Transdermal fentanyl: acute analgesic clinical studies. The transdermal therapeutic system (TTS) is a novel technique of drug administration that can mimic long-term continuous intravenous infusions in maintaining stable drug plasma concentrations. Fentanyl, a potent lipid-soluble synthetic opioid, has been incorporated into such a system and has undergone preliminary clinical trials in postoperative patient populations to assess analgesic efficacy and incidence of undesirable side effects (pruritus, nausea and vomiting, urinary retention, respiratory depression). In general, when applied 2 hr preoperatively, a TTS (fentanyl) patch (in different doses) provides moderate-to-good analgesia for a variety of surgical procedures for periods of up to 3 days. Most patients will require small amounts of systemically administered opioids for supplementary analgesia, especially in the first 24 postoperative hr. The incidence of side effects such as nausea and vomiting varies between studies but can be as high as 70%. Clinically significant respiratory depression is rare but was reported in several of the studies. TTS (fentanyl) is a simple and useful technique for the control of postoperative pain.


The history and development of the fentanyl series. In the last two decades, opioid analgesics have assumed an important place in general anesthetic practice in the United States. Part of the reason for this has been the introduction of the potent new agonists fentanyl, sufentanil, and alfentanil. Because of problems with morphine-oxygen anesthesia (incomplete amnesia, occasional histamine-related reaction, marked increases in intra- and postoperative respiratory depression), a suitable alternative was sought but not found among existing opioids. A breakthrough came in 1960, when fentanyl was synthesized, laying the foundation for a better understanding of the structure-activity relationships of narcotic analgesics and stimulating interest in developing compounds with even greater potency and safety margins. Investigators interested in opioid anesthesia began to study fentanyl in animals and then in humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was evaluated as an anesthetic in patients undergoing mitral valve and coronary artery surgery. Changes in cardiovascular dynamics with induction doses ranging from 8 to 30 micrograms/kg consisted of small decreases in heart rate and arterial blood pressure. All other cardiovascular variables studied, including cardiac output, remained unchanged, even with additional doses up to 100 micrograms/kg. It was determined that fentanyl had use as a narcotic anesthetic, despite its potential for cardiovascular depression and stimulation, respiratory depression, muscle rigidity, and, occasionally, incomplete anesthesia. Since the introduction of fentanyl, two other potent synthetic opioids have been introduced into clinical practice--sufentanil and alfentanil.


Transdermal fentanyl: long-term analgesic studies. Alternative routes of drug delivery have particular relevance for use in chronic pain. When the pain experience is constant or nearly constant, a continuous infusion of drug is an ideal way to achieve effective pain relief. Early experience with the transdermal application of fentanyl in chronic cancer pain suggests that it is a safe, noninvasive, effective method of managing pain. The first experience with the use of transdermal fentanyl in cancer pain was reported by Miser and colleagues in 5 patients. They demonstrated that steady-state blood concentrations of fentanyl were linearly related to the transdermal fentanyl dose. The terminal elimination half-life was approximately 34 hr. Zech and colleagues studied 13 patients with chronic cancer pain. Pain relief was obtained and was correlated with plasma fentanyl levels. The largest experience so far was reported in 39 patients in a multicenter trial conducted by Simmonds and colleagues. The median fentanyl dose was 100 micrograms/hr (range, 25-525 micrograms/hr). The initial dose of fentanyl from morphine conversion (6:1) was adequate in 50% of patients and titrated upward by 72 hr for the remaining 50%. Patients wore the system for a median of 84 days (range, 5-365 days). Median supplementary daily dose of morphine was 105 mg/day (range, 0-720 mg/day). The system was able to be maintained through a variety of concomitant events. This experience demonstrated the safety and clinical effectiveness of transdermal fentanyl. The transdermal therapeutic system (fentanyl) is a promising advance in achieving noninvasive, continuous drug administration for the management of chronic cancer pain.


Transdermal fentanyl: suggested recommendations for clinical use. Transdermal fentanyl offers the advantage of providing continuous administration of a potent opioid in the absence of needles and expensive drug-infusion pumps for the treatment of cancer pain. When transdermal fentanyl is initiated, it may be necessary to change the dose every 24-48 hr until an appropriate dose is titrated to the needs of the patient. This should be done by providing short-acting opioids as rescue analgesics for breakthrough pain. Well-accepted principles established for chronic opioid use in cancer pain management should apply to the administration of transdermal fentanyl as well. These include dose titration, the coadministration of adjuvant drugs to counteract opioid side effects and enhance analgesia, and the need to reassess the patient continuously for recurrent tumor and other new sources of pain. Further clinically relevant studies are needed and include 1) the determination of the relative potency of transdermal fentanyl, especially in comparison with oral and parenteral morphine; 2) a prospective study of the side-effect profile of transdermal fentanyl in relationship to oral morphine; and 3) the role of oral transmucosal administration of fentanyl in selection of starting doses of transdermal fentanyl and as a means to provide rescue doses for breakthrough pain.


Transdermal fentanyl: clinical trial at the University of Colorado Health Sciences Center. Transdermal fentanyl is a new fentanyl delivery system recently approved by the FDA for use in patients with chronic pain. In an open-label clinical trial, 5 patients with cancer pain were switched to transdermal fentanyl patches. Patients were evaluated with visual analogue scales (VAS) for pain, mood, and pain relief. A Functional Living Index--Cancer and a symptom questionnaire were filled out 2 wk and 4 wk after initiation of transdermal fentanyl patches. After 2 wk of treatment all patients had VAS improvements in pain control. Patients experienced a decrease in constipation, improved appetite, and improved mood. One patient had drowsiness, which limited dose. The improvements in pain control allowed these patients to perform tasks that they had previously not felt well enough to do.


Transdermal fentanyl: seeding trial in patients with chronic cancer pain. In this study, 6 patients with pain from advanced cancer were enrolled in a multicenter, open-label seeding trial of transdermal fentanyl. Following equianalgesic dose conversion, transdermal fentanyl patches were applied every 3 days. Mean fentanyl dosage doubled by week 2 and tripled by week 4. Pain control improved in all patients. There were no significant changes in mood, constipation, nausea, sedation, daily activities, or interpersonal relationships from pretrial to posttrial analyses. Following the study period, 5 patients were monitored for a mean total of 55 days with a mean final fentanyl dose of 240 micrograms/hr. As part of a comprehensive cancer pain management program, transdermal fentanyl appears to be safe and effective, and should prove to be a useful addition to currently available opioid analgesics.


Transdermal fentanyl for chronic cancer pain: detailed case reports and the influence of confounding factors. Patients were entered into an open label study to evaluate the efficacy of transdermal fentanyl as an analgesic for chronic cancer pain. The clinical course of 3 patients is described as well as an emphasis on the apparent influence of confounding factors, i.e., factors unique to each patient that appeared to affect that individual's analgesic requirements. Our anecdotal clinical experience suggests that transdermal fentanyl is an acceptable, efficacious, and safe means of pharmacologic management for patients with chronic cancer pain. Our results reinforce the concept that cancer pain is a dynamic, multiply determined process and that, as a result, the effects of a single intervention are difficult to analyze.


Transdermal fentanyl use in hospice home-care patients with chronic cancer pain. In this study, 11 cancer patients who experienced severe pain were treated with transdermal fentanyl. Of the 11 patients, 7 completed the 4-wk protocol. Of the 4 patients who did not complete the study, 3 died due to disease progression, and 1 was withdrawn by the primary physician. Patients' pain level, mood, and quality of life were evaluated before starting the transdermal fentanyl patch system and again at 2 and 4 wk. Data from the 7 patients who completed the study showed no statistical differences in pain level, mood, or quality of life at any of the three time points. Starting doses ranged from 25 micrograms/hr to 325 micrograms/hr, with increases from 0% to 300%. There were no significant adverse reactions to the medication. The hospice patients chose to continue with the transdermal fentanyl system for pain control after completing the study.


Management of cancer pain with transdermal fentanyl: phase IV trial, University of Iowa. A multicenter study was conducted to determine the patient and physician acceptability of transdermal fentanyl in the management of cancer-related pain. In this study, 10 cancer patients at the University of Iowa received transdermal fentanyl after discontinuing their prior opioid analgesic; 7 patients completed questionnaires before and at 2 and 4 wk following transdermal fentanyl application. There was no significant difference in visual analogue scale scores for pain or mood. Verbal pain descriptor scores improved at 2 wk (P less than .05). There was a nonsignificant tendency toward increased depression and nausea; however, patients spent less time thinking about their illness and felt their cancer was less disruptive to their closest friends/relatives. Constipation, appetite, drowsiness, and concentration were not statistically different. Patients reported improved sleep habits at 2 wk (P less than .05) and tended to require less help with eating, dressing, washing, and using the bathroom. All patients completing the study chose to continue transdermal fentanyl for their cancer pain management. In summary, these data demonstrate the analgesic efficacy of the transdermal fentanyl system and suggest that some patients with cancer-related pain could benefit from its use.


Transdermal fentanyl: clinical pharmacology. The transdermal therapeutic system (TTS) fentanyl has been designed for rate-controlled drug delivery. It provides a convenient regimen for the use of a drug previously limited by a short duration of action and a noninvasive parenteral route for a drug that is unsuitable for oral administration. TTS fentanyl has been developed to provide continuous controlled systemic delivery of fentanyl base for 72 hr. It is a rectangular, transparent unit composed of a protective peel strip and four functional layers. The amount of fentanyl released from each system (25 micrograms/hr per 10 cm2) is proportional to the surface area. So far, four patch sizes are available (10-40 cm2). When the system is applied, a fentanyl depot concentrates in the upper skin layers. Fentanyl plasma concentrations are not measurable until 2 hr after application, and it takes 8-16 hr latency until full clinical fentanyl effects are observed. Steady-state serum concentrations are obtained after several sequential 72-hr applications, and these are maintained for as long as a system is applied. Following removal, serum fentanyl concentrations decline gradually and fall about 50% in approximately 16 hr. This prolonged apparent elimination half-life occurs because fentanyl continues to be absorbed from the skin. Transdermal fentanyl transport is essentially the same between the chest, abdomen, and thigh. The skin-permeability constant is about 0.0125 mL/hr/cm2, much lower than the regional blood supply to a chest-skin area. Because of potential permeability variations among individuals, a special rate-controlling membrane in the system provides additional control of drug release.(ABSTRACT TRUNCATED AT 250 WORDS)


Cognitive failure in patients with terminal cancer: a prospective study. In a prospective open study, 61 consecutive patients with terminal cancer admitted to the hospital underwent cognitive assessment using the Mini-Mental State Questionnaire three times a week between admission and discharge or death. Mini-Mental State Questionnaire score upon admission was 28 +/- 1.5 in patients who were discharged (N = 14), and 25 +/- 3 in patients who died in the hospital (N = 47, P less than 0.01). The forty-seven patients who died in the hospital presented a total of 66 episodes of cognitive failure (CF) that were defined as a score of less than 24 or a drop of greater than 30% in the score on the Mini-Mental State Questionnaire. Of these 47 patients, 39 (83%) presented CF an average of 16 days before death. Upon detection of CF, a complete medical examination, laboratory evaluation, computerized tomography of the brain if indicated by abnormal findings on medical examination, and a complete medication review were performed. The cause of CF could not be established in 37 (56%) cases. Drugs, sepsis, and brain metastasis were the most frequently detected causes and were present in 6, 4, and 4 cases, respectively. In addition, 22 episodes (33%) of CF improved (10 episodes spontaneously and 12 episodes as a result of treatment). Our findings suggest that CF is extremely prevalent during the last weeks of life and, consequently, informed consent for therapeutic or research procedures or resuscitation may be impossible to obtain reliably at that stage.


