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We reviewed the case records of suicides in Marion County, Indiana (Indianapolis) and in surrounding counties from 1984 through 1992. Out of 1203 suicides, there were 14 in which armed, on-duty police officers were confronting, pursuing, or apprehending the subject of the death investigation. All subjects were male, and the peak age range was 30 to 34 years. The head, especially the right temple, was the usual site of the fatal wound. More than half of the incidents started as domestic disputes with a wife or girlfriend. Many of the others occurred when police officers pursued or arrested a suspect wanted for a previous felony. Ethanol was involved in less than half of the cases, and drugs were not a factor. In at least four cases, the presence of police was a factor that precipitated the suicide. The histories of the 14 cases demonstrate the potential for controversy and the challenges for forensic scientists investigating suicides during police confrontations.

Common paving materials--concrete and asphalt--pose an unusual and complex barrier to disinterment and examination of human remains. Although not commonly encountered, these materials are seen with sufficient frequency to justify consideration of the procedures and equipment necessary for disinterment. Over a seven year period we have encountered paving materials seven times. In each of these cases, the material was slightly different in quality, and different tools--including heavy construction equipment--were necessary. Sometimes the paving material could be managed without heavy power tools, but occasionally specialized construction tools have proven very useful.

Objective: To determine if depression scores and depressive symptoms are higher in patients with rheumatoid arthritis (RA) than among those with other rheumatic disorders; and to describe norms for the Arthritis Impact Measurement Scale (AIMS) depression scale., Methods: A 100% sample of all clinic visits of 6,153 consecutive patients with rheumatic disease seen in an outpatient rheumatic disease clinic during a 10-year period. 19,122 AIMS depression scores were utilized. For each patient an average depression score was calculated. Covariates included age, sex, education level, ethnic origin, and number of clinic visits., Results: RA depressive symptoms and depression scores did not differ from all other clinic patients (taken as a whole). Patients with fibromyalgia had significantly more abnormal scores., Conclusion: Depression scores are not higher or depressive symptoms more common in patients with RA compared with other clinic patients. By every measure depression is increased in fibromyalgia. The notion that patients with RA have increased depression or are somehow more susceptible to depression is not supported by the data and should be abandoned.

Objective: To determine the extent to which clinical variables and changes in clinical variables explain depression and depression changes in patients with rheumatoid arthritis (RA)., Methods: 713 patients with RA attending an outpatient rheumatology clinic were studied at their 2 most recent clinic visits as part of their ordinary rheumatic disease care. Six demographic variables and 7 clinical variables were assessed including the Arthritis Impact Measurement Scale depression score, Stanford Health Assessment Questionnaire Functional Disability Index (HAQ-DI), visual analog scale (VAS) pain scales, joint count, grip strength, am stiffness, and erythrocyte sedimentation rate. Change scores representing the difference between the scores at the last and the next to last visit were calculated for all clinical variables., Results: About 20% of the variance in depression change scores was explained by changes in clinical variables. The amount of variance explained appeared to be inversely related to the time between visits. Thirty-four percent of the variance in current levels of depression scores was explained by current clinical and demographic variables. The most important predictors of depression score and depression change were VAS Pain and HAQ-DI. At the last clinic visit between 11 and 16% of the depression score was explained by changes in depression scores since the previous clinic visit., Conclusion: Clinical changes explain 20% of depressive changes between visits, while 34% of current depression scores are explained by current clinical status. Changes in pain and HAQ-DI predict changes in depression.

