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J Hardy

Publications and source records attributed to J Hardy.

At least 271 records · Page 15Linked to original sources
PubMed1994

Insertion of a pathogenic mutation into a yeast artificial chromosome containing the human amyloid precursor protein gene.

The genetic modelling of human disease would be considerably facilitated if pathogenic mutations could be inserted into transgenes which were then expressed in an appropriate manner. Yeast artificial chromosomes (YACs), when used as transgenes appear to direct expression with the correct temporal and spatial distribution. Here we demonstrate that it is comparatively straightforward to introduce pathogenic mutations into such YACs by the use of the 'pop-in, pop-out' procedure, by inserting an Alzheimer-causing mutation (APP717Val-->lle) into an APP-containing YAC which has previously been used as a transgene. The significance of these procedures for the modelling of human disease is discussed.

Alzheimer Disease↗
PubMed1994

Effect of phenylephrine on hemodynamics and splenic dimensions in horses.

Pharmacologically induced splenic contraction might be useful during certain medical or surgical procedures in horses. The effects of phenylephrine, an alpha 1-adrenergic receptor agonist, on hemodynamic function and splenic dimensions were examined in 6 healthy adult horses. Phenylephrine infusion (1, 3, or 6 micrograms/kg of body weight/min for 15 minutes) resulted in a dose-related increase in mean pulmonary artery pressure; right atrial pressure; systolic, mean, and diastolic arterial pressures; and packed cell volume (P = 0.0001). Concurrent decreases in heart rate and specific cardiac output (P = 0.0001) were detected, but stroke volume did not vary significantly. The rate-pressure product was increased only at the highest phenylephrine dosage (P = 0.012). Bradycardia was observed at all dosages during drug infusion, and second-degree atrioventricular block was detected in 88% of horses during infusion. Phenylephrine administration caused dose-dependent splenic contraction, as detected by ultrasonographic measurements of splenic area and thickness (P = 0.0001). At the 3- and 6-micrograms/kg/min infusion rates, splenic area was reduced to 28 and 17% of baseline measurement, respectively. Splenic dimensions had returned to baseline values by 35 minutes after the end of infusion. Infusion of phenylephrine at a dosage of 3 micrograms/kg/min for 15 minutes can be used to induce splenic contraction in horses.

Animals↗
PubMed1994

Alzheimer's disease. Clinical molecular genetics.

The study of the genetics of AD has shown that at least three loci are involved in causing the disease: (1) the APP gene, in which a series of mutations cause the disease to develop in 50- to 60-year-old patients; (2) the ApoE gene in which genetic variability (the E4 allele) is a predisposing factor for the development of late-onset disease; and (3) an as-yet-unidentified chromosome 14 locus that causes the onset of AD before 50 years of age. These genetic findings point to a single process: fibrillar beta-amyloid deposition as central to the pathogenesis of the disease. These genetic findings are already being used as an aid to the diagnosis of AD, and it is likely that their use in this regard will increase. The need for the genetic education of primary care physicians and the general public is of great importance so that informed debate about appropriate use of genetic data for diagnosis of AD can take place.

Alzheimer Disease↗
PubMed1993

Alzheimer's disease: molecular genetics and transgenic animal models.

Disease-causing mutations in the amyloid precursor protein (APP) gene have been found on chromosome 21 during the last 2 years in some early onset Alzheimer's disease (AD) families. Genetic evidence shows that other genes than the APP are also involved in the aetiology of AD. Linkage to a loci on chromosome 14 has been found in early onset disease. The identification of APP mutation has led to the realization that APP mismetabolism is a central event in the aetiology and pathogenesis of the disease. Experiments to test this in transgenic mice have so far met with little success. There are many possible explanations for the problems to generate transgenic mice. These include the possibilities that mice are incapable of developing AD for reasons dependent on their APP sequence; and that appropriate regulation of APP gene is required for pathology to develop. Current attempts that seem promising to model the disease pathology are the use of homologous recombination to insert the pathogenic mutation and transfection of YACs into transgenic animals.

Aged↗
PubMed1993

"Prion dementia".

Explore the source record for details and available documents.

Dementia↗
PubMed1993

A novel silent variant at codon 711 and a variant at codon 708 of the APP sequence detected in Spanish Alzheimer and control cases.

Pathogenic mutations have been identified in exons 16 and 17 of the beta-amyloid precursor protein (APP) gene in some cases of early onset Alzheimer's disease. Screening of these exons in a number of familial and sporadic cases of Alzheimer's disease in Spain, resulted in the identification of a novel silent variant at codon 711 whose relevance to the AD pathogenesis remains unclear. The 708 variant was also detected in one of normal controls.

Alzheimer Disease↗
PubMed1993

Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene reveals the beta-amyloid sequence to be normal in cases of the parkinson dementia complex of Guam.

