LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues.

Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular cardiac dysfunction. Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2. Biopsy of skeletal muscle demonstrated disrupted immunostaining of LIMS2. This is the first report of mutations in LIMS2 and resulting disruption of the integrin linked kinase (ILK)-LIMS-parvin complex associated with LGMD.

Isolated brain metastases as first site of recurrence in prostate cancer: case report and review of the literature.

Fewer than 2% of patients with metastatic prostate cancer (pca) develop brain metastases. Autopsy series have confirmed the rarity of brain metastases. When present, brain metastases occur in end stage, once the pca is castrate-resistant and spread to other sites is extensive. Here, we present a rare case of a patient with pca who developed a solitary parenchymal brain metastasis as first site of relapse 9 years after radical therapy. The patient underwent craniotomy and excision of the tumour. A second recurrence was also isolated to the brain. In the literature, pca patients with brain metastases have a poor mean survival of 1-7.6 months. The patient in our case report experienced a relatively favourable outcome, surviving 19 months after his initial brain relapse.

Diagnostic Accuracy of Arterial Spin-Labeling, Dynamic Contrast-Enhanced, and DSC Perfusion Imaging in the Diagnosis of Recurrent High-Grade Gliomas: A Prospective Study.

BACKGROUND AND PURPOSE: For patients with high-grade gliomas, the appearance of a new, enhancing lesion after surgery and chemoradiation represents a diagnostic dilemma. We hypothesized that MR perfusion without and with contrast can differentiate tumor recurrence from radiation necrosis. MATERIALS AND METHODS: In this prospective study, we performed 3 MR perfusion methods: arterial spin-labeling, DSC, and dynamic contrast enhancement. For each lesion, we measured CBF from arterial spin-labeling, uncorrected relative CBV, and leakage-corrected relative CBV from DSC imaging. The volume transfer constant and plasma volume were obtained from dynamic contrast-enhanced imaging without and with T1 mapping using modified Look-Locker inversion recovery (MOLLI). The diagnosis of tumor recurrence or radiation necrosis was determined by either histopathology for patients who underwent re-resection or radiologic follow-up for patients who did not have re-resection. RESULTS: There were 26 patients with 32 lesions, 19 lesions with tumor recurrence and 13 lesions with radiation necrosis. Compared with radiation necrosis, lesions with tumor recurrence had higher CBF (P = .033), leakage-corrected relative CBV (P = .048), and plasma volume using MOLLI T1 mapping (P = .012). For differentiating tumor recurrence from radiation necrosis, the areas under the curve were 0.81 for CBF, 0.80 for plasma volume using MOLLI T1 mapping, and 0.71 for leakage-corrected relative CBV. A correlation was found between CBF and leakage-corrected relative CBV (r s = 0.54), volume transfer constant, and plasma volume (0.50 < r s< 0.77) but not with uncorrected relative CBV (r s = 0.20, P = .29). CONCLUSIONS: In the differentiation of tumor recurrence from radiation necrosis in a newly enhancing lesion, the diagnostic value of arterial spin-labeling-derived CBF is similar to that of DSC and dynamic contrast-enhancement-derived blood volume.

NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.

Central nervous system myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials. Many disorders promote damage to and eventual loss of the myelin sheath, which often results in significant neurological morbidity. However, little is known about the fundamental mechanisms that initiate myelin damage, with the assumption being that its fate follows that of the parent oligodendrocyte. Here we show that NMDA (N-methyl-d-aspartate) glutamate receptors mediate Ca2+ accumulation in central myelin in response to chemical ischaemia in vitro. Using two-photon microscopy, we imaged fluorescence of the Ca2+ indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX completely blocked the ischaemic Ca2+ increase in oligodendroglial cell bodies, but only modestly reduced the Ca2+ increase in myelin. In contrast, the Ca2+ increase in myelin was abolished by broad-spectrum NMDA receptor antagonists (MK-801, 7-chlorokynurenic acid, d-AP5), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM077 and ifenprodil). In vitro ischaemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2 and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits are present for the formation of functional NMDA receptors. Our data show that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, our finding that the Ca2+ increase was mediated in large part by activation of myelinic NMDA receptors suggests a new mechanism of axo-myelinic signalling. Such a mechanism may represent a potentially important therapeutic target in disorders in which demyelination is a prominent feature, such as multiple sclerosis, neurotrauma, infections (for example, HIV encephalomyelopathy) and aspects of ischaemic brain injury.

