Clinical study and follow-up of 100 patients with the antiphospholipid syndrome

OBJECTIVES: To study the clinical characteristics at diagnosis and during follow-up of patients with the antiphospholipid syndrome (APS) and to analyze the influence of treatment on their outcome. PATIENTS: One hundred patients with APS were included (86% female and 14% male; mean age, 36 years). Sixty-two percent had primary APS and 38% had APS associated with systemic lupus erythematosus (SLE). The median length of follow-up was 49 months. RESULTS: Fifty-three percent of the patients had thromboses, 52% had thrombocytopenia, and 60% of the women had pregnancy losses. Patients with APS associated with SLE had a higher prevalence of hemolytic anemia (P = .02), thrombocytopenia (platelet count lower than 100 x 10(9)/L) (P = .004), antinuclear antibodies (P = .0002), and low complement levels. Fifty-three percent of the patients with thrombosis had recurrent episodes (86% in the same site as the previous thrombotic event). Recurrences were observed in 19% of the episodes treated with long-term oral anticoagulation, in 42% treated prophylactically with aspirin, and in 91% in which anticoagulant/antiaggregant treatment was discontinued (P = .0007). Multivariate analysis showed that prophylactic treatment and older age had an independent predictive value for rethrombosis. Prophylactic treatment during pregnancy (usually with aspirin) increased the live birth rate from 38% to 72% (P = .0002). CONCLUSIONS: Patients with APS have a high risk of recurrent thromboses. Long-term oral anticoagulation seems to be the best prophylactic treatment to prevent recurrences. Prophylactic treatment with aspirin during pregnancy reduced the rate of miscarriages remarkably.     

CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging efficiency but increased risk of severe infections

OBJECTIVE: The main objective of this work was to decrease the incidence of relapse after autologous stem cell transplantation with a "double purging" procedure. METHODS: We used a "positive" (CD34) and "negative" (CD19) double selection method to improve the efficacy of "single purging" of hematopoietic harvests in poor-prognosis lymphoproliferative disorders. All patients included in the study had a positive molecular marker of their disease. Minimal residual disease (MRD) was studied by flow cytometry and PCR techniques during the purging procedure and after transplantation. RESULTS: Twenty-six patients fulfilled entry criteria. Median age of patients was 50 years (range: 33-66); 17 were male and 9 female. Thirteen (50%) of the patients mobilized an adequate number of CD34+ cells (>or=3 x 10(6)/kg) to proceed with the double-selection protocol. Twelve of the 13 harvests became PCR negative after purging. Ten patients were grafted with the selected products and all but one engrafted without delay. After a median follow-up of 30 months, 2 of 10 patients suffered a molecular relapse at 7 and 19 months respectively. The earlier relapse was observed in the patient who received a MRD+ product. Only one patient experienced a clinical relapse. Three patients died due to obliterans bronchiolitis, pneumococcal sepsis, and septic shock of unknown origin, respectively, and three others presented life-threatening infections. CONCLUSION: Therefore, CD34+/CD19+ positive/negative selection is an effective purging approach in patients with chronic lymphoproliferative disorders. This favorable effect is, however, counterbalanced by the high frequency of life-threatening infections.     

Late T-lymphocyte and monocyte activation in coronary restenosis. Evidence for a persistent inflammatory/immune mechanism?

AIMS: This study was made to determine if restenosis after percutaneous coronary angioplasty is associated with acute or chronic inflammatory/immunologic activity, and explored possible relationships with latent infection. PATIENTS AND METHOD: Forty-six consecutive patients underwent elective PTCA and 6 months of angiographic follow-up. Peripheral venous blood samples were obtained at baseline, 24-48 h, and 4-6 months post-intervention. Flow-cytometric methods were used to measure early and late circulating leukocyte activation status. Il-6 and TNF-alpha cytokines, and Il-2 soluble receptor concentrations were determined in all plasma samples. Chlamydia pneumoniae and Cytomegalovirus antibody assays were performed to detect infectious disease. RESULTS: Angiographic coronary stenosis developed in 27 out of 46 patients. At 6 months of follow-up, these patients showed a significant increase in circulating cytotoxic T-lymphocytes CD3+/CD56+ (18.8 7.1 vs 6.12 2.7%; p = 0.005) and activated monocytes (CD11b: 1,383 624 vs 990 484 MFI, p = 0.025; CD64: 76.0 28.7 vs 56.7 21.8 MFI; p = 0.014), with no apparent relation to increased cytokines or latent infectious disease. CONCLUSIONS: Restenosis appears to be associated to inflammatory and immunological activity that persists 6 months after coronary intervention. No relationship was found with the infections studied. The presence of inflammatory activity 4-6 months after PTCA suggess that pharmacological therapeutic interventions to prevent restenosis should be maintained for months.     

