Mechanical Thrombectomy in Nighttime Hours: Is There a Difference in 90-Day Clinical Outcome for Patients with Ischemic Stroke?

BACKGROUND AND PURPOSE: Few data are available regarding the influence of the timing of ischemic stroke management, such as daytime and nighttime hours, on the delay of mechanical thrombectomy, the effectiveness of revascularization, and clinical outcomes. We aimed to investigate whether admission during nighttime hours could impact the clinical outcome (mRS at 90 days) of patients with acute ischemic stroke treated by mechanical thrombectomy. MATERIALS AND METHODS: We retrospectively analyzed 169 patients (112 treated during daytime hours and 57 treated during nighttime hours) with acute ischemic stroke in the anterior cerebral circulation. The main outcome was the rate of patients achieving functional independence at 90 days (mRS ≤2), depending on admission time. RESULTS: In patients admitted during nighttime hours, the rate of mRS ≤ 2 at 90 days was significantly higher (51% versus 35%, P = .05) compared with those admitted in daytime hours. Patients in daytime and nighttime hours were comparable regarding admission and treatment characteristics. However, patients in nighttime hours tended to have a higher median NIHSS score at admission (P = .08) and to be younger (P = .08), especially among the mothership group (P = .09). The multivariate logistic regression analysis confirmed that patients in nighttime hours had better functional outcomes at 90 days than those in daytime hours (P = .018; 95% CI, 0.064-0.770; OR = 0.221). CONCLUSIONS: In a highly organized stroke care network, mechanical thrombectomy is quite effective in the nighttime hours among acute ischemic stroke presentations. Unexpectedly, we found that those patients achieved favorable clinical outcomes more frequently than those treated during daytime hours. Larger series are needed to confirm these results.

Thymic function is a major determinant of onset of antibody-mediated rejection in heart transplantation.

Thymic function decreases progressively with age but may be boosted in certain circumstances. We questioned whether heart transplantation was such a situation and whether thymic function was related to the onset of rejection. Twenty-eight antithymocyte globulin-treated heart transplant recipients were included. Patients diagnosed for an antibody-mediated rejection on endomyocardial biopsy had a higher proportion of circulating recent thymic emigrant CD4+ T cells and T cell receptor excision circle levels than other transplanted subjects. Thymus volume and density, assessed by computed tomography in a subset of patients, was also higher in patients experiencing antibody-mediated rejection. We demonstrate that thymic function is a major determinant of onset of antibody-mediated rejection and question whether thymectomy could be a prophylactic strategy to prevent alloimmune humoral responses.

Submandibular puncture of the facial vein: an original route for endovascular therapy of cavernous sinus dural fistulas.

INTRODUCTION: Carotid cavernous sinus fistulas are a potentially severe pathology. Their basic standard treatment is an occlusion of the CCF performed by retrograde venous catheterization via the inferior petrous sinus. When the inferior petrous sinuses are occluded, other alternative venous routes are possible with various subsequent difficulties and risks. We report an original and safe method for endovascular treatment using submandibular puncture of the facial vein. CLINICAL CASES: We report 4 cases of patients with severe unilateral carotid cavernous sinus fistula associated with the occlusion of both inferior petrous sinuses. A submandibular surgical puncture of the ipsilateral inferior facial vein permitted the catheterization of the fistula. Complete occlusion of carotid cavernous sinus fistula was obtained by using a combination of microcoils and Onyx™. DISCUSSION: When inferior petrous sinuses are occluded, endovascular treatment of carotid cavernous sinus fistulas is more difficult. After reviewing the other treatment options reported in the literature and their respective advantages and adverse effects, we describe an original technique based on the surgical puncture of the ipsilateral facial vein. The occlusion of the fistula is then obtained by using a combination of microcoils and Onyx™. CONCLUSION: When the inferior petrous sinuses are occluded, an endovascular treatment for a carotid cavernous sinus fistula can be performed using an original and secure method. This method relies on a simple surgical puncture of the facial vein in the submandibular region, which then permits a retrograde catheterization of the carotid cavernous sinus fistula with no significant risk.

