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Biomedical subjects

B Smith

Publications and source records attributed to B Smith.

At least 127 records · Page 7Linked to original sources
PubMed1998

DNaseY: a rat DNaseI-like gene coding for a constitutively expressed chromatin-bound endonuclease.

A rat gene, designated DNaseY, encoding a 36 kDa endonuclease was identified and cloned. Sequence analysis of the cDNA showed it to be the rat homologue of human DNAS1L3. The DNaseY gene product had 42% identity to DNaseI, including conserved critical active site residues, the essential disulfide bridge, the calcium binding domain, and a signal peptide, as well as 2 of the 3 signature boxes. Significantly, DNaseY had 2 nuclear localization signals and was more basic (pI 9.5) than DNaseI (pI 4.8). The DNaseY gene contained a number of exons similar to that of DNaseI, separated by much larger introns, resulting in a gene of >17 kb compared to <4 kb gene of DNaseI. The 36 kDa DNaseY gene product was catalytically inactive but was converted to an active 33 kDa endonuclease following processing of the hydrophobic signal peptide. Antibody generated against peptides representing the predicted amino acid sequence of DNaseY cross-reacted with a 33 kDa nuclear protein which possessed endonucleolytic activity. The enzyme was active over a broad pH range (optimum pH 7-8), was Ca2+/Mg2+-dependent, was inhibited by Zn2+, and was capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends. Furthermore, the DNaseY gene was expressed constitutively in all cells and tissues tested, but it was not transcriptionally up-regulated in apoptotic cells. All these features were consistent with a role in the early stages of apoptotic DNA fragmentation.

Amino Acid Sequence↗
PubMed1998

Lipocortin 1 co-associates with cytokeratins 8 and 18 in A549 cells via the N-terminal domain.

An affinity chromatography strategy was used to search for proteins in A549 cells which interact with the N-terminus of lipocortin 1 (annexin 1). Using the biologically active fragment Lc13-25 as the affinity ligand, two proteins of molecular weight (m.w.) 52 and 48kDa were extracted. Affinity blots of these proteins bound iodinated Lc13-25. Partial tryptic digests of these proteins were analysed by matrix assisted laser desorption mass spectrometry and found to display fragmentation patterns with a strong similarity to those of cytokeratin 8 and 18 respectively. Subsequent blotting with a panel of specific cytokeratin antibodies strongly supported the idea that the two proteins were cytokeratin 8 and cytokeratin 18. Cytokeratin 8 was isolated from A549 cells in intermediate filament (IF) preparations which were also found to contain lipocortin 1 as a potential intermediate filament associated protein (IFAP). This association persisted throughout cycles of IF assembly and disassembly. Dual-labelling immuno-histochemistry in A549 cells showed strong co-localization of lipocortin 1 and cytokeratin 8. The implications of this finding are discussed in the light of the biological activity and possible function of lipocortin 1.

Annexin A1↗
PubMed1998

Psychotropic drugs in breast milk: no evidence for adverse effects on prepulse modulation of startle reflex or on cognitive level in infants.

Reversals in modulation of the startle reflex probably reflect maturational processes in the central nervous system. This study has investigated the longitudinal changes in prepulse modulation of the blink reflex in three groups of individual infants: (a) breast-fed infants of mentally ill mothers who were prescribed selected psychotropic drugs, (b) bottle-fed infants of similarly ill and medicated mothers, and (c) breast-fed infants of healthy control mothers. The acoustic stimulation paradigm and neurophysiological methods were similar to those used in previous studies and, in addition, the infants' development was simultaneously assessed using the Bayley Scales of Infant Development. All the infants were found to be developing normally and across all three groups we observed a clear transition in prepulse modulation of the eye-blink reflex from small inhibition or facilitation in early infancy (1-4 months) to a robust facilitation in middle infancy (5-8 months). This reversal probably reflects the changing balance of developing neural function in normal infants. There were, therefore, no discernible effects in breast-fed infants of exposure to small doses of antidepressant or neuroleptic drugs.

Acoustic Stimulation↗
PubMed1998

Distribution of macromolecular dyes in brain using positive pressure infusion: a model for direct controlled delivery of therapeutic agents.

