Progression of primary APS (Hughes syndrome) into serological SLE: case report

An Arab woman presented with a history of multiple foetal losses and spontaneous venous thromboembolism, which recurred on several occasions. The presence of antiphospholipid antibodies in the absence of other clinical and serological features of systemic lupus erythematosus (SLE), including negative antinuclear antibodies (ANA), confirmed the diagnosis of primary antiphospholipid syndrome (PAPS). More than 15 years after the beginning of clinical events and 10 years after diagnosis, she progressed into the immunological domain of SLE without concurrent clinical features. The patient exhibited weakly positive ANA of a speckled pattern, strongly positive anti (ds) DNA antibodies and false positive VDRL. Lymphopenia has not been observed at any stage of the follow-up. Although the evolution of PAPS into SLE has been infrequently reported, this seems to be another case suggesting that PAPS in some patients may be an early manifestation of lupus. Received: 10 April 2000 / Accepted: 15 June 2000     

The effects of antiphospholipid antibodies obtained from women with SLE/APS and associated pregnancy loss on rat embryos and placental explants in culture

Recurrent fetal loss occurs in approximately 1% of women. Autoimmune causes have been suggested as a factor in some of these cases. High rates of intrauterine fetal growth retardation and increased incidence of prematurity is associated with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). We found in previous studies that sera from SLE/APS patients when used as a culture medium for rat embryos were found to reduce embryonic growth and development, induce a high rate of embryonic anomalies and death and damage the yolk sac morphologically and functionally. In order to investigate the direct effect of IgG purified from women with SLE/APS on the growth and viability of embryos, we cultured 11.5-day-old rat embryos in their yolk sacs in the presence of IgG purified from SLE/APS patients with recurrent pregnancy loss (RPL). The IgG affected directly the embryo and yolk sac, reducing their growth. The purified IgG positive for anticardiolipin/anti-DNA antibodies reduced yolk sac and embryonic growth more than sera negative for these antibodies but positive for antiphosphatydilserine and for antilaminin. Monoclonal antiphosphatydilserine reduced yolk sac growth but the embryos remained intact. Following the observed damage to the yolk sac we cultured human placental explants at 5.5-8 weeks of pregnancy in sera from SLE/APS patients for 96 hours and found that these sera reduced placental trophoblastic cell growth, reduced their proliferation rate and increased their rate of apoptosis. Successful treatment of the women resulted in a correction of the damage induced in the cultured rat embryos and in the cultured placental explants.     

Asymptomatic bacteriuria in women with diabetes mellitus: effect on renal function after 6 years of follow-up

BACKGROUND: The long-term consequences of asymptomatic bacteriuria (ASB) on renal function in women with diabetes mellitus (DM) are unknown. METHODS: A prospective study was performed among women with type 1 or type 2 DM. Women with ASB (diagnosis based on findings from 1 urine culture specimen) were compared with women without ASB for differences in renal function development and incidence of hypertension. RESULTS: A total of 644 women were included in the study (296 with type 1 DM and 348 with type 2 DM; mean [SD] age, 51 [15] years) and followed up for a mean (SD) duration of 6.1 (1.9) years. The prevalence of ASB was 17%. In women with DM and ASB, the creatinine clearance decreased from 87 mL/min (1.45 mL/s) at baseline to 76 mL/min (1.27 mL/s) at study end point; in women with DM without ASB the creatinine clearance decreased from 97 to 88 mL/min (from 1.62 to 1.47 mL/s). In the multivariate analyses, adjusted for age, length of follow-up, duration of DM, and microalbuminuria at baseline, no association was found between ASB and the relative or the absolute decrease in creatinine clearance; the same results were shown also when women with DM type 1 and women with DM type 2 were analyzed separately. Women with ASB developed hypertension more often than women without ASB (54% vs 37%; P = .045), but there was no significant association in the multivariate analysis (odds ratio, 1.5; 95% confidence interval, 0.7-3.6). CONCLUSION: Women with DM (type 1 or type 2) with ASB do not have an increased risk for a faster decline in renal function or the development of hypertension after 6 years of follow-up.     

