Early human thymocyte proliferation is regulated by an externally controlled autocrine transforming growth factor-beta 1 mechanism

Early thymocytes undergo extensive proliferation after their entry into the thymus, but cellular interactions and cytokines regulating this intrathymic step remain to be determined. We analyzed the effects of various T-cell growth factors and cellular interactions on in vitro proliferation of early CD2+CD3/TCR-CD4-CD8- (triple negative [TN]) human thymocytes. Freshly isolated TN cells were then assayed for their growth capacity after incubation with CD2I+III-monoclonal antibody (MoAb), recombinant human interleukin-2 (IL-2), IL-7, and/or IL-4. These cells displayed significant proliferative responses with IL-4, IL- 7, or CD2-MoAb+IL-2. The addition of recombinant transforming growth factor beta (TGF beta) or autologous irradiated CD3+CD8+CD4- cells to TN cell cultures dramatically decreased their growth responses to IL-2 and IL-7, whereas IL-4-induced proliferation was less sensitive to growth inhibition. We thus asked whether the CD8+ cell-derived inhibitory effect was due to TGF beta. The addition of neutralizing anti-TGF beta MoAb completely abolished CD8+ cell-derived inhibition of TN cell growth. Analysis of CD8+ cell-derived supernatants indicated that these cells had low TGF beta 1 production capacity, whereas TN cells secrete significantly high levels of TGF beta 1. Cell fixation studies showed that TN cells were the source of the TGF beta. TGF beta 1 released from TN cells was in the latent form that became the active inhibitory form through interaction of TN cells with CD8+ cells. Together, these data suggest a role for TGF beta 1 as an externally controlled, autocrine inhibitory factor for human early thymocytes, with a regulatory role in thymic T-cell output.     

Libri novi

Ohne Zusammenfassung     

The pathophysiology of polycystic ovary syndrome: trying to understand PCOS and its endocrinology

The pathophysiology of the polycystic ovary syndrome (PCOS) encompasses inherent ovarian dysfunction that is strongly influenced by external factors, such as disturbances of the hypothalamic-pituitary-ovarian axis and hyperinsulinaemia. Exaggerated gonadotrophin releasing hormone (GnRH) pulsatility results in hypersecretion of luteinising hormone (LH), which has effects both on ovarian androgen production and oocyte development. Disturbed ovarian-pituitary and hypothalamic feedback accentuates the 0gonadotrophin abnormalities. Hyperinsulinaemia is secondary both to insulin resistance at the periphery and to abnormal pancreatic beta cell function. PCOS runs in families and a number of genetic abnormalities appear to result in features of the syndrome and account for the heterogeneity of the symptoms. Environmental influences, such as nutrition and lifestyle, further influence expression of the syndrome.     

Experience of parenthood, couple relationship, social support, and child-rearing goals in planned lesbian mother families

BACKGROUND: The phenomenon of planned lesbian families (i.e., two-mother families in which the child was born to the lesbian relationship) is relatively new and very little research has been conducted among those families. The overall aim of this research was to examine whether planned lesbian mother families differ from heterosexual families on factors that are assumed to influence the parent-child relationship, such as experience of parenthood, child-rearing goals, couple relationship, and social support. METHOD: A hundred lesbian two-mother families were compared with 100 heterosexual families having naturally conceived children. A variety of measures were used to collect the data, including questionnaires and a diary of activities kept by the parents. RESULTS: Lesbian parents are no less competent or more burdened than heterosexual parents. Both lesbian and heterosexual parents consider it important to develop qualities of independence in their child. However, 'conformity' as a child-rearing goal is less important to lesbian mothers. Furthermore, lesbian social mothers feel more often than fathers in heterosexual families that they must justify the quality of their parenthood. CONCLUSION: There are few differences between lesbian couples and heterosexual couples, except that lesbian mothers appear less attuned to traditional child-rearing goals and lesbian social mothers appear more to defend their position as mother.     

Optimization of attenuation correction for positron emission tomography studies of thorax and pelvis using count-based transmission scans

The quality of thorax and pelvis transmission scans and therefore of attenuation correction in PET depends on patient thickness and transmission rod source strength. The purpose of the present study was to assess the feasibility of using count-based transmission scans, thereby guaranteeing more consistent image quality and more precise quantification than with fixed transmission scan duration. First, the relation between noise equivalent counts (NEC) of 10 min calibration transmission scans and rod source activity was determined over a period of 1.5 years. Second, the relation between transmission scan counts and uniform phantom diameter was studied numerically, determining the relative contribution of counts from lines of response passing through the phantom as compared with the total number of counts. Finally, the relation between patient weight and transmission scan duration was determined for 35 patients, who were scanned at the level of thorax or pelvis. After installation of new rod sources, the NEC of transmission scans first increased slightly (5%) with decreasing rod source activity and after 3 months decreased with a rate of 2-3% per month. The numerical simulation showed that the number of transmission scan counts from lines of response passing through the phantom increased with phantom diameter up to 7 cm. For phantoms larger than 7 cm, the number of these counts decreased at approximately the same rate as the total number of transmission scan counts. Patient data confirmed that the total number of transmission scan counts decreased with increasing patient weight with about 0.5% kg(-1). It can be concluded that count-based transmission scans compensate for radioactive decay of the rod sources. With count-based transmission scans, rod sources can be used for up to 1.5 years at the cost of a 50% increased transmission scan duration. For phantoms with diameters of more than 7 cm and for patients scanned at the level of thorax or pelvis, use of count-based transmission scans is feasible and results in statistically more consistent transmission scans as compared with fixed transmission scan duration.     

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications

This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.     

An observational study of Yasmin in the management of women with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is the commonest endocrine disturbance affecting women in the reproductive age group and encompasses signs of hyperandrogenism, menstrual cycle disturbances and obesity. Some of the symptoms of PCOS may be ameliorated by the combined oral contraceptive pill (COCP). METHODS: A pilot observational study was carried out in a university teaching hospital setting to determine whether the clinical and biochemical features of PCOS are ameliorated by a new COCP, Yasmin, which contains a new progestogen, drosperinone. Treatment with Yasmin was given for 6 months to 17 patients. RESULTS: Thirteen patients (76%) completed 6 months of therapy. Good cycle control was achieved in all patients. Percentage body fat increased, with no overall change in body mass index. Fasting insulin and triglyceride concentrations rose significantly. Serum total testosterone concentrations fell with a concomitant rise in sex hormone binding globulin levels. Hirsutism scores did not change significantly in the 12 women who were clinically hirsute. There was, however, a significant improvement in the acne scores. Four of the 17 patients dropped out of the trial between Cycles 3 and 5 due to side effects. CONCLUSIONS: Yasmin provides good cycle control for women with PCOS, with an improvement in acne over 6 months but not in other symptoms of the syndrome.     

What is polycystic ovary syndrome? Are national views important?

Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentation in some, whilst in others there is a severe disturbance of reproductive, endocrine and metabolic function. There has been much debate about phenotype and, more recently, genotype. There has also been scepticism in some quarters, with a feeling that we may be looking at one end of a spectrum that is in reality 'normal', or perhaps a consequence of the modern disease of obesity. Whilst the polycystic ovary is at the centre of the syndrome, it is external effects such as hyperinsulinism, that influence its expression. There is no consensus on the definition of PCOS and so studies that compare epidemiology and treatments often have very different starting points, and so cannot be compared. In this debate we wish to re-explore our current thinking on PCOS, with a particular emphasis on the British and European perspective and invite others to contribute to the discussion which could form the basis for an international consensus.