Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration.

BACKGROUND: Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. METHODS: We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured. RESULTS: Spectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures. CONCLUSIONS: We show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases.

Stereological estimation of eye volume using the Pappus method.

The estimation of object volume from rotationally randomised sections relies on an ancient geometrical principle due to the Alexandrian mathematician Pappus. In this paper we describe two studies that make estimates of eye volume using a stereological version of the Pappus principle. The first study uses a design-based version of the Pappus theorem to make estimates of eye volume in Sprague-Dawley rats and the second uses a model-based implementation for estimating eye volume in juvenile Dover sole. In the sole study we compare the estimates of volume with estimates made using the Cavalieri method and show that the Pappus method gives identical volume estimates with a markedly lower coefficient of variation (2.5%) than the Cavalieri method (13.5%).

Geographical inequality in the provision of carotid endarterectomy in Scotland. Scottish Vascular Audit Group.

BACKGROUND: Carotid endarterectomy (CEA) is a proven method of stroke prevention in patients with symptomatic and asymptomatic high-grade internal carotid artery stenosis. This study examined whether site of residence affects access to CEA in Scotland. METHODS: Scottish Morbidity Record hospital discharge data were collected by the Information and Statistics Division of the National Health Service in Scotland and analysed for the interval 1 January 1989 to 31 December 1995. The number of CEAs performed in the hospitals of each of the 15 regional Health Boards, and CEA rate per 100000 population resident in each Health Board region, were determined. RESULTS: In 1989, 65 CEAs were performed in the hospitals of five Health Boards and in 1995, 431 CEAs were performed in nine Health Boards. In 1989, the CEA rate per 100000 resident population varied between 0 (four regions) and 4 (one region), with one region significantly different from Scotland as a whole (P<0.001). In 1995, the CEA rate varied between 0 (two regions) and 19 (one region), with two regions significantly different from Scotland as a whole (P< 0.01). CONCLUSION: Despite a sixfold increase in the number of CEAs being performed, and a rise in the number of centres performing CEA, there is increasing geographical inequality in the provision of CEA in Scotland.

Tissue distribution and hepatic ultrastructural effects of aflatoxin B1 in Japanese quail.

Fertile, Japanese quail eggs were injected with graded levels of aflatoxin B1 (AFB1) dissolved in ethanol. Hatchability varied inversely with the quantity of AFB1 administered. The generated quail were utilized in studies of AFB1 distribution and its effects upon hepatic ultrastructure. Putative AFB1 was detected within the livers of two quail 6 h after dosing, although the AFB1 distribution was inconsistent between the individuals. Electron microscopy revealed that liver parenchymal cells from AFB1-treated exhibited mitochondrial pleomorphism 6 h after dosing, a rare observation in control tissue.

The influence of aphakia and vitrectomy on experimental retinal toxicity of aminoglycoside antibiotics.

To study the effect of lens and vitreous surgery on the dose threshold of aminoglycoside-induced retinal toxicity, we performed extracapsular lens extraction (Group 1) or lensectomy and vitrectomy (Group 2) on Dutch Belted rabbits. A single dose of amikacin or gentamicin ranging from 100 to 4,000 micrograms was administered intravitreally. Retinal toxicity was examined by light and transmission electron microscopy seven days after injection. Both groups showed retinal toxicity after 400 micrograms of gentamicin or 1,500 micrograms of amikacin, doses identical to those causing toxicity in intact, phakic rabbit eyes. Thus, neither surgical procedure increased the toxic threshold of injected aminoglycoside. Given the accelerated aminoglycoside clearance reported in aphakic eyes, these findings imply that the mechanism of aminoglycoside toxicity may be related to peak drug concentration rather than duration of tissue exposure.

Comparative toxicity of intravitreal aminoglycoside antibiotics.

