Memory complaints and increased rates of brain atrophy: risk factors for mild cognitive impairment and Alzheimer's disease.

AIM: To determine rates of cerebral atrophy in individuals with symptoms of memory loss but no objective cognitive impairment (SNCI) and their association with future cognitive decline. METHODS: Thirty-two SNCI subjects, 16 with mild cognitive impairment (MCI) and 27 control subjects had clinical assessment and magnetic resonance imaging at baseline and 1 year later. Rates of whole brain atrophy (WBA), hippocampal atrophy (HA) and ventricular enlargement (VE) were measured. Our outcome was clinical diagnosis at 2 years after entry into the study. RESULTS: The MCI group had greater rates of WBA, HA and VE than both controls and SNCI subjects. As a group SNCI subjects did not have significantly greater rates of atrophy than the controls. However, SNCI subjects who progressed to MCI or dementia had increased rates of atrophy compared with those who remained stable. DISCUSSION: Individuals with memory complaints but no objective memory deficits, who progress to MCI or dementia, have increased rates of cerebral atrophy.

A comparison of methods for the automated calculation of volumes and atrophy rates in the hippocampus.

Hippocampal atrophy rates have been used in a number of studies in Alzheimer's disease (AD) to assess disease progression and are being increasingly utilized as an outcome measure in clinical trials of new pharmaceutical agents. Owing to the labor-intensive nature of hippocampal segmentation, more automated approaches are required for such analysis. In this study we compared methods of automatically segmenting the hippocampus (single-person template and template library) on the baseline image in a group of probable AD (n=36) and control (n=19) subjects with serial images. Using the method that gave most similar results to manual, three automated methods of calculating change within the hippocampal region were compared: fluid change calculated using (1) Jacobian change or (2) region propagation and (3) boundary shift. Rates were compared with manual measures. We found that segmentation of baseline hippocampus was most accurate using a template library combined with morphological operations (intensity thresholding plus one conditional dilation). This gave a voxel similarity of 0.69 (0.05) and 0.72 (0.06) in controls and probable AD subjects respectively compared with manual measures. Atrophy rates within these regions were most similar to the manual rates using the boundary shift integral (mean difference from manual rate 0.03% (1.29) in controls and 0.48% (2.44) in AD). A template library segmentation approach, together with morphological operations, provides a segmentation accurate enough to quantify relative change over time. The change over time can then be calculated automatically using boundary shift or fluid measures, with boundary shift giving most similar results to manual.

Automatic calculation of hippocampal atrophy rates using a hippocampal template and the boundary shift integral.

We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR images without manual delineation of hippocampi. This method was applied to a group of Alzheimer's disease (AD) (n=36) and control (n=19) subjects and compared with manual methods (manual segmentation of baseline and repeat-image hippocampi) and semi-automated methods (manual segmentation of baseline hippocampi only). In controls, mean (S.D.) atrophy rates for manual, semi-automated, and automated methods were 18.1 (53.5), 15.3 (50.2) and 11.3 (50.4) mm3 loss per year, respectively. In AD patients these rates were 174.6 (106.5) 159.4 (101.2) and 172.1 (123.1) mm3 loss per year, respectively. The automated method was a significant predictor of disease (p=0.001) and gave similar group discrimination compared with both semi-automated and manual methods. The automated hippocampal analysis in this small study took approximately 20 min per hippocampal pair on a 3.4 GHz Intel Xeon server, whereas manual delineation of each hippocampal pair took approximately 90 min of operator-intensive labour. This method may be useful diagnostically or in studies where analysis of many scans may be required.

Improved reliability of hippocampal atrophy rate measurement in mild cognitive impairment using fluid registration.

MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval+/-SD: 2.01+/-0.11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean+/-SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2.13+/-1.62; right: 2.36+/-1.78 and for regional fluid registration: forward: left: 2.39+/-1.68; right: 2.49+/-1.52 and backward: left: 2.21+/-1.51; right: 2.42+/-1.49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0.99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0.798; right: 0.850) compared with regional fluid registration (forward: left: 0.985; right: 0.988 and backward: left: 0.975; right: 0.989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.

Combining short interval MRI in Alzheimer's disease: Implications for therapeutic trials.

Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.99(2) + (0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by approximately 56%, equating to a approximately 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

Interpolation artefacts in non-rigid registration.

