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The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD
Improved Measurement of the Pseudoscalar Decay Constant
We present a new determination of the Ds decay constant, f_{Ds} using 5
million continuum charm events obtained with the CLEO II detector. Our value is
derived from our new measured ratio of widths for Ds -> mu nu/Ds -> phi pi of
0.173+/- 0.021 +/- 0.031. Taking the branching ratio for Ds -> phi pi as (3.6
+/- 0.9)% from the PDG, we extract f_{Ds} = (280 +/- 17 +/- 25 +/- 34){MeV}. We
compare this result with various model calculations.Comment: 23 page postscript file, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
Lattice Calculation of Heavy-Light Decay Constants with Two Flavors of Dynamical Quarks
We present results for , , , and their ratios in
the presence of two flavors of light sea quarks (). We use Wilson light
valence quarks and Wilson and static heavy valence quarks; the sea quarks are
simulated with staggered fermions. Additional quenched simulations with
nonperturbatively improved clover fermions allow us to improve our control of
the continuum extrapolation. For our central values the masses of the sea
quarks are not extrapolated to the physical , masses; that is, the
central values are "partially quenched." A calculation using "fat-link clover"
valence fermions is also discussed but is not included in our final results. We
find, for example,
MeV, , MeV, and , where in each case the first error is
statistical and the remaining three are systematic: the error within the
partially quenched approximation, the error due to the missing strange
sea quark and to partial quenching, and an estimate of the effects of chiral
logarithms at small quark mass. The last error, though quite significant in
decay constant ratios, appears to be smaller than has been recently suggested
by Kronfeld and Ryan, and Yamada. We emphasize, however, that as in other
lattice computations to date, the lattice quark masses are not very light
and chiral log effects may not be fully under control.Comment: Revised version includes an attempt to estimate the effects of chiral
logarithms at small quark mass; central values are unchanged but one more
systematic error has been added. Sections III E and V D are completely new;
some changes for clarity have also been made elsewhere. 82 pages; 32 figure
A case of eosinophilic granuloma of the skull in an adult man: a case report
Eosinophilic granuloma is very rare benign bone tumor which presents in more than 90% in children under the age of ten. There is predominance for males. It is usually found at flat and long bones. The skull and vertebral spine is often affected. We report a case of 57 year-old man who gradually developed local pain at his skull and orbit. A soft, movable, palpable and tender mass was found at the left temporal bone. The pain deteriorated after an accidental injury at skull and remained so. The clinical examination revealed no pathological findings. The patient was a doctor who smoked and consumed alcohol daily. He had a history of cardial infraction and psoriatic arthritis. X-rays and CT revealed a round lytic defect at the skull. Its borders were sharp and its size was 1.6 × 1.8 cm. No periostic reaction or bone formation was noted. Scintigraphy depicted a lytic lesion without radionuclide enhancement. Thus we suspected an eosinophilic granuloma. An attempt to excise the tumor failed as it had already eroded the underlying temporal bone. The external meninga was affected but not the internal one. Histological diagnosis with dominance of Langerhans cells set the diagnosis. A second surgery was done and the eosinophilic granuloma was extracted. After eight months the gap was bridged with plastic heterologous transplant. After the curettage the patient received antibiotics and five cycles of radiotherapy. The aesthetic result was excellent. The patient's head has a normal hairy appearance. No tenderness, swelling or recurrence is recorded until now
The Emergence of Miller's Magic Number on a Sparse Distributed Memory
Human memory is limited in the number of items held in one's mind—a limit known as “Miller's magic number”. We study the emergence of such limits as a result of the statistics of large bitvectors used to represent items in memory, given two postulates: i) the Sparse Distributed Memory; and ii) chunking through averaging. Potential implications for theoretical neuroscience are discussed
Recombinant adenovirus IL-24-Bax promotes apoptosis of hepatocellular carcinoma cells in vitro and in vivo
Gene therapy promises to become an alternative choice for the treatment of hepatic cancer. In many cancers, the delivery of chimeric proteins by adenovirus vector has been reported to induce apoptosis. This study was performed to evaluate whether the recombinant adenovirus interleukin (IL)-24-Bax can induce apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Several recombinant adenoviruses were constructed, and the expression of their encoded proteins was measured. The effects of the recombinant adenovirus on hepatocellular carcinoma cells and the normal hepatocyte cell line were investigated through cell viability and apoptosis assays after the cells were treated with Ad.Luc, Ad.IL-24, Ad.Bax or Ad.IL-24-Bax. The mechanism involved was also explored. A tumor-bearing mouse model was used to evaluate the effects of the adenovirus on tumor volume and cell apoptosis in vivo. Ad.IL-24-Bax selectively suppressed growth of hepatocellular carcinoma cells and induced apoptosis, but it had little influence on the normal hepatocytes. The mechanism of this response may include the effect of the 10HRE/VEGF385 promoter and the synergistic effect of IL-24 and Bax. Ad.IL-24-Bax also suppressed tumor growth in nude mice and induced apoptosis. Ad.IL-24-Bax may be a useful tool for gene therapy of hepatic cancer
Constructing Fluorogenic Bacillus Spores (F-Spores) via Hydrophobic Decoration of Coat Proteins
Background: Bacterial spores are protected by a coat consisting of about 60 different proteins assembled as a biochemically complex structure with intriguing morphological and mechanical properties. Historically, the coat has been considered a static structure providing rigidity and mainly acting as a sieve to exclude exogenous large toxic molecules, such as lytic enzymes. Over recent years, however, new information about the coat’s architecture and function have emerged from experiments using innovative tools such as automated scanning microscopy, and high resolution atomic force microscopy. Principal Findings: Using thin-section electron microscopy, we found that the coat of Bacillus spores has topologically specific proteins forming a layer that is identifiable because it spontaneously becomes decorated with hydrophobic fluorogenic probes from the milieu. Moreover, spores with decorated coat proteins (termed F-spores) have the unexpected attribute of responding to external germination signals by generating intense fluorescence. Fluorescence data from diverse experimental designs, including F-spores constructed from five different Bacilli species, indicated that the fluorogenic ability of F-spores is under control of a putative germination-dependent mechanism. Conclusions: This work uncovers a novel attribute of spore-coat proteins that we exploited to decorate a specific layer imparting germination-dependent fluorogenicity to F-spores. We expect that F-spores will provide a model system to gai
Axonal transport deficit in a KIF5A–/– mouse model
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A–/–) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A–/– mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A–/– motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A–/– sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract
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