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Parkinson's Disease
Volume 2011, Article ID 804041, 10 pages
Critical Aspects of Clinical Trial Design for Novel Cell and Gene Therapies
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Received 15 September 2011; Accepted 13 October 2011
Academic Editor: Yoshikazu Ugawa
Copyright © 2011 Zinovia Kefalopoulou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS).
1. Introduction
Current antiparkinsonian oral drug therapies, with the dopamine (DA) precursor levodopa (L-dopa) remaining the most effective, allow remarkable symptomatic control over the cardinal motor features of Parkinson's disease (PD) in the first years after diagnosis, by restoring the characteristic nigrostriatal DA deficit. Unfortunately, the pharmacotherapeutic window shrinks over time, and treatment is complicated by the onset of motor fluctuations ("ON/OFF" phenomena) and L-dopa induced dyskinesias (LIDs), while signs such as balance disorders, gait freezing, autonomic disturbances, dementia, or affective changes, refractory to dopaminergic substitution, appear [1–3]. Continuous delivery of the DA agonist apomorphine (subcutaneously) or L-dopa (intraduodenally) and surgical strategies such as deep brain stimulation (DBS) provide relief in advanced PD patients with severe motor complications [4–6]. These therapeutic advances, nevertheless, do not influence the underlying neurodegenerative process and have limited effects on L-dopa nonresponsive clinical manifestations, which are now clearly recognized as causes of major disability in late-stage PD [3, 7, 8]. Hence, there is a pressing demand for innovative approaches. Cell replacement therapies and gene transfer through viral vectors into the degenerated host brain have been investigated as alternatives to surpass the shortcomings of conventional symptomatic treatment in PD. Taken together, evidence accumulated so far has provided promising results and proof-of-principle that therapeutic benefits can be achieved, but also generated several unresolved concerns and limitations regarding both these technologies. In this paper, we discuss a number of critical issues that future clinical trials should clearly address before cell-based and gene therapies are considered as clinically relevant treatment options for PD.
2. Choosing the Right Intervention
2.1. Cell Replacement Strategies
Since the late 1980s, over 300–400 PD patients worldwide have received transplants of human fetal ventral mesencephalic (VM) tissue, rich in post-mitotic DA neurons. The experience accumulated from open-label studies suggested significant clinical benefits across multiple parameters in patients receiving grafted cells accompanied by a general reduction in pharmacological requirements [9–11]. Two double-blind, placebo-controlled transplantation trials showed variable efficacy of transplants and occurrence of side effects, including "off medication" or "graft induced" dyskinesias (GIDs) [12, 13]. Furthermore, a decade after transplantation, it was observed that the PD pathologic process might propagate from host to grafted cells, as indicated by decrease in staining for the DA transporter (DAT) and the presence of intracellular inclusions identical to Lewy bodies [14–16]. Nevertheless long-term follow-up of one of these trials showed consistent efficacy using both clinical and imaging outcome measures [17].
Retrospective analysis of clinical trials and further basic science research have sought to explore factors explaining variability in results of cell transplantation open-label series and double-blind trials and determine whether the most successful cases, which had L-dopa withdrawn and exhibited major clinical improvement for several years, could be reproducible. A number of technical parameters regarding tissue procurement and preparation, such as the age and number of donor fetuses, graft dissection procedures, storage length and conditions, tissue dissociation before transplantation (into pieces or crude cell suspensions), or the use of ancillary neuroprotective strategies to increase graft survival (i.e., glial-derived neurotrophic factor (GDNF), lazaroids), are likely to have an important role [18–20]. It is therefore highly possible that superior and consistent results can be achieved with further optimization of the graft procedure and overall transplant protocol. It has become evident that future trials should attempt graft purification by minimizing the serotonergic (5-HT) component of the grafted tissue, likely to be involved in the development of GIDs, use surgical procedures that give rise to the optimum distribution of cells over the putamen, and adopt an effective mode of carefully monitored immunosuppression for at least 6–12 months post graft [18, 21].
Nevertheless the shortage of embryonic donor tissue, difficulties in standardization of cell material (the age at the time of abortion, exact number of donors per putamen) as well as ethical concerns associated with the procurement of tissue from aborted human fetuses make routine clinical application for this type of cell replacement therapy impractical. Alternative cell sources such as autografts of sympathetic neurons from the adrenal glands or xenograft tissue (porcine mesencephalic embryonic neurons) have been abandoned because of discouraging clinical and graft survival results and significant side effects [22–24].
Recent progress in the stem cell field has provided impetus to the cell replacement approach. Stem cells of human origin, potentially able to provide an unlimited supply of standardized DA neurons, may be considered as the most promising future source for a cell-based therapy for PD [25]. Cells with the desired molecular, morphological, and electrophysiological profile of A9 substantia nigra DA neurons can be generated from different stem cell sources in vitro, following various differentiation protocols, and can reverse behavioural deficits after transplantation in animal PD models. Embryonic stem cells (ESCs), neural stem cells (NSCs) isolated from embryonic/fetal or adult brain, pluripotent nonneuronal/mesenchymal stem cells (bone marrow, umbilical cord), or the more recently discovered reprogrammed somatic cells such as induced pluripotent SC (iPS) or directly induced neuronal (iN) cells represent potential alternative sources for transplantable material, each having different advantages and disadvantages when considered for a clinical based application (Table 1) [26–32].
The generation of these cells has highlighted the unresolved issue whether entirely pure DA cell populations will be sufficient, since the nondopaminergic neurons and most probably glial compartments present in the embryonic mesencephalic grafts used so far may be important for the differentiation and function of the grafted DA neurons per se, as well as constituting important cellular factories for creating reparative microenvironment at the host's brain [33]. Irrespective of the cell origin, the methods of their harvest, the number of cells available, the mean number of cells injected and their biochemical characteristics will all have to be standardized and sites certified and inspected to ensure their clinical grade before participation in multicentre trial programmes.
At the present time fetal VM tissue still remains the best standard against which to test future sources of cells for dopaminergic cell replacement in PD. In this context, a new European multicentre project, called TransEuro, was recently launched to further investigate the optimization of the collection, preparation, and storage of fetal tissue for grafting, the selection of the optimal patient group for grafting, evaluate the cause of GIDs, and confirm the efficacy of the transplant technique.
