The development of ethical guidance for medical practitioners by the General Medical Council.
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Education, Medical↗
Biomedical subjects
R G Smith
Publications and source records attributed to R G Smith.
Designing a biological monitoring program to assess community exposure to chromium: conclusions of an expert panel.
The possible benefits of biological monitoring of large groups of people potentially exposed to environmental contaminants has become an area of much interest in recent years. Because chromite-ore processing residue has been found in some soils in northern New Jersey, urinary chromium monitoring of people in the community was evaluated as a potentially useful tool. In an attempt to identify those who could be exposed and to quantify the magnitude of exposure to the chromium in these soils, the New Jersey Department of Health (NJDOH) initiated a public health screening project. In 1992, the NJDOH proposed to evaluate over 4000 people who lived or worked near these sites. Volunteers were administered a questionnaire and were given a limited physical examination, and a single spot urine sample was collected. Because of the difficulties in using urinary chromium to assess low-level exposure and the potential implications of any regulatory decisions that could be based on the results of this project, a panel of experts was convened to evaluate the protocol. The panel consisted of five scientists and physicians with expertise in toxicology, dermatology, epidemiology, biological monitoring, and analytical chemistry. Like a World Health Organization group, the panel concluded that although urine biomonitoring can be useful in evaluating high levels of exposure to chromium, it is not reliable for assessing low-level exposure similar to that which may have occurred in northern New Jersey. The panel also noted that when urinary biomonitoring is to be used to assess the public's possible exposure, a large number of precautions must be taken to ensure the accuracy and usefulness of the results. The single most important recommendation was to collect a second, and perhaps a third, spot urine (or 24-h urine) sample before concluding that a person may be routinely overexposed. These suggestions are applicable to designing a biomonitoring program for nearly any environmental contaminant to which a community may be exposed. A review of scientific literature associated with biological monitoring of chromium is provided.
Absorption↗
The action of amyotrophic lateral sclerosis immunoglobulins on mammalian single skeletal muscle Ca2+ channels.
1. The planar phospholipid bilayer technique was used to study the T-tubule skeletal muscle dihydropyridine (DHP)-sensitive calcium (Ca2+) channel. To improve the signal-to-noise ratio, Ca2+ channel activity was recorded using both 800-50 and 500-50 mM NaCl gradients. 2. Ca2+ channels were characterized by their cation selectivity and pharmacological profile. The mean open time for channels identified by these techniques was increased by the DHP agonist Bay K 8644 (2 microM), while it was decreased by the DHP antagonist nifedipine (5 microM). Nifedipine also reduced Ca2+ channel amplitude levels. 3. Immunoglobulins G (IgG) from three amyotrophic lateral sclerosis (ALS) patients (n = 14 experiments), one myasthenia gravis (MG) patient (n = 3 experiments) and one healthy individual (n = 4 experiments), were tested on Ca2+ channel activity at a final concentration of 3 mg/ml. 4. Channel mean open time, mean closed time and time integral for the current were not modified by normal IgG (n = 4 experiments). Similarly, MG IgG did not reduce channel activity (n = 3 experiments). 5. ALS IgG reduced the mean open time of DHP-sensitive Ca2+ channel activity in twelve out of fourteen experiments. In addition, in five out of twelve experiments, ALS IgG stabilized the channel to a smaller amplitude level. 6. ALS IgG reduced Ca2+ channel activity in a side-selective fashion, probably corresponding to the external side of the channel. 7. These results suggest that ALS IgG action on DHP-sensitive Ca2+ channels is not mediated by second messengers, thus favouring a direct mechanism for interaction with the DHP receptor complex.
Amyotrophic Lateral Sclerosis↗
Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: phase I-II study.
From June 1988 to July 1991, 20 patients with locally advanced rectal or rectosigmoid cancer were treated prospectively with a strategy of combining preoperative irradiation and fluorouracil chemotherapy before surgical resection. The preoperative radiation dose was 5,000 cGy, and fluorouracil chemotherapy was administered on the first and last 3 days of irradiation in an intravenous bolus dose of 500 mg/m2. In a median follow-up of 25 months, the local regional failure rate was 10%. The 3-year actuarial overall survival and disease-free survival were 92% and 82%, respectively. Twenty percent of the surgical specimens showed no residual tumor, and only 10% showed positive lymph nodes. Significant leukopenia occurred in 10% of patients. Preoperative irradiation and fluorouracil chemotherapy increased surgical downstaging and improved local regional control. The overall toxicity was acceptable. The results of this particular multimodality approach was encouraging and warrant further investigation in phase III trials.
Adult↗
Fab fragments from amyotrophic lateral sclerosis IgG affect calcium channels of skeletal muscle.