A comparison of the Hopkins Pain Rating Instrument with standard visual analogue and verbal descriptor scales in patients with cancer pain. A self-contained, portable, pain rating instrument that provides an immediate result for documentation purposes was developed to improve pain assessment in cancer patients. The Hopkins Pain Rating Instrument (HPRI) is a 5 x 20 cm plastic visual analogue scale (VAS) with a sliding marker that moves within a groove that measures 10 cm. The side facing the patient resembles a traditional VAS while the opposite side is marked in cm to quantify pain intensity. This psychometric study, which employed a descriptive correlational design, evaluated the reliability and validity of the HPRI by comparing it with a traditional VAS and verbal descriptor scale (VDS). Outpatients with and without pain and inpatients with pain rated their major pain site with the three instruments, which were presented in random order. This was followed by a mental status exam and re-rating of pain with the same instruments to assess test--retest reliability. Completing the study were 71 patients with a variety of cancers and a mean age of 52.8 years. Of these patients, 68% had pain and 54% were receiving opioid analgesics. The most common pain sites were the back, leg, and epigastric areas. On initial and repeat testing, there were high correlations between the HPRI and the VAS (r = 0.99, P less than 0.0001) and the VDS (r = 0.85, P less than 0.0001). The correlation coefficients for test--retest reliability for the HPRI, VAS, and VDS were 0.97, 0.97, and 0.94 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Pediatric patient-controlled analgesia with morphine versus meperidine. To assess prospectively any difference in either analgesia or side effect frequency with morphine versus meperidine, 50 patients, ages 8-16 years, were randomly assigned to receive postoperative patient-controlled analgesia (PCA) with either morphine or meperidine. A numerical rating scale pain score was obtained from each patient twice a day, and any nausea, vomiting, pruritus, or urinary retention requiring catheterization was noted. No significant difference in the incidence of side effects was noted between the morphine and meperidine groups; however, pain scores during morphine PCA were significantly less than those during meperidine PCA (P less than 0.001). These results suggest that morphine is the better opioid for pediatric PCA.


Phenytoin as a coanalgesic in cancer pain. The efficacy of phenytoin (PHT), buprenorphine (Bu), and Bu+PHT for the relief of cancer pain of various etiologies was evaluated in a randomized, double-blind study of 3 groups, each comprised of 25 patients. Treatment duration was 1 month. PHT (100 mg by mouth twice daily) provided greater than 50% pain relief to 18 patients (72%) and greater than 75% relief to 4 (16%). Bu (0.2 mg sublingually twice daily) gave 21 patients (84%) greater than 50% relief and 15 patients (60%) greater than 75% relief. Of the Bu-treated patients, 8 had major side effects, while none of the PHT-treated patients experienced significant untoward reactions. Combined therapy (PHT, 50 mg PO+Bu 0.1 mg SL twice daily) provided greater than 50% pain relief to 22 patients (88%) and greater than 75% to 18 (72%); only 3 patients experienced a significant side effect. This study suggests that phenytoin has mild-to-moderate pain-relieving properties of its own and can significantly enhance buprenorphine analgesia. By permitting a lower opioid dose, it may reduce the occurrence of opioid-related side effects. PHT's lack of serious side effects, as well as its documented anxiolytic and antidepressant actions, may add to its comparative usefulness. Further clinical trials of PHT as a coanalgesic and/or adjuvant agent in cancer pain are warranted.


Clinicians' quick reference guide to postoperative pain management in adults. Pain Management Guideline Panel. Agency for Health Care Policy and Research, US Department of Health and Human Services. The management of pain is an important part of a health professional's role. The challenge for clinicians is to balance pain control with concern for patient safety and side effects of pain treatments. This is the first of two articles that summarize the highlights of the Agency for Health Care Policy and Research's Panel to develop clinical practice guidelines for the management of pain. This first article includes a summary of the methods used to develop the guidelines and the clinical highlights of pain assessment and management in adults.


Clinicians' quick reference guide to acute pain management in infants, children, and adolescents: operative and medical procedures. Pain Management Guideline Panel. Agency for Health Care Policy and Research, US Department of Health and Human Services. The management of pain is an important part of a health professional's role. The challenge for clinicians is to balance pain control with concern for patient safety and side effects of pain treatments. This is the second of two articles presenting the clinical highlights of the Agency for Health Care Policy and Research's Panel to develop clinical practice guidelines for pain management. This article presents the clinical highlights related to the assessment and management of pain in infants and children.


The use of urinary catheters in terminally ill cancer patients. Recent reports have commented on the need to improve our knowledge and management of urinary problems in terminally ill patients. We conducted a prospective study in 61 consecutive patients admitted to our palliative care unit (PCU), who were assessed for urinary problems, use of urinary catheters, and management of problems associated with the catheters. A total of 74% (45 of 61) of the patients required a catheter before death, with 23 (38%) being admitted to the PCU with a catheter, and 22 patients (36%) requiring a catheter during admission to PCU. We present our findings regarding the duration of catheter use, indications for catheters, type of catheters used, and complications of catheters. The data collected suggest that, although urinary problems and catheter use are common in terminal illness, if strict guidelines are followed there is no demonstrable mortality, and morbidity associated with catheter use is outweighed by patient benefit.


Intestinal obstruction in patients with widespread intraabdominal malignancy. The clinical course of 28 patients with surgically documented widespread intraabdominal malignancy who developed intestinal obstruction was reviewed. Of 26 patients, 13 responded to initial conservative management. In the ten patients treated surgically, there was significant morbidity in 80% and a postoperative mortality of 40%. Reobstruction occurred in 11 patients, responded poorly to therapy, and was associated with a short life expectancy. These results support the use of conservative therapy in the management of intestinal obstruction due to widespread intraabdominal malignancy, with emphasis on the palliation of symptoms and maintenance of quality of life.


Children's venipuncture pain: influence of technical factors. Several aspects of venipuncture technique were evaluated to assess their relationship to reported pain. Subjects were 514 children aged 5-17 who had venipuncture performed by a technician in a hospital outpatient laboratory. A research assistant timed the duration of venipuncture and then obtained visual analogue pain scores from the children following venipuncture. Blood volume obtained from venipuncture was also measured. The technician who performed the procedure, amount of blood drawn, and time required to complete the venipuncture did not contribute to the prediction of children's pain. Age and anxiety, which were treated as covariates, were significant predictors of pain. The distribution of pain experienced by children was positively skewed and about one-third of children were above the mean pain score. From the results of this study, venipuncture pain can be recommended for the study of issues in children's pain. Further, the findings recommend the development and utilization of interventions to reduce children's venipuncture pain.


Opioids: clinical use as anesthetic agents. Opioids (narcotic analgesics) are widely used in the practice of anesthesia for preanesthetic medication, systemic and spinal analgesia, supplementation of general anesthetic agents, and as primary anesthetics. The last use is particularly widespread for major surgical operations, especially those involving patients with cardiovascular disease. The use of opioids in anesthetic doses is based on the absence of cardiac depression by the opioids. As with all anesthetic drugs, the opioids have limitations and side effects, but for the most part, these are easily managed on the basis of knowledge of their pharmacology. The key to their efficient use is careful titration of dose according to the individual patient's responses to the drug as well as to noxious stimulation. Although there is a very wide margin of safety, allowing administration of enormous doses intraoperatively when the patient's ventilation is supported mechanically, the disadvantage of using doses far in excess of the individual patient's need is a prolonged recovery from anesthesia with the risk of postoperative ventilatory depression. Titration of the dose can be facilitated by computer-controlled infusion pumps with the benefit that the recovery time from anesthetic doses can be appropriate for the individual patient and surgical procedure, and postoperative analgesia can be continued by patient-controlled analgesia, which is another example of computer-controlled opioid infusion. Although specific opioid antagonists are available, their use to antagonize residual anesthetic effects is potentially hazardous.


Symptomatic benefit of supplemental oxygen in hypoxemic patients with terminal cancer: the use of the N of 1 randomized controlled trial. The symptomatic effects of oxygen on the dyspnea of terminally ill cancer patients have not been clearly established. Therefore, the decision to administer oxygen is frequently made on an individual basis. We report on the use of N of 1 randomized clinical trial to compare the symptomatic benefit of respiratory failure due to terminal ovarian cancer. A 53-yr-old female patient underwent 6 randomized double-blind crossover trials between oxygen 5 L/min delivered by mask and air 5 L/min delivered by mask. Each treatment period lasted 5 min. The mean saturation of oxygen during the baseline period was 84% +/- 3%, versus 84% +/- 4% on air (P,NS) and 94% +/- 4% on oxygen (P less than 0.001). The mean visual analogue scale (VAS) for dyspnea was 77 +/- 4 during the baseline period as compared to 51 +/- 7 after air (P less than 0.001), and 40 +/- 5 after oxygen (P less than 0.001). The patient and the investigator chose oxygen blindly in 5 of 5 cases, air in 0 and 1 case, and no choice was made in 1 and 0 case, respectively. In 4 cases the patient considered the difference between oxygen and air to be of "much importance," and in one case to be of "moderate importance." No significant treatment, period, or interaction between period and treatment was detected for the difference in the VAS. We conclude that oxygen was significantly better than air for symptomatic improvement in this patient. The N of 1 technique is a simple and reliable method for the assessment of individual patients' response to oxygen.


Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster. Morphine-induced constipation can lead to therapeutic disasters by several mechanisms. It can be readily prevented by administration of appropriate laxatives, but the importance of this simple intervention is often overlooked. Problems resulting from uncontrolled constipation include not only fecal impaction and spurious diarrhea, but also pseudoobstruction of bowel causing abdominal pain, nausea and vomiting, and serious interference with drug administration and absorption. Cancer pain may also be exacerbated. All of these contribute unnecessarily to morbidity and costs of health care. A case that exemplifies many of these problems is presented and discussed.


Tissue plasminogen activator, plasminogen activator inhibitor, and other parameters of fibrinolysis in the early stages of taurocholate acute pancreatitis in rats. It is well known that fibrinolytic activity in the early stages of acute experimental pancreatitis (AEP) as assessed by euglobulin lysis time (ELT) is depressed. The aim of this study was to evaluate changes in the fibrinolytic system in the early stages of taurocholate AEP in rats. Tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor 1 (PAI-1) activity, plasminogen, alpha 1 proteinase inhibitor (alpha 1 PI), alpha 2 antiplasmin (alpha 2 AP), antithrombin III (AT III), fibrinogen, and ELT were measured 0.5, 1, 3, and 6 h after the induction of taurocholate AEP in rats, as well as in sham-operated animals and the control group, which was not submitted to any operation. T-PA activity decreased significantly after 3 and 6 h of AEP; PAI activity had a time course reverse to t-PA and was parallel to alpha 1 PI activity. ELT was slightly prolonged after 0.5, 1, and 3 h, whereas alpha 2 AP activity and plasminogen levels increased significantly; AT III activity was increased after 1 h in comparison to control group. Sham operation caused nonsignificant changes in fibrinolysis. Increase of PAI activity and decrease of t-PA could be a reasonable explanation for inhibited plasma euglobulin fibrinolytic activity noted in the early period of AEP.


Nonparallel patterns of circadian pancreatic and biliary secretions in fasting rats. We compared the circadian patterns of pancreatic and biliary secretions in fasting rats. For this purpose, indwelling plastic catheters were placed in 10 male Wistar rats (300-320 g) for the collection of biliary and pancreatic secretions. After small samples were taken for analysis, pancreatic and biliary secretions were recirculated into the duodenum by an additional connecting system. The rats were adapted to an inverse night-day cycle by artificial light during the night (8 PM-8 AM) and by darkroom housing at daytime (8 AM-8 PM). During a 24-h fasting period, samples of bile (100 microL) and pancreatic juice (20 microL) were taken every hour for determination of the following parameters: pancreatic and biliary flow rate, protein, amylase, lipase, trypsin, and bile acid output. Peak pancreatic flow rate (1.96 +/- 0.05 mL/h.kg) was achieved toward the end of the dark period at 7 PM. A significant increase of pancreatic secretion could be achieved merely by turning the lights off, a significant decrease by turning the lights on. Similar circadian patterns were found for pancreatic protein, amylase, and lipase output with peak secretions at 7 PM. An increase of nearly 5x was found between minimal (15.64 +/- 0.65 mg/h.kg) and maximal (72.43 +/- 2.83 mg/h.kg) pancreatic protein output. The amplitude was highest for amylase; peak amylase output (13740 +/- 832 U/h.kg) was about 18-fold above minimal output (758 +/- 44.3 U/h.kg). Conversely, the peak of trypsin concentration in pancreatic juice (1095 +/- 17.8 U/mL) occurred during the light period when flow rates were lowest.(ABSTRACT TRUNCATED AT 250 WORDS)


Urinary phospholipase A2 excretion in chronic pancreatic diseases. This study was performed to investigate the behavior of phospholipase A2 (PLA2) in serum and urine of patients with chronic pancreatic diseases and to ascertain whether any factors influenced the results. In 30 controls, 45 patients with pancreatic cancer, 54 with chronic pancreatitis, and 64 with extrapancreatic diseases, serum and urinary PLA2, pancreatic isoamylase and RNase, and urinary N-acetylglucosaminidase (NAG) were measured. Serum PLA2 levels were higher in patients with chronic pancreatitis than in all the other groups. In our patients, only occasionally was urinary PLA2 elevated, the increase occurring almost exclusively in the presence of an acute inflammatory disease, e.g., relapsed chronic pancreatitis or active inflammatory bowel disease. A correlation was found between serum PLA2 and serum RNase, an indicator of tissue damage, but not between serum PLA2 and pancreatic isoamylase. Urinary PLA2 output was correlated with its renal input and with RNase output. No correlation was found between PLA2 output and pancreatic isoamylase or NAG urinary excretion. In conclusion, (1) the determination of serum PLA2 activity may be an aspecific test of pancreatic disease; (2) PLA2 urinary excretion occasionally increases, especially in the presence of severe phlogosis, which occurs in chronic pancreatitis, in particular during relapse; and (3) irrespective of the tissue origin of urinary PLA2, its increased excretion may be accounted for in part by its increased circulating levels. It is, however, more likely the consequence of a renal tubular dysfunction, which is sometimes found in patients with pancreatic diseases.


Effect of SMS 201-995 on exocrine pancreatic secretion in a patient with external pancreatic fistula. The effect of SMS 201-995 on pancreatic exocrine function was studied. The SMS 201-995 was administered to a patient with an artificial external pancreatic fistula following pancreaticoduodenectomy. Variations in pancreatic exocrine function were assessed by determining the volume and components of the fistula fluid during the following periods: 5 d prior to SMS 201-995 administration, for 5 d during actual administration, and for 5 d after it had been discontinued. The SMS 201-995 was administered by subcutaneous injection of 100 micrograms every 12 h for the first 2 d and then 100 micrograms every 6 h for 3 d. This experiment demonstrated that SMS 201-995 has a strong inhibitory effect on pancreatic exocrine function, markedly reducing the amount of fistula fluid and the production of amylase, total protein, and bicarbonate.


Urinoma masquerading as pancreatic pseudocyst. In this article, we report on a patient with recurrent pancreatitis who had received multiple celiac plexus injections for control of pain, and then developed a cystic mass adjacent to the body and tail of the pancreas suggestive of a pancreatic pseudocyst. The cystic mass proved to be a urinoma. The distinction between pancreatic pseudocyst and urinoma was made by CT scan with intravenous contrast utilizing delayed films, which demonstrated leakage of contrast into the cystic structure. This is the first report of a urinoma that resembled a pancreatic pseudocyst.


The relationship between extended periods of immobility and decubitus ulcer formation in the acutely spinal cord-injured individual. Several variables may influence the development of decubitus ulcers during the acute treatment phase following spinal cord injury. Three independent variables were studied: level of injury, completeness of injury and length of time immobilized. Of these, length of immobilization exceeding 6 hours was associated with subsequent development of a sacral or occipital decubitus at a statistically significant level (p = .0094). The presence of a complete injury was associated with decubitus formation at a noticeable but statistically insignificant level (p = .0759). Cervical injuries were not associated with an increased rate of decubitus formation. Results suggested that initial treatment of acute spinal cord injuries should include the use of pressure relieving maneuvers or devices as soon as possible, especially in patients with anticipated extensive immobilization. Recognizing that risk of decubitus formation increases with immobilization time, the period of time involved in initial diagnosis and intervention should be kept to a minimum. This is particularly true in patients with complete spinal cord injuries.


Multiple sclerosis: will it come between us? Sexual concerns of clients and their partners. Multiple sclerosis (MS), an unpredictable neurologic disease, is sometimes called the crippler of young adults. This crippling effect often involves sexual functioning. Sexuality is an issue that is frequently difficult for clients, their partners and health care providers to discuss. To address this difficulty, a teaching pamphlet entitled, MS ... Will it Come Between Us? was produced. Open communication and creativity are helpful in dealing with problems frequently encountered by clients with MS: fatigue, impotence, decreased vaginal lubrication, bladder and bowel dysfunction. The pamphlet helps clients with these issues as well as the basics of sexuality as a whole.


Acoustic neuroma: postoperative vertigo and the mechanisms of compensation. Ninety-five percent of patients with acoustic neuroma experience some degree of vertigo preoperatively, postoperatively or both. Postoperative vertigo is often a debilitating condition that results when the eighth cranial nerve is severed during surgery to resect a tumor growing around the vestibular portion of this nerve. Thus, surgery for acoustic neuroma affects the membranous labyrinth, which is the functional part of the vestibular apparatus and is primarily concerned with equilibrium. Compensation for impaired equilibrium may be by biofeedback in the vestibular pathways, visual control, exercise or drug therapy. Nurses can significantly influence the recovery of acoustic neuroma patients by encouraging and reinforcing exercise and other mechanisms of vestibular compensation.


Multidisciplinary approaches to management of acute head injury. The formation of a multidisciplinary head injury team at St. Michael's Hospital has served to improve the quality of care for acutely head-injured patients. The multidisciplinary team follows the patient from the neurosurgical intensive care unit to the early rehabilitation phase. Treatment for the patient and family focuses on physical, cognitive and psychosocial areas. Cooperation of the various medical and paramedical professionals facilitates earlier and more comprehensive treatment for patients and their families, while enhancing research.


The effects of lidocaine on intracranial hypertension. In head-injured adults sudden increases in intracranial pressure (ICP) frequently occur in response to noxious stimuli, such as endotracheal suctioning (ETS). Transient increased ICP may have potentially harmful effects upon head-injured patients. One intervention clinicians believe to be efficacious in blunting ICP response to ETS is administration of lidocaine hydrochloride. This article critiques studies that examined effects of lidocaine in attenuating the ICP response to suctioning and similar stimuli. The literature to date, while providing conflicting results, does demonstrate tentative support for the use of lidocaine prior to ETS as a means of attenuating a rise in ICP. Support was found for the intratracheal route of administration. Additionally when intratracheal lidocaine was coupled with muscle relaxants or other anesthetic agents administered at appropriate times prior to suctioning, large rises in ICP may be effectively blunted.


