Pathological drivers of neurodegeneration in suspected non-Alzheimer's disease pathophysiology.

BACKGROUND: Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of ß-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in ß-amyloid-negative subjects. METHODS: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. ß-amyloid status (A+/A-) was determined by CERAD score and neurodegeneration status (N+/N-) by hippocampal volume. RESULTS: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A-N+) had significantly more neuropathological diagnoses than A+N+. In the A- group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. CONCLUSION: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of ß-amyloid was supported.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Modifiable vascular risk factors, white matter disease and cognition in early Parkinson's disease.

BACKGROUND AND PURPOSE: Dementia in Parkinson's disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors (VRFs) may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of VRFs on PD are needed. To that end, we aimed to quantitate white matter hyperintensities (WMH) in early PD, measure associations with VRFs and examine relationships between WMH and longitudinal cognition. METHODS: Participants in the Parkinson's Progression Markers Initiative study (141 patients with PD, 63 healthy controls) with adequate baseline structural brain magnetic resonance imaging data were included. Hypertension and diabetes history, and body mass index were combined to create a vascular risk score. WMH were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery. RESULTS: In the PD group, vascular risk score was associated with WMH for total brain (ß = 0.210; P = 0.021), total white matter (ß = 0.214; P = 0.013), frontal (ß = 0.220; P = 0.002) and temporal (ß = 0.212; P = 0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (ß = -0.040; P = 0.007) and greater WMH (ß = -0.029; P = 0.049). Higher temporal WMH burden was associated with great decline over time in verbal memory (ß = -0.034; P = 0.031). CONCLUSIONS: In early PD, modifiable VRFs are associated with WMH on brain magnetic resonance imaging. Temporal WMH burden predicts decline in verbal memory. WMH may serve as a surrogate marker for the effect of VRFs on cognitive abilities in PD.

Distortion product otoacoustic emissions in geriatric dogs.

Recordings of distortion product otoacoustic emissions (DPOAE) were taken from 28 geriatric dogs aged 12.2 ± 2.2 years and 15 control dogs aged 5.9 ± 3.0 years (mean ± standard deviation) to demonstrate frequency-specific changes in cochlear responses. Recordings were performed for primary frequencies of 2-12 kHz in 2 kHz increments. Brainstem auditory evoked response (BAER) recordings were also made from geriatric dogs for comparison with DPOAE responses. Significant decreases in DPOAE response amplitudes were observed at frequencies of 6-12 kHz in geriatric dogs compared to control dogs, reflecting loss of cochlear outer hair cells along the length of the cochlea. Significant decreases in response amplitudes were not seen at frequencies of 2 or 4 kHz. Decreases in BAER response amplitudes subjectively paralleled the depressed DPOAE amplitudes. No significant linear regression relationships were found for DPOAE response amplitude vs. age despite the progressive nature of age-related hearing loss. The reductions in response at all frequencies starting at the age where dogs are considered geriatric indicate that age-related hearing loss begins earlier in the life span. DPOAE recordings provide a means to assess cochlear function across different portions of the auditory spectrum for assessing hearing loss associated with aging, and potentially for losses from other causes of decreased auditory function.

Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats.

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

3D photography is as accurate as digital planimetry tracing in determining burn wound area.

BACKGROUND: In the paediatric population careful attention needs to be made concerning techniques utilised for wound assessment to minimise discomfort and stress to the child. AIM: To investigate whether 3D photography is a valid measure of burn wound area in children compared to the current clinical gold standard method of digital planimetry using Visitrak™. METHOD: Twenty-five children presenting to the Stuart Pegg Paediatric Burn Centre for burn dressing change following acute burn injury were included in the study. Burn wound area measurement was undertaken using both digital planimetry (Visitrak™ system) and 3D camera analysis. Inter-rater reliability of the 3D camera software was determined by three investigators independently assessing the burn wound area. RESULTS: A comparison of wound area was assessed using intraclass correlation co-efficients (ICC) which demonstrated excellent agreement 0.994 (CI 0.986, 0.997). Inter-rater reliability measured using ICC 0.989 (95% CI 0.979, 0.995) demonstrated excellent inter-rater reliability. Time taken to map the wound was significantly quicker using the camera at bedside compared to Visitrak™ 14.68 (7.00)s versus 36.84 (23.51)s (p<0.001). In contrast, analysing wound area was significantly quicker using the Visitrak™ tablet compared to Dermapix(®) software for the 3D Images 31.36 (19.67)s versus 179.48 (56.86)s (p<0.001). CONCLUSION: This study demonstrates that images taken with the 3D LifeViz™ camera and assessed with Dermapix(®) software is a reliable method for wound area assessment in the acute paediatric burn setting.

