Up-regulation of HLA-G expression in cervical premalignant and malignant lesions.

The human leukocyte antigen G (HLA-G) molecule, a non-classical major histocompatibility complex class I antigen, exhibits highly limited tissue distribution and gene variation. Recent studies indicate strong immunoinhibitory properties in tumor cells that may favor their escape from anti-tumor immune responses. However, the role of HLA-G in cervical premalignant and malignant lesions has not been defined clearly. In our study, HLA-G expression was studied in cervical tissue from 119 patients with lesions and 22 normal cervical tissue specimens by immunohistochemistry. HLA-G was expressed in 45% (54/119) of cervical lesion-containing tissues while it was rarely detectable (0/22) in the control specimens (P = 0.000). ROC curve analysis showed that HLA-G has an area under the curve (AUC) of 0.694. Furthermore, we investigated soluble HLA-G expression in the plasma of 172 patients with cervical lesions and 20 healthy controls. Significant increases were also observed in soluble HLA-G levels (median, 191.4 vs 45.18 U/ml, P < 0.001). The relative operating characteristic (ROC) curves for soluble HLA-G (sHLA-G), squamous cell carcinoma (SCC), and carbohydrate antigen 125 (CA125) show an AUC of 0.710, 0.634, and 0.588, respectively. At the cut-off values of 108.20 U/ml for sHLA-G, 1.5 ng/ml for SCC, and 35 U/ml for CA125, the sensitivity was 73.30%, 47.83%, and 44.83%, respectively. The detection of soluble HLA-G in plasma may have significance in the early detection of cervical malignant lesions.

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk.

The functional consequences of missense variants are often difficult to predict. This becomes especially relevant when DNA sequence changes are used to determine a diagnosis or prognosis. To analyze the consequences of 12 missense variants in patients with mild forms of ataxia-telangiectasia (A-T), we employed site-directed mutagenesis of ataxia-telangiectasia mutated (ATM) cDNA followed by stable transfections into a single A-T cell line to isolate the effects of each allele on the cellular phenotype. After induction of the transfected cells with CdCl2, we monitored for successful ATM transcription and subsequently assessed: 1) intracellular ATM protein levels; 2) ionizing radiation (IR)-induced ATM kinase activity; and 3) cellular radiosensitivity. We then calculated SIFT and PolyPhen scores for the missense changes. Nine variants produced little or no correction of the A-T cellular phenotype and were interpreted to be ATM mutations; SIFT/PolyPhen scores supported this. Three variants corrected the cellular phenotype, suggesting that they represented benign variants or polymorphisms. SIFT and PolyPhen scores supported the functional analyses for one of these variants (c.1709T>C); the other two were predicted to be "not tolerated" (c.6188G>A and c.6325T>G) and were classified as "operationally neutral." Genotype/phenotype relationships were compared: three deleterious missense variants were associated with an increased risk of cancer (c.6679C>T, c.7271T>G, and c.8494C>T). In situ mutagenesis represents an effective experimental approach for distinguishing deleterious missense mutations from benign or operationally neutral missense variants.

Changes in axial length following trabeculectomy and glaucoma drainage device surgery.

