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Biomedical subjects

G Gamba

Publications and source records attributed to G Gamba.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.

The K+-Cl- cotransporters (KCCs) belong to the gene family of electroneutral cation-chloride cotransporters, which also includes two bumetanide-sensitive Na+-K+-2Cl- cotransporters and a thiazide-sensitive Na+-Cl- cotransporter. We have cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members of this gene family. The KCC3 and KCC4 cDNAs predict proteins of 1083 and 1150 amino acids, respectively. The KCC3 and KCC4 proteins are 65-71% identical to the previously characterized transporters KCC1 and KCC2, with which they share a predicted membrane topology. The four KCC proteins differ at amino acid residues within key transmembrane domains and in the distribution of putative phosphorylation sites within the amino- and carboxyl-terminal cytoplasmic domains. The expression of mouse KCC3 in Xenopus laevis oocytes reveals the expected functional characteristics of a K+Cl- cotransporter: Cl--dependent uptake of 86Rb+ which is strongly activated by cell swelling and weakly sensitive to furosemide. A direct functional comparison of mouse KCC3 to rabbit KCC1 indicates that KCC3 has a much greater volume sensitivity. The human KCC3 and KCC4 genes are located on chromosomes 5p15 and 15q14, respectively. Although widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and KCC4 is expressed in muscle, brain, lung, heart, and kidney. The unexpected molecular heterogeneity of K+-Cl- cotransport has implications for the physiology and pathophysiology of a number of tissues.

Amino Acid Sequence↗
PubMed1999

Meta-analysis of six clinical phase III studies comparing lomefloxacin 0.3% eye drops twice daily to five standard antibiotics in patients with acute bacterial conjunctivitis.

BACKGROUND: Lomefloxacin 0.3% ophthalmic solution twice daily has been compared in patients with bacterial conjunctivitis in six randomized double-blind or investigator-masked phase III studies with either chloramphenicol 0.5% 5x/day, gentamicin 0.3% 4x/day, fusidic acid 1% 2x/day, tobramycin 0.3% 4x/day or norfloxacin 0.3% 4x/day. METHODS: A meta-analysis of all individual data of these six studies was performed. A total of 582 patients with clinically diagnosed bacterial conjunctivitis were evaluated by slit-lamp examination with grading of eight key signs and symptoms and by conjunctival swab cultures at baseline, on day 3-5 and on day 7-9. Success of therapy, local tolerance and safety were evaluated at termination. In vitro sensitivity of the ocular isolates to 6-10 antibiotics was evaluated by disk diffusion tests. RESULTS: Two hundred and ninety patients treated with lomefloxacin 0.3% (LF) and 292 patients treated by one of the control antibiotics (combined control group, CCG) were enrolled in the studies. Two hundred and seventy-eight LF and 283 CCG patients were evaluable for the intent-to-treat (ITT) analysis, while 85 LF and 95 CCG patients had bacteria above the pathological threshold and formed the core subpopulation. The mean cumulative sum score in the LF group was 9. 47 on day 1, and decreased by 5.70 on day 3-5 and by 8.10 on day 7-9. In the CCG it decreased significantly less: it was 9.19 at baseline, decreased by 5.15 on day 3-5 and by 7.33 on day 7-9. Swab counts decreased in the LF and CCG group similarly, with the major decrease observed between day 1 and day 3-5. Most of the organisms considered resistant in vitro were still eradicated with the regimen used. Of the few surviving organisms also isolated on the next follow-up visit, one isolate in the LF group and seven in the CCG showed decreased in vitro sensitivity towards the treatment antibiotic used. Local tolerance was good or excellent, without any significant differences except for burning sensation, which lasted significantly longer in the CCG group than in the LF group. Adverse events were observed in 18 LF and 23 CCG patients; four LF and three CCG patients had to be withdrawn. All adverse events were non-serious. CONCLUSION: Lomefloxacin eye drops used with a loading dosage followed by a twice daily regimen proved as effective, safe and well tolerated as five established standard treatments used at a 2, 4 or 5 times daily regimen, caused less discomfort upon instillation, and showed a lower risk to generate or select new resistant strains.

