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The past two decades have seen a great improvement in the care of people with Prader–Willi syndrome (PWS), particularly with regard to control of diet and behaviour management. Has this affected mortality rates or thrown up new issues regarding premature ageing or dementia? We investigated two aspects of ageing in people with PWS: (1) an estimate of mortality over 9 years in a cohort of people with PWS, originally recruited in 1998–2000; and (2) premature ageing or dementia in people aged ⩾40 years.
(1) A follow-up of the population-based 1998–2000 cohort to investigate the subsequent mortality rate; and (2) the recruitment and structured assessment of all members of the Prader–Willi Syndrome Association UK (PWSA-UK) aged ⩾40 years who agreed to participate.
Follow-up of the population-based 1998–2000 cohort gave a mortality rate of at least 7/62 over 9 years (1.25% per annum; 20 untraced), age at death was between 13 and 59 years. Twenty-six members of the PWSA-UK aged ⩾40 years were recruited, 18 of whom had a genetic diagnosis (gd) of PWS. Twenty-two (14 gd) showed no evidence of dementia. Four, with possible symptoms, are described in more detail; all are female, of maternal uniparental disomy (mUPD) genetic subtype, or have a disomic region, and all have a long history of psychotic illness.
The mortality rate in people with PWS seems to be declining. The subgroup of people with PWS due to UPD or disomic region with female gender and a history of psychosis may be at risk of early onset dementia.
A lot of thought and debate goes into the drafting of a constitution. Fundamental interests of society are affected by the choices made about constitutional design and constitutional language. Political opportunities are created or foreclosed by constitutional choices. Values, interests, and groups are recognized, valorized, neglected, or worse. Whether the process of creating a constitution is relatively open and participatory or relatively closed and elitist, the stakes are high and the process of constitution making is a deliberate one.
But after constitutions are drafted, they must be put into practice. No matter how carefully and thoughtfully crafted at their origins, constitutions must still be interpreted and implemented over time to remain effective and relevant. Disputes over constitutional meaning quickly arise under every constitution, and new problems emerge that challenge the ingenuity of those who seek to adhere to pre-existing constitutional commitments and to operate within an established constitutional framework. The constitutional project does not end with a moment of founding. A successful constitutional enterprise requires ongoing efforts at constitutional maintenance, and sometimes significant revision.
Xasta flies appear to segregate five types of gametes in unequal numbers, namely two which contain both or neither of the chromosomes affected by the translocation and inversions, two further classes which contain one affected and one unaffected chromosome, and finally the remainder which have an unbalanced chromosomal content. These conditions are necessary to fit the results observed in crosses involving the Xasta stock. Xasta exhibits balanced polymorphism under crowded conditions and this may be due to the production of toxic substances by Xa larvae which delay the development of wild type-larvae.
The idea of a constitutional freedom of association was embraced by the U.S. Supreme Court in the mid-twentieth century as implicit in the First Amendment. Although initially endorsed by the Court as a fundamental freedom that was necessarily entwined with the freedom of speech when confronted with cases in the 1930s and 1940s of local government officials cracking down on speakers and assemblies discussing strikes and labor unions, the justices were far more divided and skeptical of freedom of association claims in cases from the mid-1940s through the early 1960s when state and national government officials were pursuing a variety of anticommunist measures. This article examines the early jurisprudential development of the constitutional freedom of association and its grounding in the First Amendment, and suggests some of the limits that the notion always carried with it. Politics and jurisprudence combined to limit its applicability in the anticommunism cases.
Psychotic illness is strongly associated with the maternal uniparental disomy (mUPD) genetic subtype of Prader–Willi syndrome (PWS), but not the deletion subtype (delPWS). This study investigates the clinical features of psychiatric illness associated with PWS. We consider possible genetic and other mechanisms that may be responsible for the development of psychotic illness, predominantly in those with mUPD.
The study sample comprised 119 individuals with genetically confirmed PWS, of whom 46 had a history of psychiatric illness. A detailed clinical and family psychiatric history was obtained from these 46 using the PAS-ADD, OPCRIT, Family History and Life Events Questionnaires.
Individuals with mUPD had a higher rate of psychiatric illness than those with delPWS (22/34 v. 24/85, p<0.001). The profile of psychiatric illness in both genetic subtypes resembled an atypical affective disorder with or without psychotic symptoms. Those with delPWS were more likely to have developed a non-psychotic depressive illness (p=0.005) and those with mUPD a bipolar disorder with psychotic symptoms (p=0.00005). Individuals with delPWS and psychotic illness had an increased family history of affective disorder. This was confined exclusively to their mothers.
Psychiatric illness in PWS is predominately affective with atypical features. The prevalence and possibly the severity of illness are greater in those with mUPD. We present a ‘two-hit’ hypothesis, involving imprinted genes on chromosome 15, for the development of affective psychosis in people with PWS, regardless of genetic subtype.
