A nido-6-manganadecaborane salt.

A new manganadecaborane has been isolated as a previously unsuspected product from the reaction of [Mn(CO)(5)Br] with K[B(9)H(14)]. The anion of tetrabutylammonium 5-bromo-6,6,6-tricarbonyl-6-manganadodecahydrodecaborate(1-), (C(16)H(36)N)[Mn(B(9)H(12)Br)(CO)(3)], has a nido cage structure. The Mn atom is bonded through three B--Mn bonds of similar length [2.221 (4), 2.224 (3) and 2.236 (3) A] and two bridging H atoms. The position of the bromo substituent breaks the twofold symmetry of the cage found in simple analogues, and this is reflected in the B--B bond parameters.

REST-VP16 activates multiple neuronal differentiation genes in human NT2 cells.

The RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) can repress transcription of a battery of neuronal differentiation genes in non-neuronal cells by binding to a specific consensus DNA sequence present in their regulatory regions. However, REST/NRSF(-/-) mice suggest that the absence of REST/NRSF-dependent repression alone is not sufficient for the expression of these neuronal differentiation genes and that the presence of other promoter/enhancer-specific activators is required. Here we describe the construction of a recombinant transcription factor, REST-VP16, by replacing repressor domains of REST/NRSF with the activation domain of a viral activator VP16. In transient transfection experiments, REST-VP16 was found to operate through RE1 binding site/neuron-restrictive enhancer element (RE1/NRSE), activate plasmid-encoded neuronal promoters in various mammalian cell types and activate cellular REST/NRSF target genes, even in the absence of factors that are otherwise required to activate such genes. Efficient expression of REST-VP16 through adenoviral vectors in NT2 cells, which resemble human committed neuronal progenitor cells, was found to cause activation of multiple neuronal genes that are characteristic markers for neuronal differentiation. Thus, REST-VP16 could be used as a unique tool to study neuronal differentiation pathways and neuronal diseases that arise due to the deregulation of this process.

Vasculitic neuropathy in a patient with inactive treated lepromatous leprosy.

A 46 year old Asian male with previously treated lepromatous leprosy developed a stepwise multifocal sensory disturbance 25 years later. Neurophysiology demonstrated marked deterioration from previous studies. Sural nerve biopsy disclosed a vasculitic process superimposed on inactive lepromatous leprosy. Immunocytochemical stains for mycobacterial antigen showed deposits within nerve and vessel walls. A delayed vasculitic neuropathy precipitated by persisting mycobacterial antigen is proposed.

A novel flexible endovascular stent for use in small and tortuous vessels.

We assessed in vivo the mode of delivery, short-term patency and cellular response to a prototype endovascular stent. The stent is designed for delivery through a modified microcatheter and is retrievable with detachment from a delivery wire effected by electrolysis. We successfully deployed 12 stents in a range of sizes from 3-4 mm in straight and angled arteries of pigs. At control angiography 3 and 6 weeks later, nine arteries were patent, two occluded and one narrowed; patency was not related to vessel or stent size. The device shows promise as a stent for intracranial arteries since it can be delivered through microcatheters small enough for intracranial navigation and provides the operator with greater control than currently available self- or balloon-expanded stents.

The porous, guidewire-directed, detachable aneurysm liner: a new concept in the endovascular treatment of intracranial aneurysms.

A new device for the endovascular treatment of aneurysms is described. It consists of a guidewire-directed porous liner or bag, detachably mounted on a microcatheter and designed to be inserted into an aneurysm and to be filled with detachable coils or other embolic agents. Several prototypes have been made. Preliminary in vitro and in vivo experiments have demonstrated its behavior in relatively wide-necked aneurysms.

Comparison of pathological diagnostic criteria for Alzheimer disease.

Because the clinical picture of Alzheimer disease (AD) is often difficult to discriminate from other dementing illnesses, the diagnosis of AD requires neuropathological confirmation. However, for the pathological diagnosis of AD, there are no unanimously accepted criteria. The three currently used sets of pathological criteria (Khachaturian: Khachaturian, Arch Neurol 1985;42:1097-105; Tiemy: Tierney et al., Can J Neurol Sci 1986; 13:424-6; CERAD: Mirra et al., Neurology 1991;41:479-86) for the disease differ from each other considerably. We applied these criteria to the first 43 consecutive subjects (37 demented) with no neuropathology other than AD-type pathology from autopsies after longitudinal prospective clinical study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). The results show that the CERAD category of definite AD corresponds closely with the cases that fulfill Tierney A3 inclusion criteria for AD. The combined CERAD categories of possible, probable, and definite AD correspond closely to cases fulfilling Khachaturian criteria forAD. The influence of a clinical diagnosis of dementia when Khachaturian and CERAD criteria were applied was considerable because between 9.3% and 90.7% of patients would have been categorized differently depending on whether clinical dementia was present or absent.