Increased pregnancy loss in young women with aortoiliac disease

BACKGROUND: During clinical evaluation of young women with peripheral arterial occlusive disease, we were surprised by the high prevalence of pregnancy loss in women with segmental stenosis confined to the aortoiliac segment. We wondered if increased occurrence of miscarriage is the result of high expression of vascular and obstetrical risk factors in these patients, or if it is related to localization of disease. In a case-control study designed to investigate risk factors for peripheral arterial occlusive disease in young women, we assessed the risk of miscarriage in these patients according to level of obstruction. METHODS: A total of 202 female patients, aged 18-49 years and 466 healthy control women from a population based case-control study, donated venous blood samples and filled out a structured questionnaire concerning classical cardiovascular risk factors and obstetrical history. In all patients, diagnosis of peripheral arterial occlusive disease was confirmed by intra-arterial angiography. Patients were classified into two groups: those with and those without stenosis of the aortoiliac segment (aortoiliac disease). RESULTS: In 77 of the 202 patients (38%) with peripheral arterial occlusive disease, the obstruction was confined to the aortoiliac segment. The occurrence of miscarriage was high (42%) in young women with aortoiliac disease. Compared to healthy controls, the risk of miscarriage increased 3-fold (OR 3.1; 95% CI 1.8-5.6) in these patients. Adjustment for obstetrical and vascular risk factors did not affect the risk estimate. CONCLUSION: This is the first study that identifies aortoiliac disease as a risk factor for pregnancy loss in young women. The risk of miscarriage is increased 3-fold in women with aortoiliac disease. The presence of vascular and obstetrical risk factors did not affect the strength of the association. Pregnancy loss could be the first sign of insufficient aortic circulation in these patients.     

Immunological abnormalities in bronchiectasis with chronic bronchial suppuration.

Fifty-three patients with bronchiectasis (chronic bronchial suppuration) of unknown cause, in whom the chronic production of purulent sputum was the prominent clinical feature, were investigated for possible immunological abnormalities. They were compared with two control groups comprising 50 patients with chronic bronchitis and emphysema and 33 patients with bronchial asthma. Forty-two patients with bronchiectasis(79%) had at least one abnormality of immunoglobulin, usually elevation of IgA, IgG or IgM. Eight patients had all three immunoglobulin levels raised and this was related to severity of disease. Similar increases in immunoglobulin levels were observed in the control groups, but the frequency and severity of these changes were significantly greater in the bronchiectasis patients. Two patients had IgA deficiency. There was a very high prevalence of rheumatoid factor (52%) and an increased prevalence of antinuclear factor (10%) in the bronchiectasis patients compared with the control groups. The presence of these autoantibodies did not correlate closely with severity of disease. Ten patients with bronchiectasis (19%) had one or more autoimmune disorders, and the association of severe bronchiectasis, Hashimoto's thyroiditis and pernicious anaemia in one patient is described in detail. The immunoglobulin changes, high incidence of autoantibodies and association with autoimmune disorders raises the possibility that in some patients with bronchiectasis (chronic bronchial suppuration) of apparent unknown cause abnormal immune mechanisms may be important in causing or perpetuating the condition.     

Roles of methylenetetrahydrofolate reductase C677T polymorphism in repeated pregnancy loss.

Congenital thrombophilia in repeated pregnancy lost (RPL) has been noted for years. Methylenetetrahydrofolate reductase (MTHFR) gene is an interesting gene, mentioned for its possible roles in RPL. There is considerable controversy regarding the clinical role of MTHFR C677T polymorphism as a risk factor of RPL. Here, a summative analysis is performed on the recent previous reports on the MTHFR C677T and its correlation to RPL. The metanalysis was performed to assess the correlation between the pattern of MTHFR C677T polymorphism and RPL. From available eight case-control studies, 752 patients and 625 controls are evaluated. The overall frequencies of 4G allele for the patients and controls are 31.5 and 33.5, respectively. According to this study, 53.1% of subjects with T allele have RLP while 55.3% of subjects without T allele have RLP. From overall risk estimation, the subjects with T alleles have 0.96 times lower risk to RLP. According to this analysis, the pattern of MTHFR C677T polymorphism might not represent a useful marker of increased risk for RPL. In addition, there was no association between pattern of MTHFR C677T polymorphism and ethnicity of the patients in this study.     

Management of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome

Pulmonary hypertension is found in about 10% of patients with systemic lupus erythematosis (SLE). Pulmonary hypertension may be present at the time of diagnosis or may develop after the diagnosis of SLE or anti-phospholipid syndrome (APS). It often presents in the reproductive years and has a significant impact on pregnancy outcome, being a significant cause of indirect maternal deaths. In our observational case series of three patients there were two deaths (66%). In cases 1 and 2 the pulmonary hypertension developed during pregnancy and deteriorated rapidly with markedly abnormal mean pulmonary artery pressures of 80 and 70 mmHg respectively prior to death. Both patients died within 48 hours of delivery. In case 3 the pulmonary hypertension was milder and was diagnosed very early in pregnancy. The patient received multidisciplinary care from the first trimester and the management of the pregnancy, delivery and the early puerperium was planned. Careful epidural anaesthesia was used and the patient had invasive monitoring on the intensive therapy unit (ITU) for 72 hours. Women with pulmonary hypertension need to be aware of the high risk of maternal mortality associated with pregnancy but we believe that an improvement in outcome can be achieved by careful assessment and the use of a multidisciplinary approach from early in pregnancy.     