AIM: This study examines the changes in axial length (AL) after trabeculectomy and glaucoma drainage device (GDD) surgery and enabled an equation to be derived allowing prediction of AL change after filtering surgery. METHODS: This was a prospective, interventional case series from the Glaucoma Service of the Doheny Eye Institute. PATIENT POPULATION: One eye of 39 patients undergoing trabeculectomy and 22 undergoing Baerveldt tube shunt implantation for uncontrolled glaucoma. INTERVENTION: These patients had AL measurements by non-contact, partial coherence interferometry preoperatively, at 1 week, 1 month, and >3 months after surgery. MAIN OUTCOME MEASURES: Axial length and intraocular pressure were compared at preoperative and postoperative visits. Postoperative intraocular pressure (IOP) was categorised as hypotonous (0-4 mm Hg), low (5-9), normal (10-17), and high (18 or more). RESULTS: There was a statistically significant reduction in IOP after 3 months of -12.8 (SD 1.5) mm Hg following trabeculectomy (p<0.001), and -10.7 (1.9) mm Hg after GDD (p<0.001). There was a statistically significant reduction in AL, which was similar after trabeculectomy and GDD at all time points (p<0.001), of -0.15 (0.03) and -0.21 (0.04) mm (1 week), -0.18 (0.02) and -0.10 (0.02) mm (1 month), and -0.16 (0.03) and -0.15 (0.03) mm (3 months). At 3 months or later the AL reduction was related to postoperative IOP and to the amount of IOP reduction (p<0.05, stepwise multiple regression). 10.2% (4/39) of trabeculectomy patients had hypotony after 3 months, with a mean AL reduction (-0.39 (0.11)) that was statistically significantly lower (p<0.01) than the other trabeculectomy eyes (-0.14 (0.15)). CONCLUSIONS: There is a small but statistically significant decrease in AL after both trabeculectomy and GDD surgery, greater in eyes that are hypotonous after surgery. The authors suggest that AL reduction can be predicted after 3 months by the formula: AL reduction (mm) = -199+0.006 x IOP reduction+0.008 x final IOP.

Obtaining maximal optic nerve length during enucleation procedures.

OBJECTIVE: To determine optimal scissor blade design and surgical approach to facilitate obtaining a long optic nerve segment during enucleation procedures. METHODS: Two hundred mock enucleations were performed with the use of a human child skull model and a silicone sphere to simulate an eye. Temporal and nasal approaches with scissor blades with noncurved, mildly curved, or strongly curved blades were tested. RESULTS: Longer optic nerve segments were obtained with mildly curved scissor blades from both temporal and nasal surgical approaches. Strongly curved scissor blades uniformly produced smaller specimens. CONCLUSIONS: Mildly curved scissors should be used for enucleation when a long optic nerve specimen is desired. Strongly curved scissors should be avoided.

Wegener's granulomatosis. Dermatological manifestations in 75 cases with clinicopathologic correlation.

BACKGROUND AND DESIGN: Mucosal and cutaneous manifestations of Wegener's granulomatosis (WG) are usually described separately. Both frequently occur at any time of the illness. The aim of this work was to analyze, retrospectively, dermatologic symptoms of 75 WG cases encountered from 1973 through 1992. All patients fulfilled the American College of Rheumatology criteria for WG. We compared clinical and histologic findings and looked for a relationship between these manifestations, disease activity, and other symptoms of WG. RESULTS: Thirty-five patients had skin or mucosa involvement. Clinical features were palpable purpura (26 cases), oral ulcers (15), skin nodules (six), skin ulcers (five), necrotic papules (five), gingival hyperplasia (three), pustules (two), palpebral xanthoma (two), genital ulcer (one), digital necrosis (one), and livedo reticularis (one). Pathologic findings depended on clinical aspects. Thirty-five involved skin or mucosa biopsy specimens were obtained from 24 patients. Nongranulomatous vasculitis was associated with purpuric lesions. Granulomatous inflammation was associated with nonpurpuric lesions. Dermatologic manifestations were associated with a higher frequency of articular and renal involvement (68% vs 25%; 80% vs 47%, respectively). Except for xanthoma, onset of skin or mucosa lesions indicated active systemic disease. These manifestations responded well to steroids and cyclophosphamide. CONCLUSIONS: Various dermatologic manifestations are frequently observed in WG. They have distinctive pathologic features and usually indicate the presence of active systemic disease, especially with kidney and joint involvement.

Ophthalmologic findings in children with congenital cytomegalovirus infection.