Stent-assisted coiling of posterior inferior cerebellar artery aneurysm complicated by arterial avulsion.

BACKGROUND: Rapid development of new devices and techniques in endovascular neurosurgery allows treatment of complex intracranial vascular lesions. These treatments, however, are not without risk. We report a case of unusual vascular laceration during stent-assisted coiling of a posterior inferior cerebellar artery (PICA) aneurysm. CASE PRESENTATION: A 75-year-old female with a recurrent, previously coiled PICA aneurysm developed avulsion of the parent vessel followed by fatal bleeding while an attempt was made to place a microcatheter across the aneurysmal neck for stent-assisted coiling. CONCLUSIONS: Pathological examination was performed to understand the mechanism of the rupture. The most likely mechanism was straightening of the significant vascular tortuosity, excessive tension on the vessel origin and avulsion upon advancement of the microcatheter over the microguidewire.

Diagnostic Accuracy of Centrally Restricted Diffusion in the Differentiation of Treatment-Related Necrosis from Tumor Recurrence in High-Grade Gliomas.

BACKGROUND AND PURPOSE: Centrally restricted diffusion has been demonstrated in recurrent high-grade gliomas treated with bevacizumab. Our purpose was to assess the accuracy of centrally restricted diffusion in the diagnosis of radiation necrosis in high-grade gliomas not treated with bevacizumab. MATERIALS AND METHODS: In this prospective study, we enrolled patients with high-grade gliomas who developed a new ring-enhancing necrotic lesion and who underwent re-resection. The presence of a centrally restricted diffusion within the ring-enhancing lesion was assessed visually on diffusion trace images and by ADC measurements on 3T preoperative diffusion tensor examination. The percentage of tumor recurrence and radiation necrosis in each surgical specimen was defined histopathologically. The association between centrally restricted diffusion and radiation necrosis was assessed using the Fisher exact test. Differences in ADC and the ADC ratio between the groups were assessed via the Mann-Whitney U test, and receiver operating characteristic curve analysis was performed. RESULTS: Seventeen patients had re-resected ring-enhancing lesions: 8 cases of radiation necrosis and 9 cases of tumor recurrence. There was significant association between centrally restricted diffusion by visual assessment and radiation necrosis (P = .015) with a sensitivity of 75% and a specificity of 88.9%, a positive predictive value 85.7%, and a negative predictive value of 80% for the diagnosis of radiation necrosis. There was a statistically significant difference in the ADC and ADC ratio between radiation necrosis and tumor recurrence (P = .027). CONCLUSIONS: The presence of centrally restricted diffusion in a new ring-enhancing lesion might indicate radiation necrosis rather than tumor recurrence in high-grade gliomas previously treated with standard chemoradiation without bevacizumab.

Correlation of Tumor Immunohistochemistry with Dynamic Contrast-Enhanced and DSC-MRI Parameters in Patients with Gliomas.

BACKGROUND AND PURPOSE: Tumor CBV is a prognostic and predictive marker for patients with gliomas. Tumor CBV can be measured noninvasively with different MR imaging techniques; however, it is not clear which of these techniques most closely reflects histologically-measured tumor CBV. Our aim was to investigate the correlations between dynamic contrast-enhanced and DSC-MR imaging parameters and immunohistochemistry in patients with gliomas. MATERIALS AND METHODS: Forty-three patients with a new diagnosis of glioma underwent a preoperative MR imaging examination with dynamic contrast-enhanced and DSC sequences. Unnormalized and normalized cerebral blood volume was obtained from DSC MR imaging. Two sets of plasma volume and volume transfer constant maps were obtained from dynamic contrast-enhanced MR imaging. Plasma volume obtained from the phase-derived vascular input function and bookend T1 mapping (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function and bookend T1 mapping (Ktrans_Φ) were determined. Plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (Ktrans_SI) were acquired, without T1 mapping. Using CD34 staining, we measured microvessel density and microvessel area within 3 representative areas of the resected tumor specimen. The Mann-Whitney U test was used to test for differences according to grade and degree of enhancement. The Spearman correlation was performed to determine the relationship between dynamic contrast-enhanced and DSC parameters and histopathologic measurements. RESULTS: Microvessel area, microvessel density, dynamic contrast-enhanced, and DSC-MR imaging parameters varied according to the grade and degree of enhancement (P < .05). A strong correlation was found between microvessel area and Vp_Φ and between microvessel area and unnormalized blood volume (rs ≥ 0.61). A moderate correlation was found between microvessel area and normalized blood volume, microvessel area and Vp_SI, microvessel area and Ktrans_Φ, microvessel area and Ktrans_SI, microvessel density and Vp_Φ, microvessel density and unnormalized blood volume, and microvessel density and normalized blood volume (0.44 ≤ rs ≤ 0.57). A weaker correlation was found between microvessel density and Ktrans_Φ and between microvessel density and Ktrans_SI (rs ≤ 0.41). CONCLUSIONS: With dynamic contrast-enhanced MR imaging, use of a phase-derived vascular input function and bookend T1 mapping improves the correlation between immunohistochemistry and plasma volume, but not between immunohistochemistry and the volume transfer constant. With DSC-MR imaging, normalization of tumor CBV could decrease the correlation with microvessel area.