2.2. Gene Therapy Approaches
Based on their functional targets (direct stereotactic injection into striatal, nigral, or subthalamic nucleus (STN) cells), and proposed mechanisms of action, gene therapy approaches can be subdivided into 3 main categories: (a) restoration of DA synthesis capacity (enzyme replacement), (b) basal ganglia circuit modulation, and (c) disease modification/neuroprotection through trophic factors. All of these approaches have identified issues in trial design relevant to future investigations.
Enzyme-replacement gene therapy in PD aims to provide an advantage over peripherally administered L-dopa through restoration of a more physiological manner of dopamine receptor stimulation and/or reduction in the side effects that accompany prolonged peripheral L-dopa administration. These approaches rely on the use of 1 or more of the key enzymes, namely, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and GTP-cyclohydrolase-1 (GCH1) to either replace DA directly (Prosavin), enhance DA synthesis from L-dopa (AADC "prodrug"), or supply continuous DOPA delivery [34]. One concern is that ectopic synthesis of DA in a cellular compartment without vesicular storage and release mechanism for this neurotransmitter could result in multiple detrimental effects, that is, exacerbation of dyskinesias, or even degenerative effects due to elevated cytosolic DA levels [35–37]. Preclinical data and open-label studies have been promising with each of these approaches without evidence of excessive dyskinesia production but beneficial effects have been modest and the dose of vector, rate of vector administration, and the extent of coverage of target tissue remain uncertain. Whether recombinant adeno-associated virus-vesicular monoamine transporter 2 (rAAV-VMAT2) should also be incorporated, that would allow transduced cells to effectively process DA, is unclear [38–44].
Basal ganglia circuit modulation via gene therapy attempts to inhibit abnormal activity in the STN by increasing the expression of glutamic acid decarboxylase (GAD) (responsible for GABA synthesis) using an AAV2 vector encoding GAD injected into the STN mimicking the effects of DBS [45], and with the aim of delivering the same effective symptomatic relief as DBS but with lower side effects and with greater convenience through long-term symptom alleviation without the need for battery changes. Results from a phase II randomized, double-blinded, multicenter, placebo-controlled trial showed modest beneficial effects [46]; however long-term efficacy and safety of this manipulation remains to be proven, and the ideal trial, that is, a randomised comparison of GAD gene therapy against STN DBS may not be commercially appealing.
The overall goal for GDNF and Neurturin (an analogue of GDNF) gene therapy is prevention or slowing of the ongoing degenerative processes, as well as strengthening and supporting the dopaminergic phenotype of endogenous nigrostriatal cells [47–49]. Trophic factor therapy is a disease-modifying approach and therefore has the added advantage over pharmacotherapy that it may theoretically alter the progression of the disease. The use of GDNF as a neuroprotectant/neurorestorative agent has been extensively investigated as a PD therapy [50–52]. Bilateral intra-putaminal injection of AAV2-vector encoding a modified form of Neurturin (CERE-120) did not demonstrate benefit at 12 months although an advantage was seen at 18 months in a double-blind randomized controlled trial [53, 54]. This raised questions regarding the retrograde transport of the vector and highlighted the need for adequate periods of follow-up in these types of trials before breaking the blinding process. A trial of Neurturin concomitantly administered to the putamen and substantia nigra is currently underway.
There are thus a range of potential gene therapy techniques that may confer benefits to PD patients under certain specific situations. The choice of the optimal intervention may, therefore, be individually tailored to specific patient groups (Table 2).
3. Patient Selection
Several clinical trials have been criticized for suboptimal patient selection [12, 13, 52, 53]. While there are inevitably limitations regarding which patients can be recruited to experimental trials of invasive and irreversible treatments, predetermined inclusion and exclusion criteria have critical impacts on the likelihood of a trial meeting its primary endpoints.
Published series of PD patients who have received fetal VM transplants indicated that the selection of patients younger than 60 years of age, and having a less severe disease (e.g., ≤ stage 3 Hoehn and Yahr scale), had better results at 12 months [12, 13]. With longer-term follow-up, these differential effects diminished [17]. However, both clinical and animal studies suggest that residual spared circuitry provides an elevated level of trophic support for newly grafted cells to thrive [18, 55], therefore it would follow that severe PD patients and those with widespread degeneration outside the striatal target should probably be excluded (at least initially) from cell and gene therapy trials. Furthermore, it is known that severity of GIDs is related to severity of dopaminergic deficit which also plays a role in the development of LIDs, therefore even though other mechanisms are undoubtedly relevant, patients with severe L-dopa-induced dyskinesias should probably not be recruited to cell therapy trials [2, 56].
There is to some extent a balanced judgement that needs to be made. With respect to any therapy with potential disease-modifying effects (cell replacement therapy or neurotrophic factor gene therapy), it seems more sensible to target the disease in its earlier stages. On the other hand, the use of experimental, invasive, irreversible techniques in a group of people with relatively mild symptoms needs consideration, in view of the small but important risks associated with functional neurosurgery, although importantly these risks tend to be less among younger people with less brain atrophy. It is possible that very early-stage patients may lack the level of degeneration necessary to stimulate trophic factor release needed to support graft survival and outgrowth, although there is only limited animal data to suggest this [55].
The degree of response to L-dopa is clearly of relevance for any dopamine replacement based therapy. PD patients with severe tremor that is nonresponsive to dopamine might, in theory, remain with major disability, despite excellent graft survival and function or cell transfection, because of tremor persistence. Exclusion of subjects without any dopaminergic deficits (SWEDDs) needs to be confirmed through routine F-dopa positron emission tomography (PET) or DAT single-photon emission computed tomography (SPECT) imaging at recruitment [57, 58]. Other debilitating symptoms in PD are also caused by pathological changes in nondopaminergic systems leading to postural instability and gait dysfunction, dementia, and autonomic disturbances. Until it is known how to repair these systems, patients in whom such features are predominant should probably not undergo cell transplantation or gene therapy.
Continuous DOPA delivery utilizes both vector-derived TH and GCH1 but differs significantly from the Prosavin approach in that it depends on endogenous striatal AADC in the host brain for DA synthesis. This therapy therefore, is likely limited to less-severely impaired patients with sufficient endogenous AADC levels. In contrast, all other gene therapy approaches could be applied to a relatively wide range population provided they exhibit a predominance of DA responsive symptoms.
In addition to age, disease severity, L-dopa responsiveness, and comorbidity based inclusion/exclusion criteria, the impact of these therapies on important genetic subgroups of patients with predominantly motor deficits needs to be determined. Preoperative genotyping for common genetic variants (e.g., parkin, LRRK2 subgroups) is to be recommended to allow planned subgroup analyses for individuals with Mendelian forms of PD.
