Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers.

BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers. METHODS: In order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms. RESULTS: Preclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset. CONCLUSIONS: EBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

Drug-induced cerebellar ataxia: a systematic review.

BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMBASE (1988 to January 2014) to identify all of the drugs that can have ataxia as an ADR and to assess the frequency of drug-induced ataxia for individual drugs. Furthermore, we collected reports of drug-induced ataxia over the past 20 years in the Netherlands by querying a national register of ADRs. RESULTS: Drug-induced ataxia was reported in association with 93 individual drugs (57 from the literature, 36 from the Dutch registry). The most common groups were antiepileptic drugs, benzodiazepines, and antineoplastics. For some, the number needed to harm was below 10. Ataxia was commonly reversible, but persistent symptoms were described with lithium and certain antineoplastics. CONCLUSIONS: It is important to be aware of the possibility that ataxia might be drug-induced, and for some drugs the relative frequency of this particular ADR is high. In most patients, symptoms occur within days or weeks after the introduction of a new drug or an increase in dose. In general, ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs.

EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.

BACKGROUND AND OBJECTIVES: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. METHODS: This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force. DIAGNOSIS: If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases. TREATMENT: Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.

Predicting water table response to rainfall events, central Florida.

A rise in water table in response to a rainfall event is a complex function of permeability, specific yield, antecedent soil-water conditions, water table level, evapotranspiration, vegetation, lateral groundwater flow, and rainfall volume and intensity. Predictions of water table response, however, commonly assume a linear relationship between response and rainfall based on cumulative analysis of water level and rainfall logs. By identifying individual rainfall events and responses, we examine how the response/rainfall ratio varies as a function of antecedent water table level (stage) and rainfall event size. For wells in wetlands and uplands in central Florida, incorporating stage and event size improves forecasting of water table rise by more than 30%, based on 10 years of data. At the 11 sites studied, the water table is generally least responsive to rainfall at smallest and largest rainfall event sizes and at lower stages. At most sites the minimum amount of rainfall required to induce a rise in water table is fairly uniform when the water table is within 50 to 100 cm of land surface. Below this depth, the minimum typically gradually increases with depth. These observations can be qualitatively explained by unsaturated zone flow processes. Overall, response/rainfall ratios are higher in wetlands and lower in uplands, presumably reflecting lower specific yields and greater lateral influx in wetland sites. Pronounced depth variations in rainfall/response ratios appear to correlate with soil layer boundaries, where corroborating data are available.

Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help.

OBJECTIVE: The purpose of this study was to identify the risk factors that are associated with increased neonatal morbidity in patients who were treated for sonographic evidence of internal os dilation and distal cervical shortening during the second trimester. STUDY DESIGN: From May 1998 to June 2000 patients between 16 and 24 weeks of gestation with the following sonographic criteria were randomly assigned to McDonald cerclage or no cerclage: internal os dilation and either membrane prolapse into the endocervical canal at least 25% of the total cervical length but not beyond the external os or a shortened distal cervix <2.5 cm. Before randomization, all patients were treated identically with an amniocentesis, multiple urogenital cultures, and therapy with indomethacin and clindamycin for 48 to 72 hours. Except for the cerclage, all patients were treated identically after randomization. Multiple variables of perinatal outcome were analyzed. A regression model with gestational age at delivery as the dependent variable was constructed and repeated with neonatal morbidity as the dependent variable. This model was applied to 3 populations: the cerclage group, the no cerclage group, and both groups combined. RESULTS: Of the 135 patients, 20 patients declined randomization, and 2 patients were diagnosed with acute chorioamnionitis. Of the 113 patients remaining, 55 patients were randomly assigned to the cerclage group, and 58 patients were randomly assigned to the no cerclage group. There were 8 rescue cerclage procedures (4 in each group). Regression analysis showed that readmission for preterm labor, chorioamnionitis, and abruption were consistently associated with early gestational age at delivery and increased morbidity. Cerclage did not affect perinatal outcome. CONCLUSION: The sonographic findings of second trimester internal os dilation, membrane prolapse, and distal cervical shortening likely represent a common pathway of several pathophysiologic processes. Use of cerclage does not alter any perinatal outcome variables. Increased neonatal morbidity in these patients appears to be associated with subclinical infection, preterm labor, and abruption.