Objective: To determine the prognosis of undifferentiated polyarthritis syndrome in the clinic compared with rheumatoid arthritis (RA)., Methods: We identified consecutive patients seen within the first 2 years of disease (and further subset into 6-month groups) diagnosed as having either RA or undifferentiated polyarthritis syndrome at the first clinic visit. Undifferentiated polyarthritis syndrome was characterized by clinical presentation, laboratory data, and American College of Rheumatology (ACR) 1958 and 1987 RA criteria. Followup evaluations were done to determine change in diagnosis, resolution of symptoms, and clinical remission of RA., Results: Undifferentiated polyarthritis syndrome was more common in the clinic than RA (638 vs 503). Of patients with RA 7.6% were symptom free an average of 6.9 years after the first clinic visit. For those with disease onset between 0-6 months and 0-2 years, complete resolution of undifferentiated polyarthritis syndrome occurred in 57.9 and 53.9% of cases, including 46.1 and 35.6% meeting ACR 1987 criteria for RA. Latex positivity was the strongest predictor of failure to resolve subsequently (25.0 and 29.2% resolution) and the best predictor of development of RA (41.7 and 43.1%)., Conclusions: Nonrheumatoid undifferentiated polyarthritis syndrome is more common in the clinic than RA. Undifferentiated polyarthritis syndrome resolves in more than half the cases, while RA remits in 7.6%. Finally, resolution of RA criteria positive undifferentiated polyarthritis syndrome occurs predominantly in those who are seronegative.

Determination of suicide as a manner of death can be a complex process. Whenever gunshot wounding is the cause of death, the anatomic clues useful for determining suicide versus homicide include wound location and range of fire. Contact intraoral gunshot wounds are much more frequently associated with suicide than with homicide. However, based on prosecuted cases, three of 66 consecutive cases of intraoral gunshot wounds were found to be homicides.

Atypical gunshot wounds are caused by a diverse set of parameters relating to weapons and ammunition. Documentation of cases where atypical gunshot wounds can be explained facilitates future interpretation of wounds in unusual cases. We report an atypical gunshot wound produced by a double-action Colt .38-caliber special handgun with a cylinder index error. Cylinder index error is caused by a misalignment between the cylinder chamber and barrel forcing cone. When properly functioning, the cylinder chamber and barrel forcing cone are held in alignment by the union of the ratchet and latch pin. In this case, misalignment was caused by wear of the ratchet and latch pin, which allowed play in the cylinder. With the weapon turned on its side, and the swing arm down, the cylinder chamber overlaps the barrel forcing cone. When fired, the index error caused lead fragments to shear off the bullet and expel laterally out the cylinder gap between the cylinder chamber and barrel forcing cone, creating fragment entrance wounds several centimeters distant from the site of contact entry.

Objective: To determine the extent of efficacy of intramuscular (im) gold in clinical practice., Methods: Ninety-eight patients who received im gold treatment for at least 1 year were assessed during ordinary clinic visits over the 12 month period following gold initiation. Assessments included joint counts, erythrocyte sedimentation rate (ESR), morning stiffness, visual analog scale (VAS) patient pain, VAS patient global, grip strength, prednisone dose, hemoglobin, and Stanford Health Assessment Questionnaire (HAQ) disability index., Results: All outcome measures showed significant improvements at one year by standardized pretest posttest differences (effect size) and by measurement of the area under the curve (AUC). Important improvement (at least 50% improvement) was common: joint count (63.3%), global severity (41.1%), ESR (48.2%), grip strength (42.7%) HAQ disability (45.3%), and morning stiffness (72.2%). Effect sizes were substantial, even after correcting for placebo effect and withdrawals. Overall improvement was clinically significant, amounting to the equivalent of 2 months without pain or disability., Conclusion: Patients receiving gold for 12 months improved significantly and importantly in all measures studied. Improvement was clinically significant, amounting to the equivalent of 2 months without pain or disability. The degree of improvement was similar to, but somewhat greater, than that seen in controlled clinical trials, and could not be explained by regression to the mean.

A review of the records for five years from the Coroner's Offices of Marion County, Indiana and Franklin County, Ohio, which have a combined population of 2.4 million, yielded 12 cases of hanging deaths in children 13 years of age or younger. The age range was 2 1/2 to 13 years and only two of the 12 victims were female. There were three unequivocal suicides, five accidental deaths and four cases where, despite extensive investigation, the manner of death remained undetermined. The scene and autopsy findings are presented and the cases discussed with regard to determination of manner of death. Additionally, the significance and pathophysiology of petechiae are discussed.