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration.

OBJECTIVE: To evaluate the distribution of white matter (WM) disease in frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) and to evaluate the relative usefulness of WM and gray matter (GM) for distinguishing these conditions in vivo. METHODS: Patients were classified as having FTLD (n = 50) or AD (n = 42) using autopsy-validated CSF values of total-tau:ß-amyloid (t-tau:Aß(1-42)) ratios. Patients underwent WM diffusion tensor imaging (DTI) and volumetric MRI of GM. We employed tract-specific analyses of WM fractional anisotropy (FA) and whole-brain GM density analyses. Individual patient classification was performed using receiver operator characteristic (ROC) curves with FA, GM, and a combination of the 2 modalities. RESULTS: Regional FA and GM were significantly reduced in FTLD and AD relative to healthy seniors. Direct comparisons revealed significantly reduced FA in the corpus callosum in FTLD relative to AD. GM analyses revealed reductions in anterior temporal cortex for FTLD relative to AD, and in posterior cingulate and precuneus for AD relative to FTLD. ROC curves revealed that a multimodal combination of WM and GM provide optimal classification (area under the curve = 0.938), with 87% sensitivity and 83% specificity. CONCLUSIONS: FTLD and AD have significant WM and GM defects. A combination of DTI and volumetric MRI modalities provides a quantitative method for distinguishing FTLD and AD in vivo.

Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia.

OBJECTIVE: Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are hypothesized to cause clinically distinct forms of primary progressive aphasia (PPA) that predominantly affect expressive speech. AD is thought to cause logopenic progressive aphasia (LPA), and FTLD may cause progressive nonfluent aphasia (PNFA). We sought to determine the value of clinical characterization, neuropsychological analysis, and MRI atrophy in predicting pathology of LPA and PNFA. METHODS: Patients with LPA (n = 19) and patients with PNFA (n = 19) were evaluated with neuropsychological assessments, structural MRI, CSF analysis, and neuropathologic examination. RESULTS: Twelve of 19 patients with LPA (63%) and 6 of 19 patients with PNFA (32%) had neuropathologic findings or CSF biomarkers consistent with AD. Neuropsychological testing showed that naming was more impaired in patients with AD, and letter-guided fluency was more affected in patients with a non-AD disorder. Voxel-based morphometry analysis revealed that in patients with AD, patients with LPA and PNFA had significant posterior-superior temporal atrophy; in patients with non-AD, patients with LPA had peri-Sylvian atrophy and patients with PNFA had dorsolateral prefrontal and insular atrophy. Receiver operator characteristic curve analysis showed that combining neuropsychological testing with MRI atrophy pattern had 90% specificity for pathology or CSF biomarkers consistent with AD, and combining clinical features with neuropsychological analysis had 100% sensitivity for pathology or CSF biomarkers consistent with AD. CONCLUSIONS: Neither PPA phenotyping nor imaging alone is a reliable predictor of pathology. Multimodal predictors, such as combining neuropsychological testing with MRI analysis, can improve noninvasive prediction of underlying pathology in nonfluent forms of PPA.

Why are patients with progressive nonfluent aphasia nonfluent?