Acute Disease↗
PubMed1999

Isoforms of the Na-K-2Cl cotransporter in murine TAL I. Molecular characterization and intrarenal localization.

We have identified several alternatively spliced cDNAs encoding mBSC1, an apical bumetanide-sensitive Na+-K+-2Cl- cotransporter from mouse kidney. Two full-length clones were isolated, designated C4 and C9, predicting proteins of 770 and 1,095 amino acids, respectively. The C4 isoforms are generated by utilization of an alternative polyadenylation site located within the intron between exons 16 and 17 of the mBSC1 gene on chromosome 2; the resultant transcripts predict a truncated COOH terminus ending in a unique 55 amino acid sequence. The predicted C4 and C9 COOH termini differ in the distribution of putative phosphorylation sites for both protein kinase A and C. Independent splicing events involve three previously described cassette exons, which are predicted to encode most of the second transmembrane domain. A total of six different isoforms are expressed, generated by the combinatorial association of three cassette exons and two alternative 3' ends. C9-specific and C4-specific antibodies detect proteins of approximately 150 and 120 kDa, respectively, in mouse kidney. Immunofluorescence and immunohistochemistry indicate expression of both COOH-terminal isoforms within the thick ascending limb of the loop of Henle (TAL). However, staining with the C4 antibody is more heterogeneous, with a decreased proportion of positive cells in the cortical TAL. Functional expression in Xenopus oocytes indicates a dominant negative function for C4 isoforms [companion study, C. Plata, D. B. Mount, V. Rubio, S. C. Hebert, and G. Gamba. Am. J. Physiol. 276 (Renal Physiol. 45): F347-F358, 1999], and the differential expression of these isoforms may contribute to functional heterogeneity of Na+-K+-2Cl- cotransport in mouse TAL.

Amino Acid Sequence↗
PubMed1999

Isoforms of the Na-K-2Cl cotransporter in murine TAL II. Functional characterization and activation by cAMP.

The functional properties of alternatively spliced isoforms of the mouse apical Na+-K+-2Cl- cotransporter (mBSC1) were examined, using expression in Xenopus oocytes and measurement of 22Na+ or 86Rb+ uptake. A total of six isoforms, generated by the combinatorial association of three 5' exon cassettes (A, B, and F) with two alternative 3' ends, are expressed in mouse thick ascending limb (TAL) [see companion article, D. B. Mount, A. Baekgaard, A. E. Hall, C. Plata, J. Xu, D. R. Beier, G. Gamba, and S. C. Hebert. Am. J. Physiol. 276 (Renal Physiol. 45): F347-F358, 1999]. The two 3' ends predict COOH-terminal cytoplasmic domains of 129 amino acids (the C4 COOH terminus) and 457 amino acids (the C9 terminus). The three C9 isoforms (mBSC1-A9/F9/B9) all express Na+-K+-2Cl- cotransport activity, whereas C4 isoforms are nonfunctional in Xenopus oocytes. Activation or inhibition of protein kinase A (PKA) does not affect the activity of the C9 isoforms. The coinjection of mBSC1-A4 with mBSC1-F9 reduces tracer uptake, compared with mBSC1-F9 alone, an effect of C4 isoforms that is partially reversed by the addition of cAMP-IBMX to the uptake medium. The inhibitory effect of C4 isoforms is a dose-dependent function of the alternatively spliced COOH terminus. Isoforms with a C4 COOH terminus thus exert a dominant negative effect on Na+-K+-2Cl- cotransport, a property that is reversed by the activation of PKA. This interaction between coexpressed COOH-terminal isoforms of mBSC1 may account for the regulation of Na+-K+-2Cl- cotransport in the mouse TAL by hormones that generate cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Dexamethasone increases eNOS gene expression and prevents renal vasoconstriction induced by cyclosporin.