Transcranial Doppler: correlation of blood velocity measurement with clinical status in subarachnoid hemorrhage. Subarachnoid hemorrhage affects approximately 30,000 people each year in North America. Up to 50% of patients who survive the initial hemorrhage experience cerebral vasospasm, often resulting in permanent disability or death. Early detection allows interventions which may prevent catastrophic complications. Diagnosing vasospasm has always been dependent on invasive testing and correlation of the clinical picture. Alterations in neurological assessment, including Glasgow Coma Scale score changes, merely reflect poor cerebral perfusion secondary to the vasospasm, and may not be apparent for days. Transcranial Doppler (TCD) ultrasonography is an exciting diagnostic alternative. This noninvasive test may be done daily at the bedside, and may accurately predict impending vasospasm.


Early enteral nutrition and length of stay in stroke patients. The effect of early enteral nutrition on length of stay (LOS) in hospitalized surgical patients has been previously documented. In this study, a sample of a large medical population (stroke patients) was examined to determine if early enteral nutrition affected LOS. A retrospective review of the medical records of nonsurgical stroke patients receiving enteral nutrition, discharged between January 1, 1988 and January 31, 1991, was undertaken. Time to initiation of enteral feeding and LOS were recorded. In patients fed within 72 hours of admission (N = 20), LOS was 20.14 (SD 12.87) days. The LOS for patients fed later than 72 hours from the time of admission (N = 32) was 29.76 (SD 20.05) days. The difference between the groups in LOS was statistically significant (p = 0.036). Although further study is warranted, we concluded that early enteral nutrition may be a factor in shortening LOS in stroke patients.


Self-efficacy as a predictor of adjustment to multiple sclerosis. The ability of self-efficacy (SE) and outcome expectations (OE) to predict adjustment to multiple sclerosis (MS) was explored. A sample of 62 respondents who had MS was used to test study hypotheses. Self-efficacy expectations predicted 24% of the variance in adjustment to chronic physical illness. Outcome expectations did not significantly add to the predictive power of SE. However, the model containing SE, OE and degree of disability predicted 51% of the variance in adjustment.


Advance directives.

Advance directives. Advance directives concerning treatment have been firmly established in our society. Reactions to them, however, are varied, especially when the health care provider possesses a different belief about the care, or non-provision of care, in a particular situation. It is important for the neuroscience nurse to be in touch with thoughts and feelings concerning a patient's treatment choice, and, when necessary, to seek input and support about those concerns. Clearly, if the nurse cannot carry out the patient's wishes, the nurse can use applicable state law provisions supported by the Patient Self-Determination Act, and request not to participate in the care of that patient. If, however, the neuroscience nurse does provide care, ethically and legally it must be done in accordance with the patient's expressed choices.


Methylprednisolone for acute spinal cord injury. Treatment with high-dose intravenous methylprednisolone is safe and may be associated with significant neurologic improvement in acute spinal cord injury patients. Accurate calculation and administration of the prescribed therapy and identification and assessment of complications should be incorporated into the overall standard of care for the acute spinal cord injury patient.


Gonococcal infection, infertility, and population growth: I. Endemic states in behaviourally homogeneous growing populations. Sexually transmitted diseases such as gonorrhoea are a significant cause of infertility in women when the infection is untreated. They have the potential to alter human population growth rates in many developing countries where sexually transmitted diseases are prevalent due to limited public health facilities for diagnosis and treatment. The authors develop a simple model describing the conditions under which such a disease can exist in a growing population in which sexual partners are chosen at random by proportionate mixing. Using the model, the impact that such a disease could have for a range of possible parameters is examined. Then a full parameter set for gonorrhoea in a developing country is estimated. Analysis demonstrates the significant influence gonococcal infection may have in reducing population growth rate in some communities. For example, the simple model predicts that a prevalence of 20% in sexually active adults results in a 50% reduction in the population growth rate. Finally, the authors discuss how potential control initiatives may change the parameter values that determine transmission and alter the demographic impact of gonorrhoea.


Gonococcal infection, infertility, and population growth: II. The influence of heterogeneity in sexual behaviour. Heterogeneity in sexual behaviour has an important influence on the transmission dynamics of sexually transmitted diseases (STDs). The authors describe the development of a simple mathematical model, incorporating such heterogeneity, to investigate the demographic impact of gonorrhoea on human population growth in developing countries where the disease is endemic. Earlier predictions, based on a model with homogeneous mixing, are shown to be in good qualitative agreement with the predictions of a more complex mathematical framework in which the population is stratified both by sex and into two subgroups representing low and high sexual activity, defined on the basis of rates of sexual partner change. Analyses also demonstrate that the pattern of mixing (assortative to random) between the sexual activity classes has an important influence on the predicted prevalence of gonococcal infection in a defined community. The more complex model supports earlier conclusions that gonorrhoea, via its impact on fertility, can significantly reduce net population growth rates.


Some results for an SEIR epidemic model with density dependence in the death rate. This paper deals with an SEIR epidemic model for an infectious disease where the death rate depends on the number of individuals in the population. It is also assumed that there is an additional death rate suffered by infected individuals. It is found that there are three steady-state values: one where the population is extinct, one where the population maintains itself at a constant level and the disease is extinct, and one where there is a unique equilibrium with disease present. An interesting and unusual feature is that it is possible for this third equilibrium to exist and be locally unstable. Numerical work and simulation show that we can have cycles of disease incidence with increasing amplitude, a constant amplitude, and a decreasing amplitude, depending on the parameter values of the model.


Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia is a common immune-mediated drug reaction that can be complicated by life-threatening arterial thrombosis. The diagnosis can be confirmed by demonstrating heparin-dependent release of radiolabeled serotonin from washed normal platelets in the presence of patient serum. However, certain serum samples from these patients produce 14C-serotonin release from some but not other normal donor platelets. We investigated this problem of donor platelet variability by studying the reactivities of 10 serum samples from patients with heparin-induced thrombocytopenia with platelets from 10 normal donors (100 serum and platelet combinations). We observed a marked variability in reactivity for patient serum and platelets from normal donors; this initially appeared random. However, closer examination indicated that the reactivities varied hierarchically. Because heparin-induced thrombocytopenia is caused by binding of heparin-dependent IgG to platelet Fc receptors, we examined whether platelet Fc receptor number or function explained the variability in platelet reactivity. We observed that platelet Fc receptor function, as measured by platelet release associated with heat-aggregated IgG, was highly correlated with platelet reactivity to heparin-induced thrombocytopenia serum samples. No significant correlation, however, was found between Fc receptor number and platelet response. Reaction of murine monoclonal antibodies that activate human platelets by means of the platelet Fc receptors was not predictive of platelet reactivity to heparin-induced thrombocytopenia serum.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment of Wilson's disease with zinc: X. Intestinal metallothionein induction. Oral zinc therapy is effective in controlling copper balance in patients with Wilson's disease and blocks the intestinal absorption of copper, as demonstrated by uptake of copper 64 and copper balance measurements. In this study, 64Cu uptake measurements were concomitantly carried out with intestinal biopsies to investigate the relationship of reduced copper absorption to the levels of intestinal metallothionein in patients with Wilson's disease at different stages of zinc therapy. A pronounced increase in intestinal metallothionein levels and a sharp drop in 64Cu absorption were found 4 to 5 days after the initiation of zinc treatment. Conversely, metallothionein levels decreased and 64Cu uptake increased on the discontinuation of zinc therapy. The data indicate that 64Cu absorption varies as a function of intestinal metallothionein level. Intestinal metallothionein levels were found to correlate linearly with urinary zinc levels, which reflect body zinc status. These findings support our hypothesis that intestinal metallothionein induction mediates decreased copper absorption observed during zinc therapy. The suppressive effect of zinc on copper absorption appears to have a half-life of about 11 days.


Training at moderate altitude: iron status of elite male swimmers. Laboratory evidence of suboptimal iron status is endemic in chronically training athletes, yet the importance of low serum ferritin values to athletic performance is unclear. The purpose of this study was to monitor iron status in nine male elite swimmers during and after a 3-week training camp at 2225 m altitude. Values for hemoglobin, hematocrit, serum iron, serum transferrin, and transferrin saturation were within the normal range and remained unchanged over the 54-day monitoring period. Serum ferritin level was significantly decreased by day 13 and continued to decline over the period at altitude. Significant recovery was observed by day 35, by which the workload and altitude were reduced. Reticulocyte counts were raised above normal values by the fifth day at altitude and remained elevated for the duration of the study, indicating increased erythropoiesis. In contrast, neither ferritin levels nor reticulocyte counts were changed in six of the nine subjects after 1 month's training at 1000 m. Food histories revealed dietary iron intakes two to three times as great as the recommended dietary allowance for iron. The draw on body iron reserves observed in this study over the heavy training period at moderate altitude indicates that adequate iron stores are necessary to provide a reservoir of iron during periods of increased iron utilization or loss. Further work is required to elucidate the sources and endpoints of the observed iron flux.


A simple carbon monoxide breath test to estimate erythrocyte turnover. Carbon monoxide is stoichiometrically released when heme is converted to bilirubin. This report describes and validates a novel technique that permits the estimation of heme turnover and red blood cell survival from the carbon monoxide concentration of end-expiratory breath samples. The end-alveolar Pco of a subject was corrected for environmental carbon monoxide exposure with a simple device that equilibrates with atmospheric carbon monoxide at the same rate as does the subject. The resultant value (endogenous Pco) was tested for its ability to predict heme turnover and red blood cell survival. Red cell survival times of 32 healthy subjects, as calculated from the endogenous Pco, averaged 101 +/- 19 days, a value close to the expected 110-day survival time; 13 patients with clinical evidence of shortened red blood cell survival times had measured erythrocyte life spans ranging from 10 to 59 days. The endogenous Pco of each of seven patients increased after red blood cell transfusion, demonstrating that this technique detected the known rapid turnover of a small fraction of transfused cells. A good correlation (r = 0.91) was observed between heme turnover calculated from endogenous Pco and total fecal biliary pigment output. Carbon monoxide measurements reflect red blood cell destruction in both the marrow and the circulation, therefore yielding shorter life spans than did chromium 51 survival studies. This breath test appears to yield a rapid, semiquantitative assessment of heme turnover and red blood cell survival that is not provided by any other presently available technique. This simple, noninvasive carbon monoxide breath test may find widespread use in the evaluation of anemia and jaundice.


