Auditing HIV Testing Rates across Europe: Results from the HIDES 2 Study.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Interleukin-18 binding protein in the sera of patients with Wegener's granulomatosis.

INTRODUCTION: In the present study, we examined the levels of the pro-inflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of Wegener's granulomatosis (WG) patients at various stages of the disease. PATIENTS AND METHODS: Sera from eight consecutive biopsy-proven systemic WG patients (four men and four women; age at diagnosis 58.4 +/- 13.8 years) were obtained longitudinally with a follow-up period of 55.2 +/- 30 months. Sera obtained from 50 healthy subjects were used as controls. RESULTS AND DISCUSSION: Serum levels of IL-18, IL-18BP, and free IL-18 obtained during an active phase of the disease (Birmingham Vasculitis Activity Score, BVAS > 10) were more than twofold higher than levels in the same patients during inactive disease stages (BVAS < 5; P < 0.002; P < 0.006, and P < 0.03 for IL-18, IL-18BP, and free IL-18, respectively). During inactive stages, the levels of these markers were comparable to those of healthy controls. The elevated levels of IL-18 and IL-18BP in sera during active stages of disease suggest a possible role in the pathogenesis and course of the WG. CONCLUSION: Despite the elevated IL-18BP levels during active disease, free IL-18 remained higher than in the inactive disease stages, suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active WG.

Internal jugular vein thrombosis following mild ovarian hyperstimulation syndrome in women with factor V Leiden mutation.

OBJECTIVE: To study two women who presented with internal jugular vein thrombosis that developed shortly after in vitro fertilization (IVF) therapy complicated by mild ovarian hyperstimulation syndrome (OHSS). METHODS: Evaluation of the past medical history, treatment, laboratory studies, and clinical outcome of both patients. RESULTS: The two patients were found to be carriers for factor V Leiden mutation (FVLM). One was homozygote and the other heterozygote for that mutation. The genetic predisposition probably contributed to the development of an early thrombosis in these patients despite the mildness of their OHSS. In the homozygote patient, the dose of low molecular weight heparin was reduced due to vaginal bleeding. Afterwards, fetal loss due to an extensive placental infarction occurred. Infarction was confined to maternal side while the fetal side vessels were spared. CONCLUSION: We suggest that women of European descent, especially those with personal or familial history of thromboembolic events, should be screened for FVLM before IVF treatment. In those found to be carriers of FVLM, preventive anticoagulation should be considered.

Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of autoantibodies directed against an epitope of the glutamate/N-methyl-D-aspartic acid (NMDA) receptor subunit NR2A (which is highly expressed in human brain) in the sera of lupus patients, and to investigate the possible correlation of these antibodies with clinical and serological manifestations of systemic lupus erythematosus (SLE). METHODS: Sera were obtained from 109 consecutive SLE patients. Controls were 65 patients with myasthenia gravis, 19 with autoimmune polyendocrine syndrome type I (APS I), and 65 healthy donors. A 15 amino acid long peptide based on a sequence within the NR2A subunit of the NMDA/glutamate receptor was synthesised. Antibodies to this peptide were determined by enzyme linked immunosorbent assay. Antibodies against double stranded DNA (dsDNA) were measured by Chrithidia luciliae assay. Disease activity was determined using the SLE disease activity index (SLEDAI). RESULTS: Sera of 34/109 SLE patients (31%) reacted specifically with the NR2A peptide compared with only 4/65 myasthenia gravis patients (6.1%, p<0.001), 1/19 APS I patients (5.3%, p<0.02), and 3/65 healthy controls (4.6%, p<0.001). No correlation was found between the presence of NR2A and dsDNA or anti-cardiolipin specific autoantibodies. In addition, no significant correlation was observed between the presence of NR2A specific antibodies and the SLEDAI score or any lupus related clinical manifestations. CONCLUSIONS: A significant number of SLE patients (31%) have NR2A specific antibodies that do not correlate with anti-dsDNA antibodies. Additional studies of lupus patients with neurological disorders should elucidate the role of NR2A specific antibodies in lupus related CNS manifestations.

Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies.

