Permanent Genetic Resources added to Molecular Ecology Resources Database 1 April 2011-31 May 2011.

This article documents the addition of 92 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Anopheles minimus, An. sinensis, An. dirus, Calephelis mutica, Lutjanus kasmira, Murella muralis and Orchestia montagui. These loci were cross-tested on the following species: Calephelis arizonensi, Calephelis borealis, Calephelis nemesis, Calephelis virginiensis and Lutjanus bengalensis.

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia.

Hippocampal sclerosis dementia (HSD) is a disease of unknown etiology and pathogenesis. To determine whether HSD cases could be reclassified as variants of frontotemporal dementia (FTD), a heterogeneous group of disorders, 18 brain autopsy cases previously diagnosed as HSD were re-evaluated. In 11 cases, ubiquitinated neuronal inclusions, similar to those of motor neuron disease inclusion dementia (MNDID), were found. Brain levels of soluble and insoluble tau were normal. Most patients with pathologic findings of HSD may actually have the MNDID variant of FTD.

Estrogen and Bcl-2: gene induction and effect of transgene in experimental stroke.

Female rodents producing endogenous estrogens are protected from stroke damage in comparison with male counterparts. This natural protection is lost after ovariectomy or reproductive senescence. The aim of this study is to determine whether estrogen reduces early neuronal injury and cell loss after ischemia by increasing the expression of Bcl-2. Male, intact female, ovariectomized, and estrogen-repleted ovariectomized rats were subjected to middle cerebral artery occlusion, and 22 hr later the level and localization of Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 mRNA and protein were increased exclusively in neurons within the peri-infarct region. Intact females and estrogen-treated castrates demonstrated increased bcl-2 mRNA and protein expression compared with males and estrogen-deficient females, accompanied by a decrease in infarct size. To test the hypothesis that the neuroprotective mechanism of estrogen functions via Bcl-2, we compared ischemic outcome in male, female, and ovariectomized wild-type mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female mice sustained smaller infarcts compared with males. Bcl-2 overexpression reduced infarct size in males, but provided no added protection in the female. Moreover, ovariectomy exacerbated infarction in wild-type females, but had no effect in Bcl-2 overexpressors. These data indicate that overexpression of Bcl-2 simulates the protection against ischemic injury conferred by endogenous female sex steroids. We concluded that estrogen rescues neurons after focal cerebral ischemia by increasing the level of Bcl-2 in peri-infarct regions and that estrogen-induced bcl-2 gene expression is an important downstream component of neuronal protection in female stroke.

(18)F-fluorodeoxyglucose positron emission tomography and MR imaging findings in Rasmussen encephalitis.

BACKGROUND AND PURPOSE: Rasmussen encephalitis is a chronic, progressive encephalitis that manifests as an abrupt-onset, intractable seizure disorder in previously developmentally normal children. The objectives of the current study were to characterize the (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MR imaging findings in Rasmussen encephalitis and to test the hypotheses that data from both imaging techniques are required to establish the diagnosis and identify the affected cerebral hemisphere in some cases. METHODS: Eleven patients with Rasmussen encephalitis were identified from a review of a computer database. The MR (n = 10) and PET (n = 11) imaging data were reviewed retrospectively and conjointly. RESULTS: On MR images, nine of 10 patients manifested bilateral cerebral atrophy that predominantly involved one hemisphere. One patient had purely unilateral cerebral atrophy. We observed foci of abnormally increased T2 signal intensity in nine of 10 patients. On FDG PET images, all patients showed extensive regions of hypometabolism within the cerebral hemisphere that showed the greatest atrophy. Discrete foci of hypermetabolism, indicative of seizure activity, were observed in six patients. The FDG PET and MR imaging findings were either stable or gradually progressive in patients with multiple imaging studies (MR, n = 5; FDG PET, n = 5). CONCLUSION: Rasmussen encephalitis is characterized by diffuse, unilateral cerebral hypometabolism on FDG PET images, with corresponding regions of cerebral atrophy on MR images. Although MR imaging data alone are sufficient to suggest a diagnosis of Rasmussen encephalitis in many cases, correlation with FDG PET data increases diagnostic confidence and allows the unequivocal identification of the affected cerebral hemisphere in patients whose MR imaging findings are subtle or distributed bilaterally.

Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations.

OBJECTIVES: Cerebral cavernous malformations are linked to mutations of the KRIT1 gene at the CCM1 locus and to mutations at two other loci, CCM2 and CCM3, for which genes are not yet identified. There is little information regarding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiology. METHODS: Morphological analysis of cavernous malformations was extended to the ultrastructural level by examining lesions from two patients by immunocytochemistry and electron microscopy. RESULTS: The lesions consisted of endothelial lined vascular sinusoids embedded in a collagen matrix. Nuclei belonging to cells distinct from endothelial cells were rare. The basal lamina of the endothelial cells consisted focally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstrated apparent gaps between endothelial cell processes where basal lamina was exposed directly to the lumen of the sinusoids. Heavy hemosiderin deposits were found underlying the vascular channels within microns of the basal lamina without evidence of disrupted vessels. No astrocytic foot processes were seen within lesions. Glial fibrillary acidic protein immunocytochemistry confirmed that astrocyte processes stopped at the border of the lesions. CONCLUSIONS: The absence of blood-brain barrier components may lead to leakage of red blood cells into these lesions and the surrounding brain in the absence of major haemorrhage, thus accounting for the propensity of cavernous malformations to cause seizures. These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype.

Deleterious effect of beta-estradiol in a rat model of transient forebrain ischemia.

Estrogen has demonstrated great potential as a therapeutic agent in focal ischemic brain injury, as exogenous beta-estradiol has proven beneficial in a variety of focal stroke models. In contrast, the relatively few studies of estrogen's efficacy in transient forebrain ischemia have produced inconsistent results. The present study was therefore designed to clarify estrogen's neuroprotective potential in selective hippocampal neuronal injury resulting from four-vessel occlusion in the rat. Female Wistar rats (normal, ovariectomized, or ovariectomized and estradiol-treated) received 5 or 10 min of ischemia. No differences in hippocampal cell loss were found amongst the groups with 10 min of ischemia. Amongst the groups with 5 min of ischemia, the mildest injury was found in the ovariectomized animals, which lost only 32% of their CA1 pyramidal cells. In comparison, mean cell losses were 54% and 49%, respectively, in intact females and in ovariectomized animals with estradiol replacement. Linear regression analysis demonstrated a highly significant relationship between cell loss and plasma estradiol levels. The mechanism by which exogenous and endogenous estrogen exacerbated the injury is unclear, as estrogen has many neuroprotective effects. On the other hand, many other reported effects of estrogen in hippocampal area CA1 might confer increased sensitivity to ischemia, either by modulating the excitatory effects of glutamate or by modifying the inhibitory effects of GABA. Determining how to modulate the various competing effects of estrogen is of both theoretical and practical importance, as it is now clear that one cannot assume that estrogen administration will always improve outcome in cerebral ischemia.

The roles of MHC class II, CD40, and B7 costimulation in CTL induction by plasmid DNA.

DNA-based vaccines generate potent CTL responses. The mechanism of T cell stimulation has been attributed to plasmid-transfected dendritic cells. These cells have also been shown to express plasmid-encoded proteins and to become activated by surface marker up-regulation. However, the increased surface expression of CD40 and B7 on these dendritic cells is insufficient to overcome the need for MHC class II-restricted CD4(+) T cell help in the priming of a CTL response. In this study, MHC class II(-/-) mice were unable to generate a CTL response following DNA immunization. This deficit in CTL stimulation by MHC class II-deficient mice was only modestly restored with CD40-activating Ab, suggesting that there were other elements provided by MHC class II-restricted T cell help for CTL induction. CTL activity was also augmented by coinjection with a vector encoding the costimulatory ligand B7.1, but not B7.2. These data indicate that dendritic cells in plasmid DNA-injected mice require conditioning signals from MHC class II-restricted T cells that are both CD40 dependent and independent and that there are different roles for costimulatory molecules that may be involved in inducing optimal CTL activity.

Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures.

We report clinical, neuropathologic and molecular genetic data from an individual affected by a familial Alzheimer disease (AD) variant. The proband had an onset of dementia at age 29 followed by generalized seizures a year later. He died at age 40. Neuropathologically, he had severe brain atrophy and characteristic histopathologic lesions of AD. Three additional neuropathologic features need to be emphasized: 1) severe deposition of Abeta in the form of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous Abeta deposits in the subcortical white matter and in the centrum semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white maner of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the proband revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importance of this case lies in the presence of ectopic neurons in the white matter, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN1 mutation may have a causal relationship with an abnormality in neuronal development.

FDG PET imaging in patients with pathologically verified dementia.

UNLABELLED: The purpose of this study was to confirm with pathologic verification 2 beliefs related to Alzheimer's disease (AD): (a) the long-standing impression that bilateral temporo-parietal hypometabolism, as noted on FDG PET imaging, is the metabolic abnormality associated with Alzheimer's disease (AD) and (b) that the sensitivity, specificity, and diagnostic accuracy of the metabolic pattern of bilateral temporo-parietal hypometabolism allows differentiation between other degenerative causes of dementia. METHODS: Twenty two individuals (8 women, 14 men) with difficult-to-characterize memory loss or dementia (using standard clinical criteria), and who eventually received pathologic confirmation of diagnosis, were evaluated. FDG PET brain scans were obtained and visually graded by an experienced nuclear medicine physician as to the presence of classic bilateral temporo-parietal hypometabolism as seen in Alzheimer's type dementia. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the metabolic pattern of bilateral temporo-parietal hypometabolism were determined using pathologic diagnosis as the gold standard. RESULTS: The clinical diagnosis of possible or probable AD was determined as the primary cause of dementia in 12 patients. The sensitivity and specificity of the clinical diagnosis for probable AD were 63% and 100%, respectively. The sensitivity and specificity of the clinical diagnosis for possible and probable AD were 75% and 100%, respectively. The sensitivity, specificity, and diagnostic accuracy of bilateral temporo-parietal hypometabolism being associated with AD were 93%, 63%, and 82%, respectively. CONCLUSION: This study confirms that bilateral temporo-parietal hypometabolism is indeed the classic metabolic abnormality associated with AD. Furthermore, in individuals with dementia whose FDG PET scans indicated a metabolic pattern other than bilateral temporo-parietal hypometabolism, a cause of dementia other than AD should be suspected. These observations may be of clinical importance in differentiating dementia syndromes. The sensitivity, specificity, and diagnostic accuracy of FDG PET are acceptable as tests to be used in the evaluation of dementia and particularly to confirm the clinical suspicion of AD.

Cognitive deficits after focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: The interpretation of cognitive data in many experimental stroke studies is problematic because middle cerebral artery occlusion (MCAO) is associated with sensorimotor alterations that may become confounding factors in cognitive testing. The purpose of the current study was to determine if it is possible to measure MCAO-induced cognitive deficits by using short durations of ischemia that do not result in alterations in sensorimotor behavior in mice. METHODS: Male C57/Bl6 mice were subjected to 60 or 90 minutes of intraluminal MCAO or sham surgery. In the first cohort of animals (n=12/group), locomotor activity, balance, and coordination were evaluated 2 weeks after surgery. In a second cohort of animals (n=10/group), the effects of 60 minutes of MCAO on subsequent learning and memory were assessed with a step-down passive avoidance task beginning 1 week after surgery. In a third cohort of animals (n=8 to 10/group), training in a passive avoidance task was completed before 60 minutes of MCAO, then retention of the task was assessed 1 week after surgery. In all animals, infarction size was determined after 14 days of reperfusion with use of cresyl violet staining and quantitative image analysis. RESULTS: There was no significant difference in infarction volume in the cerebral cortex or caudoputamen after 60 versus 90 minutes of MCAO. However, there was a significant increase in latency to move 1 body length in the 90-minute MCAO group compared with the 60-minute MCAO and sham groups. In 2 additional cohorts of animals, 60-minute MCAO was associated with a deficit in the acquisition and retention of a passive avoidance task regardless of whether the task training occurred before or after MCAO. CONCLUSIONS: Long-term cognitive deficits can be induced in mice by using a short duration of MCAO (60 minutes) that does not result in concomitant sensorimotor deficits.