4. Study Objectives/Endpoints
The primary objective of either cell transplantation or gene transfer paradigms is to demonstrate significant improvement across predetermined clinical parameters in a defined patient group [59]. For most gene therapy programmes the objective remains the demonstration of clinical improvement of specific symptoms, while neurotrophic factor gene therapy and cell therapy aim to be restorative. These divergent aims both require robust measures of longitudinal quantitative assessment.
The most widely accepted measure of PD severity is the Unified PD Rating Scale (UPDRS-Movement Disorders Society modified version) which can be rated in a practically defined "OFF" condition, that is, after 12 hours since last dose of dopaminergic therapy. Accompanying this scale, quantitative measurements of speed (timed tests) can also add objectivity to the assessment of treatment response over time [60]. However, the "OFF" medication evaluation is a somewhat artificial condition, given that many drugs, including L-dopa, are known to have additional "long duration effects" [61]. Changes of the long-term response to L-dopa patterns per se would be worth considering when comparing pre- and post-intervention "OFF" medication states, particularly in exogenous L-dopa-dependent gene therapy approaches [62]. Furthermore, most patients spend the majority of their time in the "ON" medication state and therefore "OFF" improvements are less relevant to their usual functional independence. In view of the diurnal variation "fluctuations" in PD motor control, common with peripheral L-dopa usage, diary data that summarises duration and severity of "ON," "OFF," and dyskinetic time can be an additional demonstration of meaningful improvement [63]. Diary data can however be of variable quality, and technology has been embraced to try and improve the reliability of data obtained [64]. Objective measurement of "On drug" and "Off drug" dyskinesia using validated scales and a consistent protocol allows treatment-related changes to be objectively and accurately quantified [65].
It has been suggested that time to reach other disease milestones such as the Hoehn and Yahr scale might be more appropriate simple measures from which to objectively judge disease progression [66], and this might be of use in trials of potentially disease-modifying approaches. Measurement of time to develop axial or cognitive symptoms would be of less value in dopamine replacement approaches. Despite this, given that some nonmotor features of PD can be DA responsive and others not, even the dopamine replacement strategies should collect data and evaluate positive or negative effects of their effects on a range of secondary endpoints including the broader nonmotor aspects of the disease, such as cognition, affective changes, autonomic symptoms, and sleep disorders, by employing validated scales [67].
Some functional neurosurgery interventions have chosen a patient oriented scale (PDQ-39) as the primary outcome measure [68]. This assessment, in tandem with physician derived assessments that systematically measure disease severity, ensures that data of robust academic value is also translated into meaningful results as prioritised by patients. Economic analyses, utilising tools such as Quality-Adjusted Life Years (QALYs) or EQ-5D, can allow evaluation of cost-effectiveness over time and should routinely be incorporated into trial design.
Biomarkers that reflect disease state or rate may also serve as surrogate endpoints in clinical trials. At present, there is no biomarker that is sufficiently well accepted to serve as a primary endpoint in a clinical trial of PD cell or gene therapy. The most relevant technologies available are the dopaminergic imaging modalities, including measuring presynaptic AADC activity using PET (18F-dopa) and the labelling of the dopamine transporter (DAT) using SPECT [69, 70]. Such neuroimaging endpoints have some advantages over clinical markers, being more objective, more sensitive, particularly in presymptomatic/early stages, however, may themselves be affected by drugs' symptomatic effects. The inclusion of these measures early in trials of cell or gene therapies does, nevertheless, provide important clues about the biological effects of these treatments. In addition, the data accumulated regarding the imaging and the eventual outcome of the patients will help to define the utility of such imaging methods in future studies. The major disadvantages are their additional expense and the fact that most commonly used imaging tools do not quantify the extrastriatal degenerative processes of PD.
Long-term follow-up is mandatory within cell replacement or gene therapy trial designs. These approaches should not realistically be expected to induce rapid disease modification in PD. A practical decision needs to be made regarding the duration of follow-up before breaking the blind in double blind trials. Even 12-month blinded follow-up may not be sufficient [53, 54]. Moreover, such invasive treatments must be shown to maintain therapeutic effects and acceptable long-term adverse event profiles on a long-term basis (through open-label extension) before they can be eligible for consideration as therapeutic options, as evidenced already [17]. Indeed, since these treatments are likely to permanently change the biology of the nervous system, lifelong follow-up of all treated patients is advised until substantial experience is accumulated.
Another important aspect of this work is to demonstrate the survival and maintenance of grafted neurons or the gene transduction efficiency of viral vectors to the desired targeted brain areas. Direct proof of such accomplishments is not possible during the life of a patient. Long-term improvements of motor functions or reductions in dopaminergic medications together with PET imaging findings may be correlated against the survival of the graft and degree of satisfactory gene transfer [12, 13, 17, 18, 53, 71]. Permission for postmortem examination should be discussed and obtained during life to enable routine examination when participants die. The postmortem examination of the grafted brains validates the clinical diagnosis of PD, also directly shows the presence of the heterotopic grafted TH neurons in the striatum, and allows a numerical estimate of the number of surviving neurons (viability) of the striatal volume, reinnervated by DA fibres, with reciprocal synaptic contacts with the host's brain. It also shows the evidence of immune events around the transplanted neurons [13]. In PD cases, postmortem studies have validated the preclinical experiments and the postulated dopaminergic reinnervation of the striatum by grafted neurons [72–74]. Moreover such histopathological studies can determine whether and to which extent grafts are affected by the PD pathologic process and indicate the involved mechanisms [14–16]. They also provide pathological evidence regarding the relationships between transplantation protocols and adverse phenomena such as GIDs [75].
Given that the occurrence of GIDs in a significant subset of grafted patients has been a major hurdle for further development of cell-based therapies for PD [12, 13, 76], a priority for future trials is to demonstrate that by refining transplantation protocols GIDs can be prevented. Notwithstanding the several theories proposed, recent experimental data have implied that neuronal composition of grafted tissue, and graft derived 5-HT hyperinnervation in particular, is involved in the pathogenesis of GIDs. High 5-HT to DA neurons and 5-HT transporters (SERT) to DAT ratios, respectively, leading to a dysregulation of DA synaptic levels, seem to be significantly contributing to the development of GIDs, and therefore, this evidence suggests that achieving normal striatal 5-HT/DA and SERT/DAT ratios following transplantation should be necessary to avoid the development of GIDs [77]. According to these data, 11C-DASB PET, a marker of SERT availability, pre- and post-transplantation, alongside with clinical assessment of dyskinesias and histopathological data when available, could serve as a useful functional imaging tool to monitor the optimization of transplantation techniques and patient selection and lead to reproducible and marked clinical improvement while escaping the troublesome complication of GIDs [78].