Discrepancy between circadian rhythms of inulin and creatinine clearance. To elucidate the disparity between circadian rhythmicity of inulin and creatinine clearance, we simultaneously measured inulin and creatinine clearances every 3 hours during 1 day in 14 normal subjects and in 8 patients with nephrotic syndrome. All patients and normal subjects had a circadian rhythm for inulin clearance with a maximum during daytime and a relative amplitude of 21% +/- 2%. For creatinine clearance a rhythm was either absent or reduced in relative amplitude (p less than 0.01). In all subjects the rate of tubular creatinine secretion was higher at minimum of inulin clearance (night) than at maximum (day). The fractional clearance (relative to inulin) of creatinine was also higher during the night: normal subjects, 1.28 +/- 0.02 versus 1.10 +/- 0.02; patients, 1.78 +/- 0.08 versus 1.45 +/- 0.05 (p less than 0.005). This demonstrates the inaccuracy of creatinine clearance as a measure of glomerular filtration rate (GFR). By subsequent blocking of the tubular secretion of creatinine with cimetidine in four normal subjects, creatinine clearance became similar to inulin clearance during day and night. This confirms that high tubular secretion of creatinine during the night counteracts the normal rhythmicity of glomerular filtration of creatinine. As a result, plasma creatinine concentration is nearly constant during a 24-hour period. In conclusion, tubular creatinine secretion has a circadian rhythm with a phase opposite to the rhythm of GFR, thus blunting or causing absence of a circadian rhythm for creatinine clearance.


von Willebrand factor antigen, tissue-type plasminogen activator antigen, and risk of death in human immunodeficiency virus 1-related clinical disease: independent prognostic relevance of tissue-type plasminogen activator. Tissue-type plasminogen activator, von Willebrand factor, and plasminogen-activator inhibitor type 1 plasma levels were measured at first consultation in 85 consecutive patients infected with human immunodeficiency virus. Patients were assigned to three groups according to clinical status: mild disease group, intermediate group, and acquired immunodeficiency syndrome group. Significant differences were found in von Willebrand factor, tissue-type plasminogen activator, and plasminogen-activator inhibitor type 1 plasma levels among the three groups: severe clinical status was associated with higher von Willebrand factor, tissue-type plasminogen activator, and plasminogen-activator inhibitor type 1 plasma levels. Significant correlations were found among these three parameters, such known biologic prognostic indicators of human immunodeficiency virus infection as IgA, anti-p24 antibodies, p24 antigenemia, CD4+ lymphocytes, beta 2-microglobulin, and the clinical status. The prognostic relevance of plasma von Willebrand factor and tissue-type plasminogen activator levels at the time of entry into the study was then investigated in a cohort of 65 of the 85 patients who had follow-up during a median period of 22 months. The median survival time for all patients was 39 months after the first consultation. A plasma von Willebrand factor level greater than 200% of the control value had a positive predictive value of 86% for determining nonsurvivors; the median survival time for such patients was 9 months after the first consultation. A positive predictive value of 100% in recognizing nonsurvivors was found for tissue-type plasminogen factor plasma levels greater than 20 ng/ml; the median survival time for these patients was 2 months after the first consultation.(ABSTRACT TRUNCATED AT 250 WORDS)


Diphosphoryl lipid A protects rats from lethal hyperoxia. Bacterial endotoxin has been shown to protect rats from lethal hyperoxia. The structure of endotoxin contains diphosphoryl lipid A (DPL) as the lipid backbone stripped of protein and polysaccharides. DPL is the component of the endotoxin molecule that has been demonstrated (in previous studies) to be responsible for the immunologic, mitogenic, pyrogenic, and lethal properties of endotoxin. Monophosphoryl lipid A (MPL) is a nonpyrogenic, nontoxic modification of the DPL molecule that retains its immunostimulatory and mitogenic properties. We hypothesized that DPL may be the actual active component of endotoxin that protects rats from lethal hyperoxia. We also hypothesized that the protection from hyperoxia that is afforded by the DPL component may be related to endogenous release of tumor necrosis factor alpha which should allow MPL to also be protective. To test these hypotheses, we performed a series of experiments in which rats were treated with endotoxin, DPL, MPL or vehicle and exposed to room air or hyperoxia. We found that DPL and endotoxin both protected rats from lethal hyperoxia, but MPL alone was not protective. Even though MPL was not protective, DPL and MPL both increased endogenous release of tumor necrosis factor alpha early after injection (peak DPL level, 3619 +/- 1500 pg/ml, peak MPL level, 4038 +/- 500 pg/ml). Protection in both the endotoxin- and DPL-treated animals was associated with increases in lung antioxidant enzyme activities. We concluded that DPL protect rats from hyperoxia but that MPL is not protective in spite of its immunostimulatory and mitogenic effects.


Functional studies on long-term cryopreserved peripheral blood mononuclear cells from patients with lung cancer and from healthy subjects. To determine the functional abilities of long-term cryopreserved peripheral blood mononuclear cells (PBMCs) from patients with lung cancer and from healthy subjects, we assayed the proliferative and plaque-forming cell (PFC) responses of cells from these individuals after the cells had been cryopreserved for up to 31 months. The stability of these cells for B and T cell quantitative assays was also determined by using their respective monoclonal antibodies. The patients' results were compared with those in healthy subjects to ascertain whether the conclusions derived from the assay of cryopreserved cells are consistent with our earlier studies on fresh cells from similar patients. The results show that proliferative and PFC responses of the frozen cells were not significantly affected by further storage, despite an initial, irreversible functional loss in some subsets of T lymphocytes and monocytes during the process of freezing. They also demonstrate that cryopreserved PBMCs from both patients and controls can be successfully utilized for B and T cell quantitative assays. The conclusions derived from the assay of cryopreserved cells are also consistent with our earlier observations on fresh cells from patients with lung cancer; those studies indicated a B cell functional abnormality caused in part by increased suppressor T cell and monocyte activity.


Effects of complement activation on platelet-activating factor and eicosanoid synthesis in rat mesangial cells. The effects of in vitro complement activation and of isolated complement components (C3a, C5a, C3b) on the activity of the microsomal enzyme acetyl coenzyme A: 1-0-alkyl-glycero-3-phosphocholine acetyl transferase (AcTr) in cultured mesangial cells and on the synthesis of prostaglandin E2 (PGE2) were assessed. In vitro complement activation induced by the introduction of purified cobra venom factor (CVF) in culture media containing human serum enhanced mesangial cell PGE2 synthesis and had no effect on microsomal AcTr activity. When media containing C6-deficient serum were used, the stimulatory effect of CVF on PGE2 synthesis was abolished. Introduction of CVF in these media enhanced mesangial cell AcTr activity. These effects were partially reversed when the C6-deficient serum was supplemented with C7-deficient serum to allow formation of the C5b-9 complex. Isolated C3a, C5a, and C3b had opposite effects on PGE2 synthesis and on AcTr activity. Specifically, all components enhanced mesangial cell PGE2 synthesis. In contrast, AcTr activity was enhanced by C3a alone; C5a had no effect, whereas C3b had an inhibitory effect. The observations indicate that in response to complement activation and specific anaphylatoxin agonists, mesangial cell eicosanoid synthesis is not coupled with changes in the activity of AcTr and PAF synthesis.


Diltiazem treatment of endotoxic shock in suckling rats. Gram-negative sepsis septic shock continues to produce significant mortality and therefore remains a major medical problem. Vasodilators have been studied in the treatment of circulatory shock. However, the effectiveness of calcium channel blockers in the treatment of newborn endotoxic shock has not been well documented. In the present study, diltiazem, a calcium channel blocker, and nitroprusside, a vasodilator, were used for the treatment of endotoxic shock in 10-day-old rats. Mortality rate, hemodynamics, and glucose metabolism were monitored. Diltiazem at a dose of 0.3 mg/kg attenuated the hypotension, bradycardia, hypoglycemia, and lactacidemia in newborn endotoxic shock. Diltiazem treatment resulted in reduced 24-hour mortality. However, 0.6 mg/kg diltiazem enhanced the hypotension, bradycardia, and lactacidemia in endotoxic shock. Nitroprusside blunted the hypoglycemia and decreased the mortality rate among rats with endotoxic shock. Afterload reduction may be responsible for the beneficial effects of 0.3 mg/kg diltiazem and nitroprusside. Diltiazem at a dose of 0.3 mg/kg reduced the lactacidemia of endotoxic shock more than nitroprusside. Therefore the effects of diltiazem may be due not only to afterload reduction but also to inhibition of cellular calcium influx. We conclude that 0.3 mg/kg diltiazem and 1.0 mg/kg nitroprusside are beneficial for the treatment of endotoxic shock in newborn rats.


Effect of chronic renal failure on intestinal transport of biotin in the rat. The present study examined the effect of chronic renal failure (RF) on biotin transport in rat intestine. Chronic RF was induced by subjecting rats to right nephrectomy and left two-thirds nephrectomy. Control rats underwent sham operation but without tissue removal and were pair fed. Transport studies were performed 5 to 6 weeks after operation. Chronic RF was found to cause a marked decrease in the maximal velocity (Vmax) of biotin mucosal-to-serosal transport in jejunal everted sacs with minimal change in the apparent Michaelis-Menten constant (Km) of the transport process. This impairment in biotin transport was found to involve the transport process of the vitamin across the brush border membrane (BBM) domain of the enterocyte as shown by studies with BBM vesicles (BBMVs). These studies with BBMV similarly showed a decrease in the Vmax of biotin transport with minimal change in the apparent Km. The impairment of biotin transport in intestinal BBMVs was not due to dissipation of the Na+ gradient across the BBM (which is the driving force of biotin movement across this membrane) because transport of sodium 22 was found to be similar in BBMVs prepared from the RF rats and the sham-operated PF control rats. These results demonstrate that chronic RF in rats causes impairment in biotin intestinal transport. This impairment is due to a decrease in the number (and/or activity) of the biotin transport carriers and involves the transport process of biotin at the BBM.


