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R Zimmer

Publications and source records attributed to R Zimmer.

At least 19 recordsLinked to original sources
PubMed1995

Apolipoprotein E genotype in patients with Alzheimer's disease: implications for the risk of dementia among relatives.

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the epsilon 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack epsilon 4 and many persons having epsilon 4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of epsilon 4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one epsilon 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of epsilon 4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one epsilon 4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.

Age of Onset↗
PubMed1995

Recursive dynamic programming for adaptive sequence and structure alignment.

We propose a new alignment procedure that is capable of aligning protein sequences and structures in a unified manner. Recursive dynamic programming (RDP) is a hierarchical method which, on each level of the hierarchy, identifies locally optimal solutions and assembles them into partial alignments of sequences and/or structures. In contrast to classical dynamic programming, RDP can also handle alignment problems that use objective functions not obeying the principle of prefix optimality, e.g. scoring schemes derived from energy potentials of mean force. For such alignment problems, RDP aims at computing solutions that are near-optimal with respect to the involved cost function and biologically meaningful at the same time. Towards this goal, RDP maintains a dynamic balance between different factors governing alignment fitness such as evolutionary relationships and structural preferences. As in the RDP method gaps are not scored explicitly, the problematic assignment of gap cost parameters is circumvented. In order to evaluate the RDP approach we analyse whether known and accepted multiple alignments based on structural information can be reproduced with the RDP method. For this purpose, we consider the family of ferredoxins as our prime example. Our experiments show that, if properly tuned, the RDP method can outperform methods based on classical sequence alignment algorithms as well as methods that take purely structural information into account.

Amino Acid Sequence↗
PubMed1994

Phylogenetic analysis of the Coscoroba coscoroba using mitochondrial srRNA gene sequences.

In order to study the phylogenetic relationships among Coscoroba, goose, and swan lineages, sequences for the complete mitochondrial small ribosomal RNA (srRNA) gene were determined from five waterfowl species. Parsimony and distance analyses support the branching of Coscoroba prior to the divergence of geese and swans, and maximum likelihood analyses give almost equal support to that pattern and to the sister group relationship between Coscoroba and swans. The monophyly of the geese was confirmed at a statistically significant level. In sequence comparisons among waterfowl, transitions increase linearly with transversions, and so we conclude that the lack of complete resolution of Coscoroba's position is not due to sequence saturation alone, but also reflects relatively close branching times.

Animals↗
PubMed1994

[The apolipoprotein E-epsilon 4 allele is a risk factor for Alzheimer disease with early and late onset].

The apolipoprotein E genotype was determined in 50 patients with clinically diagnosed and prospectively confirmed Alzheimer's disease of mild to moderate severity and in 50 healthy age- and sex-matched controls. The frequency of the epsilon 4 allele was increased in the patients irrespective of the age at onset and of a possible familial transmission of the disease. It was associated with a relative risk of 2.97. In patients who experienced first symptoms after the age of 65 years there was an inverse correlation between the number of epsilon 4 alleles and age at onset. The results suggest that in the absence of amyloid precursor protein mutations and of a gene which has not yet been precisely localized on chromosome 14, apolipoprotein E is involved in the pathogenesis of Alzheimer's disease. It probably exerts its influence by an acceleration or retardation of amyloid formation and/or tau hyperphosphorylation.

Aged↗
PubMed1991

[Visual evoked potentials in Alzheimer's and Parkinson disease].

Harding et al. suggested at first that an increase of P2 latency in flash VEP without an increase of P2 latency in pattern reversal VEP may be a diagnostic marker of Alzheimer's disease. Up to now there is no convincing evidence for this hypothesis. The purpose of the present study was to examine this hypotheses in an extended group of patients with Alzheimer's disease (n = 36). In addition, a group of patients with Parkinson's disease (n = 8) without dementia syndrome and a group of healthy elderly controls (n = 46) was investigated in order to determine the sensitivity and specificity of these VEP parameters. The results confirmed significant group differences between patients with Alzheimer's disease and healthy controls concerning the increase of Flash P2 latency and unchanged latency of P2 in the pattern reversal VEP. No significant correlations were found between duration of illness and mental test scores. The group differences of P2 latency in the flash VEP for patients with Parkinson's disease and healthy controls were also significant. Therefore, the increase of flash P2 latency in VEP does not seem to be specific for Alzheimer's disease nor for dementia syndrome. The pathological mechanism causing the flash P2 latency increase in a remarkable number of neuropsychiatric patients should be elucidated in further experimental investigations.

Aged↗
PubMed1991

[Manifestations of Alzheimer's disease in daily living].

From the perspective offered by diagnostic criteria, cognitive rating scales and psychometric tests, Alzheimer's disease appears to be primarily a continuous decline of memory and intelligence. Changes in other areas of behaviour often go unrecognized at examination or are considered insignificant. A completely different view is offered by the reports of care-givers. Here, impairment of everyday activities, abnormal emotional and social behaviours are the most important features. To examine the everyday manifestation of Alzheimer's disease at greater detail, a questionnaire for care-givers was developed. Observations of patients' behaviours as recorded on this instrument demonstrate the presence of significant changes of affect and drive even in mild stages of the disorder. They show only weak associations with cognitive symptoms and cannot be explained as psychological reactions. The non-cognitive aspects of Alzheimer's disease deserve particular diagnostic and therapeutic interest.