OBJECTIVE: To investigate the cognitive and neural basis for nonfluent speech in progressive nonfluent aphasia (PNFA). BACKGROUND: Nonfluent speech is the hallmark feature of PNFA, and this has been attributed to impairments in syntactic processing, motor-speech planning, and executive functioning that also occur in these patients. Patients with PNFA have left inferior frontal atrophy. METHODS: A large semi-structured speech sample and neuropsychological measures of language and executive functioning were examined in 16 patients with PNFA, 12 patients with behavioral-variant frontotemporal dementia (bvFTD), and 13 age-matched controls. Speech fluency was quantified as words per minute (WPM) in the semi-structured speech sample. Stepwise linear regression analyses were used to relate WPM to grammatic, motor-speech planning, and executive aspects of patient functioning. These measures were then related to cortical thickness in 8 patients with PNFA and 7 patients with bvFTD using structural MRI. RESULTS: WPM was significantly reduced in patients with PNFA relative to controls and patients with bvFTD. Regression analyses revealed that only grammatic measures predicted WPM in PNFA, whereas executive measures were the only significant predictor of WPM in bvFTD. Cortical thinning was significant in PNFA relative to controls in left inferior frontal and anterior-superior temporal regions, and a regression analysis related this area to reduced WPM in PNFA. Significant cortical thinning associated with limited grammatic processing also was seen in the left inferior frontal-superior temporal region in PNFA, and this overlapped with the area of frontal-temporal thinning related to reduced WPM. CONCLUSION: Nonfluent speech in PNFA may be due in part to difficulty with grammatic processing associated with left inferior frontal and anterior-superior temporal disease.

Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration.

OBJECTIVE: To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD). METHODS: Letter ("FAS") and semantic ("animal") fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10). RESULTS: Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy. CONCLUSIONS: Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.

Long-term results of a prospective trial of mantle irradiation alone for early-stage Hodgkin's disease.

BACKGROUND: To determine the long-term treatment outcome and late effects of mantle irradiation alone in selected patients with early-stage Hodgkin's disease. METHODS: Between 1988 and 2000, 87 patients with pathologic stage (Ann Arbor) I-IIA or clinical stage IA Hodgkin's disease were entered on to a prospective trial of mantle irradiation alone. Patients with B symptoms, large mediastinal adenopathy, or subcarinal or hilar involvement were excluded. The median doses to the mantle field and mediastinum were 36 Gy (range 30.3-40) and 38.6 Gy (range 30.6-44), respectively. The actuarial freedom from treatment failure (FFTF) and overall survival (OS) rates were calculated using the Kaplan-Meier technique. RESULTS: The median follow-up was 107 months (range 23-192). Thirteen of 87 patients (15%) relapsed at a median of 30 months (range 5-62). The 5- and 10-year actuarial FFTF rates were 86% and 84.7%, respectively. All 13 patients who relapsed are alive without evidence of disease at a median of 84 months (range 30-156) post-salvage therapy. Five patients developed a second malignancy at a median of 93 months (range 27-131). The 10-year actuarial risk of a second malignancy was 4.5%. There have been two deaths to date, both due to second malignancies. The 10-year OS rate was 98.2%. CONCLUSION: In selected patients with early-stage Hodgkin's disease, mantle irradiation alone has an excellent long-term survival rate, comparing favorably with the previous standard treatment of extended-field radiation therapy and the current standard of combined modality therapy.

Inherited myopathy of great Danes.

A hereditary, non-inflammatory myopathy occurring in young great Danes with distinctive histological features in muscle biopsy specimens is reviewed. Onset of clinical signs is usually before one year of age and both sexes are affected. Clinical signs are characterised by exercise intolerance, muscle wasting, and an exercise-induced tremor. Although most affected dogs have a severe form of the disease, occasional dogs may have a less pronounced form and survive into adulthood with an acceptable quality of life. Litters containing affected puppies are born to clinically unaffected parents, and an autosomal recessive pattern of inheritance is likely. All recorded cases have had fawn or brindle coat coloration. Elevated serum creatinine kinase concentrations and spontaneous electrical activity in skeletal muscles are frequently found. While originally reported (Targett and others 1994) as a central core myopathy in this breed, the histochemical characteristics of the distinct cytoarchitectural structures differ from those of the well-characterised central core myopathy in human beings. In fact, these structures differ from any known myopathy in human beings and likely represents a unique non-inflammatory myopathy affecting dogs. Until this myopathy is characterised further, the name inherited myopathy in great Danes is suggested.

