Rapid cognitive decline: not always Creutzfeldt-Jakob disease.

A patient with rapidly progressive cognitive decline over an approximately four month period was suspected to have sporadic Creutzfeldt-Jakob disease. Features thought to support this diagnosis included psychiatric symptoms (anxiety and depression), visual hallucinations and a visual field defect. However, the finding of papilloedema broadened the differential diagnosis. Although standard brain imaging and electroencephalography had shown only non-specific abnormalities, subsequent cerebral angiography disclosed an intracranial dural arteriovenous fistula. Following embolisation, the patient made a good functional recovery. Intracranial dural arteriovenous fistula merits consideration in any patient with subacute cognitive decline, and should be included in the differential diagnosis of sporadic Creutzfeldt-Jakob disease.

Regional variation in survival before and after pediatric heart transplantation--an analysis of the UNOS database.

Geographic variation occurs in a variety of health outcomes. Regional influences on outcomes before and after listing for pediatric heart transplantation have not been assessed. Review of the UNOS dataset identified 5398 pediatric (≤ 18 years) patients listed for heart transplantation 2000-2011. Patients were stratified based on the region of listing. Regional-level variables were correlated with individual risk-adjusted outcomes. Mean time spent on the waitlist varied from 91.0 ± 163 days (Region 6 [R6]) to 248.1 ± 493 days (R4, p < 0.0001). Regions with more transplant centers (p < 0.0001) and fewer transplants (p = 0.0015) had higher waitlist mortality. Risk-adjusted individual waitlist mortality varied from 6.9% (R1, CI 6.2-7.8) to 19.2% (R5, CI 18.0-20.6). Waitlist mortality was higher for individuals awaiting transplant in regions with more listings per center (OR 1.04, CI 1.01-1.08) and lower in regions with more donors per center (OR 0.95, CI 0.90-0.99 per donor). Posttransplant risk-adjusted survival varied across regions (R4: 5.4%, CI 4.2-7.4; R7: 18.0%, CI 12.4-32.5), but regional variables were not correlated with outcomes. Outcomes among children undergoing heart transplantation vary by region. Factors leading to increased competition for donor allografts are associated with poorer waitlist survival. Equitable allocation of cardiac allografts requires further investigation of these findings.

Lobar atrophy in frontotemporal dementia: diagnostic and prognostic implications.

We review the practical importance of lobar atrophy in frontotemporal dementia (FTD), for diagnosis and prognosis. We discuss specific patterns of frontotemporal atrophy that denote clinical and pathological subtypes of FTD (e.g. semantic dementia). We also discuss the unsatisfactory clinical experience of interpreting MRI scans in individual FTD cases, especially the behavioural presentations (without aphasic or motor impairments). This issue is explored by examining the FTD phenocopy concept. Lobar atrophy emerges as a key observation in defining behavioural FTD patients whose symptoms are likely to progress. In a situation where objective clinical data are few, we highlight the importance of applying caution before diagnosing FTD is the absence of visible brain atrophy.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

A 5-year follow-up study of an atypical case of myotonic dystrophy.

This study presents 5-year follow-up data on NG, a woman with adult onset myotonic dystrophy and progressive cognitive decline who was first described by Wilson et al. The extent of the cognitive impairment is atypical of symptom-onset in adulthood and of paternal inheritance, both of which apply to this case. Together, the present and earlier studies report the results of regular neuropsychological assessments over a 16-year period. Severe impairment in executive functioning, episodic and semantic memory were apparent early in the history, while visuospatial skills and working memory were only mildly impaired after 16 years of follow-up. There was also a progressive dyslexia, initially characterized by the regularization errors typical of surface dyslexia, but subsequently dominated by visual/phonological reading errors. This pattern of impairment is not typical of myotonic dystrophy but resembles semantic dementia. Whilst the deficits may be attributable wholly to myotonic dystrophy pathology, the co-existence of a form of semantic dementia is also possible. It is noted that the aggregation of tau protein is a neuropathological feature common to both diseases.

The human perirhinal cortex and semantic memory.

