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Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously characterized a calmodulin gene from the organism Drosophila melanogaster. In the higher vertebrates a multi-gene system for encoding calmodulin is present and, in at least one invertebrate species, genes encoding highly related calmodulin isotypes exist. We have therefore searched for additional calmodulin genes within D. melanogaster. Although our searches were sensitive enough to detect a relatively divergent gene encoding a calmodulin family protein, we were unable to detect any additional genes for calmodulin per se. Further studies of the structure and expression of the single calmodulin gene of D. melanogaster have established that the gene contains a tiny additional 5' exon encoding only 50 residues of the 5' leader. Sequencing at the 3' terminus has established that the two transcript size classes derived from the gene are produced as a result of alternative polyadenylation site usage. The relative abundance of the two size classes of mRNAs differs throughout the life cycle, indicating developmental regulation of polyadenylation site usage.

Despite the known medical safety and success of vaginal birth after cesarean section, rates of planned repeat cesarean sections remain high. The process involved in women's decisions to choose vaginal birth after cesarean section or repeat cesarean section was investigated by a questionnaire study at a private and a public hospital. Women were questioned regarding timing, influence of others, reasons for their choice, satisfaction with the decision, etc. Results from 160 respondents showed that over half the women identified themselves as the primary decision maker. Physicians exerted more influence on the decisions of patients at the public hospital than on the patients at the private hospital. Overall, social exigencies appeared to play a more important role than an assessment of the medical risks in making these decisions.

Ethanol's effects on erythrocyte membrane lipid composition were examined in male squirrel monkeys divided into three groups receiving three different regimens: Controls were fed a chemically defined liquid diet, and low and high ethanol primates were given diets with vodka substituted isocalorically for 12% and 24% of calories, respectively. After membrane lipid extraction, phospholipid mass, class composition, and fatty acid profiles were measured in each group. Although there were no differences in the total phospholipid mass, the low ethanol primates had significantly elevated phosphatidylethanolamine in their membranes as compared with the other monkeys. Membrane phospholipid fatty acid profiles showed no differences among the three groups. There were also no differences in the animals' plasma liver enzymes. Results of this investigation suggest that, despite the absence of nutritional deficiencies and liver malfunction, low amounts (12%) of dietary ethanol cause elevations in phosphatidylethanolamine that may represent a specific change in the membrane's inner leaflet where this phospholipid is located. These results may have clinical significance because ethanol-induced modifications in membrane lipids may contribute to alterations in fluidity and lead to pathologic changes in function.

Transient hilar and mediastinal lymphadenopathy accompanying right-sided bacterial endocarditis without concurrent roentgenographically-demonstrable pulmonary parenchymal abnormalities has not, to our knowledge, been previously reported. The roentgenographic finding of hilar or mediastinal lymphadenopathy should not be considered incompatible with the diagnosis of bacterial endocarditis in the appropriate clinical setting. Possible mechanisms for the development of lymphadenopathy secondary to bacterial endocarditis are discussed.

During the 1960s, three modalities of treatment aimed at rehabilitation of the drug abuser (methadone maintenance, outpatient drug free treatment, and the residential therapeutic community) were developed. Large amounts of public and private monies have gone to supporting these modalities; little evaluation as to the efficacy of such rehabilitation efforts has been done. This paper attempts to delineate the evaluative research efforts undertaken in the drug abuse field to date. In addition, the findings of an eight-year evaluation of six drug treatment programs in Newark, NJ are presented. The authors propose a paradigm for quick, effective evaluation of drug and alcohol programs at minimal cost.

Patients who take nonsteroidal anti-inflammatory drugs (NSAID) and who experience bleeding after cardiopulmonary bypass (CPB) are treated empirically with platelet transfusions because of the unavailability of rapid and accurate diagnostic clotting function tests. Therefore, a Sonoclot Analyzer (Sienco, Inc, Morrison, CO), which measures the change in the viscoelastic properties of recalcified whole blood, was used to assess platelet function in 51 patients undergoing CPB for cardiac surgery. Seventeen patients (group 1) taking NSAID were compared with 34 patients who were not taking NSAID (group 2). Blood samples were drawn for Sonoclot analysis before and after CPB. Chest tube drainage was measured for 24 hours postoperatively in both groups. Clot retraction, measured by the down slope on the Sonoclot signature, decreased significantly in group-1 patients, although values obtained for both groups were in the normal range. No difference was found between groups when Sonoclot signatures were compared, requirements for replacement of clotting factors or platelets, chest tube blood drainage, and unscheduled return to the operating room for bleeding. It is concluded that patients taking NSAID did not experience increased bleeding after cardiopulmonary bypass and that empiric platelet transfusion seemed unnecessary. In addition, the Sonoclot Analyzer seems to be a useful and sensitive instrument for rapidly assessing platelet function in the operating room.