Dissociation of numbers and objects in corticobasal degeneration and semantic dementia.

BACKGROUND: Semantic memory is thought to consist of category-specific representations of knowledge that may be selectively compromised in patients with neurodegenerative diseases, but this has been difficult to demonstrate reliably across object categories. METHODS: The authors evaluated performance on several simple measures requiring number representations (including addition and magnitude judgments of single digits), and on a task that requires object representations (an object naming task) in patients with corticobasal degeneration (CBD; n = 13) and semantic dementia (SD; n = 15). They also examined regional cortical atrophy using voxel-based morphometric analyses of high resolution structural MRI in subgroups of five CBD patients and three SD patients. RESULTS: CBD patients were consistently more impaired on simple addition and magnitude judgment tasks requiring number representations compared to object representations. Impaired performance with numbers in CBD was associated with cortical atrophy in right parietal cortex. By comparison, SD patients demonstrated a greater impairment on a naming task requiring object representations relative to their performance on measures involving number representations. This was associated with left anterior temporal cortical atrophy. CONCLUSION: The cognitive and neuroanatomic dissociations between CBD and SD are consistent with the hypothesis that number and object representations constitute distinct domains in semantic memory, and these domains appear to be associated with distinct neural substrates.

Design of new questionnaires to measure quality of life and treatment satisfaction in hypothyroidism.

INTRODUCTION: This paper reports work undertaken to design two new condition-specific questionnaires for use in hypothyroidism: the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) and the Underactive Thyroid Treatment Satisfaction Questionnaire (ThyTSQ). METHODS: Semistructured interviews exploring quality of life (QoL) and experiences of treatment were conducted with 30 women and 8 men with hypothyroidism, (mean age, 51.9; range, 29-79 years), 37 of 38 treated with thyroxine, recruited from hospital clinics and primary care. RESULTS: Despite thyroxine treatment, most interviewees reported negative impact of hypothyroidism on QoL, particularly on energy, physical capabilities, motivation, physical appearance, and weight. The newly designed ThyDQoL has 18 domains covering these and other aspects of life affected by hypothyroidism. It is an individualized measure of patients' perceived impact of hypothyroidism on their QOL, which takes into account the importance of personally applicable life domains to the patient. A 7-item measure of satisfaction with current treatment was designed (ThyTSQ-Present) but interviews also indicated the need for a separate 4-item section measuring satisfaction with past treatment around the time of diagnosis (ThyTSQPast). CONCLUSIONS: The ThyDQoL and ThyTSQ questionnaires have good face validity and content validity for adults with hypothyroidism. They are now ready for use in clinical research and psychometric evaluation.

Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency.