5. Data Analysis
When designing a clinical trial, the number of participants required to reliably answer the clinical question should be carefully considered. Sample size calculations require estimates of effect size and variance of that effect size with relation to the primary outcome measure [79]. This can of course lead to impossibly high numbers given that, in novel cell or gene therapies, estimates of effect size and variance may be crude with limited precision or may only exist for outcome measures aside from the major variable of interest. Statistical rigour is at risk of being sacrificed in the face of the need to perform novel, clinically relevant, and yet affordable trials. Phase II trials with low power or even pilot trials with limited precision should involve experienced statistical support during protocol development, funding application, ethical review, and recruitment and not simply during data analysis and manuscript preparation. This said, in a disorder such as PD that invariably shows relentless progression, short-term blinded comparisons can be complimented by long-term open label follow-up which together can limit the extent of influence due to placebo effects and observer bias. Choosing a cohort sample size is necessarily a fine balance of logistical and pragmatic/ethical considerations that includes and takes account of experienced statistical advice. The selection of appropriate analytical tests, multivariate models, and thresholds for judging significance emerge from this careful planning.
6. Sham Surgery Implementation
Double-blind placebo-controlled trial designs are the essential tools to establish the clinical efficacy of any intervention by minimising bias or placebo effects. Cell replacement or gene therapies for PD represent invasive techniques, requiring direct surgical access to the site of delivery in the brain. "Sham surgery", the placebo approach taken in most studies [12, 13, 53], thus, requires an elaborate performance, during which many of the procedures involved in the actual treatment are simulated, often including some invasive element such as burr hole creation. Even though the actual risk is quite low and medically significant complications are rare, these approaches are much more invasive than a typical placebo and the risk of short-term pain, stress, and disability during recovery is virtually certain, and therefore, the use of sham surgery is not without ethical controversy [80]. Protocols that involve "awake surgery" require an elaborate pantomime to maintain blinding such that patients remain uncertain regarding their treatment allocation. The completeness of the blinding procedure should therefore be routinely systematically recorded through patient interview.
Additional risks emerge in protocols requiring general anaesthesia, immunosuppression therapy, and/or significant irradiation exposure for repeated functional imaging scans during evaluation periods, necessary for maintaining the blinding protocol. It is without doubt that substantial and long-lasting placebo effects can occur in PD trials, which might be even more pronounced when surgical interventions are involved, however, some investigators doubt the scientific rationale for using sham surgery for neurotransplantation or gene transfer studies, in the first place [81, 82]. They argue that PD is known to be a progressive degenerative disease that does not improve in its normal natural history, and most likely any placebo effects will wane on the long term. Given that PD trials often involve subjective rating scales as the primary outcome measure, which are vulnerable not only to placebo effects, but to other forms of bias as well, it is currently difficult to escape the demand for sham surgery controlled trials. Still, the use of double-blind sham-surgery-controlled trials should be justified by sufficient preclinical and open-label evidence and considered once neurobiological and technical parameters are standardized. The ethical integrity of sham surgery implementation depends on the ability of the investigators to inform potential subjects about the procedures and the risks involved. Inevitably proof of efficacy for any of the current approaches will compare effects against "placebo" or sham surgery to enable blinding but given the proven effectiveness of existing proven functional neurosurgery—for example, STN DBS, future trials of novel symptom relieving interventions might require comparison against these "conventional" treatment approaches albeit necessarily in an open label manner.
7. Current Challenges and Future Perspectives
The experimental field of restorative neurology continues to advance with implementation of cell replacement or gene-transfer-based approaches to treat patients with PD. Both strategies have generated a consensus demonstrating their capacity for structural and molecular brain modification in the adult brain. The source of tissue/cells remains a major subject under consideration for future clinical trials and it is still unknown which cell type(s) may offer the ideal substrate for a transplantation-based protocol in PD. With respect to gene therapy paradigms, the optimal vector, therapeutic protein, and target site remain to be defined, as does, of course the risk of adverse effects associated with both these techniques.
The requirements for either cell or gene therapies to become clinically competitive treatments for PD are very high. Relief of motor symptoms can be achieved, to a variable extent, by oral medication supplemented by alternative route drug delivery (e.g., apomorphine injections and intrajejunal L-dopa gel) or DBS for advanced-stage disease. Cell and gene therapy treatments will, therefore, have to demonstrate an advantage either in terms of neuroprotection/repair, or in terms of clinical efficacy or safety over both currently available medical and surgical alternatives. The absence of implanted hardware and no need for recurrent battery changes, percutaneous tubes and pumps may represent an advantage over these options in terms of patient convenience. Currently, the safety, efficacy, and disease-modifying capacity of cell and gene therapies remain to be unequivocally proven, and the commercial costs and necessary surgical expertise for their successful delivery will inevitably limit their availability in many countries.
Far fewer treatment options address the nonmotor aspects of PD, such as dementia, neuropsychiatric symptoms, autonomic failure, and sleep abnormalities, which dominate the clinical, caregiver, and financial burden in advanced stages of the disease [3, 8]. It is tempting to speculate that restoration of the nigrostriatal DA system might physiologically restore DA innervation to extrastriatal regions and thereby improve deficits related to cortical and brain stem dopamine deficiency or could even have consequences that extend to the nondopaminergic neurons. It is possible that those nonmotor symptoms with a focal subcortical anatomical basis represent further symptoms that may respond to targeted gene therapy, while transplantation of different cell types (e.g., glia) might provide more widespread benefits than are currently contemplated [83, 84].
The number of parameters that will conceivably influence the outcome of clinical trials of cell or gene therapies is very high. We are currently at a stage where an "explanatory" approach is required to demonstrate that these interventions can have useful effects in the hands of very experienced teams recruiting highly selected patients. Whether any positive findings can be subsequently reproduced on a "pragmatic" basis with broader patient inclusion criteria, and in anticipation of inevitable technical advances and refinement of surgical parameters will be critical in terms of future widespread adoption of any of these interventions.
Conflict of Interests
There is no actual or potential conflict of interests in relation to this paper.