Studies in macaque monkeys indicate that the perirhinal cortex in the temporal lobe participates in object memory. This function may be analogous to aspects of human semantic memory (knowledge of objects, concepts, faces and words). To date, the status of perirhinal cortex has not specifically been investigated in patients with semantic deficits as seen in semantic dementia, the temporal lobe variant of frontotemporal dementia. High-resolution three-dimensional magnetic resonance imaging was performed in subjects with semantic dementia and Alzheimer's disease (characterized in its early stages by selective episodic memory impairment) and in healthy age-matched controls. Hippocampal, perirhinal, temporopolar and entorhinal cortex volumes were measured by outlining areas on successive scan slices according to recognized landmarks. The entorhinal and hippocampal regions were further subdivided into anterior and posterior parts. In keeping with the hypothesized contribution of the perirhinal cortex to semantic memory function, we found greater involvement of this region, together with the temporopolar and anterior entorhinal cortices, in semantic dementia than in either Alzheimer's disease patients or control subjects. Performance on a range of semantic tests also correlated with perirhinal volume. Bilateral reduction in hippocampal volume compared with controls was seen in Alzheimer's disease. In conclusion, atrophy of the human perirhinal cortex, and of directly connected areas, was associated with semantic memory impairment but not episodic memory impairment, as predicted from the primate work.

Modelling of the radiated field from multi-element capacitive micromachined ultrasonic transducers.

This paper presents results from a theoretical model of the ultrasonic fields radiated by a 3x3 assembly of capacitive micromachined ultrasonic transducer (cMUT) sources on the same silicon substrate. These predictions have, for the first time, been compared directly to the fields measured experimentally using a scanned miniature detector. This work indicates that there is minimal cross-coupling between source elements, and demonstrates that it is possible to predict successfully the field characteristics of various geometries of such cMUT elements, with a view to the development of future imaging systems.

Stroke in surgery of the thoracic aorta: incidence, impact, etiology, and prevention.

OBJECTIVES: To determine the incidence, impact, etiology, and methods for prevention of stroke after surgery of the thoracic aorta. METHODS: A total of 317 thoracic aortic operations on 303 patients (194 male, 109 female) aged 13 to 87 years (mean 61 years) were reviewed. There were 218 procedures on the ascending aorta and arch and 99 on the descending aorta. Of the 218 procedures on the ascending aorta and arch, 86 involved cardiopulmonary bypass, 122 involved deep hypothermic circulatory arrest, 2 involved antegrade cerebral perfusion, and 8 involved "clamp and sew" or left heart bypass. Of the 99 procedures on the descending aorta, 20 involved "clamp and sew," 69 involved left heart or full bypass, and 10 involved deep hypothermic circulatory arrest. A total of 206 cases were elective and 97 were emergency operations. RESULTS: Twenty-three (7.3%) of 317 patients had a stroke. Fifteen strokes occurred in operations on the ascending aorta and 8 in operations on the descending aorta (6.9% vs 8.1%; P =.703). Stroke occurred in 16 (16.5%) of 97 emergency operations and 7 (3.4%) of 206 elective operations (P =.001). In the 300 patients surviving the operation, stroke was a significant predictor of postoperative death (9/23 [39.1%] vs 23/277 [8.3%]; P =.001). Analysis of operative reports, brain images, and neurologic consultations revealed 15 of the 23 strokes were embolic, 3 were ischemic, 3 hemorrhagic, and 2 indeterminate. Patients with stroke had longer intensive care unit stays (18.4 vs 6.8 days; P =.0001), longer times to extubation (12.7 vs 3.8 days; P <.0012), longer postoperative stays (31.4 vs 14.3 days; P =.001), and decreased age-adjusted survival (relative risk 2.775; P =.0013). After implementation of a rigorous antiembolic regimen, both strokes and mortality trended downward. CONCLUSIONS: (1) Stroke complicates surgery of both the ascending and descending thoracic aorta and warrants consideration in decision making. (2) Strokes are largely embolic. (3) Antiembolic measures for particles and air are essential, including gentle aortic manipulation, thorough debridement, transesophageal echocardiography to identify aortic atheromas, carbon dioxide flooding of the field, and (in descending cases) proximal clamp application before initiating femoral perfusion.

Familial patterns of thoracic aortic aneurysms.

