In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease.

OBJECTIVE: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. METHODS: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. RESULTS: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. CONCLUSIONS: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.

Rate and correlates of weight change in Huntington's disease.

OBJECTIVE: To determine the rate and correlates of weight change in a large, well characterised sample of patients with Huntington's disease followed at 44 sites by the Huntington Study Group. PARTICIPANTS AND METHODS: Weight change was assessed in 927 adults with a definite diagnosis of Huntington's disease who were followed prospectively for (mean (SD)) 3.4 (1.4) years. The unified Huntington's disease rating scale was used to assess weight, motor dysfunction (including chorea and dystonia), depressive symptoms, and functional decline. RESULTS: Random effects modelling determined that patients gained an average of 0.11 (1.7) kg/year and their chorea scores increased by 0.36 (0.78) points/year. There were significant but weak relations between weight loss and increasingly severe chorea (r = -0.13), worse baseline motor performance (r = -0.12), less severe baseline depressed mood (r = 0.14), and poorer baseline independence ratings (r = 0.07). Patients who were within 0 to 2 years of symptom onset at the time of the baseline visit gained more weight than those with longer disease duration. CONCLUSIONS: Weight loss following symptom onset is not a consistent feature of Huntington's disease. The mechanisms contributing to weight change in this condition are unclear and probably multifactorial. Future studies examining asymptomatic carriers of the mutation could be helpful in identifying incipience of low body weight and may be better suited for identifying clinical correlates of weight loss than studies in symptomatic patients.

Preclinical evaluation of 5-aminolevulinic acid-based photodynamic therapy for canine transitional cell carcinoma.

As a prelude to photodynamic therapy, 5-aminolevulinic acid (ALA) was given orally to healthy dogs. ALA-induced protoporphyrin IX (PpIX) fluorescence significantly increased in the mucosa of the urinary bladder in an ALA dose-dependent fashion. Vomiting occurred after ALA administration in 70% of the dogs but did not affect PpIX fluorescence. ALA-based photodynamic therapy (PDT) of the urinary bladder in healthy dogs caused only submucosal oedema within the bladder wall. No haematologic or serum biochemistry abnormalities were observed after ALA administration. Microscopic haematuria was observed in all the dogs after PDT but was mild and self limiting. ALA-based PDT was administered to six dogs with transitional cell carcinoma (TCC) of the lower urinary tract. ALA-based PDT resulted in tumour progression-free intervals from 4 to 34 weeks in five dogs; one dog with pre-existing hydronephrosis died shortly after PDT. Dogs with TCC represent an outbred, spontaneous, tumour model for developing PDT protocols for humans with bladder cancer.

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD.

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.

Use of laser photocoagulation for treatment of cutaneous angiomatosis in one dog and two cats.

One dog and 2 cats were evaluated because of multiple progressively enlarging cutaneous vascular plaques. Biopsies were performed and revealed small well-circumscribed dermal nodules of dilated fully enclosed blood-filled spaces lined by single layers of endothelial cells aligned on thin fibrous walls, with minimal mitotic activity. A diagnosis of cutaneous angiomatosis was made in all 3 animals. Cutaneous angiomatosis is a progressive proliferative lesion of vascular tissue involving the dermis and subcutaneous tissues of dogs and cats. Lasers of selected wavelengths have been used to induce photothermal coagulation of hemoglobin-containing cutaneous lesions in humans; argon-pumped dye and neodymium:yttrium-aluminum-garnet lasers were used to treat the cutaneous lesions in the animals of this report. Laser treatment may provide an alternative to wide surgical resection or limb amputation for management of this condition in veterinary patients.

Cortical bone healing following laser osteotomy using 6.1 microm wavelength.