BACKGROUND: Sex hormones have been shown to influence the immune system and to modify the course of autoimmune disorders. OBJECTIVE: To examine the effects of the oestrogen antagonist tamoxifen on the course of systemic lupus erythematosus (SLE) in (NZBxNZW)F1 mice. METHODS: Groups of 8 week old (NZBxNZW)F1 female mice were treated with tamoxifen (800 micro g/mouse; twice a week) or with double distilled water for four months. Mice were evaluated monthly for the presence of autoantibodies directed against DNA and nuclear extract (NE) by enzyme linked immunosorbent assay (ELISA). White blood cells and thrombocytes were quantified by a cell counter and proteinuria by combistix kit. At 6 months of age, all mice that did not die spontaneously were killed and evaluated for the presence of glomerular immune deposits by indirect immunofluorescence assay. IgG isotypes of autoantibodies in the mouse sera and glomeruli were determined by gamma chain specific antibodies. RESULTS: Tamoxifen treatment significantly reduced autoantibody production directed against either NE or DNA. The latter reduction was mainly in autoantibodies of the IgG3 isotype. Furthermore, tamoxifen had significant beneficial effects on the course of SLE in (NZBxNZW)F1 mice. At 6 months of age, 40% of the untreated mice died spontaneously, whereas all the tamoxifen treated mice were still alive. All untreated mice showed severe thrombocytopenia and persistent proteinuria, with diffuse glomerular immune deposits of IgG2a and IgG3 isotypes in their kidneys. In contrast, the tamoxifen treated mice had a normal number of thrombocytes and only minimal proteinuria. Moreover, glomerular immune deposits were detected in <40% of the tamoxifen treated mice. The latter were mainly of the IgG2a but not of the IgG3 isotype. CONCLUSION: The results clearly show the remarkable therapeutic effects of tamoxifen on SLE of (NZBxNZW)F1 female mice and suggest that these beneficial effects are related to the specific reduction of IgG3 autoantibodies.

Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies.

Two peptides, based on the sequences of the complementarity-determining regions (CDR) 1 and 3 of a pathogenic murine monoclonal anti-DNA autoatibody that bears the 16/6 idiotype (Id), were shown to either prevent or treat an already established systemic lupus erythematosus (SLE) in two murine models of lupus. Two additional peptides based on the human monoclonal anti-DNA, 16/6 Id were synthesized. This study was undertaken in order to investigate the ability of the CDR-based peptides to immunomodulate SLE-associated responses of peripheral blood lymphocytes (PBL) of SLE patients. PBL of 24 of the 62 SLE patients tested proliferated in vitro following stimulation with the human 16/6 Id. Peptides based on the CDRs of both the human and murine anti-DNA autoantibodies inhibited efficiently and specifically the 16/6 Id-induced proliferation and IL-2 production. The latter inhibitions correlated with an up-regulated production (by 2.5-3.5-fold) of the immunosuppressive cytokine, TGF-beta. Overall, the results of our study demonstrate that the CDR-based peptides are capable of down-regulating in vitro autoreactive T cell responses of PBL of SLE patients. Thus, these peptides are potential candidates for a novel specific treatment of SLE patients.

Limited polyarteritis nodosa of the male and female reproductive systems: diagnostic and therapeutic approach.

BACKGROUND: Polyarteritis nodosa (PAN) is a multisystem necrotising small and medium sized vasculitis that when left untreated carries a grave prognosis, with a five year survival of 10-15%. Prolonged immunosuppressive treatment with cyclophosphamide and steroids leads to high remission rates while carrying the risk of life threatening complications. The diagnostic and therapeutic approach for patients with isolated genital tract PAN is not well defined. OBJECTIVE: To present the management and follow up of two patients with limited PAN localised to the male and female reproductive system. CASE REPORTS: A 26 year old man presented with an "acute scrotum". He was afebrile and had no other sign or symptom. Laboratory tests, including complete blood count, erythrocyte sedimentation rate, liver and renal function tests, C reactive protein, antinuclear antibody, cryoglobulins, complement levels, antineutrophil cytoplasmic antibodies, and hepatitis B surface antigen, were all normal. His left testis was excised. Histopathology disclosed PAN of medium sized arteries with testicular infarction but no signs of torsion or infection. The other patient was a 51 year old woman who had had a total hysterectomy for a uterine myoma; incidentally PAN of the uterus and fallopian tubes was discovered. Neither patient received any immunosuppressive treatment after surgical removal of the affected organ. On prolonged follow up (clinical and laboratory evaluation) both patients are healthy with no sign of local recurrence or systemic PAN.

Anticardiolipin autoantibodies in serum samples and cryoglobulins of patients with chronic hepatitis C infection.