Voxel based non-rigid registration of images involves finding a similarity maximising transformation that deforms a source image to the coordinate system of a target image. In order to do this, interpolation is required to estimate the source intensity values corresponding to transformed target voxels. These interpolated source intensities are used when calculating the similarity measure being optimised. In this work, we compare the extent and nature of artefactual displacements produced by voxel based non-rigid registration techniques for different interpolators and investigate their relationship to image noise and global transformation error. A per-voxel similarity gradient is calculated and the resulting vector field is used to characterise registration artefacts for each interpolator. Finally, we show that the resulting registration artefacts can generate spurious volume changes for image pairs with no expected volume change.

Design, development and performance of a novel multidose dry-powder inhaler.

The authors describe the design and development of a breath-actuated multidose dry-powder inhaler and summarize the in vitro and in vivo data demonstrating its robustness and performance in the laboratory and during clinical use. Drugs for the treatment of asthma--including budesonide, beclomethasone dipropionate and salbutamol--when formulated with lactose powder as a carrier and dispensed via this device, have exhibited clinical efficacy and safety profiles comparable with standard pressurized metered-dose inhalers and dry-powder formulations.

An ab initio approach to the understanding of cytochrome P450-ligand interactions.

1. We describe the application of novel ab initio quantum mechanical methods to the study of ligand interactions with cytochrome P450cam (CYP101). 2. We find that our techniques accurately describe the transition from a low-spin state to a high-spin state of the haem Fe3+ on binding of a substrate. Furthermore, our methods correctly predict that a large fraction of low-spin character is retained on binding of an inhibitor. 3. We demonstrate the use of 'computational experiments' to elucidate key features of the mechanism of interaction. This leads us to identify a new mechanism for the suppression of the low- to high-spin transition on binding of an inhibitor, namely the shortening of the bond between the Fe atom and the coordinated S atom of the cysteine axial ligand.

Design of lifting gear for a plastination laboratory.

Conventional lifting gear based on steel components can be safely used in a laboratory where acetone is used provided that: (a) the circumstances under which significant amounts of acetone vapour will be present are known and can be controlled and (b) operating practices are imposed to prevent the use of the lifting gear at times when acetone vapour may be present in explosive concentrations.

Ab initio molecular modeling in the study of drug metabolism.

We discuss the use of ab initio quantum mechanical methods in drug metabolism studies. These methods require only the positions and atomic numbers of the atoms to be specified and offer greater transferability than conventional molecular modeling techniques. This fact, coupled with the accuracy of our approach, permits 'computational experiments' to be performed, allowing details of reaction mechanisms to be understood. We review the application of these methods to the cytochrome P450 superfamily of enzymes. There is much interest in understanding the mechanisms of these enzymes due to their participation in a wide range of metabolic processes including drug activation/deactivation. We find that our methods accurately reproduce the low- to high-spin transition of the haem Fe on binding of a substrate. Furthermore, we identify a new mechanism for the suppression of this spin transition, namely the shortening of the bond between the Fe atom and the coordinated S atom of the cysteine axial ligand. These results indicate that ab initio molecular modeling may be usefully applied in the study of drug metabolism and that further study of intermediate states in the P450 reaction cycle would be beneficial, particularly those which are not accessible using conventional experimental approaches.

Nasogastric and nasoenteric intubation.

Among the most commonly performed nonvascular procedures in hospitalized patients are the placement of nasogastric tubes and nasoenteric feeding tubes. Large-bore nasogastric tubes are commonly used for both diagnostic and therapeutic purposes; small-bore nasoenteric tubes are used primarily for intestinal feeding. The techniques of insertion, methods of ensuring proper positioning, and the potential complications of these devices are similar, and thus they are reviewed together in this article.

Respiratory failure and death following acute inhalation of mercury vapor. A clinical and histologic perspective.

A family of four was exposed to toxic levels of mercury vapor while attempting to extract silver from mercury amalgam. All four suffered respiratory failure and subsequent death despite chelation therapy with dimercaprol. Histologic findings at autopsy were similar in all four cases demonstrating a progression of acute lung injury that appeared related to postexposure day survival. There were no clinical signs of extrapulmonary manifestations despite toxic serum mercury levels. Although serum mercury levels decreased in response to the mercury chelating agent dimercaprol, serum levels remained in the toxic range and no clinical response was observed. Acute inhalational exposure to high concentrations of mercury vapor causes pneumonitis that can lead to respiratory failure and death. This continues to be a health hazard in both the workplace and the home environment.

Pulmonary edema in renal transplant patients.