Accelerated bone loss in post-menopausal women with mild primary hyperparathyroidism

OBJECTIVES Osteopenia is regarded as an indication for parathyroidectomy in primary hyperparathyroidism. However, uncertainty exists as to the extent and degree of the skeletal effects in those with mild disease. We sought to determine whether mild primary hyperparathyroidism affects the rate of bone loss in post-menopausal women.
DESIGN Prospective 2-year comparison of rates of bone loss throughout the skeleton in 17 post-menopausal women with untreated mild asymptomatic primary hyperparathyroidism, and 48 age-matched, eucalcaemic controls.
RESULTS The women with primary hyperparathyroidism had a greater annual rate of loss of bone mineral density (BMD) of the total body (mean ± SE, primary hyperparathyroidism −1.15 ± 0.31%, controls −0.39 ± 0.10%; P  = 0.04) and its spine subregion (primary hyperparathyroidism −2.08 ± 0.88%, controls 0.04 ± 0.35%; P  = 0.02). Lumbar spine BMD tended to decline in the primary hyperparathyroidism group (−0.35 ± 0.33%) in contrast to the control group (+ 0.28 ± 0.22%) ( P  = 0.10). There were no significant differences between the groups in rates of change of BMD in the legs or the proximal femur. In the primary hyperparathyroidism group, the rate of total body bone loss in the eight women known at study entry to have had long-standing (>5 years) primary hyperparathyroidism was −1.52 ± 0.61%/year, similar to that of the whole group.
CONCLUSION Primary hyperparathyroidism is associated with an increased rate of loss of total body bone mineral density in post-menopausal women. Prolonged disease duration is therefore likely to be associated with an increasing risk of osteopenia, such that skeletal surveillance and interventions designed to reduce bone loss should be considered.     

Hypocomplementemia in the absence of autoantibodies in women with recurrent pregnancy loss

BackgroundAccumulating data suggest an immunopathogenic role for the complement system as a causative element in pregnancy loss (PL). Formation of pathogenic antibodies with activation of the classical pathway may have a role, but this mechanism fails to characterize the majority of cases with recurrent PL. We established the prevalence of hypocomplementemia without circulating autoantibodies in women with recurrent PL.MethodsIn a retrospective case control study, 201 women with recurrent PL (two or more PL) and 30 healthy women who had normal pregnancies but no PL were studied. Serum levels of C3, C4, and factor B were determined by nephelometry. Total hemolytic activity of the complement system (CH100) was investigated by radial immunodiffusion test.ResultsThe prevalence of hypocomplementemia [low levels of C3, C4, FB or CH100 (with normal concentrations of C3, C4 and FB)] was significantly higher in women with recurrent PL (22,4 %) in comparison with controls (6.6 %; p = 0.019). C3, C4, FB hypocomplementemia or low CH100 were observed in 13 (6,5 %), 19 (9,4 %), 13 (6.5 %) and 7 (3,5 %) women with recurrent PL, respectively. Among patients with C3, C4, FB or CH100 hypocomplementemia, 10, 18, 12 and 5 patients had no circulating autoantibodies [antinuclear antibodies, anticardiolipin antibodies or antithyroid antibodies], respectively. In all, hypocomplementemia, in the absence of autoantibodies, was observed in 38 (18,9 %) women with recurrent PL in a significantly higher frequency than controls (n = 2, p = 0.049).ConclusionsHypocomplementemia, in the absence of autoantibodies was observed in a group of women with recurrent PL which might suggest a role of the complement system in the pathogenesis of PL in these patients.     

The dynamism of cutaneous lupus erythematosus: mild discoid lupus erythematosus evolving into SLE with SCLE and treatment-resistant lupus panniculitis

We present a 47-year-old Caucasian female who initially presented with mild discoid lupus erythematosus that evolved into systemic lupus erythematosus with subacute cutaneous LE and treatment-recalcitrant lupus panniculitis. Conventional therapy with antimalarials, systemic steroids, azathioprine, cyclophosphamide, methotrexate, and pulse doses of methylprednisolone did not control the course of the disease. Cyclosporin-A treatment led to clinical improvement and maintained remission.     

