Biomedical subjects
Publications and source records attributed to S Murphy.
Campylobacter jejuni is the most common bacterial cause of gastroenteritis and is often missed by routine stool cultures. Patients may present with a clinical syndrome and endoscopic findings that are similar to acute ulcerative colitis. Ciprofloxacin is currently the recommended antibiotic therapy.
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The receptors for epidermal growth factor (EGF) and thyroid hormone (T3) are prototypes, respectively, of transmembrane signaling proteins and nuclear transcription regulatory proteins. Oncogenic homologs of these two receptor genes, v-erbB and v-erbA, cooperate with each other in cellular transformation and blockage of erythrocytic differentiation. As a first step toward investigating this cooperation, we have studied the relationship between the normal homologs of these two receptors in A431 cells. Treatment of these cells with T3 has no significant effect on EGF receptor gene transcription but leads to a drastic decrease in the steady-state level of receptor mRNA. The down-regulatory effect is visible by 2 h and persists up to 8 h, but EGF receptor mRNA returns to normal (sometimes higher than normal) level by 48-72 h. The T3-induced decrease in EGF receptor mRNA (found during 2-8 h of T3 treatment) is due to a specific destabilization of EGF receptor mRNA. The 5.6-kb mRNA that encodes the full-length transmembrane EGF receptor is preferentially degraded. The half-life of the 2.6-kb mRNA that encodes the aberrant C-terminally truncated receptor is unaffected by T3. In other studies we found that T3 decreases the rate of synthesis of the full-length EGF receptor protein and reduces its steady-state amount. Overall the results demonstrate a negative regulatory effect of T3 in post-transcriptional control of EGF receptor expression, and raise interesting questions regarding the mechanism of this down-regulation, and the possible roles of T3 receptors in the control of EGF receptor function.
We studied the delivery of aerosolized cromolyn sodium to intubated babies, and evaluated the effect of changes in delivery techniques. In addition, we compared these results with an in vitro model of aerosol delivery. Cromolyn sodium was used as a marker because once the drug is absorbed, it is excreted unchanged, approximately 50% in urine and 50% in bile. We demonstrated that, in vitro, a conventional, jet-type nebulizer aerosolized 20.5% of a test dose of cromolyn, and only 5.5% of the dose was recovered after passage through 60 cm of ventilator tubing and an endotracheal tube adapter. This increased to 44.5% nebulized and 19% recovered when the volume nebulized was increased from 2 mL to 5 mL. A submicronic nebulizer aerosolized 40% and delivered 33.5% of the test dose. A 20 mg dose of nebulized cromolyn sodium was used as a test dose in infants, after which urine was collected for 4 hours. Forty-three urine samples were collected, after the delivery of cromolyn test doses, from nine babies (16-128 days old) intubated for bronchopulmonary dysplasia. Both the jet and submicronic nebulizers were tested in two positions: 1) in place of the ventilator humidifier, and 2) at the endotracheal tube adapter. There were no statistically significant differences in cromolyn delivery for any system configuration. In all situations, means of less than 0.1% of the test dose were recovered in the urine. We estimated that in all cases, less than 1% of the test dose (approximately 50-100 micrograms of cromolyn) had been deposited in the lung. These results show that although the submicronic nebulizer aerosolized cromolyn more efficiently, no additional cromolyn could be detected in infants. We speculate that a significant portion of the smaller particles are exhaled.
Assessing the presence and severity of bronchiectasis (BR) and mucoid impaction (MI) of the airways in cystic fibrosis (CF) is difficult by non-invasive methods. We hypothesized that scoring ultrafast computerized tomograms (UFCT) of the chest for BR and MI could be useful in detecting early lung changes in 28 patients with CF. To do this, UFCT scores were compared to established clinical and chest X-ray (CXR) scores. Results showed that UFCT scores correlated highly with clinical (r = 0.88) and CXR (r = 0.93) scores, and several pulmonary function tests. Regression analysis indicated that BR influenced clinical and CXR scores more than MI. Both BR and MI were found in all areas of the lungs without a major propensity for one region, although there was significantly more BR in the right upper lobe than the right lower lobe. In patients with CXR score greater than or equal to 21 BR was present in 8/9 and MI in 3/9, while in those with CXR score less than 21 UFCT showed BR in 19/19 and MI in 17/19. We conclude: 1) scored UFCTs correlate well with CXR and clinical scores; 2) BR influences clinical and CXR scores more than MI; 3) UFCTs detect BR and MI in CF patients with minimal evidence of pulmonary disease; and 4) CXR scores less than 21 reflect the presence of both BR and MI.
