A. G. Prentice

A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies

Fluconazole is widely used as antifungal prophylaxis but it is ineffective against Aspergillus. Itraconazole has a broader spectrum of activity but the capsules give erratic bioavailability in neutropenic patients. We compared itraconazole oral solution (which has an improved pharmacokinetic profile) with fluconazole for antifungal prophylaxis.

Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia.

Summary. We have treated 52 patients with chronic lymphocytic leukaemia (CLL) with fludarabine; 12 developed severe autoimmune haemolysis. Only three had a previous history of haemolytic anaemia. Six out of eight patients retreated with fludarabine after control of their haemolysis developed an exacerbation of the haemolytic anaemia. The cause of autoimmune phenomena in CLL is not known, but our findings reinforce the view that they are caused by a disturbance in immunoregulatory T cells. Fludarabine is a known suppressor of T‐cell function.

The plasminogen activator system in women with polycystic ovary syndrome

OBJECTIVE To evaluate the plasminogen activator system in women with polycystic ovary syndrome (PCOS). DESIGN Case-control study. SETTING A district general hospital in the United Kingdom. PATIENT(S) Eleven women with PCOS and 12 controls. INTERVENTION(S) Venipunctures for assays of the plasminogen activator system. MAIN OUTCOME MEASURE(S) Euglobulin clot lysis times, plasminogen activator inhibitor 1 (PAI-1) activity, fibrinogen, plasminogen, and alpha-2 antiplasmin concentrations in plasma. RESULT(S) Women with PCOS may had a significantly longer euglobulin clot lysis time (mean +/- SD, 389 +/- 164 minutes vs. 220 +/- 110 minutes), a higher PAI-1 activity (mean +/- SD, 19.7 +/- 12 arbitrary units (AU) per mL vs. 10.9 +/- 7.9 AU/mL), and a higher fibrinogen level (mean +/- SD, 4.02 +/- 0.64 g/L vs. 3.15 +/- 0.6 g/L) compared to controls. CONCLUSION(S) Women with the PCOS may have an imbalance in the plasminogen activator system that is tilted toward a reduced production of the proteolytic enzyme plasmin. Systemically, this may increase their risk of cardiovascular disease, but at cellular level in the ovaries, it may result in impaired follicular rupture and anovulation.

Modulation of Apoptosis with Cytokines in B-Cell Chronic Lymphocytic Leukaemia

In B chronic lymphocytic leukaemia (B-CLL) non-proliferating peripheral blood (PB) B cells have a long life span in vivo. In cultures, these cells die spontaneously by apoptosis. Interleukin (IL) 4 inhibits spontaneous apoptosis (SA) and promotes survival of B-CLL B cells in vitro. No such effect is observed in PB B cells from normal healthy donors. The anti-apoptotic effect of IL4 is independent of mitogen-induced cell activation but depends on the concentration of IL4. The protective effect of IL4 is specific and it is significantly reduced or abolished with anti-IL4 antibody. Interferon (IFN)-gamma and alpha- IFN also protect B-CLL B cells from apoptosis in vitro. Sera from B-CLL patients have increased levels of IFN-gamma when compared with sera from healthy donors. In addition, B-cells in B-CLL express detectable levels of IFN-gamma mRNA. Other cytokines, namely ILl, IL2, IL6 and IL7 do not affect SA of B-CLL B cells. By contrast, IL5 and antibody to apolipoprotein-1 (APO- 1) receptor increase SA significantly and in a dose-dependent manner. Interleukin 4 protects B-CLL B cells from IL5-, anti(alpha) APO-1- and steroid-induced apoptosis. The mode of action of the cytokines inducing apoptosis or protecting B-CLL B cells from dying is largely unknown. Recently the bcl-2 proto-oncogene has been associated with prolonged cell survival. However, the involvement of bel-2 in spontaneous, cytokine-induced or steroid-induced apoptosis in B-CLL has been controversial. Some authors have reported down-regulation of bcl-2 protein expression in B-CLL B-cells undergoing SA or in steroid-treated cells with IL4 preventing this down-regulation. By contrast, others observed no significant loss of bcl-2 protein expression in steroid-, alpha-APO-1 - and IL5-treated cells when compared with untreated or fresh cells. Also, no correlation between bcl-2 protein expression and protection with IL4 has been reported. In conclusion, in B-CLL IL4, IFN-gamma and alpha-IFN promote the survival of the leukaemic cells. These cytokines may therefore be involved in the pathogenesis of the B-CLL.

Raised plasminogen activator inhibitor‐1 (PAI‐1) is not an independent risk factor in the polycystic ovary syndrome (PCOS)

BACKGROUND It has been postulated that an insulln‐driven increase in plasminogen activator inhibitor‐1 (PAI‐1) levels may link insulin resistance to anovulatory infertility in women with PCOS and that It may place them at increased risk of thromboembolic disease. However, previous studies have been conflicting because many have failed to control for body mass index (BMI) which may affect PAI‐1. The aim of this study was to investigate PAI‐1 activity in women with PCOS and to compare it with unaffected controls of a similar BMI.