Amyotrophic lateral sclerosis (ALS) is a human disease involving upper and lower motoneurons. In this paper we studied the action of specific antigen-binding site (Fab) fragments of immunoglobulins from ALS patients on dihydropyridine (DHP)-sensitive Ca2+ channel function in situ. Ca2+ channels in single mammalian skeletal muscle fibers tested by the double Vaseline gap technique and single Ca2+ channels reconstituted into bilayer were tested in these experiments. Although the observed current-voltage relationship was not modified by the addition of Fab fragments (1.5 mg/ml), peak Ca2+ current (ICa) was significantly reduced. The effect of these Fab fragments on the peak ICa reached a stable value after 60 min of incubation. ALS Fab fragments also slowed the ICa rising phase and increased the rate of tail current deactivation. Studies with double pulses demonstrated that ICa inactivation time course, voltage dependence, and recovery were not modified by ALS Fab fragments. Fab fragments from normal subjects and heat-inactivated Fab fragments from ALS patients did not induce any modification on the charge movement and ICa. In single channel studies, ALS Fab fragments reduced channels amplitude. These data support the concept of an immunological interaction between the circulating antibodies from ALS patients and DHP-sensitive Ca2+ channels.
Amyotrophic Lateral Sclerosis↗
A novel non-peptidyl growth hormone secretagogue.
Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.
L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.
Animals↗
The ventricular assist device patient.
This article provides an overview of ventricular assist devices, which are mechanical pumps that circulate blood within the body. At the present time, these devices are used to provide a "bridge to transplantation" of the heart or to maintain adequate circulation while the heart recovers from injury. Permanent implantation of these devices may soon become a reality. Use of this technology can tremendously impact the recipient's life and adaptation to their circumstances may be difficult. Topics related to the process of adjustment are presented. These include quality of life issues such as optimization of patient care, dealing with the occurrence of complications, limitations in mobility, and possible termination of support. Facing these issues requires great courage and will likely affect personal growth and deepen relationships. Caregivers can be instrumental in helping to meet the basic physical, emotional and spiritual needs of these patients.
Adaptation, Psychological↗
Analysis of the reinforcement and extinction components in DRO contingencies with self-injury.
Previous research has shown that self-injurious behavior (SIB) maintained by positive reinforcement may be reduced under differential-reinforcement-of-other-behavior (DRO) contingencies. In this study, we conducted an analysis of the reinforcement and extinction components of DRO while treating the self-injury of 3 women with developmental disabilities. A functional analysis revealed that each subject's SIB was maintained by positive reinforcement in the form of attention. Subsequent reinforcer assessments identified preferred and nonpreferred stimuli for later use in conjunction with DRO. Results showed high rates of SIB for all 3 subjects during baseline, which persisted when DRO was implemented without the relevant extinction component (withholding of attention for SIB) for 2 of the subjects. Low rates of SIB were observed for all subjects when DRO plus extinction was implemented or when extinction was implemented alone, suggesting that extinction may be a critical component of DRO schedules.
Adult↗
Experimental analysis and treatment of multiply controlled self-injury.
A functional analysis of the self-injurious behavior (SIB) of 3 adults with profound developmental disabilities showed that each engaged in SIB in more than one assessment condition. Such outcomes may result from a failure to isolate the variable maintaining SIB, or they may reflect multiple sources of control over SIB. In order to identify more clearly the determinants of SIB, each subject was exposed to a series of treatments appropriate to one or both of the apparent functions of SIB. These treatments, applied sequentially on baselines appropriate to each behavioral function, identified the maintaining variables for SIB through differential outcomes across baselines. Results indicated that the SIB of 2 subjects was multiply controlled, confirming the outcomes of the functional analysis. However, the SIB of the 3rd subject was eliminated using a treatment designed for a single function, suggesting spurious results of the original assessment. Alternative interpretations of undifferentiated assessment data are discussed, as are analysis and treatment issues related to multiply determined behavior disorders.
Adult↗
Extinction of self-injurious escape behavior with and without instructional fading.
Three individuals with developmental disabilities participated in a study of the treatment of self-injurious behavior (SIB) maintained by negative reinforcement (escape from educational tasks). Treatment was implemented in a multiple baseline design across subjects, in which two treatments were compared in a multielement format. Both treatment conditions included an escape-extinction component in which SIB no longer produced escape. One of the conditions also included a fading component in which the frequency of instructions was initially reduced to zero and then was gradually faded back in across sessions until the instructional rate matched that of the original baseline. Results indicated that extinction alone reduced SIB to the end-of-treatment criterion in fewer sessions than did extinction plus fading for all 3 subjects. For 2 of the 3 subjects, however, there was an initial increase in the frequency of SIB at the outset of treatment with extinction (an extinction burst) that was not observed when extinction was combined with the fading component.
Adult↗
The role of attention in the treatment of attention-maintained self-injurious behavior: noncontingent reinforcement and differential reinforcement of other behavior.
Because there are potentially serious limitations to differential reinforcement of other behavior (DRO) (which is probably the most widely used treatment procedure for behavior problems), we examined an alternative procedure--noncontingent reinforcement (NCR). Three females with developmental disabilities, all of whom engaged in severe self-injurious behavior, participated. During a pretreatment functional analysis, each subject's self-injury was shown to be differentially sensitive to social attention as a maintaining consequence. Next, each subject was exposed to a DRO treatment and an NCR treatment. During DRO, attention was delivered contingent on the absence of self-injury for prespecified intervals. During NCR, attention was delivered on a fixed-time schedule that was not influenced by the subject's behavior. Results showed that both procedures were highly effective in reducing self-injury, probably because the functional reinforcer for self-injury was used during treatment. Furthermore, there was evidence that NCR attenuated several of the limitations of DRO. These results are particularly interesting in light of the long experimental history of NCR as a control rather than as a therapeutic procedure.
