Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy.

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

OSIRIS-REx Contamination Control Strategy and Implementation.

OSIRIS-REx will return pristine samples of carbonaceous asteroid Bennu. This article describes how pristine was defined based on expectations of Bennu and on a realistic understanding of what is achievable with a constrained schedule and budget, and how that definition flowed to requirements and implementation. To return a pristine sample, the OSIRIS-REx spacecraft sampling hardware was maintained at level 100 A/2 and <180 ng/cm2 of amino acids and hydrazine on the sampler head through precision cleaning, control of materials, and vigilance. Contamination is further characterized via witness material exposed to the spacecraft assembly and testing environment as well as in space. This characterization provided knowledge of the expected background and will be used in conjunction with archived spacecraft components for comparison with the samples when they are delivered to Earth for analysis. Most of all, the cleanliness of the OSIRIS-REx spacecraft was achieved through communication among scientists, engineers, managers, and technicians.

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.

Glial hyaluronate-binding protein in polar spongioblastoma.

Glial hyaluronate-binding (GHA) protein is a 60 kDa glycoprotein isolated from human white matter by affinity chromatography on immobilized hyaluronate. It is localized in white matter astrocytes by immunofluorescence with monoclonal antibodies. Amino acid sequences have not revealed similarities with other proteins except cartilage extracellular matrix proteins, the region of similarity being located within the hyaluronate-binding region. Cryostat sections of 13 intracranial neoplasms removed at surgery were tested for the presence of GHA protein by indirect immunofluorescence with monoclonal antibodies. These included seven astrocytomas, one oligodendroglioma, one medulloblastoma and one spinal cord ependymoma. All tumors were negative with the exception of one astrocytoma in which the GHA protein-positive areas had the typical appearance of polar spongioblastoma, i.e. small cells palisading around blood vessels and very delicate glial fibrillary acidic (GFA) protein-positive fibrils. Conversely, neoplastic as well as reactive GFA protein-positive astrocytes were GHA protein-negative. We suggest that polar spongioblastoma derives from a GHA protein-positive glial precursor and pertinent to this suggestion is the observation that the periventricular germinal layer was found GHA protein-positive in a 22-week human fetus.

Prognostic limitations of the Daumas-Duport grading scheme in childhood supratentorial astroglial tumors.

The Daumas-Duport grading scheme (DDGS) is a commonly used method for determining the grade of a tumor. It scores 4 histologic features and is used as a prognostic tool in adult astroglial tumors. This system of assigning children to prognostically homogeneous groups has not been evaluated. The Childhood Brain Tumor Consortium (CBTC) database includes 327 children with a CBTC assigned World Health Organization (WHO) diagnosis of supratentorial astroglial tumor and histologic features necessary for Daumas-Duport grading. We compared survival estimates for tumors within and between DDGS grades using a slightly broadened definition of endothelial prominence. The DDGS yielded only 3 histologic groups in children and only 2 prognostically differing groups. Subgroups within DDGS grades had significantly different survival distributions. The summing of 4 disparate histologic features in the DDGS is inadequate for the assessment of childhood supratentorial astroglial tumors. A classification system more fully summarizing the complete histologic content of tumors is most likely to provide diagnoses useful for clinical purposes.

New structure, the "olfactory pit," in human olfactory mucosa.

A whole-mount immunocytochemical method was devised to study the olfactory receptor neurons on the surface of the human olfactory mucosal sheet. Antibodies to neuron-specific tubulin and/or microtubule-associated protein 5 and phosphorylated neurofilament protein were used. Specimens taken at autopsy from 56 patients ranging in age from 2 days to 92 years revealed a structure not previously described, an olfactory pit. Round or oval openings with a diameter of 50 to 500 microns were observed on the surface of the olfactory epithelium in the whole-mount specimen. The morphology, number, and distribution of these openings varied among the different individuals. A detailed analysis of these structures was carried out by rehydrating and sectioning the whole-mount specimens. The olfactory pit (OP) is a blind pouch lined with olfactory epithelium (OE), which appears as an invagination of OE into the connective tissue, with a depth varying between 150 and 200 microns. In some sections through an OP, a thick axon bundle emerging from the bottom of the pouch was visible. The extension and termination of this axon bundle in the central nervous system has not been explored. We have found OPs in monkey olfactory mucosa, but none in rodents. The function of the pit specialization is unclear, but it appears to be a feature of normal, young epithelium. The configuration of the blind pouch may prolong odorant association with the olfactory receptor neurons, or the OP may contain specialized neurons that have not yet been recognized by morphological, biochemical, or functional techniques.