Audiometric pure tone, speech, and psychoacoustic data were obtained from a patient who had worn a promontory electrode for two years. Subsequently the promontory implant was replaced by a scala tympani electrode (cochlear implant) and testing was repeated. Warbled tone thresholds ranged from 52-68 dB SPL for the octave frequencies 250-8000 Hz with the cochlear implant (CI), and from 65-74 dB SPL with the promontory electrode (PE). Speech discrimination scores were better with the CI than with the PE, although performance on an environmental sounds test was slightly better with the PE. Smaller intensity difference limens (DLs) were obtained with the CI (1 dB) than with the PE (about 4 dB). Frequency discrimination was poor with both electrode systems. The CI provided better frequency DLs at 250, 500, and 1000 Hz; the PE produced better DLs at 2000 Hz. When the CI was combined with a hearing aid worn on the better implanted ear, performance improved over that with either prosthesis alone.

Of 802 voluntary patients admitted to the detoxification unit of a comprehensive treatment system, 69% completed detoxification but only 9.6% of thest patients sought long-term treatment. The demographic profile of detoxification patients differed somewhat from that of patients in long-term treatment. The authors suggest that new approaches, including legal pressure, are needed to induce detoxification patients to accept prolonged therapy.

Identification errors for initial consonants of consonants-vowels-consonants-vowels from lists A and B of the Nonsense Syllable Test were analyzed for 10 normal-hearing and 8 sensorineural hearing-impaired listeners. The Nonsense Syllable Test stimuli were presented binaurally through earphones at 6 increasing sensation levels. Listeners' verbal responses were recorded and transcribed, converted to symmetric confusion matrices, and submitted to analysis of individual differences scaling for symmetrical matrices. Results from 2- through 5-dimensional analyses revealed that voicing, place of articulation, frication, and sibilancy were the salient features used by both listener types in their perceptions of the initial consonants. Findings suggest that consideration of composition of the stimulus set is important when assessing a listener's response to specific speech discrimination tests.

We have adapted the cryopreparative methods designed for the radioautography of diffusible substances (Stumpf and Roth, 1966, 1967) to produce freeze-fried sections of soft tissues for electron probe microanalysis. This report concerns the evaluation of these methods for use with X-ray microanalysis with particular reference to: (1) the preservation of cellular morphology, (2) the introduction of structural artefact by ice crystal formation, (3) the preservation of natural elemental distributions under experimental conditions where known quantities of diffusible elements are present, (4) the effects of ice crystal formation upon possible artefactual elemental redistributions, (5) the effect of section thickness on elemental quantitation, and (6) the effect of tissue excision on element translocation. Freeze-dried sections were prepared from mouse pancreas and from 20% (w/v) solutions of bovine serum albumin (BSA) and gelatin containing known amounts of inorganic salts and were analysed in a scanning electron microscope fitted with energy dispersive X-ray detecting equipment. With the preparative methods used, the morphology of pancreatic acinar cells was well preserved. Acinar cell boundaries, nuclear boundaries, chromatin, nucleoli, ergastoplasm and zymogen granules were readily discernible. Ice crystals were present within sections of BSA, but 70% had a cut surface area < 1 micrometer2 and over 90% had a cut surface area of < 2 micrometer2. Characteristic peak-to-continuum ratios of elements in the BSA sections remained constant over an order of magnitude change in magnification. Elemental redistributions were not detected until the magnification was such that the analysed area fell totally within the confines of a single ice crystal. No differences in elemental peak-to-continuum values were obtained between 2 and 4 micrometer sections of the gelatin-salt solution. Tissue excision did not cause element translocations when compared to tissues frozen in situ. We conclude that this method is valid for preparing tissues for microanalysis under our conditions (analysis of nuclear, cytoplasmic, and secretory compartments) and is limiting only when analyses are conducted at very high magnifications.