BACKGROUND: Direct infusion of therapeutic agents into the brain is a novel technique that has the potential for bypassing the blood-brain barrier and delivering high concentrations of therapeutic agents into the brain parenchyma. We have developed a model to characterize the distribution of Evans Blue (MW 960) and Blue Dextran (MW 2 x 10(6)) in rat brain using a positive pressure infusion system. METHODS: Evans Blue and Blue Dextran were infused in volumes of 20, 40, 60, 100, 140, and 180 microL into the caudate putamen of female Fischer rats over a period of 2 h with rates of infusion varying between 0.167 microL and 1.5 microL/min. During the infusions, the pressure generated in the infusion system and intracranial pressure were measured using a fiberoptic pressure monitoring system. After infusions, the volumes of distribution of the dye molecules were measured from 3-mm thick sections using video microscopy and computer image analysis. Histologic changes during the infusion were studied using snap freezing and hematoxylin/eosin staining of cryosections. RESULTS: Volumes of distribution for Evans Blue were greater than those for Blue Dextran. There was extensive spread of each dye in the ipsilateral hemisphere and also across the corpus callosum to the opposite hemisphere. Infusion/interstitial pressures peaked during the first 5 min of the infusion period, after which pressures dropped to a plateau value that remained relatively constant during the remainder of the infusion. Histologic findings suggest that this phenomenon is an important transition process that is likely to play a role in the pattern of distribution of macromolecules infused by this technique. No marked changes in intracranial pressure were noted during the infusion procedure. CONCLUSIONS: Direct positive pressure infusion into the brain has great potential in the treatment of brain tumors and other central nervous system disorders using both high and low molecular weight compounds (immunotoxins, protein conjugates, pharmacologic agents, oligonucleotides, and viral vectors).

Animals↗
PubMed1998

Neuroleptic drugs in breast-milk: a study of pharmacokinetics and of possible adverse effects in breast-fed infants.

BACKGROUND: Very little is known about the pharmacokinetics of neuroleptic drugs in breast-feeding mothers and their infants or about possible adverse effects in the infants. METHOD: Twelve mothers who breast-fed their infants were prescribed haloperidol, chlorpromazine or trifluoperazine. Two methods, enzyme immunoassay (EIA) and high performance liquid chromatography (HPLC) were used to assay these drugs in samples from mothers, but infants' samples were assayed only by the more sensitive EIA. Repeated clinical and developmental assessments of the breast-fed infants were carried out up to 30 months of age. The control subjects were 18 bottle-fed infants whose mothers were also prescribed neuroleptic or mood-stabilizing drugs. RESULTS: The total concentrations of neuroleptic drugs and their principal metabolites in maternal plasma were correlated with concentrations in fore-milk. Infants were ingesting up to 3% of the maternal daily dose per kg body weight and small amounts of the drugs were detected in infants' plasma and urine. Concentrations of haloperidol in the adult range were found in plasma from 2 of 5 infants assayed by EIA but there was no evidence of any acute or delayed adverse effects. Three other breast-fed infants whose mothers were prescribed both haloperidol and chlorpromazine showed a decline in their developmental scores from the first to the second assessment at 12-18 months. CONCLUSION: More extensive longitudinal studies are needed but, in the meantime, there appears to be grounds for caution if breast-feeding mothers are prescribed doses of single or two neuroleptic drugs at the upper end of their recommended ranges.

Adult↗
PubMed1998

Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Rizatriptan 022 Study Group.

Rizatriptan is a novel 5-HT1B/1D agonist which is rapidly absorbed after oral administration. The efficacy and tolerability of oral rizatriptan (5 mg and 10 mg) were examined in this multicenter, double-blind, outpatient study of 1473 migraineurs which featured randomized, placebo-controlled treatment of migraine recurrences. On experiencing moderate or severe migraine headaches, patients rated headache severity prior to dosing and at 30-minute intervals for 2 hours after dosing. Onset of effect was seen as early as 30 minutes after dosing with rizatriptan 10 mg. At 2 hours postdose, the percentage of patients with pain relief was significantly higher after rizatriptan 5 mg (62%) or 10 mg (71%) compared with placebo (35%). Complete relief was also significantly higher after rizatriptan 5 mg (33%) and 10 mg (42%) compared with placebo (10%). In patients experiencing headache recurrence after initial benefit, further relief was obtained in 71% with rizatriptan 5 mg (placebo 54%) and in 82% with rizatriptan 10 mg (placebo 44%). Complete relief of recurrent headache was obtained in 36% with rizatriptan 5 mg, 49% with rizatriptan 10 mg, and 15% with placebo (P < 0.05). The most common drug-related adverse experiences were dizziness, somnolence, asthenia/fatigue, and nausea (the incidences of which were low and dose related). There was no increase in the incidence of adverse experiences after use of up to three doses of rizatriptan within 24 hours. We conclude that both doses of rizatriptan are effective and well tolerated in the acute treatment of migraine and migraine recurrence, with the 10-mg dose preferred as it is more effective with a faster onset of action.