Comparison of the Diagnostic Accuracy of DSC- and Dynamic Contrast-Enhanced MRI in the Preoperative Grading of Astrocytomas.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging parameters can be biased by poor measurement of the vascular input function. We have compared the diagnostic accuracy of dynamic contrast-enhanced MR imaging by using a phase-derived vascular input function and "bookend" T1 measurements with DSC MR imaging for preoperative grading of astrocytomas. MATERIALS AND METHODS: This prospective study included 48 patients with a new pathologic diagnosis of an astrocytoma. Preoperative MR imaging was performed at 3T, which included 2 injections of 5-mL gadobutrol for dynamic contrast-enhanced and DSC MR imaging. During dynamic contrast-enhanced MR imaging, both magnitude and phase images were acquired to estimate plasma volume obtained from phase-derived vascular input function (Vp_Φ) and volume transfer constant obtained from phase-derived vascular input function (K(trans)_Φ) as well as plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (K(trans)_SI). From DSC MR imaging, corrected relative CBV was computed. Four ROIs were placed over the solid part of the tumor, and the highest value among the ROIs was recorded. A Mann-Whitney U test was used to test for difference between grades. Diagnostic accuracy was assessed by using receiver operating characteristic analysis. RESULTS: Vp_ Φ and K(trans)_Φ values were lower for grade II compared with grade III astrocytomas (P < .05). Vp_SI and K(trans)_SI were not significantly different between grade II and grade III astrocytomas (P = .08-0.15). Relative CBV and dynamic contrast-enhanced MR imaging parameters except for K(trans)_SI were lower for grade III compared with grade IV (P ≤ .05). In differentiating low- and high-grade astrocytomas, we found no statistically significant difference in diagnostic accuracy between relative CBV and dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: In the preoperative grading of astrocytomas, the diagnostic accuracy of dynamic contrast-enhanced MR imaging parameters is similar to that of relative CBV.

Preoperative prognostic value of dynamic contrast-enhanced MRI-derived contrast transfer coefficient and plasma volume in patients with cerebral gliomas.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging-derived plasma volume obtained in tumor and the contrast transfer coefficient has not been well-established in patients with gliomas. We determined whether plasma volume and contrast transfer coefficient in tumor correlated with survival in patients with gliomas in addition to other factors such as age, type of surgery, preoperative Karnofsky score, contrast enhancement, and histopathologic grade. MATERIALS AND METHODS: This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. The contrast transfer coefficient and plasma volume obtained in tumor maps were calculated directly from the signal-intensity curve without T1 measurements, and values were obtained from multiple small ROIs placed within tumors. Survival curve analysis was performed by dichotomizing patients into groups of high and low contrast transfer coefficient and plasma volume. Univariate analysis was performed by using dynamic contrast-enhanced parameters and clinical factors. Factors that were significant on univariate analysis were entered into multivariate analysis. RESULTS: For all patients with gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). In subgroups of high- and low-grade gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). Univariate analysis showed that factors associated with lower survival were age older than 50 years, low Karnofsky score, biopsy-only versus resection, marked contrast enhancement versus no/mild enhancement, high contrast transfer coefficient, and high plasma volume obtained in tumor (P < .05). In multivariate analysis, a low Karnofsky score, biopsy versus resection in combination with marked contrast enhancement, and a high contrast transfer coefficient were associated with lower survival rates (P < .05). CONCLUSIONS: In patients with glioma, those with a high contrast transfer coefficient have lower survival than those with low parameters.