Exons 16 and 17 of the beta-amyloid precursor protein gene has been sequenced in individuals with the amyotropic lateral sclerosis/Parkinson's dementia complex of Guam to test the hypothesis that this disease is an allelic variant of Alzheimer's disease and to test whether sequence differences within beta-amyloid in this population contributes to the non-deposition of this peptide in the disorder. The sequence was normal.

Aged↗
PubMed1993

Randomized controlled comparison of antitachycardia pacing algorithms for termination of ventricular tachycardia.

OBJECTIVES: This study compared the efficacy and safety of two antitachycardia pacing algorithms in the treatment of ventricular tachycardia. BACKGROUND: There is agreement that antitachycardia pacing should be adapted to tachycardia rate and be delivered in a burst, but the ideal pacing pattern is not well understood. Effective antitachycardia pacing burst patterns include those with a between-burst decrement (SCAN) with or without an additional within-burst decrement (RAMP). METHODS: Prospective randomized crossover comparison of two antitachycardia pacing algorithms (RAMP vs. SCAN) on identical induced sustained ventricular tachycardias was performed. RESULTS: Sixty-five ventricular tachycardias (mean cycle length 364 +/- 74 ms) from 37 invasive studies performed in 29 patients were studied; 86% of patients had coronary artery disease and 72% were receiving antiarrhythmic therapy at the time of study. Of the 65 tachycardias, 40 were identical pairs and 25 were unpaired (including 8 with a > 30-ms difference in cycle length of induced ventricular tachycardia pairs). In the paired pacing trials, conversion to sinus rhythm occurred, respectively, in 85% of SCAN versus 90% of RAMP protocols (p = 0.63, power = 93%) and within 1.4 +/- 0.7 versus 1.7 +/- 1.1 attempts (p = 0.41). Discordance for pacing success was seen in three pairs. In unpaired trials, conversion to sinus rhythm occurred in 73% and 57%, respectively (p = 0.68, power = 88%). Tachycardia acceleration during pacing occurred in 7 (11%) of 65 attempts (5 SCAN, 2 RAMP). Acceleration in unpaired ventricular tachycardia trials was correlated with tachycardia cycle length. Failure to convert ventricular tachycardia was associated with a shorter tachycardia cycle length (p < 0.05). CONCLUSIONS: In the patients studied, adaptive antitachycardia pacing was safe and effective and, when successful, occurred within three attempts of an 8-beat adaptive burst algorithm. Changes in burst pattern did not affect pacing safety or efficacy. Antitachycardia pacing success was dependent on induced ventricular tachycardia cycle length.

Aged↗
PubMed1993

Sotalol and type IA drugs in combination prevent recurrence of sustained ventricular tachycardia.

OBJECTIVES: This study assessed the efficacy of the combination of sotalol and either quinidine or procainamide in preventing sustained ventricular tachycardia inducibility and recurrence and prospectively evaluated the ability of the drug combination to prevent ventricular tachycardia recurrence when the arrhythmia remained inducible but was modified. BACKGROUND: Individual antiarrhythmic drugs are often ineffective in preventing the induction and recurrence of sustained ventricular tachycardia. Beta-adrenergic blockade and prolongation of refractoriness may be important components of successful antiarrhythmic therapy in patients with ventricular tachycardia. We reasoned that the combination of sotalol, which has beta-adrenergic blocking properties and prolonged ventricular refractoriness, and quinidine or procainamide, two agents that slow conduction and prolong refractory periods, would be effective therapy in such patients. METHODS: We administered low dose sotalol (205 +/- 84 mg/day) plus quinidine sulfate (1,278 +/- 479 mg/day) or procainamide (2,393 +/- 1,423 mg/day) to 50 patients with spontaneous sustained ventricular tachycardia or fibrillation and inducible ventricular tachycardia. RESULTS: In 21 (46%) of 46 patients, ventricular tachycardia was rendered noninducible at electrophysiologic study (group I), and in 17 patients (37%), inducible tachycardia was modified according to prospectively identified criteria (group II), for a combined 83% response rate. Ventricular refractory periods increased from 252 +/- 24 to 316 +/- 28 ms and from 265 +/- 33 to 316 +/- 24 ms in groups I and II, respectively (p < 0.001), but from 234 +/- 19 to only 286 +/- 13 ms in the group of patients with unmodified ventricular tachycardia inducibility (n = 8, group III, p < 0.001). Cycle length of induced ventricular tachycardia slowed from 324 +/- 62 to 432 +/- 70 ms in group II patients (p < 0.001), whereas it slowed less in group III patients (279 +/- 73 to 314 +/- 63 ms, p = NS). Forty-two of the 50 patients (including all patients in groups I and II) were discharged on treatment with the drug combination. After 25 +/- 19 months of follow-up, the actuarial recurrence rate of ventricular tachycardia was 6%, 6% and 11% at 1, 2 and 3 years, respectively. Among patients in whom this drug combination was unsuccessful at electrophysiologic study (group III) and in those who received alternative therapy after combination therapy was discontinued because of side effects, actuarial recurrence rates were 9%, 14% and 32% at 1, 2 and 3 years, respectively. CONCLUSIONS: The combination of sotalol plus quinidine or procainamide markedly prolongs ventricular refractoriness and slows induced ventricular tachycardia in a high proportion of patients. Patients with modified or noninducible tachycardia have a low rate of arrhythmia recurrence in follow-up. This drug combination deserves further evaluation.