We investigated vowel perception by 15 subjects using the single-electrode cochlear implant used at the House Ear Institute in Los Angeles. Subjects were postlingually deaf adults having histories of unsuccessful hearing aid use and a minimum of 6 to 12 months experience with the implant. Eleven American English vowels spoken by a male talker were tape recorded, digitized, analyzed, and controlled for the experiments. The stimuli were audio-recordings of both natural and loudness-matched vowels. Subjects rated the dissimilarity of both the naturally spoken and the loudness-matched vowels, and performed identification of the latter. Two normal-hearing subjects served as controls for the dissimilarity tasks. Multidimensional scaling, hierarchical clustering, and percent correct identification analyses were used to help determine the perceptual features used by the subjects in their judgments. Generally, the normal-hearing subjects took advantage of second formant (F2) frequency information. The cochlear-implant users relied primarily upon fundamental (F0) and first formant (F1) frequency information and demonstrated difficulty in vowel identification. No major differences were noted for the natural versus loudness-matched vowels. F2 information, requisite for accurate vowel recognition, did not correspond to any of the perceptual dimensions discerned in the results obtained from implant subjects.

W-22 lists were given at 40 db re SRT with a Maico MA-24B audiometer and attachments to 20 normal-hearing adults in quiet and in combination with either wide-band or speech-spectrum noise at S/N = 0, monaurally by earphone and binaurally by loudspeaker(s). No systematic L-R differences were observed. DS in quiet by any condition was at or near 100%. Mean DS in noise by monaural earphone was 79.80 +/- 13.3 for wide-band noise and 54.7 +/- 12.7 for speech-spectrum noise. When speech and noise were from two different loudspeakers placed +/- 45 degrees from midline, DS was 90.8 +/- 9.5 for wide-band noise and 88.1 +/- 7.8 for speech-spectrum noise. When both speech and noise came from the same loudspeaker, DS was 79.10 +/- 10.3 for wide-band noise and 57.0 +/- 21.8 for speech-spectrum noise. These values are proposed as provisional norms for clinical facilities using these conditions and employing similar instrumentation.

The impact of continuous perfusion cell culture technology on production of one and two chain human rtPA, as well as monoclonal IgG and IgM, will be reviewed. Perfusion as compared to batch systems improve the quality of the product in the conditioned media in terms of biological activity and structural integrity. This significantly increases downstream recovery and daily production output of final purified material. These findings are a consequence of the ability of perfusion technology to 1) maintain cells intact at high cell density; 2) effectively reduce serum content to approximate serum free conditions; and 3) minimize residency time of labile product within the 37 degrees C environment of the bioreactor.

A comparison was made between listeners' perceptions of low frequency (LF) acoustic and electric stimuli. One normal-hearing S participated, and 3 profoundly deaf pts with intracochlear electrode systems. All Ss described their auditory perceptions to pulsatile and sinusoidal stimuli from 5 to 60 c/s. LF acoustic and electric stimuli produced similar auditory perceptions; no tactual component was found to electrical stimuli, although tactual components have been reported for LF acoustic stimuli; and at 5 c/s perceptual differences were noted between pulsed and sinusoidal stimuli, differences believed to be related to the degree of neural synchrony elicited by the two types of stimulus. This study provides direct support for the theory that in normal listeners LF auditory perception is attributable to a neural volley mechanism.

In this case, inappropriately labeling the child as "allergic to local anesthetics", resulted in her inability to receive appropriate dental care. It was a major disservice to her and led to the potentially serious consequences of neglecting the dental disease present. The small caries lesions that would have required amalgam restorations at five years of age progressed to painful toothaches requiring stainless steel crowns and pulpal treatment. Although adverse reactions to local anesthetics are uncommon, most dentists can anticipate encountering a patient who will have an adverse reaction to a local anesthetic. This case ilustrates the need for dentists to be knowledgeable regarding the signs and symptoms of the potential adverse reactions and their appropriate management. Most importantly, prevention is based upon knowledge of anatomy, dose determination, and the use of proper armamentarium and technique, which are key factors in making a safe and effective drug even safer.

Male squirrel monkeys fed ethanol at variable doses were used to assess whether alcohol enhances de novo synthesis of high density lipoprotein (HDL) cholesterol in vivo. Monkeys were divided into three groups: 1) Controls fed isocaloric liquid diet; 2) Low Ethanol monkeys fed liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) High Ethanol animals fed diet plus vodka at 24% of calories. High Ethanol primates had significantly higher levels of HDL nonesterified cholesterol than Control and Low Ethanol animals while serum glutamate oxaloacetate transaminase was similar for the three treatments. There were no significant differences between the groups in HDL cholesteryl ester mass or specific activity following intravenous injection of labeled mevalonolactone. By contrast, High Ethanol monkeys had significantly greater HDL nonesterified cholesterol specific activity with approximately 60% of the radioactivity distributed in the HDL3 subfraction. This report provides the first experimental evidence that ethanol at 24% of calories induces elevations in HDL cholesterol in primates through enhanced de novo synthesis without adverse effects on liver function.