Ultrasound criteria in the diagnosis of polycystic ovary syndrome (PCOS)

Not all women with the polycystic ovary syndrome (PCOS) on ultrasound (US) will have the syndrome, and clinical and biochemical features of PCOS may be present without US features. The sensitivity of US in detecting PCOS was, therefore, prospectively determined in 72 women (32 PCOS and 40 controls). The most sensitive features were the presence of 10 or more follicles (82% and 69% in the left and right ovary) and a peripheral distribution of follicles (81.8% and 71.9% in the left and right ovary). Although ovarian enlargement and stromal brightness were not as sensitive as the previous criteria, stromal brightness was most specific. Combining all the criteria predicted a diagnosis of PCOS or control correctly in 86.4% of cases. This study shows that established US criteria of polycystic ovaries remain of value in the diagnosis of PCOS; however, the discrepancy between the left and right ovaries is an interesting but unexplained finding.

Autoimmune Haemolysis in Patients with B-CLL Treated with Chlorodeoxyadenosine (CDA)

We have treated 19 B-chronic lymphocytic leukaemia (B-CLL) patients with CDA (Leustat, Janssen-Cilag). Four patients developed severe autoimmune haemolytic anaemia, and 2 of these had severe reticulocytopenia due to red cell aplasia/hypoplasia. Two patients died as a complication of the haemolysis one during the primary episode, with a clinical course suggestive of transfusion associated graft-versus-host disease (taGVHD), and one following a relapse of haemolysis. The onset of haemolysis occurs within 4 cycles of CDA therapy and is temporally related to the T-lymphocyte nadir induced by CDA. The presence of a positive DAT prior to therapy in 3 of 4 patients developing haemolysis suggests that the CDA induced T-lymphocytopenia may exacerbate the tendency of certain CLL patients to autoimmune haemolysis.

Effect of anti-APO1 on Spontaneous Apotosis of B Cells in Chronic Lymphocytic Leukaemia: The Role of bel-2 and Interleukin 4

The cell surface protein apolipoprotein 1 (APO1) is expressed on various cell types including malignant lymphoid cells. Triggering of APO1 protein with antibody (Ab) induces apoptosis in APO1-expressing cells. We examined the effect of anti (alpha) APO1 Ab on spontaneous apoptosis (SA) and bcl-2 expression in B cell chronic lymphocytic leukaemia (B-CLL) in vitro. We also investigated the anti-apoptotic activity of interleukin 4 (IL4) on the aAPO1-induced apoptosis in B-CLL cells. Although expression of APO1 on B-CLL cells was not detectable by immunofluorescence, alpha APO1 Ab induced apoptosis in these cells. At 24 hours in culture the number of apoptotic cells was increased by a mean percentage (%) of 27% (range: 21-38) in only half of the cases studied. But in all twelve cases studied, at 48 hours alpha APO1 increased SA by a mean of 72% (range: 26-114) (P < .001) and at 72 hours, the mean % increase was 69% (range: 31-96) in 6/7 cases (P < .001). This effect was alpha APO1 concentration dependent. Interleukin 4 significantly protected B-CLL cells against alpha APO1-induced apoptosis by a mean of 53% (range: 28-76) (P < .001). This protection was specific to IL4 and it was significantly reduced or abolished with alpha IL4 Ab. Expression of bcl-2 protein in untreated cultures was not significantly different from that of the alpha APO1-treated cells; the mean equivalent of soluble fluorochrome (MESF) (range) was 4.9 (3.0-6.8) and 5.2 (3.5-6.0) respectively (P > 0.2). In fresh B-CLL cells the MESF (range) was 4.5 (2.4-6.6). Thus alpha APO1 Ab induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression and partially blocked by IL4.

Are women with polycystic ovary syndrome resistant to activated protein C

OBJECTIVE This study was performed to test the hypothesis that an increased prevalence of activated protein C (APC) resistance in women with polycystic ovary syndrome (PCOS) puts them at increased risk of miscarriage and thrombosis. DESIGN Case control study. SETTING A district general hospital in the United Kingdom. PATIENT(S) Forty-one women with PCOS and 25 controls. INTERVENTION(S) Clinical histories, ultrasound scans, and venepunctures. MAIN OUTCOME MEASURE(S) Diagnosis of PCOS or control, clinical histories, APC resistance according to an activated partial thromboplastin time-based assay. RESULT(S) There was no significant difference in the proportion of women with APC resistance in both groups (three women in the PCOS group [7%] vs. one woman in the control group [4%]). The prevalence of APC resistance in the entire study population was 6.5%. In the PCOS group, 29% (12/41) gave a positive family history of thrombosis compared with 8% (2/25) in the control group. None of the women with a positive family history of thrombosis had abnormal antithrombin 111, protein C, or protein S levels. CONCLUSION(S) This study suggests that women with PCOS may have the same prevalence of APC resistance as the background population and that APC resistance may not put them at a higher risk of thrombosis or miscarriage compared with the case of the general population.

Immunohistochemical detection of plasminogen activator inhibitor-1 in polycystic ovaries

Anovulation in women with polycystic ovary syndrome (PCOS) is incompletely understood. The concentration of the glycoprotein plasminogen activator inhibitor-1 (PAI-1) is raised in insulin resistance. This has been described in the granulosa and theca cell layers of the animal but not the human ovary. This study was performed to investigate the location of PAI-1 in the human ovary and investigate whether it may contribute to anovulation in PCOS. PAPI-1 was localized immunohistochemically and quantitated using computer image analysis in 17 ovarian follicles from fwe women with a diagnosis of PCOS and compared with 15 follicles from six normal ovaries. PAI-1 was predominantly found in the granulosa and theca cells in both polycystic and normal ovaries. Image analysis did not reveal a difference in the PAI-1 signal from polycystic compared with normal ovaries. This study shows that PAI-1 plays a role in human ovulation, but its role in PCOS requires further research.