Mechanical thrombectomy in acute ischemic stroke: catch device.

BACKGROUND AND PURPOSE: Mechanical thrombectomy presents today a promising alternative to traditional stroke therapies. Our aim with this study was to evaluate the safety and efficacy of the Catch mechanical thrombectomy device in the treatment of acute stroke and report the angiographic results and clinical outcomes. MATERIALS AND METHODS: We performed an analysis of 40 consecutive patients with ischemic stroke treated with the Catch device at our academic center. Forty patients were treated with the device: 25 with anterior circulation stroke and 15 with posterior circulation stroke. Thirty seven (92.5%) patients received an additional treatment to aid revascularization, including 36 patients treated with rtPA (mean dose of 35 mg). RESULTS: The mean age was 63.5 years (range, 31-82 years; 55% men). The median NIHSS score at presentation was 18 (range, 3-38). The mean symptom-to-procedure start time was 440 minutes (range, 150-2637 minutes). Recanalization (TIMI 2-3) was achieved in 26/40 (65%). Symptomatic hemorrhage occurred in 18%. Procedural complications occurred in 6 patients without clinical consequences: 4 clot fragmentations and 2 vasospasms. Data were missing for 4 patients at 90 days. Ninety-day mortality was 41%; good 90-day functional outcome (mRS, ≤ 2) was achieved by 39% (14/36). Good neurologic outcomes at 90 days were more frequent (56.5% versus 7.7%), and mortality rates were lower (30% versus 61.5%) with successful compared with unsuccessful recanalization. CONCLUSIONS: In our retrospective case series, the Catch device appears effective in achieving recanalization and improving 90-day outcome in patients with acute ischemic stroke.

Specificity of anti-Nef antibodies produced in mice immunized with DNA encoding the HIV-1 nef gene product.

Mice immunized with plasmid DNA encoding Nef regulatory protein of human immunodeficiency virus type 1 developed high levels of anti-Nef antibodies. After 4 intramuscular injections of 100 microg plasmid DNA, anti-Nef antibodies reached titers up to 2 x 10(4). A significant specific antibody response was maintained for at least 16 months. Using a set of seven 31-66 mer synthetic peptides covering the entire sequence of Nef, we analysed the specificity of ant-Nef antibodies. Interestingly, specific antibodies produced in response to Nef expressing plasmid DNA did not recognize the linear peptides except the long C-terminal peptide (aa 141-205) for 3 of the 10 sera. With anti-Nef antibodies produced in mice immunized with the protein Nef without any adjuvant, the same restraint epitope binding was found. Only 3 of the 5 Nef positive sera reacted with the C-terminal peptide. This suggests that specific antibodies induced by plasmid DNA as well as by the non-denatured protein recognize conformation-dependent epitopes. On the contrary, anti-Nef antibodies from mice immunized with the protein in Freund's adjuvant showed a broader epitope reactivity pattern. Interestingly, the analysis of immunoglobulin isotype profiles of antibodies generated by the different protocols of immunization showed that plasmid DNA immunization induced predominantly IgG2a, whereas immunization with Nef protein, with or without adjuvant, yielded a preponderance of IgG1 antibodies.

Characterization of humoral immune responses induced by immunization with plasmid DNA expressing HIV-1 Nef accessory protein.

Mice immunized with plasmid DNA encoding Nef accessory protein of human immunodeficiency virus type 1 developed high levels of anti-Nef antibodies which were maintained for at least 16 months. These antibodies produced in response to Nef-expressing plasmid DNA did not recognize the linear peptides except the long C-terminal peptide for three of the ten sera. With anti-Nef antibodies produced in mice immunized with the protein Nef without any adjuvant, the same restraint epitope binding was found. On the contrary, anti-Nef antibodies from mice immunized with the protein in Freund's adjuvant showed a broader epitope reactivity pattern. Interestingly, the analysis of immunoglobulin isotype profiles of antibodies generated by the different protocols of immunization showed that plasmid DNA immunization induced predominantly IgG2a, whereas immunization with Nef protein, with or without adjuvant, yielded a preponderance of IgG1 antibodies.