A syndrome heralded by fever, deterioration of graft function, respiratory failure accompanied by pulmonary infiltrates has been termed "transplant lung." We hemodynamically studied eight such patients. At the height of their illness, pulmonary artery wedge pressure (PAWP) was elevated to 19.3 +/- 2.6 mm Hg along with mean pulmonary artery pressure (PAP) of 35.0 +/- 3.8 mm Hg in presence of increased cardiac index (CI) of 4.9 +/- 0.9 L.m2.min. Pathophysiology of pulmonary edema appears to include high left ventricular filling pressures, pulmonary hypertension, alterations of oncotic hydrostatic gradient, and increased cardiac output. A partial reversal of pulmonary hypertension was observed with dialysis or diuresis. Our data suggest incipient renal failure and fluid accumulation as the etiology of hemodynamic pulmonary edema in "transplant lung."

Absent right superior vena cava.

A patient is presented in whom pulmonary artery catheter insertion fortutiously demonstrated persistent left superior vena cava on two separate occasions. Further studies with venogram and a first pass nuclear scan demonstrated total absence of the right superior vena cava. Although this anomaly is commonly associated with intracardiac defects and rhythm disturbances only the latter was seen in our patient. Invasive hemodynamic monitoring is frequently performed in the majority of modern intensive care units. The bedside technique used for insertion of a Swan-Ganz catheter using only pressure monitoring for advancing the catheter has relatively few complications. One such complication is misplacement along an anomalous route where the catheter may take to the heart. We have recently treated a patient on two separate occasions who had a persistent left superior vena cava with absent right superior vena cava.

Haemodynamic effects of prenalterol in patients with coronary heart disease.

The haemodynamic effects of prenalterol, a new selective beta-1 adrenoreceptor agonist, have been studied in patients with coronary heart disease. The drug was administered intravenously in a dosage of 0.5 to 2.5 micrograms/kg body weight to 20 patients undergoing coronary angiography and to 10 patients with a recent myocardial infarction, who had clinical evidence of left ventricular dysfunction. Left ventricular performance was enhanced in both groups of patients--left ventricular dP/dt (max) increased by 33 per cent and the systolic time intervals, pre-ejection period, and the ratio of pre-ejection period and left ventricular ejection shortened by 28 and 21 per cent, respectively. Cardiac output and stroke volume increased with no change in heart rate nor in left ventricular filling pressure. These results indicate that prenalterol enhances the contractile state of the myocardium without altering heart rate, and suggest that prenalterol could be of value in the management of patients with coronary heart disease, who have impaired left ventricular function.

New antiarrhythmic agents. 1. Primary alpha-amino anilides.

Thirty-two alpha-amino anilides with various substituents in the aromatic ring and in the alpha position are described. Their abilities to protect mice against chloroform-induced fibrillation and to elicit toxicity were determined. Substitution of an alkyl or aryl group in the alpha position enhanced the antifibrillatory activity. In most cases, increased potency was accompanied by increased toxicity. Eleven compounds were tested in dogs with surgically induced myocardial infarction; most showed antiarrhythmic activity. 2-Aminopropiono-2',6'-xylidide, tocainide, was chosen for clinical investigation.

Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine.

The tolerance and pharmacokinetic properties of mepivacaine and prilocaine were compared following i.v. infusion of 250 mg (0.88 and 0.97 mmol respectively) of each drug in five healthy volunteers. Side-effects were minor and occurred in only two subjects during the infusion of mepivacaine. Plasma concentrations of mepivacaine were greater in each subject than the corresponding values for prilocaine. The elimination half-life of mepivacaine was generally longer than that for prilocaine, whereas the total body clearance of prilocaine was consistently greater than the corresponding value for mepivacaine. For each subject the clearance of prilocaine substantially exceeded normal heptic blood flow and therefore an extra-hepatic site of metabolism of prilocaine has been postulated.

Cardiovascular effects of prenalterol (H133/22) in normal man.

1 Prenalterol, (S-(-)-1-(4 hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride) a cardio-selective beta-adrenergic receptor agonist, was infused intravenously into six normal male volunteers to determine the cardiovascular effects of this drug. 2 On different occasions, each volunteer received a placebo infusion, an infusion of 0.5 mg prenalterol and an infusion of 1 mg prenalterol. Cardiac output (impedance cardiography), arterial pressure (sphygmomanometry), heart rate and ECG were measured throughout. 3 Prenalterol produced a statistically significant increase in cardiac output and at the end of the infusion this increase was 24% with 0.5 mg and 29% with 1 mg, mainly due to an increase in stroke volume (18% and 17%) with a lesser change in heart rate (+2 and +7 beats/min). Pulse pressure increased but mean arterial pressure showed little change. Peripheral resistance fell by 18% and 20%. As indicated by systolic time indices myocardial contractility increased. 4 Prenalterol at plasma concentrations in excess of 20 nmol l-1 produced significant inotropic effects but did not markedly increase heart rate at concentrations of 60 nmol l-1.