Possible neuroprotective role of clusterin in Alzheimer’s disease: a quantitative immunocytochemical study

Clusterin is a secreted glycoprotein that is expressed in response to tissue injury both in peripheral organs and in the brain. Recent studies have shown a substantial increase in clusterin mRNA in pyramidal neurons of the hippocampus and the entorhinal cortex in Alzheimer’s disease (AD), with clusterin immunoreactivity occurring in neuropil threads, neurofibrillary tangles (NFT), and senile plaques. To elucidate further the role of this protein in the degenerative process, a quantitative study of its distribution in the cerebral cortex of non-demented and AD patients, all older than 85 years of age, was performed using immunocytochemistry. Using a stereological approach, we found that in cortical areas affected in AD, such as the entorhinal, inferior temporal and superior frontal cortices, the percentage of NFT-free neurons displaying clusterin immunoreactivity was significantly higher than that in non-demented cases. No such increase in the density of clusterin-immunoreactive neurons was seen in cortical areas that were less affected in the disease process. Furthermore, clusterin immunoreactivity was rarely observed in NFT-containing neurons. In conjunction with previous observations in peripheral tissues, these data suggest that clusterin may have a neuroprotective role, and that in AD, low cellular expression of this protein may be associated with neuronal degeneration and death. Received: 25 April 1997 / Revised: 20 August 1997 / Revised, accepted: 6 October 1997     

Intravenous pulse methylprednisolone therapy for acute treatment of serpiginous choroiditis

PURPOSE: To evaluate the safety and efficacy of high-dose intravenous steroid therapy (HDIST) for the acute treatment of vision-threatening serpiginous choroiditis. METHODS: Retrospective review of the records of five patients with serpiginous choroiditis who were treated with HDIST (1 g methylprednisolone for three days) in addition to their standard immunosuppressive treatment. The visual acuities and improvement of ocular signs after HDIST were evaluated. RESULTS: Twelve episodes of macula-threatening choroiditis in five patients with serpiginous choroiditis were treated during a seven-year period. All patients responded to HDIST with evidence of a decrease in intraocular inflammation immediately after and complete restoration of visual acuity within 10 days of commencing treatment. In one patient, medical intervention was required because of gastric distress. During the follow-up, three out of five patients experienced new attacks and two patients developed subretinal neovascularization. CONCLUSION: HDIST is effective in controlling severe vision-threatening serpiginous choroiditis and in improving visual function in a short period of time. However, the effect of this treatment in long-term disease control is uncertain.     

Selective pudendal arteriography.

Selective pudendal arteriography is indicated in selected cases of male impotence when there is a strong presumption that peripheral arterial lesions are responsible for it. These lesions are classified as: (a) traumatic; (b) obstructive in thrombo-angiitis or atheroma, and (c) dysplasic. Selective arteriography will confirm the diagnosis and indicate the nature of the obstruction, its degree and extension.     

Abdominal aortic endograft proximal collapse resulting in aortic aneurysm rupture

An 82-year-old man was transferred to our emergency department due to acute abdominal pain. He had undergone an endovascular abdominal aortic aneurysm repair (EVAR) six years ago. An intravenous contrast-enhanced abdominal computed tomography revealed the rupture of the abdominal aortic aneurysm (AAA) with a large retroperitoneal hematoma. A Talent (Medtronic, Santa Rosa, CA, USA) modular bifurcated endoprosthesis had vertically collapsed approximately 7 cm after losing its infrarenal fixation. As a result, it led to the repressurization of the aneurysm sac and rupture. The patient was successfully treated by placing three Talent (Medtronic) aortic cuffs. To our knowledge, this is the first reported case of endograft collapse that has manifested with aortic aneurysm rupture. Although they are gradually declining, considerable rates of complications create the 'Achilles' heel' of endovascular repair of AAAs. A lifelong follow-up strategy for patients treated for AAA with EVAR is essential for the early detection and treatment of complications of the procedure.     

Analysis of mandibular motion following unilateral and bilateral alloplastic TMJ reconstruction

The purpose of this study was to analyse the masticatory patterns and range of motion (maximal incisal opening (MIO), protrusion and lateral excursion) in patients who have had unilateral and bilateral temporomandibular joint (TMJ) replacement with an alloplastic prosthesis, and compare them to each other and to normal controls. Mandibular motion was examined in 18 patients, who had undergone alloplastic TMJ reconstruction, 13 with a bilateral prosthesis and 5 with a unilateral prosthesis, and in 13 normal controls. A statistically significant difference (P < 0.01) for MIO and maximum lateral excursion was observed between the bilateral group and the control group. Maximum protrusion was only statistically significantly different (P < 0.05) between the bilateral group and the control group. For the unilateral group, a statistically significant difference (P < 0.01) was seen only with maximum contralateral excursion when compared with controls. No statistically significant difference existed in MIO and protrusion between the unilateral and bilateral groups. Even though maximum ipsilateral lateral excursion was greater for the unilateral group than either left or right maximum lateral excursion by the bilateral group, this difference was not statistically significant. This study provided an in vivo analysis of mandibular motion following alloplastic TMJ reconstruction.     

Ro 60 functions as a receptor for β2‐glycoprotein I on apoptotic cells

Objective

The autoantigens 60‐kd Ro/SSA (Ro 60) and β₂‐glycoprotein I (β₂GPI) are both displayed on the surface membrane of apoptotic cells. Epitope‐spreading experiments have suggested that these autoantigens may be present as a complex on the apoptotic cell surface. This study was undertaken to investigate whether β₂GPI interacts with Ro 60 on apoptotic cells and alters the binding of anti–Ro 60 IgG.

Methods

The interaction between soluble recombinant Ro 60 fragments and β₂GPI was investigated in vitro by direct and saturation binding assays using native human β₂GPI and recombinant domain deletion mutants. Binding of β₂GPI to early and late apoptotic cells was assessed by multiparameter flow cytometry, and specificity of binding was determined by competitive inhibition with soluble recombinant Ro 60 and anti–Ro 60 IgG.

Results

The Ro 60 fragment expressing a surface‐exposed epitope (apotope) bound with high affinity (K_d = ∼15 nM) to domain V of β₂GPI in vitro. Beta₂‐glycoprotein I bound to the surface of apoptotic cells in a dose‐dependent manner and was blocked by the Ro 60 apotope fragment. In reciprocal competitive inhibition studies, β₂GPI blocked the binding of anti–Ro 60 autoantibodies to apoptotic cells in a dose‐dependent manner, and anti–Ro 60 IgG inhibited the binding of β₂GPI. Moreover, β₂GPI showed a 2‐fold increase in binding to apoptotic cells that overexpress Ro 60 on the surface.

Conclusion

These results demonstrate that Ro 60 functions as a novel receptor for β₂GPI on the surface of apoptotic cells. The formation of Ro 60–β₂GPI complexes may protect against anti–Ro 60 autoantibody–mediated tissue injury.

     

The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100,000 and 1:200,000 epinephrine

OBJECTIVES: The authors conducted a randomized, double-blind, two-way crossover clinical trial to compare the pharmacokinetics and cardiovascular effects of 11.9 milliliters of 4 percent articaine hydrochloride (HCl) plus 1:100,000 epinephrine (A100) with those of 11.9 mL of 4 percent articaine HCl plus 1:200,000 epinephrine (A200). METHODS: During two testing sessions, the authors administered injections of A100 and A200 over a seven-minute period (in one-cartridge doses unless otherwise noted): maxillary right first molar infiltration, maxillary left first molar infiltration, maxillary right first premolar infiltration, maxillary left first premolar infiltration, right inferior alveolar injection, left inferior alveolar injection, right long buccal infiltration (one-half cartridge) and left long buccal infiltration (one-half cartridge). They analyzed venous blood samples for articaine levels. They used noninvasive acoustic tonometry to measure a variety of cardiovascular parameters over a two-hour period. RESULTS: Plasma concentration curves of articaine over time were similar for both solutions, with peak concentrations and times to maximum concentration being 2,037 nanograms per milliliter and 22 minutes for A100 and 2,145 ng/mL and 22 minutes for A200. At the 10-minute point, the mean systolic blood pressure and heart rate were significantly elevated (P < .05) with A100 versus A200. CONCLUSIONS: Maximum dose recommendations for the A100 solution also can be applied to the A200 solution. A200 produces less cardiovascular stimulation than does A100. CLINICAL IMPLICATIONS: A200 is as safe as A100, and may be preferable to A100 in patients with cardiovascular disease and in those taking drugs that reportedly enhance the systemic effects of epinephrine.     

Management of surgical failures

Surgical intervention is appropriate in a small percentage of patients with temporomandibular joint disorders when it is based on a specific diagnosis of intracapsular pathology not amenable to nonsurgical modalities. Expected advances in our understanding of the complex molecular, biochemical, and genetic factors that influence these disease states clearly will allow less invasive techniques and even obviate the need for some open arthroplastic interventions altogether in the future. In the meantime, reasonable, well-intentioned surgeons must rely on the current body of surgical knowledge to use surgery as judiciously as possible.     

Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V

OBJECTIVE: Results of previous studies suggest that anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in complex with beta2GPI activate platelets in a dysregulated manner, potentially contributing to the prothrombotic tendency associated with the antiphospholipid syndrome (APS). We undertook this study to investigate the possible contribution of the GPIb-IX-V receptor to platelet activation mediated by the anti-beta2GPI antibody-beta2GPI complex. METHODS: In vitro methods were used in the present study. The interaction between beta2GPI and the GPIbalpha subunit of the GPIb-IX-V receptor was delineated using direct binding and competitive inhibition assays. The interaction between the anti-beta2GPI antibody-beta2GPI complex and platelets was studied using a novel method in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by two methods; one involved measuring thromboxane B2 production and the other involved assessment of the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta intracellular signaling pathway. The contribution of the GPIbalpha receptor to platelet activation induced by the anti-beta2GPI antibody-beta2GPI complex was assessed by observing the influence of 2 anti-GPIbalpha antibodies (AK2 and SZ2) directed against distinct epitopes. RESULTS: This study showed that beta(2)GPI could bind to the GPIbalpha receptor. The anti-beta2GPI antibody-beta2GPI complex was able to activate platelets, and this effect was inhibited by anti-GPIbalpha antibody directed against epitope Leu-36-Gln-59, but not by anti-GPIbalpha antibody directed against residues Tyr-276-Glu-282. CONCLUSION: Our findings show that inappropriate platelet activation by the anti-beta2GPI antibody-beta2GPI complex via the GPIbalpha receptor may contribute to the prothrombotic tendency associated with APS.