BACKGROUND: Cytomegalovirus (CMV) infection is the most common congenital viral infection in the United States, affecting 0.5% to 2% of live births. Approximately 90% of infected infants are asymptomatic at birth. We undertook this study to determine the incidence and etiology of visual impairment and other ophthalmologic abnormalities in children with congenital CMV infection. METHODS: We prospectively evaluated 42 symptomatic and 83 asymptomatic children with congenital CMV infection, along with 21 control patients. One or more comprehensive ophthalmologic examinations were performed on each patient. The frequency and etiology of visual impairment and other ophthalmologic problems were tabulated for each patient. RESULTS: Nine of 42 (22%) patients in the symptomatic group had moderate to severe visual impairment in 16 eyes. Visual impairment was primarily due to optic atrophy in 6 of 16 (37%) eyes, macular scars in 2 of 16 (13%) eyes, and cortical visual impairment in 8 of 16 (50%) eyes. In comparison, none of 83 asymptomatic patients had severe visual impairment (P <.001). One asymptomatic patient had mild unilateral visual impairment caused by a macular scar. Strabismus developed in 12 of 42 (29%) symptomatic patients compared with 1 of 83 (1.2%) asymptomatic patients (P <.001). CONCLUSIONS: Visual impairment and strabismus are common in patients with symptomatic congenital CMV infection and rare in patients with asymptomatic congenital CMV infection. Visual impairment may be caused by cortical, optic nerve, and/or retinal abnormalities. Infants with symptomatic congenital CMV infection should undergo careful ophthalmologic screening and follow-up examinations.

Incidence of presumed cytomegalovirus retinitis in HIV-infected pediatric patients.

INTRODUCTION: Large population studies of adult patients suggest an incidence of cytomegalovirus (CMV) retinitis as high as 19% to 20% as a late complication of adult HIV infection. We conducted this prospective study of a large cohort of HIV-infected children to determine the incidence of CMV retinitis in HIV-infected children. METHODS: From January 1984 to August 1997, 173 HIV-infected children were followed up for an average of 55.3 months (13-164 months). The patients were seen in the Department of Pediatrics at least once every 6 months. Ophthalmologic examinations were initiated when a patient's CD4 count dropped below 50 or sooner if required for ophthalmologic or other indications. Ophthalmologic examination was then repeated every 6 months. RESULTS: A total of 116 (67%) of 173 patients underwent ophthalmologic examination. Four (3.4%) of 116 patients had CMV retinitis at a mean time of 17.3 months (8-38 months) after their CD4 counts dropped below 20. None of the 4 patients with CMV retinitis had subjective visual complaints despite advanced retinitis. Three patients had bilateral and 1 patient had unilateral CMV retinitis. CONCLUSIONS: CMV retinitis occurred infrequently in HIV-infected pediatric patients and was diagnosed only in patients with a CD4 count below 20. Routine ophthalmologic screening examinations may not be necessary in pediatric patients until the CD4 count is below 20. Because children may not complain of decreased vision, at-risk children should undergo frequent ophthalmologic examination.

Stereoacuity and depth perception decrease with increased instrument magnification: comparing a non-magnified system with lens loupes and a surgical microscope.

PURPOSE: To evaluate the effect of instrument magnification used in eye surgery on stereoacuity and depth perception. METHODS: Twenty-one subjects (10 clinical ophthalmologists familiar with loupes and operating microscopes and 11 non-ophthalmologists) with normal near vision and stereoacuity were tested with the Randot Stereotest viewed unmagnified, with a 4x loupes (450 mm focal length), and with a 16x operating microscope. RESULTS: Total scores: 8 errors in 210 test steps with the unmagnified observations, 25/210 with loupes, and 30/210 with the microscope. The statistical differences in these scores were "statistically highly significant" for all three tests (p = 0.002); and "significant" for the unmagnified versus loupe (p = 0.007) and unmagnified versus microscope (p = 0.002). Test viewing through the microscope, the greatest errors occurred (total errors = 1840 seconds of arc), less with the loupes (total 1150") and least without magnification (total 220"). Errors and scores for 10 experienced ophthalmologists were no different (p > or = 0.55, p = 1.00) from the 11 non-ophthalmologist subjects. CONCLUSIONS: Stereoacuity and depth perception decrease when viewing a test target with loupes or with a microscope, with the effect worsening as magnification increases. Familiarity with the magnifying equipment did not improve stereoacuity.

[Arterial manifestations of Behçet's disease. 12 cases]. / Manifestations artérielles de la maladie de Behçet. Douze observations.