Case of the month: June 1997--a 42 year old man with left facial weakness.

A 42 yr old male presented with left facial weakness. MRI showed lesions affecting the distal seventh nerve and third division of the trigeminal nerve. The seventh nerve was biopsied and showed a malignant epithelioid schwannoma. The patient underwent extensive resection followed by irradiation. This is one of very few examples of intracranial malignant peripheral nerve sheath tumors and the first reported example of an intracranial malignant epithelioid schwannoma. The literature is reviewed and completeness of resection appears to be the most pertinent prognostic factor.

Neurotensin terminals form synapses primarily with neurons lacking detectable tyrosine hydroxylase immunoreactivity in the rat substantia nigra and ventral tegmental area.

A light and electron microscopic double antigen localization technique was employed to examine the fine structural relationship between neurotensin-containing axon terminals and dopaminergic neurons in the substantia nigra and ventral tegmental area of the rat. At the light microscopic level, neurotensin-immunoreactive terminals were densely distributed throughout the substantia nigra pars compacta and ventral tegmental area in close proximity to tyrosine hydroxylase-immunoreactive somata and dendrites. On electron microscopic examination, direct synaptic connections were identified between neurotensin-immunoreactive axon terminals and tyrosine hydroxylase-immunopositive perikarya and dendrites. However, only 8.2% and 8.8% of the neurotensin-immunoreactive axonal profiles detected in the substantia nigra and ventral tegmental area, respectively, were found in direct apposition with tyrosine hydroxylase-immunostained elements. In turn, only 9.3% and 10.0% of tyrosine hydroxylase immunoreactive dendrites sampled from the substantia nigra and ventral tegmental area, respectively, were seen in contact with neurotensin immunopositive axon terminals. However, neurotensin-immunoreactive and tyrosine hydroxylase-immunolabelled elements were frequently identified in close anatomical proximity (less than 5 microns) to one another. These results are interpreted in light of the selective association of neurotensin receptors with dopaminergic neurons in the substantia nigra and ventral tegmental area to suggest a predominantly parasynaptic mechanism of action for neurotensin in the ventral midbrain.

Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain.

Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

The ontogeny of NADPH-diaphorase neurons in serum-free striatal cultures parallels in vivo development.

Nitric oxide synthase is co-localized with somatostatin and neuropeptide Y in a subpopulation of striatal interneurons that stain selectively for NADPH-diaphorase. We studied the ontogeny of diaphorase-positive neurons in striatal serum-free cultures derived from 15-16-day-old CD1 mice. NADPH-diaphorase staining was detected as early as embryological day 18 in vivo and day 5 in vitro. Over the next seven days the number of neurons staining for NADPH-diaphorase increased rapidly and then levelled off at about 0.5-1% of the total neuronal population both in vivo and in vitro. The cultured diaphorase neurons were also similar to their in vivo counterparts in terms of morphology and dendritic branching. Striatal neurons expressing NADPH-diaphorase exhibit similar ontogeny, morphology and neurochemical characteristics in vivo and in serum-free primary neuronal cultures. The culture system may represent a useful model for studying this important subgroup of striatal neurons.

The ontogeny of NADPH-diaphorase neurons in serum-free striatal cultures parallels in vivo development.

Nitric oxide synthase is co-localized with somatostatin and neuropeptide Y in a subpopulation of striatal interneurons that stain selectively for NADPH-diaphorase. We studied the ontogeny of diaphorase-positive neurons in striatal serum-free cultures derived from 15-16-day-old CD1 mice. NADPH-diaphorase staining was detected as early as embryological day 18 in vivo and day 5 in vitro. Over the next seven days the number of neurons staining for NADPH-diaphorase increased rapidly and then levelled off at about 0.5-1% of the total neuronal population both in vivo and in vitro. The cultured diaphorase neurons were also similar to their in vivo counterparts in terms of morphology and dendritic branching. Striatal neurons expressing NADPH-diaphorase exhibit similar ontogeny, morphology and neurochemical characteristics in vivo and in serum-free primary neuronal cultures. The culture system may represent a useful model for studying this important subgroup of striatal neurons.