Activities of Daily Living↗
PubMed1990

Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects.

The interaction of clomipramine and moclobemide with alcohol was compared in a double blind parallel groups study in 24 healthy volunteers. Moclobemide was given at the highest recommended therapeutic dose (200 mg t.i.d.) and clomipramine in a subtherapeutic dose (25 mg b.i.d.) because of its poor tolerance in healthy subjects. Psychometric evaluations were performed during a placebo run-in phase; after a 5-day treatment period; assessments were made before, and again 1 h and 4 h after alcohol ingestion. Alcohol doses were pre-determined for each subject in order to produce a blood alcohol concentration of 0.6 g/l 1 h after alcohol intake and this individual alcohol dose was given on test days. The day before alcohol intake tests for autonomic functions were made to assess the anticholinergic effects of the drugs. Alcohol significantly increased body sway, decreased critical flicker fusion frequency, prolonged choice reaction time, impaired copying skills, impaired memory and increased the subjective feelings of satisfaction and tension. Drugs increased the effect of alcohol on body sway and this was essentially due to clomipramine. Clomipramine both without and with alcohol increased body sway, prolonged choice reaction time more than did moclobemide. Clomipramine seemed to diminish alcohol-induced memory impairment in one of the memory tests used. Subjects taking clomipramine had significantly more adverse effects after alcohol ingestion than did subjects of the moclobemide group. In contrast to moclobemide, clomipramine produced a moderate but significant drop in standing systolic blood pressure and a clear inhibition of salivary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.

1. The effects of two reversible, predominantly monoamine oxidase-A (MAO-A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400-200-400 mg day-1) on monoamine metabolites and psychometric performance were compared in a double-blind placebo controlled crossover study in 12 healthy subjects. 2. After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8. Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). Urine was collected for measurements of normetanephrine and 3-methoxytyramine excretion. Psychometric performance (short- and long-term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening). 3. Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA. The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P less than 0.001) and the overall decrease in HVA was 38% and 20% (P less than 0.005) on moclobemide and toloxatone, respectively. 4. Before the next drug intake, MAO-A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone. 5. Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5-hydroxytryptamine (5-HT) as judged by the fall in plasma 5-HIAA concentration. Neither drug influenced plasma NA concentration. 6. A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone. The urinary excretion of 3-methoxytyramine was significantly raised by moclobemide but not by toloxatone. 7. Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.

Adult↗
PubMed1990

Potentiation of the pressor effect of intravenously administered tyramine during moclobemide treatment.

Potentiation of the pressor effect of tyramine (TYR) by intravenous (i.v.) injection during moclobemide treatment was investigated in healthy volunteers and in depressed patients. The TYR sensitivity factor (TSF) is calculated as the ratio between the dose of TYR required to raise systolic blood pressure by 30 mmHg (TYR 30) without drug and that required with drug. After single-dose administration the TYR 30 for 100 mg moclobemide was 1.8 mg, and those for moclobemide 200 and 300 mg 1.6, compared with 3.2 for placebo, giving corresponding TSF values of 1.7, 2.0 and 2.0 respectively. Twenty-four hours after moclobemide intake, only the 300-mg dose yielded a mean TYR 30 value significantly different from placebo. The same doses of moclobemide given 3 times daily for 1 week resulted in a peak TSF of 2.0 with 100 mg, 2.9 with 200 mg and 3.3 with 300 mg (the latter dose being higher than normally recommended for 3 times daily administration). Nevertheless, 24 h after the last 300-mg dose the TSF was 1.2, similar to that of a single dose. In a study of 17 depressed female patients treated with moclobemide 100 mg 3 times daily, no relevant differences were found in TSF values from those of the volunteers. The authors conclude that, because of the short-lasting, reversible and selective MAO-A-inhibiting effect of moclobemide, there is no marked interaction with tyramine given by i.v. injection. No relevant difference was seen between depressed patients and healthy volunteers in the tyramine pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents↗
PubMed1990

Interaction between orally administered tyramine and moclobemide.

This article describes a standardized oral tyramine pressor test designed to give information on safety aspects in the real everyday life situation where tyramine is ingested only with food. Results showed that significantly higher doses of tyramine were required to raise standing blood pressure by at least 30 mmHg (TYR 30) when it was taken with food than when subjects fasted. The same test was then conducted in 8 healthy volunteers during treatment with moclobemide 200 mg 3 times daily and tranylcypromine 10 mg 3 times daily. With moclobemide the mean TYR 30 dose was 306 mg, and the ratio of this to baseline was 5.0. With tranylcypromine, however, the mean TYR 30 dose was only 35 mg and the TSF ratio 38.2. The potentiation by tranylcypromine was thus 7.6 times greater than that of moclobemide. When tyramine was given in the food under treatment with MAO inhibitors, the TYR 30 doses were larger than those obtained under fasting conditions, but the TSF ratios were not altered. When the tyramine was given in a protein-rich or a lipid-rich meal, the previously established TYR 30 had significantly less effect on the blood pressure. The lowest TYR 30 dose during moclobemide treatment is at least 150 mg tyramine, an amount contained in about 300 g strong cheese or 100 g of yeast extract. These quantities are unlikely to be consumed in a normal meal. The corresponding TYR 30 dose for tranylcypromine, however, is only 20 mg tyramine, which can easily be contained in a fairly normal portion of strong cheese (40 g).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Relationship between tyramine potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide and other MAO inhibitors.

