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Biomedical subjects

R A Lewis

Publications and source records attributed to R A Lewis.

At least 163 records · Page 9Linked to original sources
PubMed1992

Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel.

1. A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock-induced seizures in mice and the ability to block the voltage-gated Na channel in N1E-115 cells, in comparison with the prototype compound, U-54494A, (+/-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-ben zam ide , a potent anticonvulsant and a Na channel blocker. 2. The pyrrolidinyl benzamide (U-49524E) was found to be effective against the electroshock-induced seizures (ED50 = 35 mg kg-1, i.p.) whereas the benzamide with a piperidinyl moiety (U-49132E) was inactive (ED50 greater than 100 mg kg-1). 3. Using whole-cell patch clamp techniques we found that U-49132E was several times less potent, with an IC50 of 396 microM as compared to 118 microM for U-49524E at the holding potential of -80 mV, and was much slower in blocking Na channels with a half-time of 10.7 +/- 1.1 min vs. 2.2 +/- 0.4 min for its counterpart. 4. Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U-54494A in that they interacted with the resting and slowly-inactivated states of the channels and exhibited a use-dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs. 5. Comparison of their physicochemical properties, shows the less potent and slowly acting U-49132E is more hydrophobic and bulkier than U-49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway.6. Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.

Animals↗
PubMed1992

Maternal uniparental isodisomy of chromosome 14: association with autosomal recessive rod monochromacy.

Rod monochromacy (complete congenital achromatopsia) is inherited as an autosomal recessive trait of unknown genetic location. The disorder is characterized by total absence of color discrimination because retinal cone photoreceptors do not develop; systemic features do not occur. A 20-year-old white female with rod monochromacy presented with short stature (less than 5th percentile), mild developmental delay, premature puberty, small hands and feet (length less than 5th percentile), minimal dysmorphism, and a reproductive history of three consecutive first-trimester miscarriages. Cytogenetic analysis showed 45,XX,rob(14;14) in all 30 cells examined. Southern analysis of DNA from the patient and her phenotypically normal mother and two brothers (her father is deceased) ascertained the parental origin of the 14;14 Robertsonian translocation. Analysis of RFLPs associated with nine VNTR probes and two dinucleotide repeat polymorphisms from chromosome 14 demonstrated that the patient had inherited two copies of a single allele, each of which was maternally derived. A fully informative RFLP analysis of three probes from chromosome 14 enabled reconstruction of the paternal haplotype and showed the lack of any paternal contribution to the subject. These data are consistent with maternal isodisomy for all portions of chromosome 14 tested by these markers. This finding suggests that rod monochromacy maps to chromosome 14, and it emphasizes the importance of uniparental isodisomy to provide a putative chromosomal assignment of a gene for a rare autosomal recessive disorder.

Chromosome Mapping↗
PubMed1992

Evidence for genetic heterogeneity in tuberous sclerosis: one locus on chromosome 9 and at least one locus elsewhere.

Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families.

Alleles↗
PubMed1991

A sibship with unusual anomalies of the eye and skeleton (Michels' syndrome).

Four siblings of nonconsanguineous parents had congenital anomalies of the anterior segment of the eyes, eyelids, and skeletal systems. Anomalies of the anterior segment included opacities of the corneal stroma, conjunctival telangiectasia, and iridocorneal adhesions. Eyelid abnormalities included blepharoptosis, blepharophimosis, and telecanthus. One sibling with extensive anterior segment anomalies developed glaucoma. All subjects had impaired vertical gaze. Oromandibular anomalies varied from cleft lip and palate to malocclusion with overbite. Additional features included subnormal intelligence, short stature, hearing loss, and clinodactyly. This spectrum of anomalies appeared to have been transmitted as an autosomal recessive syndrome.

Abnormalities, Multiple↗
PubMed1991

Multiple endocrine syndrome type IIb in early childhood.

A 3-week-old girl who was born with club feet had signs of failure to thrive. On physical examination the child appeared normal; she had no abnormalities in the mucous membranes of the mouth, the eyelids, or in the neck, and her other systems, including heart, chest, abdomen, and neurologic systems, were clinically normal. Radiologically, the gastrointestinal tract was normal, but rectal biopsy showed neuromas. Her serum calcitonin level was measured both at basal and after pentagastrin stimulation at 5 weeks of age and found to be high, but whether it was consistent with the normal level at this early age or was caused by medullary thyroid carcinoma was not clear. At 3 months, the corneal nerves of both eyes were examined and showed considerable thickening, and multiple endocrine syndrome type IIb was suspected. The serum calcitonin level at 8 and 14 months was increased. A total thyroidectomy was done, and C-cell nodular hyperplasia and adenomatosis was found in the isthmus. The postoperative serum calcitonin level decreased to low normal and did not increase after pentagastrin stimulation. To the authors' knowledge, this case represents the youngest patient diagnosed with multiple endocrine syndrome type IIb in the absence of family history of the disease.

Calcitonin↗
PubMed1991

A 3-month comparison of 1% and 2% carteolol and 0.5% timolol in open-angle glaucoma.

Carteolol, a nonselective beta-adrenergic antagonist with intrinsic sympathomimetic activity, was compared in 1% and 2% topical solutions with 0.5% timolol in 105 patients with primary open-angle glaucoma. In this double-masked, randomized 3-month trial, all three preparations significantly lowered intraocular pressure throughout the study, with no significant differences being observed. There were also no significant differences among the three preparations with regard to ocular or systemic adverse reactions, including heart rate and blood pressure.