Acute Disease↗
PubMed1998

Quality of life during and between hemodialysis treatments: role of L-carnitine supplementation.

End-stage renal disease affects every aspect of a patient's life, including perception of health and quality of life. It is likely that a hemodialysis patient's perceptions of health-related quality of life directly influence compliance with medical, nursing, and nutritional prescriptions. Because L-carnitine supplementation is known to enhance muscle strength and energy in hemodialysis patients, we hypothesized that L-carnitine supplementation would enhance a hemodialysis patient's perception of health-related quality of life. To test this hypothesis, 1 g L-carnitine or placebo was administered orally to 101 patients immediately before and after every hemodialysis treatment for 6 months. To assess health-related quality of life from the patient's perspective, the Medical Outcomes Study Short Form 36 instrument was administered before the study and at 1.5-month intervals for the duration of the study. In addition, a 10-item questionnaire designed to assess common intradialytic symptoms was administered at the end of each dialysis treatment. Other parameters analyzed included Kt/V(urea) and level of nutrition. In the 6-month group, oral L-carnitine supplementation had an early positive effect on general health (P < 0.02) and physical function (P < 0.03), but the perceived effect was not sustained throughout the 6 months of the study. In the 3-month group, L-carnitine supplementation improved vitality (P < 0.02) and general health (P < 0.01). There was no association between Kt/V(urea) and perceived health-related quality of life. Serum albumin concentration was directly correlated to how patients perceived the quality of their lives.

Administration, Oral↗
PubMed1998

Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy.

BACKGROUND: Many studies have shown the efficacy of patient-controlled analgesia (PCA). However, it is not clear whether PCA has clinical or economic benefits in addition to efficient analgesia. The current study was designed to evaluate these issues by comparing PCA with regularly administered intramuscular injections of opioids after hysterectomy. METHODS: This prospective study included 126 patients who underwent abdominal hysterectomy and were randomly assigned to receive PCA or regularly timed intramuscular injections of morphine during a period of 48 h. Doses were adjusted to provide satisfactory analgesia in both treatment groups. Pain at rest and with movement, functional recovery, drug side effects, and patient satisfaction were measured using rating scales and questionnaires. The costs of PCA and intramuscular therapy were calculated based on personnel time and drug and material requirements. RESULTS: Comparable analgesia was observed with the two treatment methods, with no significant differences in the incidence of side effects or patient satisfaction. The medication dosage had to be adjusted significantly more frequently in the intramuscular group than in the PCA patients. The PCA did not favor a faster recuperation time compared with intramuscular therapy in terms of times to ambulation, resumption of liquid and solid diet, passage of bowel gas, or hospital discharge. The results of the economic evaluation, which used a cost-minimization model and sensitivity analyses, showed that PCA was more costly than regular intramuscular injections despite the fact that no costs for the pump were included in the analyses. Cost differences in nursing time favoring PCA were offset by drug and material costs associated with this type of treatment. CONCLUSIONS: Compared with regularly scheduled intramuscular dosing, PCA is more costly and does not have clinical advantages for pain management after hysterectomy. Because of the comparable outcomes, the general use of PCA in similar patients should be questioned.

Analgesia↗
PubMed1998

Activation of L-type calcium channel by tolazoline derivatives: role of isothiocyanate moiety.