BACKGROUND AND OBJECTIVE: Use of laser wavelengths in the 6.1 microm (amide I) to 6.45 microm (amide II) regions and a macropulse width of 4.0 microseconds delivered by a computer-controlled delivery system have produced clean, deep cortical bone ablations with minimal collateral thermal injury and no char formation. The purpose of this study was to evaluate the healing of cortical bone following 6.1 microm wavelength laser osteotomy using a 4.0 microsecond pulse, and compare that response to the response of similar osteotomies made with a standard pneumatic surgical bone saw. STUDY DESIGN/MATERIALS AND METHODS: Sixteen mature rabbits were divided equally into 2, 4, 6 and 8-week post-surgical survival groups. A nitrogen driven sagittal bone saw and an FEL generating 6.1 microm wavelength in 4.0 microsecond macropulses of 22.5 +/- 2.5 mJ/pulse directed into a 200 microm diameter spot were used to make 6.6 mm linear cuts into rabbit tibial cortex, and the healing response over time was monitored. Bone saw cuts were made halfway through the thickness of the cortex. Laser cuts were directed by a computer-controlled delivery system, and were either partial or full thickness cortical cuts. Location of the cortical bone cuts (saw or laser, partial or full thickness cut, proximal or distal, medial right or medial left tibia) were randomly assigned. At each predetermined post-surgical time point, rabbits of the appropriate group were euthanized, and the tibias of each subject collected, processed for histologic evaluation, and analyzed by light microscopy. RESULTS: At 2 weeks post-surgery, bone saw cuts showed no evidence of a healing response, while both the partial and full laser cut sites were filled with trabecular bone and primitive bone marrow. By 4 weeks post-surgery, the bone saw cuts showed filling of the defect with trabecular bone and primitive marrow, and an intense osteonal remodeling of the original cortex adjacent to the cuts was evident. All laser cut defects were filled, reactive periosteal bone was being converted to osteons and consolidating, and secondary osteons were appearing in the original cortex. At 6 weeks following surgery, the bone saw defects were filed with a mixture of woven and lamellar bone. All laser defects were filled with lamellar osteons and woven bone, the osteons were remodeling from primary to secondary osteons. By 8 weeks following the surgery, all bone saw and laser cut specimens revealed complete healing. CONCLUSIONS: Histologic evaluation of osteotomy sites made in skeletally mature rabbit tibia using the 6.1 microm wavelength, 4.0 microsecond macropulse FEL, delivered at 6 Hz at the osteotomy site, reveals a healing response which is at least as good as the healing of bone saw osteotomies, and appears to proceed at a faster rate during the first 2-4 weeks following surgery.

Detection of mild cognitive deficits in Parkinson's disease patients with the WAIS-R NI.

The relative insensitivity of traditional IQ tests to mild cognitive deficits has led investigators to develop a version of the widely used Wechsler intelligence scales that allows quantitative analysis of underlying qualitative responses. This instrument, the Wechsler Adult Intelligence Scale-Revised as a Neuropsychological Instrument (WAIS-R NI) was administered to 16 Parkinson's disease (PD) patients and 30 normal controls (NC). The 2 groups did not differ significantly in mean age or education, or on their mean Mattis Dementia Rating Scale score. Relative to NC participants, PD patients showed decreased visual attention span, longer response latencies, slower visuomotor processing, and more stimulus-bound errors. Many of the WAIS-R NI measures were able to detect cognitive impairment in a greater percentage of patients than the traditional WAIS-R measures, making it easier to identify deficits that could affect quality of life early in the course of the disease.

Three words three shapes: A clinical test of memory.

Three Words - Three Shapes was designed as an easy "bedside" test for elderly patients that assesses verbal and nonverbal memory within the same modality. In the present study, it was administered to patients with probable Alzheimer's disease (PRAD), a control group of non-demented older subjects (NC) and a group of patients with Korsakoff's amnesia (KA). Incidental recall and several other measures of learning, retention and recognition differentiated control from PRAD and KA subjects. PRAD and KA subjects' performance was similar, but there were some material-specific interactions. This test is relatively easy and some of the derived measures could prove useful in staging amnesia progression beyond the earliest stages of PRAD when more difficult tests yield floor effects.

Comparison of cortical bone ablations by using infrared laser wavelengths 2.9 to 9.2 microm.

BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the ablation of cortical bone at wavelengths across the near and midinfrared region. STUDY DESIGN/MATERIALS AND METHODS: An free electron laser generating 4-micros macropulses at specific wavelengths between 2.9 and 9.2 microm was used to ablate cortical bone. The same pulse intensity, repetition rate, radiant exposure, number of pulses, and delivery was used for each wavelength. Tissue removal, collateral thermal injury, and morphologic characteristics of the ablation sites were measured by light and scanning electron microscopy, and compared with the infrared absorption characteristics of cortical bone. RESULTS: Within the parameters used, bone ablation was found to be wavelength dependent. Incisions were deepest where protein has strong absorption, and were most shallow where mineral is a strong absorber. No char was observed on ablation surfaces where 3.0, and 5.9-6.45 microm wavelengths were used. CONCLUSIONS: The use of wavelengths in the 6.1-microm amide I to 6.45-microm amide II region, with the pulse characteristics described, were the most efficient for cutting cortical bone and produced less collateral thermal injury than cutting with a surgical bone saw. This study confirms previous observations that the ablation mechanism below plasma threshold is consistent with an explosive process driven by internal vaporization of water in a confined space and demonstrates that ablation is enhanced by using wavelengths that target the protein matrix of cortical bone.

Preclinical study in cats of the pro-photosensitizer 5-aminolevulinic acid.

OBJECTIVE: To determine whether feline cells were able to convert 5-aminolevulinic acid (ALA) to protoporphyrin IX (PpIX) in vivo and in vitro, whether i.v. administration of ALA to healthy cats resulted in adverse effects, and whether PpIX accumulated in a squamous cell carcinoma (SCC) of a cat. ANIMALS: 4 healthy adult cats and 1 adult cat with a cutaneous SCC. PROCEDURE: In vitro production of PpIX was determined by incubating Crandell feline kidney cells with ALA. Effects of ALA administration and in vivo production of PpIX were determined by administering ALA (100, 200, or 400 mg/kg of body weight) to healthy cats and collecting skin biopsy specimens for up to 24 hours after drug administration. Blood samples were collected for CBC and serum biochemical analyses, and necropsies were performed. Accumulation of PpIX in a SCC was determined by treating a cat with a facial SCC with ALA and collecting specimens of the tumor and adjacent grossly normal skin. RESULTS: Incubation of ALA with feline cells resulted in time- and dose-dependent cytoplasmic accumulation of PpIX in vitro. After i.v. ALA administration, PpIX was detected in all tissues examined, with the highest fluorescence intensity in epithelia and in squamous cell carcinoma. The tumor-to-skin fluorescence intensity ratio was 5. All cats developed hepatotoxicoses. CONCLUSIONS AND CLINICAL RELEVANCE: Results from this limited number of cats suggest that ALA may be a useful photosensitizer in cats, but that doses > 100 mg/kg, i.v., may not be safe.

Norms for letter and category fluency: demographic corrections for age, education, and ethnicity.

Letter and category fluency tasks are used to assess semantic knowledge, retrieval ability, and executive functioning. They appear to be useful in detecting different types of dementia, but accurate detection of neuropsychological impairment relies on appropriate normative data. Multiple regression analysis was used to develop demographically corrected norms for letter and category fluency in 768 normal adults. T-score equations were developed on a base subsample of 403, and crossvalidated on a separate subsample (n = 365). Participants ranged in age from 20 years to 101 years; in educational level from 0 to 20 years; 55% were Caucasian and 45% were African American. Together, age, education, and ethnicity were significant predictors of letter and category fluency performance, accounting for 15% and 25% of variance, respectively. Formulas and tables for converting raw fluency scores to demographically corrected T scores are presented.

Effective laser ablation of bone based on the absorption characteristics of water and proteins.

