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The psychometric and classification literatures have illustrated the fact that a wide class of discrete or network models (e.g., hierarchical or ultrametric trees) for the analysis of ordinal proximity data are plagued by potential degenerate solutions if estimated using traditional nonmetric procedures (i.e., procedures which optimize a STRESS-based criteria of fit and whose solutions are invariant under a monotone transformation of the input data). This paper proposes a new parametric, maximum likelihood based procedure for estimating ultrametric trees for the analysis of conditional rank order proximity data. We present the technical aspects of the model and the estimation algorithm. Some preliminary Monte Carlo results are discussed. A consumer psychology application is provided examining the similarity of fifteen types of snack/breakfast items. Finally, some directions for future research are provided.
Edited by
Michael Bach, Institute for Research and Development on Inclusion and Society, Ontario and Toronto Metropolitan University,Nicolás Espejo-Yaksic, Exeter College, Oxford, Universiteit Leiden and University College Cork
The concept of will plays a role in CRPD Article 12 in two different ways: one explicit and one implicit. The concept makes its explicit appearance in the provisions of Article 12 that address the need for safeguards. Specifically, CPRD Article 12(4) requires states parties to ensure that “measures relating to the exercise of legal capacity respect the rights, will and preferences of the person” (emphasis added). But already in this formulation we can detect the second, implicit reliance on the concept of the will. For this call to respect the will of persons with disabilities pertains specifically to measures concerning the exercise of legal capacity. As we shall find in detail below, the very idea of legal capacity itself implicates the concept of the will, as well as a broader legal doctrine of the will and practices of ascription and attestation in which that concept is embedded. In contemplating the next steps in the ongoing struggle for disability rights (and in understanding some recent setbacks in that struggle), we therefore need to come to terms with the concept of the will – not least because the legal doctrine of the will has long functioned to exclude persons with disabilities from full participation in society and full enjoyment of their rights.
My plan is as follows. I begin in Section 1 with some ancient history, examining one of the oldest recorded law reforms in Europe, together with an episode from the history of its interpretation in early modern times. In these episodes from the history of law reform we can trace the social and legal architecture of an ancient regime of legal capacity in which the concept of the will came to occupy a crucial place. I then turn in Section 2 to contemporary law in Europe and Latin America, analysing modern civil codes in order to show that and how the concept of will plays a role as a legally primitive notion. In Section 3, I consider ways in which the legal doctrine of the will structures and constrains practices of will-ascription, will-attestation and will-nullification in ways that exclude persons with significant cognitive and psychosocial disabilities from full enjoyment of legal capacity.
Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants.
Methods
In vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice.
Results
In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 μM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice.
Conclusions
Preclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity.
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.
Despite the environmental stresses that mangrove forests experience – including fluctuating salinity, low soil oxygen and buffeting by waves – they can be highly productive. Facilitation, defined here as the benefits to an organism by the minimisation by neighbouring organisms of biotic or physical stress, may help explain this. Theory suggests that facilitation is likely in stressful environments, and trees and shrubs have been found to be particularly likely to exhibit facilitation. Hence, we should find facilitation in mangrove forests, and this chapter summarises new and published evidence for its existence. Facilitation occurs at a wide range of scales and during all different points in a mangrove tree's life. Amelioration of hydrodynamic and dessicative stresses can be important during seedling establishment and early growth. Interactions with fauna, including crabs and ants, can sustain tree production and help defend against herbivores. Ecosystem-scale facilitation helps ensure resilience in the face of changes such as sea-level rise. Hence facilitation is common in mangroves, and the challenge now is to gain a theoretical understanding of when and where to expect it.
Using data from the Alberta Health Care Insurance Plan, the prevalence of motor neurone disease (MND) was estimated for the Province of Alberta, Canada. Between January 1, 1994 and December 31, 1995, 208 cases of MND (125 males, 83 females) were identified from physician billing records giving a period prevalence of 7.38 (8.9 for males, 5.9 for females) per 100,000 population. On prevalence day, July 1, 1995, there were 171 cases (103 males, 68 females) of MND giving a point prevalence estimate of 6.07 (7.3 for males, 4.8 for females) per 100,000 population. Males were more likely to be diagnosed (OR = 1.52, 95% CI 1.1, 2.1) with MND and there was an increased risk of receiving a diagnosis with increasing age (χ2trend = 281, p < 0.001). The mean age of the cases was 59.2 years (58.5 for males, 60.3 for females) and did not differ significantly between the sexes. Geographically, there was no statistically significant difference in the prevalence across regions of the Province. During the study period, 28% of the cases had died (30% of males, 25% of females). The prevalence of MND in Alberta, is among the highest reported in the literature and requires additional investigation to verify these estimates and identify possible causative factors.
There is a high and increasing proportion of
single-parent families in Jamaica. This has raised
concerns about the potential impact of single-parent
families on the social, cognitive and behavioural
development of children, including their sexual
relationships. The aim of this study was to
investigate the association between being raised in
a single-parent family and age of sexual debut among
young people in Jamaica. The study was
cross-sectional in design, and based on a
multi-stage sampling procedure. The study was
conducted in July/September 2016. The study sample
comprised 233 respondents (110 males and 123
females) aged from 18 to 35 years (mean 26.37 years;
SD 5.46). Respondents completed a self-administered
questionnaire with questions on socio-demographic
characteristics, family structure, sexual debut and
current sexual behaviour. Ninety-seven (41.7%)
respondents grew up in single-parent families. A
total of 201 (86.3%) had had sex (102 males and 99
females). Their mean age of sexual debut was 15.51
years (SD 3.41). Sixty-five (32.3%) had early sexual
debut (<16 years). Respondents from
single-parent families were more likely to have had
early sexual debut (56.9%; n=37)
compared with those from two-parent families (43.1%,
n=28;
p=0.004). Only 44.6%
(n=29) of those who experienced
early sexual debut used a condom during their first
sexual encounter compared with 73%
(n=100) of those who had a later
sexual debut (≥16 years;
p=<0.001). A single-father
family structure was a significant predictor of
early sexual debut (AOR 5.5; 95%CI: 1.1–25.8). The
study found a significant association between
single-parent family structure and age of sexual
debut.