OBJECTIVE: Chronic hepatitis C virus (HCV) has been linked to extrahepatic autoimmune phenomena. In addition, a variety of autoantibodies are found in patients with HCV. The prevalence, nature, and clinical significance of anticardiolipin (aCL) autoantibodies in serum samples of patients with HCV were therefore investigated. PATIENTS AND METHODS: A prospective study of 48 consecutive patients with chronic HCV with no evidence of previous hepatitis B virus (HBV) infection or any other autoimmune disorder. Thirty patients with HBV and 50 healthy volunteers matched for age and sex served as control groups. Anticardiolipin antibodies in the serum samples and cryoprecipitates were measured by a sensitive enzyme linked immunosorbent assay (ELISA). The beta(2) glycoprotein I (beta(2)-GPI) dependency was determined by carrying out aCL assays in the presence or absence of fetal calf serum samples. RESULTS: High levels of IgG aCL antibodies were detected in serum samples of 21/48 (44%) patients with HCV. These autoantibodies showed no beta(2)-GPI dependency. The control groups had much lower levels of aCL antibodies (20% in the patients with HBV and none in the normal volunteers). Cryoprecipitates from four patients with HCV (three aCL positive; one aCL negative) were further isolated. In two of the three aCL positive patients, specific cardiolipin reactivity was shown in the cryoprecipitates. The group of patients with HCV and aCL antibodies in their serum showed significantly higher total IgG levels, a higher incidence of antinuclear antibodies, and viraemia (HCV RNA) than the aCL negative patients. None of the patients with HCV and aCL antibodies showed any clinical manifestations related to those autoantibodies. CONCLUSIONS: This study clearly shows a high prevalence of IgG aCL antibodies in the serum of patients with HCV and the localisation of these antibodies in some cryoprecipitates. The role of these autoantibodies on the course of HCV infection and their clinical significance has not yet been determined.

CD24 is a marker for human breast carcinoma.

CD24 is a small, mucin-type glycosylphosphatidylinositol-linked cell surface molecule expressed by neutrophils, pre B lymphocytes and certain human tumor cell lines. CD24 has been identified as a ligand for P-selectin in both mouse and human cells. We previously reported that the P-selectin-CD24 binding pathway is important for the binding of the breast carcinoma cell line KS to platelets and the rolling of these cells on endothelial P-selectin. In the present study we have analyzed the expression of CD24 on human breast carcinoma cell lines and on fresh breast carcinoma specimens using the CD24-specific antibody ML-5. Our study clearly demonstrates that CD24 is abundantly expressed on cell lines and fresh tissues of breast carcinomas. We find a differential expression of CD24 in breast carcinomas (cytoplasmic pattern) versus benign breast lesions (apical pattern). Moreover, the intensity of CD24 expression increases with the histological grade of the tumor. Thus, CD24 expression might be a useful marker for human breast carcinoma and play a role in facilitating metastasis by the interaction between tumor cells and platelets or endothelial cells.

Primary multifocal lymphoma of bone presenting as hypercalcemic crisis: report of a rare manifestation of extranodal lymphoma.

Primary non-Hodgkin's lymphoma of bone is uncommon and usually manifests clinically as localized bone pain. Here we report a woman who presented with hypercalcemic crisis and extensive investigation revealed a primary multifocal lymphoma of bone. The course of the disease was very aggressive and despite intensive supportive care and urgent chemotherapy the patient died within 1 month. Since her blood PTH and calcitriol levels were suppressed and her parathyroid-hormone-related peptide (PTHrp) was mildly elevated, we believe that release of cytokines combined with PTHrp, as well as extensive osteolytic lesions, were the causes of the hypercalcemia. This is an unusual presenting symptom of lymphomas and to the best of our knowledge severe symptomatic hypercalcemia and crisis has never been reported in primary lymphoma of bone before.

Acute femoral artery thrombosis associated with functional protein C deficiency as the presenting manifestation of acute monocytic leukemia.

Acute leukemia may be linked to disturbances of the coagulation system, which are usually due to hyperviscosity because of disseminated intravascular coagulation or a high white cell count. We report a unique case of femoral artery thrombosis as the beginning symptom of acute monocytic leukemia (M5) associated with a low level of functional protein C. The patient had multiple recurrent episodes of thrombosis with low levels of functional protein C associated with the relapse of the leukemia. A review of the literature shows that this is an extremely rare phenomenon.

Idiopathic calcitriol-induced hypercalcemia. A new disease entity?

We describe 3 patients with a prolonged history of hypercalcemia. The patients did not take any vitamin supplements. All patients had low parathyroid hormone (PTH), high calcitriol (1,25(OH)2D3), and high angiotensin-converting enzyme (ACE) blood levels. There was no evidence of sarcoidosis of any other underlying disease in the results of an extensive workup. Treatment with prednisone resulted in normalization of calcium levels in all patients. They remained dependent on low-dose prednisone on a subsequent prolonged follow-up.

[Budd-Chiari syndrome].

