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Biomedical subjects

J L Smith

Publications and source records attributed to J L Smith.

At least 343 records · Page 19Linked to original sources
PubMed1989

Placebos in clinical trials of peptic ulcer. ACG Committee on FDA-Related Matters.

Placebo use in controlled clinical trials is often challenged as being unethical, as though the investigator in a clinical trial and the clinician are in conflict, one interested primarily in scientific validity, the other in patient care. This paper will review the specific issues in trials for short term (4-8 wk) peptic ulcer disease, demonstrating that controlled trials utilizing placebo are worthwhile, are safe, offer distinct advantages over alternative trials, and impose no real ethical conflict. The ethics regarding the use of a placebo for a controlled trial have been reviewed previously in this column (1). Placebo controls are appropriate in therapeutic trials when 1) standard therapy is either unavailable, of unproven efficacy, or possesses unacceptable side effects, 2) placebo itself is an effective therapy, or 3) the ongoing disease has little adverse effect on the patient. Furthermore, the use of placebo is considered advisable (2), "when the disease process is characterized by frequent spontaneous exacerbations and remissions." Certainly, peptic ulcer is such a disease. It has been argued that the decision to utilize placebo might be between only two individuals, the physician and his patient (3), but realistically, many more must approve the trial, through multi-center participation, involvement by the pharmaceutical industry, and peer review (including human research committee approvals).

Clinical Trials as Topic↗
PubMed1989

Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux disease.

To determine the relation between the sensation of pain in gastroesophageal reflux and the pH of the refluxate, we studied 25 individuals with symptomatic gastroesophageal reflux and positive Bernstein tests. We quantitatively assessed the sensitivity of the esophageal mucosa to pain associated with the intraesophageal infusion of eight different HCl solutions (pH 1, 1.5, 2, 2.5, 3, 4, 5, and 6). Test solutions were infused at 8 ml/min through an eight-lumen catheter with the orifices placed 5 cm above the lower esophageal sphincter. Each subject received all eight solutions in a double-blind randomized fashion. The time-to-pain onset increased with increasing pH; i.e., there was a highly significant difference between the time-to-pain and pH (p less than 0.001), with the time-to-pain significantly longer with increasing pH (r = 0.77). In addition to more rapid onset of pain, all subjects experienced pain with the pH 1 and 1.5 solutions, 80% had pain with the pH 2.0 solution, and half had pain with solutions of pH 2.5-6. Fifteen of these subjects underwent 24-h pH monitoring and these tests were examined for factors associated with pain. Only 64% of all pain episodes were associated with a pH drop of less than 4; the lowest pH obtained was not different between episodes with and without pain. Reflux episodes resulting in pain were significantly longer than those without pain and were more often associated with a recently preceding painful episode. Overall, none of the data from the 24-h pH monitoring was useful for predicting pain. The acid infusion studies and the 24-h pH data, taken together, suggest episodes of pain sensitize the patient for subsequent pain.

Adult↗
PubMed1988

Spicy food and the stomach. Evaluation by videoendoscopy.

We used videoendoscopy to investigate the effect of eating spicy foods on the gastric mucosa. We employed four meals: a bland meal of unpeppered steak and french fries (negative control), a bland meal with 1950 mg of aspirin (positive control), a spicy Mexican meal (30 g of jalapeño peppers), and a pepperoni pizza. Twelve subjects (eight men and four women, aged 24 to 43 years) were studied in a randomized, crossover trial with the test meal given at the noon and evening meals; each subject received all four test meals. Each study consisted of a baseline endoscopy, which was repeated approximately 12 hours after the last test meal. Gastric and duodenal damage was scored using a modification of the Lanza scale. Eleven of 12 individuals taking the bland meal plus aspirin developed multiple gastric erosions (median score, C; which equates with "severe" injury). In contrast, the median endoscopic score for the other three meals was 0. Single cases of a single erosion were present after the Mexican meals and after the pizza meals. Another experiment was done to examine the effect of spices directly on the gastric mucosa; approximately 30 g of fresh jalapeño peppers was ground in a food processor and then placed directly into the stomach. Endoscopy after 24 hours revealed no visible mucosal damage. The ingestion of highly spiced meals by normal individuals is not associated with endoscopically demonstrable gastroduodenal mucosal damage.

Adult↗
PubMed1988

Evaluation of a facility for family medicine vocational training.

Vocational training for family medicine/general practice has been accepted and implemented in much of the Western world, and implementation locally is being investigated. A large public sector primary care service has been evaluated as a potential facility for providing part of a vocational training programme. The conclusions drawn are positive.

Day Care, Medical↗
PubMed1988

Refinement at 1.4 A resolution of a model of erabutoxin b: treatment of ordered solvent and discrete disorder.