BACKGROUND: Collateral thermal damage and residual char formation have severely limited the use of conventional lasers in the surgical preparation of bony tissue. Thermal damage from lasers can be minimized by selecting a wavelength that is strongly absorbed and by reducing the laser pulse duration. In contrast to the fixed wavelengths and microsecond pulse intervals of conventional lasers, the Vanderbilt free electron laser (FEL) can be set at wavelengths ranging from 2.1 to 9.8 microm, and the pulse duration can be reduced to a series of 1 to 2 picosecond (ps) micropulses delivered in succession over intervals of 4 microsecond macropulses. The purpose of this study was to compare the morphologic and chemical changes induced in the near-surface region of bone following exposure to the FEL at 3.0, 6.1, and 6.45 microm wavelengths. The selected wavelengths coincide with the vibrational modes of proteins and water within bone. METHODS: Under general anesthesia, laser incisions were made in the tibias of 14 skeletally mature rabbits. Laser parameters included 22.5+/-2.5 mJ/pulse delivered in individual 4 microsecond macropulses at a repetition rate of 30 Hz, focused to 200 microm and 500 microm spot sizes. Laser incisions were made using a computer-assisted surgical program, and control incisions were created with a bone saw. Rabbits were euthanized after the final incision, tibias recovered, and non-decalcified specimens processed for light microscopy. Separate samples were prepared for FTIR (Fourier transform infrared) photoacoustic spectroscopic analysis. RESULTS: The light microscopy sections of the ablation defects created at the differing wavelengths showed similar features, i.e., 2 zones of collateral damage, a zone generally < 10 mm of extensive thermal damage, and a wider zone of empty lacunae. In comparing treated and untreated surfaces, the spectral differences were limited to a relative decrease in intensity of the amide II and III absorption peaks in all laser-treated surfaces. CONCLUSIONS: Spectroscopic and histologic results indicated minimal thermal damage to bone ablated at 3.0, 6.1, and 6.45 microm wavelengths using the FEL (Fourier transform infrared) at the specified parameters. The FTIR photoacoustic spectroscopic results suggest that the char layer is limited to an area less than approximately 6 microm from the surface.

Clinical preconditions and treatment modality: effects on pulp surgery outcome.

BACKGROUND: The purpose of this research was to evaluate the factors affecting the outcome of localized laser pulp surgery in the canine model. STUDY DESIGN/MATERIALS AND METHODS: Pulpal exposures 2 mm and 5 mm in diameter were prepared in eight healthy teeth in each of five dogs. The total of 40 teeth were left open to infection from the oral cavity for 3 hours or 72 hours; 2-3 mm of surface pulpal tissue were then removed using a fresh diamond bur or a CO2 laser emitting@9.3 microns, at 3.5 W average power in the Superpulse mode. Teeth were monitored clinically and radiographically by one blinded, pre-standardized clinician for 3 months. RESULTS: Chi-square test and Fisher's Exact test (2-tail) results associated laser treatment with significantly better clinical and radiographic outcome (P < 0.001). Using regression analysis, duration of pulpal exposure to contamination by the oral environment was identified as primary determinant for treatment outcome within the laser-treated and control groups (P = 0.0018). CONCLUSION: Clinical preconditions significantly affect the outcome of pulp surgery treatments.

Suspected ehrlichial infection in five cats from a household.

Ehrlichiosis is a poorly recognized condition of cats that may be associated with anemia, leukopenia, thrombocytopenia, or dysproteinemia. Affected cats may have indirect fluorescent antibody titers to Ehrlichia canis and E risticii. We reviewed the clinical evaluation and response to treatment of 5 cats in a household where ehrlichial disease was suspected as the cause of recurrent leukopenias and thrombocytopenias. All of the cats had E risticii indirect fluorescent antibody titers and western blot confirmation of antibodies to 4 of the 9 major antigens of E risticii. Response to doxycycline was monitored serologically and hematologically in each cat, and indicated that administration of doxycycline at a dosage of 10 mg/kg of body weight, PO, every 12 hours, for a minimum of 21 days is necessary for treatment of this condition.

CO2 laser treatment of traumatic pulpal exposures in dogs.