Out of 196 patients with Behçet's disease, 12 (10 men and 2 women, mean age 34 +/- 7 years) had non-coronary arterial lesions. Behçet's disease was complete in 4 patients. The arterial lesions had appeared 8.6 +/- 8 years on average (20 years at most) after the first sign of the disease. Three patients showed evidence of stenosis or occlusion involving one or several arteries. Eight patients had both stenotic and aneurysmal lesions. One patient had an arteriovenous fistula. Another developed a false aneurysm at the site of introduction of a femoral catheter. Yet another patient developed an anastomotic aneurysm one year after implantation of an abdominal aortic graft. In 2 cases histology showed fragmentation of the media associated with vasculitis of the vasa vasorum. Two patients with pulmonary aneurysm died of massive haemoptysis. In 2 patients combined corticosteroid and cyclophosphamide therapy failed to prevent the development of aneurysmal lesions. Phlebitis was associated with arterial involvement in 7 patients. Comparison between patients with or without arterial lesions showed no significant difference in time of onset of Behçet's disease, sex, main clinical features and presence of HLA B5. Aneurysmal lesions respond poorly to medical treatment, and surgery is mandatory. Since recurrence at the site of anastomosis is possible, prolonged monitoring is required.

[Tuberculosis and systemic diseases. Apropos of 16 cases]. / Tuberculose maladie et maladies systémiques. A propos de 16 cas.

METHODS: We analyzed retrospectively 16 patients between 1976 and 1993 (six men, ten women, mean age: 49-year-old) suffering from connectivitis. HIV-negative and receiving corticosteroids, combined for six of them with immunosuppressive therapy, and suffering from tuberculosis. RESULTS: The mean period between first signs and diagnosis was 51 days (3-190 d). Tuberculosis was pulmonary (n = 10) of which 4 miliary, pleurisy (n = 3), lymphadenitis (n = 5). We only observed one meningitis, one otitis and one female genital tuberculosis. Six patients had more than one localisation. Diagnosis was proven bacteriologically eight times, histologically six times and for three patients diagnosis was certain because of efficacy of antituberculosis antibiotherapy. Evolution was always good, with antituberculosis antibiotherapy of maximum 18 months, without sequella. Because rifampicin enzymatic induction, connectivitis worsened in five patients. An increase in corticotherapy was necessary for these five patients. CONCLUSION: This series confirmed the frequently extrapulmonary feature of tuberculosis in immunosuppressed patients, the long delay of diagnosis and the risk of exacerbation of underlying disease with rifampicin.

[Mesenteric venous thrombosis: early diagnosis with abdominal CT scan and screening for coagulopathies. Six observations]. / Thromboses veineuses mésentériques: apports diagnostiques du scanner abdominal et de la recherche d'une coagulopathie. Six observations.

PURPOSE: Mesenteric venous thrombosis is an uncommon entity whose diagnosis is difficult because the symptoms are nonspecific. Yet early recognition of this disease helps avoid the evolution towards mesenteric infarction. METHODS: We describe clinical symptoms and hypercoagulable states discovered in six patients with superior mesenteric venous thrombosis. RESULTS: Five of six patients were admitted to hospital for abdominal pain whose mean duration was 9 days before the diagnosis of venous thrombosis was made. Three of them had a fever. Two patients had a past history of deep venous thrombosis. All patients had a hypercoagulable state and three of them had two associated disorders of coagulation. In all cases, abdominal CT scan had permitted the diagnosis of mesenteric venous thrombosis. An anticoagulant therapy was conducted successfully in five of six patients. CONCLUSION: A CT abdominal scan done early in the case of nonspecific abdominal pain, since the patients had a previous history of venous thrombosis, may permit a nonsurgical treatment of mesenteric venous thrombosis. A screening for thrombophilia must always be carried out since coagulation disorders are very frequently the recognised causes in mesenteric venous thrombosis.

[Deep venous thrombosis in Behçet's disease. 106 localizations in a series of 177 patients]. / Les thromboses veineuses profondes dans la maladie de Behçet. 106 localisations sur une série de 177 malades.