The latter stages in the refinement of the protein erabutoxin b are described. The crystal structure of the 62-residue protein has been refined to a conventional R factor of 0.144 by stereochemically restrained least-squares methods using diffraction data to a limit of 1.4 A spacings. Emphasis was placed on determining as accurately as possible the solvent structure and the structures of heterogeneous groups in the protein. The final model includes two conformers for each of seven side chains and for an octapeptide segment. A total of 111 sites for water molecules have been located as well as one sulfate ion with a total of 68 site occupancies. 65 of the solvent sites overlap either with protein atoms belonging to groups in two alternative conformations or with other solvent sites. Dual protein conformers and overlapping solvent sites were both included in the least-squares refinement. Individual thermal and occupancy parameters were refined for solvent molecules. An analysis of these parameters has provided useful structural information.

Chemical Phenomena↗
PubMed1988

Nosocomial aseptic meningitis associated with administration of OKT3.

An outbreak of nosocomial aseptic meningitis involving four renal allograft recipients on the transplant service occurred in July 1986, shortly after the release of the murine monoclonal antibody OKT3 for therapy for acute allograft rejection. No bacteria, fungi, or viruses were isolated from cultures of the cerebrospinal fluid of the four patients. All four had acute allograft rejection treated with OKT3 and developed signs and/or symptoms of meningitis within 72 hours of receiving the drug. To identify potential risk factors, the four patients with aseptic meningitis were compared with 12 patients on the renal transplant service in July 1986 who did not have signs or symptoms of meningitis. The development of aseptic meningitis was strongly associated with administration of OKT3. Because of this association, prospective surveillance of meningitis in patients receiving OKT3 was instituted. From November 1986 to May 1987, three (14%) of 21 patients treated with OKT3 developed aseptic meningitis. The clinical course of aseptic meningitis associated with OKT3 appears to be benign and self-limited. Nonetheless, this observation warrants continued surveillance of OKT3 therapy.

Antibodies, Monoclonal↗
PubMed1988

Neuromuscular patterns of stereotypic hindlimb behaviors in the first two postnatal months. I. Stepping in normal kittens.

Neuromuscular patterns associated with the development of hindlimb stepping behaviors were studied from birth to postnatal day 60 in normal kittens. Hindlimb muscles were chronically implanted with EMG electrodes at birth to characterize interlimb coordination and intralimb synergies during development of overground and treadmill stepping. Airstepping was also examined but seldom occurred after the second postnatal week. All kittens performed stepping under each condition, including weight-supported stepping, by postnatal day 3. The number of sequential steps on the treadmill and overground increased with age and cycle periods decreased. At onset, stepping behaviors were characterized by adult-like EMG patterns. Interlimb coordination was typified by alternating extensor bursts of similar duration. Extensors at the knee and ankle were coactive during the stance phase, and extensor burst durations were strongly correlated with the cycle periods over a wide range of stepping frequency. Ankle flexor and extensor muscles were reciprocally active during postural tremor, bouts of airstepping, and weight-supported steps on the treadmill and overground. The duration of the reciprocal flexor bust did not vary with cycle period or age. Observations of stepping behaviors and adult-like EMG patterns during initial postnatal development were contingent on optimal testing conditions. Taken together, the data suggest that pattern-generating circuits for regulating interlimb coordination and intralimb muscle synergies are potentially functional prior to the normal ontogenetic onset of locomotion. Perhaps the prolonged postnatal development of locomotion reflects the time required to establish adaptive mechanisms, such as postural control and agility, rather than spinal pattern-generating circuits for locomotion.

Animals↗
PubMed1988

Neuromuscular patterns of stereotypic hindlimb behaviors in the first two postnatal months. II. Stepping in spinal kittens.

From birth to postnatal day 60, neuromuscular patterns for airstepping and treadmill stepping were assessed in kittens spinalized (T12) at birth (Day-1) or at the end of the second postnatal week (Day-14). Within 72 h after spinalization, all kittens displayed stepping motions, but exteroceptive facilitation (e.g. tail pinch) was required to initiate and sustain both behaviors. In Day-14 spinal kittens, the hindlimbs spontaneously and alternately airstepped, but in Day-1 spinal kittens exteroceptive stimulation was usually necessary to evoke airstepping, and the hindlimbs stepped synchronously. Kittens in both groups developed atypical neuromuscular patterns; flexor bursts were nearly twice as long in duration as extensor bursts. Development of bipedal treadmill stepping was similar for Day-1 and Day-14 spinal kittens, but differed from that for normal kittens. Tested at the same belt speeds, stepping was more easily elicited in spinal kittens, bouts of repetitive stepping were longer, and cycle periods were shorter than in normal kittens until postnatal week 6. Spinal kittens, however, seldom exhibited adequate weight support during hindlimbs stepping, and the neuromuscular patterns associated with bipedal stepping were atypical. For spinal kittens, the relationship between the extensor burst duration and the cycle period was reduced substantially, and flexor activity was initiated earlier in the step cycle and was longer in duration than that for normal kittens. These atypical intralimb synergies may have been the consequence of altered lumbosacral circuits produced by the spinal transection. It is also possible that these spinal circuits, lacking rostral input, were particularly susceptible to abnormal motion-dependent feedback resulting from reduced hindlimb weight support.