Post-translational processing of the neurotensin/neuromedin N precursor in the central nervous system of the rat--II. Immunohistochemical localization of maturation products.

The neurotensin/neuromedin N precursor molecule possesses four lysine-arginine dibasic residues which represent potential sites of cleavage by proteolytic maturation enzymes. As shown in the preceding paper, all of these dibasic residues are cleaved to a variable extent in rat brain. The aim of the present study was to localize immunohistochemically the resulting maturation products using site-specific antibodies directed against neurotensin, as well as against the exposed KLPLVL (K6L) and EKEEVI (E6I) sequences of the precursor. In a first set of experiments, each antigen was singly labelled in serial adjacent sections through the rat brain using a peroxidase-antiperoxidase technique. In a second series of experiments, neurotensin and either E61 or K6L antigens were double labelled in pairs using indirect immunofluorescence and visualized by confocal microscopy. In both types of preparations, immunoreactivity for all three antigens was detected in nerve cell bodies and axon terminals. In the absence of colchicine pretreatment, labelled nerve cell bodies were sparse in both neurotensin- and E6I-immunostained material and virtually undetectable in K6L-immunoreacted sections. By contrast, terminal immunostaining was intense and comparable in distribution for both neurotensin and E6I in most regions examined. K6L axonal labelling showed the same topographic pattern as that of E6I and neurotensin but was consistently weaker, except in the globus pallidus, where both E6I- and K6L-immunoreactive arbors were more widespread than those of neurotensin. These results suggest that the cleavage of the dibasic sites adjacent to the E6I and K6L sequences is more extensive in certain brain regions than in others. Colchicine pretreatment markedly increased the number of neurotensin- and, to a lesser extent. E6I-immunoreactive perikarya throughout the rat brain. However, it only marginally augmented the number of K6L-immunoreactive cell bodies, which remained sparse throughout. These results suggest that the maturation cleavages exposing the E6I and K6L sequences occur further distal to the cell body than the one giving rise to neurotensin. Both E6I- and K6L-immunoreactive perikarya were essentially confined to areas displaying neurotensin immunoreactivity. Furthermore, E6I and K6L antigens were shown in double labeling experiments to be present in the same cells as neurotensin, indicating that even if it is quantitatively different among brain regions, the basic pattern of neurotensin/neuromedin N precursor processing remains qualitatively similar throughout the brain.

Light and electron microscopic localization of retrogradely transported neurotensin in rat nigrostriatal dopaminergic neurons.

We previously demonstrated the existence of a retrograde axonal transport of radioactivity to the substantia nigra pars compacta following injection of mono-iodinated neurotensin in rat neostriatum. In the present study, the topographical and cellular distribution of this retrogradely transported material was examined by light and electron microscopic autoradiography. Four and a half hours after unilateral injection of [125I]neurotensin in the caudoputamen, retrogradely labelled neuronal cell bodies were detected by light microscopic autoradiography throughout the ipsilateral substantia nigra pars compacta as well as within the ventral tegmental area and retrorubral field. In semithin sections, silver grains were prevalent over the perinuclear cytoplasm of neuronal cell bodies but were also detected over neuronal nuclei. Analysis of electron microscopic autoradiographs revealed that the vast majority (greater than 85%) were associated with neuronal perikarya, unmyelinated and myelinated axons, dendrites and terminals. Within the soma, a significant proportion of silver grains (16% of somatic grains) was detected over the nucleus. However, the majority were identified over the cytoplasm where they often encompassed cytoplasmic organelles, including rough endoplasmic reticulum, mitochondria, Golgi apparatus, lysosomes, and multi-vesicular bodies. In dendrites and axons, a substantial percentage of silver grains (63-89%) was localized over the plasma membrane. A minor proportion (13% of total) of the autoradiographic labelling was detected over myelin sheaths, astrocytes, and oligodendrocytes. The present results are consistent with previous light-microscopic evidence for internalization and retrograde transport of intrastriatal neurotensin within nigrostriatal dopaminergic neurons. They further suggest that retrogradely transported neurotensin may be processed along a variety of intracellular pathways including those mediating degradation in lysosomes and recycling in rough endoplasmic reticulum. The detection of specific autoradiographic labelling in the nucleus supports the concept that neurotensin alone, or complexed to its receptor, might be involved in the regulation of gene expression through direct or indirect interactions with nuclear DNA. Consequently, the retrograde transport of neurotensin in nigrostriatal dopaminergic neurons might provide a vehicle through which events occurring at the level of the axon terminal may initiate long-term biological responses.

