine the influence of the blockade of group I metabotropic glutamate receptors (mGluRs) on the haloperidol-induced catalepsy and proenkephalin mRNA expression in the rat striatum. Bilateral, intrastriatal injection of AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid, 3-15 microg/0.5 microl), a selective antagonist of group I mGluRs, inhibited catalepsy induced by haloperidol (0.5 mg/kg i.p.). Repeated intrastriatal AIDA administrations (3 x 15 microg/0.5 microl, 3 h apart) counteracted the haloperidol-induced (3 x 1.5 mg/kg s.c., 3 h apart) increase in the proenkephalin mRNA expression in that structure. The present study indicates that the blockade of the striatal group I mGluRs may inhibit parkinsonian akinesia by normalizing the function of the striopallidal pathway.     

Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction

Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.     

Assessment of selected co-stimulatory, adhesion and activatory molecules and cytokines of Th(1)/Th(2) balance in acute lymphoblastic leukemia in children

INTRODUCTION: Recent years have seen a rise in the importance of cytokine production and co-stimulatory/activatory molecule expression in the immune response in leukemia. The aim of our study was to assess the function of T lymphocytes in children with acute lymphoblastic leukemia (ALL) during remission induction based on selected cytokine and co-stimulatory/activatory molecule expression. MATERIAL/METHODS: The study group consisted of 50 children with ALL (B cell precursor). Peripheral blood samples were taken before treatment (day 0), after the prednisone prophase (day 8), and during (day 15) and after (day 33) remission induction. The percentages of T cells with interferon (IFN)-gamma (Th(1)), interleukin (IL)-4 (Th(2)) and IL-2 receptor (IL-2R), CD28, CTLA-4, CD38, ICAM-1, and HLA-DR expression were assessed by tricolor flow cytometry. RESULTS: At the time of diagnosis we noted higher percentages of T cells with adhesion molecule ICAM-1, activation molecule CD38 expression, and an increased population of Th(2 )cells (IL-4) compared with the control group. During and after remission induction we observed a decreased population of CD38(+) T cells, elevated percentages of helper T lymphocytes with IL-2R expression, and a rise in helper T lymphocytes producing IFN-gamma (Th(1)). During fever/infection, higher levels of activated T lymphocytes (CD4(+)HLA-DR(+), CD8(+)HLA-DR(+)), a rise in Th1, and no change in Th(2 )populations were observed. CONCLUSIONS: The results suggest T cell activation and Th(2 )predominance at the time of diagnosis and during remission induction in ALL in children. These results confirm the involvement of cellular immunity in the leukemic process and can be used in immune therapy in leukemia.     

A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C

Overall treatment results of chronic hepatitis C have improved markedly with the introduction of pegylated interferon-alpha (PEG–IFN-) and ribavirin combination therapy. However, cure rates in the most common genotype 1 infection are still unsatisfactory. IFN- dose–response studies on viral kinetics suggest that inadequate dosing might be a key factor but drug levels have hardly been tested, which is in part due to difficulties in measuring this cytokine in patient samples. We have shown recently that hepatitis C virus (HCV) replicons are highly sensitive to IFN-. In this report we tested whether the replicon system could be used as a sensitive bioassay to determine the amount of biologically active IFN- in serum or heparinized plasma of patients under therapy. To facilitate the measurements, a stably replicating subgenomic HCV RNA was developed that carries the gene encoding the firefly luciferase. Dose response studies with IFN- demonstrate that the amount of expressed luciferase directly correlates with the level of HCV replication. By using this cell-based assay, serum samples of HCV patients treated with different types and doses of IFN- were analyzed in parallel to IFN- standards made by serial dilutions of the same type of IFN- the patient was treated with. Based on nonlinear logistic models serum concentrations corresponding to 1.3–19 U/ml were determined in patients under standard or high dose IFN- therapy, and from 3.8 to 4.1 ng/ml in patients treated with PEG IFN-. In conclusion, the HCV-replicon based bioassay allows determining the levels of biologically active IFN- in serum and heparinized plasma of patients under treatment.     

Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia

Diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to coronary artery disease (CAD). In a case-control study we determined the prevalence of two common MTHFR polymorphisms, C677T and A1298C, in 161 male patients under the age of 50 years with angiographically documented CAD and compared it to that in 211 healthy controls. Genotyping was also performed in a random population sample, consisting of 149 men and 121 women at an average age of 40 years. The studied group had classic risk factors of atherosclerosis but did not differ in fasting plasma homocysteine, folic acid, and vitamin B12 levels in either the control group or population sample. The frequency of the 1298C allele was significantly higher in CAD (0.304) than in controls (0.199) or the population sample (0.235). Allele 1298C showed a significant association with early-onset CAD both in homozygotes and in heterozygous carriers. These findings were further supported by comparisons with the population sample. Homozygosity for allele 677T showed a tendency to associate with CAD. Allele 1298C of MTHFR is associated with early-onset CAD (carriers- RR = 1.71, 95% CI: 1.13-2.59; homozygotes- RR = 3.09, 95% CI: 1.36-7.02), even when blood homocysteine levels are not elevated.     

Prevalence of menstrual pain in relation to the reproductive life history of women from the Mayan rural community

BACKGROUND: The prevalence of menstrual pain in Western societies is relatively high and has been shown to be related to many factors (e.g. age, menarche age, parity, menstrual cycle regularity, cigarette smoking, dietary habits). However, less data are available for traditional societies, within which there are, presumably, not as many potentially disturbing factors that could influence menstrual symptoms as in Western societies. AIM: The study seeks to determine the prevalence of dysmenorrhoea, and the factors related to menstrual pains in women with natural fertility (i.e. without hormonal forms of contraception). SUBJECTS AND METHODS: 177 non-smoking women between 18 and 45 years of age living in one Mayan village (Yaxcaba, Yucatan, Mexico) were the subjects of this study. The method of logistic regression was used with the dichotomous dependent variable being the presence or absence of menstrual pain together with such independent variables as age, age at menarche, number of pregnancies, age when giving birth to the first child, the weight at interview and BMI. RESULTS: The general prevalence of the menstrual pains was 28%. There was only one variable influencing dysmenorrhoea, namely the age at which women give birth to their first children. Those mothers who gave birth to their first child at an earlier age (at mean age of 19.4 vs 21.1 years) had a lower prevalence of dysmenorrhoea. CONCLUSION: In the studied traditional society the main factor related to menstrual pain was the age at which woman first gave birth. It is hypothesized that an earlier start to reproductive life in some way decreases the sensitivity of the uterus to prostaglandins.     

Eosinophilic myocarditis in allergic angiitis and granulomatosis (Churg-Strauss syndrome)

Allergic angiitis and granulomatosis (Churg-Strauss syndrome) is one of the rare form of idiopathic (primary) vasculitis. It is characterized by asthma, blood hypereosinophilia and typical microscopic features: nectrotizing vasculitis, tissue infiltration by eosinophils and extravasal granulomas. We present an autopsy case of 55-years old man with Churg-Strauss syndrome complicated by eosinophilic myocarditis.