Studies have investigated the pharmacologic mechanism of 2-(4'-isothiocyanatobenzyl) imidazoline (IBI) and analogs for interaction with imidazoline receptors (IRs), alpha-adrenergic receptors (alpha-ARs), and calcium channels in cardiovascular muscle systems. IBI differs from tolazoline by substitution of an electrophilic isothiocyanato (NCS) group. Unlike tolazoline, which is a partial alpha-AR agonist, IBI produced an irreversible, slow-onset, and sustained contraction of rat aorta with an median effective concentration (EC50) value of 5 microM, and a maximal contraction (116%) greater than that of phenylephrine (100%) and tolazoline (59%). The IBI-induced contractions were dependent on calcium channels and independent of alpha-ARs or IRs. Similarly, structure-activity relation studies in rat aortic smooth muscles on a series of synthesized IBI analogs indicated that NCS analogs, but not those without the NCS group, exhibited effects by a non-alpha-AR, non-IR, but a calcium channel-dependent mechanism. Thus the presence of an intact IBI ring in these analogs is not a requirement for these activities. Further, IBI inhibited dihydropyridine (DHP, [3H]PN 200-110 and [3H]Bay K 8644) binding to L-type calcium channels of T-tubule membranes in rabbit skeletal muscle. In contrast to nifedipine, IBI and NCS derivatives (nifedipine-NCS, naphazoline-NCS) only partially (50-88%) displaced specific binding of these radioligands. A single site of noncooperative interaction was observed for nifedipine (nH = 0.97), whereas tolazoline-NCS (IBI, nH = 1.46) and nifedipine-NCS (nH = 1.37) exhibited a positive cooperativity in binding to DHP sites. These receptor-binding data indicate that NCS derivatives bind to L-type calcium channels and interact allosterically with DHP-binding sites. Direct binding of the NCS group to specific nucleophilic protein sites of the calcium channel may be responsible for its activation and the subsequent contractile effects of IBI.

Adrenergic alpha-Agonists↗
PubMed1998

An externally powered, multichannel, implantable stimulator-telemeter for control of paralyzed muscle.

An implantable integrated stimulator and telemetry system has been developed. The system is capable of fulfilling the stimulus and telemetry needs of advanced functional neuromuscular stimulation (FNS) applications requiring multiple channels of stimulation and multiple channels of sensor or biopotential sensing. This system provides a command control structure, an inductive radio frequency link providing power to the implant device as well as two-way transcutaneous communication, an ASIC for decoding the command and for providing functional control within the implant, and modular circuitry providing the application specific implant functions. Biocompatible hermetic packaging, lead systems, and in-line connectors suitable for long-term implantation, provide encapsulation for the circuitry and access to the electrodes and sensors used in the application. The first implant configuration realized from this modular system is targeted for clinical implementation in persons with tetraplegia at the C6 level for restoration of hand function, using wrist position as the command control source. The implant device realized has ten channels of stimulation and telemetry used to control and sense a joint angle transducer implanted in the radio-carpal joint of the wrist. A prototype device has been fabricated and is undergoing testing in an animal.

Algorithms↗
PubMed1998

Fluoxetine in breast-milk and developmental outcome of breast-fed infants.

BACKGROUND: Selective serotonin reuptake inhibitors are currently the most widely prescribed antidepressant drugs. There are only four published studies of breast-feeding mothers and their infants in which the mothers were taking fluoxetine. METHOD: Four mothers who took fluoxetine and their breast-fed infants were studied. Samples of plasma, breast-milk and urine were taken from the mothers and of plasma and urine from infants for assays of drug and metabolite concentrations. Bayley Scales of Infant Development were repeatedly used to assess cognitive and psychomotor development of the infants. RESULTS: Fluoxetine and norfluoxetine were detected in all samples of maternal plasma (range of total concentration 138-427 ng/ml) and in breast-milk (range 39-177 ng/ml). Amounts of both fluoxetine and norfluoxetine in infants' plasma and urine were below the lower limit of detection. All infants were observed to be developing normally and showed no abnormal findings on neurological examination. CONCLUSIONS: Much larger databases are needed but these four cases do not provide any evidence to suggest that women who are maintained on therapeutic doses of fluoxetine should discontinue breast-feeding their infants if they wish to breast-feed.

Breast Feeding↗
PubMed1998

Growth and survival of Listeria monocytogenes in vacuum-packaged ground beef inoculated with Lactobacillus alimentarius FloraCarn L-2.

A culture of the psychotrophic strain FloraCarn L-2 of Lactobacillus alimentarius was added to ground beef (pH 5.4) inoculated with two isolates of Listeria monocytogenes able to grow in refrigerated ground beef. The ground beef was vacuum-packaged and stored for 9 weeks at 4 degrees C. Populations of inoculated L. monocytogenes initially were 6.3 to 6.4 log10 CFU/g and increased to 7.4 log10 CFU/g in ground beef with no added lactobacilli. Addition of L. alimentarius L-2 or its antibiotic-resistant mutant SRL-2 reduced the final populations of L. monocytogenes to 4.3 or 4.1 log10 CFU/g, respectively. L. alimentarius L-2 did not produce bacteriocins or hydrogen peroxide in vitro. The antilisterial effect of L. alimentarius observed in laboratory media and ground beef is attributed to lactic acid (ca. 50 mM) produced by growing cultures.

