Endometrial safety and tolerability of AERODIOL(R) (intranasal estradiol) for 1 year.

OBJECTIVE: the purpose of this study was to assess the endometrial safety and patient acceptability of a pulsed estrogen therapy provided by S21400 (intranasal 17 beta-estradiol) in the treatment of postmenopausal symptoms. DESIGN: postmenopausal women (n=408) entered an open-label, community based, multicentre trial. Patients received S21400 plus sequential (>90% of patients) or continuous progestogen. Treatment was initiated with a standard daily dose of 300 microg but dose adaptation was possible every 3 months from 150 to 600 microg daily. Endometrial biopsies were performed at entry and at 12 months, and bleeding patterns were recorded at 3-monthly intervals throughout the trial. RESULTS: 71% of patients received 300 microg per day S21400 throughout the study, 3% had their dose decreased, 19% had their dose increased and 7% had their dose both decreased and increased. Three hundred and eleven biopsies were obtained after 12 months of treatment, there were no cases of endometrial hyperplasia. The 95% confidence interval [CI] for the rate of incidence was 0-1.2%. Cyclical bleeding occurred in 82% of sequential treatment cycles. Unexpected bleeding occurred in 5% of the treatment cycles. Presence of unexpected bleeding varied according to the treatment regimen, 15 and 4% of the cycles with combined continuous and sequential regimen, respectively. Unexpected bleeding was mostly spotting. Nasal treatment was well accepted. Nasal symptoms (itching sensation, rhinorrhea and sneezing) were mostly mild in intensity and they led to treatment withdrawal in approximately 3% of patients. The rate of treatment continuation was 85% at 1 year. CONCLUSIONS: S21400, in combination with continuous or sequential progestogen, exhibits good endometrial safety and patient acceptability in postmenopausal women.

[Menopause and hormone replacement therapy]. / A menopausa és hormonpótló kezelés.

Due to the improving life expectancy of women spend third of their active life after the menopause. Estrogen deficiency can be caused by both natural and artificial menopause. The lack of estrogen can directly worsen the quality of life and epidemiological evidence suggests association with development of certain diseased states. Hormone replacement with natural estrogens has been proven to be successful for various indications: it reduces the menopausal vasomotor and psychological symptoms thus improving quality of life. It can also be used to prevent harmful effects of estrogen deficiency in various organs. Literature review supports the role of estrogen in atherosclerosis and osteoporosis prevention. Further evidence required establishing the role of estrogens in secondary prevention of coronary artery disease. Also needs to be explained why the beneficial effects of estrogen therapy in osteoporosis seem to disappear soon after cessation of therapy. Currently the relative risk increase of breast cancer during long-term hormone replacement therapy cannot be exactly measured. Nevertheless, substantial reduction of mortality in estrogen receptor positive breast cancer can also be seen with women on hormone replacement as compared to controls. Some data support the negative correlation of residual but still detectable, endogen estrogen and atherosclerosis and similarly to osteoporosis. The same residual estrogen levels seem to correlate positively with breast cancer. The recognition (and further acceptance) of the role of the residual estrogens might have influence on the indication, choice and dosage of preparation and duration of hormone replacement therapy. Overall evidence is in favor of the need medical attention for menopause: which ranges from preventive screening to long term hormone replacement therapy. The decision to treat requires the risks and benefits taken into consideration. This highly specialized care is provided in menopause clinics in Hungary. New oestrogen like agents are being developed like the selective estrogen receptor modulators, the tibolone and the phyto-estrogens. They provide tissue-specific effect acting as estrogen agonistics, sustaining the beneficial preventive and therapeutic effects of the estrogens, but in the breast and endometrial tissue they behave like estrogen antagonists avoiding the side effects of the current used oestrogens. They might play a significant role in the treatment of menopause in the future.

The structure of a highly virulent Theiler's murine encephalomyelitis virus (GDVII) and implications for determinants of viral persistence.