This work was undertaken at UCL/UCLH and was funded in part by the Department of Health NIHR Biomedical Research Centres funding scheme. The Unit of Functional Neurosurgery, UCL Institute of Neurology, Queen Square, London is supported by the Parkinson's Appeal. Dr. T. Foltynie is supported by the Parkinson's Appeal and holds grants from Parkinson's UK, the Cure Parkinson's Trust, and the Brain Research Trust is on the organising committee for the Transeuro project supported by an EU FP7 grant, and is on the Data Management Committee for the Prosavin trial. Dr. Z. Kefalopoulou is supported by the Transeuro EU FP7 grant. Dr. I. Aviles-Olmos is a Ph.D. student supported by the Cure Parkinson Trust.
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text:
Eye catching Wordpress custom theme design
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text: Last weekend I received the 4.04 OTA. Now my Smart Actions ain't so smart - the screen time out is supposed to be OFF, since I use a dock at work. But it doesn't follow the rule. Since it's part of the Moto Package, I can't uninstall and reinstall. Options: a) nothing b) wait for MotoFix c) use Phone Weaver or d)??? Any thoughts?


text:
1. Light/Sun Exposure - Full to partial sun.
2. USDA Hardiness Zones - Winter hardy in zone 7 to 11. In zones 3 to 6, we recommend planting in a container so you can bring the plant indoors before the first frost.
3. Planting Distance - 2 feet apart in ground. One plant per 12-inch or larger container.
4. Mature Height/Spread - 3 to 4 feet tall with a spread of 6 to 14 inches.
5. Bloom Time - Summer to fall.
6. Planting Instructions -
Important: Thoroughly rehydrate the plant and its surrounding soil before planting so it may properly adapt to its new location. We recommend submersing the root zone of the plant in a container of water for 2-3 minutes while you prepare for planting.
1. Remove and discard the clear plastic bag from around the plant.
2. After watering, separate the root ball from its pot by holding the plant upside down in one hand and gently squeezing the sides of the pot with the other. Do not yank on the stem; the plant should easily slide out of the pot with just slight pulling.
3. Prepare the root ball for planting by gently disturbing the roots with your fingers, fork, or gardening tool. Loosen any roots that have begun winding around the soil ball and prune any rotted or damaged roots. This will encourage the roots to begin growing outward into the new soil.
4. Dig a hole twice as wide and twice as deep as the plant's root ball. Partially backfill the hole with soil and place the plant into the hole. The top of the root ball should be level with the ground surrounding the hole. Refill the hole with soil, firming the soil around the plant with your fingers. Check to be sure the plant is not planted too deeply. If it is, raise the plant carefully and refirm the soil.
5. Water thoroughly.
Although these plants will perform well in average garden soils of all types, we recommend having your soil tested periodically by the local County Extension Office. These tests can determine if the soil needs any amendments to enhance your plants' growth and performance. See below for our recommended practice to improve your soil without any additional testing:
1. Spade or till the soil to a depth of 12-18 inches.
2. To provide nutrients and improve drainage, add organic matter to your soil by mixing in a 2 to 4-inch layer of dehydrated manure, garden compost, shredded leaves, and/or peat moss.
3. After active growth begins, periodically feed with Cottage Farms' water soluble Carefree Bud-N-Flower Booster. Plants in containers need more frequent watering and feeding, especially when in active growth and bloom.
Water - Adequate and consistent watering is essential during the plant's first year in your garden. Infrequent, long soakings of water that thoroughly saturate the soil surrounding the root zone are more effective than frequent light applications of water that may wet the top of the soil only.
Due to individual plant needs, geographical and environmental conditions, a specific watering schedule is hard to define; however, as a rule of thumb you should not allow the soil to completely dry out. During periods of drought and extreme summer heat, you may need to water as often as every day.
Overwatering can be as damaging as under watering. Be sure that the area surrounding your plant does not become a water-holding bog and that there is adequate drainage to move excess water away from the plant.
Mulching - Apply a 2-4 inch layer of shredded bark, compost or other organic mulch around your plants to promote moisture retention, maintain even soil temperatures, and to discourage weed growth.
Weeding - Keep the area around your plants free of weeds. Weeds compete with all plants for food, water and light. Walk around the garden periodically and pull weeds, including the roots, as soon as you see them.
Grooming - Clip off dead or unsightly growth to maintain attractive form and shape.
Feeding - Feed your plants once every 2-3 weeks during the growing season with a water-soluble fertilizer such as Cottage Farms' Carefree Bud-N-Flower Booster. Discontinue feeding after September 1st so your plants can harden off for winter dormancy. Resume fertilizing when new growth appears in the spring.
Winterizing - Zones 7 to 11 in ground plantings will go dormant in the ground. You may apply a winter mulch of evergreen boughs, straws or leaves to give added protection for the root system during the winter months.
Containerized plantings can be moved indoors to a cool spot (i.e., unheated garage, shed) in winter where the plants will go dormant in the container. Be sure to check the soil moisture every 2 to 3 weeks and water as needed.
In spring, remove the mulch from in-ground plantings. Also, bring containerized plants back out into the garden sunlight where they will immediately begin to repeat their yearly garden performance.
Zones 3 to 6 these plants will not survive freezing temperatures. Dig the bulbs up about 2 weeks after the first fall frost in your area causes the foliage to die back. Allow the bulbs to dry in a shady frost free location for a few days. Remove any excess soil and trim the stems back to about 2 to 4 inches. Store the bulbs in peat moss in a location where the temperature stays around 40 to 50 degrees F.
Inspect the stored bulbs periodically throughout the winter and discard any that are rotting or mushy. If any of the bulbs are too dry and beginning to shrivel lightly mist them with some water.
Replant the bulbs each spring after the danger of frost has passed.
CAUTION: Not all plant material is edible. Though most plants are harmless, some contain toxic substances which can cause headaches, nausea, dizziness, or other discomforts. As a general rule, only known food products should be eaten. In case of ingestion, please contact your local poison control center at once and advise them of the plant ingested. Keep out of reach of children.
© 2001 - 2018 Cottage Farms Direct


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Zucchini and Pasta
I just made this as a side dish for Easter and it was good.
Meanwhile, in a large skillet cook onion, carrot, and garlic in
hot oil for 5 minutes or till tender.
Add tomatoes, zucchini, fennel seed, and crushed red pepper.
Bring to boiling; reduce heat.
Simmer, uncovered, for 3 minutes.
Stir in pasta.
Heat through.
Makes 4 side dish servings.
