Osteitis fibrosa cystica, coeliac disease and Turner syndrome. A case report.

Today, osteitis fibrosa cystica is seldom present in primary hyperparathyroidism while it is mainly observed in uraemic osteodystrophy. We describe the case of a 54-year-old woman who was found to have huge bone cysts due to osteitis fibrosa cystica in the long bones. A parathyroid adenoma was identified and removed. Coeliac disease and Turner syndrome were diagnosed. Metabolic bone disease due to secondary hyperparathyroidism is common in coeliac disease; however, osteitis fibrosa cystica has not yet been described.

Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis.

It is still uncertain which, if any, immunologic parameters may help diagnose a renal flare of lupus nephritis. Anti-C1q antibody (Ab) titers have been elevated in patients with lupus with renal involvement, but little information is available on whether the titers are different in quiescent and active phases of lupus nephritis. In this study, we compared anti-C1q Ab titers with other serological test results in 48 patients with biopsy-proven lupus nephritis to assess which parameter could offer the best reliability for differentiating between quiescent and active phases of lupus nephritis. Serum C3 and C4 levels, as well as anti-double-stranded DNA, antiendothelial cell, anti-C1q, and antiphospholipid Ab titers, were evaluated in patients with quiescent renal disease (38 samples) and those with clinical evidence of renal activity (23 samples). Only anti-C1q Ab titers correlated with active renal disease in both univariate (P < 0.0001) and multivariate analysis (P < 0.0001), with a sensitivity of 87% and a specificity of 92%. In six patients, immunologic parameters were measured serially. In all patients, the high anti-C1q Ab titers returned to normal values after treatment-induced remission. The other serological parameters did not show a significant association with renal disease activity. In patients with biopsy-proven lupus nephritis, anti-C1q Ab titers appear to be strongly related to renal disease activity. Their measurement may be useful for confirming the diagnosis of renal flares of lupus nephritis.

Anti-beta2 glycoprotein I antibodies cause inflammation and recruit dendritic cells in platelet clearance.

Scavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite proinflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the beta2 Glycoprotein I (beta2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se intemalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1beta, TNF-alpha, or IL-10, beta2GPI bound to activated platelets and was required for their recognition by anti-beta2GPI antibodies. DCs internalised platelets opsonised by anti-beta2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-alpha and IL-1beta by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-10. We conclude that anti-beta2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.

OBJECTIVE: To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro. METHODS: Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS). RESULTS: Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. CONCLUSION: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Anti-beta2 glycoprotein I antibodies prevent the De-activation of platelets and sustain their phagocytic clearance.

Exposure to phosphatidylserine (PS) tags dying and senescent cells for removal and identifies activated platelets. In this study we followed the fate of PS-exposing platelets in the presence of antibodies purified from Systemic Lupus Erythematosus (SLE) and primary Anti-phospholipid Syndrome (APS) patients' sera by beta2GPI affinity chromatography. Thrombin-activated platelets exposed PS and associated to beta2GPI. Both events were required for recognition by antibodies. Human monocyte-derived macrophages phagocytosed activated platelets only. Each macrophage internalized an average of 3.16+/-0.2 platelets after 60 min at 37 degrees C. Phagocytosis did not increase after longer incubations (4.65+/-0.26 platelets internalized by each macrophage after 300 min). Recognition of platelets by anti-beta2GPI antibodies significantly increased phagocytosis (P< 0.01). Upon withdrawal of thrombin, platelets downregulated PS (PS exposure t(1/2): 242 min) and the ability to be recognized by macrophages. Purified beta2GPI bound to PS-exposing platelets (association t(1/2): 250 min). Phosphatidyl serine exposure and beta2GPI association had virtually identical kinetics. Antibody binding prolonged the exposure of the beta2GPI/PS complex (t(1/2): >1200 min). The ability to phagocytose opsonized platelets was accordingly sustained (5.3+/-0.2 opsonized platelets were internalized by each macrophage after 60 min and 9.4+/-0.3 after 300 min). Anti-beta2GPI antibodies therefore poise activated platelets in a PS-exposing status, preventing the recycling of their function and favoring their phagocytic clearance.

Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I.

OBJECTIVE: To investigate the in vitro ability of antiphospholipid antibodies (aPL) to bind human trophoblast cells and to affect gonadotropin secretion and invasiveness. METHODS: Antiphospholipid antibody IgG from women with recurrent miscarriages, beta2-glycoprotein I (beta2GPI)-independent IgG aPL human monoclonal antibody (mAb) (519), and IgM anti-beta2GPI human mAb (TMIG2) were investigated for their binding to trophoblasts cultured for various amounts of time, their ability to affect invasiveness of Matrigel-coated filters, and their release of human chorionic gonadotropin (hCG). RESULTS: Polyclonal IgG aPL, as well as mAb 519 and TMIG2, bound to trophoblasts, the highest binding being found when cells displayed the greatest amount of syncytium formation. TM1G2 binding was found to be betaGPI dependent. Both polyclonal and monoclonal aPL, but not the controls, significantly reduced hCG release and Matrigel invasiveness. CONCLUSION: These findings suggest that aPL recognition of both anionic PL and adhered beta2GPI on trophoblast cell structures might represent a potential pathogenetic mechanism for defective placentation in women with the antiphospholipid syndrome.

Anti-endothelial cell IgG fractions from systemic lupus erythematosus patients bind to human endothelial cells and induce a pro-adhesive and a pro-inflammatory phenotype in vitro.

Affinity purified immunoglobulin G (IgG) fractions from systemic lupus erythematosus (SLE) patients positive for anti-endothelial cell antibodies (AECA) bind human umbilical vein endothelial cell (HUVEC) monolayers. In vitro incubation of serial protein concentrations of SLE AECA IgG induces a dose-dependent endothelial activation: i) increase of functional adhesion of the monocytic cell line U937; ii) upregulation of E-Selectin, ICAM-1, VCAM-1 expression evaluated by a cell solid-phase enzyme linked immunoassay; and iii) increased secretion of interleukin (IL)-6 in the culture supernatants. Control experiments carried out with HUVEC monolayers incubated with IgG fractions from normal healthy controls or from AECA negative SLE sera do not affect at all endothelial adhesion molecule expression or pro-inflammatory cytokine secretion. The AECA IgG effects are not related to both anti-phospholipid or anti-DNA activities. Taken together the findings suggest that these autoantibodies might be important in recruiting and in activating mononuclear leukocytes responsible for vessel wall infiltration and raise the possibility that AECA might display a pathogenic role in SLE vessel damage.

Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: role of opsonizing anti-beta2-glycoprotein I antibodies.

OBJECTIVE: To verify whether opsonization of apoptotic cells skews the outcome of apoptotic cell antigen presentation by dendritic cells (DCs). METHODS: RMA cells, which were engineered with a mutant ovalbumin (OVA) protein and were devoid of the leader secretory sequence (OVA-RMA), underwent ultraviolet irradiation to induce apoptosis. Binding of anti-beta2-glycoprotein I antibodies (anti-beta2GPI) and phagocytosis of apoptotic cells were assessed by flow cytometry and confocal microscopy. Presentation of processing antigens and major histocompatibility complex (MHC) class II-restricted or MHC class I-restricted antigens was assessed using OVA-specific T cell hybridomas. RESULTS: Anti-beta2GPI facilitated presentation of epitopes from internalized apoptotic cells to MHC class II-restricted, but not to class I-restricted, T lymphocytes. DCs challenged with supernatants of apoptotic cells did not activate OVA-specific T cells, making it unlikely that anti-beta2GPI complexed with antigen released from dying cells plays a role in antigen presentation. DCs challenged with low numbers of anti-beta2GPI-opsonized apoptotic cells secreted interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and IL-10 in an autocrine/paracrine manner. CONCLUSION: Opsonization influences the outcome of the disposal of low numbers of apoptotic cells by DCs. This implies that soluble factors bound to apoptotic cells modulate their immunogenicity.

Recurrent Salmonella sepsis and aortitis in a patient with hepatocellular carcinoma.