Administration, Topical↗
PubMed1991

Two-dimensional time resolved X-ray diffraction of muscle: recent results.

This report provides a preliminary sketch of the results obtained in a two-dimensional time resolved X-ray diffraction study of "live" frog sartorius muscles undergoing isometric tetani. These results demonstrate the recently developed capability to record time resolved (10 msec time resolution), two-dimensional X-ray diffraction diagrams throughout the cycle of contraction. The correlation between the time courses of the diffraction features in the whole of the diffraction diagram establishes a sequence of structural events, which suggest that during the transition from rest to the plateau of tension and the subsequent recovery, the following sequence of events takes place: a) Following the activation phase, which is best monitored by the increase of intensity on the second actin layer line at 18.0 nm spacing (5), there is the onset of three dimensional disorder due to the filaments losing their axial alignment and the myosin heads rotating azimuthally and moving radially outwards. A set of low-angle layer lines, following the actin based spacings seen in rigor (i.e., at spacings of ca. 36.5-37.5, 24.0 and 18.0 nm) become visible and those at ca. 24.0 and 18.0 nm appear to increase in intensity during this phase with a time course that cannot be determined accurately because of the proximity of the neighbouring first, second and third myosin layer lines and the weakness of these diffraction features. Whether the first of these layer lines increases or not is difficult to ascertain. Moreover, proper account of the loss in crystallinity during the development of tension must be made before the comparisons in intensity between the rest and peak of tension states have any significance. Nevertheless, these features together with the behaviour of the equatorial reflections and the meridional region of the third myosin layer line indicate that a sizeable fraction of the crossbridges may become axially disposed with an actin based periodicity. The formation of this complex does not immediately result in the generation of tension. The labelling of the thin filaments is also reflected in the main actin layer lines at 5.9 and 5.1 nm. b) The tension generating phase is monitored by the intensity changes in the meridional region of the third myosin layer line, which are best explained by a change in the orientation/conformation of the tension bearing crossbridges, (which probably adopt a more perpendicular orientation to the filament axis). c) At the end of stimulation, the crossbridges return to an axial spacing and axial orientation (although not yet azimuthal) similar to the one at rest.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

A rapid screening method for the assessment of benzodiazepine receptor-related physical dependence in mice. Evaluation of benzodiazepine-related agonists and partial agonists.

We have developed a model of benzodiazepine-type physical dependence in which mice were injected subcutaneously with the test compound on a fixed schedule (0800 and 1600 for 3 days, the PM dose = AM dose x 2). If tolerated, then a starting dose of 150 mg/kg/day was generally used initially and the dose was lowered to 15 and 1.5 mg/kg/day in subsequent assays if the higher doses were active in the test. Twenty-four hours after the last dose, the mice received an intravenous injection of flumazenil (2.5 mg/kg), and 5 min later they were tested for electroshock seizure thresholds by an up-down titration method. Flumazenil-precipitated withdrawal was manifested by a lowering of the mA seizure threshold. We have found that compounds with benzodiazepine agonist properties significantly lower these thresholds in a dose-related fashion. For example, the following compounds (lowest effective mg/kg/day dose) were active in this regard, chlordiazepoxide (150), diazepam (15), flurazepam (15), alprazolam (15), triazolam (15), midazolam (15), zopiclone (150), Ro 16-6028 (150), and Ro 17-1812 (150). In contrast, zolpidem (150), tracazolate (15), and CL 218872 (15) did not cause physical dependence by this criterion. This rapid and simple screening test may be readily used to predict the physical-dependence-inducing properties of compounds that act at the benzodiazepine receptor.

Animals↗
PubMed1991

Men's changing social roles in the 1990s: emerging issues in the psychiatric treatment of men.

In the last two decades, men's social roles have changed to incorporate the increasing time they spend with their families, their greater concern about adult children's leaving or returning home, and alternative sexual preferences and life-styles. One related development is the increased amounts of psychiatric distress reported by men in recent years. Mental health professionals should be familiar with these and other complex issues specific to men and with how such issues might manifest themselves in psychotherapy.

Double Bind Interaction↗
PubMed1991

Three different frameshift mutations of the tyrosinase gene in type IA oculocutaneous albinism.

Mutations in the gene for the pigment-producing enzyme tyrosinase are responsible for type IA (tyrosinase-negative) oculocutaneous albinism (OCA). Most reported mutations have been single base substitutions. We now report three different frameshift mutations in three unrelated individuals with type IA OCA. The first individual has a single base deletion within a series of five guanidines, resulting in a premature stop codon in exon I on one allele and a missense mutation at codon 382 in exon III on the homologous allele. The second individual is a genetic compound of two separate frameshift mutations, including both the same exon I single base deletion found in the first individual and a deletion of a thymidine-guanidine pair, within the sequence GTGTG, forming a termination codon (TAG) in exon I on the homologous allele. The third individual has a single base insertion in exon I on one allele and a missense mutation at codon 373 in exon III on the homologous allele. The two missense mutations occur within the copper Bbinding region and may interfere with either copper binding to the enzyme or oxygen binding to the copper. These five different mutations disrupt tyrosinase function and are associated with a total lack of melanin biosynthesis.

Albinism, Oculocutaneous↗