Print Recipe (without
the ads)


text:
We all love Logic Apps Logic apps literally allows us to solve an integration challenge within minutes. This however does
Category: Logic Apps
Integration Magic – End-to-End Scenario part 2
In our previous post, I guided you through setting up a WCF service and protecting it using URL Authentication. Although
No more excuses; protect your (Azure) Soap/rest API, ALWAYS! – End-to-End Scenario part 1
Intro you don't want to know, how many times I've encountered web apps / API's which are publically accessible


text:
SWEETEST of sweets, I thank you : when displeasure
Did through my bodie wound my minde,
You took me thence ; and in your house of pleasure
A daintie lodging me assign'd.
Now I in you without a bodie move,
Rising and falling with your wings :
We both together sweetly live and love,
Yet say sometimes,
God help poore Kings
Comfort, 'Ile ; for if you poste from me,
Sure I shall do so, and much more :
But if I travell in your companie,
You know the way to heavens doore.
Herbert, George.
The Poetical Works of George Herbert.
New York: D. Appleton and Co., 1857. 81.
Engraving designed by Birket Foster.
to Works of George Herbert
Site copyright ©1996-2000
Anniina Jokinen
. All Rights Reserved.
Created by
Anniina Jokinen
on May 25, 2000.


text:
Ignoring system-wide mouse settings by Logitech Options
Endorphinity last edited by Pesala
It appears that Vivaldi doesn't honor system-wide settings specified by Logitech Options. I cannot use the "back" and "forward" actions assigned to mouse scroll wheel's left and right tilts, respectively, while this works, e.g., in Safari and Firefox. Please verify and file a bug, if needed.
OS X 10.11.6, build 15G1212
Device: Logitech M535 (Bluetooth)
Logitech Options v.6.35.142


text:
Healing Properties of Garlic
Maybe you've met people who eat garlic while fasting, and at very early hours in the morning. The truth is that many are still surprised by this practice, and this may be due to the unpleasant taste of this product. You probably don't know that the people who are used to consuming it know well the healing properties that garlic could contribute beneficially to the proper functioning of your body.
Garlic contains really wonderful properties, which help regulate the functioning of your body at different levels, and is certainly one of the most healing foods that may exist. Find out about the healing properties of garlic below!
History of Garlic
In ancient times, garlic was used primarily for its antibiotic properties, and both Roman and Greek soldiers used to eat a moderate amount of garlic with the aim of preventing all kinds of anomalies, and ate it before and after all battles. While for the Egyptians, garlic fulfilled aother purpose, for example, they consumed it for aphrodisiac purposes. On the other hand, in the Himalayas, it's still used in various dishes, and do so to strengthen the immune system and at the same time, oxygenate the body.
History has certainly changed a bit, and in many parts of the world garlic is used for culinary purposes, without this meaning that it is wrong, but if you start to know all of garlic's properties, this will surely begin to change. Many people prefer not to include it in their menu because of the strong odor that characterizes it, but it's important to include it so you can get many of the benefits, which will be reflected directly in your health.
We're going to share some properties that garlic contains, so if it's your preference, you can begin to include in your diet, at least one garlic clove per day.
Improves the Cardiovascular System
This wonderful food helps to improve the cardiovascular system, and at the same time, reduces cholesterol levels in the blood. This occurs by controlling the production of cholesterol by the liver, and as if that wasn't enough, increases the production level of good cholesterol (HDL). In regards to the cardiovascular system, garlic helps dilate the blood vessels, making it easier for blood circulation, and also prevents problems such as arteriosclerosis.
Eliminates parasites
Garlic is also used to fight many microorganisms that can hardly be eliminated with common medications. This is because it has antiparasitic properties and fights a few of them, such as Tapeworm, making your body much cleaner and creating an unpleasant atmosphere for all of these parasites.
Cares for the skin
Did you know that garlic is one of the best sources of vitamin C, A, B1 and B2? So, if you consume it constantly, it makes you have more beautiful and healthy skin, and it will also keep you younger and much stronger, and at the same time it will help improve your eyesight and prevent respiratory diseases. Certainly, things that all of us want to achieve.
Similarly, garlic helps fight the flu and inflammatory problems, but beware! You must not over consume this food because it can be counterproductive. So, it's recommended for you to consume it in moderate quantities; one or two garlic cloves per day will be great for you.
Now that you know some of the most beneficial properties that garlic will contribute to your health, we invite you to start consuming this food, whether you include in your meals, so that it's much easier to ingest, or if you prefer to consume it on an empty stomach, and allow yourself to get the greatest benefits from this plant. Remember the importance of getting the most from all of the healing properties of garlic!


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This girder bridge is in the Sunny Hills area of Fullerton. The Pacific Electric branch to Fullerton crossed over the Union Pacific Anaheim Branch at this location. The UP line (barely visible to the left of the tree trunk) is little used and has been cut back to Fullerton in recent years. Photo by Mike Palmer, February 2003.
This is a former Pacific Electric line, originally built in 1917. Passenger service ran until the late 1930s, and freight service continued until around 1962, when this line was abandoned. PE (and later SP) used the parallel Union Pacific branch to serve Fullerton for a few more years. Much of the surviving right of way travels through a residential area, and much of that segment is now the Juanita Cooke trail. It is not paved, and is used by joggers, trail bikes riders, horseback riders, etc. The most distinctive feature still in existence is a short girder bridge over the still (barely) active UP line. A short segment of the branch remains in use at the north end, near the junction with the UP (SP-PE) La Habra branch.
Add your comments
I have a question on how to contact the railroad about the abandoned lines that run behind my property, which are the LaHabra to Fullerton rails I believe. Any help you can give is much appreciated!
Lisa Blocher
Fullerton, CA
Use your address to look in www.historicaerials.com as they have both old aerials & USGS Topographic maps.
Andy Jackson
Santa Fe Springs , CN
ike Lisa Blocher's query, who is in charge of the cleaning and maintenance of the la habra to fullerton inactive railways. It is clogged and flooded right now and rain will still come. 01-21/2017.
Do you have any pictures or information about La Habra to Fullerton?


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The higher education bill is expected to address more aspects of higher education than just headline tuition fees issues.
The bill will replace upfront fees with tuition fees that are repayable after graduation. An Office for Fair Access will be created, as will an Arts and Humanities Research Council.
The new student complaints mechanism will become legally binding, and control of student finance for Wales will be devolved to the Welsh Assembly.
Tuition fees and bursaries
Annual tuition fees will rise to up to £3,000 and will vary between institutions and courses. Bursaries for less well-off students will be introduced, worth up to £2,700 a year including fee remission.