Aged↗
PubMed1993

Familial Alzheimer's disease. A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine-->glycine).

Ten affected individuals are described from a kindred with autosomal dominant familial Alzheimer's disease in which a mutation in the amyloid precursor protein gene results in a valine to glycine substitution at amyloid precursor protein 717 which co-segregates with the disease. The mean age at onset of symptoms was 52 years with a range from 40 years to 67 years. The median duration of the disease was 11 years, with a range of 7-16 years. All individuals fulfilled the National Institute for Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. A homogeneous clinical and neuropsychological pattern was evident within the family. Myoclonic jerks, seizures, depression and a lack of insight were common features. Positron emission tomography demonstrated biparietal bitemporal hypometabolism in the one affected individual who was studied. The diagnosis was confirmed histopathologically in one individual.

Adult↗
PubMed1993

High prolactin levels in patients with Cushing's disease without pathological evidence of pituitary adenoma.

OBJECTIVE: This study was designed to compare the clinical and biochemical features of patients with Cushing's disease without pathological evidence of pituitary adenoma (n = 11) to those in whom a pituitary ACTH adenoma was documented (n = 11). DESIGN: The clinical and biochemical features of 11 patients with Cushing's disease without pathological evidence of pituitary adenomas were compared to 11 subjects with ACTH-secreting adenomas. The patients underwent transsphenoidal microsurgery between 1979 and 1989. During surgery, when an adenoma was not visualized, a partial hypophysectomy of the central mucoid wedge was performed. MEASUREMENTS: Cushing's disease was established by the clinical features of hypercortisolism and the high levels of 24-hour free urinary cortisol with no suppression in response to low, but with suppression in response to high, doses of dexamethasone. Basal and post TRH-GnRH plasma prolactin, FSH and LH levels were assessed in each patient before transsphenoidal microsurgery. RESULTS: Similar results were observed in patients with and without ACTH-secreting adenomas regarding cure rate, and free urinary cortisol levels both basal and after 2 days of dexamethasone, 8 mg daily. After surgery, plasma cortisol levels in cured patients were lower in subjects with ACTH-secreting adenomas than in those without pituitary tumours (P < 0.05). Areas under the curve of PRL (P < 0.002) and LH (P < 0.04) were significantly higher in patients without pituitary adenoma after TRH-GnRH administration. Compared to controls, the peak prolactin level after TRH-GnRH administration was higher in patients without pituitary adenoma (P < 0.005) and lower in those with ACTH adenoma (P < 0.005). Furthermore, a peak prolactin level equal to or greater than 1410 mU/l during the TRH-GnRH test was found in 11/11 patients without ACTH adenoma and 3/11 patients in the other group (P < 0.001), while the CT-scan findings were suggestive of pituitary adenoma in six patients of each group. CONCLUSION: This study suggests that patients with Cushing's disease without pituitary adenomas can be distinguished from those with ACTH-secreting adenomas by their high prolactin levels after TRH-GnRH administration.

Adenoma↗
PubMed1993

Assessment and treatment of equine humeral fractures: retrospective study of 54 cases (1972-1990).

Fractures of the humerus were diagnosed in horses at The Ohio State University Veterinary Teaching Hospital. Twenty-four horses (44.4%) were destroyed after radiographic assessment (mean age of 5.0 years). Surgical treatment was elected in 13 horses (24.1%, mean age of 0.42 years). Conservative management, consisting of prolonged stall rest, was chosen for 17 horses (31.5%, mean age of 2.2 years). In the surgically treated group, 3 foals (23.1%) all less than 2 months of age at the time of fracture and treated with intramedullary stack pinning, survived and became athletically sound. After conservative treatment, 9 (52.9%) horses were considered successful, 4 becoming athletically sound and 5 becoming pasture sound. The mean age at the time of presentation in the 9 horses considered successful was 1.81 years. With current fixation techniques, conservative management of equine humeral fractures appears to be as good an option as surgical treatment.

Age Factors↗