Hyperglycemia and apoptosis: mechanisms for congenital malformations and pregnancy loss in diabetic women.

Congenital malformations are the leading cause of perinatal death among infants of diabetic women. Abnormal fuel metabolism and hyperglycemia have been shown to disturb embryogenesis during the earliest pre- and postimplantation stages in mice. This review presents a new model to explain, in part, adverse pregnancy outcomes associated with diabetes. In this model, by altering gene expression in developing tissues, raised glucose concentrations led to premature programmed cell death in key progenitor cells of the mouse blastocyst or in emerging organ structures in the mouse postimplantation embryo, resulting in abnormal morphogenesis or miscarriage. Although recent studies are still somewhat speculative and have currently only been explored in the mouse, this paradigm is supported by examples in other cell systems, which include human-derived cell lines, thereby suggesting that these findings are also applicable to human pregnancy.     

Effect of body weight loss on blood pressure after 6 years of follow-up in stage 1 hypertension

BACKGROUND: Although it is known that weight reduction reduces blood pressure (BP) in overweight patients, the optimal body weight (BW) loss in terms of BP response is not yet established. We evaluated the relationship between decrease in BW and BP over time in 796 stage 1 hypertensives. METHODS: The 166 subjects who lost BW were divided into four groups according to percent of BW loss at the end of a 74-month follow-up (G1, >2% to 5%, G2, >5% to 9%, G3, >9% to 13%, and G4, >13%) and were compared to the 219 subjects without changes in BW (G0, -2% to +2%). The BW increased (>2%) in the remaining 411 subjects. RESULTS: Among subjects with BW loss there was a progressive decrease in final systolic BP associated with BW loss category up to G3 (P = .007), therefore at the end of follow-up G3 had systolic BP 6.2 mm Hg lower than G0 (P = .06). However, among G3 and G4 subjects systolic BP decrease was almost identical (-6.2 nu -5.7 mm Hg, respectively, P = not significant). Similar results were obtained for diastolic BP, which declined up to G3 (P = .013). G3 had final diastolic BP 3.6 mm Hg lower than G0 (P = .037), whereas change in diastolic BP in G4 subjects was similar to that in G0 (-0.9 nu +0.1 mm Hg, respectively, P = not significant). Similar results were obtained in the group with body mass index (BMI) >27 kg/m(2). CONCLUSIONS: Our results indicate that in stage 1 hypertensives followed for more than 6 years the dose-response relationship between BW loss and decrease in BP is not linear irrespective of initial BW. The BW loss >13% of initial weight did not elicit additional BP decrease.     

Urological abnormalities in young women with severe constipation.

Anorectal and urodynamic studies were carried out in 10 young women with severe constipation and the results compared with those obtained in controls. The lowest volumes that provoked a desire to defecate (constipated 200 +/- 50 v controls 110 +/- 10 [mean +/- SEM] ml: p less than 0.05), and a desire to micturate (constipated 560 +/- 40 v controls 295 +/- 15 [mean +/- SEM] ml: p less than 0.001), were significantly greater in constipated patients compared with controls. The maximum tolerable rectal volume (380 +/- 30 v 290 +/- 20 [mean +/- SEM] ml: p less than 0.05) and the bladder capacity (720 +/- 50 v 540 +/- 10 [mean +/- SEM] ml: p less than 0.001) were also increased in the constipated subjects compared with controls. Electromyographic studies show failure of relaxation of the external anal sphincter (EAS) on attempted defecation in all 10 patients; and eight of these patients actually contracted their EAS when they strained to defecate, causing a functional outlet obstruction. Urodynamic studies showed normal urinary flow rates, normal detrusor pressures and normal radiology during voiding. Thus, these studies suggest that constipated patients have an increase in capacity and a reduction in sensitivity in the urinary bladder as well as in the rectum, but showed no evidence of obstruction to urine flow.     

Cardiac abnormalities in young women with anorexia nervosa.