Each university will keep the cash raised from variable fees in return for a pledge to widen access.
The government will not ask universities to pay into a centralised system that redistributes revenue raised by the elite universities, which are expected to charge higher fees but have less demand for their bursaries, to the modern universities, which are expected to charge lower fees and have high demand for their bursaries.
Instead, the widening access premium is likely to be increased at the expense of the teaching grant, in effect redistributing money to those institutions with a large proportion of under-represented students.
Office for Fair Access
An access regulator to oversee student admissions will be created.
Admissions policies will remain the responsibility of individual universities and colleges. But institutions wishing to charge fees higher than the flat rate, currently £1,125, will have to have access agreements approved by Offa. These agreements will set out the action universities must take to safeguard and promote access.
But Offa could implement the English funding council's plans to set sector-wide targets for widening participation and retention.
The funding council had also proposed that the submission of widening-participation strategies would become a condition of grant. Offa might implement this.
Student complaints
The bill will provide for the decisions of the new Office of the Independent Adjudicator to become legally binding. This new mechanism for dealing with student complaints will replace the antiquated visitor system.
In the interim before the OIA's decisions become legally binding, institutions have been asked to join a voluntary scheme.
The independent adjudicator is Dame Ruth Deech, a former principal of St Anne's College, Oxford, appointed in October 2003.
Arts and Humanities Research Council
A new research council, the Arts and Humanities Research Council, will be created. Funded through the Office of Science and Technology, it will have the same legal standing as the existing six scientific research councils.
Student finance in Wales
The bill will pave the way for the Welsh Assembly to take charge of student finance in Wales. The Welsh Assembly has ruled out variable fees until 2007.


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I kinda lost my way for a few months too many.
This past winter was brutal by contemporary standards. I remember far more vicious winters in my youth, but the past few decades have been more benign. Not so this year. We had a rough go of it.
It felt as if winter would never end. Day after day, it was either snowing or bitter cold. I didn't stray far from home all that much. Heck, the aging battery in my car failed me so often, I found myself stranded more often than not.
It wasn't as if I minded the bitter cold. I kinda find it bracing when my nostrils glue together during frigid times. (Grooved on it, even, while riding on chair lifts over frozen slopes at midnight in my 20's). No, what did me in was the duration of the entire affair.
In years past, I would begin my cycling season in March. I'd ramp up the miles in April and hit full stride in May. Not this year. The weather was so inhospitable that I began riding only in late April. My rides in May were few and far between.
I suffered and struggled.
What I hadn't realized was how much physical damage I suffered from a long winter's inactivity. I'm no brown bear that can hibernate all winter long to wake to spring and spring to action. My winter's hibernation led to pronounced decrepitude.
My early forays on my bicycle(s) catapulted me into a near-panic state. My body was failing me. I had no strength, no endurance or resilience.
I found myself feeling truly old.
I found myself struggling in ways I've never struggled before.
I thought I understood the meaning of "aging" in my 50's. I was only half right. There's more to aging than meets a 50-year old eye. At age 63, my cataritic eyes have witnessed far more.
For the first time in my life, I felt truly old and vulnerable. I lost confidence in my physical abilities. And my mind, alas, was engulfed by a truly dark "brain cloud."
My birthday came and went. Family and friends called or sent their best wishes. I did not pick up the phone nor acknowledge their kind thoughts. Shame on me for that. Acts of kindness and generosity deserve/warrant appreciation. Damn that brain cloud!
I was in a miserable state for a few months too many.
I began grappling with finality. I remembered how I argued with my Father to consider early retirement. When he was 62, I saw how physically depleted he had become. I feared he would not live much longer unless he retired. I promised (a promise kept) that I would finance his "golden years." As I had hoped, he retired at 62, but perished by age 66.
At age 63, today, I realize (with a shudder) I'm every bit as physically depleted as my Father was at my age.
I struggle with that.
* * *
Lest you think this is nothing more than a melancholy post, there's more to this story.
It is early August. Today, I cycled for over four hours and traversed more than fifty miles. I reveled in the strength that had returned to my legs. I was grateful for this day.
What I witnessed was this:
The sun hangs lower on the horizon. My days are growing shorter. Still, the shadows beguile. The air shimmers. I feel the change in the air, the change of the seasons and I find it all so ineffably beautiful and meaningful.
The wind blew from the north and felt so fresh, so azure pure, that I gave thanks.
I felt a gratitude that only an aging being can feel.
* * *


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WGBH Openvault
Ray Ferguson Organ Concert
Ray Ferguson Organ Concert as Part of Cabot Organ Concert Series at Symphony Hall, Boston, Massachusetts
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(AP): The Bengals rallied late with a Carson Palmer to Andre Caldwell touchdown to defeat the Ravens 17-14 Sunday. MEB saw this coming all the way and went with the Bengals at +9 1/2. Our members are loving the Bengals this week as they move to 4-1 on the season.
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In further proof that Hollywood can be tough on a marriage, there's sad news to report out of TLC's wildly popular series Little People, Big World. Stars Matt and Amy Roloff are splitting up after 26 years of marriage.
The reality stars announced a separation this week, just as TLC is set to air a special about the family later this month.
The Portland, Oregon farmers were picked for the reality show because they have dwarfism, a condition defined as reaching an adult height of 4 feet, 10 inches or less. They let the public in on what it's like to live with their particular disability, but also what life is like raising four kids -- twins Jeremy and Zack, 23, Molly, 20, and Jacob, 17 -- and farming.
The split isn't one that will really surprise fans -- after all, the Roloffs have been pretty open about their marital strife, even letting TLC cameras film their "marriage saving" trip to Costa Rica with the kids last year and their pretty constant bickering about their family farm and day-to-day life. Divorce rumors have been flying since at least 2010.
Of course, it's hard to say how much of the stress was due to having the cameras around; this could happen to any couple (and frequently does). But surely being in the spotlight when you're going through something like this doesn't make it any easier.
According to a release from the couple, Matt will remain in the family guest house while they figure out what they'll do. The Roloffs issued the following statement to fans:
We sincerely appreciate the unwavering support, understanding and prayers from our family, friends and many fans. May God bless you.
Here's hoping they can work it out, but if not, that things remain amicable ... even though their kids are grown, it's still going to be tough on them.
Are you a fan of Little People, Big World? What did you think of the Roloffs' dynamic on the show?