Cyclosporin A (CsA)-induced renal vasoconstriction (RV) is attributed to an imbalance in vasoactive factors release. Dexamethasone (Dex) exerts a renal vasodilatory effect by a mechanism not yet characterized. This study evaluates whether the effect of Dex is mediated by NO and whether it prevents CsA-induced RV. Micropuncture studies were performed in six groups of uninephrectomized rats treated for 7 days with the following: vehicle (Veh); Veh + 4 mg/kg dexamethasone (Veh+Dex); 30 mg/kg CsA; CsA+Dex; vehicle + 10 mg/kg nitro-L-arginine methyl ester (Veh+L-NAME); and Veh+Dex+L-NAME. NO synthase (NOS) isoform mRNA levels were evaluated in renal cortex and medulla by semiquantitative RT-PCR analysis in the first four groups. Dex produced renal vasodilation, which was blocked by concomitant L-NAME administration, and the effect of Dex was associated with higher cortical and medullary endothelial NOS (eNOS) and cortical inducible NOS (iNOS) mRNA levels. In the CsA group, Dex prevented RV, restoring glomerular hemodynamics to control values. These changes were associated with further enhancement of eNOS and restoration of medullary iNOS and neuronal NOS (nNOS) expression. We conclude that Dex prevents CsA-induced RV, and its vasodilator effect could be mediated by increased intrarenal generation of NO, secondary to enhanced expression of eNOS and iNOS.

Animals↗
PubMed1999

Abnormalities in thrombin-antithrombin pathway in AL amyloidosis.

Various pathogenic factors have been proposed to explain the abnormal hemostasis observed in AL amyloidosis. Since imbalance between clotting factors and inhibitors could play a pathogenic role in both hemorrhagic and thrombotic manifestations, we investigated the thrombin-antithrombin pathway in 35 patients with AL amyloidosis. Ten patients suffered from bleeding while 3 patients experienced deep venous thrombosis. Thrombin time was prolonged in 29 subjects, the mean values of antithrombin III activity (ATIII Act) were significantly lower than those of antithrombin III antigen (ATIII Ag) with loss of relationship between these two different techniques of ATIII detection, normally observed in healthy controls. In 19 patients increased levels of thrombin-antithrombin (TAT) complexes were present. Crossed immunoelectrophoresis of ATIII, performed in presence of heparin, evidenced ATIII forms with reduced binding capacity to heparin and TAT complexes of various electrophoretic mobilities. In conclusion, the impairment of the thrombin-antithrombin pathway, in association with the low ATIII biological activity, might play a pathogenic role in the hypercoagulable state reported in AL amyloidosis, despite the higher frequency of bleeding manifestations.

Adult↗
PubMed1999

[Lack of effect of cicletanine and its sulfoconjugated metabolite on the thiazide receptor expressed in Xenopus oocytes].

UNLABELLED: Although the renal receptor at which cicletanine acts is unknown, cicletanine was assumed to act like thiazide diuretics. Here we tested cicletanine and its natriuretic metabolite, cicletanine-sulfate, for inhibitory activity against the thiazide-sensitive NaCl cotransporter expressed in Xenopus oocytes. The renal thiazide-sensitive NaCl cotransporter was expressed in Xenopus laevis oocytes injected with rat cRNA TSCr (TSCr: thiazide-sensitive cotransporter from rat kidney) and both, racemic (+/-) cicletanine and its sulfoconjugated metabolite were tested for inhibitory activity against oocyte 22Na+ uptake catalyzed by this cotransporter. Polythiazide was used as reference thiazide. Polythiazide fully inhibited NaCl cotransporter function with IC50 approximately 1.2 x 10(-7) M. Conversely, neither cicletanine, nor cicletanine sulfate were able to inhibit such cotransporter, i.e.: a minimum concentration of 10(-4) M of cicletanine was necessary to induce a slight cotransporter inhibition (29.5 +/- 18.2%). Cicletanine sulfate was inactive, even at 10(-4) M. IN CONCLUSION: (i) the natriuretic metabolite of cicletanine (cicletanine sulfate) is unable to inhibit thiazide-sensitive NaCl cotransporter and (ii) inhibition of such cotransporter by cicletanine required concentrations equal or higher than 10(-4) M--concentrations much more higher than urinary therapeutic ones in humans (approximately 10(-6) M). These results clearly demonstrate that cicletanine does not act like thiazide diuretics.