A retrospective study of 177 patients (137 male, 40 female) with a disease that fulfilled the criteria of complete or incomplete Behçet's disease showed 106 thrombotic lesions of a venous trunk in 62 (35%) of these patients, superficial phlebitis and retinal vein thrombosis excluded. The incidence of thrombosis was unrelated to race and sex. The venous lesions were single in 38 cases and multiple in 24 cases, including 4 with more than 4 territories involved. Arterial lesions were also present in 7 cases. The lesions were located in the sural (n = 63), iliofemoral (n = 14), inferior vena cava (n = 13), superior vena cava (n = 3), axillary (n = 2) and cerebral (n = 13) veins or territories. Thrombosis developed during the first 4 years of Behçet's disease in one half of the patients. It preceded the aphthosis by 1 to 10 years in 11 cases, was concomitant with it in 15 cases and appeared more than 10 years after the diagnosis in 8 cases. Pulmonary embolism occurred in 11 patients, requiring clipping of the vena cava in 2, but it was never lethal. However, 2 of the 5 patients who died had venous thrombosis (Hughes Stovin syndrome). Thirty-eight patients could be followed up for 12 to 192 months (mean 43) under anticoagulant or antiplatelet therapy. Five vascular recurrences (13%) were observed, 2 of them (1 arterial graft thrombosis, 1 cerebral thrombosis) under anti-vitamin K agents. Cerebral thrombosis (9 men, 4 women) accounted for 27% of the neurological lesions; its prognosis was favourable in the 7 patients successfully treated with anticoagulants. Thrombosis could not be explained. Haemostasis studies showed a decrease of fibrinolytic activity compared to a group of normal subjects and an increase in fibrinogen, factor VIII and Willebrand's factor levels; these abnormalities did not seem to be specific. Thus, phlebitis truly is an element of Behçet's disease. Until its mechanism is better understood, effective anticoagulant therapy in cases with proven thrombosis and preventive antiplatelet therapy in the other cases seem to be rational measures.

[Relapse of Wegener's granulomatosis. Retrospective study of 18 cases]. / Rechutes de la granulomatose de Wegener. Etude rétrospective de 18 cas.

During a mean therapeutic follow-up of 4 years, 25 out of 61 patients with Wegener's granulomatosis had one or several relapses. As in 7 of them the initial diagnosis had proved erroneous, this study concerns the remaining 18 patients who together totalled 31 relapses after the correct diagnosis was made. Twenty relapses occurred early on, within 4 months of a change in treatment, and they corresponded to recurrent activity of the disease. Ten relapses occurred later on, after treatment had been discontinued or kept at maintenance dose level. The relapses appeared as early as the first year in 41 percent of the cases. The ENT region was affected in 61 percent of the patients. Nine relapses occurred in the absence of treatment, including 6 which took place 1 to 8 years after treatment. Three relapses occurred less than 3 months after a prednisone and oral cyclophosphamide therapy was initiated. Compared with the group of patients without relapse, those in the relapse group were younger, more often treated with azathioprine and cyclophosphamide administered intravenously, and followed up for a longer period; their probability of survival was also higher. In case of early relapse after withdrawal of treatment the mean duration of that treatment had been shorter than in the absence of relapse. None of the patients whose treatment had been stopped more than 20 months after its onset had an early relapse. These data prompted us to make the following proposals: initially, cyclophosphamide should be administered as bolus injections (the time required to obtain results is then shorter than with the oral route), and maintenance therapy should last at least 20 months. Azathioprine should be used only when cyclophosphamide is contra-indicated. The relative indications for intravenous and oral cyclophosphamide remain to be determined. Discontinuing all treatments is a difficult decision to make, but even then the patients should be under close supervision in view of the possibility of late relapses.

[Value of "bolus" cyclophosphamide injections in Behçet's disease. Experience of 17 cases]. / Intérêt des "bolus" de cyclophosphamide dans la maladie de Behçet. Expérience de 17 cas.

Seventeen patients with Behçet's disease were treated with intermittent intravenous bolus injections of cyclophosphamide. Twelve patients had severe eye lesions, 7 had central neurological disorders and 2 had both ocular and central nervous system involvement. Cyclophosphamide was given during 4 weeks on average, in mean doses of 922 +/- 127 mg. Each patient received an average of 10 +/- 5 injections. The drug was generally well tolerated; only one patient developed moderate and transient hepatocytolysis. Visual acuity was improved in 12 of the 22 eyes with active lesions, and signs of inflammation disappeared in all cases. Neurological improvement was observed in 5 of the 7 patients affected, with complete regression of the disorders in 2 of them. In 16 patients who were also under corticosteroid therapy, steroid dosage could be significantly reduced by 44 +/- 11 mg per day.

