Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide

SL(2,R) Chern-Simons, Liouville, and Gauge Theory on Duality Walls

We propose an equivalence of the partition functions of two different 3d gauge theories. On one side of the correspondence we consider the partition function of 3d SL(2,R) Chern-Simons theory on a 3-manifold, obtained as a punctured Riemann surface times an interval. On the other side we have a partition function of a 3d N=2 superconformal field theory on S^3, which is realized as a duality domain wall in a 4d gauge theory on S^4. We sketch the proof of this conjecture using connections with quantum Liouville theory and quantum Teichmuller theory, and study in detail the example of the once-punctured torus. Motivated by these results we advocate a direct Chern-Simons interpretation of the ingredients of (a generalization of) the Alday-Gaiotto-Tachikawa relation. We also comment on M5-brane realizations as well as on possible generalizations of our proposals.Comment: 53+1 pages, 14 figures; v2: typos corrected, references adde

The matrix model version of AGT conjecture and CIV-DV prepotential

Recently exact formulas were provided for partition function of conformal (multi-Penner) beta-ensemble in the Dijkgraaf-Vafa phase, which, if interpreted as Dotsenko-Fateev correlator of screenings and analytically continued in the number of screening insertions, represents generic Virasoro conformal blocks. Actually these formulas describe the lowest terms of the q_a-expansion, where q_a parameterize the shape of the Penner potential, and are exact in the filling numbers N_a. At the same time, the older theory of CIV-DV prepotential, straightforwardly extended to arbitrary beta and to non-polynomial potentials, provides an alternative expansion: in powers of N_a and exact in q_a. We check that the two expansions coincide in the overlapping region, i.e. for the lowest terms of expansions in both q_a and N_a. This coincidence is somewhat non-trivial, since the two methods use different integration contours: integrals in one case are of the B-function (Euler-Selberg) type, while in the other case they are Gaussian integrals.Comment: 27 pages, 1 figur

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

<p>Abstract</p> <p>Background</p> <p>Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (<it>Neurology </it>2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD.</p> <p>Methods</p> <p>Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale.</p> <p>Results</p> <p>Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg).</p> <p>Conclusions</p> <p>TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov registration number (initial study): NCT00219804</p

Neuroanatomy and cadaver dissection in Italy: History, medicolegal issues, and neurosurgical perspectives.

Despite the significant Italian tradition of important anatomical studies, an outdated law historically influenced by the Catholic church restricts the use of cadavers for teaching and scientific purposes. The object of the present paper was to trace the historical evolution of the Italian anatomical tradition, particularly neuroanatomical studies, in relation to the juridical regulations on the use of cadavers today. Special attention was paid to the opportunities offered to neurosurgery by using cadavers and to the scientific and social issues in neurosurgical training in the twenty-first century. Considering the new Common European Constitution, the authors advocate a political solution from the European community to improve the quality of training in the disciplines with a social impact such as neurosurgery

Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons

Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS

Contending with Spiritual Reductionism: Demons, Shame, and Dividualising Experiences Among Evangelical Christians with Mental Distress

The belief that mental distress is caused by demons, sin, or generational curses is commonplace among many evangelical Christian communities. These beliefs may have positive or negative effects for individuals and groups. Phenomenological descriptions of these experiences and the subjective meanings associated with them, however, remain somewhat neglected in the literature. The current study employed semi-structured interviews with eight evangelical Christians in order to idiographically explore their experiences of mental distress in relation to their faith and wider communities. Through an interpretative phenomenological analysis, two superordinate themes were constructed: negative spiritualisation and negotiating the dialectic between faith and the lived experience of mental distress. Participants variously experienced a climate of negative spiritualisation, whereby their mental distress was demonised and dismissed, and they were further discouraged from seeking help in secular institutions and environments. Participants often considered such dismissals of their mental distress as unhelpful and stigmatising and experienced heightened feelings of shame and suffering as a result. Such discouragement also contributed to the process of othering and relational disconnection. Alongside a rejection of church teachings, which exclusively spiritualised psychological distress, participants negotiated a nuanced personal synthesis of faith, theology, and distress, which assumed a localised and idiographic significance. This synthesis included advocating for the uptake of aetiological accounts, which contextualised mental distress in terms of the whole person and resisted de-politicised, dichotomised, and individualistic narratives. Results are discussed in relation to a broad range of literature in the field, while further research suggestions are provided.N/