Chondrichthyan spines and dermal denticles are reported from the Middle Pennsylvanian Minturn Formation, Eagle County, Colorado. The most common element is a dorsal finspine referred to Ctenacanthus buttersi St. John and Worthen, 1883. Some of the specimens are more complete distally than the holotype and only previously figured specimen of C. buttersi. Less common remains include a dorsal finspine referred to Acondylacanthus nuperus St. John and Worthen, 1883, a smooth-ribbed dorsal finspine close to “Ctenacanthus” furicarinatus Newberry, 1875, a spine fragment probably referrable to Physonemus sp., and two large-noded dorsal finspines probably referrable to two different species of Bythiacanthus. Dermal denticles are referred to Petrodus patelliformis M'Coy, 1848. Ctenacanthus buttersi finspines and some large cladodont teeth, referred to “Symmorium” occidentalis (Leidy), 1859, may belong to the same species. This conjecture is based mainly on the relative abundances of chondrichthyan teeth found at the same locality.
The development of positron emission tomography (PET) has enabled us to perform in vivo measurements of certain aspects of regional cerebral function. Regional cerebral glucose metabolism may be readily quantified with [18F] fluoro-2-deoxyglucose (FDG) and presynaptic dopaminergic function may be studied with the labelled dopa analog 6-[18F] fluoro-L-dopa. We have applied a model to the analysis of 6-FD/PET data with which in vivo age-related changes in dopaminergic function may be demonstrated in normal subjects. With this technique, we have studied a series of asymptomatic MPTP-exposed subjects and have shown evidence of subclinical nigrostriatal pathway damage. Studies of regional cerebral glucose metabolism with FDG in early Huntington's disease have shown a characteristic impairment in caudate function which precedes the development of caudate atrophy. In addition, some asymptomatic individuals who are at risk for HD have caudate hypometabolism. We feel that, at the present time, PET provides information which is complementary to the clinical examination in establishing a diagnosis of HD. In the future these studies may also help in the investigation of at risk individuals
Background: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine–responsive axial signs would correlate with NMS severity. Methods: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. Results: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. Conclusions: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.
We report here six families with Parkinson's disease in whom the onset of symptoms tended to occur at approximately the same time irrespective of the age of the patient. The mean difference in the time of onset in different generations was 4.6 years while the mean difference in age of onset in children and parents was 25.2 years. We construe this pattern of age separation within families as suggestive of an environmental rather than genetic cause. Support for this view derives from the lack of correlation between occurrence of the disease and the degree of consanguinity. We conclude that our findings are in accord with the hypothesis which attributes the cause of some cases of Parkinson's disease to early, subclinical environmental damage followed by age-related attrition of neurons within the central nervous system.
As many as 20% of individuals with the clinical diagnosis of Parkinson's disease (PD) do not have the characteristic neuropathologic features of PD at post mortem. The striatonigral degeneration (SND) subtype of multiple system atrophy is one of the categories of pathology which may be incorrectly diagnosed as PD on the basis of clinical presentation. SND may be associated with increased iron deposition in the putamen which can be detected with magnetic resonance imaging.
Methods:
We have estimated regional brain iron content in a patient with probable SND, using a novel imaging method developed in our laboratory, and have compared the results in this patient to those which we have previously reported in patients with PD and in age-matched controls.
Results:
We observed that putamenal iron content was increased in our SND patient, beyond the 95% confidence limit for inclusion in the PD group, even when considering clinical severity. In contrast, pallidal and thalamic iron were within the PD range.
Conclusions:
The demonstration of increased putamenal iron content may be a useful adjunctive investigative procedure in patients with suspected SND.
Dopamine agonists have yielded two important advances to our understanding of the basal ganglia – they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons – a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect.
The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson’s disease, but as yet there is no firm evidence.
In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.
Positron emission tomography provides a method for the quantitation of regional function within the living human brain. Studies of cerebral metabolism and blood flow in patients with Huntington’s disease, Parkinson’s disease and focal dystonia have revealed functional abnormalities within substructures of the basal ganglia. Recent developments permit assessment of both pre-synaptic and post-synaptic function in dopaminergic pathways. These techniques are now being applied to studies of movement disorders in human subjects.
During the investigation of intractable epilepsy, neuronal migration anomalies [NMA] were discovered in three patients. The first patient had abnormally positioned gray matter within the walls of both lateral ventricles. The second patient had a post operative cystic area in the right parietal-occipital lobes and an area of NMA within the right temporal lobe. The third patient had abnormally thickened gray matter in the right operculum. Long term CCTV-EEG monitoring of these three patients revealed ictal discharges originating from the area of abnormal gray matter in patients 2 and 3. PET scanning showed the areas of NMA in all three patients to have similar metabolic activity to normal gray matter. These cases illustrate the value of various imaging modalities and suggest some interesting physiology of a spectrum of neuronal migration anomalies.