Curcumin and curcumin derivatives inhibit Tat-mediated transactivation of type 1 human immunodeficiency virus long terminal repeat.

The transcription of HIV1 provirus is regulated by both cellular and viral factors. Various evidence suggests that Tat protein secreted by HIV1-infected cells may have additional action in the pathogenesis of AIDS because of its ability to also be taken up by non-infected cells. Curcumin [diferuloylmethane or 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the yellow pigment in turmeric Curcuma longa (Linn). It exhibits a variety of pharmacological effects including antiinflammatory and antiretroviral activities. Here, we demonstrated that curcumin used at 10 to 100 nM inhibited Tat transactivation of HIV1-LTR lacZ by 70 to 80% in HeLa cells. In order to develop more efficient curcumin derivatives, we synthesized and tested in the same experimental system the inhibitory activity of reduced curcumin (C1), which lacks the spatial structure of curcumin; allyl-curcumin (C2), which possesses a condensed allyl derivative on curcumin that plays the role of metal chelator; and tocopheryl-curcumin (C3), which enhances the antioxidant activity of the molecule. Results obtained with C1, C2 and C3 curcumin derivatives showed a significant inhibition (70 to 85%) of Tat transactivation. Despite the fact that tocopheryl-curcumin (C3) failed to scavenge O2.-, this curcumin derivative exhibited the most activity; 70% inhibition was obtained at 1 nM, while only 35% inhibition was obtained with the curcumin.

Structure/antigenicity relationship of cyclic and linear peptides mimicking the V3 loop of HIV2 envelope glycoprotein.

We report the structure and antigenicity of the third variable region (V3) of the HIV2 envelope glycoprotein by the use of linear and cyclic peptides. To this end, a peptide mimicking this region was synthesized and purified, both as an iodoacetamidated linear peptide and a disulphide-bridged cyclic peptide. The cross-reactivity of three monoclonal antibodies (mAbs) produced against the envelope glycoprotein gp140 with the linear and cyclic peptides was tested with ELISA. The results showed that the cyclic peptide is a better ligand for the 3 mAbs 125-F, 125-J and 125-K. The avidity of the mAb/peptide interaction was further analysed by determining the concentration of linear or cyclic peptide leading to 50% inhibition of mAb-peptide complex formation (K0.5). The K0.5 value of mAb 125-F, which displayed the best reactivity with gp140, was estimated to be 5 times higher for the linear (K0.5 = 1.5 x 10(-6) M) than for the cyclic peptide (K0.5 = 3 x 10(-7) M). This indicates a higher affinity of mAb 125-F for the cyclic peptide. mAb 125-J, which exhibited a lower avidity for the gp140 compared to mAb 125-F, had a similar affinity for the cyclic and the linear peptides (K0.5 = 3 x 10(-7) M). mAb 125-K had the lowest reactivity with gp140 and its binding to adsorbed peptide could not be inhibited by the soluble linear or cyclic peptide used up to 10(-5) M. These results suggest that cyclic peptides may have a higher propensity for adopting a native-like structure for the peptide/antibody interaction. Nuclear magnetic resonance experiments at 25 degrees C in phosphate buffer pH 5.4, however, showed that neither peptide displayed a well-defined structure.

Human plasmatic apolipoprotein H binds human immunodeficiency virus type 1 and type 2 proteins.

Apolipoprotein H (apo H), isolated from human plasma albumin solution, was shown to capture HIV-1-related antigens from antigen-positive sera (HIV-1 AG+) of AIDS patients, by using HIV-1-specific polyclonal antibodies. In an enzyme-linked immunosorbent assay and ligand blot and dot assays, apo H was able to bind recombinant retroviral HIV antigens, especially Gag proteins p18 of HIV-1, p26 of HIV-2, and Env gp160 of HIV-1. Binding was shown to be pH and NaCl dependent, with an optimum at acidic pH and low ionic strength. Specificity was demonstrated by saturation of this binding and inhibition either by homologous competition or by specific antisera. Binding was also observed in cell line-harvested viral proteins. The mechanism of this apo H-polyspecific binding is discussed in relation to conformational changes due to the influence of lipids or detergents.