Accuracy of clinical operational diagnostic criteria for Alzheimer's disease in relation to different pathological diagnostic protocols.

In this study we analysed the accuracy of two sets of clinical diagnostic criteria, the NINCDS/ADRDA and DSM-III-R, in relation to the currently used pathological diagnostic criteria for Alzheimer's disease (AD), the Khachaturian criteria, the Tierney A3 criteria and the CERAD protocol. The sensitivity of the individual clinical diagnostic criteria, NINCDS/ADRDA and DSM-III-R, is poor (34-58%) irrespective of the pathological diagnostic criteria applied for the definite diagnosis of AD. The combination of the NINCDS/ ADRDA 'possible' and 'probable dementia of the Alzheimer type' (DAT) categories has a high sensitivity (91-98%). However the combination resulted in very poor specificity (40-61 %). Thus, none of the clinical diagnostic criteria is satisfactory. We found similar results when we analysed the predictive value of these clinical diagnostic criteria. The positive predictive value of NINCDS 'probable DAT' category and that of the DAT diagnosis by DSM-III-R is very high (89-100%). This makes the use of these categories suitable for research purposes. However, the negative predictive value of both diagnoses is poor (33-63%), making these criteria unsuitable for diagnostic purposes in clinical practice.

The effects of additional pathology on the cognitive deficit in Alzheimer disease.

The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and pathological exercise. The clinical discrimination of AD from other types of dementia may be complicated when the patient suffers from more than one disease. In particular the concomitant presence of other neurological conditions may significantly influence the severity of cognitive deficit. In this study we analyze the extent of the influence of vascular and other neurodegenerative pathology on the cognitive deficit in a consecutive series of 88 prospectively assessed elderly subjects. We find that, for any given level of cognitive deficit, the densities of either all plaques or neuritic plaques alone in the neocortex are significantly lower in cases of AD mixed with other CNS pathology than in cases of AD with no other CNS pathology. In AD combined with cerebrovascular disease, the total plaque density makes a significant contribution to cognitive deficit, while neurofibrillary tangle (NFT) densities do not. In contrast, in pure AD tangle density is the major determinant of cognitive deficit. Our findings draw attention to the influence of coexisting brain pathologies on the clinical manifestation of dementia in subjects with AD. These findings indicate that pathological diagnostic criteria for AD should take into account such additional pathology in demented subjects. They also improve understanding of the circumstances in which the amyloid component of AD can play a decisive role in precipitating clinical dementia.

The nature of thrombosis induced by platinum and tungsten coils in saccular aneurysms.

PURPOSE: To compare the efficacy and biocompatability of electrolytic and mechanically detachable embolization coils of two metal types. METHODS: Experimental saccular aneurysms in pigs were used to assess embolization induced by platinum or tungsten coils. Longitudinal angiographic and histologic studies were performed on treated and untreated (control) aneurysms to compare thrombosis and cellular responses after embolization with electrolytically detachable platinum coils and with mechanically detached tungsten coils. RESULTS: Fewer tungsten than platinum coils were needed to induce thrombosis. The inflammatory response within the aneurysmal lumen was more florid in embolized aneurysms than in control aneurysms. No difference was found in the timing or extent of accumulation of eosinophils, lymphocytes, or polymorphs between the two coils used. Giant cell responses were more marked in treated aneurysms; tungsten coils more than platinum coils. The amount of collagen and fibrosis present increased over the study period and was similar in treated and control aneurysms. CONCLUSION: The coil type influenced the initial cellular response but had little effect on the rate or degree to which blood clot within the aneurysm was replaced by fibrous tissue.

Neuropathological assessment of the lesions of significance in vascular dementia.

OBJECTIVES: To better define the neuropathology of vascular dementia. METHODS: The neuropathological findings in 18 elderly, undemented subjects free of cerebrovascular disease were compared with 19 elderly undemented subjects who had cerebrovascular disease (many of whom had had a "stroke") and 24 elderly demented subjects who had cerebrovascular disease, but no other pathology to account for dementia. Cases in all groups were selected for absence or no more than very mild Alzheimer type pathology. RESULTS: Microvascular brain damage in the form of severe cribriform change and associated subcortical white matter damage and microinfarction were correlated with a history of dementia. Severe cribriform change was much more common and microinfarction somewhat more common in the demented group with vascular disease than the undemented group with vascular disease (P=0.0006 and P=0.031 respectively). Other findings of note were that congophilic angiopathy had a greater prevalence in the vascular dementia group than the control group, single cerebral infarcts were more common in the group who were undemented with vascular disease than in the group with dementia and vascular disease (P=0.0028), and the last group lacked evidence of macroscopic infarction more often than the first (P=0.034). There was a non-significant trend for the ratio of infarcted:uninfarcted tissue in one cerebral hemisphere to be higher in the group with dementia and vascular disease than in the group with vascular disease but no dementia. CONCLUSIONS: Microvascular disease, not macroscopic infarction, was the chief substrate of vascular dementia in this series of cases.