A 62 years old man was admitted to hospital because of fever; a small superficial hepatic nodule was showed by ultrasonography. Blood cultures grew Salmonella enteritidis. Cefotaxime was administered for ten days. Fever promptly disappeared but one week later recurred with abdominal and back pain. Cultures grew again Salmonella enteritidis. Biopsy of the hepatic nodule showed hepatocarcinoma. Computed abdominal tomography showed a paraaortic mass. Angiography demonstrated hematoma communicating with the aortic lumen. The patient underwent revascularization of the involved aortic tract and resection of the hepatic nodule. Histology showed suppurative aortic endarteritis and a well-differentiated hepatocellular carcinoma with a large area of suppurative necrosis. The recovery of Salmonella species as of any uncommon bacteria from blood should warrant a through research of underlying disease, especially cancer.

Human beta 2-glycoprotein I binds to endothelial cells through a cluster of lysine residues that are critical for anionic phospholipid binding and offers epitopes for anti-beta 2-glycoprotein I antibodies.

Beta 2-Glycoprotein I (beta 2GPI) is a phospholipid-binding protein recognized by serum autoantibodies from the anti-phospholipid syndrome both in cardiolipin- and beta 2GPI-coated plates. We found that: 1) recombinant wild-type beta 2GPI bound to HUVEC and was recognized by both human monoclonal IgM and affinity-purified polyclonal IgG anti-beta 2GPI anti-phospholipid syndrome Abs; and 2) a single amino acid change from Lys286 to Glu significantly reduced endothelial adhesion. Double and triple mutants (from Lys284,287 to Glu284,287, from Lys286,287 to Glu286,287, and from Lys284,286,287 to Glu284,286,287) completely abolished endothelial binding. A synthetic peptide (P1) spanning the sequence Glu274-Cys288 of the beta 2GPI fifth domain still displayed endothelial adhesion. Another peptide (P8), identical with P1 except that Cys281 and Cys288 were substituted with serine residues, did not bind to HUVEC. Anti-beta 2GPI Abs, once bound to P1 adhered to HUVEC, induced E-selectin expression and up-regulated IL-6 secretion. Control experiments conducted with irrelevant Abs as well as with the P8 peptide did not show any endothelial Ab binding nor E-selectin and IL-6 modulation. Our results suggest that: 1) beta 2GPI binds to endothelial cells through its fifth domain; 2) the major phospholipid-binding site that mediates the binding to anionic phospholipids is also involved in endothelial binding; 3) HUVEC provide a suitable surface for beta 2GPI binding comparable to that displayed by anionic phospholipids dried on microtiter wells; and 4) the formation of the complex between beta 2GPI and the specific Abs leads to endothelial activation in vitro.

Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies.

OBJECTIVE: To verify whether antiphospholipid antibodies (aPL) recognize and opsonize apoptotic human cells. METHODS: Apoptosis was induced via CD95 crosslinking or ultraviolet irradiation. IgG and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies were purified from patient sera by affinity chromatography. The aPL that bound to apoptotic cells were assessed by flow cytometry, and the subdomains recognized were identified by confocal microscopy. Human macrophages were derived from monocytes, and their ability to phagocytose 3H-labeled apoptotic bodies, whether opsonized or not opsonized by aPL, was assessed. Tumor necrosis factor alpha (TNF alpha) secretion was evaluated by enzyme-linked immunosorbent assay. RESULTS: The aPL, but not control Ig or Ig from aPL-negative patients, bound to apoptotic cells, but not to viable cells. Nuclear antigens were not recognized. Opsonization of apoptotic cells by aPL substantially enhanced recognition and binding by scavenger macrophages, with massive TNF alpha secretion. CONCLUSION: Antiphospholipid antibodies facilitate apoptotic cell clearance by macrophages and trigger TNF alpha release, possibly enhancing the immunogenicity of the autoantigens they contain.

Apoptotic cell clearance in systemic lupus erythematosus. II. Role of beta2-glycoprotein I.