Bacteriocins↗
PubMed1998

Human brain tumors and exposure to metal and non-metal elements: a case-control study.

BACKGROUND: Primary brain tumors are among the most deadly of all cancers, with a 1-year survival rate of 52%. Certain elements, such as nickel, cadmium, chromium, arsenic, and beryllium, are established carcinogens in other organs. Silicon and titanium are suspected carcinogens and other elements are known to promote or inhibit the rate of tumor growth. Knowledge about the carcinogenicity of these elements in the brain is limited. In this study, we investigated the potential role of these elements as risk factors for human brain tumors. METHODS: In a case-control study, we assessed brain biopsies from 12 patients with various types of primary brain tumors and in tumor-free brain tissue from 6 autopsy cases. We used energy-dispersive X-ray analysis (EDX) to determine if there were significant differences in the concentration of the study elements in tumors and in control brains. RESULTS: In a bivariate analysis, a statistically significant association was observed between the presence of brain tumors and the concentrations of silicon (p = 0.01), magnesium (p = 0.01), and calcium (p = 0.03). Zinc was also associated with a borderline significance (p = 0.05). No association was observed for nickel (p = 0.74). Although the magnitude of the observed association was estimated using multiple logistic regression analyses, the relative risk estimates were imprecise because of insufficient sample size. Further research using a larger sample size is needed to elucidate the role of these elements in human brain carcinogenesis.

Aged↗
PubMed1998

Area and depth of surfactant-induced corneal injury correlates with cell death.

PURPOSE: In previous studies in which in vivo confocal microscopy (CM) was used, quantifiable differences were identified in the corneal epithelium and stroma for surfactants producing different degrees of ocular irritation. In the present study, in vivo confocal microscopy was used to determine area and depth of the initial corneal changes, and the correlation of the data to cell death was characterized by ex vivo live-dead assay. METHODS: In four groups of rabbits (12 animals each), 10 microl surfactants known to produce slight, mild, moderate, or severe irritation was applied to the central cornea of one eye; 4 untreated rabbits served as controls. Measurements of group total mean epithelial thickness, epithelial cell area, and depth of keratocyte loss in four corneal regions were made by in vivo CM in 6 rabbits of each group and in 4 control animals at 3 hours and in the remaining rabbits at 3 hours and 1 day. Corneas were then removed and fixed for conventional histologic examination (two eyes/treatment/group), or regions were excised and placed in culture media containing 2 microM calcein-acetoxymethyl ester (calcein-AM) and 4 microM ethidium homodimer. Using laser scanning CM, the number of dead epithelial or stromal cells in a 300 x 300 x 170 microm (in the x, y, and z axes, respectively) volume of the cornea was determined. RESULTS: Confocal microscopy showed that application of the slight irritant resulted in decreased epithelial thickness at 3 hours (41.2+/-2.6 microm in treated eyes versus 43.6+/-3 microm in control eyes; n=6 and 4, respectively) and a significant decrease (P < 0.001) in epithelial cell size (630+/-203 microm2 versus 1427.2+/-90.7 microm2). On day 1, mild, moderate, and severe irritants caused complete loss of epithelium and disappearance of keratocytes to a depth of 30.8+/-10.7 microm, 47.2+/-10.4 microm, and 764.6+/-159.6 microm (n=6, 5, and 6), respectively. At 3 hours, live-dead assay detected more dead epithelial cells as a percentage of total surface cells (49.2+/-4.5% in slightly irritated eyes versus 20.9+/-3.2% in control eyes), significantly correlating with the measurement by in vivo CM of average epithelial cell size in each eye (r=-0.96; P < 0.005). On day 1, mild and moderate irritants showed increasing stromal cell death from 9.8+/-16.2 cells to 36.4+/-17.7 cells, which significantly correlated with the depth of stromal injury determined by in vivo CM (r=0.79; P < 0.00001). No surviving keratocytes were detected in severely irritated eyes. CONCLUSIONS: The data support the hypothesis that differences in surfactant-induced ocular irritation are directly related to area and depth of acute corneal injury.

Animals↗