Twelve children with cerebral palsy ages 18 months to eight years received custom-molded DESEMO seats. All had markedly abnormal motor function manifested in spastic, athetoid, or mixed patterns of movement. None sat independently or were expected to gain such function. Three had minimal head control, and the remaining nine had fair head control. All were inadequately positioned in commercially available seats. The custom-molded DESEMO seat was clinically evaluated with regard to its ability to produce overall relaxation, assist head control, enhance feeding, improve upper extremity function, and prevent deformities. Also assessed were parents' acceptance of the device, cost, cosmesis, convenience, and its capacity to accommodate growth. Seven children utilized the seat as an insert for a motorized wheelchair. The secure positioning provided by this device permitted operation of a standard hand operated joystick control. Two seats were used as floor sitters, allowing the children to participate in peer group activities. Feeding improved dramatically with two children, as evidenced by weight gain and decreased feeding time. Three children with kyphotic spinal deformities showed no improvement or progression of their curves despite the seating device. The positioning device assisted head control for 10 children but failed to enhance head control in the remaining two. The overall cost of the device, including orthotist and physical therapist time, is $640.00 (1985). The average growth potential of the seat is six to nine months.

Two residential therapeutic communities for female addicts--one coeducational and the other all female--encountered serious problems shortly after their formation. The authors found that the male and female staff of the coeducational program had quite different perceptions of the purposes and characteristics of the women's part of the program. In both programs the female staff held such strongly ambivalent feeling toward their roles as women and authority figures that they had difficulty functioning effectively. The authors suggest the need for research that will identify the female addict's special needs, and a restructuring of programs to meet those needs. Further, training programs for female staff must enable them to distinguish between their own ideals and their clients' needs.

Male squirrel monkeys fed ethanol (ETOH) at variable doses were used to determine whether alcohol modifies levels of plasma low density lipoproteins (LDL) in addition to increasing high density lipoproteins (HDL). Because we earlier showed that high alcohol consumption enhances lipoprotein cholesterol synthesis, experiments were also performed to further assess whether ETOH alters lipoprotein clearance and plasma transfer processes in vivo. Monkeys were divided into three groups: Controls fed isocaloric liquid diet; and Low and High ETOH animals fed liquid diet with vodka substituted isocalorically for carbohydrate at 12 and 24 of the calories, respectively. High ETOH primates had significantly more LDL lipid and protein while serum glutamate oxaloacetate transaminase was similar for the three groups. Although removal of 3H LDL cholesteryl ester (CE) from the plasma compartment was not affected by dietary ETOH, transfer of LDL CE to HDL was impaired in the High ETOH group suggesting a mechanism for the enlarged circulating pool of LDL. Transfer of 14C HDL CE to lower density lipoproteins was similar for the three groups. However, ETOH at both doses delayed clearance of radiolabeled HDL CE from circulation. Thus besides enhancing synthesis of lipoproteins, ETOH at a moderately high dose (24% of calories) influences lipoprotein levels in primates by modifying lipid transfer processes (LDL) as well as by altering clearance (HDL) without adversely affecting liver function.

A series of phage clones overlapping the single calmodulin gene locus of Drosophila melanogaster has been isolated and the exons of the gene positioned and sequenced within these clones. A calmodulin cDNA clone of the electric eel was used to identify these clones and to position the two major protein-coding exons of the gene. cDNA clones for D. melanogaster calmodulin were then isolated, characterized and used to identify the remaining exons. The gene consists of four exons separated by three introns of 3400 to 4300 bases in length. Exon 1 consists of the 5' untranslated region and the initiator ATG; exon 2 encodes amino acid residues 1 to 58.3; exon 3 encodes residues 58.3 to 139.3; and exon 4 encodes residues 139.3 to 148 and the 3' untranslated region. From the sequence of the 3' untranslated region and the lengths of the cDNA clones, two or three polyadenylation sites are indicated. Sequences potentially involved in the control of transcription of the gene and splicing of the mRNA product have been identified. Comparison of the intron-exon structures of the D. melanogaster calmodulin gene, the chick calmodulin gene, and other genes of the troponin C superfamily reinforces previous hypotheses that these genes arose from a common progenitor and permits identification of four introns that were probably present in the progenitor gene structure. The D. melanogaster calmodulin gene contains three of these introns, and the chick gene contains all four. These gene comparisons also indicate that the region of these genes encoding Ca2+-binding loop 3 is highly variable in structure. The chick and D. melanogaster calmodulin genes differ in this region, the chick gene containing a fifth intron here that is absent from the D. melanogaster gene.

