Biomedical subjects
Publications and source records attributed to T Malone.
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Several novel N-type voltage sensitive calcium channel blockers showed high affinity in the IMR32 assay and efficacy in the anti-writhing model. Herein, we describe the design, synthesis, SAR studies, biological data, physicochemical properties and pharmacokinetics of this 4-piperidinylaniline series.
OBJECTIVE: To compare self-administered versions of three questionnaires for detecting heavy and problem drinking: the CAGE, the Alcohol Use Disorders Identification Test (AUDIT), and an augmented version of the CAGE. DESIGN: Cross-sectional surveys. SETTING: Three Department of Veterans Affairs general medical clinics. PATIENTS: Random sample of consenting male outpatients who consumed at least 5 drinks over the past year ("drinkers"). Heavy drinkers were oversampled. MEASUREMENTS: An augmented version of the CAGE was included in a questionnaire mailed to all patients. The AUDIT was subsequently mailed to "drinkers." Comparison standards, based on the tri-level World Health Organization alcohol consumption interview and the Diagnostic Interview Schedule, included heavy drinking (> 14 drinks per week typically or > or = 5 drinks per day at least monthly) and active DSM-IIIR alcohol abuse or dependence (positive diagnosis and at least one alcohol-related symptom in the past year). Areas under receiver operating characteristic curves (AUROCs) were used to compare screening questionnaires. MAIN RESULTS: Of 393 eligible patients, 261 (66%) returned the AUDIT and completed interviews. For detection of active alcohol abuse or dependence, the CAGE augmented with three more questions (AUROC 0.871) performed better than either the CAGE alone or AUDIT (AUROCs 0.820 and 0.777, respectively). For identification of heavy-drinking patients, however, the AUDIT performed best (AUROC 0.870). To identify both heavy drinking and active alcohol abuse or dependence, the augmented CAGE and AUDIT both performed well, but the AUDIT was superior (AUROC 0.861). CONCLUSIONS: For identification of patients with heavy drinking or active alcohol abuse or dependence, the self-administered AUDIT was superior to the CAGE in this population.
Previous X-ray crystallographic studies have revealed that the catalytic domain of a DNA methyltransferase (Mtase) generating C5-methylcytosine bears a striking structural similarity to that of a Mtase generating N6-methyladenine. Guided by this common structure, we performed a multiple sequence alignment of 42 amino-Mtases (N6-adenine and N4-cytosine). This comparison revealed nine conserved motifs, corresponding to the motifs I to VIII and X previously defined in C5-cytosine Mtases. The amino and C5-cytosine Mtases thus appear to be more closely related than has been appreciated. The amino Mtases could be divided into three groups, based on the sequential order of motifs, and this variation in order may explain why only two motifs were previously recognized in the amino Mtases. The Mtases grouped in this way show several other group-specific properties, including differences in amino acid sequence, molecular mass and DNA sequence specificity. Surprisingly, the N4-cytosine and N6-adenine Mtases do not form separate groups. These results have implications for the catalytic mechanisms, evolution and diversification of this family of enzymes. Furthermore, a comparative analysis of the S-adenosyl-L-methionine and adenine/cytosine binding pockets suggests that, structurally and functionally, they are remarkably similar to one another.
M.HhaI, M.TaqI and COMT are DNA methyltransferases (MTases) which catalyze the transfer of a methyl group from the cofactor AdoMet to C5 of cytosine, to N6 of adenine and to a hydroxyl group of catechol, respectively. The larger catalytic domains of the bilobal proteins, M.HhaI and M.TaqI, and the entire single domain of COMT have an alpha/beta structure containing a mixed central beta-sheet. These domains have very similar folding. By allowing appropriate 'insertions' or 'deletions' in the backbones of the three structures, it was possible to find more conserved motifs in M.TaqI and COMT. The similarity in protein folding and the equivalence of amino-acid sequences revealed by the structural alignment indicate that many AdoMet-dependent MTases may share a common catalytic domain structure.
The dunce (dnc) gene of Drosophila melanogaster encodes cAMP phosphodiesterase (PDEase) and is required for learning/memory and female fertility. The gene is structurally complex, demonstrated in part by Northern blotting experiments which detected multiple RNAs ranging in size from 4.2 to 9.6 kb (1 kb = 10(3) bases or base-pairs). To characterize these RNAs and to understand their sequence heterogeneity, we isolated and analyzed 29 new and independent cDNA clones representing the dnc RNAs. Restriction mapping, hybridization analysis and sequence determination of these cDNA clones and the corresponding genomic exons resolved these into six different classes. Exons defined by the cDNA clones are distributed over more than 148 kb of genomic DNA, with some exons being used alternatively among the RNAs. The RNAs are transcribed from at least three initiation sites: two of these were mapped by parallel S1-nuclease and primer extension experiments. In addition, some of the heterogeneity is generated by using varying lengths of a 3'-untranslated trailer sequence. Altogether, the results indicate that the size and sequence heterogeneity of dnc transcripts results from transcription initiation at multiple sites, alternative splicing, and processes which generate different 3' ends. The existence of multiple protein products is suggested by the alternative use of exons which code for portions of the open reading frame. The protein variation potentially includes N-terminal differences coded for by transcript-specific 5' exons and internal differences arising from the optional inclusion of a 39 base-pair exon and from the alternative use of two 3' splice sites separated by six base-pairs. Expression of a cDNA clone in yeast containing a large portion of the open reading frame produced cAMP PDEase activity identical in properties to the Drosophila enzyme affected by the dnc mutation. The results suggest that the remarkable structural complexity of dnc may reflect an intricate control of the spatial and/or temporal expression of various isoforms of cAMP PDEase.