RNA polymerase II (pol II) transcription complexes initiated from the adenovirus major late promoter can become blocked both in vitro and in vivo at a specific site within the first intron of the transcription unit. In vitro, polymerases that fail to read through the major late attenuation site remain stably bound to the template in a ternary complex that is indefinitely blocked from continuing elongation, a phenomenon referred to as "arrest." Elongation factor SII has been shown both to promote readthrough of this and other arrest sites and to stimulate a previously unknown 3' to 5' exonuclease activity of pol II. We have proposed that the two activities are related and that SII promotes readthrough by means of the enhancement of the exonuclease activity. In the experiments reported here, we have tested several features of that model. In particular, we have examined the hypothesis that SII stimulates readthrough by allowing the polymerase to undergo multiple cycles of removal and resynthesis of RNA bases preceding the attenuation site. In addition, we present experimental support for the proposal that the length of time polymerase pauses at the attenuation site is important to the efficiency of arrest. The results of these experiments are discussed in the context of the model.

Aaron Antonovsky's Sense of Coherence (SOC) questionnaire with its 3 subscales is designed to measure strengths within individuals that allow them to survive in the face of extreme stresses, including chronic illness. We administered the SOC to 1333 patients with rheumatic disorders. Although the instrument had high alpha reliability, factor analysis did not support the concept of distinct subscales. The SOC was strongly related to the Arthritis Impact Measurement Scales anxiety and depression scores (r = -0.63 to -0.69), less strongly related to clinical variables (r = -0.20 to -0.33), and was minimally related to demographic variables. When psychological variables were controlled for, almost no association between the SOC and clinical variables remained (r = 0.06). Whether the SOC will be more useful than standard psychological instruments awaits the result of ongoing studies.

This study retrospectively reviewed 142 fatal cases of aortic laceration. Data were collected from the autopsy reports (including toxicology results) and included the circumstances of the injury. In the case of automobile crashes this included the direction of impact, time of day, and vehicular damage. Seventy percent of the victims were men with a mean age of 37.5 years; 30% were women with a mean age of 46 years. Thirty-five percent of the 142 victims had elevated blood alcohol levels. Fifty-four percent of the lacerations were located at the classic site (the isthmus). The majority of the aortic lacerations (102) were sustained in automobile crashes. Of these, 42% were broadside collisions and 58% were head-on collisions. Seventy-three percent and 67% of the victims in broadside and head-on collisions, respectively, had aortic lacerations at the classic site. The results suggest that the pathogenesis of aortic rupture involves a lateral oblique compression impact to the chest, which causes thoracic mediastinal structures to shift and deflect the aortic arch, resulting in severe shearing and stretching at the isthmus. The use of seat belts and air bags may reduce the number of aortic injuries.

Relatively little information is available concerning the incidence of sudden death in athletes in the United States. The present study provides annual incidence rates of sudden athletic deaths in Marion County, Indiana, home of Indianapolis, the "amateur sports capital of the world." The overall incidence was 0.04% (18 athletic deaths in 44,481 forensic necropsies). This incidence varied slightly over the 6-year study period: 1985 (0.06%), 1986 (0.03%), 1987 (0.04%), 1988 (0.09%), 1989 (0%), 1990 (0.01%). Of the 18 sudden athletic deaths, 88% were cardiac in origin. A retrospective analysis of preparticipation screening efforts suggests that most of the cardiac conditions responsible for death could have been detected.

The incidence of various types of cardiovascular disease was evaluated in 2007 consecutive forensic patients. Cardiovascular deaths accounted for 22.8% of the study patients and atherosclerotic coronary heart disease was the most common type of cardiac disease (18%). Among subjects dying of atherosclerotic coronary disease, sudden death was three times more frequent than acute myocardial infarction. Expected cardiac findings included the incidence of severe coronary atherosclerosis (21%), floppy mitral valves (5%), and congenital bicuspid aortic valves (1%). Major cardiac findings occurred in 32% and minor cardiac findings were found in 40%. Only 17% of hearts were anatomically normal. An unexpected cardiac necropsy finding included the high frequency of myocardial bridges (23%). Unexpected cardiac findings included the low incidence of acute myocarditis (0.6%) and common finding of tunneled epicardial coronary arteries ("myocardial bridges") (23%).