Keith E. Whittington, Professor of Politics Princeton University,
Neal Devins, Goodrich Professor of Law; Professor of Government; and Director Institute of Bill of Rights Law, Marshall-Wythe School of Law, College of William & Mary,
Hutch Hicken, Attorney with Litchford and Christopher Orlando, Florida
The United States Congress delegates a significant portion of its legislative work to its committees. Even though the power and independence of committees has varied over time, the observation of a young Woodrow Wilson in the late nineteenth century remains largely true today: “The House sits, not for serious discussion, but to sanction the conclusions of its Committees as rapidly as possible. It legislates in its committee-rooms; … so that it is not far from the truth to say that Congress in session is Congress on public exhibition, whilst Congress in its committee-rooms is Congress at work.” Congress both “deliberates and legislates” in committee.
Congressional committees are nonetheless largely uncharted territory for constitutional scholars. The new scholarly interest in extrajudicial constitutional interpretation largely ignores the congressional committee system generally and its routine work. When it focuses on the legislature at all, this scholarship limits its sights to floor debates or committee activities of extraordinary interest, such as the Senate Judiciary Committee hearings on the nomination of Robert Bork to the Supreme Court. But, if committees are the primary sites in which Congress both deliberates and legislates, an adequate picture of congressional efforts to interpret and implement the Constitution will have to take into account the normal work of the committees.
Committee hearings provide a useful window into congressional deliberation. Hearings do not provide direct access to the investigation and negotiation that ultimately produces legislative action. But as staged events for public consumption, hearings do provide useful information.
The exercise of constitutional review by an independent and active judiciary is commonly regarded as against the interest of current government officials, who presumably prefer to exercise power without interference. In this article, I advance an “overcoming obstructions” account of why judicial review might be supported by existing power holders. When current elected officials are obstructed from fully implementing their own policy agenda, they may favor the active exercise of constitutional review by a sympathetic judiciary to overcome those obstructions and disrupt the status quo. This provides an explanation for why current officeholders might tolerate an activist judiciary. This dynamic is illustrated with case studies from American constitutional history addressing obstructions associated with federalism, entrenched interests, and fragmented and cross-pressured political coalitions.
Ten years from now, what kinds of issues of interest to politics will
dominate the agenda of the United States Supreme Court? Will a dominant
approach to constitutional interpretation emerge to guide the justices in
their handling of these significant cases?Keith E. Whittington is professor of politics at Princeton
University and visiting professor of law at the University of Texas,
Boar taint is a major meat quality defect, which affects about 10% of entire male pigs. It is due to an excessive accumulation of skatole and androstenone in adipose tissue. One of the reasons for accumulation of these compounds is a low rate of their metabolism. Androstenone is metabolised in liver via the enzyme 3-beta-hydroxysteroid dehydrogenase (HSD). This enzyme is well characterised in the testis, where it participates in the synthesis of steroids, while its properties in liver are unknown. The aim of the present study was to characterise and compare properties of HSD from pig liver versus pig testis when metabolising androstenone.
Boar taint is off-odours in cooked pork from uncastrated male pigs. It is caused by an excessive accumulation of skatole and androstenone in backfat. Accumulation of skatole is due to a low expression and activity of hepatic enzyme CYP2E1. The mechanism of androstenone accumulation is not clear. It could be due to low activity and expression of 3ß-hydroxysteroid dehydrogenase (HSD), an enzyme metabolising androstenone in liver. On the basis of our previous in vivo experiments with castrated animals we suggest that accumulation of skatole is regulated by androstenone. Castrated pigs manifest lower levels of skatole and androstenone and higher CYP2E1 expression. We hypothesise that high levels of androstenone inhibits CYP2E1 expression and hence, reduces the rate of hepatic skatole metabolism. The aims of the present study were (i) to investigate the expression of androstenone-metabolising enzyme HSD in liver of pigs with high and low skatole and androstenone deposition; (ii) to investigate the effect of androstenone on expression of the skatole-metabolising enzyme CYP2E1 in vitro (in cell culture).
In striking contrast to the legislatures in most modern democracies, Congress retains an important place in American politics and policy making. Especially in recent years, this has led many observers to question the importance of the presidency and bureaucracy to the real work of American governance and the extent to which political actors in the executive branch generally exercise power. This narrative of congressional dominance has been particularly bolstered by recent scholarly interest in principal-agent models of interbranch relations. The assumption of congressional centrality, however, obscures many important features of American politics. Over the course of American history, institutional development in particular has often been driven by either autonomous executive action or conflicts between Congress and the executive. We develop an approach for assessing executive power in institutional politics and illustrate the logic of executive influence with three cases: the rise of federal food-and-drug and forestry regulation, and the growth of the federal farm extension service in the early twentieth century; the rise of the national security state in the mid-twentieth century; and the evolution of budgeting and spending practices over the course of the twentieth century.
