T-lymphocyte-epithelial-cell interactions: integrin alpha(E)(CD103)beta(7), LEEP-CAM and chemokines.

The epithelia are the avascular layers of cells that cover the environment-exposed surfaces of the body. It appears that T cells localize to selected sites in or adjacent to epithelia via the selective expression of adhesion molecules and chemokine receptors on T cells. These bind to counter-receptors and to chemokines expressed by epithelial cells. Recently, there has been an advance in our understanding of the interaction of the alpha(Ebeta7) integrin with its epithelial cell ligand, E-cadherin. In addition, a new adhesion molecule has been identified on non-intestinal epithelial cells, termed lymphocyte-endothelial-epithelial-cell adhesion molecule (LEEP-CAM). Finally, there have been advances in our understanding of the role of skin- or gut-epithelia-derived chemokines in regulating activated T cell homing to these sites.

Lymphocyte adhesion to epithelia and endothelia mediated by the lymphocyte endothelial-epithelial cell adhesion molecule glycoprotein.

Upon encountering the relevant vascular bed, lymphocytes attach to endothelial adhesion molecules, transmigrate out of circulation, and localize within tissues. Lymphocytes may then be retained at microanatomic sites, as in tissues, or they may continue to migrate to the lymphatics and recirculate in the blood. Lymphocytes also interact transiently, but with high avidity, with target cells or APC that are infected with microbes or have taken up exogenous foreign Ags. This array of adhesive capabilities is mediated by the selective expression of lymphocyte adhesion molecules. Here, we developed the 6F10 mAb, which recognizes a cell surface glycoprotein designated lymphocyte endothelial-epithelial cell adhesion molecule (LEEP-CAM), that is distinct in biochemical characteristics and distribution of expression from other molecules known to play a role in lymphocyte adhesion. LEEP-CAM is expressed on particular epithelia, including the suprabasal region of the epidermis, the basal layer of bronchial and breast epithelia, and throughout the tonsillar and vaginal epithelia. Yet, it is absent from intestinal and renal epithelia. Interestingly, it is expressed also on vascular endothelium, especially high endothelial venules (HEV) in lymphoid organs, such as tonsil and appendix. The anti-LEEP-CAM mAb specifically blocked T and B lymphocyte adhesion to monolayers of epithelial cells and to vascular endothelial cells in static cell-to-cell binding assays by approximately 40-60% when compared with control mAbs. These data suggest a role for this newly identified molecule in lymphocyte binding to endothelium, as well as adhesive interactions within selected epithelia.

Calnexin expression does not enhance the generation of MHC class I-peptide complexes.

We investigated the requirement for calnexin in the biogenesis of MHC class I molecules. Mutant human cells lacking calnexin were infected with recombinant vaccinia viruses encoding mouse MHC class I molecules, Kd, Kb, Kk, Dd, Db, and Ld. Flow cytometry indicated that each of the six MHC class I allomorphs was transported to the cell surface at similar rates in calnexin-deficient cells and transfectants expressing calnexin. For Kb and Kd, the calnexin-independent biogenesis occurred regardless of whether the MHC class I molecules contained human or mouse beta 2-microglobulin. Also addressed was the effect of calnexin on the surface expression of Kb molecules bearing the immunodominant peptide from ovalbumin (OVA257-264). This was detected with a recently described monoclonal antibody specific for the Kb/peptide complex. Calnexin expression had no significant effect on the formation of Kb/peptide complexes generated from full-length OVA, cytosolic OVA257-264, or endoplasmic reticulum-targeted OVA257-264, which was expressed in the presence of the herpes simplex virus ICP47 protein to ensure detection of TAP-independent peptide-MHC class I complexes. Complementary results were obtained with TAP-independent formation of Kd/ peptide complexes. These findings indicate that calnexin is not required for the efficient assembly of MHC class I molecules with TAP-dependent or independent peptides.

A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes.

Newly assembled major histocompatibility complex (MHC) class I molecules, together with the endoplasmic reticulum chaperone calreticulin, interact with the transporter associated with antigen processing (TAP) through a molecule called tapasin. The molecular cloning of tapasin revealed it to be a transmembrane glycoprotein encoded by an MHC-linked gene. It is a member of the immunoglobulin superfamily with a probable cytoplasmic endoplasmic reticulum retention signal. Up to four MHC class I-tapasin complexes were found to bind to each TAP molecule. Expression of tapasin in a negative mutant human cell line (220) restored class I-TAP association and normal class I cell surface expression. Tapasin expression also corrected the defective recognition of virus-infected 220 cells by class I-restricted cytotoxic T cells, establishing a critical functional role for tapasin in MHC class I-restricted antigen processing.

Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP.

Assembly of MHC class I-beta 2 microglobulin (beta 2m) dimers in the endoplasmic reticulum involves two chaperones. Calnexin has previously been shown to interact with free class I heavy chains. Here, we show that the related chaperone, calreticulin, binds human class I-beta 2m dimers prior to peptide loading. Calreticulin remains associated with at least a subset of class I molecules when they, in turn, bind to TAP. Further evidence suggests that the interaction of class I-beta 2m dimers with TAP occurs via a novel uncharacterized 48 kDa glycoprotein, tapasin, which can bind independently to TAP and class I-beta 2m-calreticulin complexes. Tapasin is absent from the mutant cell line .220, in which class I-TAP association and peptide loading is defective.

Large cerebral arteriovenous malformations: experience with 27 cases.

BACKGROUND: The management of large cerebral arteriovenous malformations is difficult. Surgical excision is often attempted after embolization. Interventional neuro-radiology is available in only a few centers. If large AVMs can be safely excised without pre-operative embolizaton, then these lesions can be treated at many neurosurgical centers. METHODS: Between January 1986 and June 1992, a total of 210 patients with cerebral AVMs were diagnosed by angiographic studies. Twenty-seven of them had large AVMs wider than 5 cm in the longest diameter. The case records of these patients were retrieved and studied. RESULTS: Two patients were treated with Bragg peak proton beam therapy. Twelve patients were treated conservatively with no improvement. Thirteen patients underwent surgery and total AVM excision was achieved in 11. None of the patients who underwent surgery had any pre- or intra-operative embolization. All the patients had no neurological deterioration post-operatively. CONCLUSIONS: Large cerebral AVMs can be treated by surgical excision alone with acceptable results.

A teratocarcinoma developing after gross total excision of a pineal teratoma in a patient with systemic lupus erythematosus.

This is a rare case of a teratocarcinoma developing at the same site one year after the gross total excision of a mature pineal teratoma. The malignant tumour arose probably from microscopic remnants of the teratoma. This patient also suffered from systemic lupus erythematosus. Autoimmune diseases have been associated with an increased risk of malignancy, and in this case may have contributed to the malignant transformation of the teratoma.

Alzheimer's disease cerebrospinal fluid antibodies display selectivity for microglia. Investigations with cell cultures and human cortical biopsies.

Previous investigations demonstrated that the cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients contains antibodies that recognize specific neuronal populations in the adult rat central nervous system (CNS). These findings suggest a pathogenic role for immunological aberrations in this disorder. To determine if antibodies may provide a means to differentially diagnose the dementias, CSF from a diversified dementia population was screened against the developing rat CNS and a cell culture system. Markings produced by AD CSF were distinctly different from those of vascular dementias (VAD) against the developing rat CNS. More importantly, some AD CSF recognized amoeboid microglia. The recognition of amoeboid microglia by antibodies in AD CSF is particularly interesting since these cells proliferate in response to nervous system disease and also engulf debris. A cell culture technique was developed to allow the rapid screening of CSF antibodies. Patient CSF produced five different types of markings in the cell culture: microglia, glioblasts, fibers, nonspecific, or negative. Correlations with these structures and the diagnosis of four different dementia populations revealed that, in comparison to the other groups, AD CSF displayed remarkable selectivity toward microglial cells. Cortical biopsies from patients suspected to have AD were incubated with the patient's own CSF and that of confirmed AD patients. Both CSF samples recognized microglial cells in the patient's cortical biopsy. The same CSF samples incubated against normal human cortical autopsy or a biopsy from a 3-mo-old child displayed negative immunoreactivity. These three approaches suggest that the presence of CSF microglial antibodies may be a means to distinguish AD patients from other dementias. The results add further support to the widely growing concept that inflammation and similar immune mechanisms may contribute to AD pathogenesis.

Surgery for brain metastases in Singapore.

The best possible treatment for a single metastasis to the brain is complete surgical excision followed by whole brain irradiation. A survey was done to determine the proportion of patients with brain metastases who had surgical excision of the lesion. The number of patients with a preoperative diagnosis of cerebral metastases who underwent surgical excision in Tan Tock Seng Hospital from 1985 to 1989 was obtained from the operation records. An average of 11 surgical excisions were done for cerebral metastases annually. To estimate the number of cases of single brain metastases seen annually in Singapore, figures of cases of cancer of the lungs, breast and colorectum from 1978 to 1982 were obtained from the Singapore Cancer Registry. Based on a conservative estimate that 20% of these cancers metastasize to the brain, that 50% are single metastasis and of these, half are suitable surgical candidates, our calculations show that there are at least 67 cases of surgically excisable single brain metastasis in Singapore annually. This means that more than 84% of patients with a single brain metastasis are not getting the best possible treatment. The reasons may be due to patients' fear of operation and to lack of awareness among physicians on advances in the management of brain metastases. Patient education and physician update on recent advances in treatment will allow patients to obtain the best possible treatment.

The management of arteriovenous malformations in children.

Between January 1941 and June 1989, 46 children below the age of 18 with an arteriovenous malformation (AVM) were managed. There were 7 patients with AVM diagnosed before the age of 2; 10 patients were diagnosed between the ages of 3 and 10; and 29 patients were diagnosed between 11 and 18. There were equal numbers of male and female patients. Twenty-five of the AVMs were large (greater than 5 cm longest diameter). All 7 AVMs diagnosed before the age of 2 were large. The usual clinical presentation was congestive heart failure, bruit and an enlarging head. Three patients underwent excision with 2 deaths and 1 excellent result. In 11 patients (aged 3-18) with AVM without history of hemorrhage, 3 had excision with 2 excellent and 1 fair result. Four remained stable. Four developed progressive deficits or hemorrhage. In 10 patients (aged 3-18) with AVM and hemorrhage who were treated medically, 7 (70%) had an episode of re-hemorrhage. Three patients had excision of AVM after re-hemorrhage, but before the age of 18 with an excellent result. Eighteen patients (aged 3-18) with AVM and a single episode of hemorrhage underwent excision with 17 excellent or good results and 1 fair result. The overall mortality was 7%. Eighty-five percent of the children with excision of AVM had an excellent or good result. The best treatment for AVM in children is surgical excision.

The anterior cavernous sinus space.

The anterior cavernous sinus space is the venous space anterior to the cavernous carotid artery. It is tetrahedral in shape with the anterior apex at the superior orbital fissure. The superomedial wall is formed by the base of the anterior clinoid process. The inferomedial wall is formed by the sphenoid bone. The lateral wall consists of two layers of dura with the oculomotor, trochlear, ophthalmic and abducens nerves in the inner layer. Medially, the posterior wall consists of the cavernous carotid artery. Laterally, it communicates with the lateral cavernous sinus space. Paraclinoid and carotid cave aneurysms may occupy this space and its microanatomy is important in the surgery of these aneurysms.

Direct surgery for carotid bifurcation artery aneurysms.

Eighteen patients with bifurcation of internal carotid artery aneurysms were treated with direct surgery. In all cases the pterional approach was used. The strategy used in dissecting the aneurysm depends on the size of the aneurysm and the length of the intracranial internal carotid artery. When the aneurysm is small, the bifurcation of the internal carotid artery can be exposed by dissecting along the internal carotid artery from a proximal-to-distal direction. The aneurysm and the perforating vessels adjacent to it are identified before the aneurysm is clipped. When the aneurysm is not small or if the intracranial segment of the internal carotid artery is long, the sylvian fissure has to be dissected open before dissection of the aneurysm and perforators is undertaken. Using this dissection strategy, 18 bifurcations of internal carotid artery aneurysms were clipped with 16 excellent, one good, and one fair result. There was no mortality.

Posterior inferior to posterior inferior cerebellar artery anastomosis combined with trapping for vertebral artery aneurysm. Case report.

A case is presented in which a giant intracranial vertebral artery aneurysm gave rise to an associated ipsilateral posterior inferior cerebellar artery (PICA) from its waist. Proximal vertebral artery ligation at C-1 was achieved. The aneurysm filled from the opposite vertebrobasilar junction. Direct intracranial trapping of the right vertebral aneurysm was followed by successful anastomosis of the proximally sectioned right PICA to the adjacent left PICA in an end-to-end fashion.

Use of experimental aneurysms to evaluate wrapping materials.

Experimental venous pouch aneurysms in rats were wrapped with muscle, bovine collagen, muslin, cotton, or polyvinyl alcohol. The rats were killed 6 or 12 weeks later, and the aneurysms were compared with control aneurysms. Bovine collagen and muscle were reabsorbed and the aneurysms were similar to the control group. Cotton, muslin, and polyvinyl alcohol caused fibrosis around the aneurysm. However, giant aneurysms were found in the muslin and polyvinyl alcohol group. Cotton appears to be the most suitable material for wrapping aneurysms. The experimental venous pouch aneurysm model in rats can be used to evaluate wrapping materials.

Giant intracranial aneurysm surgery: the role of microvascular reconstruction.

The surgical management of 62 anterior circulation giant intracranial aneurysms is presented. Women were affected three times as frequently as men. Thirty-two patients presented with local mass effect, which was the most common mode of presentation, while 26 patients had subarachnoid hemorrhage. Three patients presented with transient ischemic attacks and three patients presented with seizures. In 16 cases the giant intracranial aneurysm involved the cavernous sinus and indirect surgery was performed. Ten patients were treated with extracranial-intracranial bypass and gradual occlusion of the proximal internal carotid artery. Six patients were treated with extracranial-intracranial bypass and trapping of the aneurysm (sudden occlusion of internal carotid artery). Sudden occlusion was poorly tolerated, and 50% of the patients developed ischemic complications. In 46 cases of giant intracranial aneurysm without involvement of the cavernous sinus, direct surgery was undertaken. In 31 patients the aneurysm could be clipped without compromise to the surrounding vessels. In 15 patients there was compromise of surrounding vessels or the aneurysm sac was excised and so microvascular reconstruction was needed. Local intracranial reconstruction was preferred whenever feasible. The results of patients who needed reconstruction were similar to those who did not need reconstruction. Overall, 84% of patients had an excellent or good outcome after surgery. The mortality was 5%.

Vascular malformations and pregnancy.

Between January 1975 and June 1989, 240 patients with cerebral vascular malformations were treated at Henry Ford Hospital. In 16 of the patients, the treatment was influenced by pregnancy. Eleven of the patients presented with hemorrhage, four with seizures, and one with hydrocephalus. There were no maternal or fetal deaths in the patients presenting with seizure or hydrocephalus. There were two maternal deaths and one fetal death among the cases presenting with hemorrhage. In the patients with seizure or hydrocephalus, the pregnancy was brought to term and obstetric indications used to determine the time and method of delivery. Hydrocephalus was treated by shunting, and seizures with medication. Antiepileptic drug levels fluctuate in pregnancy and hence were closely monitored to ensure therapeutic levels. Vascular malformations are the most common cause of subarachnoid hemorrhage in pregnancy. The risk of rebleed in the same pregnancy is about 27%. If an arteriovenous malformation ruptures during pregnancy and the patient's condition deteriorates, appropriate emergency surgery should be done. In stable patients, our policy has been to bring the pregnancy to term and then electively perform a craniotomy to excise the arteriovenous malformation.

Superficial temporal and occipital artery bypass pedicles to superior, anterior inferior, and posterior inferior cerebellar arteries for vertebrobasilar insufficiency.

Eighty-three patients underwent 85 intracranial to extracranial pedicle bypass anastomosis procedures to the posterior circulation. There were 15 patients with occipital artery (OA) to posterior inferior cerebellar artery (PICA) anastomosis, 20 patients with OA to anterior inferior cerebellar artery (AICA) anastomosis, and 50 patients with superficial temporal artery (STA) to superior cerebellar artery (SCA) anastomosis. All patients had transient ischemic attacks (TIA's) suggestive of vertebrobasilar ischemia. Twenty-seven patients had crescendo TIA's or stroke in evolution and were considered to be clinically unstable. All patients had severe bilateral distal vertebral artery or basilar artery disease. Twenty-two patients had bilateral vertebral artery occlusion and three had basilar artery occlusion. In this series, 69% had complete resolution of symptoms; the mortality rate was 8.4% and the morbidity rate 13.3%. Clinically stable patients did better than unstable patients. The STA-SCA anastomosis was well tolerated and technically less demanding than the OA-PICA or OA-AICA anastomosis procedures. Patients with symptomatic severe bilateral vertebral or basilar artery disease have a grave prognosis and the option of a surgical arterial pedicle revascularization procedure should be offered to them.

Intracranial vertebral endarterectomy.

Intracranial vertebral endarterectomy was performed on six patients with vertebrobasilar insufficiency in whom medical therapy failed. The patients underwent operations for stenotic plaque in the intracranial vertebral artery with the opposite vertebral artery being occluded, hypoplastic, or severely stenosed. In four of the patients, the stenosis was mainly proximal to the posterior inferior cerebellar artery (PICA). In this group, after endarterectomy, the vertebral artery was patent in two patients, and their symptoms resolved; in one patient the endarterectomy occluded, but the patient's symptoms improved; and in one patient the endarterectomy was unsuccessful, and he continued to have symptoms. In one patient, the plaque was at the origin of the PICA. The operation appeared technically to be successful, but the patient developed a cerebellar infarction and died. In one patient the stenosis was distal to the PICA. During endarterectomy, the plaque was found to invade the posterior wall of the vertebral artery. The vertebral artery was ligated, and the patient developed a Wallenburg syndrome. The results of superficial temporal artery to superior cerebellar artery anastomosis are better than those for intracranial vertebral endarterectomy for patients with symptomatic intracranial vertebral artery stenosis. The use of intracranial vertebral endarterectomy should be limited to patients who have disabling symptoms despite medical therapy, a focal lesion proximal to the PICA, and a patent posterior circulation collateral or bypass.

Thrombolytic therapy and posterior circulation extracranial-intracranial bypass for acute basilar artery thrombosis. Case report.

Basilar artery thrombosis has a very poor prognosis. A 56-year-old comatose man with acute basilar artery occlusion was successfully treated with local urokinase infusion which reopened the basilar artery and revealed a midbasilar stenotic plaque. This procedure was followed by a superficial temporal artery to superior cerebellar artery anastomosis for protection of the posterior circulation.