OBJECTIVE: To analyze the contribution of beta2-glycoprotein I (beta2-GPI) to apoptotic cell recognition by antiphospholipid antibodies (aPL) and macrophages from patients with autoimmune disease. METHODS: Phosphatidylserine expression by Jurkat cells undergoing apoptosis upon CD95 crosslinking or ultraviolet irradiation was verified by confocal microscopy of cells stained with fluorescein isothiocyanate-labeled annexin V. Beta2-GPI was purified by heparin/cationic-exchange chromatography and was biotinylated or used to purify beta2-GPI-specific antibodies by affinity chromatography. Binding to apoptotic cells was assessed by flow cytometry. The clearance of 3H-labeled, apoptotic cells by macrophages was assessed by beta counting. RESULTS: The array of epitopes generated by beta2-GPI association with apoptotic cells specifically targets their recognition and is required for their opsonization by human aPL. Nevertheless, beta2-GPI is not required for apoptotic cell clearance by human macrophages in the absence of aPL. CONCLUSION: The proinflammatory clearance of aPL-opsonized apoptotic cells, but not the nonphlogistic clearance of apoptotic cells by scavenger macrophages, depends on beta2-GPI.

Ultrasound guided percutaneous fine-needle biopsy in a case of eosinophilic gastroenteritis.

Eosinophilic gastroenteritis is a rare disease; clinical features depend on which intestinal layer is involved. In our report a 70-year-old woman presented with intestinal subocclusion and ascites. Endoscopic biopsies of gastric mucosa were negative. Ultrasound guided percutaneous fine-needle biopsy showed muscle infiltration by eosinophils of muscle layer of the stomach and jejunum. Muscular and serosal disease are usually diagnosed only by laparotomy or laparoscopy.

Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-beta 2-glycoprotein I antibodies react in vitro with endothelial cells through adherent beta 2-glycoprotein I and induce endothelial activation.

OBJECTIVE: To investigate the ability of human anti-beta 2-glycoprotein I (anti-beta 2 GPI) antibodies to recognize the cofactor adherent on endothelial cells (EC) and to modulate endothelial functions. METHODS: Six human affinity-purified polyclonal anti-beta 2 GPI IgG and 2 IgM monoclonal antibodies (MAb) were obtained from patients with the antiphospholipid syndrome. The antibodies were tested for their ability to 1) bind to endothelial monolayers through the adherent beta 2 GPI and 2) modulate endothelial adhesion molecule expression and interleukin-6 (IL-6) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) secretion. RESULTS: The affinity-purified IgG and the MAb with anti-beta 2 GPI activity, but not the respective controls, displayed EC binding, which declined on cells incubated in serum-free medium and was restored in a dose-dependent manner by exogenous human beta 2 GPI. After EC binding, both polyclonal and monoclonal antibodies up-regulated adhesion molecule expression. Anti-beta 2 GPI MAb also significantly increased IL-6 and 6-keto-PGF1 alpha secretion. CONCLUSION: These findings support the hypothesis that anti-beta 2 GPI antibodies bind and activate EC through the adherent cofactor beta 2 GPI, likely leading to a procoagulant state.

International survey on the management of patients with SLE. II. The results of a questionnaire regarding neuropsychiatric manifestations.