Animals↗
PubMed1988

Neuromuscular patterns of stereotypic hindlimb behaviors in the first two postnatal months. III. Scratching and the paw-shake response in kittens.

Neuromuscular patterns of scratching and the paw-shake response were studied in normal kittens from birth to postnatal day 60. Onset of both behaviors coincided with the development of secure weight-bearing posture and occurred on postnatal day 21 for scratching and postnatal day 26 for paw shaking. At onset, cycle periods for scratching (5-6 Hz) and paw shaking (8-10 Hz) were similar to that for adult cats, and EMG patterns were adult-like. The scratch cycle consisted of reciprocal flexor and extensor bursts of equal duration, while the shake cycle consisted of coactive knee extensor and ankle flexor bursts alternately active with ankle extensor bursts. The lack of scratching and paw shaking during the first 3 postnatal weeks and the adult-like EMG patterns at onset are consistent with the hypothesis that pattern-generating circuits within lumbosacral segments are available early in development but inhibited by the rostral neuraxis until postural control is sufficient to accommodate the response. To eliminate rostral inputs, including descending input critical for postural control, kittens were spinalized at the T12 level, and onset of paw shaking was accelerated. In kittens spinalized at birth, paw-shake onset occurred on postnatal day 14, while in kittens spinalized on postnatal day 14, onset occurred 48 h after spinalization. In all spinal kittens, however, knee extensor activity was disrupted and not normal by postnatal day 60. Mature neuromuscular patterns for scratching and paw shaking are available at onset of the behavior during normal development. Spinalization hastens the onset of paw shaking but the normal neuromuscular synergy is disrupted as well as the temporal structure of the multi-cycle response. Disruptions following spinalization may be due to altered development of spinal pattern generators or aberrant feedback from atypical hindlimb motions due to a retardation of hindlimb growth and an alteration of muscle contractile properties in spinal kittens.

Age Factors↗
PubMed1988

Crystallographic structure analysis of lamprey hemoglobin from anomalous dispersion of synchrotron radiation.

The molecular structure of lamprey hemoglobin was previously determined and refined by conventional crystallographic analysis. In this study, the structural analysis has been repeated in the course of developing the method of multiwavelength anomalous diffraction (MAD) for phase determination. New experimental and analytical procedures that were devised to perform this determination should have general applicability. These include an experimental design to optimize signal strength and reduce systematic errors, experimental evaluation of anomalous scattering factors, and a least-squares procedure for analyzing the MAD data. MAD phases for the structure at 3 A resolution are as accurate overall as the multiple isomorphous replacement (MIR) phases determined previously.

Animals↗
PubMed1988

Role of cell-cycle in regulating neuroepithelial cell shape during bending of the chick neural plate.

Neuroepithelial cells transform from spindle-shaped to wedge-shaped within the median and paired dorsolateral hinge points of the bending neural plate, but the mechanisms underlying these localized changes are unclear. This study was designed to evaluate further the hypothesis that localized "wedging" of neuroepithelial cells during bending involves basal cellular expansion resulting from alteration of the cell-cycle. Neurulating chick embryos were treated with tritiated thymidine, and transverse sections through the midbrain were examined autoradiographically. Parameters of the cell-cycle as well as nuclear position and size were assessed in the median hinge point, which contains predominantly wedge-shaped cells, and in adjacent lateral areas of the neural plate, which contain predominantly spindle-shaped cells. Both the DNA-synthetic phase and non-DNA synthetic portion of the cell-cycle were significantly longer in the median hinge point than in lateral neuroepithelial areas, some nuclei in both regions were located basally during these phases, and virtually all basal nuclei in the median hinge point were large. Additionally, the mitotic phase was significantly shorter in the median hinge point than in lateral areas. We present a model to explain how alteration of the cell-cycle in the median hinge point could generate wedging of cells in this region.

Animals↗
PubMed1988

Intragastric accumulation of Evan's blue as a method for assessing aspirin-induced acute gastric mucosal injury in humans.