Hemodynamic effects of high dietary intakes of sodium or chloride in the Dahl salt-sensitive rat. In the Dahl salt-sensitive (Dahl-S) rat, a high sodium without chloride diet (NaAA) and a chloride without sodium diet ("X"Cl) do not increase arterial pressure to the same extent as a high NaCl diet. To explain these differences, hemodynamic responses to acute volume expansion were compared in conscious Dahl-S and Dahl salt-resistant (Dahl-R) rats fed either 7% NaCl, NaAA, or "X"Cl diets for 5 weeks. Before acute volume expansion, on each of the three diets, mean arterial pressures and total peripheral resistances were higher (p less than 0.01) in Dahl-S than in Dahl-R rats, and in Dahl-S, arterial pressure was higher (p less than 0.05 or less) on the 7% NaCl intake than on the other two diets. No group differences were found in cardiac index (thermodilution). Right atrial pressure was also elevated (p less than 0.01) in Dahl-S rats on the 7% NaCl diet. In response to acute volume expansion, arterial pressure did not change, and the decrement of total peripheral resistance was greater in Dahl-S rats than in Dahl-R rats on each of the three diets (p less than 0.05 or less). Assuming that reductions of peripheral resistance in response to acute volume expansion reflect withdrawal of sympathetic tone, these results suggest that sympathetic tone is increased comparably on each of the diets in Dahl-S rats. As suggested by the increased right atrial pressure, higher arterial pressure induced by 7% NaCl may be related to an expanded intravascular volume in conjunction with increased neural activity.


Lipoproteins and apolipoproteins in human pleural effusions. We investigated the lipoproteins and apoproteins in human serum and pleural effusions of different origin: transudates, inflammatory exudates, and malignant exudates. Transudates had a low cholesterol content of 35 +/- 12 mg/dl (mean +/- SD) because of low levels of low-density lipoprotein (LDL) cholesterol--representing 16% of serum levels--whereas inflammatory exudates (cholesterol 92 +/- 26 mg/dl) and malignant exudates (cholesterol 86 +/- 6 mg/dl) exhibited high levels of LDL, with 67% and 69% of serum levels. Apolipoprotein (apo) B level corresponded with LDL and presented with multiple split-products in sodium dodecyl sulfate-polyacrylamide gel electrophoresis in exudative effusions. LDL levels in effusions correlated with serum levels in exudates but did not correlate with those in transudates. In contrast, lipoprotein(a) appeared in all effusions from patients with detectable serum levels. The isoforms were similar as demonstrated by immunoblotting. Differences were found in the composition of the high-density lipoprotein (HDL) fraction: transudates had cholesterol-rich HDL when compared with serum. HDL particles of malignant exudates were poor in cholesterol, and isoelectric focusing demonstrated more sialized apolipoprotein E. A strongly abnormal HDL level with accumulation of cholesterol was found in a long-standing tuberculous effusion. In conclusion, cholesterol in acute effusions is bound to lipoproteins and derived from the blood. The difference in total cholesterol levels between transudates and exudates is based on the lack of LDL in transudates. Transudates show the lipoprotein characteristics of interstitial fluid. Alterations of lipoproteins occur in chronic inflammation and in malignancy with possible de novo synthesis of apolipoprotein E by tumor cells. Lipoprotein(a) accumulates independently from LDL in the pleural space, a finding that supports the view that the physiologic function of lipoprotein(a) is located in the interstitial space.


Effects of insulin-like growth factor-I (IGF-I) infusion and dietary tri-iodothyronine (T3) supplementation on growth, body composition and plasma hormone levels in sex-linked dwarf mutant and normal chickens. This study used a sex-linked dwarf mutant (SLD) chicken to evaluate growth-promoting and metabolic effects of recombinant human insulin-like growth factor-I (rhIGF-I) treatment. The SLD chicken is characterized by a 30% reduction in body weight and by high plasma GH levels, low plasma IGF-I and triodothyronine (T3) levels and very low GH binding on liver membranes, suggesting reduced functional GH receptors compared with normal chickens. The effects of a continuous s.c. infusion by osmotic mini-pump of 0.1 mg rhIGF-I/kg per day from 4 to 8 weeks of age on body weight, bone growth and body composition were investigated in female SLD and normal chicks. In addition, half of the birds received a dietary supplement of T3 (0.1 parts per million). Plasma levels of IGF-I, GH, T3, thyroxine and insulin were followed during the treatment. In normal chicks, rhIGF-I infusion had no effect on growth and little effect on plasma hormone levels except for a decrease in plasma insulin. In dwarf chicks, rhIGF-I infusion slightly increased body weight but had no effect on longitudinal bone growth. In addition, plasma GH levels were decreased and T3 levels remained lower than in normal chicks. Normal and dwarf chicks showed a decrease in abdominal fat after both IGF-I administration and T3 supplementation, the treatments having additive effects in dwarf chicks only. The combined rhIGF-I and T3 treatment restored a quasi-normal hormonal pattern in dwarf chicks, except for insulin which remained lower than in normal chicks. These results suggest that IGF-I in the chicken has no direct endocrine effect on statural growth.


Characterization of inhibin and related proteins in bovine fetal testicular and ovarian extracts: evidence for the presence of inhibin subunit products and FSH-suppressing protein. Bovine fetal gonads have been shown previously to contain inhibin bio- and immunoactivity although the ratio of these activities was markedly lower in testicular compared with ovarian extracts throughout gestation. The basis for this difference is examined in this study. Fetal testicular and ovarian high-speed supernatant preparations from bovine fetuses aged 180 to 270 days of gestation were sequentially fractionated by dye affinity chromatography, gel permeation chromatography, reversed phase high-performance liquid chromatography and preparative polyacrylamide gel electrophoresis and monitored by inhibin radioimmunoassay and in-vitro bioassay. Three immunoactive fractions were identified in testicular extracts with molecular masses of 30 kDa (Peak I), 43 kDa (Peak IIa) and 29 kDa (Peak IIb). Peak I material only was bioactive. On the basis of these characteristics, Peak I is probably 31 kDa inhibin as previously described, and Peaks IIa and IIb are probably different inhibin alpha subunit precursor fragments. In ovarian extracts, two bio- and immunoactive fractions were identified with molecular masses of 30 kDa (Peak I) and 29 kDa (Peak II). On the basis of size, and biological and immunological activities, the ovarian extract Peak I material is probably bovine 31 kDa inhibin, while the Peak II material is probably a novel inhibin-like protein. FSH-suppressing protein (or follistatin) bio- and immunoactivities were also identified in both testicular and ovarian extracts. It is concluded that the low ratio of inhibin biological/immunological activity in testicular extracts is attributed to the presence of high concentrations of immunoactive alpha subunit precursor fragments which are low to non-detectable in ovarian extracts. These results support our previous hypothesis that, in contrast to the ovary, the inhibin alpha subunit is produced in excess in the fetal testis.


Specificity of steroid hormone-induced sex determination in a turtle. The specificity of steroid hormone-induced sex determination was investigated in the red-eared slider, Trachemys scripta, a turtle with temperature-dependent sex determination. All eggs were incubated at either a female-producing temperature (31 degrees C) or a male-producing temperature (26 degrees C) and received control or experimental treatments at stage 17-18 of embryonic development. A variety of treatments induced female sex determination at the male-producing temperature. Oestradiol-17 beta, diethylstilboestrol (DES) (an oestrogen agonist) and norethindrone (NET) (a progestin with reputed oestrogenic as well as anti-oestrogenic properties) were the most effective in inducing female sex determination. Other reputed oestrogen antagonists/partial agonists (i.e. tamoxifen, nafoxidine and clomiphene citrate) were also capable of inducing female sex determination, but to a lesser extent. A high dosage of testosterone resulted in the production of some females (7 of 15 hatchlings) whereas dihydrotestosterone had no detectable effect on sex determination. This latter finding suggests that testosterone could be acting via aromatization to oestradiol-17 beta. A few females resulted from eggs that had been treated with aromatase inhibitor, 1,4,6-androstatrien-3,17-dione (ATD) (3 of 97), the antiandrogen hydroxyflutamide (1 of 55) and progesterone (3 of 36), suggesting the possibilities of non-specific effects of these compounds when used in large dosages. Alternatively, metabolites of these compounds may be oestrogenic. Collectively, the results at the male-producing temperature are consistent with the hypothesis that steroid-induced female sex determination is mediated via an oestrogen-specific receptor.(ABSTRACT TRUNCATED AT 250 WORDS)


Opioid modulation of FSH, growth hormone and prolactin secretion in the prepuberal gilt. The role of endogenous opioid peptides (EOP) in modulating GH, prolactin (PRL) and FSH secretion was evaluated in prepuberal (P) gilts. In experiment I, P gilts received 1 (n = 2), 3 (n = 3) or 6 (n = 3) mg naloxone (NAL)/kg body weight i.v. Blood was collected every 15 min for 2 h prior to and 2 h after NAL and an additional 1 h after 100 micrograms gonadotrophin-releasing hormone (GnRH) i.v. In experiment II, P and mature (M) gilts were ovariectomized. Three weeks after ovariectomy, P and M gilts were injected twice a day for 10 days with either 0.85 mg progesterone (P4)/kg body weight or oil vehicle (V), resulting in the following groups: PP4 (n = 11), PV (n = 10), MP4 (n = 11) and MV (n = 10). All gilts received 1 mg NAL/kg body weight on the last day of treatment. Blood samples were collected every 15 min for 4 h before and 2 h after NAL and an additional 1 h after 100 micrograms GnRH i.v. In experiment III, six P and five M gilts were ovariectomized and surgically implanted with intracerebroventricular (i.c.v.) cannulae. Blood was collected every 15 min for 3 h before and 3 h after i.c.v. injection of 500 micrograms morphine in artificial cerebrospinal fluid (CSF) or 250 microliters CSF. In experiment I, all doses of NAL failed to alter PRL secretion, while NAL increased (P less than 0.05) GH secretion in three out of eight gilts. However, NAL suppressed (P less than 0.05) FSH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)