Hypertonic saline worsens infarct volume after transient focal ischemia in rats.

BACKGROUND AND PURPOSE: Hypertonic saline (HS) has been advocated as a hyperosmolar agent for the treatment of cerebral edema, especially after traumatic brain injury. We tested the hypothesis that continuous intravenous HS administered during reperfusion from transient focal cerebral ischemia attenuates infarct volume. METHODS: Halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. At the onset of reperfusion, rats received a 10-mL/kg intravenous bolus of 0.9% saline (SAL, n=8) or 7.5% SAL (chloride:acetate 50:50, n=8) followed by a continuous infusion for 22 hours. In a second series of experiments, ischemic damage was determined in cohorts treated with equivolumetric 3% saline (n=8) or 20% mannitol (n=8). In a third series, regional cerebral blood flow was measured ([(14)C]iodoantipyrine autoradiography) at 6 hours of reperfusion in 7.5%-SAL-treated (n=5) or SAL-treated (n=5) animals. RESULTS: In SAL rats, serum Na(+) was 137+/-3 and 138+/-2 mEq/L (mean+/-SEM) at baseline and 22 hours of reperfusion, respectively. In 7.5% SAL, serum Na(+) was 136+/-2 and 154+/-2 mEq/L at baseline and reperfusion, respectively. Physiological variables and reduction in laser-Doppler signal during MCAO and early reperfusion were not different between the 2 treatment groups. Cortical infarct volume was larger in 7.5%-SAL-treated rats (121+/-14 mm(3); 30+/-3% of contralateral cortex; P<0.05) than in SAL (64+/-15 mm(3); 16+/-4% of contralateral cortex). Striatal infarct volume was unchanged by HS therapy. Ipsilateral cortical tissue volume was increased relative to the contralateral side (by 26+/-5% with SAL; by 41+/-5% with 7.5% SAL). In contrast, ischemic damage was unaffected by 3%-SAL or 20%-mannitol treatment compared with SAL. Regional cerebral blood flow during reperfusion was heterogeneous in all animals, but there was no evidence of postischemic hypoperfusion or blood flow maldistribution in 7.5%-SAL-treated animals. CONCLUSIONS: These data demonstrate that hypernatremia resulting from postischemic HS infusion worsens cortical infarct volume in transient focal cerebral ischemia. The deleterious effect is not linked to exacerbation of delayed hypoperfusion during early reperfusion (6 hours); however, blood flow defects at later recovery time points remain to be excluded. These results may have implications for HS therapy in clinical ischemic stroke.

Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study.

