Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that overexpression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in FVB/N mice. These abnormal FVB/N mice demonstrate various cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, decreasing wild-type Htt levels increased the frequency of this disorder, while over-expression of HTT completely prevented it. Examination of the mechanism underlying huntingtin’s ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by altering huntingtin levels has ramifications related to Huntingtin-lowering therapies in development to treat HD.

Demonic possession was in the early modern period defined in opposition to other conditions likely to cause the same symptoms, like "naturall" disease on the one hand and hypocrisy on the other. In early modern constructions of religious experience, hypocrisy was always an important issue. Hypocrisy, moreover, sometimes becomes a vital issue in accounts of the supernatural. Hypocrisy and anxieties about hypocrisy, and about fraud, the point where legal authority concerns itself with hypocrisy, were endemic in early modern stories of demonic possession, unsurprisingly since the Devil "knows too well how to play the Hypocrite". For Zachary Taylor, Lancashire nonconformists were political subversives fomenting civil dissension under the "Hypocrisy" of claims to religion and motivated by an unholy mix of "Hypocrisy and Enthusiasm". Hypocrisy may, in the context of demonic encounters, be a more complex phenomenon than Samuel Harsnett and his confederates can acknowledge, only one part of a complex tangle of conscious and unconscious motivations.

In 1655 the ghost of her husband appeared to Catherine Bowen. In 1691 Richard Baxter, in The Certainty of the Worlds of Spirits, collated witness statements about this extraordinary event. This article investigates this account as both typical and atypical of seventeenth-century ghost stories, and how in this period narratives were constructed around allegedly true stories of the supernatural. It also follows the story into the twentieth century, when the colonel's descendant Elizabeth Bowen retold it. It suggests that, in both her family history Bowen's Court (1941) and her short fiction, especially "The Demon Lover" (1942), Bowen is not only influenced by but also comments, directly or indirectly, on the seventeenth-century case.

Witchcraft, Witch-Hunting, and politics in early modern England, by Peter Elmer, Oxford, Oxford University Press, 2016, 384 pp., £65.00 (hardback), ISBN 978-0-1987-1772-0The supernatural has lately emerged as a key theme in studies of early modern Europe, with witchcraft continuing to be a particularly richly researched area. While few historians would disagree that politics shaped patterns of witch-hunting in early modern England (1), none has as yet argued this as comprehensively or in as much detail as Peter Elmer in this important, infuriating book. Elmer's arguments are properly complex, circling back to key ideas and teasing away at apparent contradictions. The specificities of local circumstances are acknowledged, but not viewed in isolation from broader developments. There is no inherent link, it is alleged, between puritanism and witch-hunting, although the evidence cited nonetheless demonstrates that most prosecutors of witches were puritans, while sceptics, in most periods, tended to be Anglicans. Witch prosecutions had potentially contradictory significance, since they sometimes served as an agent of consensus, bringing communities together against a common enemy, but could equally lead to acute polarization (7). Elmer aspires to deal with both witchcraft theory and the practices of witch hunting, although he properly notes that there is no simple or necessary relationship between the two. Moreover, while theories and metaphors of witchcraft were remarkably consistent and long-lived, the actual prosecution of witches was not a regular or uniform process (1); explaining its peaks and troughs in terms is one of the achievements of the book. Witch prosecutions, Elmer argues, happened at times when the authorities found their sense of order threatened. When a government, even a puritan government, felt its authority secure, as in Dorchester between 1629 and 1637, there were no witch trials (85), although they continued elsewhere. He concludes that witch trials ended in the early eighteenth century not so much with the coming of the new science - many of those who continued to argue for the reality of witchcraft and the propriety of its prosecution were advocates of the new science - but as a more pluralistic polity (298) emerged. This is not a new argument - Stuart Clark, Michael Hunter and others have voiced similar views - but Elmer's arguments are well supported and offer fresh insights into some important cases.Elmer organises his book in chronological order, from the reign of Elizabeth to the end of the witch-hunts. Elizabethan and Jacobean accusations of witchcraft (Chapter 2) are represented as primarily expressions of tension between puritans and conformists as the Church of England sought to establish and reinvent itself. Unlike his father, Charles I (Chapter 3) was uninterested in witchcraft; he had other things to think about, and his particular brand of sacral royal absolutism represented itself as invulnerable to demonic threat, though metaphors of witchcraft were prominent in theology, literature, and theatre. In this section, Elmer follows closely in the footsteps of his mentor and model Stuart Clark's Thinking with Demons, and arrives at similar conclusions. In the 1640s (Chapter 4), however, especially in Matthew Hopkins' East Anglia, witchcraft re-emerged as a terrifying threat as local communities became ever more politicized and struggled against external and internal enemies to construct a godly society (115). After the Restoration (Chapters 5-7), as political and religious allegiances grew ever more unstable (175), witchcraft belief increasingly moved out of the mainstream and became associated with dissent. At the same time, changing views on medicine and the care of the insane also changed the ways witchcraft was conceptualised. The last witchcraft accusations - Richard Hathaway's apparently fraudulent claim that Sarah Moredike had bewitched him in 1701 and the case of Jane Wenham, the last woman to be found guilty of witchcraft in England, in 1712 - were the result of party factionalism. …