OBJECTIVE: To determine the diagnostic and therapeutic approach used in clinical practice for the management of systemic lupus erythematosus (SLE) patients with primary SLE-mediated neuropsychiatric (NP) manifestations. METHODS: A questionnaire was drawn up to assess how clinicians manage various clinical manifestations of SLE. A portion of this questionnaire was designed to assess how clinicians diagnose and treat primary NP-SLE. Most of the questions in the NP-SLE section consisted of lists of different clinical manifestations and laboratory or radiological studies that participants were asked to rate on a scale of importance [from 1 (extremely important) to 5 (not important)] to the diagnosis of primary NP-SLE. The questionnaire also assessed how different NP manifestations are treated in clinical practice. The relative importance of each clinical manifestation was determined through its mean score, and the agreement among participants on each issue was determined using the coefficient of variation (CV). Fifty-nine lupus centers participated in the NP-SLE portion of the survey. RESULTS: The clinical manifestations which were considered to be of extreme or major importance for the diagnosis of primary NP-SLE were seizures, psychosis, transverse myelitis, stroke, transient ischemic attack (TIA) and aseptic meningitis. Among the radiological and laboratory studies, only brain magnetic resonance imaging (MRI) and antiphospholipid antibodies (aPL) achieved "extremely important" mean scores (between 1 and 2). aPL testing was used routinely in the majority of patients (mean 96.8%; CV = 0.1), while brain MRI was used less frequently (mean 56.5%; CV = 0.61). Only brain MRI and cerebral angiography were considered to be helpful in differentiating cerebral vasculopathy from multi-infarct (mean score = 1.6 and 1.9, respectively), whereas a prompt response to treatment with increased doses of steroids was considered helpful in differentiating SLE-related psychosis from steroid-induced psychosis (mean score = 1.58). The results of aPL testing, coagulation tests for the lupus anticoagulant, an brain MRI were considered to be of extreme or major importance in decisions involving treatment with anticoagulant or anti-platelet therapy. Symptomatic therapies, such as heparin, or anti-convulsant, anti-platelet, oral anticoagulant, and antipsychotic therapy were the most widely used. Corticosteroids were the most frequently used immunosuppressive therapy. The administration of other immunosuppressive agents as specific treatment for NP-SLE was uncommon. CONCLUSIONS: Our survey found that in clinical practice, the NP manifestations currently considered to be diagnostic of primary SLE-mediated CNS involvement are not limited to those included in the American Rheumatism Association (ARA) criteria, e.g. seizures and psychosis. Antiphospholipid antibodies appeared to be the laboratory parameter most frequently relied upon in the diagnosis of NP-SLE, and in decisions regarding treatment. Apart from that, only brain MRI and, in selected cases, cerebral angiography seemed to be of real help in diagnosis. The lack of consensus regarding the treatment of primary NP-SLE manifestations most probably reflects both the complex nature of neurological illness in SLE patients and the lack of clear diagnostic criteria.

International survey on the management of patients with SLE. III. The results of a questionnaire regarding renal involvement.

OBJECTIVE: To assess the practice patterns in the management of lupus nephritis (LN) of physicians dealing with systemic lupus erythematosus. METHODS: A multiple choice questionnaire was sent to 135 lupus centers, mainly in Europe. It was divided into 4 sections, one of which regarded LN. Sixty-one centers (40%) sent the questionnaire back before the meeting; however two of them did not fill out the LN section. Therefore, 59 valid LN questionnaires were collected and analyzed. Statistical evaluation was performed using frequency analysis and the chi-square test. RESULTS: In 50 centers (85%), renal biopsy is performed in all patients with clinically evident renal involvement, and in most of them it is repeated in cases of relapse and/or ineffectiveness of treatment. Oral steroid alone is the therapy preferred by 67% of responding physicians in patients with WHO class II LN. Multi-drug therapy is favoured by 57% in patients with class III LN, by 79% for mild-to-moderate forms of class IV LN (IVm), by 84% for moderate-to-severe forms of class IV LN (IVs), by 47% for mild-to-moderate forms of class V LN (Vm), and by 65% for moderate-to-severe forms of class V LN (Vs). Steroids plus cyclophosphamide (CYPH) is the association most commonly used for class III, IVm and IVs LN, having been indicated by 70%, 80% and 88% of the centers, respectively. Furthermore, pulse CYPH is largely preferred to oral CYPH by the majority of centers. It is worth noting that 41 centers (70%, p < 0.01) utilise the same drugs in the treatment of both WHO class IVm and IVs LN. No clear trends in the use of multi-drug associations were identifiable in the treatment of class V LN. Moreover, most of the centers (64%) said that they rely on histologic parameters in order to define renal prognosis and that they consider the chronicity index to be the best predictor of poor renal outcome (74% of the centers). CONCLUSIONS: It was possible to identify some clear trends in the behaviour of physicians who are "expert" in lupus patients: (i) they perform a renal biopsy in order to charaterize the LN and repeat it when they are faced with relapse or ineffective therapy; (ii) they treat WHO class II LN with oral steroids alone and class III and IV LN with steroids associated with CYPH (CYPH, generally in a pulse regimen); and (iii) they define renal prognosis by means of histologic predictors, especially the chronicity index. However, no trend seemed to exist for the treatment of class V LN, particularly Vm.