To obtain evidence concerning short-term and long-term efficacy of clinical and health status measures in rheumatoid arthritis (RA), we conducted two observational studies--a 6-month study of 233 patients receiving methotrexate and a 10-year study of 157 patients receiving multiple treatments in a rheumatic disease clinic. Results of the 6-month study yielded effect sizes for treatment similar to the meta-analyses reported by Felson [corrected] et al. (Arthritis Rheum 33:1449-1461, 1990) and the controlled trials of methotrexate reported by Weinblatt et al. (Arthritis Rheum 33:330-338, 1990), suggesting that observational studies provide valid measurements of treatment effect. The effect size for the Health Assessment Questionnaire (HAQ) was 0.5. By contrast, the 10-year study suggested that standard clinical variables changed little and were not useful in assessing RA outcome, while the effect size of the HAQ was -2.39. These data continue to underscore the differences between short-term trials and the long-term outcome of RA, and suggest an important place for the HAQ or similar instruments in all phases of RA evaluation and assessment.

The eukaryotic transcription factor TFIID recognizes and binds a promoter sequence element called the TATA box. We have analyzed the interaction of yeast TFIID with the consensus TATA box sequence of the adenovirus major late promoter. To facilitate this detailed characterization, we developed a method for obtaining quantitative information from a gel retardation (bandshift) assay, allowing measurement of the rate and extent of TFIID-TATA box complex formation. Using this assay and DNase I protection assays, we determined that the association rate constant for TFIID binding to the major late promoter was too low to be consistent with a simple diffusion-limited association, suggesting that the binding proceeds by a multi-step pathway. Furthermore, we found that the slow rate of TFIID binding reported by other research groups was not the consequence of a rate-limiting conformational change, as has been previously suggested. Instead, we observed that the formation of a stable TFIID-TATA box complex was relatively rapid (complete in less than 1 min) at saturating concentrations of TFIID. We have proposed a two-step pathway consistent with the observed kinetics and have considered the possible contributions of each step to the overall rate of TFIID binding. This study lays the groundwork for a systematic characterization of the interaction of TFIID with additional TATA box sequences, including an experimental test of the possibility that different steps in the binding reaction are rate-limiting for different promoters.

Transcription elongation in a nuclear extract in vitro is efficiently blocked by Sarkosyl at a specific site downstream of the adenovirus major late (ML) promoter at which regulated transcription arrest has also been observed in vivo. In the experiments reported here, we examined the response of the polymerase to the ML attenuation site in two assay systems: 1) purified RNA polymerase II (pol II) transcribing tailed templates and 2) elongation complexes formed on immobilized templates and then depleted of elongation factors by extensive washing. Efficient site-specific arrest occurred in both systems, demonstrating that recognition of the site is an intrinsic property of the polymerase. However, the elongation properties of washed elongation complexes and purified pol II were not equivalent. In particular, the efficiency of arrest of washed elongation complexes was influenced both by the promoter from which transcription was initiated and by DNA sequences upstream from the attenuation site that did not contribute to the arrest of purified pol II. The polymerase and washed elongation complexes both remained in stable ternary complexes at the ML site with a lifetime of hours; addition of the elongation factor SII to these complexes promoted resumption of elongation. The efficiency of arrest in both systems was dependent on the solution concentration of the nucleotide incorporated at +187 (just beyond the attenuation site), indicating that pausing is an important part of the arrest mechanism. Based on this and other findings, we argue that the polymerase assumes an altered, elongation-incompetent conformation when arrest occurs.

Scientific misconduct--fabrication, falsification, plagiarism or other deviations from ethical standards--is not new or unique to any discipline. Although nurses have not been included in publicized cases of misconduct, nursing is not immune. Circumstances that may be related to misconduct such as pressures to publish and to earn tenure, inadequate supervision of young scientists, limitations of the peer review system, and excessive numbers of publications by an individual are present or could develop within the profession. Careful socialization of young scientists, modifications in tenure and promotion guidelines, and replication studies are suggested as ways to prevent misconduct within nursing.