Budd Chiari syndrome is a rare disorder resulting from occlusion of hepatic venous drainage by hepatic vein thrombosis or by a membranous web in the inferior vena cava. In western countries the commonest causes are myeloproliferative disorders and hypercoagulable states. Presentation may be acute with rapid accumulation of ascites and hepatic failure, or subacute with symptoms developing over a few months. A chronic progressive form has also been described. On presentation there is usually abdominal pain, ascites, and hepatosplenomegaly; hepatic encephalopathy is found in about a third. Noninvasive, ultrasound-Doppler is recommended in diagnosis, and has a high correlation with hepatic venography. Liver biopsy is required for therapeutic decisions. Those with advanced hepatic failure or severe fibrosis on liver biopsy are referred for hepatic transplantation. When biopsy shows only hepatic congestion and inflammatory infiltrates, portosystemic shunting is recommended. We present a 61-year-old woman with ascites and hepatosplenomegaly that had developed over the courses of a few months. Budd-Chiari syndrome with chronic myelofibrosis and congenital protein C deficiency were diagnosed. Portosystemic shunt was performed but death from sepsis followed shortly.

Severe hepatotoxicity on beginning propylthiouracil therapy.

We report a case of propylthiouracil (PTU)-induced cholestatic hepatotoxicity in Graves' disease that developed 1 day after beginning PTU. After clinical recover, liver abnormalities persisted for 5 years. Percutaneous liver biopsy and the eventual normalization of enzyme levels excluded permanent liver damage as a result of PTU therapy. Thus prolonged elevation of serum enzymes is consistent with the diagnosis of PTU-induced hepatotoxicity, which may recover completely.

CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells.

P-selectin (CD62P) is a Ca2+-dependent endogenous lectin that can be expressed by vascular endothelium and platelets. The major ligand for P-selectin on leukocytes is P-selectin glycoprotein ligand-1 (PSGL-1). P-selectin can also bind to carcinoma cells, but the nature of the ligand(s) on these cells is unknown. Here we investigated the P-selectin binding to a breast and a small cell lung carcinoma cell line that are negative for PSGL-1. We report that CD24, a mucin-type glycosylphosphatidylinositol-linked cell surface molecule on human neutrophils, pre B lymphocytes, and many tumors can promote binding to P-selectin. Latex beads coated with purified CD24 from the two carcinoma cell lines but also neutrophils could bind specifically to P-selectin-IgG. The binding was dependent on divalent cations and was abolished by treatment with O-sialoglycoprotein endopeptidase but not endoglycosidase F or sialidase. The beads were stained with a monoclonal antibody (MoAb) to CD57 (HNK-1 carbohydrate epitope) but did not react with MoAbs against the sialylLe(x/a) epitope. The carcinoma cells and CD24-beads derived from these cells could bind to activated platelets or P-selectin transfected Chinese hamster ovary cells (P-CHO) in a P-selectin-dependent manner and this binding was blocked by soluble CD24. Transfection of human adenocarcinoma cells with CD24 enhanced the P-selectin-dependent binding to activated platelets. Treatment of the carcinoma cells or the CD24 transfectant with phosphatidylinositol-specific phospholipase C reduced CD24 expression and P-selectin-IgG binding concomitantly. These results establish a role of CD24 as a novel ligand for P-selectin on tumor cells. The CD24/P-selectin binding pathway could be important in the dissimination of tumor cells by facilitating the interaction with platelets or endothelial cells.

HCV hepatitis associated with anticardiolipin antibody and a cerebrovascular accident. Response to interferon therapy.

A 54-year-old man with chronic hepatitis C virus (HCV) developed quadrihemianopsia caused by lacunar brain infarction. Extensive evaluation revealed high titers of anticardiolipin antibodies (ACA). Following interferon treatment (6 x 10(6), three times a week for 2 months and 3 x 10(6) for another 7 months), liver transaminase levels decreased to normal, HCV RNA in blood was no longer detectable, concomitantly with the disappearance of the ACA. The patient remained clinically stable without evidence for either HCV activity (RNA) or ACA or further thromboembolic events.

Palmar fasciitis and polyarthritis associated with ovarian carcinoma in a young patient. A case report and review of the literature.

Palmar fasciitis and polyarthritis (PFPA) is an uncommon syndrome characterized by progressive and extensive rheumatic disease. It has usually been associated with neoplasms, most commonly in elderly patients, preceding or accompanying the diagnosis of malignancy. We report a case of a 25-year-old patient with severe deforming PFPA preceding the diagnosis of carcinoma of the ovary. The histopathological findings of diffuse fibrosis, connective tissue proliferation and vasculitis with C3 and IgM deposits in subcutaneous tissue and synovia may further clarify the possible pathogenesis of this unique syndrome.