Aspirin administration results in gastric mucosal damage. Although the pathogenesis of these lesions remains unclear, in animals it appears that increased vascular permeability precedes development of grossly visible lesions. We examined the effect of aspirin administration on gastric vascular permeability in eight healthy subjects. We used gastric accumulation of Evan's blue dye (which is bound to albumin) as a marker of vascular integrity and assessed gastric accumulation of Evan's blue, blood, and DNA during serial 10-min washes. Both bleeding and Evan's blue in the gastric washings increased with time after administration of aspirin in an acid solution (P less than 0.01). Evan's blue increased from a median value of 8 micrograms/10 min to 24.5 micrograms/10 min period after 60 min of aspirin administration. By 20 min after aspirin administration, the accumulation of Evan's blue in the gastric wash was significantly greater than the initial aspirin period (P less than 0.05). Blood loss increased from 147 to 650 micrograms Hgb/10-min period. The increase in bleeding rate did not become significant until 40 min after the first aspirin dose. Our study showed that aspirin-induced gastric mucosal damage can be detected by assessing accumulation of Evan's blue in the gastric contents after aspirin administration. Studies in which various doses of aspirin or other agents are administered will be required to confirm whether the increased vascular permeability actually precedes bleeding in man. Measurement of Evan's blue dye in the gastric contents appears to provide a qualitative (and possibly quantitative) and sensitive early index of gastric mucosal injury.

Adult↗
PubMed1988

Autoantibodies in paraneoplastic cerebellar degeneration bind to cytoplasmic antigens of Purkinje cells in humans, rats and mice and are of multiple immunoglobulin classes.

Purkinje cell autoantibodies in sera of six female patients with paraneoplastic cerebellar degeneration (PCD) were investigated by indirect immunofluorescence for immunoglobulin isotype and species specificity. Four patients had gynecologic cancer, one breast cancer and one lymphoma. Control sera from 125 patients were negative for Purkinje cell antibodies of IgG, IgM and IgA isotypes. These included neurologically normal cancer patients, cancer patients with paraneoplastic syndromes not involving the cerebellum and patients with non-neoplastic neurologic disorders. IgG antibodies in the six PCD sera bound to discrete cells in the cerebellum of human, rat and mouse (titers 1000-128,000). Antibodies of IgM class were additionally found in two sera (titers 100 and 500) and IgA in a third serum (titer 1000). Antibodies of each isotype gave a similar staining pattern, highlighting the cytoplasm of Purkinje cells in a coarse granular pattern, and the peripheral cytoplasm of discrete molecular layer cells. Antibodies of IgE class were not found. Rodent cerebellar tissue was found to be a useful substitute for human tissue in clinical testing for Purkinje cell antibodies, and has the advantage of being readily available in highly viable state. Its use should facilitate further characterization of the autoantigen(s) of PCD, and possibly the development of an animal model involving passive transfer of immunoglobulins. Screening for IgM and IgA Purkinje cell antibodies in addition to IgG may increase the yield of positive results in clinical serological testing.

Animals↗
PubMed1988

Phenotypic and genotypic heterogeneity of peripheral T-cell lymphoma.

A series of 21 phenotypically characterised T-cell lymphomas histologically defined as lymphocytic, lymphoblastic, immunoblastic, AILD type, pleomorphic, T-zone and Lennert's T-cell lymphoma, were investigated for T-cell receptor (TcR) and immunoglobulin (Ig) gene rearrangements. Phenotypic analyses of frozen sections and cell suspensions were heterogeneous and in many cases no single T-cell marker recognised all of the malignant cells. Data derived by staining with antibodies reactive with antigens in paraffin embedded tissue were consistent with T NHL in all cases except lymphoblastic lymphoma. TcR gene rearrangements were observed in lymphocytic, lymphoblastic and immunoblastic lymphoma, however, in the remaining 14 phenotypically and histologically defined peripheral T-cell lymphomas, 2 showed rearrangement of TcR gamma and beta genes consistent with T NHL and 2 showed Ig JH rearrangements only, suggestive of either reactive T-cell populations masking cryptic disease or presence of tumour populations with aberrant gene rearrangement and expression of T lineage antigens. No Ig or TcR gene rearrangements were found in the remaining 10 cases, in which morphologically identifiable tumour cells comprised 10-90% of the cell population. In 3/6 cases tested some CD3 positive cells failed to stain with WT31 or beta F1, monoclonal antibodies that recognise determinants on combined TcR gamma beta or TcR beta chains respectively. Whether these cases represent tumours arising from an undetermined cell of origin or polyclonal expansions of T-cells remains to be determined. Our results confirm the phenotypic heterogeneity of histologically defined peripheral T-cell lymphoma and indicate that in these particular histological subtypes gene rearrangement analysis can also yield heterogeneous results which may be unhelpful in determining cell lineage and clonality.

DNA Probes↗