OBJECTIVE: Growth hormone (GH) is known to be required for physical well-being. Although it is also widely believed to be important for quality of life (QoL) and psychological health, there is less supportive evidence. The objective of this study was to investigate the psychological effects of discontinuation of GH replacement from adults with severe GH deficiency (GHD). DESIGN: A double-blind, placebo-controlled trial in which GH replacement therapy was discontinued for 3 months from 12 of 21 GH-deficient adults, where nine continued with GH replacement. PATIENTS: GH-treated adults (10 men, 11 women), all with severe GHD (peak GH < 7.7 mU/l on provocative testing), mean age 44.9 years (range 25-68 years). MEASUREMENTS: Semi-structured interviews were given at baseline and end-point plus questionnaires that included a new hormone-deficiency specific, individualized, QoL questionnaire (HDQoL), the General Well-being Index (GWBI), the Well-being Questionnaire (W-BQ12), the Short-Form 36 health status questionnaire (SF-36), the Nottingham Health Profile (NHP) and the General Health Questionnaire (GHQ). RESULTS: Three months after baseline the serum total IGF-I of placebo-treated patients fell from normal, age-related levels (mean 26.6 +/- 13.2 nmol/l) to levels indicative of severe GHD (11.6 +/- 6.6 nmol/l) (P<0.001). Psychological symptoms of GH withdrawal, reported in interviews at end-point by placebo-treated patients, included decreased energy, and increased tiredness, pain, irritability and depression. Patients who believed they knew which treatment they had received correctly identified the treatment (GH or placebo) at end-point (chi2=11.25, P<0.01). Significant between-treatment-group differences in change scores were found for SF-36 General Health (P<0.01), W-BQ12 Energy (P<0.01) and HDQoL do physically (P<0.05), indicating reduced general health, reduced energy and greater perceived impact of hormone deficiency on physical capabilities in the placebo-treated group at end-point relative to GH-treated patients. CONCLUSION: Withdrawal of GH treatment from adults with severe GH deficiency has detrimental psychological effects.

Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults.

GH is an important regulator of fat metabolism at rest, but it is not known whether it regulates fat metabolism during exercise. To determine whether physiologic concentrations of GH influence fat metabolism during exercise, we randomized 16 GH-deficient adults, receiving long-term (mean duration, 5 yr) GH replacement, to either continue GH (n = 8) or receive identical placebo (n = 8) for a 3-month period. Metabolic studies, at rest, during and following exhaustive exercise were carried out at baseline and at the end of the 3 months. The rate of appearance of glycerol (glycerol Ra, an index of lipolysis) and free fatty acids (FFA, FFA Ra) and the rate of disappearance of FFA (FFA Rd) in the plasma were measured using infusions of (2)H(5)-glycerol and 1-(13)C-palmitic acid. Changes in body composition were assessed using dual-energy x-ray absorptiometry scanning and anthropometric measurements. In the baseline studies, exercise resulted in an increase in plasma glycerol and FFA concentrations, glycerol Ra, FFA Ra, and FFA Rd (P < 0.001). Three months of GH withdrawal resulted in reductions in plasma glycerol and FFA, glycerol Ra, FFA Ra, and FFA Rd at rest (P < 0.05 vs. baseline) and during exercise (P < 0.05 vs. baseline and vs. GH treated). Lean body mass decreased after 3 months of GH withdrawal, but total body fat, trunk fat, waist circumference, and the sum of skinfold thicknesses increased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). Fasting insulin and homeostasis model assessment of insulin resistance decreased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). In summary, GH withdrawal for 3 months resulted in reductions in release of glycerol and FFA into the circulation and uptake of FFA into the tissues during intense exercise. These changes were accompanied by reduced lean body mass and increased total body and trunk fat. Further studies are required to determine whether reduced mobilization of fat during exercise contributes to reduced exercise capacity and increased body fat in GH-deficient adults.

Evaluation of two health status measures in adults with growth hormone deficiency.

