Alzheimer's disease. In search of the soluble.
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Biomedical subjects
Publications and source records attributed to J Hardy.
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Twenty patients (aged 50 +/- 21 years and mean left ventricular ejection fraction 37 +/- 17%) with recurrent ventricular arrhythmias were treated with an investigational, implantable combined antitachycardia-pacing cardioverter defibrillator. The device's telemetry capabilities include both stored (1-second snapshots) and real-time display of endocardial and device-circuit signals. The device can store these before, during and after up to 50 tachycardia and antitachycardia pacing episodes. All stored events are indexed to a 24-hour internal clock. During 10.1 +/- 5.1 months of follow-up, the device was used in 11 of 20 patients. In the entire group, antitachycardia pacing was activated on 44 +/- 14 occasions per patient (total 874) and shock delivery occurred on 8 +/- 14 occasions per patient (total 156). Reconstruction by stored telemetry of all device-therapy episodes was possible. Twenty-six percent of all shocks delivered were not appropriate and were due to atrial arrhythmias in 2 patients and dysfunction of the sensing lead in 3. The absence of a relation between symptoms and appropriate shock delivery was documented in 1 patient. Antitachycardia pace acceleration occurred in 5.3% of cases; 7% of attempts at pacing were unsuccessful and needed shock therapy. It is concluded that the enhanced telemetry available in newer antitachycardia devices enables more accurate assessment of device use and enhances diagnosis of inappropriate therapy delivery.
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Pharyngeal or esophageal trauma was diagnosed in 9 horses after nasogastric intubation. Evidence of trauma (edema or ulceration) was detected in the pharynx of 3 horses and in the esophagus of 6 horses. Complications associated with nasogastric intubation were first observed in 5 horses while they were intubated and in 4 horses after extubation. Clinical signs of pharyngeal or esophageal trauma were similar, and included salivation, bruxism, coughing, and nasal discharge. Treatment, including extubation, enteral feeding through a small nasogastric tube, or esophagostomy distal to the affected site, was attempted in 6 horses. Three of 6 treated horses survived, but 4 of 5 horses with perforated esophagus were euthanatized.
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The brain of a 61-year-old patient with familial Alzheimer's disease, showing a missense (valine----glycine) mutation at codon 717 of the amyloid precursor gene, has been examined at postmortem. Sections of brain showed pathological features entirely typical of Alzheimer's disease with no unusual characteristics. It seems therefore that this particular mutation is indeed pathogenic and that the altered amyloid precursor protein resulting from expression of this mutation is processed in a way that triggers or promotes the pathological cascade of Alzheimer's disease.
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A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.
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The molecular mechanisms of the cytopathology of Alzheimer's disease are very rapidly being elucidated. However, the factors that restrict the effects of this disease to specific neuroanatomical systems are less well understood. In this brief article a possible hypothesis is outlined to explain this apparent specific localization.
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Although mutations in the beta-amyloid precursor protein gene (APP) on chromosome 21 cause some cases of early-onset Alzheimer's disease (AD), most cases evidently do not have mutations in APP. We analysed ten early-onset families for linkage to APP and markers elsewhere in the genome. One family (F172) was consistent with linkage to chromosome 21 and was subsequently found to have an APP Val to Ile mutation. Of the others, all but one were consistent with linkage to markers in the middle long arm of chromosome 14. However, no family showed independent evidence of linkage with two point analysis and only one showed independent evidence of linkage on multipoint analysis. Therefore, we cannot rule out heterogeneity at these loci although tests for heterogeneity were not significant.
A large family with autosomal dominant segregation of presenile dementia, and other neurological and behavioural features is described. At various times, family members have carried diagnoses of Alzheimer's disease, Huntington's disease, Parkinson's disease, myoclonic epilepsy, atypical dementia, Pick's disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Molecular genetic studies have enabled classification of this disease at the molecular level as one of the group of inherited prion diseases. Here we describe the phenotype of inherited prion disease (PrP 144 bp insertion).