Association of Mycoplasma penetrans with human immunodeficiency virus infection.

A cross-sectional study was done to determine the seroprevalence of Mycoplasma penetrans in human immunodeficiency virus (HIV) type 1-seropositive and -seronegative persons recruited in France. The data were analyzed with respect to the sociodemographic, clinical, and biologic status of the patients. M. penetrans seropositivity was associated with HIV infection (18.2% of HIV-seropositive vs. 1.3% of HIV-seronegative persons were M. penetrans-seropositive; P < .001). M. penetrans infection was predominantly but not exclusively associated with homosexual practices in HIV-seropositive subjects and thus presumably sexually transmitted. M. penetrans seroprevalence increased with progression of HIV-associated disease. No association was found between M. penetrans and Kaposi's sarcoma. Thus, there is an unambiguous association between M. penetrans and HIV, particularly among homosexual persons, but its clinical significance remains to be investigated.

Rheumatoid factor associated with a secretory component in rheumatoid arthritis.

The authors' objective was to study the serum secretory immunoglobulin A (S-IgA) concentration and the presence of rheumatoid factor (RF) complexed with a secretory component (SC) in rheumatoid arthritis (RA). Sixty-three RA patients were studied. There were 49 healthy subjects in the control group. The S-IgA concentration and the presence of IgA isotype RF were determined by ELISA in the serum. The presence of SC complexed to RF (SC-RF) was studied by a sandwich-type enzyme-linked immunosorbent assay with an antibody against the SC used to capture S-immunoglobulin, and associated anti-globulin activity was revealed with a peroxidase-conjugated human IgG Fc fragment. We observed a significant increase in S-IgA in RA (mean 76.8 micrograms/ml +/- 152.9 S.D.), as compared to controls (mean 13.6 micrograms/ml +/- 11.9 S.D.) (P < 0.01). Forty-one per cent of RA patients presented a S-IgA concentration above the upper threshold, but we did not observe any association with disease activity. S-IgA concentration was correlated with the presence of IgA-RF. Twenty-seven RA patients had a positive SC-RF versus one in the control group (P < 0.01). The presence of SC-RF was associated with an increased S-IgA concentration (P < 0.0001), and the presence of RF-IgA (P < 0.002). However, no association with disease activity was noted. Our study showed that serum S-IgA was increased in RA, and that part of the RF were complexed with SC. These results suggest contribution of mucosal lymphocytes in the pathogenesis of RA.

Analysis of monoclonal rheumatoid factors obtained from the B-cell repertoire in rheumatoid arthritis.

We have sought to determine whether rheumatoid factors (RF) produced in rheumatoid arthritis (RA) were different from physiological RF produced in normal, healthy adults. RF-secreting clones were established following Epstein-Barr virus (EBV) stimulation of peripheral blood lymphocytes. Ten RF-secreting clones were established from seven RA patients and 16 from six healthy controls. All monoclonal RF (MRF), except two in each group, were monoreactive and ten of these were shown to have low to medium affinity for IgG,Fc, irrespective of their origin. A majority (74%) of the MRF bound to protein A, indicating that genes of the VHIII family were preferentially used for synthesizing these autoantibodies. The expression of cross-reactive idiotypes (CRI) by the MRF did not allow distinction between those derived from RA patients and controls. The VHI-associated CRI G8 and VHIII-associated CRID12 were expressed at low frequency in both panels of RF. These CRI have been shown to be expressed at high frequency in RF paraproteins. However, the idRQ idiotype was expressed within both panels of RF. A possible distinction between polyreactive and monoreactive MRF appeared to be light chain usage since all (four) polyreactive RF used lambda chains while the normal kappa/lambda ratio was observed for monoreactive RF. The frequency of EBV-activated cells secreting IgM bearing CRI or secreting RF was determined and showed that CRI expression occurred with a higher frequency than did RF, suggesting a dissociation between CRI expression and RF activity.

The B cell repertoire in rheumatoid arthritis. III. Preferential homing of rheumatoid factor-producing B cell precursors in the synovial fluid.