OBJECTIVE: To evaluate the psychometric properties of two health status measures for adults with growth hormone deficiency (GHD): Nottingham Health Profile (NHP) and Short-Form Health Survey (SF-36). DESIGN: (1) A cross-sectional survey of adults with treated or untreated GHD to assess reliability and validity of the questionnaires. (2) A randomized, placebo-controlled study of 3 months' GH withdrawal from GH-treated adults to assess the sensitivity of the questionnaires to change. PATIENTS: (1) A cross-sectional survey of 157 patients with severe GHD (peak GH < 10 mU/l on provocative testing), mean age 48.9 years (range 23-70 years), who had either received GH replacement therapy for at least 6 months immediately prior to the study or had not received GH treatment in the previous 6 months. (2) GH treatment was withdrawn from 12 of 21 GH-treated adults, all with severe GHD (peak GH < 7.7 mU/l on provocative testing), mean age 44.9 years (range 25-68 years). MEASUREMENTS: The NHP and SF-36 were used once in the cross-sectional survey, but twice in the GH-withdrawal study, at baseline and end-point (after 3 months). RESULTS: (1) Cross-sectional survey. Both questionnaires had high internal consistency reliability with subscale Cronbach's alphas of > 0.73 (NHP) and > 0.78 (SF-36). Calculation of an NHP Total Score, occasionally reported in the literature, was shown to be inadvisable. Overall, patients with GHD were found to have significantly worse perceived functioning than the UK general population in SF-36 subscales of General Health, Bodily Pain, Social Functioning, Physical Functioning, Role-Emotional, Role-Physical, and Vitality. Although neither questionnaire found significant differences between GH-treated and non-GH-treated patients, there were correlations with duration of GH treatment (P < 0.01) for GH-treated patients in SF-36 Mental Health (r = 0.29, N = 87) and SF-36 Vitality (r = 0.33, N = 88), indicating improvement with increasing treatment duration. The SF-36 was also more sensitive than the NHP to sex differences: men had significantly better health status compared with women (P < 0.05) in all SF-36 subscales but Mental Health, but only in one NHP subscale (Physical Mobility). (2) GH-withdrawal study. Significant between-group differences in change were found in SF-36 General Health [t(17) = 2.76, P = 0.013, two-tailed] and SF-36 Mental Health [t(17) = 2.41, P = 0.027, two-tailed]: patients withdrawn from GH reported reduced general health and mental health at end-point. The NHP found no significant change. CONCLUSIONS: The SF-36 is a better measure than the NHP of health status of people with GH deficiency because of its greater discriminatory power, with ability to detect lesser degrees of disability. It also has superior sensitivity to some subgroup differences and superior sensitivity to change compared with the NHP. The SF-36 is highly acceptable to respondents, and has very good internal consistency reliability. The SF-36 is recommended to measure the health status of adults with GH deficiency.

Utilization of health care services by patients with chronic obstructive pulmonary disease.

In order to identify healthcare resource use patterns associated with chronic obstructive pulmonary disease (COPD), resource utilization (RU) data collection was integrated into a randomized, double-blind placebo-controlled study of Viozan (sibenadet HCl). This study enrolled patients with symptomatic, smoking-related COPD, randomized to receive sibenadet or placebo for a 52-week treatment period. A questionnaire establishing typical pre-trial, COPD-related RU was completed by each patient. Subsequent data were collected by means of an Interactive Voice Response System (IVRS) at 30-day intervals (14 time points) during the study and in the follow-up period. The IVRS system facilitated data collection and minimized inconvenience to the patient. Compliance with the requirement to record details of the healthcare services during the year-long study was high. No overall trend for lower RU was associated with sibenadet therapy, which correlates with the lack of sustained clinical effect seen in studies conducted concurrently. These data do, however, provide valuable information on RU associated with COPD and insights into adjustments associated with changes in disease course. Physicians were seen to be the most common source of care for patients with COPD and more of the patients with severe COPD (stage III) than mild (stage I) were seen to utilize the most expensive resources (e.g. inpatient hospital care). For those patients who experienced an exacerbation during the trial (irrespective of treatment group), resource use was increased during the periods when an exacerbation was reported when compared with the periods before or after an exacerbation. The proportion of cases attending the physician doubled and with a trip to the Emergency Room (ER) increased approximately ninefold during the reporting period in which the exacerbation occurred compared with the previous month. This study has shown that use of an IVRS, even in elderly patients, is an effective means of gathering RU data over long periods. The study findings suggest that the advent of effective therapeutic interventions, particularly any with the ability to minimize exacerbations and limit disease progression, could impact on the health care services used and potentially reduce associated costs.

Pulmonary edema associated with child abuse: case reports and review of the literature.

Pulmonary edema has been an unreported finding in the evaluation of abused children. We describe 2 cases of pulmonary edema in abused infants, 1 after confessed suffocation and the other after inflicted head injury. A review of the literature regarding postobstructive and neurogenic pulmonary edema suggests useful inferences for the forensic evaluation of maltreated children who present with this finding.