Interferon expression in the testes of transgenic mice leads to sterility.

A plasmid containing the mouse interferon-alpha 1 gene under control of the mouse metallothionein-I promoter was used for the construction of transgenic mice. Four transgenic mice (two males and two females) were obtained containing 1 to over 10 copies of the introduced DNA. Both males appeared to be sterile. One of the female mice founded a transgenic strain in which the foreign DNA was transmitted to her offspring in a Mendelian fashion. In this strain most male animals are sterile or turn sterile with time. Northern blot analysis of several tissues of these animals shows that expression of the introduced interferon gene occurs only in the testis. In some of the animals biologically active interferon could also be detected in testes homogenates. Histological examination of testis tissue shows an ongoing degeneration of spermatogenic cells leading to calcium deposits and complete atrophy of the seminiferous tubules.

Syngeneic monoclonal antibodies directed against Rauscher virus-induced myeloid leukemic cells: isolation and characterization.

Hybridomas producing syngeneic monoclonal antibodies (MAbs) were prepared by fusion of spleen cells of BALB/c mice, which were immunized with sublethal doses of RMB-I cells. This cell line originates from a Rauscher virus (R-MuLV)-induced myeloid leukemia and forms tumors when re-inoculated into mice. MAbs were characterized as regards their reactivity against virally and non-virally induced cell lines. Two selected MAbs, IC5F5 and 4D2B4, were analyzed further. Their binding to subcellular structures was determined, and so were the properties of the antigens to which they are directed. MAb IC5F5 is of the IgG2A and 4D2B4 of the IgG2b subclass. Both bind to R-MuLV-infected or -transformed cell lines and are not mutually competitive. The antibodies do not react with other murine and human myeloid leukemic cells. As shown by immuno-electron microscopy, these MAbs have affinity to the cell membrane of non-virus producing RMB-I cells. When lysates of purified virus were analyzed, the MAbs were found to be directed to the gag precursor protein Pr65, and one of them (IC5F5) also to be directed to the core protein p12. In RMB-I cells, binding occurs to a 50-kDa glycoprotein and 2 proteins of 26 and 29 kDa. Since RMB-I cells do not produce virus, but express aberrant viral proteins, these MAbs are tumor-specific and useful for immunotherapy.

The detection of virally induced tumors by 131I- and 125I-labeled syngeneic monoclonal antibodies.

The binding of the syngeneic monoclonal antibodies IC5F5 and 4D2B4 to Rauscher virus-induced myeloid leukemic (RMB-1) cells was analyzed in vivo in tumor-bearing BALB/c mice. To verify it these antibodies bind specifically to RMB-1 cells, purified antibodies were iodinated with the isotopes 125I and 131I. Mice previously inoculated with tumor cells were injected with these labeled monoclonal antibodies and the plasma clearance and the tissue distribution were determined. The clearance in tumor-bearing animals was faster than in control mice. The tissue distribution was corrected for nonspecific accumulation by scoring for an unrelated antibody. Calculation of a localization index showed that IC5F5 binds at least 4.5 times more specifically to tumor cells than to other tissues. A preferential localization of radioactivity in s.c. tumor tissue was seen in the scanning of animals injected with 131I-labeled antibodies. The most direct proof of specific binding was observed in autoradiograms of animals treated with 125I-labeled antibodies. Small islands of tumor cells in the livers of mice inoculated i.v. had a high density of grains compared to other tissues and also compared to tumor cells in mice treated with unrelated monoclonal antibodies. These results show efficient targeting of these monoclonal antibodies and make immunotherapy of these myeloid leukemic cells possible.