OBJECTIVE: We sought to compare the frequencies of precursors producing IgM rheumatoid factors (IgM-RFs) in synovial fluid and peripheral blood B cells from patients with rheumatoid arthritis (RA). METHODS: We used limiting-dilution analysis of Epstein-Barr virus-activated B cells from seropositive and seronegative patients. B cell precursors producing IgM against insulin, an irrelevant autoantigen, were also assessed for comparison. RESULTS: On average, IgM-RF-producing precursors were 15-fold higher in the synovial fluid than in the peripheral blood of seropositive RA patients, but not in seronegative RA patients. The frequency of B cell precursors producing IgM against insulin was lower in the synovial fluid than in the peripheral blood of both the seropositive and the seronegative patient groups; moreover, the concentrations were similar in both groups. CONCLUSION: The findings provide evidence against a nonspecific accumulation of IgM-producing cells in the synovial fluid, and suggest that there is an active attraction of the RF-producing B cell precursors toward sites of inflammation in RA.

The B cell repertoire in rheumatoid arthritis. II. Analysis of rheumatoid factors bearing the IdRQ cross-reactive idiotype.

With the view of studying whether rheumatoid factors (RFs) produced in rheumatoid arthritis (RA) were different from those synthesized in physiological situations, we analyzed the usage of a cross-reactive idiotype (IdRQ) previously reported to be specific for RA RFs. Using EBV immortalization of circulating B cells, we prepared monoclonal RFs from patients with RA and matched controls. In both groups between 1/2 and 2/3 of the monoclonal RFs bore IdRQ. Using limiting dilution analysis, we studied the frequencies of the EBV-activated B cells able to synthesize immunoglobulins bearing IdRQ. In patients and in controls, on average, 1/3 of the RF-secreting cells used IdRQ and around 2/3 of the synthesized IgM bearing IdRQ were devoid of RF activity. These results show that precursor cells containing the germline gene encoding IdRQ are present in similar quantities in RA patients and healthy individuals, and that the IdRQ cross-reactive idiotype, although interesting for the study of the B cell repertoire, is probably not useful as a marker for susceptibility to RA.

The B cell repertoire in rheumatoid arthritis. I. Frequency of EBV-inducible circulating precursors producing autoantibodies.

The frequency of B cell precursors producing antibodies against various autoantigens (Fc fragment of IgG, F(ab')2 fragment of IgG, type II collagen, cytoskeleton filaments and insulin) was determined in patients with rheumatoid arthritis (RA) using immortalization of peripheral blood B cells by the Epstein-Barr virus (EBV) and limiting dilution analysis. Equally large numbers of B cell precursors producing IgM-rheumatoid factors (RFs) were present in the peripheral blood of seronegative and seropositive RA patients and of controls. On average, 1 out of 15,000 B cells could be induced by EBV to secrete IgM-RFs, which represents 0.5-1% of the EBV-induced proliferating clones. By cloning or somatic hetero-hybridization of EBV cell lines derived from patients and controls, we obtained two types of monoclonal RFs: one polyreactive, reacting with Fc but also with the other autoantigens tested, and the other monoreactive, reacting with Fc only and that previously had only been found in the RA B cell repertoire. Moreover, patients and controls had similar numbers of circulating B cell precursors secreting IgM antibodies against other autoantigens that might be regarded as specific targets of RA (F(ab')2 fragment of IgG and type II collagen), and against cytoskeleton filaments that are targets of natural autoantibodies, increased in RA. The frequencies of EBV-induced B cells producing antibodies against all these autoantigens were of the same order of magnitude as the frequency of EBV-induced B cells producing RFs. The patients also possessed a similar number of precursors producing antibodies against insulin, an autoantigen irrelevant to the pathogenesis of the disease, taken as control. These data tend to demonstrate no abnormality in the autoantibody repertoire of B cells activable by EBV in RA, especially those secreting RFs. In vitro spontaneous RF secretion by circulating B cells was observed in seropositive RA patients but not in seronegative patients and in the controls tested. We enumerated the number of B cells spontaneously secreting RFs in seropositive RA patients and found that it correlated with the serum RF titer, but not with the number of RF-secreting B cells activated by EBV. The mean frequency values of B cells secreting RFs either spontaneously or after EBV infection were of the same order of magnitude, showing that the expanded population of in vivo-activated B cells was not (at least partially) infectable by EBV. This raised the possibility that EBV triggers a repertoire which may not reflect the status of B cells secreting autoantibodies in autoimmune diseases.