GDVII is a highly virulent Theiler's murine encephalomyelitis virus (TMEV) which causes acute encephalitis in mice, while the BeAn and DA strains are the less virulent TMEV which cause chronic demyelinating disease in the central nervous system as a result of persistent infection. Purified GDVII virus isolated from infected BHK-21 cells was crystallized and its structure was determined to 3.5-A resolution by X-ray crystallography. In contrast to other TMEV structures, the VP1 C-terminus of GDVII virus has an ordered conformation that forms a hook over the VP3 knob near the threefold axis. Comparisons with the atomic structures of the less virulent BeAn and DA viruses revealed significant structural variations in a major site (cluster B) on the protruding surface loop puff B of VP2. Puff B is located near the VP3 GH loop region which is structurally analogous to the host receptor attachment site of the major serogroup of human rhinoviruses. Mutations at residue 1101 in VP1 and residue 2141 in VP2, which are also near the VP3 GH loop and adjacent to cluster B, were previously shown to influence persistence of DA virus. These observations indicate that the characteristic interaction with the host receptor through these sites may potentially alter TMEV persistence.

Crystallization and preliminary X-ray diffraction studies of Theiler's virus (GDVII strain).

Theiler's murine encephalomyelitis virus (TMEV) is a member of the picornavirus family. Mice infected with TMEV serve as models for the study of human neurological diseases including multiple sclerosis. Preparations of the GDVII strain of Theiler's virus have been crystallized using the hanging drop technique. When exposed to high intensity synchrotron radiation, these monoclinic crystals diffracted X-rays to at least 3.0 A resolution. The unit cell has a C-centered lattice with dimensions: a = 575.2 A, b = 324.0 A and c = 558.4 A, beta = 108.2 degrees. The molecular mass and cell dimensions imply that there is an entire virus particle per asymmetric unit, suggesting the presence of 60-fold non-crystallographic redundancy. This GDVII crystal form appears to be suitable for high-resolution structure determination.

Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

Depending on the strain, Theiler murine encephalomyelitis virus (TMEV) may cause acute encephalitis or chronic demyelinating disease, which is associated with viral persistence in mice. Persistent central nervous system infection and demyelination by the less-virulent TMEV has provided a useful animal model for the human demyelinating disease multiple sclerosis. The less-virulent BeAn strain of TMEV was crystallized and its atomic structure was determined by x-ray crystallography. The alpha-carbon coordinates of the closely related Mengo virus were used to calculate the initial phases to 3.5 A resolution and the interpretable electron density map was produced by 10 cycles of 30-fold noncrystallographic molecular replacement averaging. The structure revealed a high degree of overall structural similarity to Mengo virus as well as substantial differences in the surface loops. These structural changes might be correlated with TMEV host-specific recognition, pH-related stability, and neurovirulence.

Altered expression of self-reactive T cell receptor V beta regions in autoimmune mice.

Intrathymic tolerance results in elimination of T cells bearing self-reactive TCR V beta regions in mice expressing certain combinations of I-E and minor lymphocyte stimulatory (Mls) phenotypes. To determine if autoimmune strains of mice have a defect in intrathymic deletion of self-reactive TCR V beta regions, expression of V beta 3, V beta 6, V beta 8.1, and V beta 11 were examined in lpr/lpr and +/+ strains of mice; MRL/MpJ(H-2K, I-E+, Mlsb,), C57BL/6J(H-2b, I-E-, Mlsb,), C3H/HeJ(H-2k, I-E+, Mlsc), AKR/J(H-2k, I-E+, Mlsa); and in autoimmune NZB/N(H-2d, I-E+, Mlsa) and BXSB(H-2b, I-E-, Mlsb) mice. The results suggest that, during intrathymic development, self-reactive T cells are deleted in autoimmune strains of mice as found in normal control strains of mice. However, the TCR V beta repertoire is skewed in autoimmune strains compared to normal strains of mice. For example, MRL-lpr/lpr mice, but not other lpr/lpr strains, had increased expression of V beta 6 relative to expression in control MRL(-)+/+ mice, which is associated with collagen-induced arthritis. These data are consistent with a model of normal affinity for negative selection of self-reactive T cells in the thymus of autoimmune strains of mice followed by expansion of autoreactive T cell clones in the peripheral lymphoid organs. The peripheral lymphoid organs of lpr/lpr mice contain an expanded population of abnormal CD4-, CD8-, 6B2+ T cells. Elimination of self-reactive peripheral T cells suggests that these abnormal cells are derived from a CD4+ subpopulation in the thymus. Flow cytometry analysis of peripheral lymph node T cells from MRL-lpr/lpr mice reveal three populations of CD4+ T cells expressing low, intermediate and high intensity of B220 (6B2). This supports the hypothesis that in lpr/lpr mice, self-reactive CD4+ T cells are eliminated in the thymus, and that these cells lose expression of CD4 and acquire expression of 6B2 in the periphery.