HYPOTHESIS: To provide evidence that genetic factors contribute to the development of thoracic aortic aneurysms (TAA) by demonstrating familial patterns of the disease. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS AND METHODS: We sought to identify familial patterns of TAA from a database of 598 patients evaluated or treated for TAA at the Yale Center for Thoracic Aortic Disease, New Haven, Conn, from January 1985 to August 1998. Of the 598 patients, 45 patients had a diagnosis of Marfan syndrome and 553 patients had no known history of any collagen vascular disorder. Of the 553 patients in the latter category, 398 patients had confirmed TAA, 66 had TAA with concomitant aortic dissections, and 89 had aortic dissections. From the group of 464 patients with TAA with or without concomitant aortic dissections, 2 interviewers attempted to contact 150 randomly selected patients for telephone screening to determine the presence of familial patterns of aortic disease. Fifteen of these patients were lost to follow-up. Complete medical and family histories of the remaining 135 patients (85 men, 50 women) were reviewed. Of the 135 individuals screened, 26 (18 men, 8 women) (19.3%) were found to belong to multiplex pedigrees. These 26 patients with familial nonsyndromic TAA were compared with the remaining 109 patients with sporadic TAA and the 45 patients with Marfan syndrome-associated TAA. MAIN OUTCOME MEASURES: Groups were examined for statistical differences in age and aortic size at the time of diagnosis, growth rates of TAA, and rates of concomitant diseases. Nonsyndromic family pedigrees were analyzed and potential modes of inheritance were determined. RESULTS: The mean age at presentation for patients with familial nonsyndromic TAA (56.8 years) was significantly younger than the mean age of presentation in sporadic cases (64.3 years, P< or =.03), and significantly older than that of patients with Marfan syndrome (24.8 years, P< or =.001). Patients with a family history of aortic aneurysms had faster growth rates (0.22 cm/y) compared with patients with sporadic TAA (0.03 cm/y) (P< or =.001) and patients with Marfan syndrome (0.10 cm/y) (P< or =.04). Familial nonsyndromic TAA in patients with a concomitant aortic dissection had a growth rate of 0.33 cm/y, which was greater than that of patients with sporadic TAA (0.10 cm/y) and patients with Marfan syndrome (0.08 cm/y) with associated aortic dissection. This growth of 0.33 cm/y was significantly faster than the overall growth rate estimate of aneurysms in patients with aortic dissection (0.14 cm/y) (P< or =.05). Ten pedigrees (38.5%) showed direct father to son transmission, consistent with an autosomal dominant mode of inheritance. Six family pedigrees (23.1%) suggested an autosomal dominant or X-linked mode of inheritance. Seven pedigrees (26.9%) suggested a recessive mode of inheritance; 2 an autosomal recessive mode, and 5 an X-linked recessive or autosomal recessive mode. The remaining 3 pedigrees displayed more complex modes of inheritance. CONCLUSIONS: This study supports the role of genetic factors influencing familial aggregation of TAA. Thoracic aortic aneurysms in association with multiplex pedigrees represent a new risk factor for aneurysm growth. Pedigree analysis suggests genetic heterogeneity. The primary mode of inheritance seems to be autosomal dominant, but X-linked dominant and recessive modes are also evident.

Artificial metalloenzymes based on protein cavities: exploring the effect of altering the metal ligand attachment position by site directed mutagenesis.

In an effort to construct catalysts with enzyme-like properties, we are employing a small, cavity-containing protein as a scaffold for the attachment of catalytic groups. In earlier work we demonstrated that a phenanthroline ligand could be introduced into the cavity of the protein ALBP and used to catalyze ester hydrolysis. To examine the effect of positioning the phenanthroline catalyst at different locations within the protein cavity, three new constructs--Phen60, Phen72 and Phen104--were prepared. Each new conjugate was characterized by UV/vis spectroscopy, fluorescence spectroscopy, guanidine hydrochloride denaturation, gel filtration chromatography, and CD spectroscopy to confirm the preparation of the desired construct. Analysis of reactions containing Ala-OiPr showed that Phen60 catalyzed ester hydrolysis with less selectivity than ALBP-Phen while Phen72 promoted this same reaction with higher selectivity. Reactions with Tyr-OMe were catalyzed with higher selectivity by Phen60 and more rapidly by Phen104. These results demonstrate that both the rates and selectivities of hydrolysis reactions catalyzed by these constructs are dependent on the precise site of attachment of the metal ligand within the protein cavity.

Structural characterization of two synthetic catalysts based on adipocyte lipid-binding protein.