OBJECTIVE--To identify the characteristics of cardiac involvement in the self-induced starvation phase of anorexia nervosa. METHODS--Doppler echocardiographic indices of left ventricular geometry, function, and filling were examined in 21 white women (mean (SD) 22 (5) years) with anorexia nervosa according to the DSMIII (Diagnostic and Statistical Manual of Mental Disorders) criteria, 19 women (23 (2) years) of normal weight, and 22 constitutionally thin women (21 (4) years) with body mass index < 20. RESULTS--13 patients (62%) had abnormalities of mitral valve motion compared with one normal weight woman and two thin women (p < 0.001) v both control groups). Left ventricular chamber dimension and mass were significantly less in women with anorexia nervosa than in either the women of normal weight or the thin women, even after standardisation for body size or after controlling for blood pressure. There were no substantial changes in left ventricular shape. Midwall shortening as a percentage of the values predicted from end systolic stress was significantly lower in the starving patients than in women of normal weight: when endocardial shortening was used as the index this difference was overestimated. The cardiac index was also significantly reduced in anorexia nervosa because of a low stroke index and heart rate. The total peripheral resistance was significantly higher in starving patients than in both control groups. The left atrial dimension was significantly smaller in anorexia than in the women of normal weight and the thin women, independently of body size. The transmitral flow velocity E/A ratio was significantly higher in anorexia than in both the control groups because of the reduction of peak velocity A. When data from all three groups were pooled the flow velocity E/A ratio was inversely related to left atrial dimension (r = -0.43, p < 0.0001) and cardiac output (r = -0.64, p < 0.0001) independently of body size. CONCLUSIONS--Anorexia nervosa caused demonstrable abnormalities of mitral valve motion and reduced left ventricular mass and filling associated with systolic dysfunction.     

Seven years experience of home management in pregnancy in women with insulin-dependent diabetes

Fifty-eight of a consecutive series of 75 pregnancies in women with insulin-dependent diabetes went into the third trimester. Diabetes was managed by home blood glucose monitoring and women were not routinely admitted at any stage before delivery. The mean number of in-patient days before delivery was 15 for the whole series but has been reduced to 9 during the past four years. Each woman performed an average of 171 blood glucose measurements during her pregnancy. Mean blood glucose (including post-prandial levels) fell significantly from 7.9 mmol/l in the first trimester to 7.3 in the second and 6.4 in the third. Mean percentage of haemoglobin A1 was within the normal range in the second and third trimesters. The cesarean section rate was high at 66% but there were no perinatal deaths. Three infants had congenital abnormalities. We conclude that home blood glucose monitoring is a safe and effective way of managing pregnant diabetic women as out-patients. The cost of meters and sticks is repaid many times over in the saving of hospital costs. In addition, home blood glucose monitoring is popular with the patients and many choose to continue it after delivery.     

Survival in patients with primary soft-tissue sarcomas treated within 6 years

Since 1988, treatment strategies for our sarcoma patients have been determined by the same team and operations performed by one surgeon. The aim of this study was to analyse prognostic data on local recurrence and survival of 101 consecutive patients who presented in our institution with the primary tumour manifestation. After a median follow-up of 35 months, the local recurrence rate was 13.5%, the mean survival time was 68 months and the 5-year survival rate was 83%. Besides positive lymph nodes (only 3 patients) the quality of resection significantly influenced local recurrences (P<0.05). Univariate predictors of mortality were tumour grade (P<0.01), tumour size (P<0.05), distant metastases (P<0.01), and resection quality (P<0.01). Multivariate predictors of mortality consisted of grade (P<0.0001), positive lymph nodes (P<0.001) and resection quality (P<0.01). In this homogeneous group of patients, excellent recurrence and survival rates could be achieved. An optimized surgical treatment not only reduces the rate of local recurrences but also augments survival time. Received: 12 March 1997 / Accepted: 14 November 1997     

Steroid hormone abnormalities in women with severe idiopathic constipation.

Patients with severe idiopathic constipation are almost exclusively women of reproductive age. To investigate the possibility of a sex hormone abnormality in this condition, we have compared a range of sex hormones during the follicular and luteal phases of the menstrual cycle in 23 healthy women (mean age 33 years) with those in 26 patients with severe idiopathic constipation (mean age 32 years, spontaneous bowel frequency less than one per week). In the patients there was a reduction in the follicular phase of progesterone (4.5 v 4 nmol/l, p = 0.006, median value, controls v patients), 17 hydroxyprogesterone (9.7 v 5.8 nmol/l, p = 0.01), cortisol (387 v 245 nmol/l, p = 0.008), testosterone (2.3 v 1.8 nmol/l, p less than 0.001), androstenedione (10.3 v 8.4 nmol/l, p = 0.02), and dehydroepiandrosterone sulphate (5.1 v 3.0 mumol/l, p = 0.03). In the luteal phase there was a reduction of oestradiol (483 v 350 pmol/l, p = 0.015), cortisol (322 v 242 nmol/l, p = 0.047), and testosterone (2.4 v 1.7 nmol/l, p = 0.003). The concentrations of sex hormone binding globulin, prolactin, luteinising hormone, and follicle stimulating hormone were not significantly different in either phase of the cycle. Women with severe idiopathic constipation have a consistent reduction in steroid hormones.