The ability of full and partial benzodiazepine receptor agonists to prevent DNA fragmentation and neuronal death after transient cerebral ischemia was investigated in the Mongolian gerbil. Diazepam (10mg/kg, i.p.) or the partial agonist imidazenil (3mg/kg, i.p.) was administered 30 and 90min after transient forebrain ischemia produced by occlusion of the carotid arteries for 5min. Treatment with diazepam completely protected CA1b hippocampal pyramidal neurons in 94% of the animals and partially protected pyramidal neurons in 6% of the animals, as assessed with a standard Nissl stain three and four days after ischemia. DNA fragmentation was examined by the terminal dUTP nick-end labeling (TUNEL) reaction. Prior to cell death, there were no TUNEL-positive neurons in area CA1b. By three days after ischemia, when neuronal degeneration was nearly complete, 14 out of 16 gerbils exhibited a positive TUNEL reaction throughout area CA1b stratum pyramidale. In 13 out of 14 gerbils treated with diazepam, no TUNEL-positive neurons were observed in this region. Imidazenil was less effective than diazepam with respect to both neuroprotection and prevention of DNA fragmentation. Three days after ischemia, six out of eight gerbils treated with imidazenil showed partial to complete neuroprotection. Imidazenil completely prevented DNA fragmentation in only one of the animals; varying degrees of TUNEL reaction persisted in the remainder. To determine whether the neurons protected by diazepam had a normal ultrastructure, gerbils were killed two to 30 days after ischemia and the hippocampal neurons in area CA1b were examined by electron microscopy. Within the first 48h after ischemia, early cytoplasmic changes of varying degrees (e.g., vacuolation, rough endoplasmic reticulum stacking, swollen mitochondria) and electron-dense dendrites were observed in gerbils not treated with diazepam. Degeneration was nearly complete by three days after ischemia. In contrast, pyramidal neuron ultrastructure appeared normal in gerbils that exhibited complete area CA1b neuroprotection (defined at the light microscope level) by diazepam when studied two, seven or 30 days after ischemia. In gerbils with partial protection of area CA1b, most of the remaining neurons exhibited varying degrees of necrosis when studied 30 days after ischemia. No apoptotic bodies were observed. We conclude that: (i) diazepam can fully protect CA1 pyramidal cells from the toxic effects of transient cerebral ischemia; (ii) when diazepam affords only partial neuroprotection, the residual CA1 pyramidal cells exhibit ultrastructural abnormalities consistent with necrotic damage; and (iii) diazepam is a more efficacious neuroprotectant than the partial benzodiazepine receptor agonist, imidazenil.

Stroke in estrogen receptor-alpha-deficient mice.

BACKGROUND AND PURPOSE: Recent evidence suggests that endogenous estrogens or hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation during ischemic stress as well as direct preservation of neuronal viability. We hypothesized that if the intracellular estrogen receptor subtype-alpha (ERalpha) is important to estrogen's signaling in the ischemic brain, then ERalpha-deficient (knockout) (ERalphaKO) female mice would sustain exaggerated cerebral infarction damage after middle cerebral artery occlusion. METHODS: The histopathology of cresyl violet-stained tissues was evaluated after reversible middle cerebral artery occlusion (2 hours, followed by 22 hours of reperfusion) in ERalphaKO transgenic and wild-type (WT) mice (C57BL/6J background strain). End-ischemic cerebral blood flow mapping was obtained from additional female murine cohorts by using [(14)C]iodoantipyrine autoradiography. RESULTS: Total hemispheric tissue damage was not altered by ERalpha deficiency in female mice: 51.9+/-10.6 mm(3) in ERalphaKO versus 60.5+/-5.0 mm(3) in WT. Striatal infarction was equivalent, 12.2+/-1.7 mm(3) in ERalphaKO and 13.4+/-1.0 mm(3) in WT mice, but cortical infarction was paradoxically smaller relative to that of the WT (20.7+/-4.5 mm(3) in ERalphaKO versus 30.6+/-4.1 mm(3) in WT). Intraocclusion blood flow to the parietal cortex was higher in ERalphaKO than in WT mice, likely accounting for the reduced infarction in this anatomic area. There were no differences in stroke outcomes by region or genotype in male animals. CONCLUSIONS: Loss of ERalpha does not enhance tissue damage in the female animal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype.

Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse.

Recent findings in animals emphasize that experimental ischemic brain damage can be strikingly reduced by estrogen: however, the neuroprotective mechanisms are not well understood. It was hypothesized that estrogen signaling via cognate estrogen receptors (ERs) within the vasculature is an important aspect of cerebral ischemic protection in the female brain, in part by amplifying intraischemic cerebral blood flow (CBF). In the present study, the hypothesis that chronic treatment with the pure ER antagonist ICI182,780 (ICI) would increase ischemic brain damage by a blood flow-mediated mechanism was investigated. Adult C57B1/6J mice were pretreated with either subcutaneous ICI (100 microg/day) or oil/ethanol vehicle for 1 week before 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. End-ischemic regional CBF was evaluated in additional cohorts using [14C]iodoantipyrine autoradiography. Infarction volume as measured by cresyl violet histology was greater in the striatum of ICI-treated females (70 +/- 3% of contralateral striatum vs. 40 +/- 12% in vehicle-treated females). Cortical injury was not enhanced relative to control animals (39 +/- 6% of contralateral cortex in ICI group vs. 27 +/- 8% in vehicle-treated group). Physiologic variables and ischemic reduction of the ipsilateral cortical laser-Doppler flow signal were similar between groups. Further, ICI treatment did not alter end-ischemic cortical or striatal CBF. The deleterious effect of ICI was limited to females, as there were no differences in stroke damage or CBF between male treatment groups. These data suggest that estrogen inhibits ischemic brain injury in striatum of the female by receptor-mediated mechanisms that are not linked to preservation of intraischemic CBF.