The goal of these studies was to develop a cost-effective medium for the storage at 22 +/- 2 degrees C of platelets for transfusion. Platelet concentrates were prepared from platelet-rich plasma in a standard fashion and resuspended in 55 mL of medium. Residual plasma was 14.4 +/- 4.3 percent of the final suspending solution. The use of a simple solution containing electrolytes and citrate, but no glucose or bicarbonate, was associated with a drop in pH to the range of 6.0 to 6.6, as a result of the production of lactic acid from the platelet glycogen and glucose present in residual plasma. When 25 mM (25 mmol/L) sodium phosphate was included as a buffer, the drop in pH was retarded, but the range throughout storage was still 6.5 to 6.8. Nonetheless, platelets stored for 5 days in this phosphate-containing medium showed satisfactory maintenance of many in vitro variables. However, there was a 10 to 35 percent reduction of in vivo recovery after isotopic labeling. There was no significant reduction in subsequent mean cell life. Because of the in vivo abnormalities, these media are not recommended for use at the present time. However, the results are encouraging and suggest that further research may lead to a satisfactory, cost-effective medium.
We have developed and tested a rat (Wistar) model of moderate concussion. Concussion is produced by controlled and repeatable mechanical fixed, closed-head injury. Moderate concussion in this model is characterized by 4 to 10 minutes of unconsciousness, absence of skull fractures or brain contusions, and few, if any, acute neurologic symptoms. By 2 hours postinjury, the subsequent trauma is further characterized by regional and global increases in cerebrovascular permeability and decreases in cerebral blood flow. Such changes are accompanied by brain swelling and two phases of elevated intracranial pressure; one lasting about 5 hours with a peak of about 10 mmHg, the other lasting more than 3 days postinjury with a peak of about 30 mmHg. Regional neurohistologic damage detected between 3 and 4 days postinjury correlates for the most part with earlier changes in regional permeability and blood flow. Significant morphologic changes which are characterized by patchy neuronal degeneration can be found in numerous forebrain locations, particularly in the frontal (coup) and entorhinal (contre coup) cortices. These observations have important parallels in human head trauma and suggest that this reliable physiological model may be a useful, relatively simple and inexpensive tool for investigating the mechanisms and therapeutics of head trauma.
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Elongated, highly polyunsaturated derivatives of linoleic acid (18:2 omega-6) and linolenic acid (18:3 omega-3) accumulate in brain, but their sites of synthesis are not fully characterized. To investigate whether neurons themselves are capable of essential fatty acid elongation and desaturation or are dependent upon the support of other brain cells, primary cultures of rat neurons and astrocytes were incubated with [1-14C] 18:2 omega-6, [1-14C]20:4 omega-6, [1-14C]18:3 omega-3, or [1-14C]20:5 omega-3 and their elongation/desaturation products determined. Neuronal cultures were routinely incapable of producing significant amounts of delta 4-desaturase products. They desaturated fatty acids very poorly at every step of the pathway, producing primarily elongation products of the 18- and 20-carbon precursors. In contrast, astrocytes actively elongated and desaturated the 18- and 20-carbon precursors. The major metabolite of 18:2 omega-6 was 20:4 omega-6, whereas the primary products from 18:3 omega-3 were 20:5 omega-3, 22:5 omega-3, and 22:6 omega-3. The majority of the long-chain fatty acids formed by astrocyte cultures, particularly 20:4 omega-6 and 22:6 omega-3, was released into the extracellular fluid. Although incapable of producing 20:4 omega-6 and 22:6 omega-3 from precursor fatty acids, neuronal cultures readily took up these fatty acids from the medium. These findings suggest that astrocytes play an important supportive role in the brain by elongating and desaturating omega-6 and omega-3 essential fatty acid precursors to 20:4 omega-6 and 22:6 omega-3, then releasing the long-chain polyunsaturated fatty acids for uptake by neurons.