Animals↗
PubMed1999

In vitro and in vivo effects of desmopressin on platelet function.

BACKGROUND AND OBJECTIVE: Desmopressin (DDAVP) may shorten bleeding time in patients with disorders of platelet function, but its mechanism of action in these conditions is still a matter of debate. In particular, contrasting results have been obtained concerning the ability of DDAVP to interact with platelets and to activate them directly. To gain further information on the DDAVP-platelet interaction, we studied the in vitro and ex vivo effects of DDAVP on platelet function. DESIGN AND METHODS: Platelet responses to DDAVP both as a single agent and in conjunction with agonists of platelet activation were investigated. For in vitro experiments platelets were obtained from healthy adult volunteers, while the ex vivo effects of DDAVP were studied in 12 patients with a bleeding disorder receiving a test dose of this drug. RESULTS: DDAVP in vitro did not induce either platelet aggregation or surface expression of the activation-dependent antigens; it did, however, greatly inhibit platelet aggregation response to vasopressin (AVP) and increased the maximal extent of platelet aggregation induced by collagen and ADP. DDAVP infusion did not promote the expression of activation antigens, but significantly enhanced ex vivo platelet aggregation stimulated by ADP and collagen. This priming effect was observed in patients with von Willebrand's disease, hemophilia A, May-Hegglin anomaly, gray platelet syndrome and Ehlers-Danlos syndrome. In all these patients bleeding time was shortened by DDAVP infusion. In contrast, neither platelet aggregation nor bleeding time was modified in two subjects with Glanzmann's thrombasthenia. INTERPRETATION AND CONCLUSIONS: Our in vitro experiments indicate that DDAVP interacts directly with platelets and facilitates their activation via other agonists. In vivo results suggest that this effect occurs and is clinically relevant in patients with platelet dysfunction responding to DDAVP with a shortening of bleeding time.

Adenosine Diphosphate↗
PubMed1998

A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers.

To assess the risk factors, natural history, and eligibility for curative treatment of early-detected hepatocellular carcinoma (HCC), 385 hemophiliacs who were treated with blood or plasma derivates for at least 10 years and had persistently elevated aminotransferase values underwent an annual screening with an abdominal ultrasound examination and measurement of the serum alpha-fetoprotein (AFP) level. Of these, 355 had serum antibody to hepatitis C virus (anti-HCV), 29 had anti-HCV and hepatitis B surface antigen (HBsAg), and one had HBsAg alone; 141 had serum antibody to human immunodeficiency virus (anti-HIV). During 48 months of follow-up study, six patients developed HCC. All HCC patients had a HCV-related cirrhosis and had been exposed to HCV risk at a median age of 40 years. All patients had a multicentric tumor, which was not eligible for curative treatment. Univariate analysis showed age, cirrhosis, and baseline AFP levels to be significantly associated with an increased risk of HCC. By multivariate analysis, the risk of HCC was infinite in patients with cirrhosis, 31.0 for those with baseline AFP higher than 11 ng/mL, and 17.9 for those more than 45 years of age. In conclusion, the risk of cancer was greater for patients infected later in life, particularly those with cirrhosis and high AFP. Annual screening of hemophiliacs with ultrasound and AFP fails to identify potentially curable tumors because the diagnosis is made at a late stage of the disease.