The pharmacodynamic properties of moclobemide, a reversible inhibitor of MAO-A (RIMA), were compared with the properties of other reversible as well as older irreversible MAO inhibitors in human subjects. All the substances supposed to have MAO-A-inhibitory activity, with the exception of toloxatone, were shown by the decrease in plasma DHPG or MHPG levels to cause inhibition ranging between 50% and 85%. Toloxatone and low doses of deprenyl (a MAO-B inhibitor) caused 20% and 17% inhibition respectively; higher doses of deprenyl, however, strongly inhibited MAO-A. MAO-B inhibition was confirmed for all nonselective and selective MAO-B inhibitors. Moclobemide and clorgyline were found to be the most highly selective MAO-A inhibitors, although both also inhibited 30% of platelet MAO-B activity. Potentiation of the tyramine pressor effect is mainly influenced by the irreversibility and degree of MAO-A inhibition. Tyramine sensitivity was raised (a factor of 10-30) by all irreversible MAO inhibitors in doses inhibiting MAO-A; it diminished with increasing reversibility. In therapeutic doses, moclobemide potentiated the intravenous tyramine pressor effect 3 times less than the old irreversible MAO inhibitors; with the highest therapeutic dose, the tyramine sensitivity factor for moclobemide is only one-seventh to one-tenth that of tranylcypromine or phenelzine. Duration of action is obviously also closely related to the reversibility of inhibition: it ranged from up to 2 days with high doses of moclobemide to 3 weeks with tranylcypromine; clorgyline and phenelzine have been shown to maintain their action for several months. The new generation of RIMAs represents a significant progress in safety.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents↗
PubMed1990

Interaction studies with moclobemide.

Drug interactions with moclobemide given to healthy subjects and depressed patients are reviewed. The drugs investigated for safety were antihypertensives, digoxin, oral contraceptives, anticoagulants and benzodiazepines. Cimetidine was studied for the pharmacokinetic effect, and possible interactions with alcohol (stimulation and/or sedation) were included. Finally, since inhibition of monoamine oxidase (MAO) can increase noradrenergic transmission, possible interaction with neuronal reuptake inhibitors such as tricyclic antidepressants (TCAs) was investigated. Whereas replacement of the older, irreversible MAO inhibitors by a TCA was held to be dangerous and to require a therapy-free interval, the studies reviewed here provide evidence that amitriptyline can replace or be added to moclobemide without any sign of impaired tolerance, need for dose reduction or a therapy-free interval. Combined administration of moclobemide and desipramine was also tolerated well. Moclobemide did not interact with the direct-interacting sympathomimetics norepinephrine and isoproterenol and only to a negligible extent with phenylephrine. The combination of moclobemide with antihypertensive agents did not cause postural hypotension or an increase in other side effects. No clinically relevant interaction was observed between moclobemide and phenprocoumon, glibenclamide, oral contraceptives, digoxin or benzodiazepines. Cimetidine increased the concentration of moclobemide in plasma after a single oral dose by about 100%. If moclobemide is to be used in a patient pretreated with cimetidine, treatment should therefore start with the lowest therapeutic dose and then be adjusted to clinical needs. Since moclobemide is devoid of anticholinergic effects, no interaction with alcohol was anticipated. High therapeutic doses (600 mg/day) induced an effect similar to that of low doses of a TCA, but with 100-300 mg no interaction with alcohol was seen, even in elderly people.

Antidepressive Agents↗
PubMed1989

Determination and comparison of the pressor effect of tyramine during long-term moclobemide and tranylcypromine treatment in healthy volunteers.

Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).

Administration, Oral↗
PubMed1988

[Dementia].

This report briefly reviews the clinical diagnosis of dementia, including the most important problems of differential diagnosis. General guidelines of therapy are presented with special reference to the modification of secondary factor which may contribute to the severity of dementia and to psychosocial approaches in the management of patients.

Aged↗
PubMed1988

Diagnosis, differential diagnosis and nosologic classification of the dementia syndrome.

Some clinical aspects of the diagnosis, differential diagnosis, and the nosologic classification of the dementia syndrome are presented. In discussing the definition of the dementia syndrome and its differentation from other organic brain syndromes, the criteria of DSM III are taken into account. Considering the nosological classification of the dementia syndrome particular emphasis is placed on the most frequent diseases in the senium, the Multi-Infarct Dementias (MID) and the primary degenerative dementias (PDD, according to DSM III). The clinical problems in differentiating MID from PDD and Morbus Pick from the dementia of the Alzheimer type in the group of are discussed in more detail.

Aged↗