Background. Prader-Willi syndrome (PWS) is a genetic disorder resulting in obesity, short stature, cryptorchidism, learning disabilities (mental retardation) and severe neonatal hypotonia. Associated with the syndrome are a number of behaviours that are sufficiently distinctive that the syndrome is considered to have a specific ‘behavioural phenotype’.
Methods. Through multiple sources we attempted to identify all people with PWS living in one region in the UK. This cohort was augmented by people with PWS from other regions, and a contrast group of people with learning disabilities of varied aetiologies. The main carers were interviewed, using structured and semi-structured interview schedules, to establish the presence and severity of specific behaviours, and PWS diagnostic criteria. The intellectual functioning and attainments of all were determined. Blood samples were obtained for genetic diagnosis from all consenting participants.
Results. Although excessive eating was recognized as a potentially severe problem in those with PWS, it was almost universally controlled by food restriction, and therefore not seen as a ‘problem behaviour’. Those with PWS differed from a learning disabled group of other aetiologies in the prevalence rates of skin picking, temper tantrums, compulsive behaviours and mood fluctuations, and also in the profile of their adaptive behaviours.
Conclusions. The study confirms the distinct behavioural phenotype of PWS. Specific behaviours occurred significantly more frequently in PWS, compared with an age and BMI matched learning disabled comparison group. A factor analysis of the behaviours involved resulted in three factors that we hypothesized to be independent, and to arise from different mechanisms.
The relationships between the level of skatole in backfat, the rate of skatole metabolism in isolated liver microsomes, hepatic cytochrome P450IIE1 content and mRNA levels were investigated in Large White ✕ Landrace (LW) and the Meishan ✕ Landrace (M) breeds. A method based on thin layer chromatography was developed and used for measurement of microsomal skatole metabolism. Skatole metabolism by liver microsomes was inhibited by diallyl sulphide, a specific inhibitor of cytochrome P450IIE1 but not by inhibitors of other P450 isoforms. We have shown that the rate of skatole metabolism by liver microsomes was proportional to the microsomal P450IIE1 content. In LW pigs there was considerable variation in cytochrome P450IIE1 expression and P450IIE1 protein level and there was a significant negative correlation between backfat skatole level and hepatic microsomal cytochrome P450IIE1 content. Pigs exhibiting low P450IIE1 content in general also showed low levels of P450IIE1 mRNA. These results show that the levels of deposition of backfat skatole in LW pigs are inversely related to the rate at which skatole can be metabolized by liver microsomes, and this in turn depends on the level of expression of cytochrome P450IIE1 mRNA in the liver. In the M breed generally the P450IIE1 protein and mRNA levels were very low and backfat skatole level was high. However the skatole level varied over a 10-fold range and there was no significant correlation with P450IIE1 protein or mRNA content. The M breed was shown to express high levels of the multidrug resistance protein in liver, and it is suggested that export of skatole from liver via this transport protein may be an additional factor regulating backfat skatole in M pigs, but not in the LW breed.
The medical findings from a population-based study of Prader-Willi syndrome (PWS) are discussed (in which birth incidence of PWS was estimated at 1:22000 and death rate at over 3% per annum). In this study the prevalence of specific medical disorders that might account for a shortened life expectancy were investigated. Of all people with a possible diagnosis of PWS, only those meeting clinical criteria and/or with a confirmed genetic diagnosis were included in the study. Sixty-six individuals, 40 males and 26 females with a mean age of 19 years (range of 0 to 46 years) agreed to participate in the population-based study group. A prevalence rate of 25% for non-insulin dependent diabetes mellitus (NIDDM) was found in adults. Mean age at onset was 20 years. Those with NIDDM had a higher past maximum body weight and a greater likelihood of positive family history. Nearly 50% across the age groups reported a history of recurrent respiratory infections. High rates of fractures (29%), leg ulceration (22% in adults), sleep disorders (20%), and severe scoliosis (15% in childhood) were also reported. It is postulated that hypotonia is a possible contributory factor to the risk of strabismus, scoliosis, and respiratory infections. Other causes of morbidity, in particular the high rates of NIDDM, may be due to a failure to manage over-eating resulting in severe obesity. Early diagnosis and clear guidance to families about these risks and how they might be prevented is recommended.
It is hypothesized that the high pain threshold may result in the presence of some illness not being apparent.
Boar taint is an offensive odour and flavour in the meat from some (perhaps 0.05) entire male pigs. It occurs when high concentrations of skatole and androstenone are reached in fat tissue. Boar taint is more common in some breeds than others and as part of an investigation into its genetic basis (Doran et al., 2001), we have studied skatole, androstenone and testosterone relationships in Large White and Meishan cross bred pigs.