Clustering of pathological features in Alzheimer's disease: clinical and neuroanatomical aspects.

We have analyzed the tendency of amyloid load, neuritic plaques and neurofibrillary tangles (NFT) in the hippocampus and neocortex to occur in clusters in 49 consecutive cases of Alzheimer's disease (AD). This clustering tendency of the pathology was analysed in relation to severity of clinical disease assessed within 6 months before death, duration and age at onset of disease and at death. Amyloid plaques showed only a slight tendency to cluster together while neuritic plaques and, even more, NFT were clearly clustered. A greater clustering tendency was associated with more severe clinical impairment with particularly strong correlations being found between the clustering tendency of NFT in the hippocampus and clinical memory deficit, and between the clustering tendency of NFT in the parietal neocortex and overall cognitive deficit. Neuritic plaques showed similar but less pronounced and robust correlations between clustering and cognitive status. In the hippocampus NFT clustering was also negatively correlated with age at death, but not duration of disease nor age of disease onset. We conclude that clustering characterises neuritic pathology but not diffuse amyloid deposits and significantly affects cognition. The discrepancies between the group diagnosed as AD-only and the patient group that contained all patients, including the ones with mixed pathology, lead us to believe that any additional pathology might have a significant effect on the cognitive status of AD patients.

Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria.

Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for diagnosis of Alzheimer's disease (AD) and coming to autopsy after longitudinal study during life. A strong correlation was found between NFT density in the hippocampus and cognitive impairment scores obtained shortly before death, particularly with scores of memory impairment. Weaker and less consistent correlations were found for hippocampal neuritic plaques and amyloid load with cognitive/memory deficits. No significant correlations were found between hippocampal pathology and either age of onset or disease duration. All three measures of hippocampal pathology were inversely correlated with the minimum medial temporal lobe (MTL) width, a measure of the MTL atrophy made from temporal-lobe-oriented X-ray computed tomography scans performed during life; the strongest correlation being between atrophy of the MTL and NFT density in the hippocampus.

Primary progressive multifocal leukoencephalopathy presenting as an extrapyramidal syndrome.

We report a 63-year-old woman with a progressive illness which began as a parkinsonian syndrome with bilateral rest tremor, limb rigidity and a gait disorder followed by cognitive decline, visuomotor apraxia and visual agnosia. She died 10 years after the onset of the illness and at autopsy the brain showed characteristic changes of progressive multifocal leukoencephalopathy (PML) with the presence of the JC virus confirmed by in situ hybridisation. Neuropathology also showed some unusual features in the form of atypical linear lesions at the cortico-white matter junction. Some of these lesions were active while others were inactive and similar to the rarely described "burnt out" lesions of PML. PML can in rare cases occur without an underlying immune disorder or malignancy (primary PML) and a parkinsonian syndrome can be produced by a predominantly white matter disorder.

Myogenin's functions do not overlap with those of MyoD or Myf-5 during mouse embryogenesis.

The four myogenic basic helix-loop-helix proteins, MyoD, myogenin, Myf-5, and MRF4, can each activate skeletal muscle differentiation when introduced into nonmuscle cells. During embryogenesis, each of these genes is expressed in a unique but overlapping pattern in skeletal muscle precursors and their descendants. Gene knockout experiments have shown that MyoD and Myf-5 play seemingly redundant roles in the generation of myoblasts. However, the role of either of these genes during differentiation in vivo has not been determined. In contrast, a myogenin-null mutation blocks differentiation and results in a dramatic decrease in muscle fiber formation, yet the role of myogenin in the generation or maintenance of myoblast populations is not known. Because myogenin possesses the same myogenic activity as MyoD and Myf-5 in vitro and the expression patterns of these three genes overlap in vivo, we sought to determine if myogenin shares certain functions with either MyoD or Myf-5 in vivo. We therefore generated mice with double homozygous null mutations in the genes encoding MyoD and myogenin or Myf-5 and myogenin. These mice showed embryonic and perinatal phenotypes characteristic of the combined defects observed in mice mutant for each gene alone. As shown by histological analysis and expression of muscle-specific genes, the numbers of undifferentiated myoblasts and residual myofibers were comparable between myogenin-mutant homozygotes and the double-mutant homozygotes. Myoblasts isolated from neonates of the combined mutant genotypes underwent myogenesis in tissue culture, indicating that no more than two of the four myogenic factors are required to support muscle differentiation. These results demonstrate that the functions of myogenin do not overlap with those of MyoD or Myf-5 and support the view that myogenin acts in a genetic pathway downstream of MyoD and Myf-5.