The effects of low to moderately high levels of dietary ethanol on complete blood counts over a 40-month period were examined in 15 primates divided into 3 treatment groups: Controls fed an isocaloric chemically defined liquid diet, and Low and High animals given diet with vodka substituted isocalorically for carbohydrate at 12 and 24% of total calories. Significant decreases (P less than 0.05) were noted in the High Ethanol group's while blood cell and red blood cell counts, as well as significant increases in their mean corpuscular volume and mean corpuscular hemoglobin. By contrast, a significant increase was seen in the white blood cell counts of animals receiving the 12% (Low) level of dietary ethanol. Analysis of plasma enzymes revealed no differences between the 3 groups in liver function. Results of this study suggest that moderately high levels (24%) of dietary ethanol in the absence of liver malfunction and nutritional deficiencies cause significant alterations in complete blood counts, while low levels (12%) of dietary ethanol cause increases in circulating white blood cell levels. Additional research is needed to determine why different doses of dietary ethanol have opposite effects on the white blood cell population.

Male squirrel monkeys were used to evaluate the effect of chronic oral nicotine intake on lipoprotein composition and metabolism. Eighteen yearling monkeys were divided into two groups: 1) Controls fed isocaloric liquid diet; and 2) Nicotine primates given liquid diet supplemented with nicotine at 6 mg/kg body wt/day. Animals were weighed biweekly, plasma lipid, glucose, and lipoprotein parameters were measured monthly, and detailed lipoprotein composition, along with postheparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity, was assessed after 24 months of treatment. Although nicotine had no effect on plasma triglyceride or high density lipoproteins (HDL), the alkaloid caused a significant increase in plasma glucose, cholesterol, and low density lipoprotein (LDL) cholesterol plus protein while simultaneously reducing the HDL cholesterol/plasma cholesterol ratio and animal body weight. Levels of LDL precursors, very low density (VLDL) and intermediate density (IDL) lipoproteins, were also lower in nicotine-treated primates while total postheparin lipase (LPL + HTGL) activity was significantly elevated. Our data indicate that long-term consumption of oral nicotine induces an atherogenic lipoprotein profile (increases LDL, decreases HDL/total cholesterol ratio) by enhancing lipolytic conversion of VLDL to LDL. These results have important health implications for humans who use smokeless tobacco products or chew nicotine gum for prolonged periods.

We have documented a single, specific binding site for [3H]pyrilamine on normal human T helper, T suppressor, B cells, and monocytes. The binding of the radioligand to its receptor is reversible with cold H1 antagonist, saturates at 40 to 60 nM, and binding equilibrium is achieved in 2 to 4 min. Using a computer program (Ligand), we calculated the dissociation constants, binding capacities, and numbers of receptors per cell for each of the different cell types. Monocytes were found to have the highest affinity (mean KD +/- SD; 3.8 +/- 4.8 nM) for [3H]pyrilamine, followed by T helper cells (KD = 5.0 +/- 6.6 nM), B cells (KD = 14.2 +/- 2.0 nM), and T suppressor cells (KD = 44.6 +/- 49.4 nM). T suppressor cells were found to express the higher number of H1 receptors per cell (35,697 +/- 15,468), followed by B cells (10,732 +/- 9060), T helper cells (6838 +/- 8167), and monocytes (5589 +/- 2266). The kinetics of binding for this radioligand was carried out in resting and mitogen-stimulated T cells over a 48-hr period. We found that the binding affinity for [3H]pyrilamine increased over the 48-hr period, whereas the number of receptors per T cell was essentially unchanged. In contrast, T cells stimulated with Con A or PHA were shown to have a greater than fourfold increase in the number of receptors per cell, whereas the binding affinity for [3H]pyrilamine decreased over the 48-hr period. Preincubation of T cells with unlabeled histamine before carrying out the radioligand binding assay resulted in a decrease in the binding affinity of the receptors to [3H]pyrilamine, but the number of receptors per cell did not change significantly. Although the function of H1 receptors on T cells, B cells, and monocytes has not been completely defined, this receptor has the potential of playing an important role in modulating the immune response.