We have analyzed the interaction of the general RNA polymerase II transcription factor TFIID with its DNA-binding site, the TATA box (consensus sequence TATAAAA). We have demonstrated that TFIID, unlike most sequence-specific DNA-binding proteins, interacts primarily within the minor groove of the DNA helix. This was established by a novel approach involving complete replacement of the thymines and adenines in the TATA box with cytosines and inosines, respectively. This substitution exchanged the major groove of TATAAAA for that of the sequence CGCGGGG, without altering the surface of the minor groove. The unusual DNA-binding properties of TFIID revealed by this study have important implications for TFIID specificity and function and, more generally, for sequence-specific recognition by DNA-binding proteins.

We studied the pain, Stanford Health Assessment Questionnaire functional disability, pain/disability ratio, and psychological scores in 1,522 patients with rheumatic disease with 7 distinct disorders. Individual differences between patients were more striking than differences among diagnostic groups. Patients with rheumatoid arthritis (RA) had the greatest disability, least pain, lowest pain/disability ratio, and least abnormal psychological scores. Highest pain and psychological distress was noted in low back pain, neck pain, and fibromyalgia (axial disorders). Disability in activities of daily living was as high in fibromyalgia as in RA, but low in axial skeletal disorders. There appears to be a continuum for disability that begins with axial but not articular disease (neck and back pain) and ends with multiple articular and periarticular involvement (RA and fibromyalgia).

In order to study the role of tyrosine autophosphorylation in insulin receptor signalling, we investigated a mutant human insulin receptor whereby the three major tyrosine autophosphorylation sites at positions 1158, 1162, and 1163 in the receptor beta-subunit were mutated to phenylalanines. When these mutant receptors were expressed in HTC rat hepatoma cells, there was no enhanced beta-subunit autophosphorylation and tyrosine kinase activity. In these cells there was enhanced insulin stimulation of [3H]AIB uptake and [3H]thymidine incorporation when compared to wild type HTC cells. The present study suggests therefore that the presence of the major insulin autophosphorylation sites is not a requirement for insulin stimulation of amino acid transport and mitogenesis.

We studied clinical and health status measures in 561 patients with rheumatoid arthritis (RA). Two hundred sixty-four patients were seen within 2 years of disease onset and followed for an additional 2 years. Four other groups were each followed for 5 years, and had disease durations of 2-7, 7-12, 12-17, and 17-22 years, respectively, at the first clinic visit. Functional disability developed very early in the course of RA and continued to worsen at about an equal rate over 22 years. Anxiety, pain scores, and self-assessed severity also increased with time, but erythrocyte sedimentation rate (ESR), morning stiffness, and joint counts were unchanged. Treatment resulted in reduction in joint counts and in nonsignificant improvements in ESR, stiffness, and psychological scores. But functional loss increased in each time period in spite of treatment. Variables most effective in controlled clinical trials are not effective as longterm measures of RA outcome.

Fatal and near-fatal maulings of humans by pit bulls have recently become a topic of major public concern, resulting in the passage of laws in some jurisdictions that make the owner of a pit bull criminally liable for manslaughter if his or her pet causes a human death. The authors recently investigated two cases in which children were fatally injured by pet dogs. In the first case, a 17-day-old girl suffered fatal abdominal injuries when attacked by a pregnant Siberian husky. A 2-year-old girl expired from neck wounds inflicted by a pit bull or a rottweiler or both. Because no expert would testify as to which dog caused the fatal injury, the owner of the animals was not charged under a statute which specified criminality only if a pit bull caused the fatal injury. We also examined a 12-year-old boy who attempted to pet a circus tiger; the animal grabbed his arm with its claws and bit off the arm at the shoulder. The arm could not be reattached, but the child survived. These cases and the differentiation of animal bites from other injuries will be presented.

We studied 122 controlled clinical trials and observational studies of second line therapy that involved 16,071 patients. The mean disease duration was 7.61 years at study entry. Controlled clinical trials were inherently short term, and 90.5% of patients were followed for 1 year or less (mean 8.8 months). The mean followup of observational studies was 31 months. Outcome assessments that included functional measurements were rare in either study type, as were considerations of socioeconomic factors. Except for methotrexate, which was used longer, half of the studies indicated discontinuation of therapy after 1.5 years. Good retention rates in studies of 3 to 12 months were not representative of longterm results, but controlled clinical trials and observational studies were similar as to retention during the first treatment year. Observational studies following controlled clinical trials can yield important information about RA treatment effectiveness not available from controlled clinical trials alone.