We compared the toxicity of the aminoglycoside antibiotics (tobramycin, amikacin, netilmicin, and kanamycin) by ophthalmoscopy, light and electron microscopy, and electro-retinography after intravitreal injection in rabbits in doses ranging from 100 to 3,000 micrograms. The earliest manifestations of toxicity were confined to the outer retina with each drug, with lamellar lysosomal inclusions in the retinal pigment epithelium as the earliest finding. However, the aminoglycosides displayed marked differences in the threshold dose required to produce toxic reactions, permitting the following ordering of toxicity: (most toxic) gentamicin greater than netilmicin = tobramycin greater than amikacin = kanamycin (least toxic).

Histochemical analysis of liver cells from short term, aflatoxin-dosed and nondosed Coturnix coturnix japonica. 1. Aflatoxin-sensitive quail.

Although aflatoxicosis in Coturnix coturnix japonica has been described, the histochemical localization of liver chemicals and the occurrence of ingested aflatoxins within blood, feces, and liver have not been described. Six to 8-week-old quail, which were intubated with a carrier with or without .3 mg mixed aflatoxins (AFB1, AFB2, AFG1, AFG2)/kg body weight were sacrificed within .25 to 5 days of intubation. Deparaffinized sections of livers were stained for lipids, nucleic acids, polysaccharides, and proteins. Other livers and excrement were homogenized and filtered homogenates as well as blood partitioned against chloroform. The aqueous phase was treated with pepsin and then partitioned, but the organic phase was analyzed directly. Organic phases of .25 to 5 day blood, feces, and liver lacked aflatoxins. Pepsin digesta of blood from males and females dosed 6 hr appeared to contain aflatoxicol (disappeared by 24 hr) and an unknown fluorescent compound, respectively. Whereas an unidentified fluorescent compound was observed within excrement of males dosed 6 hr, female excrement contained a fluorescent compound with an AFB1 Rf (disappeared by 24 hr). Although the liver of males dosed 6 hr had three fluorescent compounds (Rfs for AFB1 and AFB2a), only one was seen within dosed females. Ultra violet absorption spectra of presumed AFB2a and aflatoxicol failed to yield their reported absorption maxima. Livers from dosed quail exhibited bile duct proliferation, cellular necrosis, vacuolization, congestion, fatty changes and mild hepatitis. Sinusoidal membranes were thickened and contained abundant periodic acid-Schiff's (PAS)-positive substances. Although livers of nondosed quail abounded with regularly shaped and uniformly distributed, Sudan IV-positive droplets, livers of dosed quail accommodated few, irregularly-shaped and positioned droplets. Hepatocyte nuclei and nucleoli of dosed quail displayed marked affinities for the Feulgen reagent and toluidine blue O, respectively. Lobules of dosed quail possessed concentrations of cells in which their entire cytoplasm was PAS positive. Treatment of sections with alpha-amylase reduced staining suggesting the presence of glycogen. Ninhydrin-positive substances were distributed throughout the liver in both DQ and non DQ with no apparent difference in intensities between the two livers. Generally the DQ showed mild hepatitis due to aflatoxicosis and the toxin altered liver histochemistry for the major classes of cellular chemicals.

Stage-related combined modality treatment of retinoblastoma. Results of a prospective study.

Forty-two consecutive patients with retinoblastoma were evaluated by a new staging system and combined modality therapy instituted according to stage. Nineteen patients had bilateral tumors and 23 had unilateral tumors. The staging system was effective in identifying subpopulations of patients and successfully predicted those at greater risk of recurrence or death. Thirty-nine of 42 patients survive (Median survival time, 42 months). Two of 4 children with tumor extension beyond the eye died while 37 of 38 children with tumor presumed confined to the eye survive. Toxicity of the chemotherapy was mild. Radiation therapy of intraocular tumor was associated with cataract formation but most children had satisfactory vision after extraction and the use of corrective lenses. Ophthalmologic findings did not always correlate with histologic extent of tumor and both should be used in planning and evaluating treatment. Recommendations are made on the role of chemotherapy and the need to reduce the morbidity of treatment.

Combination chemotherapy for osteosarcoma.