Judging from repetitious appearances of her marital arms in the painted line-endings, the Psalter-Hours John Rylands Library Latin MS 117 probably belonged to Jeanne of Flanders (c.1272–1333), daughter of Count Robert III of Flanders and in 1288 second wife to Enguerrand IV of Coucy. Yet the line-endings also contain some 1,800 diminutive painted escutcheons, many of which refer to other members of the local nobility active during the 1280s. This study, based on an exhaustive survey of the total heraldic and codicological evidence, suggests that the majority of the extant Psalter predated the Hours and that the two parts were combined after the 1288 marriage. The ‘completed’ manuscript bears witness to major events that unfolded in and around the Coucy barony over the course of the decade. It suggests a complex relationship between Jeanne of Flanders and a lesser member of the local nobility, a certain Marien of Moÿ, who may have served as her attendant.

In seventeenth-century cheap print on supernatural themes, the reader is often struck by gaps, silences, and things that do not quite add up. The article explores ways of reading between the lines to expose and perhaps make sense of these discontinuities. It asks what cultural work is performed by the supernatural in such texts, and speculates on the uses served by ghosts, fairies and demons both in the self-representation of subaltern, often female, individuals and in the textual strategies of the pamphlet writers.

Reviewed by: Eighteenth-Century Authorship and the Play of Fiction: Novels and the Theater, Haywood to Austen Jacqueline Pearson (bio) Emily Hodgson Anderson . Eighteenth-Century Authorship and the Play of Fiction: Novels and the Theater, Haywood to Austen. New York and London: Routledge, 2009. xiii+181pp. US$95. ISBN 978-0-415-99905-2. Emily Hodgson Anderson's interesting but ultimately frustrating book analyses work by five women writers, Eliza Haywood, Frances Burney, Elizabeth Inchbald, Maria Edgeworth, and, briefly, Jane Austen. All are best known as novelists, but they also wrote plays, and their novels incorporate, and are shaped by, tropes of theatricality. They "depict characters who perform their feelings" (7), thereby challenging eighteenth-century, and our, assumptions about subjectivity. The stage offered a "model of identity that assumed the possibility of a gap ... between external appearance and internal essence" (9), and the authors appropriate this model in their prose fiction. In different ways, they "privilege emotion as the defining, consistent component of identity": for Haywood the key emotion is love; for Burney suffering; Inchbald "treats feelings much more comprehensively"; and Edgeworth, for whom drama is primarily a tool of her lifelong concern for education, "associates thinking and feeling" (10, 11). Hodgson Anderson meticulously and suggestively shows how key themes and techniques of the plays are continued in the prose fiction. Moreover, she considers not only the literary work of these writers, but also the work of self-construction, emphasizing how the obstacles they face as women writers are represented through theatrical metaphors. For an eighteenth-century woman, writing, and even claiming a self, become "theatrical" acts (12). These assumptions are substantiated in some subtle and suggestive close reading. Today's recession-panicked scholarly publishers favour short books, and Hodgson Anderson's (only 139 pages exclusive of acknowledgments and notes) has the strengths and weaknesses that this truncated format imposes. It is concise, focused, and properly selective; but at the same time I would have liked to see some links developed more, or at least made more explicit, and at points more time needs to be spent on signposting the argument and explaining key terms. As well, surprising gaps remain: Aphra Behn, an obvious candidate for consideration as an author of both fiction and drama, is relegated to a few brief mentions. [End Page 446] (Admittedly, she is not an author of the eighteenth century, technically considered; but neither is Jane Austen, who dominates the epilogue.) More seriously, the pressure to be concise generates abstractions and generalizations when the reader would sometimes like something more weightily specific. It can also sometimes leave the reader wishing for clearer development of some of the identified paradoxes. Is Haywood's Fantomina raped by Beauplaisir? She forms a "Stratagem" to enable her to be "sweetly forced," a stratagem that might be as much about her "desire for expression" (23) as her desire for sex, but is being forced a mode of expression? When Fantomina is exposed by going into labour in public at a ball, in what sense is what betrays her not "the body per se" (33)? The reader is mobilized to take part in the debate, to fill in those parts of the argument that seem to be missing or vestigial. In addition, the argument sometimes has odd holes in it. The enlightening section on Burney's Cecilia (1782), for example, focuses on "what happens to women who are silenced," and argues that "Burney's fascination with the spectacle of the insensible female body" manifests itself in scenes of the performance of "collapse and insensibility" (56, 57) that are central to the novel. This is demonstrated entirely through the figure of Albany's nameless fiancée, dead long before the novel opens, whose story is read in detail as symptomatic of what happens to women who internalize injunctions to be silent, proper, decorous. Burney's life-writings show numerous examples of performances of femininity so exaggeratedly decorous that one suspects them of being acts of rebellion, and so this reading is convincing. But it is strange to read this marginal figure but not the central episodes in which Cecilia herself also collapses into insensibility. Cecilia is, after all, the heroine, and Hodgson...