A set of specimens has been collected, preserved, and organized specifically for the teaching of forensic pathology, odontology, and anthropology. Plastination of soft tissue, whole organs, bones, and teeth has proven valuable in preserving delicate, friable, and calcined specimens. The dry, odorless, biologically inert specimens are durable and resistant to damage caused by handling. Subtle features of soft tissue pathology are well preserved. Patterned injuries change due to shrinkage, but remain easily recognizable. Plastinated whole jaws are still readily identifiable from antemortem records. Radiographic density is essentially unchanged. Putrid and charred specimens become quite manageable.

A set of specimens has been collected, preserved, and organized specifically for the teaching of forensic pathology, odontology, and anthropology. Plastination of soft tissue, whole organs, bones, and teeth has proven valuable in preserving delicate, friable, and calcined specimens. The dry, odorless, biologically inert specimens are durable and resistant to damage caused by handling. Subtle features of soft tissue pathology are well preserved. Patterned injuries change due to shrinkage, but remain easily recognizable. Plastinated whole jaws are still readily identifiable from antemortem records. Radiograph density is essentially unchanged. Putrid and charred specimens become quite manageable.

Divorce has been considered to be increased in rheumatoid arthritis (RA), perhaps as a result of the stress of serious chronic illness. We studied marital status in 7,293 consecutive rheumatic disease patients attending an outpatient rheumatic disease clinic. Divorce was associated with age, sex, population size, and ethnic origin, but when these factors were controlled for, divorce was not more common in the 1,267 patients with RA. Age and sex adjusted divorce percentages for RA and non-RA patients were 6.9 and 6.8 compared with a U.S. percentage of 7.6. Patients with RA, however, were almost 5 times less likely to be remarried after divorce than patients with osteoarthritis.

A prospective nonrandomized phase II study was begun in 1985 using concurrent split-course radiation and chemotherapy in the treatment of locally advanced non-small-cell cancer of the lung. Patients were treated with 3,000 cGy of radiation in 15 fractions to the chest, together with 100 mg/m2 cisplatin on day 1 and 1,000 mg/m2/day 5-fluorouracil infusion on days 1-4. The radiation and chemotherapy were then repeated after a 1-week break. Twenty-one patients were treated, with five patients having a complete response and nine patients having a partial response for an overall response rate of 67%. With a minimum of 24 months follow-up, five patients remain alive. Median survival for the entire group is 11.6 months. The toxicity of the treatment regimen was acceptable. These results do not differ significantly from survivals of similar patients treated with radiation alone, including a series from our own institution. The literature on concurrent chemotherapy and radiation is reviewed and possible future approaches to this tumor are discussed.

Transcription from the adenovirus major late (ML) promoter has previously been shown to pause or terminate prematurely in vivo and in vitro at a site within the first intron of the major late transcription unit. We are studying the mechanism of elongation arrest at this site in vitro to define the DNA sequences and proteins that determine the elongation behavior of RNA polymerase II. Our assay system consists of a nuclear extract prepared from cultured human cells. With standard reaction conditions, termination is not observed downstream of the ML promoter. However, in the presence of Sarkosyl, up to 80% of the transcripts terminate 186 nucleotides downstream of the start site. Using this assay, we showed that the DNA sequences required to promote maximal levels of termination downstream of the ML promoter reside within a 65-base-pair region and function in an orientation-dependent manner. To test whether elongation complexes from the ML promoter were functionally homogeneous, we determined the termination efficiency at each of two termination sites placed in tandem. We found that the behavior of the elongation complexes was different at these sites, with termination being greater at the downstream site over a wide range of Sarkosyl concentrations. This result ruled out a model in which the polymerases that read through the first site were stably modified to antiterminate. We also demonstrated that the ability of the elongation complexes to respond to the ML termination site was promoter specific, as the site did not function efficiently downstream of a heterologous promoter. Taken together, the results presented here are not consistent with the simplest class of models that have been proposed previously for the mechanism of Sarkosyl-induced termination.