Anti-endothelial cell IgG antibodies from patients with Wegener's granulomatosis bind to human endothelial cells in vitro and induce adhesion molecule expression and cytokine secretion.

OBJECTIVE: To elucidate the role of anti-endothelial cell antibodies (AECA) in vascular inflammation in patients with Wegener's granulomatosis (WG). METHODS: IgG fractions from 3 AECA-positive WG patients, IgG from 3 AECA-negative WG patients, and IgG from healthy donors were tested for their ability to: a) bind to endothelial cells and to display complement-dependent or antibody-dependent cellular cytotoxicity, b) modulate cell membrane expression of adhesion molecules, as evaluated by cytofluorometry and by immunoenzymatic assay, and c) induce the secretion of interleukin-1 beta (IL-1 beta), IL-6, IL-8, and monocyte chemotactic protein 1 (MCP-1). RESULTS: We found that AECA IgG from WG patients do not display any significant cytotoxicity but are able to up-regulate the expression of E-selectin, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and to induce the secretion of IL-1 beta, IL-6, IL-8, and MCP-1. CONCLUSION: AECA in patients with WG could play a potential pathogenetic role by activating endothelial cells, and thus facilitating leukocyte recruitment and adhesion to endothelial surfaces, rather than by displaying a cytotoxic activity.

Fish oil supplementation in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia is associated with premature coronary heart disease. In patients with familial hypercholesterolemia, monotherapy with hydroxymethylglutaril coenzyme. A reductase inhibitors rarely achieves the goal of desirable low-density lipoprotein levels. Epidemiological studies suggest that populations with a high dietary intake of marine n3 fatty acids are protected against coronary heart disease. Hepatic synthesis and secretion of very low density lipoproteins are reduced during fish oil supplementation while other effects on lipid and lipoprotein metabolism are controversial. Fourteen patients affected by familial heterozygous hypercholesterolemia on chronic treatment with simvastatin were enrolled in a double blind, placebo controlled, randomized crossover trial that evaluated the effect of fish oil ethyl ester (Esapent, 5.1 g/day) on lipid and lipoprotein serum concentrations. Total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apoprotein B, apoprotein AI, lipoprotein (a) did not show any significant variation during the four week treatment period with fish oil ethyl ester. The present data suggest that the possible favourable influence of fish oil on the progression of atherosclerosis in these high-risk patients might involve mechanisms which are different from lipid metabolism.

Pravastatin-associated myopathy. Report of a case.

A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.

Beta 2 glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome.

OBJECTIVE: To investigate the immunohistological distribution of beta 2-glycoprotein I (beta 2 GPI) and placental anticoagulant protein I (PAP-I) in normal and pathological placentae of patients with antiphospholipid (aPL) antibody associated recurrent fetal loss. These proteins are 2 natural anticoagulants able to interfere with aPL antibody binding. METHODS: Placentae from 4 patients with primary antiphospholipid antibody syndrome (pAPS), from 2 patients with aPL negative systemic lupus erythematosus (SLE) and from 7 healthy women were studied. Cryostatic placental sections were tested by indirect immunofluorescence using polyclonal anti-PAP-I and anti-beta 2GPI antisera as well as purified IgG and anti-beta 2GPI monoclonal antibody. The same tissue sections were also tested by direct immunofluorescence with FITC-F(ab)2 goat antihuman IgG. RESULTS: We found that (a) the placental distribution of PAP-I was comparable in normal and pathological specimens; (b) on the contrary, increased beta 2GPI deposition was present on the trophoblast surfaces of placentae obtained from patients with persistent raised titers of aPL antibodies. Comparable IgG deposition on villi surface was also found in aPL positive but not in control placentae. CONCLUSION: Our data are consistent with the hypothesis that high titer aPL binds to a beta 2GPI phospholipid complex in placentae of women with recurrent fetal loss but that a quantitative deficiency of PAP-I does not play a pathogenetic role in aPL associated fetal loss.