Malignant melanoma presenting as an intrathymic tumor: a primary thymic melanoma?

The identification of malignant melanoma in a visceral organ of nonepidermal origin is not an uncommon occurrence. Frequently, these cases are solitary metastases that present years after a thin epidermal melanoma has been diagnosed (and sometimes forgotten). However, primary visceral melanomas have been reported that have not been preceded by an epidermal lesion. We describe herein a unique case of melanoma presenting as a primary intrathymic tumor. The patient had no previous history of epidermal melanoma, and extensive workup did not reveal evidence for an alternative primary site. The tumor exhibited histologic features characteristic of melanoma, including an abundance of large pleomorphic cells with eosinophilic cytoplasm, prominent nucleoli, and S100 protein and ultrastructural analysis revealed stage II and stage III melanosomes. The patient remained free of disease until intrathoracic recurrence was detected on a computed tomographic scan 14 months later. The lack of clinical history and physical findings of melanoma at presentation, the intrathymic location of the tumor, and the pattern of recurrence suggest that this case likely represents a primary thymic melanoma, a previously unreported entity.

In vivo three-dimensional reconstruction of rat brain axonal projections by diffusion tensor imaging.

The in situ assessment of axonal projections of the brain has been severely limited by the lack of noninvasive techniques to study this type of anatomy. We show here that in vivo three-dimensional (3D) reconstruction of axonal projections can be achieved using a rapid 3D high-resolution diffusion-weighted imaging technique combined with a recently designed fiber reconstruction algorithm. As a first example, neuronal pathways in the rat brain were probed. Eight well-known fiber projections; genu and splenium of corpus callosum, internal and external capsule, fimbria, anterior commissure, optic tract, and stria terminalis were tracked and shown to be in agreement with the location of these known axonal projections. The experiment took 2 hr and shorter times should be possible in the clinical situation. By combining anisotropy information with fiber tracking, the anisotropy of individual projections was also documented. Magn Reson Med 42:1123-1127, 1999.

Autosomal dominant juvenile amyotrophic lateral sclerosis.

Juvenile amyotrophic lateral sclerosis (ALS) is a form of chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset prior to age 25 years. We report the clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4). Patients ranged in age from 12 to 85 years (mean 45 years) and the mean age of onset was 17 years. Distal weakness and atrophy was associated with pyramidal signs (43/49) and normal sensation (44/49). Motor conduction studies (n = 8) showed reduced evoked amplitudes and normal conduction parameters. Sensory conduction studies (n = 8), quantitative sensory testing (n = 4) and intracutaneous sensory fibres in skin biopsies (n = 6) were normal in all patients tested. Electromyography showed distal more than proximal chronic partial denervation and reinnervation (n = 8). Post-mortem spinal cord tissue demonstrated atrophic spinal cords with marked loss of anterior horn cells and degeneration of corticospinal tracts, as well as loss of neurons in the dorsal root ganglia and degeneration of the posterior columns. Axonal spheroids were present in the grey matter of the spinal cord, the dorsal root entry zones and the peripheral nerves. Motor and sensory roots, as well as peripheral nerves, showed significant axonal loss. Swellings were prominent around motor neurons, probably representing changes in presynaptic terminals. These studies define autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4) and extend the clinical, pathological and genetic heterogeneity of familial ALS and juvenile ALS.