To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine and -phenylalanine derivatives. With use of a [3H]CPP receptor binding assay, significant binding activity was observed to be critically dependent on both the position of substitution and length of alkyl spacing groups. Two compounds, 4-(phosphonomethyl)-phenylglycine (6, PD 129635) and 3-(phosphonomethyl)phenylalanine (15, PD 130527), displayed receptor-binding affinity comparable to that of APH. Like APH, these compounds were also effective in antagonizing both the proconvulsant and lethal action of NMDA-administered retrobulbar in the mouse. Data are also provided which compare directly the binding efficacy of these compounds against that disclosed recently for the related NMDA antagonist 18 (NPC 451). A preliminary comparison of the structures showing good receptor-binding affinity and in vivo antagonist activity suggests that the NMDA receptor prefers a "folded" rather than "extended" conformation.
The effect of prolonged (2 h) hypocarbia on cerebral blood flow, oxygen delivery, extraction, and consumption was studied in eight, 1- to 4-day-old piglets. Hyperventilation to PaCO2 less than 20 mm Hg acutely (30 min) decreased cerebral blood flow and oxygen consumption. Cerebral oxygen consumption was subsequently restored via increases in cerebral blood flow and thus, cerebral oxygen delivery. Cerebral oxygen extraction rose from a normocarbic baseline of 50 to 75% with acute hypocarbia and was maintained at this level. The percent decrease in blood flow to the cerebrum was greater than that to other brain regions during hypocarbia.
Based on a comprehensive and systematic knee evaluation, the clinician can develop an effective individualized rehabilitation program. Goals are established for the patient by examining their individual needs and allowing adequate progression as directed by the patient's response and ongoing status. The patient should be subjectively and objectively reassessed at each treatment session and have any necessary modifications made in this program at that time.
Mechanisms of knee injury are very complex and depend on multiple factors. The purpose of this article was to describe mechanisms of knee injury. Causes of knee injury include microtrauma and macrotrauma. For microtrauma, mention was made of the accumulation of inflammatory reactions that eventually produces clinical signs and symptoms. For macrotrauma, particular emphasis was placed upon immediate injuries resulting in straight one-plane instabilities and transverse plane rotatory instabilities.
Knee rehabilitation is nearly as complex as the knee itself. The general and specific and specific programs and exercises presented are to be used eclectically. Rehabilitation must not be of a cookbook nature but rather individualized to fit the needs of the patient. The emphasis of rehabilitation must be dictated by the demands the individual places upon the knee. Rehabilitation must degenerate into function!
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The dunce locus of Drosophila melanogaster is considered to house a gene involved in memory, because flies carrying lesions at the locus have shortened memory of several different conditioned behaviours. Our recent partial characterization of the gene at the molecular level, along with prior genetic and biochemical evidence, recently provides compelling evidence that the gene codes for the enzyme cAMP phosphodiesterase. The observation that the gene encodes at least six overlapping poly(A)+ RNA molecules ranging in size from 4.2 to 9.5 kilobases (kb) (ref. 8), suggests that the gene is extraordinarily complex. Here we provide the sequence of a dunce complementary DNA clone and the corresponding genomic coding regions which show that the organization of the gene is elaborate. The cDNA clone defines dunce exons which are separated by a large intron of 79 kb. More importantly, at least two other genes are shown to reside within the large intron, including the well-defined glue protein gene, Sgs-4. The location of dunce exons relative to the molecular breakpoints of chromosomal aberrations with defined cytological positions indicates that the dunce gene extends over more than five polytene chromosome bands.
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This study investigated the effects of passive warming on the biomechanical properties of the musculotendinous unit. Paired tibialis anterior (TA) and extensor digitorum longus (EDL) muscles in the rabbit hindlimb were passively heated to different temperatures and then subjected to controlled strain injury. The parameters examined were: 1) percent increase in length to failure, 2) force to failure, 3) energy absorbed by the musculotendinous unit to failure, and 4) site of failure. Warmed (39 degrees C +/- 0.5 degrees C) TA (P less than or equal to 0.01) and EDL (P less than or equal to 0.05) muscles achieved a greater increase in length from rest before failing than did their contralateral controls at 35 degrees C +/- 0.5 degrees C. In both the TA and EDL the force at failure was greater at 35 degrees C than at 39 degrees C, although the difference was significant for only the EDL (P less than or equal to 0.05). The energy absorbed (area beneath the length-tension curve) by both the TA and EDL was greater at 39 degrees C, but these differences were not significant. All muscles failed at the distal musculotendinous junction. These data suggest that passive warming increases the extensibility of the musculotendinous unit and may thereby reduce its susceptibility to strain injury.