[Effectiveness of intravenous immunoglobulins in polymyositis and dermatomyositis. An open trial in 15 patients]. / Efficacité des immunoglobulines intraveineuses dans les polymyosites et dermatomyosites. Etude ouverte chez 15 malades.

Polymyositis (PM) and dermatomyositis (DM) are dysimmune diseases usually treated with corticosteroids and immunosuppressants. Human polyvalent immunoglobulins administered intravenously (IgIV) are known to be effective in some dysimmune diseases. Between August 1987 and September 1989 we conducted an open trial of IgIV in 15 patients (mean age 44 +/- 14 years) with either PM (12 cases) or DM (3 cases) associated with a collagen disease in 2 patients. In 14 of these 15 patients the conventional treatments (corticosteroids, immunosuppressants, plasmapheresis, total body irradiation, lymphopheresis) had failed. One patient was seropositive for picornavirus and received IgIV as initial treatment. IgIV infusions were given 4 +/- 3.9 years on average after the onset of PM or DM. Twelve of the 15 patients received another treatment, starting at least 6 weeks before IgIV and pursued without dosage increase, which consisted of corticosteroids (11 cases), methotrexate (5 cases) or plasmapheresis (1 case). Human polyvalent immunoglobulins for intravenous use were prescribed in doses of 2 g/kg/monthly course. All but two patients (1 course) received 3 to 6 courses on average. The IgIV infusions were well tolerated in 12 patients; 3 patients showed allergic manifestations which regressed. Therapeutic effectiveness was evaluated by muscle testing and by repeated assays of creatine phosphokinase (CPK). Clinical improvement, usually perceptible after the first course, was observed in 13/15 patients; it was associated with a more than 30 percent decrease of the initial CPK level in 13 patients and with a reduction of associated therapies in 9 patients. In the entire patient population a statistically significant lowering of mean CPK value was observed as early as in the first course (P less than 0.001). In view of their effectiveness, rapid action and safety, intravenous Ig infusions may be regarded as an interesting treatment in PM or DM patients.

[Treatment of pulmonary vasculitis]. / Traitement des vascularites pulmonaires.

Pulmonary vasculitides require major therapeutic regimens which, though symptomatic, are often effective. Corticosteroids have greatly changed the prognosis of most of these vasculitides, particularly polyarteritis nodosa and the Churg and Strauss syndrome. Cyclophosphamide must be added for Wegener's granulomatosis although the route of administration is still under discussion. Plasma exchanges are rarely indicated. Other treatments for Wegener's granulomatosis including combined trimethoprim-sulfamethoxazole in limited forms and methotrexate in sub-acute systemic forms are currently under study. A better understanding of the underlying mechanisms, including the role of antineutrophil cytoplasmic antibodies, and especially the identification of the causative factors will lead to an aetiologic treatment still unknown today.

[Treatment of lupus erythematosus disseminatus]. / Traitement du lupus érythémateux disséminé.

Corticosteroids have transformed the prognosis of systemic lupus erythematosus (SLE), but no further advance has been achieved during the last few years. Treatment of SLE rests on the use, as rational as possible, of those therapeutic tools that are available. However, diagnosing SLE does not necessary, they must be given promptly in effective doses whilst preventing their side-effects, notably by the simultaneous management of atheroma factors. Non-steroidal anti-inflammatory agents and synthetic antimalarial drugs may be used to replace corticosteroids or reduce their dosage. Severe forms of SLE which are function- or life-threatening require immunosuppressants, the best one being cyclophosphamide administered monthly as intravenous bolus injections, as this drug has been shown to be effective and to have low morbidity. Plasmapheresis is exceptionally needed. The risk of thrombogenesis due to the frequently associated "antiphospholipid syndrome" can be avoided by anticoagulants or antiplatelets the respective indications of which have not yet been clearly determined. SLE being a chronic disease, patient's compliance with treatment is very important and justifies the efforts made to train and inform these young male or female patients.