Cultured dermal papilla cells from androgen-dependent human hair follicles (e.g. beard) contain more androgen receptors than those from non-balding areas of scalp. Androgens stimulate hair growth in many areas, e.g. the beard; they also induce regression and balding on the scalp with increasing age in genetically disposed individuals. The cause(s) of this biological conundrum is unknown but age-related; androgen-potentiated changes also occur in the prostate. The mesenchyme-derived dermal papilla situated at the base of the hair follicle is thought to play an important role in regulating the growth and development of the follicular epithelium. Since androgens probably act on the hair follicle via the dermal papilla, cultures of dermal papilla cells from human hair follicles with differing responses to androgens in vivo have been established and their ability to bind androgens assessed. Receptor binding was assayed by saturation analysis (0.05-10 nmol/l) using the synthetic non-metabolizable androgen, [3H]mibolerone. Shionogi 115 cells were also assayed as a positive control. Specific high-affinity low-capacity androgen receptors were identified in 12 dermal papilla primary cell lines with similar characteristics to established androgen receptors. Cells from androgen-sensitive follicles (beard, scrotum and pubis) contained higher levels of androgen receptors than those derived from relatively androgen-insensitive non-balding scalp follicles whether the receptor content was calculated in relation to cell number, protein or DNA content of the cells. These results support the hypothesis that androgens act on hair follicles via the dermal papilla in vivo and demonstrate that dermal papilla cells exhibit an altered phenotype in culture which depends on the body site from which they were derived.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypophysectomy prevents the castration-induced increase in porphyrin concentrations in the harderian glands of the male golden hamster: a possible role for prolactin. The Harderian glands of golden hamsters contain high concentrations of porphyrin pigments, with female hamsters having considerably higher porphyrin concentrations than males. Castration of male hamsters leads to a rapid increase in porphyrin concentrations; testosterone treatment of females has the opposite effect, suggesting a central role for androgens in inhibiting the realization of high porphyrin concentrations by this organ. Previous studies in our laboratories have shown, however, that administration of a dopamine agonist to castrated hamsters prevents the normal increase in Harderian porphyrins from occurring. This suggests that prolactin is necessary for low androgen levels to lead to maximal increases in Harderian porphyrin concentrations. The present study tested the hypothesis that prolactin is involved in the control of Harderian porphyrin levels in the golden hamster. Although hypophysectomy of male hamsters reduced serum testosterone to levels in castrated hamsters, the resultant increase in Harderian porphyrin concentrations was much less than that seen after a similar period of castration. Furthermore, combining the two procedures (castration and hypophysectomy) also led to a blunted increase in Harderian porphyrin, suggesting that a pituitary hormone is necessary for low testosterone levels to lead to increased porphyrins. Evidence that this pituitary hormone is prolactin comes from the observations that eliminating all pituitary hormones except prolactin, by severing the connection of the pituitary with the hypothalamus or transplanting the pituitary to a distant site (beneath the kidney capsule) led to greatly augmented Harderian porphyrin levels, in intact or castrated male hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of in-vivo administration of insulin-like growth factor-I on the rate of glucose utilization in the soleus muscle of the rat. This study investigated the effects of insulin-like growth factor-I (IGF-I) administered to rats in vivo on the soleus muscle isolated from these rats. In order to study the interactions between IGF-I and insulin, the soleus muscles were incubated in the presence of various concentrations of insulin. IGF-I (190-200 micrograms) was given twice daily; the rats were killed 1 h after one injection of IGF-I (acute administration) or after treatment with IGF-I for 10 days (prolonged administration). The level of IGF-I in plasma was increased by approximately 100% after acute administration and by around 30% after 10 days of treatment with IGF-I. Acute administration of IGF-I to the rats increased the flux of glucose to hexose monophosphate and the rates of lactate formation and glycogen synthesis in the soleus muscles; however, the responsiveness of these muscles to insulin was lost: the increase in the rate of glucose utilization by IGF-I at physiological concentrations of insulin (10 or 100 mU/l) was similar to that observed at maximal concentrations of insulin (1000 mU/l). Similar results were obtained after prolonged treatment of the rats with IGF-I; however, the increase in the rate of glucose utilization was less pronounced than when IGF-I was given acutely and the muscles were still capable of responding to insulin.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of administration of growth hormone on plasma and intracellular levels of thyroxine and tri-iodothyronine in thyroidectomized thyroxine-treated rats. We have studied the effects of the administration of GH on plasma levels and peripheral production of tri-iodothyronine (T3) from thyroxine (T4) in thyroidectomized male Wistar rats given a continuous i.v. infusion of T4 (1 microgram/100 g body weight per day) and GH (120 micrograms per day) for 3 weeks. Tracer doses of 131I-labelled T3 and 125I-labelled T4 were added to the infusion. At isotopic equilibrium (10 days after the addition of 125I-labelled T4) the rats were bled and perfused. The plasma appearance rate for T3 was higher (10.6 +/- 1.3 vs 8.4 +/- 2.8 pmol/h per 100 g body weight, P = 0.05) and plasma TSH was lower (246 +/- 24 vs 470 +/- 135 pmol/l, P less than 0.01) in GH-treated rats. The amount of T3 in liver (12.3 +/- 2.8 vs 5.5 +/- 1.7 pmol/g wet weight, P less than 0.01), kidney (11.5 +/- 1.4 vs 6.5 +/- 1.4 pmol/g wet weight, P less than 0.01) and pituitary (8.8 +/- 2.7 vs 4.8 +/- 0.5 pmol/g wet weight, P less than 0.01) was higher than in controls, mainly as a result of an increased local production of T3 from T4, but plasma-derived T3 was also higher in most organs. We found an increased intracellular T3 concentration in the pituitary which may be responsible for the lower plasma TSH concentration in the GH-treated rats. Since the increase in locally produced T3 is found particularly in liver, kidney and pituitary, typical organs that express 5'-deiodinase activity, we suggest that GH acts on thyroid hormone metabolism by stimulating type-I deiodinase activity.


The identification of 125I-labelled iodomelatonin-binding sites in the testes and ovaries of the chicken (Gallus domesticus). The existence of 125I-labelled iodomelatonin-binding sites in chicken ovaries and testes was investigated. The specific binding of 125I-labelled iodomelatonin to chicken ovarian and testicular tissue satisfies all the criteria for a binding site. It was rapid, stable, saturable, reversible, specific and of high affinity. Equilibrium studies showed that total and non-specific binding increased over a range of 5-150 pmol 125I-labelled iodomelatonin/l tested, with specific binding reaching saturation towards the middle range of radioligand concentrations. Scatchard analyses indicated a dissociation constant (Kd) of 36.5 +/- 5.3 pmol/l (means +/- S.E.M.) in the membrane preparations of chicken testes at the middle point in the period of light and a maximum number of binding sites (Bmax) of 0.93 +/- 0.40 fmol/mg protein (n = 6). In membrane preparations of chicken ovaries, the Kd was 102.2 +/- 27.3 pmol/l and the Bmax was 2.77 +/- 0.38 fmol/mg protein (n = 6). Equilibrium and kinetic dissociation constants in the picomolar range indicate high-affinity and physiologically relevant 125I-labelled iodomelatonin-binding sites. Competitive inhibition studies determined the following order of relative potency for inhibition of 125I-labelled iodomelatonin-binding to chicken gonadal membranes: 6-chloromelatonin greater than melatonin greater than N-acetylserotonin much much greater than 5-hydroxytryptamine, tryptamine, 5-methoxytryptophol, 1-acetylindole-3-acetic acid, 5-hydroxyindole-3-acetic acid and L-tryptophan. The presence of 125I-labelled iodomelatonin-binding sites suggests a direct pineal-gonadal connection in the chicken.


N-methyl-D-aspartate does not prevent effects of melatonin on the reproductive and thyroid axes of male Syrian hamsters. The reproductive and thyroid status of male Syrian hamsters maintained on long days (14 h light, 10 h darkness) were assessed after 10 weeks of daily injections of pharmacological doses of melatonin (25 micrograms s.c.) and/or N-methyl-DL-aspartic acid (NMDA, 0.025-6 mg i.p.), a compound with receptor sites in the central nervous system which are known to affect reproduction. Melatonin given during the late light phase decreased reproductive organ weights and levels of serum and pituitary prolactin and serum thyroxine (T4); these results are similar to published reports on the effects of chronic short photoperiod treatment of this species. Reproductive organ weights, T4 levels and values for prolactin did not differ significantly between groups receiving only melatonin and those receiving NMDA in addition to melatonin; likewise these variables did not differ significantly between groups receiving only either NMDA or saline. NMDA alone and in combination with melatonin increased serum tri-iodothyronine (T3). The brown adipose tissue enzyme T4 5'-deiodinase demonstrated an increased activity in the presence of NMDA, with the lowest dosage eliciting the most significant effect. Previous studies have demonstrated that NMDA reverses the reproductive effects of short photoperiod. The results of this study show that NMDA is incapable of preventing the inhibitory reproductive effects of exogenously administered melatonin. These observations are consistent with the proposal for a site of action for NMDA on neural regions more proximal than those altered by melatonin; alternatively, NMDA may interfere with neurotransmitter actions in the pathway controlling melatonin production.


Distribution of the nuclear thyroid-hormone receptor in extraocular and skeletal muscles. The correlation between the occurrence of Graves' ophthalmopathy and Graves' hyperthyroidism may indicate a role for tri-iodothyronine (T3) hormone in the pathogenesis of Graves' ophthalmopathy. In Graves' ophthalmopathy the recti eye muscles are greatly enlarged whereas skeletal muscles seem unaffected. The distribution of the nuclear T3 receptor was studied in normal human and rat eye and skeletal muscles with immunohistochemistry using mouse (monoclonal) antibodies, and by in-situ hybridization for the detection of mRNA encoding the T3-receptor protein. Nuclear staining with T3-receptor antibodies was found in all types of tissues studied. Cytoplasmic staining occurred predominantly in the muscle fibres of the orbital layer of the eye muscles and was generally absent or very low in skeletal muscle fibres and hepatocytes. Immunostaining could be inhibited by preabsorbing the antibodies with bacterially expressed T3-receptor protein, implying specificity. The presence of nuclear and cytoplasmic hormone-free T3 receptor sites was indicated after preincubation of sections with T3 hormone; T3-receptor immunostaining decreased and T3-hormone staining increased. In-situ hybridization clearly revealed the presence of alpha-1 and beta-1 forms of the T3-receptor mRNA in liver, skeletal muscles, and orbital and intermediate layers of the eye muscles. The data demonstrate the presence of T3 hormone-receptor molecules in the extraocular and skeletal muscles. The different susceptibilities of these muscles to Graves' hyperthyroidism may relate to the quantitative differences in T3 hormone-receptor distribution.