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Following the identification of mutations in the beta-amyloid precursor protein (APP) gene in familial, early onset Alzheimer's disease (AD), we have developed a screening protocol using single strand conformation analysis (SSCA) to screen exon 17 for the known mutations within APP. In addition, we used this protocol to screen the other seventeen exons of APP and a three hundred and thirty base pair regulatory region of the promoter for new mutations in 9 families with early onset AD. Exons 16 and 17, which encode the deposited beta-amyloid peptide, were screened in a further 10 families. Our screening procedure identifies all the reported mutations within APP. While we have identified a further family with APP717 Val-->Ile, we did not find any previously undescribed mutations. Screening of other exons of APP in 2 families in which we have previously reported mutations at APP717, failed to reveal other sequence abnormalities supporting the hypothesis that the mutations at APP717 cause the disease in these families. These data suggest that mutations in APP are a rare cause of familial early onset AD (3/21 families tested) and that within APP most, possibly all, mutations which cause AD are in exon 17.
Chronic constrictive pericarditis was diagnosed in a 6-year-old Thoroughbred mare based on the clinical findings of right congestive heart failure, hyperechoic pericardium without pericardial effusion, and a dip-and-plateau shape of the right ventricular pressure curve with equilibration of the diastolic pressures in all cardiac chambers. Treatment was attempted by partial pericardiectomy using a right lateral thoracotomy approach. Because of severe epicardial involvement recurrence of the constrictive pathology was noted 6 weeks after the surgical procedure. However, in selected cases in which the disease process is limited to the pericardium, partial pericardiectomy may offer a mode of therapy in horses suffering from constrictive pericarditis.
Little is known about delivery of aerosolised steroids to neonatal patients undergoing assisted positive pressure ventilation and after extubation. A rabbit model has been established to investigate factors influencing drug delivery. Beclomethasone dipropionate, in a metered dose inhaler, was radiolabelled with technetium 99m. The mass median aerodynamic diameter of the aerosol was 3.3 (2.0) microns and the impactor measurements confirmed that the technetium distribution corresponded with that of the drug particles. The metered dose inhaler was actuated into a collapsible spacer that was used to ventilate and deliver aerosol to anaesthetised rabbits by a tracheostomy. From each actuation of the drug 2.9 (0.4)% of the aerosol deposited in the trachea and main bronchi and 1.2 (0.4)% in the lung. When the drug was delivered by a spacer device, with face-mask attachment, to rabbits breathing freely through a tracheostomy, aerosol deposition increased to 4.4 (2.1)% in the trachea and main bronchi and 1.9 (0.9)% in the lung lobes. The maximum change in systolic blood pressure after administration of aerosol by the collapsible spacer was a decrease of 13%. The methods described may prove useful for the delivery of inhaled steroids to neonatal patients likely to develop bronchopulmonary dysplasia.
The results of the treatment of tuberculosis have been evaluated among 407 patients distributed into 268 cases of pulmonary tuberculosis with positive smears (TP+), 70 pulmonary forms with negative smears (TP-) and 69 cases of extrapulmonary tuberculosis (TEP). A group 1 of 361 patients including new cases and late relapses and consisting of 236 TP+, 59 TP- and 66 TEP has been put through the treatment pattern: 2S6H7T7 + 10H7T7 or 2S6H7 + 10S2H2. Group 2, of 21 patients consisting of failures, early relapses and previously but irregularly treated cases, was given a pattern: 2R7E7H7Z7 + 10R2H2. In group 3, 25 new cases were given a short treatment: 2R7E7H7Z7 + 4R7H7. In group 1 we have recorded 68.42% cured patients, 8.59% failures and 14.40% neglects of treatment. The remaining 8.59% include deceased, transfers and patients put through extended treatment. The rate of cure was better among TEP patients (95.46%) than among TP- patients (79.66%) and TP+ patients (58.05%); failures were proved to be more frequent among TP+ patients (11.88%) than among TP- patients (3.39%) and TEP patients (1.51%). In group 2 and 3 successes have amounted to 95.24% and 84% respectively. Considering rates of cure, irregular treatments, neglects and failures with standard patterns (group 1), it appears to be desirable that rifampicin-including short patterns are added to antitubercular therapeutic strategies of developing countries.