Adipocyte lipid-binding protein (ALBP) is a small (14.5 kDa) 10-stranded beta-barrel protein found in mammalian fat cells. The crystal structures of various holo-forms of ALBP have been solved and show the fatty acid ligand bound in a large (approximately 400 A3) cavity isolated from bulk solvent. Examination of the cavity suggests that it would be a good site for the creation of an artificial catalyst, as numerous well defined crystal structures of ALBP are available and past studies have shown the conformation to be reasonably tolerant to modification and mutagenesis. Previous work has shown ALBP to be a good protein scaffold for exploring enantio- and stereoselective reactions; two constructs, ALBP attached to either a pyridoxamine or a phenanthroline group at C117, have been chemically characterized. Both modified proteins have been crystallized and their structures solved and refined. The X-ray models have been used to examine the origin of the chiral selectivity seen in the products. It is apparent that these covalent adducts reduce the internal cavity volume, sterically limiting substrate interactions with the reactive groups, as well as solvent access to potential intermediates in the reaction pathway.

Prediction of vocational outcome based on clinical and demographic indicators among vocationally ready clients.

This study examined the clinical and demographic correlates of work skills and vocational outcome for persons with psychiatric disabilities. The same clinical, demographic, work skills, and vocational outcome instruments were administered to 275 persons working toward their vocational goals at three psychosocial rehabilitation centers. Data regarding vocational outcomes were collected quarterly over a period of 3 1/4 years. Using multivariate statistical techniques, clinical and demographic variables that predict work skills and future vocational outcomes were identified. The implications of the findings for program administrators, system planners, and researchers are discussed.

Relationships between psychiatric symptomatology, work skills, and future vocational performance.

OBJECTIVE: Experts do not agree on what, if any, relationships exist between diagnosis, symptomatology, work skills, and the future vocational performance of persons with severe mental illness. The objective of this study was to longitudinally examine such relationships, using a sample of clients who were attending psychosocial rehabilitation programs. METHODS: Subjects were 275 clients of three psychosocial rehabilitation programs who had expressed a vocational goal. They were assessed at intake into the study and then quarterly until they left the rehabilitation program. The variables examined included symptoms, measured by the Brief Psychiatric Rating Scale; diagnosis; work skills, measured by the Griffiths Work Behavior Scale; and vocational status at end-point. RESULTS: Among subjects remaining in the study for one year, both symptomatology and work skills improved significantly. Moderately significant negative correlations were found between symptoms and work skills; subjects who became employed had lower symptom scores and higher work skills than persons who never became employed. CONCLUSIONS: Although a moderate relationship was found between symptomatology and work skills, symptoms should not be considered a proxy measure for vocational functioning among persons with severe mental illness. Participation in psychosocial rehabilitation programs appeared to have a salutary effect on symptoms and work skills.

Intracerebral haemorrhage due to amphetamine abuse: report of two cases with underlying arteriovenous malformations.

Amphetamine abuse may be complicated by intracerebral, subdural or subarachnoid haemorrhage. The causative mechanism is probably a combination of vasculitis and induced hypertension. Most cases of intracerebral haemorrhage are subcortical. Only one case of amphetamine-induced intracerebral haematoma where there was also an underlying arteriovenous malformation has been previously reported. We report two cases of intracerebral haematoma due to amphetamine abuse where an underlying AVM was found at the time of surgery. This possibility should be considered in cases of amphetamine-induced intracerebral haemorrhage.

Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis.

OBJECTIVE: Recent studies have suggested that patients receiving thyroxine are at increased risk of osteoporosis. We set out to measure bone mineral densities in two groups of post-menopausal women receiving thyroxine replacement therapy (those with serum TSH levels persistently suppressed or non-suppressed) and to compare the results in both groups with those of the local control population. DESIGN: Cross-sectional study. PATIENTS: Seventy-eight post-menopausal women who had been treated with thyroxine for primary autoimmune or idiopathic hypothyroidism for a minimum of 5 years, 44 with TSH persistently suppressed and 34 non-suppressed. One hundred and two control subjects. MEASUREMENTS: Forearm bone mineral density at proximal and distal sites as measured by single-photon absorptiometry. RESULTS: Results were expressed as Z-scores, i.e. number of standard deviations from the mean of a 5-year age-band from the local control population. Mean Z-scores at proximal and distal sites for the non-suppressed patients were -0.03 and -0.07 and for the suppressed patients were -0.20 and -0.25, representing a decrease in bone mineral density of at most 5% in the suppressed patients. The differences between the three groups were not statistically significant. CONCLUSION: In this patient population, the reduction in bone mineral density due to thyroxine is small. It is unlikely to be of clinical significance and should not on its own be an indication for reduction of thyroxine dose in patients who are clinically euthyroid.