A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3.

OBJECTIVE: The objective of this double-blind, placebo-controlled, randomized study was to evaluate the efficacy of varenicline (Chantix), a partial agonist at α4ß2 neuronal nicotinic acetylcholine receptors used for smoking cessation, in patients with spinocerebellar ataxia (SCA) 3. METHODS: Patients with genetically confirmed SCA3 were randomly assigned to receive either varenicline (4 weeks for titration and 4 weeks at a dose of 1 mg twice daily) or placebo. Outcome measures included changes in the Scale for the Rating and Assessment of Ataxia (SARA) scores at endpoint (8 weeks) compared with baseline, a timed 25-foot walk and 9-hole peg test, measurements of mood and anxiety, and adverse events. RESULTS: Twenty patients with SCA3 (mean age = 51 ± 10.98 years; mean disease duration = 14 ± 9.82 years; mean SARA score = 16.13 ± 4.67) were enrolled in the study, and data on 18 patients were analyzed in period I. The most common side effect associated with varenicline was nausea. Improvements were noted in the SARA subsections for gait (p = 0.04), stance (p = 0.03), rapid alternating movements (p = 0.003), and timed 25-foot walk (p = 0.05) and Beck Depression Inventory scores (p = 0.03) in patients taking varenicline compared with those taking placebo at endpoint, with a trend toward improvement in the SARA total score (p = 0.06) in the varenicline group. CONCLUSIONS: In this controlled study, varenicline significantly improved axial symptoms and rapid alternating movements in patients with SCA3 as measured by SARA subscores and was fairly well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that varenicline improved the axial functions of gait, stance, and timed 25-foot walk but did not improve appendicular function, except for rapid alternating movements, in adult patients with genetically confirmed SCA3.

Drug induced liver injury secondary to interferon-beta (IFN-beta) in multiple sclerosis.

Post marketing studies of Interferon-beta (IFN beta) therapy in multiple sclerosis (MS) have demonstrated surprisingly high rates of hepatotoxicity. Grade 3 hepatotoxicity (AST and ALT > 5 to 20 upper limit normal) or higher has been observed in as many as 1.4% of MS patients on IFN beta. We report three cases of IFN beta induced hepatitis in MS and discuss the pathology findings and possible mechanisms of drug-induced liver injury.

Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

Congenital myotonic dystrophy pathology and somatic mosaicism.

We present the pathology and molecular genetic analysis of an infant with congenital myotonic dystrophy. The proband/infant, born at 35 weeks' gestational age to a mother with myotonic dystrophy and 750 CTG repeats, was markedly hypotonic and had severe cardiomyopathy. She died after 16 days of life. At autopsy, skeletal and heart muscles were immature and had a decrease in contractile elements. DNA CTG trinucleotide repeat analysis of the proband demonstrated 2,480 repeats in blood and a slightly greater number of repeats in skeletal muscles, viscera, and gray matter. Corresponding to the clinical course and pathology, cardiac tissues displayed somatic mosaicism, with repeats ranging from 2,760 to 3,220.

Patterning activities of vertebrate hedgehog proteins in the developing eye and brain.

BACKGROUND: The hedgehog (hh) family of secreted signaling proteins is responsible for developmental patterning in a variety of systems, including the neural tube, limbs and somites. Within the neural tube, at the level of the spinal cord, products of the vertebrate gene sonic hedgehog (shh) are proposed to function as a ventral patterning influence, with the capability of inducing floor plate and motor neurons. RESULTS: We report the isolation of tiggy-winkle hedgehog (twhh), a novel member of the zebrafish hh gene family. Both twhh and shh are expressed in the ventral midline of the embryonic zebrafish neural tube and brain, but twhh expression becomes limited to the neural tube, whereas shh is also expressed in the notochord. Both genes are expressed in the developing brain, in domains that include a discrete region in the floor of the diencephalon, located between the sites of the future optic stalks. Using pax-2 and pax-6 as markers of proximo-distal fate within the developing eye, we found that ectopic expression of either hh gene promoted proximal fates and suppressed distal fates. In contrast, proximal fates were lost in cyclops mutant embryos, which lack twhh- and shh-expressing forebrain cells. Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. CONCLUSIONS: These findings suggest that secreted signals encoded by members of the hedgehog gene family, emanating from the ventral midline of the neural tube, not only play important roles in dorso-ventral patterning of the brain but also appear to constitute an early patterning activity along the proximo-distal axis of the developing eyes.