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We studied the steady-state rate staircase in isolated rat ventricular cells stimulated at frequencies ranging up to 6 Hz at 37 degrees C. When contractility was measured as displacement of the cell edge, amplitude of motion decreased while stimulation rates were increased from rest to 1 Hz (negative staircase). With further increases in the rate of stimulation to 6 Hz, amplitude of motion increased for each increment in stimulation rate (positive staircase). Ryanodine at a concentration of 100 nM was a negative inotrope and abolished the rested state contraction and the negative staircase seen between rest and 1 Hz (P less than 0.05) but had no significant effect on twitch amplitude or the staircase at stimulation rates between 1 and 6 Hz. L-type Ca2+ channel inhibition with verapamil (0.2 microM) had little effect on twitch or the negative staircase from rest to 1 Hz, but twitch amplitude was diminished and the staircase was converted from positive to negative at stimulation rates between 1 and 6 Hz (P less than 0.05). We conclude that in rat ventricular cells studied at 37 degrees C, the rate staircase is biphasic: negative from rest to 1 Hz and positive from 1 to 6 Hz. This phenomenon is dominated by Ca2+ release from the sarcoplasmic reticulum at rates less than 1 Hz and by Ca2+ entry through L channels at rates greater than 1 Hz.
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Corticosteroids have been used in the therapy of acute, severe asthma since the early 1950s. Numerous randomized, double-blind, placebo-controlled trials in adults and children have proven corticosteroids to be efficacious. Only the results from less rigorously designed trials have failed to show a beneficial effect. The onset of response, dose, and mode of administration have been relatively well defined; however, other aspects (i.e., duration of therapy, need to taper the dose, and risks of multiple short bursts) require further study. Early institution of corticosteroids in well-defined patient populations will decrease the need for hospitalizations. However, administration of corticosteroids to every patient presenting to the clinician's office or emergency room prior to aggressive bronchodilator therapy is unwarranted. All patients demonstrating an incomplete response or the inability to maintain a complete response following one to two hours of aggressive bronchodilator therapy should receive a course of corticosteroids. Courses as short as three to five days have proven efficacy in outpatients, whereas hospitalized patients usually are treated for seven to ten days. The duration of therapy depends on the individual rate of response.
The principal goal of treatment of the acute exacerbation of asthma is the rapid reversal of the airway obstruction which is best accomplished by the frequent administration of inhaled beta 2-agonists. In addition, the early addition of systemic corticosteroids improves the response in patients who incompletely respond to beta 2-agonists. If present, hypoxemia should be corrected with administration of supplemental oxygen. Close monitoring of the patient's response to treatment is essential and if the patient is over 4 years of age and can cooperate, this should include peak expiratory flow rate (PEFR) measurement.
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Adenine and guanine nucleotide metabolism of platelet concentrates (PCs) was studied during storage for transfusion at 22 +/- 2 degrees C over a 7-day period using high-pressure liquid chromatography. There was a steady decrease in platelet adenosine triphosphate (ATP) and adenosine diphosphate (ADP), which was balanced quantitatively by an increase in plasma hypoxanthine. As expected, ammonia accumulated along with hypoxanthine but at a far greater rate. A fall in platelet guanosine triphosphate (GTP) and guanosine diphosphate (GDP) paralleled the fall in ATP + ADP. When adenine was present in the primary anticoagulant, it was carried over into the PC and metabolized. ATP, GTP, total adenine nucleotides, and total guanine nucleotides declined more slowly in the presence of adenine than in its absence. With adenine, the increase in hypoxanthine concentration was more rapid and quantitatively balanced the decrease in adenine and platelet ATP + ADP. Plasma xanthine rose during storage but at a rate that exceeded the decline in GTP + GDP. When platelet ATP + ADP was labeled with 14C-adenine at the initiation of storage, half of the radioactivity was transferred to hypoxanthine (45%) and GTP + GDP + xanthine (5%) by the time storage was completed. The isotopic data were consistent with the presence of a radioactive (metabolic) and a nonradioactive (storage) pool of ATP + ADP at the initiation of storage with each pool contributing approximately equally to the decline in ATP + ADP during storage. The results suggested a continuing synthesis of GTP + GDP from ATP + ADP, explaining the slower rate of fall of GTP + GDP relative to the rate of rise of plasma xanthine. Throughout storage, platelets were able to incorporate 14C-hypoxanthine into both adenine and guanine nucleotides but at a rate that was only one fourth the rate of hypoxanthine accumulation. All of these data should be helpful in improving the function and viability of PC as currently stored for 5 days, in devising methods for storage beyond 5 days, and in the development of synthetic media for PC storage.
Mucosal intra-epithelial nerve terminals have been found in the colon of the toad, Bufo marinus. Co-localized in the fibres are calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) and substance P (SP)-LI. The intraepithelial nerves are likely to be terminals of primary afferent sensory neurones. Fibres with vasoactive intestinal peptide (VIP)-LI or neuropeptide Y (NPY)-LI also supply the mucosa but do not penetrate the epithelium.
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