Image via TLC


text: A device that can convert continuous laser light into numerous ultrashort pulses and that is small enough to fit on a computer chip has been created by researchers at Purdue University and the National Institute of Standards and Technology (NIST), who said the breakthrough technology may have applications in more advanced sensors, communications systems and laboratory instruments. Dubbed a "microring resonator," the device creates ultrashort pulses that repeat at rates corresponding to hundreds of billions per second. The microring is about 80 µm in diameter (the width of a human hair) and is fabricated from silicon nitride, which is compatible with silicon materials widely used for electronics. Infrared light from a laser enters the chip through a single optical fiber and is directed into the microring by a waveguide. Researchers have created a tiny "microring resonator" small enough to fit on a computer chip (at left). The device converts continuous laser light into numerous ultrashort pulses, a technology that might have applications in more advanced sensors, communications systems and laboratory instruments. At right is a grooved structure that holds an optical fiber leading into the device. (Image: Birck Nanotechnology Center, Purdue University) These pulses have many segments that correspond to different frequencies, or frequency combs. By precisely controlling the frequency combs, the team hopes to create advanced optical sensors that detect and measure hazardous materials or pollutants. The comb technology also has potential for a generation of high-bandwidth electrical signals with possible applications in wireless communications and radar. The light originates from a continuous-wave laser, also called a single-frequency laser, which is a very common type of laser. "The intensity of this type of laser is constant, not pulsed, but in the microring the light is converted into a comb consisting of many frequencies with very nice equal spacing," said Purdue's Andrew Weiner. "The microring comb generator may serve as a competing technology to a special type of laser called a mode-locked laser, which generates many frequencies and short pulses. One advantage of the microring is that they can be very small." According to the team, the laser light undergoes nonlinear interaction while inside the microring, generating a comb of new frequencies that is emitted out of the device through another optical fiber. "The nonlinearity is critical to the generation of the comb," said Purdue doctoral student Fahmida Ferdous. "With the nonlinearity, we obtain a comb of many frequencies, including the original one, and the rest are new ones generated in the microring." The research is published online in the journal Nature Photonics. For more information, visit: www.purdue.edu or www.nist.gov


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text: HI This is my first post. I have joined this forum to try to get the most out of my new Ipad! I am probably the least tech savvy person on the this forum but I am very willing to learn. My most important interests are setting up my Ipad for my work sales presentations. I am a Wholesale Rep in the furniture industry. I have two different companies I sell and have almost 5000 sku in my combined lines. I want to find the easiest and most organized way to put my presentations on the Ipad. For the last three years I have been lugging around about 150lbs worth of sales bags, pictures, notepad, and binders. Its tough to keep organized and frankly not fun to lug around! I hope the Ipad can be a partial cure and in a perfect world the cure all! I would love any advice or input! Thank you in advance! Sorry for poor Spelling/grammar!


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Can Boston, battered like many American cities by federal and state budget cuts, survive its latest Christmas present? That's the question beleaguered city officials are asking, following passage by the state Legislature this past weekend of a bill designed to hoist the city from its fiscal abyss.
The subject of the debate surrounding the bill, ostensibly, was finance: how to restructure Boston's fiscal affairs.
Underneath, however, the issue was political. Under discussion was the personality of Mayor Kevin H. White - one of the longest-serving and most controversial mayors in America - and his severely strained relationship with the state Legislature.
The occasion should have been one for jubilation. The so-called ''Tregor bill ,'' passed after 11 months of often-Byzantine political maneuvering, allows Boston to borrow up to $75 million and to levy several new taxes.
But it departs in crucial ways from the home-rule bill originally submitted by Mayor Kevin H. White and the City Council. And the city, although hanging from a fiscal thread and continuing to lay off firemen, policemen, and teachers, has threatened to challenge the bill's legality in court.
''Boston needs a sound fiscal plan now,'' said a statement issued by the mayor's office following Senate passage of the modified bill, ''but in our opinion the version approved today is not the one.''
An even more ominous assessment came from a spokesman for the firm underwriting the city's municipal bonds. ''The bill is a nullity,'' said Francis X. Meaney, counsel to the Merrill Lynch White Weld Markets Group, adding that ''no bonds can be issued.''
The bond sale is needed, say city officials, to offset a battery of financial pressures, including:
* Proposition 2 1/2, the statewide measure limiting property-tax collections to 2 1/2 percent of assessed value.
* The ''Tregor'' case, putting the city under court order to give tax rebates to previously overassessed property owners.
* School overspending, which since 1972 has produced deficits totaling more than $73 million.
Under these pressures, the city's bond rating - the stamp of approval that helps potential investors judge the security of the bonds - has slipped from ''investment grade'' into the lower and more speculative ranges. The city has already cut its budget by 21 percent below last year's figure, and citizens are complaining loudly about dirty streets, unkempt parks, and lack of security services.
Yet in spite of the financial hardships (so severe that the city nearly exhausted its snow-removal budget during its first storm earlier this month), the mayor continues to oppose the bill.
He has based his opposition to the Legislature's bill on what he calls a matter of principle. Under state law, a home-rule bill - submitted by a single municipality and intended to affect only its own governance - may be amended by the legislators only in technical ways. But the Legislature, responding to a widespread feeling that Boston's affairs have been mismanaged for years, stripped away several key provisions of the bill - including a measure giving the superintendent of schools much broader powers.
The school board, which has virtually unlimited spending powers, has been a prime source of criticism from potential bondholders, who want the spending leak sealed.
But critics of the city's version of the bill say it would in effect shift control of schools from the school board to the mayor's office.
Some observers view the mayor's threat of court action as a grandstand play. His threat - as well as the layoffs of policemen and firemen, producing predictible outcries from city residents - may have been designed to pressure the 19-member Boston delegation to come quickly to the city's rescue.
But the threat failed, leaving the mayor between a rock and a hard place. If he accepts the Legislature's measure, he will have lost a prestigious battle and yielded up some of his power - though the school reform, seen by many observers both inside and outside of the White camp as a necessary step in improving the schools, could come at a later time.
But if Mayor White (or any other citizen) actually brings the measure to court, the process of haggling out some kind of rescue bill could begin all over again - with the city's resources continuing to dwindle.


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This information is useful when substantiating a claim of a particular source of a sample of honey. Honey derived from one particular source plant is more valuable than honey derived from many types of plants. The price of honey also varies according to the region it comes from.
In summary, melissopalynology is used to combat fraud and inaccurate labelling of honey.