Zebrafish wnt8 and wnt8b share a common activity but are involved in distinct developmental pathways.

The specification of the vertebrate body plan is dependent on numerous signaling molecules, including members of the Wnt family. We have identified two zebrafish wnt8 paralogs related to Xwnt-8B and Xwnt-8, respectively. A RT-PCR assay demonstrated that wnt8 is expressed maternally, with transcripts detected throughout embryogenesis, whereas wnt8b transcripts were first detected during late gastrulation. The wnt8 transcripts at 50% epiboly are spatially restricted to those cells at the blastoderm margin, overlying gsc-expressing cells in the axial hypoblast. During late gastrulation, wnt8 was no longer detected in the marginal cells at the dorsal midline and by mid-segmentation, transcripts were found in the presumptive tail bud. In contrast, wnt8b expression is spatially restricted to prospective neuroepithelium, and later to neural-specific structures. Overexpression of both wnts results in two major phenotypes: radialized embryos and embryos with anterior defects. These phenotypes were preceded by significant changes in the spatial expression patterns of gsc and ntl transcripts, reminiscent of activities of Xwnt-8 in Xenopus, and consistent with a role for wnt8 in the specification or patterning of mesoderm.

Asymmetric catalepsy after right hemisphere stroke.

We describe the appearance of left hemineglect and striking cataleptic posturing, more prominent in left-sided extremities, in a patient without psychiatric illness. Neuroimaging demonstrated a large posterior right hemisphere infarct involving the parietal, occipital, and temporal lobes, the insula, and caudate. Additional movement abnormalities that comprise the full catatonia syndrome were absent, including stereotypy, mannerisms, ambitendency, automatic obedience, mutism, negativism, and echopraxia. Catatonia has been reported to be produced by lesions of diverse etiology affecting the frontal lobe, limbic system, diencephalon, or basal ganglia. In these cases, catalepsy has been manifest only rarely, and motor signs that are present are generally bilateral. This case demonstrates that asymmetric catalepsy can be produced by right hemisphere stroke, and provides partial support for earlier clinical literature relating catalepsy and the parietal lobe.

Functional contouring of the palatal vault for improving speech with complete dentures.

A method for functionally modifying the contour of the palatal vault of maxillary complete dentures was described. This can be achieved at the trial stage of the denture construction and incorporated in the finished denture. Alternatively, the procedure can be accomplished at the time of insertion and the palatal vault modified with self-polymerizing acrylic resin. The immediate speech achieved by the modification is much more normal and eliminates the waiting and training period after denture insertion. Because the modification of the palatal vault is achieved by the functional contact of the tongue during articulation, the tongue does not have to adapt to the presence of the denture in order to achieve "normal speech." One of the advantages of the method is the ease with which it can be performed in a clinical setting and the minimal requirement of any extra material or equipment. Moreover, no special skills are needed to achieve successful results, which can be exceptionally gratifying.

Identification of transcalciferin as a major component of human parotid saliva by crossed immunoelectrophoretic mapping.

Human parotid saliva collected from Stenson's duct during sour candy-stimulated salivation was studied by crossed immunoelectrophoresis (X-IEP). Eleven antigens were identified in a pool of salivas from 10 adult, caucasoid males and females. Four were related to serum antigens, three being previously known: IgG, IgA and albumin. The fourth was identified as Gc globulin, also known by function as transcalciferin. Salivary Gc is electrophoretically different from serum Gc, migrating as an alpha 2-beta component rather than as an alpha 1 globulin. The quantities of 8 of the 11 antigens detected by X-IEP were compared for salivas from 10 subjects. These quantities and their ratios to each other were highly variable, indicating idiosyncratic secretory patterns. Only quantities of amylase were moderately consistent from donor to donor. Quantitatively, Gc is a major antigen in parotid saliva. Large proportions of a salivary antigen, alpha 1c, were found in two of the 10 subjects--adult males who never had developed caries. Among the other 8 subjects, all with caries, proportions of alpha 1c were much lower, and 2 subjects lacked it. None of the other antigens measured showed any correlation with caries resistance. The nature and function of alpha 1c are unknown.