Adolescent↗
PubMed1998

Expression of dipeptidylaminopeptidase IV/CD26 in peripheral blood lymphocytes of hemophilic subjects.

CD26 antigen, a 110 kDa membrane glycoprotein with exopeptidase activity (DAP IV), is an activation marker of T lymphocytes preferentially expressed on CD4+ memory cells and involved in T cell proliferation and IL-2 production after antigenic stimulation. We employed cytochemical and immunocytochemical techniques to study DAP IV/CD26 expression in circulating lymphocytes from 40 hemophilic patients, chronically treated with coagulation factors, in order to verify the possible involvement of this molecule in the immunological alterations of hemophilia. In all the hemophiliacs DAP IV activity was significantly lower than in the controls, independently of the quantity of blood transfused and previous exposure to viruses. This reduction may be responsible for the impaired proliferative response of lymphocytes to antigens and mitogens, notoriously observed in hemophilia. Whereas in the group of HIV- patients CD26 expression was similar to that of normal controls, in the 8 HIV+ hemophilic patients both percentages of positive lymphocytes and intensity of staining were significantly lower. In only 4 of the 8 cases was this deficit associated with CD4+ cell depletion. The significant selective loss of CD26 expression observed in HIV+ patients is probably an early event after HIV infection and seems to occur even before CD4 cell depletion. In conclusion, evaluation of DAP IV/CD26 might be a useful option for monitoring the immunological alterations of all hemophilic patients, HIV positive or not, chronically treated with coagulation factors.

Adolescent↗
PubMed1998

Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression.

The role of nitric oxide (NO) during cyclosporin renal vasoconstriction was evaluated by glomerular hemodynamic and histological changes produced by chronic NO synthesis inhibition and neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) NO syntheses mRNA expression in renal cortex and medulla. Uninephrectomized rats treated during 7 days with vehicle (Veh), cyclosporin A (CsA) 30 mg/kg, CsA + nitro-L-arginine methyl ester (L-NAME), and Veh + L-NAME (10 mg/dl) in the drinking water were studied. Increase in arterial pressure and afferent and efferent resistances, as well as decrease in glomerular plasma flow, ultrafiltration coefficient, and single-nephron glomerular filtration rate were significantly greater with CsA + L-NAME than with CsA alone. The increase in afferent resistance was higher with CsA + L-NAME than with Veh + L-NAME. In addition, glomerular thrombosis, proximal tubular vacuolization, and arteriolar thickening were more prominent. In renal cortex, eNOS mRNA expression exhibited a 2.7-fold increase in CsA, whereas, in medulla, nNOS and iNOs expression were lower in CsA than in Veh, while eNOS tended to increase. Our results support the hypothesis that NO synthesis is enhanced at cortical level during CsA nephrotoxicity, counterbalancing predominantly preglomerular vasoconstriction. Higher NO production could be the result of increased eNOS mRNA expression.

Animals↗
PubMed1998

Electroneutral Na-coupled cotransporter expression in the kidney during variations of NaCl and water metabolism.

The purpose of the present study was to analyze the long-term regulation of renal bumetanide-sensitive Na+-K+-2Cl- cotransporter and thiazide-sensitive Na+-Cl- cotransporter gene expression during changes in NaCl and water metabolism. Male Wistar rats exposed to high or low NaCl intake, saline loading, dehydration, water loading, and furosemide administration during 7 days were studied. Control groups had access to regular food and tap water. Rats were kept in metabolic cages for 4 days before and during the experiment to determine daily urinary electrolyte excretion and osmolarity. At the end of the experiment, creatinine clearance and serum electrolyte levels were also measured. Kidneys were excised and macroscopically subdivided into cortex and outer and inner medulla. Total RNA was extracted from each individual cortex or outer medulla by use of the guanidine/cesium chloride method. The Na+-K+-2Cl- cotransporter expression in outer medulla total RNA was assessed by nonradioactive Northern blot analysis and the Na+-Cl- cotransporter expression in renal cortex total RNA was assessed by semiquantitative polymerase chain reaction. Experimental maneuvers were adequately tolerated, and all groups developed the appropriate renal response to each challenge. However, the level of expression of both cotransporters did not change in any model, except for a 2.8-fold increase in the Na+-Cl- cotransporter expression during dehydration. We conclude that nephron adaptation to 7-day modifications in NaCl and water metabolism does not include changes in the amount of electroneutral sodium-coupled cotransporter gene expression at the mRNA level.

