Neural transplantation in Huntington disease: long-term grafts in two patients.

OBJECTIVE: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation. METHODS: Methods used were pathologic examination, histochemistry, and immunohistochemistry. RESULTS: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells. CONCLUSIONS: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.

Deciding the fate of supernumerary frozen embryos: a survey of couples' decisions and the factors influencing their choice.

OBJECTIVE: To investigate the decisions that couples make regarding supernumerary frozen embryos, the factors influencing these decisions, and the degree of difficulty involved in reaching a decision; and to canvass attitudes toward donating embryos to stem-cell research. DESIGN: Anonymous postal survey. SETTING: A large, private IVF clinic in a major city in Victoria, Australia. PATIENT(S): A consecutive cohort of couples who contacted the Monash IVF clinic in relation to embryos in long-term storage. INTERVENTION(S): Subjects completed a survey regarding decisions about surplus frozen embryos. MAIN OUTCOME MEASURE(S): Couples' decision regarding supernumerary embryos and reasons for the decision, experience of deciding, and attitudes about embryo donation for stem-cell research. RESULT(S): Forty percent (123/311) returned completed questionnaires. The most common decision was donation to research (42%). Altruistic motives and desire not to waste embryos were determinants of embryo donation. Determinants of disposal were not wanting a full sibling to existing children and opposition of embryo research. Forty-five percent found deciding distressing. The majority (69%) approved of embryo donation to stem-cell research. CONCLUSION(S): Most couples preferred embryos to come to some use rather than being disposed of. Almost half the sample reported finding the decision making distressing. A majority approved of embryo donation for stem-cell research.

Reaction time and movement time after embryonic cell implantation in Parkinson disease.

BACKGROUND: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. OBJECTIVES: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. DESIGN: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. INTERVENTIONS: Random assignment to embryonic tissue implants or placebo (sham) operation. MAIN OUTCOME MEASURES: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state. RESULTS: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001). CONCLUSIONS: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.

Donation of embryos for stem cell research--how many couples consent?

BACKGROUND: The huge potential of human embryonic stem cells has been a subject of wide discussion as regards the ethical and legal justification of using human embryos for establishing such cell lines. The opinions of infertile couples and their willingness to donate their supernumerary embryos for stem cell research have not been investigated earlier. METHODS: We conducted an analysis of the answers of couples who were asked to give informed consent as regards donating their embryos for stem cell research in our IVF unit in 2001-2002. RESULTS: Ninety-two percent of the couples gave informed consent as regards establishing and characterizing embryonic stem cell lines from the embryos which could not be used in their infertility treatment. Discussion in the Swedish media during May to December, 2001 regarding the importance and ethical justification of stem cell research made informing the couples easier. CONCLUSION: A high proportion, 92%, of couples who underwent infertility treatment in Sweden preferred donating their supernumerary embryos for stem cell research rather than letting them be discarded.

Neural transplantation: restoring complex circuitry in the striatum.

During the last 30 years, the promise of neural transplantation as a therapeutic strategy for neurodegenerative disease has been slowly recognised. Across the world, clinical transplants of embryonic primary dopamine neurones have been shown to ameliorate some of the motor deficits in Parkinson s disease (PD) patients, and more recently, systematic clinical trials have been initiated for the replacement of striatal projection neurones lost in Huntington's disease (HD). Clinical transplantation as a prospective therapy for HD poses a particular set of difficulties. The hallmarks of this neurodegenerative disease include extensive loss of medium spiny long-distance projection neurones of the caudate and putamen, affecting downstream target nuclei, the globus pallidus and substantia nigra, leading to dysregulation of motor control. In addition, extensive loss of cortical neurones that form the afferent systems to the basal ganglia leads to widespread cognitive decline. If transplantation therapy is to succeed in replacing degenerating neurones in HD and reinstating controlled function of complex basal gan-glia circuitry, the new neurones must be able to develop specific long-distance projections that can form accurate and functional connections with neurones in precise target regions. Our ongoing studies are aimed at addressing how we can improve the function of striatal transplants, in particular to optimise the reformation of precise long-distance connections and to re-establish normal motor and cognitive function. In particular, we have investigated optimal requirements for embryonic primary tissue to achieve these aims, and also the potential of other cell sources to provide long-distance projection neurones and reconnect complex circuitry. This review describes current progress of experiments to optimise the reconstruction of neuronal circuitry using primary embryonic tissue transplants, as well as our current initiatives to use neural stem cells or precursors to replace long distance projection neurones in the degenerating basal ganglia.

[The differentiation of locus coeruleus neurons after their allotransplantation into the preliminarily denervated hippocampus of white rats]. / Differentsirovka neironov golubovatogo mesta posle ikh allotransplantatsii v predvaritel'no denervirovannyi gippokamp belykh krys.

The suspension of embryonic locus coeruleus (LC) was transplanted into outbred albino rat hippocampus after its preliminary 6-hydroxy-dopamine-induced denervation. Immunohistochemical and morphometric analysis revealed that 3 months after the transplantation, embryonic noradrenergic LC cells which have completed their histogenesis in recipient hippocampus, appear as differentiated multipolar and fusiform cells, typical to LC. Intrahippocampal allotransplants of rat embryonic LC were also demonstrated to normalize the level of orientation activity in an open area, that was significantly reduced after administration of 6-hydroxy-dopamine to the animals.

[Clinical use of placental blood cells]. / Utilisation clinique des cellules de sang placentaire.

Human cord and placental blood provides a rich source of hematopoietic stem cells. On the basis of this finding, umbilical cord blood stem cells have been used to reconstitute hematopoiesis in children with malignant and non malignant diseases after treatment with myeloablative doses of chemoradiotherapy. Early results show, that a single cord blood provides enough hematopoietic stem cells to provide short and long term engraftment, that the incidence and severity of graft versus host disease has been low even in HLA mismatched transplants. These results are encouraging enough, to embark on large scale banking of cord blood for purposes of future allogeneic and autologous stem cell transplantation, to promote studies on the unique properties of fetal and neonatal hematopoiesis, to study the immunological properties of cord blood cells, to initiate investigations on gene transfer into human cord blood cells for future gene therapy trials. This review will briefly summarize the current knowledge on cord blood transplantation as well as the future development of research on this unique source of hematopoietic stem cells.

[The transplantation to adult animals of fetal small intestine]. / Peresadka vzroslym zhivotnym tonkoi kishki plodov.

Use of the ectopic growth (culture) of foetal small intestine in vivo as a model for study of normal and pathological development of an organ or its different structures was shown to be possible. Complete structural and functional development of foetal small intestine was reached under certain conditions of its implantation.