Early Guillain-Barré syndrome without inflammation.

A patient with typical acute Guillain-Barré syndrome died 72 hours after his first symptoms occurred, and an autopsy was performed 8 hours after his death. Extensive sampling of cranial and peripheral nerves, sensory ganglia, and autonomic nerves showed only minimal inflammatory lymphocytic and macrophage infiltrates. This case, one of the earliest studied extensively, represents an extreme example of a noninflammatory mechanism that has been proposed in some cases of Gullain-Barré syndrome.

Polyneuropathies associated with IgM monoclonal gammopathies.

We studied ten patients with IgM monoclonal gammopathies. Five had M proteins that reacted with myelin-associated glycoprotein (MAG) and five had no recognizable antinerve activity. The neuropathy in the MAG-reactive patients was homogeneous by clinical and laboratory analysis, while the neuropathy in the MAG-nonreactive patients varied considerably. Both groups responded well to immunosuppressive therapy, which lowered the concentration of the serum M protein. The homogeneity of the MAG-reactive patients and their response to sustained lowering of the M protein levels support the concept that the IgM M protein directly damages nerve fibers and is the proximate cause of the polyneuropathy.

Lateral thalamic infarcts.

A patient with occlusion of the proximal posterior cerebral artery (PCA), a lateral thalamic infarct, and hemisensory loss later developed hemianopia and hemiparesis and had extensive PCA territory infarction in the midbrain, the lateral portion of the thalamus, and the occipital lobe noted at necropsy. Two other patients had lateral thalamic infarcts on computed tomography, normal angiographic findings, and presumed thalamogeniculate artery branch occlusion. There are three clinical syndromes associated with lateral thalamic infarction: (1) hemisensory loss, hemiataxia, and involuntary movements; (2) pure sensory stroke; and (3) sensory-motor stroke. Ataxia, adventitious movements, and sensory loss are due to infarction of the lateral, posterolateral, and posteromedial ventral nuclei caused by occlusion of the PCA proximal to the thalamogeniculate artery branches or by occlusion of large thalamogeniculate arteries. Pure sensory and sensory-motor strokes are due to smaller infarcts in the posterolateral-posteromedial ventral complex and adjacent internal capsule caused by occlusion of penetrating artery branches of the thalamogeniculate arteries.

A case of Balamuthia mandrillaris meningoencephalitis.

Balamuthia mandrillaris is a newly described pathogen that causes granulomatous amebic encephalitis, an extremely rare clinical entity that usually occurs in immunosuppressed individuals. We report a case of pathologically proven Balamuthia encephalitis with unusual laboratory and radiologic findings. A 52-year-old woman with idiopathic seizures and a 2-year history of chronic neutropenia of unknown cause had a subacute illness with progressive lethargy, headaches, and coma and died 3 months after the onset of symptoms. Cerebrospinal fluid (CSF) glucose concentrations were extremely low or unmeasurable, a feature not previously described (to our knowledge). Cranial magnetic resonance imaging scans showed a single large temporal lobe nodule, followed 6 weeks later by the appearance of 18 ring-enhancing lesions in the cerebral hemispheres that disappeared after treatment with antibiotics and high-dose corticosteroids. The initial brain biopsy specimen and analysis of CSF samples did not demonstate amebae, but a second biopsy specimen and the postmortem pathologic examination showed Balamuthia trophozoites surrounded by widespread granulomatous inflammation and vasculitis. The patient's neutropenia and antibiotic use may have caused susceptibility to this organism. Amebic meningoencephalitis should be considered in cases of subacute meningoencephalitis with greatly depressed CSF glucose concentrations and multiple nodular lesions on cerebral imaging. Arch Neurol. 2000;57:1210-1212

Progressive myopathy in hyperkalemic periodic paralysis.