Pulsatile secretion of LH in the ram: a re-evaluation using a discrete deconvolution analysis. The purpose of the present experiment was to characterize LH secretion pulsatility in rams by analysing the instantaneous secretion rate profile obtained by deconvoluting the plasma concentration profile. Plasma LH concentration profiles were obtained by collecting blood samples every 6 min for 24 h during two different sessions separated by an interval of 15 days. Individual kinetic parameters of ovine LH (oLH) were determined following i.v. injection of oLH. By deconvoluting the plasma concentration profile, it was shown that a pulse has an effective duration of only 20.41 +/- 7.69 (S.D.) min whereas the mean duration estimated from measurement of plasma concentrations was 61.00 +/- 15.16 min. The number of pulses was similar before and after deconvolution (7.80 +/- 1.99 vs 9.70 +/- 3.44 pulses/24 h respectively). Using deconvolution the calculated production rate was 2.26 +/- 0.94 micrograms/kg per 24 h, about 50% of this production being located in the pulses. Statistical analysis of pulsatility revealed that pulse occurrence was a nonperiodic event and that the amplitude of LH pulses and the associated amount of LH released were correlated with the duration of the preceding quiescence period, but had no statistically significant influence on the duration of the following quiescence period.


Production of parathyroid hormone-related protein by the mammary gland of the goat. Parathyroid hormone-related protein (PTHRP) has been quantified by sensitive specific immunoassays in mammary venous blood and milk from 7 days before to 7 days after parturition in the goat. A significant venous-arterial concentration gradient in plasma PTHRP 1-86 concentrations was demonstrated across the mammary gland, indicating that PTHRP enters the maternal circulation and may have a role in calcium homoeostasis during lactation. Significant and sustained increases in mammary venous and milk PTHRP 1-86 concentrations were found from 1 day before parturition to 7 days afterwards, with peak concentrations of 1.57 +/- 0.58 pmol/l (plasma) and 8.69 +/- 2.95 nmol/l (milk) (mean +/- S.E.M.) occurring on day -1 and the day of parturition respectively. Estimates of the mammary output of PTHRP into plasma in four goats averaged 9% (range 1-25%) of that secreted into milk. Suppression of maternal prolactin concentrations by bromocriptine significantly reduced milk yield and the mammary venous PTHRP concentration, without affecting the concentration of PTHRP in milk. In conclusion, parturition in the goat is associated with a sustained increase in secretion of PTHRP into both plasma and milk; the former may be involved in maternal calcium homoeostasis, whereas the latter may have a role in the neonate.


Kinetics of placental lactogen in mid- and late-gestation ovine fetuses. Placental lactogen (PL) is found in fetal plasma throughout gestation, and PL receptors occur on many types of fetal cells. In this study, the entry rate of PL into the fetal circulation was estimated by injection of 125I-labelled ovine PL into two mid- and four late-gestation fetuses. At both ages, PL appears to be distributed into two body pools. One pool has a rapid half-life (approximately 9 min) and a volume of distribution approximately 8% of body weight, while the second pool has a longer half-life (approximately 45 min) and a distribution volume only 4% of body weight. The first pool is presumably blood plasma, but the physiological identity of the second pool is unknown. The effective half-life of PL is approximately 15 min, and the liver is suggested as a probable major site of degradation. These estimates were confirmed in late gestation by measuring fetal plasma concentrations of PL in response to a continuous infusion of unlabelled PL. The kinetic parameters estimated in this study can be used to determine the quantity of exogenous hormone required to alter PL concentration in fetal plasma in a predictable manner.


The relationship between neonatal mortality and hospital level. The relative safety of the small obstetrics unit compared with that of the larger or more technologically sophisticated units remains controversial. The purpose of this study was to examine the relationship between neonatal mortality and the level of perinatal services present in the hospital of birth. Logistic regression was used to model neonatal mortality as a function of race, weight, and hospital level. Hospitals were classified into five categories using the volume of deliveries and the level of perinatal services available. Both black and white infants born at Level I-A hospitals who weighed less than 2250 (5 lb) fared worse than those born at Level III hospitals. There were no other statistically significant differences between the remaining hospital levels at any weight, although there was a trend toward improved mortality for white babies weighing less than 1500 g (3 lb, 5 oz) born at Level III centers. Level II-B hospitals, which also had neonatal intensive care available, did not demonstrate this trend. The results of this study support the safety of facilities with lower levels of care for delivery of normal birthweight infants and the need for continued centralized delivery of higher levels of care for high-risk patients.


The information needs of family physicians: case-specific clinical questions. Physicians must be able to rapidly obtain information that answers specific patient-related clinical questions. This study describes the information-seeking process in the office practices of family physicians. We observed and recorded the information-seeking and information-obtaining behavior of 30 family physicians in their offices. Based on 172 hours of observation and 602 patient visits, family physicians sought answers to an average of only one clinical question for every 15 patients seen. Urban physicians sought answers to more questions than rural physicians (one question for every 9 patients, as compared with one question for every 24 patients; P less than .05). The frequency of seeking information was not related to the physician's age. Busier physicians (those seeing more patients per hour) tended to ask fewer questions (correlation coefficient (r) = -.34, P = .06). Drug-prescribing questions were the most common type; second most common were orthopedic questions. Colleagues and the Physicians' Desk Reference were the most often used resources. Eight percent of the questions were not answered. Among family physicians, patient-related questions are infrequently asked and highly specific. Most questions are rapidly answered using colleagues and books, not journals or computers.


Are Papanicolaou smears enough? Acetic acid washes of the cervix as adjunctive therapy: a HARNET study. Harrisburg Area Research Network. The Papanicolaou smear has a false-negative rate ranging from 10% to 50%. Adjunctive screening methods for detecting cervical disease are thus of interest. We studied an adjunctive acetic acid wash of the cervix to detect additional cases of cervical disease not found by the Papanicolaou smear. All women attending six family practice offices for health maintenance during the period August 1989 through April 1990 were examined (N = 2827). Papanicolaou smears were obtained using a Cytobrush and wooden spatula. Each subject's cervix was also visually examined 1 minute after application of 5% acetic acid. Women with abnormal Papanicolaou smear results or abnormal acetowhite areas on visual inspection of the cervix underwent colposcopy. Ninety-three cases of biopsy-proven condyloma or cervical intraepithelial neoplasia (CIN) were found on the basis of abnormal Papanicolaou smear results alone, 33 on the basis of abnormal acetic acid wash results alone, and 14 on the basis of abnormal results from both a Papanicolaou smear and an acetic acid wash. The prevalence of CIN was 3%. The overall positive predictive value for abnormal results obtained by acetic acid wash was .55 (95% CI = .43 to .63). Using a 1-minute 5% acetic acid wash improves the detection of cervical disease by 30%. Consideration should be given to augmenting the Papanicolaou smear with this safe, simple, and effective technique on premenopausal women during regular health maintenance examinations.


Identifying ABO incompatibility in newborns: selective vs automatic testing. Two approaches to identifying blood group (ABO) incompatibility in infants have been suggested. The routine approach is to automatically perform blood type and direct antiglobulin tests on every infant born to a mother with type O blood. The selective approach is to test only significantly jaundiced infants. One hundred thirteen infants of mothers with type O blood were tested automatically and 188 other infants were tested selectively. Charts of the infants were reviewed for jaundice recognition and management. Jaundice recognition and management and mean peak bilirubin levels did not differ significantly between the two groups. However, three of the infants who were tested selectively had bilirubin levels above 342 mumol/L (20 mg/dL). Two infants were readmitted for phototherapy despite automatically having had their cord blood tested. All infants requiring phototherapy were clinically jaundiced before 48 hours of age. Selective cord blood testing was found to be a reasonable, less expensive alternative to routine testing. However, in clinical settings in which newborns are often discharged before the third day of life, automatic cord blood testing may be preferable. All infants discharged before 48 hours of age need close clinical follow-up regardless of the testing protocol used.


Primary care research funding sources.

Primary care research funding sources. Numerous studies and anecdotal reports have identified lack of funding as a major obstacle to recruiting young physicians to academic medicine and to developing research in primary care. The focus of this study is the comparison of funding sources reported for published research in the primary care disciplines of family medicine, general internal medicine, pediatrics, and obstetrics and gynecology. Articles from a representative sample of the journals of each discipline were eligible for review and inclusion in the study if the work was an original research article. The eligible articles were reviewed and classified by specialty and by funding source. The reported funding sources were categorized into federal, private foundation, local, discipline specific, corporate, and none. After all of the articles had been categorized, 40 articles from each discipline that had not reported any funding source were randomly selected. The primary author of each study was then contacted by telephone for a structured interview to verify the absence of reported funding in the published study. Eligible published articles used in this study numbered 319 in family medicine, 208 in general internal medicine, 522 in obstetrics and gynecology, and 888 in pediatrics. There was a statistical difference between the disciplines regarding the source of funding (chi 2 = 223.0, P less than .0001). Family medicine research was funded primarily by federal and discipline sources. Obstetrics and gynecology research was funded primarily by federal, private foundation, and corporate sources. General internal medicine research and pediatric research were funded primarily by federal and private foundation sources. The majority of the research articles in all four disciplines did not report any funding source. All four disciplines had diverse sources of funding with many similarities and relatively few differences. An important finding of the study was the amount of unfunded research conducted and published in these primary care disciplines.


The effect of patient education on pediatric immunization rates. Over the last decade, the immunization rate among preschool children has decreased, especially in the lower socioeconomic population. During this period, reports of outbreaks of immunizable diseases, especially pertussis and measles, have correspondingly increased. This study was designed to evaluate the effect of a brief patient education encounter with new mothers on pediatric immunization rates. Two hundred thirty-eight mothers and infants were assigned to an intervention or control group. On the first day postpartum, the mothers in the intervention group participated in a 10- to 15-minute discussion on the importance of immunizations and were given a patient education handout. A reminder letter was mailed to the intervention group at 2 months postpartum. The control group received no special intervention. Infants were followed for their 2- and 4-month immunizations for diphtheria, pertussis, and tetanus and oral polio vaccine (DPT/OPV). At 1 year of age, the infants' immunization records were assessed for the completion of their first three DPT/OPV immunizations. There was no statistically significant difference, by chi-square analysis, in the immunization rates of the control and intervention groups at 2, 4, or 12 months of age. At 1 year of age, 29 of 122 (24%) of the control group had received all three DPT/OPV immunizations, compared with 33 (28%) of 116 infants in the intervention group. Concordant with similar studies, the immunization rate among infants of parents of lower socioeconomic status (26%) is low. An educational intervention presented to mothers in the postpartum period did not improve the rate of immunization by the age of 12 months. There are undoubtedly several reasons for this failure. Other means to improve immunization rates of infants should be developed and tested.