Anti-F(ab')2 antibody response to the injection of anticlass II HLA alloantibodies in patients with rheumatoid arthritis.

Placenta eluted gamma globulins (PEGG) contain antibodies against class II HLA antigens and have been used for treating patients with rheumatoid arthritis (RA). In view of the potential use of antibodies to class II HLA for treating autoimmune diseases we looked for the immunobiological effects of PEGG injections in patients. No modulation of class II HLA was seen at the surface of circulating mononuclear cells after one week of daily PEGG injections. In some patients, antibodies to F(ab')2 fragments of PEGG-IgG were produced. These antibodies reacted against F(ab')2 of any IgG as well and did not prevent anticlass II HLA antibodies from binding to class II HLA, thus showing no characteristics of classical antiidiotypic antibodies. The appearance of anti-F(ab')2 antibodies was not correlated with the clinical course of the disease. Their significance is discussed.

Studies of possible antiidiotypic control mechanisms in Graves' disease.

Serum from 55 patients with active Graves' disease and 55 patients who had received successful treatment (in whom the disease was inactive) were examined for the presence of possible antiidiotypic antibodies with an enzyme-linked immunosorbent assay (ELISA) for anti-F(ab')2. Murine IgG monoclonal antibodies (Mabs) against human thyroid-stimulating hormone (TSH) and human TSH receptors were also used as antigens in parallel ELISA assays. Patients with active and patients with inactive Graves' disease showed elevations of IgG anti-F(ab')2 antibodies when compared with normal controls. Similarly, both active and inactive Graves' disease sera showed higher levels of IgG anti-LE4, a mouse Mab to human TSH, than was seen with normal controls. However, F(ab')2 isolated from sera reacting with LE4 in the ELISA did not inhibit binding of the LE4 Mab with labeled TSH in a fluid phase competition assay. Patients with inactive Graves' disease showed higher ELISA reactivity with two different murine anti-TSH receptor Mabs than was recorded with either active Graves' or normal controls. A rough inverse correlation was noted between strongly positive ELISA reactions against these two Mabs with anti-TSH receptor specificity and the ability of immunoglobulins from inactive Graves' sera to stimulate increases in cyclic adenosine monophosphate (cAMP) in the normal rat thyroid cell line assay. Untreated Graves' sera showing high cAMP release only rarely showed elevated ELISA reactivity against Mabs with anti-TSH receptor activity.

Identification of class II HLA alloantibodies in placenta-eluted gamma globulins used for treating rheumatoid arthritis.

Placenta-eluted gamma globulins (PEGG) have been recently and successfully used in the treatment of patients with rheumatoid arthritis. PEGG, eluted at acid pH from large pools of human placentas, contained 99% IgG material. Sephacryl S300 gel filtration revealed a main fraction (76%) of native IgG accompanied by 10% aggregates and 14% digested fragments (as identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoelectrophoresis with specific antisera). Previous in vitro data had suggested that alloantibodies to class II HLA antigens were present in this preparation. This study confirms that PEGG and F(ab')2 fragments were able to inhibit stimulating cells in mixed lymphocyte reactions. Additional findings showed that: IgG from PEGG were cytotoxic for the non-T cell population; IgG or F(ab')2 from PEGG bound only to class II HLA-bearing cells; F(ab')2 from PEGG were able to block the complement-mediated cytotoxicity of anti-HLA-DR and anti-DQw1 alloantibodies. These data confirm the presence of class II HLA alloantibodies in PEGG. These antibodies may account for the clinical improvement reported in patients with rheumatoid arthritis. Our findings are similar to recent data showing that the injection of anti-Ia antibodies in experimental animal models decreases the autoimmune process.