A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.

Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan: muscle biopsy findings in 4 patients.

Muscle biopsies of 4 patients with the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan showed lymphocytic infiltrates with occasional eosinophils largely restricted to interstitial fibrous tissue and perivascular areas. There was inflammation and fibrosis of muscle spindle capsules in 3 patients. In the 2 sickest patients, there was profound muscle atrophy, affecting both muscle fiber types.

Dental chair intracerebral hemorrhage.

A 52-year-old woman had a fatal intracerebral hemorrhage after dental manipulation. Normotensive in the past, the initial blood pressure was high but rapidly returned to normal. Necropsy showed no vascular malformation or evidence of hypertensive vascular disease. Clinical and experimental data show that stimulation of trigeminal fibers can cause important changes in blood pressure and pulse.

Orbital myositis and giant cell myocarditis.

A 65-year-old woman developed progressive, bilateral ophthalmoplegia, with thickened extraocular muscles on CT. One month later, a cardiac arrhythmia led to her death. Pathologically, the extraocular and skeletal muscles showed diffuse mononuclear cell inflammation, while the heart contained granulomatous myositis. This patient's syndrome of idiopathic, orbital myositis and giant cell myocarditis may be a distinct nosologic entity.

Needle muscle biopsy with the automatic Biopty instrument.

Needle muscle biopsies are less traumatic and easier to do than open biopsies, but their main disadvantage is the small specimen size. One hundred and five patients underwent needle biopsies with a 14-gauge spring-loaded device that guillotines the muscle automatically (Bard Radiology). Fifty patients had more than one muscle biopsy. One hundred and forty-six of 155 specimens contained over 200 muscle fibers, some as many as 500 fibers. Having evaluated various needles, we found the Bard Biopty instrument more efficient than manual needles and open biopsy techniques, and it provides muscle specimens for pathologic interpretation that are comparable with open surgical procedures.

Homolateral hemiparesis as an early sign of cerebellar mass effect.

A patient with Wallenberg's syndrome and an inferior cerebellar infarction developed progressive hemiplegia ipsilateral to the infarction as cerebellar edema emerged. An MRI showed diagonal displacement of the medulla with impaction of the pyramids against the clivus; the hemiplegia resolved after posterior fossa decompression. In the pathologic specimen, the pyramids were flattened and showed small subpial ischemic lesions. Progressive ipsilateral hemiparesis in the setting of cerebellar infarction is an early sign of posterior fossa mass effect similar to the Kernohan's notch phenomenon.

Location of human pyramidal tract in the internal capsule: anatomic evidence.

A patient with a small infarct located posteriorly in the internal capsule had 9 years of weakness of the contralateral face, arm, and leg. At necropsy, it was found that degeneration of the corticospinal tract was almost complete in the midbrain and medullary pyramid. This case supports the increasing evidence that the human pyramidal tract is located in the third quarter of the posterior limb of the internal capsule.

Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy.

A 64-year-old woman had bilateral facial weakness, mild peripheral neuropathy, incoordination, and impaired balance. A corneal transplant had been performed for corneal lattice dystrophy. Sural nerve biopsy showed mild axonal neuropathy with deposits of amyloid in the perineurium. Histochemical studies showed amyloid protein AA in the nerve, but not in cornea or muscle.

Amyotrophic lateral sclerosis: thyrotropin-releasing hormone and histidyl proline diketopiperazine in the spinal cord and cerebrospinal fluid.

In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.

Fatal brainstem stroke following internal jugular vein catheterization.

Neurologic complications of central venous catheterization are uncommon, and there are no reports of cerebrovascular events. We report a case of massive postoperative vertebrobasilar territory stroke following internal jugular vein cannulation due to inadvertent vertebral artery injury. Autopsy revealed thrombosis at the site of puncture wound in the right vertebral artery, with emboli present in the distal basilar artery.