Brain serotonin transporter binding in non-depressed patients with Parkinson's disease

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [¹¹C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (−22%), caudate (−30%), putamen (−26%), and midbrain (−29%). However, only a slight non-significant reduction (−7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.     

Load to failure of common meniscal repair techniques: Effects of suture technique and suture material

Success of meniscal repair with early or immediate motion depends on the ability of the suture fixation to withstand the loads applied. Vertical and horizontal mattress suture techniques were tested using 2-0 Ethibond, and 0-PDS and 1-PDS sutures (Ethicon, Somerville, NJ). Mulberry knot technique was tested with 0-PDS and 1-PDS sutures. Twenty menisci (60 sutures) were tested for each suture material. Sutures were placed 3 to 4 mm from the peripheral edge of the meniscus with double barreled cannulas for vertical and horizontal mattress techniques or a spinal needle for the mulberry knot technique, reproducing clinical techniques of meniscal repair. Mechanical testing of suture fixation was performed to failure at a rate of 10 mm/min on a MTS material testing system (MTS Systems Corp. Minneapolis, MN). Suture pullouts were reported as the load displacement to failure from the inner fragment only, because clinical failure would ensue should a suture pull through the inner fragment of a tear. Vertical mattress technique with 1-PDS suture had significantly greater load to failure than any other combination (P < .05). Analysis of variance showed that the vertical mattress technique had statistically superior pullout strength (P < .0001) compared with the horizontal mattress and mulberry knot techniques, which were statistically similar. There were significant differences (P < .0001) between suture types, with 1-PDS proving best compared with 0-PDS, which was stronger than 2-0 Ethibond. Selection of suture material had the greatest impact on vertical mattress load to failure and was not important to the strength of the other techniques.     

Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy

: A rising prostate specific antigen (PSA) following treatment for adenocarcinoma of the prostate indicates eventual clinical failure, but the rate of rise can be quite different from patient to patient, as can the pattern of clinical failure. We sought to determine whether the rate of PSA rise could differentiate future local versus metastatistic failure.

: Two thousand six hundred sixty-seven PSA values from 400 patients treated with radiotherapy for localized adenocarcinoma of the prostate were analyzed with respect to PSA patterns and clinical outcome. Patients had received no hormonal therapy or prostate surgey and had ?4 PSA values post-treatment PSA rate of rise, determined by the slope of the natural log, was classified as gradual (< 0.69 log (ng/ml)/year, or doubling time (DT) > 1 year), moderate (0.69-1.4 log (ng/ml)/year, or DT 6 months-1 year), or rapid [>1.4 log (ng/ml)/year, or DT < 6 months].

: SIxty-one percent of patients had non-rising PSA following treatment; 25% of patients with rising PSA developed clinical failure, and 93% of patients with clinical failure had rising PSA. The rate of rise discerned different clinical failure patterns. Local failure occurred in 23% of patients with moderate rate of rise versus 7% with gradual rise (p = 0.0001). Metastatic disease developed in 46% of those with rapid versus 8% with moderate rise (p < 0.0001). By multivariate analysis, in addition to rate of rise, PSA nadir and rate of decline predicted local failure; those with post-treatment nadir of 1–4 ng/ml were five times more likely to experience local failure than nadir < 1 ng/ml (p = 0.0002). Rapid rate of rise was the most significant independent predictor of metastastic failure.

: The rate of PSA rise following definitive radiotherapy can predict clinical failure patterns, with a rapidly rising PSA indicating metastatic recurrence and moderately rising PSA local recurrence. This information could potentially dirent therapy; if the rise predicts metastatic failure hormonal therapy could be cosidereed, while aggressive salvage therapy may benefit subclinical local recurrence identified by a moderate rate of PSA rise.     

Striatal monoamine neurotransmitters and metabolites in dominantly inherited olivopontocerebellar atrophy.

We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.     

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.     

Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.      

Effects of green tea polyphenols on murine transplant-reactive T cell immunity

Green tea polyphenols (GrTP), the active ingredient of green tea, may have immunosuppressive properties, but whether and how GrTP affect transplant-reactive T cells is unknown. To address this, we tested the effects of GrTP on in vitro and in vivo transplant-reactive T cell immunity. GrTP inhibited IFNgamma secretion by cultured monoclonal T cells and by alloreactive T cells in mixed lymphocyte reactions. Oral GrTP significantly prolonged minor antigen-disparate skin graft survival and decreased the frequency of donor-reactive interferon gamma-producing T cells in recipient secondary lymphoid organs compared to controls. In contrast to other hypothesized actions, oral GrTP did not alter dendritic cell trafficking to lymph nodes or affect metalloproteinase activity in the graft. This is the first report of an immunosuppressive effect of GrTP on transplant-reactive T cell immunity. The results suggest that oral intake of green tea could act as an adjunctive therapy for prevention of transplant rejection in humans.     

Refinement and distinction of the chromosome 10p candidate tumor suppressor region in human gliomas

Our recent studies have shown that telomeric 10p is frequently deleted in both low and high grade gliomas. Other studies have shown an invariant association of erb-b amplification and loss of chromosome 10. It has not been determined whether this association was specific for a particular locus on chromosome 10. We sought to assess this by examining tumors, for both 10p loss and gene amplification. 55% of tumors showed some degree of allelic imbalance at 10p15. Amplification of erb-b, c-myc, and a mitochondrial cDNA probe, recently found to be amplified in diverse grades of gliomas was assessed. erb-b and the mitochondrial cDNA probe showed amplification in 28% of the tumors; c-myc gene was amplified in only one astrocytoma. No significant association was noted when comparing the presence of a specific amplified gene, and loss of loci on chromosome. Chromosome 10p15 shows significant loss in glial tumors, and is independent of the chromosome 10 region associated with erb-b amplification. The region at 10p15 is distinct in harboring a putative tumor suppressor gene in gliomas, and is involved earlier in the multi-step pathway to glial tumor malignancy.