Because of the great risk for development of pulmonary metastases following amputation for osteosarcoma, 24 consecutive patients with "clinically localized" osteosarcoma of an extremity were given adjuvant combination chemotherapy with adriamycin-cyclophosphamide-high-dose methotrexate-citrovorum factor. Thirteen of these patients remain free of tumor from 11 to 48 months following amputation. The median disease-free survival is estimated to be 18 months and the median survival 27 months. No relapses have been observed in any patients surviving free of disease beyond 23 months. Combination chemotherapy was also given to 16 patients whose disease was not localized; eight with pulmonary metastases at or following diagnosis, one with nodal metastases at diagnosis, two with osteosarcoma following radiation therapy for other malignant tumors, three with osteosarcoma of flat bones, one with parosteal osteosarcoma, and one with multifocal osteosarcoma. Three of this latter group of patients are surviving free of tumor at 8, 17, and 19 months from diagnosis. Two young patients died from complications of methotrexate and adriamycin toxicity.

Factors leading to delay in the diagnosis and affecting survival of children with head and neck rhabdomyosarcoma.

Rhabdomyosarcoma of the head and neck often presents with vague symptoms which mimic other disease conditions. These factors lead to undue delay in the establishment of the correct diagnosis and the delivery of acceptable therapy, including surgery, radiation therapy, and chemotherapy. There is, however, evidence of improved results of treatment of these tumors since the addition of multiple drug chemotherapy to surgery and radiotherapy.

Colorectal carcinoma in adolescents implications regarding etiology.

Between October, 1974 and December, 1976, 13 adolescent patients with far-advanced, poorly differentiated colorectal carcinoma had been referred to a pediatric cancer center. All patients received chemotherapy with vincristine, methyl-CCNU and 5-fluorouracil. Five of 13 patients are living, one of whom remains disease-free after 12 months of chemotherapy. Four of the patients were from urban areas and nine from rural areas. One of four from urban areas had intimate exposure to chemicals used in the production of cotton and soy beans. Eight of nine patients from rural areas also had exposure to farm or agricultural chemicals, and three of these patients were intimately involved with the spraying operations. Suggestions regarding etiology and causative factors for the development of carcinoma of the colon in adults have previously been advanced. Results of these studies suggest that alternate etiologies must be suggested for adolescent colorectal carcinoma.

Osteosarcoma during pregnancy.

Four white women who developed osteosarcoma during pregnancy were referred for treatment, 2 prior to delivery and development of metastases, and 2 after delivery and development of metastases. After amputation, these patients received combination chemotherapy with either vincristine-cyclophosphamide or adriamycin-cyclophosphamide followed by high-dose methotrexate with leucovorin rescue. Two patients survived, 1 tumor-free and 1 with bony and soft tissue metastases. Management of pregnant patients with osteosarcoma should include the use of adjuvant systemic chemotherapy to prevent detectable metastases. This treatment should follow amputation or resection and early termination of pregnancy.

Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity.

Results of treatment for osteosarcoma of the extremity have been poor with metastases usually causing death within 2 years following diagnosis. Because of the great risk of development of metastases, 20 patients have received adjuvant chemotherapy with Adriamycin, cyclophosphamide and high-dose methotrexate-leucovorin rescue for up to 12 months following amputation for osteosarcoma. Sixteen of these patients are surviving; 11 are free of evident tumor from 6 to 34 months following amputation. Five patients were found to have pulmonary metastases while receiving chemotherapy and three patients developed metastases following completion of chemotherapy. One patient died following her third treatment with high-dose methotrexate-leucorovin rescue. Other toxicity included nausea, vomiting, mucosal ulcerations, infections, hematologic abnormalities, changes in kidney and liver functions tests, and minor coagulation abnormalities. The natural history of osteosarcoma may have been modified by the use of these agents for periods exceeding the median time to predicted detection of pulmonary metastases. Microscopic metastases of some patients were eradicated by this adjuvant chemotherapy. For patients who developed metastases, these metastases were delayed in their time of detection and in their number at the time of detection.