Adult↗
The Lambert-Eaton syndrome.
This rare myasthenic disorder is the first neurologic disease found to be caused by antibodies against an ion channel complex. It presents an unusual opportunity to clarify the pathobiology of so-called receptor diseases, as well as to gain better understanding of the normal biology of acetylcholine release and its effect on neuromuscular junctions.
Autoimmunity↗
Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis.
BACKGROUND AND METHODS: Sporadic amyotrophic lateral sclerosis is a chronic, progressive degenerative disease of the motor neurons of the spinal cord and motor cortex. The cause is unknown. Recent electrophysiologic studies in animals indicate that immunoglobulins from patients with this disease alter presynaptic voltage-dependent calcium currents and calcium-dependent release of neurotransmitters. To determine whether similar interactions might be identified biochemically, we used an enzyme-linked immunosorbent assay (ELISA) to detect the reaction of serum IgG with purified complexes of L-type voltage-gated calcium channels from rabbit skeletal muscle. The results from patients with amyotrophic lateral sclerosis were compared with those obtained from patients with other types of motor neuron disease, patients with autoimmune and non-autoimmune neurologic diseases, and normal subjects. RESULTS: Serum samples from 36 of 48 patients with sporadic amyotrophic lateral sclerosis (75 percent) contained IgG that reacted with L-type calcium-channel protein, and serum reactivity on ELISA correlated with the rate of disease progression (Spearman rank-correlation coefficient, 0.62). Reactive serum was present in only 1 of 25 normal subjects and 1 of 35 control patients with no motor neuron disease. Antibodies to L-type voltage-gated calcium channels were identified in 6 of 9 patients with Lambert-Eaton syndrome, and in 3 of 15 patients with Guillain-Barré syndrome. CONCLUSIONS: Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with amyotrophic lateral sclerosis, and antibody titers correlate with the rate of disease progression. Together with previous data, these results suggest a role for autoimmune mechanisms in the pathogenesis of sporadic amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis↗
Serious professional misconduct arising out of dental anaesthesia and sedation.
This paper reviews three recent decisions of the Judicial Committee of the Privy Council on appeal from decisions of the Professional Conduct Committee of the General Dental Council, in which questions of general anaesthesia, sedation and resuscitation were raised. The recommendations of the Poswillo Report on general anaesthesia, sedation and resuscitation in dentistry of March 1990 are considered with respect to these three cases, and an assessment made as to whether or not the incidents which gave rise to them would have occurred had the recommendations been implemented. The implications of the Poswillo Report for the maintenance of professional standards of conduct by the General Dental Council in relation to the use of general anaesthesia, sedation and resuscitation are discussed.
Anesthesia, Dental↗
Aromatase enzyme activity and sex determination in chickens.
During development, the genotype of the zygote determines the nature of the gonad, which then determines the male or female phenotype. The molecular events underlying this process are just beginning to be defined. A single treatment of chicken embryos with an aromatase inhibitor (which blocks the synthesis of estrogen from testosterone) at a stage when their gonads were bipotential caused genetic females to develop a permanent male phenotype. These sex-reversed females developed bilateral testes that were capable of complete spermatogenesis and had the physical appearance and behavior of normal males. This result identifies aromatase as a key developmental switch in the sex determination of chickens.
Animals↗
Computational model of the on-alpha ganglion cell receptive field based on bipolar cell circuitry.
The on-alpha ganglion cell in the area centralis of the cat retina receives approximately 450 synapses from type b1 cone bipolar cells. This bipolar type forms a closely spaced array (9 microns), which contributes from 1 to 7 synapses per b1 cell throughout the on-alpha dendritic field. Here we use a compartmental model of an on-alpha cell, based on a reconstruction from electron micrographs of serial sections, to compute the contribution of the b1 array to the on-alpha receptive field. The computation shows that, for a physiologic range of specific membrane resistance (9500-68,000 omega.cm2) and a linear synapse, inputs are equally effective at all points on the on-alpha dendritic tree. This implies that the electrotonic properties of the dendritic tree contribute very little to the domed shapes of the receptive field center and surround. Rather, these shapes arise from the domed distribution of synapses across the on-alpha dendritic field. Various sources of "jitter" in the anatomical circuit, such as variation in bipolar cell spacing and fluctuations in the number of synapses per bipolar cell, are smoothed by the overall circuit design. However, the computed center retains some minor asymmetries and lumps, due to anatomical jitter, as found in actual alpha-cell receptive fields.
Animals↗
A simple and safe technique of left ventricular venting.
Left ventricular venting has many physiologic and practical benefits. A venting technique is described that employs a simple, closed system which allows the perfusionist to monitor left ventricular distention. By monitoring the left ventricular volume the perfusionist can regulate the degree of negative pressure on the vent and thus reduce the chance of air entering the heart.
Coronary Artery Bypass↗