BACKGROUND AND OBJECTIVE: Successful non-devitalizing treatment of localized pulpal lesions in mature teeth is not ensured using conventional endodontic techniques. The objective of this study was to evaluate CO2 laser surgical treatment of pulpal exposures in canine patients. STUDY DESIGN/MATERIALS AND METHODS: 17 permanent teeth with pulpal exposures of < or = 48 h duration received localized laser pulp surgery. Laser Parameters: pulse duration: 0.01 s, pulse interval: 1.0 s, spot size: 0.004 cm2, fluence: 276 J/cm2. Exposures were dressed with CaOH and Glass ionomer. Clinical and radiographic evaluations were performed by one blinded clinician 24 and 52 weeks after treatment. RESULTS: 15/17 laser-treated teeth assessed over > or = 1 year post-treatment remained clinically and radiographically healthy. CONCLUSION: These results demonstrate the feasibility of using the CO2 laser for localized pulp surgery. Further studies must optimize laser parameters and identify the range of clinical pathologies which can be treated using this modality.

Photodynamic therapy in veterinary medicine: current status and implications for applications in human disease.

The historical development and published veterinary applications of photodynamic therapy are reviewed. Potential animal models, using naturally-occurring diseases in veterinary patients, for the future development of photodynamic therapy are described.

Neuropsychological assessment of severely demeted elderly: the severe cognitive impairment profile.

BACKGROUND: Although the assessment of cognitive functioning in the late stages of Alzheimer's Disease (AD) is important for identifying abilities that may improve communication and interactions with severely impaired patients in clinical and institutional settings and for assessing the efficacy of pharmacologic agents and behavioral interventions for the treatment of AD, few adequate instruments exist for measuring the cognitive capacities of these severely demented individuals. OBJECTIVES: To evaluate the reliability and validity of the Severe Cognitive Impairment Profile (SCIP), a measure of neuropsychological functioning in severely demented patients, and compare it with other available instruments. DESIGN AND METHODS: We administered the Mattis Dementia Rating Scale (DRS), Mini-Mental State Examination (MMSE), SCIP, and Severe Impairment Battery (SIB) to 41 severely demented patients with AD participating in an AD research center. We used (1) Spearman rank correlation coefficients to assess interrater and test-retest reliability and construct validity of the SCIP; (2) one-way analysis of variance with post hoc comparisons to examine performance on the SCIP and the SIB at different levels of dementia severity; and (3) descriptive statistics to establish the sensitivity of the SCIP to cognitive functioning in a subgroup of very severely demented patients. RESULTS: Interrater and test-retest reliability correlation coefficients were highly significant for total SCIP score (r=0.99 and r=0.96, respectively) as well as for all SCIP subscales. High correlations were also found between SCIP scores and two widely used tests of global cognitive functioning, the DRS (r=0.91) and the MMSE (r=0.84), suggesting good construct validity. The SCIP was able to significantly differentiate between four groups of severely impaired patients divided by level of dementia severity, while the SIB was unable to differentiate between the less severely demented groups. A subgroup of 16 very severely demented patients (DRS score, <50 points) obtained an average of 45% of total possible points on the SCIP, compared with an average of 1% and 21% of total possible points on the MMSE and DRS, respectively. After approximately 1 year of decline, 12 severely demented patients with AD were able to correctly answer an average of more than 58% of the items on the SCIP, compared with only 30% on the DRS and 20% on the MMSE. CONCLUSIONS: The SCIP is a reliable, valid measure of neuropsychological functioning in severely demented patients with AD with the ability to avoid both floor and ceiling effects and to evaluate a wider range of cognitive abilities than other tests used with severely impaired individuals.

Multifactor behavioral treatment of chronic sleep-onset insomnia using stimulus control and the relaxation response. A preliminary study.

Sleep latency changes following behavioral interventions for sleep-onset insomnia are only moderate because the majority of insomniacs do not achieve good sleeper status at posttreatment. This study evaluated the efficacy of a multifactor behavior intervention consisting of stimulus control and relaxation-response training (n = 10) compared to stimulus control alone (n = 10) for sleep-onset insomnia. Only the multifactor subjects' mean posttest sleep latency fell within the good sleeper range. They also exhibited a 77% improvement on mean sleep-onset latency compared to the stimulus control group (63%). Thus a multifactor intervention may be more effective than stimulus control alone for treatment of sleep-onset insomnia.