Scenes of books and reading are often prominent in accounts of early modern women's encounters with the supernatural. This reveals a number of significant things about the way reading was conceptualized in the period, especially about the anxieties on the part of (largely educated male) authors about the extension of reading to the young, the female, and the lower class, and the fantasies of these subjects to transgress a demandingly bibliocentric Protestant culture. In these narratives, three elements converge-the supernatural, the uncontrollable act of reading and the leaky female body-all of which raised anxieties about proper boundaries, rational subjectivity, and the power of the state and church to authorize meanings and control behaviour, leading to the representation of reading as essentially uncanny.

This article reads Trodden down Strength, by the God of Strength, the 1647 narrative of the demonic obsession and subsequent conversion of Joan Drake (died 1625) as a text which problematises the conventions of the Puritan conversion narrative, gendered subjectivities, and Calvinist theology. The 'Relater', who called himself Hart On-Hi, tells contradictory stories, especially centring around narrative and his own role as narrator, family, reading and theatricality. The tensions between competing narratives and the discontinuities in the text are captured through verbal repetition and contradiction, theatrical allusion, and typographical innovation. Whereas the classic conversion narrative has been seen as a story whose happy ending is achieved through self-surrender, this text deals with both narrative and agency more ambiguously, showing self-possession as a necessary condition for self-surrender.

556 Reviews England's First Family ofWriters:Mary Wollstonecraft, William Godwin, Mary Shel ley. By Julie A. Carlson. Baltimore and London: JohnsHopkins University Press. 2007. ix+328pp. ?35.50. ISBN 978-0-8018-8618-8. The worst thing about JulieA. Carlson's subtly argued and scholarly book is the title. 'Firstfamily seems ameaningless bit ofmediaspeak, ironic since theGodwin Shelley group is characterized by their ideological opposition to the family as an institution (forGodwin because individual affection sabotages the universal bene volence on which political justice depends; for Wollstonecraft because the family, despite itsattractions, oppresses women and limits their contribution to public life; and forShelley, lifelongmotherless child, almost lifelongwidow, because familywas so fragile). Carlson builds on thework of critics such asWilliam St Clair to give a sense of themassive shared literaryprogramme of the group, backed up by detailed close readings from a broad range of texts.As inher previous book, on Coleridge and Ro mantic theatricality (In theTheatre ofRomanticism: Coleridge, Nationalism, Women (Cambridge: Cambridge University Press, 1994)), she gives fresh new perspectives on neglected texts?Godwin's Essay on Sepulchres and the Life of Chaucer, Mary Shelley's 'Fields of Fancy'?and on 'minor*genres; an especially illuminating chapter focuses on theirwriting for children. The group can hardly, indeed, be considered apart from each other, since each both facilitates and undermines the others. Reversing traditional literaryhistories, Carlson locates Percy Bysshe Shelley on themargins: literally so, since he emerges fullyonly in the last chapter. The earliest accounts of P.B.S. represented him as a Romantic colossus 'by extracting him from his texts on family or his context in the family* (p. 239), and Carlson returns him to that context, showing him profoundly influenced byWollstonecraft and Godwin, and 'derivative' (p. 3) of theirwork even inwhat seem hismost individualistic claims. The book has twomain sections, 'Revising Family' and 'Life Works'. Rather than a single trajectory,Carlson offers variations on key themes: reading and writing, central in the lifeand work of the group, all ofwhom, in self-analysis and fiction, 'ascribe life-changing moments to books* (p. 2); thewriting of lives; the struggle to define the role of, and construct oneself as, a public intellectual (in the case of twomembers, in defiance of conventional ideologies of gender); the complicated opposition of private and public spheres; trauma, memory, and commemoration. The family itself is also a recurrent theme,with family reform central to the political theory of at least Godwin and Wollstonecraft. Even Mary Shelley, generally seen as themost domestic of the three, is engaged in reconfiguring public and private spheres,most famously in the ability of the Frankenstein family to absorb outsiders (with the catastrophic resultswhich are figuredby themonster). The book's main achievements include a clear and sympathetic view ofGodwin, warts and all; his lack of emotional intelligence, but also his willingness to learn and take risks, and his real originality as a writer. Carlson also presents a revisionary picture ofMary Shelley, no longer the conservative 'perpetualmourner* (p. 162) who turned self-pity into a fineart,but a public intellectual indialogue with her father's MLR, 104.2, 2009 557 work, especially his Essay on Sepulchres, and taking literallyhis idea of cherishing the illustrious dead as a public, political duty asmuch as private therapy. This is not an easy book to read. It isdensely written and sometimes abstract, so that some sentences require repeated reading, and may not give up all their secrets even then.Carlson also has an irritating liking for slashes?con/fusion, life/writing, im/personal, auto/biographical?whose full significance sometimes eludes me. But the book is full of acute and lucid observations, generous in its resurrection of little-known texts, and I have noted a number of issues and sentences that Iwant to continue to think about as I return to the primary texts. University of Manchester Jacqueline Pearson The Publishing History ofVncle Tom's Cabin, 1852-2002. By Claire Parfait. Aldershot: Ashgate. 2007. x+269 pp. ?55. ISBN 978-0-7546-5514-5. This book is much more interesting than itsdry and slightly inaccurate title suggests. Claire Parfait has compared themany different editions ofHarriet Beecher Stowe's Uncle Tom's Cabin, from the appearance of the firstinstalment...