A novel method for boronating antibodies without loss of immunoreactivity, for use in neutron capture therapy.

The search for suitable boron containing compounds for 10B neutron capture therapy (BNCT) is based on the principle that boron atoms must be delivered specifically to tumour cells at a concentration high enough to be effective without being toxic to normal cells. Specificity may be achieved through monoclonal antibodies. However, it has been difficult to conjugate large numbers of boron atoms to the antibody molecules without inactivating them. We have devised a strategy to do this indirectly through the use of a boronated glutamate-lysine polymer in conjunction with biotin and streptavidin.

Myogenin is required for late but not early aspects of myogenesis during mouse development.

Mice with a targeted mutation in the myogenic basic helix-loop-helix regulatory protein myogenin have severe muscle defects resulting in perinatal death. In this report, the effect of myogenin's absence on embryonic and fetal development is investigated. The initial events of somite differentiation occurred normally in the myogenin-mutant embryos. During primary myogenesis, muscle masses in mutant embryos developed simultaneously with control siblings, although muscle differentiation within the mutant muscle masses was delayed. More dramatic effects were observed when secondary myofibers form. During this time, very little muscle formation took place in the mutants, suggesting that the absence of myogenin affected secondary myogenesis more severely than primary myogenesis. Monitoring mutant neonates with fiber type-specific myosin isoforms indicated that different fiber types were present in the residual muscle. No evidence was found to indicate that myogenin was required for the formation of muscle in one region of the embryo and not another. The expression patterns of a MyoD-lacZ transgene in myogenin-mutant embryos demonstrated that myogenin was not essential for the activation of the MyoD gene. Together, these results indicate that late stages of embryogenesis are more dependent on myogenin than early stages, and that myogenin is not required for the initial aspects of myogenesis, including myotome formation and the appearance of myoblasts.

Relative roles of plaques and tangles in the dementia of Alzheimer's disease: correlations using three sets of neuropathological criteria.

We have performed a quantitative analysis of the amyloid load (plaques), neuritic plaques and neurofibrillary tangles (NFT) in the frontal, temporal and parietal association cortices of autopsied brains from 49 prospectively evaluated patients with Alzheimer's disease (AD) diagnosed according to three sets of published pathological criteria. These patients had been assessed clinically with psychological testing of cognitive abilities within 6 months of death. Correlations were sought between severity of pathological change and cognitive status before death, duration of disease and age at death. Using Khachaturian and CERAD criteria highly positive correlations were obtained between the extent of cognitive deficit and the density of NFT in frontal and parietal lobes. The percentage area of cortex occupied by amyloid in the parietal lobe was correlated to the cognitive deficit only in the CERAD-diagnosed cases. The density of all amyloid plaques (AP) showed no correlation with the extent of cognitive deficit, but the densities of neuritic plaques did correlate with cognitive deficit. Both amyloid load and tangle densities were positively correlated with disease duration. All these correlations were reduced or absent in a subgroup of cases fulfilling the Tierney et al. A3 diagnostic criteria for AD. We found no pathological measure that correlated with the age of patients at death. Amyloid loads and NFT densities showed highly significant but selective positive correlations, the most striking being between temporal lobe NFT density and frontal and parietal lobe amyloid load and between temporal lobe NFT density and frontal and parietal lobe NFT densities. Correlations involving AP density as a measure of amyloid load were almost always less significant than those involving the percentage area of cortex occupied by amyloid, suggesting that the latter measures amyloid load more accurately. However, the highest correlations of NFT densities were with neuritic plaque densities. Overall this study highlights the relevance of neuritic changes (revealed by NFT and neuritic plaques) and the irrelevance of amyloid plaques to the dementia of AD.

Endovascular coil occlusion of experimental aneurysms: partial treatment does not prevent subsequent rupture.

Experimental aneurysms with a high propensity to spontaneous rupture were used to assess the efficacy of endosaccular packing with platinum coils. Lateral aneurysms, surgically constructed in pigs from vein allographs, were untreated or treated by partial or total endovascular packing with coils. All untreated aneurysms (4/4) ruptured and most (3/4) partially treated aneurysms also ruptured. None of 6 aneurysms in which the lumen was occluded by 90% or more ruptured or demonstrated regrowth on subsequent angiography. Partial treatment was therefore not effective in preventing delayed haemorrhage. These findings suggest that subtotal endovascular treatment may not be protective after aneurysmal subarachnoid haemorrhage.

A three-dimensional system for planning orthognathic surgery. A case report.

Conventional records are often inadequate for planning correction of complex dentofacial deformities. A treatment planning system, consisting of computed tomographic-generated jaw models mounted on a special articulator, allows for presurgical decisions about the correctness of surgical movements or the need for alternative approaches.