Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest that the zQ175 knock-in line could be a suitable model for the evaluation of therapeutic approaches and early events in the pathogenesis of HD.
Initial diagnosis is achieved via analysis of metanephrine levels followed by CT or MRI.• Half of phaeochromocytomas are diagnosed incidentally on abdominal imaging.
Phenotyping with traditional behavioral assays constitutes a major bottleneck in the primary screening, characterization, and validation of genetic mouse models of disease, leading to downstream delays in drug discovery efforts. We present a novel and comprehensive one-stop approach to phenotyping, the PhenoCube™. This system simultaneously captures the cognitive performance, motor activity, and circadian patterns of group-housed mice by use of home-cage operant conditioning modules (IntelliCage) and custom-built computer vision software. We evaluated two different mouse models of Huntington’s Disease (HD), the R6/2 and the BACHD in the PhenoCube™ system. Our results demonstrated that this system can efficiently capture and track alterations in both cognitive performance and locomotor activity patterns associated with these disease models. This work extends our prior demonstration that PhenoCube™ can characterize circadian dysfunction in BACHD mice and shows that this system, with the experimental protocols used, is a sensitive and efficient tool for a first pass high-throughput screening of mouse disease models in general and mouse models of neurodegeneration in particular.
Huntington's disease (HD) is a progressive neurodegenerative disease marked by psychiatric and motor problems. Recently, these findings have been extended to deficits in sleep and circadian function that can be observed in HD patients and in HD mouse models, with abnormal sleep patterns correlating with symptom severity in patients. Here, we studied the behavior of the BAC HD mouse model using an 24/7 automated system; the results indicate significant lengthening of the circadian period in the mutant mice. These results reinforce previous findings in HD models and symptomatic HD patients, indicating that circadian dysfunction is a core feature of HD.
Idiopathic, cryptogenic, or tropical splenomegaly, as it is variously termed, is often encountered at the Mulago Hospital in Kampala. Trowell (1950) reported several cases in which no good reason could be found for gross splenomegaly, and discussed the current theories of aetiology. Leather (1961) made the important observation that many cases had a mild portal hypertension in the absence of any evidence of cirrhosis on liver biopsy. Of the 41 cases he investigated 29 showed sinusoidal infiltrates by lymphocytes, histiocytes, and plasma cells, an appearance that had been noted elsewhere in the tropics by Fawdry (1955) from Aden, and by Chaudhuri et al. (1956) from India.The present report describes a series of cases of marked splenomegaly admitted to the New Mulago Hospital, Kampala, in which combined clinical, haematological, parasitological, and pathological investigations were carried out to assess the cause and effect of the large spleens. Materials and MethodsOver a period of eight months 64 patients with marked splenomegaly were investigated in the New Mulago Hospital, Kampala.Routine haematological investigations were prepared by standard techniques (Dacie, 1956). In five patients the red-cell survival and splenic uptake were estimated, using 5Cr-tagged red cells (Mollison and Veall, 1955), and the sites of red-cell destruction were assessed by the method of Hughes Jones and Szur (1957 BudtzOlsen, 1952;Atkinson and Sherlock, 1954). Splenic puncture specimens were examined for malaria parasites and leishmaniae. Initially, random peripheral thick blood was examined for malaria parasites and trypanosomes, but in the latter part of the study a minimum of 10 consecutive daily blood films were examined for malaria parasites by two observers.Stools were examined by the formol-ether-concentration technique (Ridley and Hawgood, 1956) for ova, cysts, and parasites. Rectal snips were examined for schistosome ova.Sera from 40 patients were examined by a fluorescent antibody technique (Voller, 1964) for the presence of malarial antibodies. Control sera from patients without splenomegaly were also examined. The antigen used was Plasmodium bastianellii.
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