Huntington disease (HD) is an adult onset, neurodegenerative disorder that results from CAG expansion in the HD gene. Recent work has demonstrated testicular degeneration in mouse models of HD and alterations in the hypothalamic–pituitary–gonadal (HPG) axis in HD patients. Here, we show that HD patients have specific testicular pathology with reduced numbers of germ cells and abnormal seminiferous tubule morphology. In the YAC128 mouse model, testicular degeneration develops prior to 12 months of age, but at 12 months, there is no evidence for decreased testosterone levels or loss of GnRH neurons in the hypothalamus. This suggests that testicular pathology results from a direct toxic effect of mutant huntingtin in the testis and is supported by the fact that huntingtin is highly expressed in the affected cell populations in the testis. Understanding the pathogenesis of HD in the testis may reveal common critical pathways which lead to degeneration in both the brain and testis.

The YAC128 mouse model of Huntington disease (HD) exhibits motor abnormalities, cognitive dysfunction and selective neuropathology which are similar to the human disease. Backcrossing YAC128 mice from the FVB/N strain onto the C57BL/6 strain and the 129 strain revealed that striatal volume loss and motor dysfunction are penetrant on all three genetic backgrounds. The severity of HD-like phenotypes in these mice is modulated by strain and this variation is not accounted for by differences in mutant huntingtin expression. In contrast, nuclear localization of mutant htt is modulated by strain and is correlated with the severity of neuropathology. Differences in phenotypic severity between the strains provide the opportunity to identify modifier genes which could impact the pathogenesis of HD. Importantly, the demonstration of penetrance across all three strains permits examining the effect of specific genes on the phenotypic severity in YAC128 mice without necessarily backcrossing onto the FVB/N strain background.

Transcriptional dysregulation caused by expanded polyglutamines (polyGlns) in huntingtin (htt) may be central to cell-autonomous mechanisms for neuronal cell death in Huntington's disease (HD) pathogenesis. We hypothesized that these mechanisms may involve the dysfunction of the transcriptional regulator CA150, a putative modifier of onset age in HD, because it binds to htt and accumulates in an HD grade-dependent manner in striatal and cortical neurons. Consistently, we report herein that CA150 expression rescues striatal cell death in lentiviral overexpression (rats) and knock-in (mouse cells) conditions for mutant htt neurotoxicity. In both systems, rescue was dependent on the (Gln-Ala)38 repeat normally found in CA150. We excluded the possibility that rescue may be caused by the (Gln-Ala)38 repeat interacting with polyGlns and, by doing so, blocking mutant htt toxicity. In contrast, we found the (Gln-Ala)38 repeat is required for the nuclear restriction of exogenous CA150, suggesting that rescue requires nuclear CA150. Additionally, we found the (Gln-Ala)38 repeat was dispensable for CA150 transcriptional repression ability, suggesting further that CA150 localization is critical to rescue. Finally, rescue was associated with increased neuritic aggregation, with no reduction of nuclear inclusions, suggesting the solubilization and nuclear export of mutant htt. Together, our data indicate that mutant htt may induce CA150 dysfunction in striatal neurons and suggest that the restoration of nuclear protein cooperativity may be neuroprotective.