Animals↗
PubMed1998

The electroneutral cation-chloride cotransporters.

Electroneutral cation-chloride cotransporters are widely expressed and perform a variety of physiological roles. A novel gene family of five members, encompassing a Na+-Cl- transporter, two Na+-K+-2Cl- transporters and two K+-Cl- cotransporters, encodes these membrane proteins; homologous genes have also been identified in a prokaryote and a number of lower eukaryotes. The cotransporter proteins share a common predicted membrane topology, with twelve putative transmembrane segments flanked by long hydrophilic N- and C-terminal cytoplasmic domains. The molecular identification of these transporters has had a significant impact on the study of their function, regulation and pathophysiology.

Animals↗
PubMed1997

Semi-quantitative PCR: a tool to study low abundance messages in the kidney.

Some specific functions are often localized to unique cellular types or structures in organs such as kidney, brain, blood, and endocrine glands. As a result, it is not uncommon that gene products, although heavily expressed in some cell types within these organs, ultimately appear as low abundance products when total RNA is probed, resulting in decreased power of the conventional Northern blot analysis. To study gene expression in these circumstances, more sensitive techniques like RNAse protection assay and quantitative or semi-quantitative PCR strategies have been developed. In the present study, we provide a detailed description of the semi-quantitative PCR strategy in our laboratory. Using specific primers to amplify fragments from the neuronal isoform of the nitric oxide synthase and the thiazide-sensitive Na+:Cl- cotransporter (low abundance messages in the kidney), we show that the semi-quantitative PCR strategy is a valuable tool when low abundance messages are to be studied.

Animals↗
PubMed1996

Thrombin activity and early outcome in unstable angina pectoris.

BACKGROUND: The blood coagulation system is frequently activated in the acute phase of unstable angina, but it is unknown whether the augmented function of the hemostatic mechanism may serve as a marker of increased risk for an early unfavorable outcome. METHODS AND RESULTS: Plasma concentrations and 24-hour urinary excretion of fibrinopeptide A were prospectively determined in 150 patients with unstable angina. All patients underwent 24-hour Holter monitoring, during which time urine was collected; at the end of this period, a blood sample was taken and coronary arteriography was performed. The patients were followed up for the occurrence of cardiac events (death and myocardial infarction) until they underwent coronary revascularization or until they were discharged from the hospital. Fibrinopeptide A plasma levels and 24-hour urinary excretion were found to be abnormally elevated in 50% and 45% of the study population, respectively. During hospitalization, 11 patients developed myocardial infarction and 2 patients died. Kaplan-Meier analysis demonstrated a significantly higher probability of developing cardiac events in patients with abnormal rather than normal plasma levels of fibrinopeptide A (P<.01), whereas no difference in outcome was observed between patients with normal and those with abnormal 24-hour urinary excretion. Cox regression analysis showed that the only variables independently related to an early unfavorable outcome were the presence of persistent ischemia during 24-hour Holter monitoring (P<.0001), the presence of intracoronary thrombosis at angiography (P=.016), and abnormal fibrinopeptide A plasma levels (P=.038). CONCLUSIONS: Patients with unstable angina pectoris and abnormal fibrinopeptide A plasma levels are at increased risk for an early unfavorable outcome.

Aged↗
PubMed1996

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry.

PURPOSE: To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND METHODS: Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death. RESULTS: Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkin's lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each). CONCLUSIONS: The present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

Adolescent↗