EQAS for peripheral blood morphology in Spain: a 6-year experience

The Spanish haematology external quality assessment scheme (EQAS), established in 1984, is run by the Spanish Haematology and Haemotherapy Association (AEHH) [Quality Assurance in Health Care 3 (1991) 75] and functions to evaluate the quality and reproducibility of the assessment of diagnostic samples by clinical laboratories. The Hospital Clinic of the University of Barcelona (HCB) serves as the EQAS Coordination Centre and follows the guidelines established by the International Committee for Standardization in Haematology [Annali dell'Istituto superiore di Sanità 31 (1995) 95; International Journal of Hematology 68 (1998) 45]. During the period 2001-2006, replicates of 25 different blood films were sent to 604 EQAS participants for cell morphology evaluation. Some patient details corresponding to the samples were disclosed, such us age, sex, haemoglobin value and white blood cell count. The participants were asked to select up to four significant morphology features using a coding list, provided by the Coordination Centre, which included significant morphological alterations that appear in haematopoietic cells. For each survey, individual results were assessed against the morphological reference results (MRR) established by the Cytology Group of the AEHH ('true' answers). This paper describes the organization of the 6-year-long study and the evaluation of laboratory performance for blood smear interpretation by the Spanish haematology EQAS. Different performance levels were detected relative to the laboratory category. Laboratories providing services to hospitalized patients showed higher performances compared with laboratories providing services to nonhospitalized patients. Pathological lymphoid cells were the most difficult to identify by the participants. To improve the results in EQAS peripheral blood morphology, the development of specific cytology educational trainings is discussed.     

The role of natriuretic peptides in volume assessment and mortality prediction in Haemodialysis patients

Background

Maintaining optimal fluid balance is essential in haemodialysis (HD) patients but clinical evaluation remains problematic. Other technologies such as bioimpedance are emerging as valuable adjuncts. This study was undertaken to explore the potential utility of the natriuretic peptides – atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the assessment of fluid status and cardiovascular risk in this setting.

Methods

This was a cross-sectional study carried out in an unselected cohort of 170 prevalent HD patients. Volume status was assessed by clinical parameters – the presence or absence of peripheral oedema, raised jugular venous pressure and basal lung crepitations; by extracellular fluid volume (ECFV) status determined by whole body bioimpedance; and by serum levels of BNP and ANP (pre- and post –dialysis). The relationships of ANP and BNP levels to clinical and bioimpedance parameters of volume status was determined. Patients were followed up for 5 years to assess the relationship of natriuretic peptide levels to mortality.

Results

Bioimpedance estimates of ECFV expansion (>105 % of ideal ECFV) was present in 52 % of patients pre-dialysis. A significant proportion (21 %) of pre-dialysis patients had a depleted ECFV (<95 % of ideal ECFV) pre-dialysis. The situation was reversed post-dialysis. A raised JVP >3 cm was the most reliable clinical sign of ECFV expansion inferred from bioimpedance measurements and natriuretic peptide levels. The vast majority of patients with this sign also had lung crepitations or peripheral oedema or both. BNP was a stronger predictor of ECFV expansion than either pre- or post-dialysis ANP. BNP was also a stronger predictor of five-year survival.

Conclusion

Serum levels of BNP have a strong relationship to both volume status and survival in HD patients. We found no clear role for measurement of ANP, though changes in blood levels may be a sensitive indicator of acute changes in volume status. Whether monitoring levels of these peptides has a role in the management of volume status and cardiovascular risk requires further study.

     

A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention

Background

To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation.

Methods

We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON–OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF–ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation.

Results

We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ²₁ = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria.

Limitations

The small sample size limited the statistical power and external validity.

Conclusion

These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects.     

Age-related variations of fat tissue fraction in normal human bone marrow depend both on size and number of adipocytes: a stereological study

Studies dealing with the number or size of individual adipose cells in human bone marrow are lacking. To ascertain whether the age-related variations in fat tissue fraction depend on the size of individual adipocytes or their number or both, a stereological study of 20 normal human bone marrow specimens was performed. A total number of 17,039 adipose cell profiles was measured and two stereological parameters were obtained in each specimen: mean diameter and number of cells per mm3 of bone marrow. With increasing age, an increasing fat tissue fraction was observed (r = 0.61; p = 0.004). The fat tissue fraction correlated positively with the size (r = 0.81; p less than 0.001) and the number/volume (r = 0.59; p = 0.006) of adipocytes. The significance of both adipocyte size and adipocyte number/volume was confirmed by stepwise multiple regression, in which the size alone explained 66.2% of fat tissue fraction and both size and number/volume explained 97.2% of fat tissue fraction. These results are discussed from a pathophysiological point of view.     

Investigation of plasma von Willebrand factor and circulating platelet aggregating activity in mitomycin C-related hemolytic-uremic syndrome

We have studied the ability of the plasma to induce aggregation of both homologous and heterologous platelets in four patients with hemolytic-uremic syndrome (HUS) associated with chemotherapy with mitomycin C (MMC). Neither platelet aggregation was elicited by patients' plasmas nor the in vitro addition of purified von Willebrand factor (vWF) had any effect on the aggregation pattern. In addition, ristocetin-induced binding of patients' vWF to formaldehyde-fixed platelets was normal, and multimeric vWF analysis revealed a normal structure of patients' plasmatic vWF whatever the clinical stage in which it was studied. These findings suggest that, in spite of the existence of common clinical and biological features in the various forms of HUS, the pathogenesis of MMC-related HUS may be, at least in part, different from that of the other forms of HUS in which both platelet-aggregating activity and alterations in the vWF are found.     

Lack of deleterious effect on bone mineral density of long-term thyroxine suppressive therapy for differentiated thyroid carcinoma

The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean +/- SD age: 51 +/- 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 +/- 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 +/- 0.148 gr/cm(2) vs 0.956 +/- 0.130 gr/cm(2) in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 +/- 0.329 gr/cm(2) vs 1.155 +/- 0.224 gr/cm(2) respectively, P < 0.05). When premenopausal (n = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma.