Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates.

This study examined the safety of intracerebral inoculation of G207, an attenuated, replication-competent herpes simplex virus type 1 (HSV-1) recombinant, in nonhuman primates. Sixteen New World owl monkeys (Aotus nancymae [karyotype 1, formerly believed to be A. trivirgatus]), known for their exquisite susceptibility to HSV-1 infection, were evaluated. Thirteen underwent intracerebral inoculation with G207 at doses of 10(7) or 10(9) PFU, two were vehicle inoculated, and one served as an infected wild-type control and received 10(3) PFU of HSV-1 strain F. HSV-1 strain F caused rapid mortality and symptoms consistent with HSV encephalitis, including fever, hemiparesis, meningitis, and hemorrhage in the basal ganglia. One year after G207 inoculation, seven of the animals were alive and exhibited no evidence of clinical complications. Three deaths resulted from nonneurologic causes unrelated to HSV infection, and three animals were sacrificed for histopathologic examination. Two animals were reinoculated with G207 (10(7) PFU) at the same stereotactic coordinates 1 year after the initial G207 inoculation. These animals were alive and healthy 2 years after the second inoculation. Cerebral magnetic resonance imaging studies performed both before and after G207 inoculation failed to reveal radiographic evidence of HSV-related sequelae. Despite the lack of outwardly observable HSV pathology, measurable increases in serum anti-HSV titers were detected. Histopathological examination of multiple organ tissues found no evidence of HSV-induced histopathology or dissemination. We conclude that intracerebral inoculation of up to 10(9) PFU of G207, well above the efficacious dose in mouse tumor studies, is safe and therefore appropriate for human clinical trials.

Pathologic findings in a steroid-responsive optic nerve infarct in giant-cell arteritis.

OBJECTIVE: To investigate the pathophysiologic mechanism of optic nerve infarction in giant-cell arteritis (GCA). BACKGROUND: Previous pathologic reports of optic nerve infarction in GCA involved patients who were blind at the time of death. The optic nerve infarcts were primarily retrolaminar in localization. Simultaneous short ciliary and ophthalmic artery vasculitis was found in all patients. METHODS: Clinical neurologic and ophthalmologic examination, temporal artery biopsy, and neuroimaging tests were performed in a patient with an anterior ischemic optic neuropathy secondary to GCA. Pathologic examination of the viscera, eye, and brain were performed at autopsy 1 month later. RESULTS: A prelaminar/retrolaminar infarct was found in this patient. Subsiding vasculitis was limited to the short ciliary arteries, sparing the central retinal, pial, and ophthalmic arteries. CONCLUSIONS: The authors believe that the visual improvement observed in this patient was the result of preserved, anterior optic nerve collateral circulation, as well as the neuroprotective and anti-inflammatory effect of the corticosteroids.

Lung carcinoma presenting as metastasis to intracranial meningioma: case report and review of the literature.

Tumor-to-tumor metastasis is rare. The authors report a case of a 52-year-old man with a 1-year history of a right parasaggital meningioma, whose clinical signs were consistent with enlarging meningioma. In preparation for surgery, the routine preoperative chest radiograph revealed a lung mass. Fine-needle aspiration of the mass revealed adenocarcinoma. The patient underwent surgical excision of the intracranial mass, which was thought to be a meningioma. However, pathologic examination revealed a transitional meningioma extensively infiltrated with deposits of metastatic carcinoma from the patient's primary lung tumor. Metastasis to meningioma was therefore responsible for the rapid enlargement of the long-standing meningioma, and caused the first clinical manifestation of primary lung carcinoma. Recurrent metastasis developed at the surgical site 5 weeks later, requiring surgical excision and postoperative radiation to prevent further recurrence. This is a highly unusual presentation for lung carcinoma and, to the authors' best knowledge, is the first such case reported. A review of the published literature revealed 20 other cases of lung carcinoma metastatic to meningioma, which were incidentally discovered on surgery or autopsy.

Activation of CNS circuits producing a neurogenic cystitis: evidence for centrally induced peripheral inflammation.

We present a model of neurogenic cystitis induced by viral infection of specific neuronal circuits of the rat CNS. Retrograde infection by pseudorabies virus (PRV) of neuronal populations neighboring those that innervate the bladder consistently led to a localized immune response in the CNS and bladder inflammation. Infection of bladder circuits themselves or of circuits distant from these rarely produced cystitis. Absence of virus in bladder and urine ruled out an infectious cystitis. Total denervation of the bladder, selective C-fiber deafferentation, or bladder sympathectomy prevented cystitis without affecting the CNS disease, indicating a neurogenic component to the inflammation. The integrity of central bladder-related circuits is necessary for the appearance of bladder inflammation, because only CNS lesions affecting bladder circuits, i.e., bilateral dorsolateral or ventrolateral funiculectomy, as well as bilateral lesions of Barrington's nucleus/locus coeruleus area, prevented bladder inflammation. The close proximity in the CNS of noninfected visceral circuits to infected somatic neurons would thus permit a bystander effect, leading to activation of the sensory and autonomic circuits innervating the bladder and resulting in a neurogenic inflammation localized to the bladder. The present study indicates that CNS dysfunction can bring about a peripheral inflammation.

Isolated facial nerve palsy from metastasis to the temporal bone: report of two cases and a review of the literature.

Isolated facial nerve paralysis is rarely the result of metastasis. We describe two cases (the fourth and fifth cases ever documented) with facial nerve palsy secondary to metastatic adenocarcinoma to the temporal bone. We also review the pathogenesis and presentation of facial nerve paralysis from metastasis and discuss a possible treatment strategy.

Proteolysis of human calcitonin in excised bovine nasal mucosa: elucidation of the metabolic pathway by liquid secondary ionization mass spectrometry (LSIMS) and matrix assisted laser desorption ionization mass spectrometry (MALDI).

PURPOSE: Two calcitonins, i.e. human calcitonin (hCT) and, for comparison, salmon calcitonin (sCT), were chosen as peptide models to investigate nasal mucosal metabolism. METHODS: The susceptibility of hCT and sCT to nasal mucosal enzymes was assessed by in-and-out reflection kinetics experiments in an in vitro model based on the use of freshly excised bovine nasal mucosa, with the mucosal surface of the mucosa facing the peptide solution. The kinetics of CT degradation in the bulk solution was monitored by HPLC. Peptide sequences of the main nasal metabolites of hCT were analyzed by using both liquid secondary ionization mass spectrometry (LSIMS), following HPLC fractionation of the metabolites, and matrix-assisted laser desorption ionization mass (MALDI) spectrometry. For sCT, the molecular weights of two major metabolites were determined by LC-MS with electrospray ionization. RESULTS: Both CTs were readily metabolized by nasal mucosal enzymes. In the concentration range studied metabolic rates were higher with hCT than with sCT. Presence of endopeptidase activities in the nasal mucosa was crucial, cleaving both calcitonins in the central domain of the molecules. CONCLUSIONS: Typically, initial metabolic cleavage of hCT in nasal mucosa is due to both chymotryptic- and tryptic-like endopeptidases. The subsequent metabolic break-down follows the sequential pattern of aminopeptidase activity. Tryptic endopeptidase activity is characteristic of nasal sCT cleavage.

Treatment of human malignant meningiomas by G207, a replication-competent multimutated herpes simplex virus 1.

We have demonstrated that replication-competent attenuated mutants of herpes simplex virus type 1 (HSV-1) have therapeutic potential for malignant gliomas. Moreover, a recently described multiple mutant HSV (termed G207) has properties which may allow human clinical trials. G207 is able to replicate within and kill cells from three human malignant meningiomas in cell culture. In nude mice harboring s.c. human malignant meningioma (F5), G207 can inhibit growth in a dose-dependent fashion. In nude mice harboring intracranial subdural human malignant meningioma (F5), one injection of G207 caused significantly decreased tumor growth and one apparent cure with neither neurological dysfunction nor pathological changes in the surrounding brain. These results suggest that G207 should be considered for therapeutic trials in the treatment of malignant meningioma refractory to currently available therapies.

Atypical cerebral aneurysm in a young child.

Autopsy findings are described of an atypical aneurysm of a large cerebral artery in a young child. The lesion is believed to have been an infective (mycotic) aneurysm. Antibiotics were administered at the time of the first leakage which had been thought to be due to a sinus infection. The sac wall exhibited a subacute pleomorphic inflammatory cell response indicative of a resolving infective aneurysm, and appearance that is likely to be encountered more often in the future.

A clinical and neuropathologic study of silk suture as an embolic agent for brain arteriovenous malformations.

PURPOSE: To evaluate the safety and efficacy of silk suture as an agent for preoperative embolization of cerebral arteriovenous malformations. METHODS: Clinical and histopathologic results were analyzed in six patients who underwent embolization of cerebral arteriovenous malformations using silk suture in combination with other agents. RESULTS: Three of the patients treated with silk hemorrhaged after embolization, and two of these patients died. Neuropathologic analysis of four patients showed acute perivascular inflammation, sometimes quite severe. CONCLUSIONS: The inflammatory response to silk may explain its effectiveness in producing vascular occlusion. However, a fulminate vasculitis theoretically can predispose to delayed hemorrhage. Other problems with silk include the pressure required to inject the agent and the inability to determine the final site of deposition of the silk. Although other embolic agents may share some of these potential difficulties, we feel that the disadvantages outweigh the advantages of silk as an embolic agent.

Type-specific identification of herpes simplex and varicella-zoster virus antigen in autopsy tissues.

To identify antigens of herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV) in human tissue, polyclonal antisera and an immunoperoxidase method were used to examine formalin-fixed, paraffin-embedded tissues from autopsy cases and experimentally infected animals. These antisera readily distinguished between HSV and VZV antigen, with no evident cross-reactivity. Antiser ato HSV-1 and HSV-2 were more strongly reactive with antigen of the homologous virus than with that of heterologous virus. This difference in immunoreactivity was used to discriminate between HSV-1 and HSV-2 antigens in experimentally infected animal tissues containing HSV antigens of known type and, by extrapolation, to distinguish between these antigens in human autopsy tissues. Thus, with appropriate antisera and tissue controls, HSV-1, HSV-2, and VZV can be identified in paraffin sections.

Characterization of artificial liposomes with free-flow electrophoresis.

Free flow electrophoresis was used to examine the influence of active substances, lipid composition and preparation method on the surface charge of the liposomes. It is also possible to test the homogeneity of a liposome population with FFE.

Disk fragment migration.

This report analyzes the most frequently observed migration paths of disk fragments in 47 patients who had extruded or sequestered disks. Observations are based principally on magnetic resonance (MR) images. When disk fragments moved in a superior (42%) or inferior (40%) direction from the donor disk, the displaced disk components were most frequently (94%) dislodged into the right or left half of the anterior epidural space (AES) and rarely straddled the midline. To explain this phenomenon, the authors investigated the anatomy of the AES by dissecting four cadaver specimens and reviewing 300 MR images of the spine. They conclude that the migrating path of a disk fragment is determined by the anatomy of the AES, a fairly well-defined space delimited posteriorly by the posterior longitudinal ligament and by membranes laterally attached to it. It consists of two compartments separated by a sagitally aligned septum. During migration, sequestered disk fragments usually stay in these compartments.

Bilateral orbital involvement in fatal giant cell polymyositis.

The case of a young woman with giant cell polymyositis is described. She had bilateral, severe, midly painful proptosis and ophthalmoplegia. Extensive pharyngeal, laryngeal, and cardiac muscle involvement occurred 18 months later coincident with fatal cardiac arrhythmia. At autopsy, extensive muscle necrosis and giant cells were noted in extraocular, pharyngeal, laryngeal, and cardiac muscle with only minimal involvement of other striated muscles.

Malassezia furfur--disseminated infection in premature infants.

Three infants, born prematurely, died after clinical illnesses of 67, 65, and 60 days from infection by Malassezia furfur. Each infant had been nourished with lipid emulsions delivered through deep-line catheters. The infections, all discovered at autopsy, were characterized by massive involvement of lungs. Two of the three had endocardial vegetations containing M. furfur; all three had lesions in liver, kidney, and spleen, and two had lesions in adrenal, pancreas, and colon. In addition, one of the infants had acute meningoencephalitis caused by M. furfur. In some of the distant organs, yeast cells of M. furfur were growing in the lumina of small vessels, filling the lumina, but causing no vasculitis or infarction. In addition to these benign collections of yeasts within vessels, there were acute inflammatory lesions as well. These were consolidation, vasculitis, granulomatous inflammation, septic thrombosis, and septic infarction of lung and foci of necrosis and inflammation in kidney and liver. Two previously reported autopsies described neonates with lesions in lung and heart. The authors' three cases for which autopsies were performed had lesions in lung and heart too but, in addition, had dissemination with acute lesions in kidney and liver. Finally, one patient had a severe meningoencephalitis caused by M. furfur.

MR imaging of neurocysticercosis.

Twenty-six patients with neurocysticercosis were studied with MR imaging to correlate their clinical presentation with the location and appearance of their neurocysticercosis lesions. Intraventricular cysts were present in 14 patients (54%), parenchymal cysts were present in 18 (69%), and intraventricular together with parenchymal cysts were present in six (23%). Intraventricular cysts were detected by mass effect, ventricular obstruction, detection of a cyst rim, and/or CSF flow void adjacent to the cyst. The intensity of most intraventricular and parenchymal cysts presumed to be viable was similar to that of CSF on both T1- and T2-weighted sequences. Cysts presumed to be degenerated had increased signal intensity on T1-weighted images, probably resulting from increased protein content. Pericystic high signal intensity surrounding lesions of various ages was seen on both proton-density- and T2-weighted images and represents gliosis, edema, and inflammation. Patients with parenchymal cysts had symptoms of seizures, while those with intraventricular cysts generally had symptoms related to obstructive hydrocephalus. Aqueductal stenosis, seen in 10 patients (38%), was possibly due to ependymal inflammation or adhesions caused by prior ventricular infection by neurocysticercosis. One patient with the racemose form of neurocysticercosis demonstrated abundant cyst wall proliferation resulting in obstructive hydrocephalus. In six patients scanned 1-6 months after oral praziquantel therapy, there was no change in the MR appearance of intraventricular cysts, while some parenchymal cysts showed evidence of degeneration. We found MR to be useful in detecting the cysts of neurocysticercosis and the accompanying signs of cyst degeneration and pericystic inflammation. MR was inferior to CT in the detection of parenchymal calcifications.

Amniotic band syndrome. Report of two cases and review of the literature.

The amniotic band syndrome, a complex collection of asymmetric congenital anomalies, is almost certainly an underdiagnosed entity. No two cases are exactly alike. Two cases are reported, each of which exhibits craniofacial, visceral, body wall, and limb anomalies, the common types of defects seen in this syndrome. The literature is reviewed, and the most commonly accepted theory of pathogenesis is discussed in juxtaposition to another major theory. The importance of recognizing this syndrome is stressed, since it very rarely recurs in families.

Rapid isolation of OmpF porin-LPS complexes suitable for structure-function studies.

A gentle and rapid isolation procedure is described yielding fractions containing better than 95% pure OmpF porin of Escherichia coli BE with different amounts of bound lipopolysaccharide (LPS). The procedure employs continuous free-flow electrophoresis (FFE) in the presence of detergent above its critical micelle concentration. Total yields of around 45% were typically obtained when porin-enriched membrane extracts were processed. By use of analytical ultracentrifugation a molecular mass of 114,000 and a sedimentation coefficient S20,w of 5.0 S were determined for porin trimers containing approximately 1 mol of tightly bound LPS. This porin readily formed 3D crystals suitable for high-resolution X-ray diffraction analysis. Three other porin-LPS isoforms isolated by FFE revealed molecular masses of 120,000, 124,000, and 151,000, suggesting that, in addition to the tightly bound LPS, 1, 2, and 8 mol of loosely bound LPS were present per mole of porin trimer. Each of the four different isoforms was suitable for reconstitution into highly ordered protein-lipid membrane arrays. The membrane crystals obtained with the 151-kDa isoform exhibited a unit cell polymorphism similar to that previously reported.