Protective effects of mutant ubiquitin in transgenic mice.

The K48R mutant ubiquitin can exert profound in vivo protective effects against a variety of insults, including agents of direct clinical relevance. The manipulation of the ubiquitin/proteasome pathway has enormous potential for clinical benefit, and it is not unreasonable to expect that such benefits will include diseases of aging.

Chromogranin A in the central nervous system of the rat: pan-neuronal expression of its mRNA and selective expression of the protein.

Chromogranin A, a glycoprotein stored in secretory granules of neuroendocrine cells, displays a widespread distribution throughout the central nervous system of a variety of species. In situ hybridization histochemistry was employed to investigate the localization of chromogranin A mRNA in the central nervous system of the rat. The previously characterized monoclonal antibody, LK2H-10, was employed in an immunohistochemical study to compare the topographic localization of the chromogranin A protein with that of its mRNA. Although the latter, as revealed by in situ hybridization, displayed a ubiquitous, pan-neuronal localization throughout the rat brain, LK2H-10 immunoreactive cell bodies and axon terminals were disposed in a widespread, but highly regionally differential, distribution. This discrepancy suggests that chromogranin A is processed in a regionally differential fashion in the rat brain to yield one or multiple variant forms, one of which is specifically recognized by LK2H-10. Catecholaminergic cell groups consistently displayed LK2H-10 immunoreactivity. LK2H-10 immunopositive axon terminals were prominent in the circumventricular organs. In addition, LK2H-10 immunoreactivity was also detected in a subset of astrocytes which demonstrated a widespread, but anatomically restricted, pattern of distribution. Consequently, the variant of chromogranin A labelled by LK2H-10 represents a novel neurochemical marker for regionally differential astrocytic diversity.

Immunocytochemical evidence for direct connections between neurotensin-containing axons and dopaminergic neurons in the rat ventral midbrain tegmentum.

A light- and electron-microscopic double antigen localization technique was employed to study cellular relationships between neurotensin (NT)-containing axons and dopaminergic neurons in the substantia nigra and ventral tegmental area of the rat. Direct contacts were observed between NT-immunoreactive axon terminals and the dendrites and perikarya of neurons containing the dopamine biosynthetic enzyme, tyrosine hydroxylase (TH). NT-positive terminals were also found to contact unlabeled dendrites and neuronal somata. These results reveal an ultrastructural substrate through which endogenous NT might influence the activity of dopaminergic neurons in the ventral midbrain tegmentum.

Malignant transformation of a dysembryoplastic neuroepithelial tumor. Case report.

A 29-year-old man presented in 1984 with a recent onset of partial seizures marked by speech arrest. Electroencephalography identified a left frontotemporal dysrhythmia. Computerized tomography (CT) scanning revealed a superficial hypodense nonenhancing lesion in the midleft frontal convexity, with some remodeling of the overlying skull. The patient was transferred to the London Health Sciences Centre for subtotal resection of what was diagnosed as a "fibrillary astrocytoma (microcystic)." He received no chemotherapy or radiation therapy and remained well for 11 years. The patient presented again in late 1995 with progressive seizure activity. Both CT and magnetic resonance imaging demonstrated a recurrent enhancing partly cystic lesion. A Grade IV astrocytoma was resected, and within the malignant tumor was a superficial area reminiscent of a dysembryoplastic neuroepithelial tumor (DNT). Data on the lesion that had been resected in 1984 were reviewed, and in retrospect the lesion was identified as a DNT of the complex form. It was bordered by cortical dysplasia and contained glial nodules, in addition to the specific glioneuronal element. The glial nodules were significant for moderate pleomorphism and rare mitotic figures. The Ki67 labeling index averaged 0.3% in the glial nodules and up to 4% focally. Cells were rarely Ki67 positive within the glioneuronal component. This case is the first documented example of malignant transformation of a DNT. It serves as a warning of the potential for malignant transformation in this entity, which has been traditionally accepted as benign. This warning may be especially warranted when confronted with complex forms of DNT. The completeness of resection in the benign state is of paramount importance.