Cardiovascular disease continues to be the single most common generic cause of sudden and unexpected deaths. Atherosclerotic coronary heart disease and acute myocardial infarction are the most prevalent forms of fatal cardiac disease observed at autopsy. Other cardiac lesions are frequently listed as causes of death, but the prevalence of such lesions as incidental findings in the general population is unknown. In this study, 470 consecutive forensic autopsies were evaluated for minor and major anomalies. The most frequently observed major congenital finding was floppy mitral valve (5%). Tunneled coronary arteries, considered minor congenital findings, were seen in 29%. Atherosclerotic coronary heart disease was the most common major acquired finding, observed in 16% of cases. Of the 470 hearts, only 8% were considered normal.

During a continuous 14-year observation period we prospectively recorded clinical data on all patients with rheumatoid arthritis (RA) attending an outpatient clinic. Six hundred seventy-one patients received 1017 new administrations of slow acting antirheumatic drugs during more than 2000 patient years of observation. The median time to discontinuation for intramuscular gold, auranofin, hydroxychloroquine or penicillamine was 2 years or less, but was 4.25 years for methotrexate (p = 0.008 vs all other drugs combined). Adverse reactions were a more common reason for discontinuation than efficacy, and both were less common in patients taking methotrexate (p less than 0.01). Neither disease duration, disease severity, or demographic factors were useful predictors of discontinuation. Since controlled clinical trials do not provide long-term outcome assessments, measurement of time to termination is a practical tool to estimate drug inefficacy.

In 1985, we began studying athletic fatalities in Marion County, Indiana (city of Indianapolis, population 779,966) U.S.A. We previously reported the data for calendar year 1985. The reviewed cases include all sudden, unexpected, or traumatic deaths of conditioned, competitive athletes in Marion County. This follow-up is a review of all athletic fatalities in Marion County that occurred from January 1986 through July 1988. All deaths during or immediately after athletic activity were reviewed, whether or not the participant was a conditioned athlete. Natural disease, especially heart disease without prior diagnosis, continues to be the most prevalent modality of death.

A charge nurse in a critical care unit assumes responsibility for the care of several acutely ill patients for an 8- to 12-hour period. Should a salary differential be paid to compensate for the responsibility? Arguments for and against paying a charge-nurse differential are presented in the following article.

We examined the effect of insulin treatment on HTC cells transfected with large numbers of either normal insulin receptors (HTC-IR) or insulin receptors defective in tyrosine kinase (HTC-IR/M-1030). In both HTC-IR and HTC-IR/M-1030 cells, 20 h of insulin treatment (1 microM) at 37 degrees C resulted in a 65% decrease in the number of binding sites with a reciprocal 6-fold increase in affinity. In contrast, treatment with 10 nM insulin (20 h, 37 degrees C) also increased receptor affinity but had a smaller effect on the number of binding sites. 125I-Insulin binding to soluble receptors from HTC-IR and HTC-IR/M-1030 cells pretreated with insulin showed results similar to those obtained in intact cells. In both HTC-IR and HTC-IR/M-1030 cells, insulin enhanced insulin receptor degradation. In HTC-IR/M-1030 cells a 1-h incubation with insulin did not change receptor number and had only a small effect on receptor affinity; also there was no effect of insulin after a 20-h incubation at 15 degrees C. Inhibiting protein synthesis by pretreatment with cycloheximide (100 microM) did not block either the decrease in receptor number or the increase in receptor affinity. Both HTC-IR and HTC-IR/M-1030 cells exhibited a very slow rate of insulin and insulin receptor internalization and no differences were seen in this parameter when HTC-IR cells were compared to HTC-IR/M-1030 cells. These studies indicate, therefore, that in cells expressing kinase-defective insulin receptors, insulin down-regulates insulin receptor number via enhanced receptor degradation, and up-regulates receptor affinity. These effects were time- and temperature-dependent, but not dependent on new protein synthesis, and suggest that activation of tyrosine kinase may not be a prerequisite for certain mechanisms whereby insulin regulates its receptor.

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.

Psychological status was investigated in 46 primary fibrositis (PF) patients, 32 with fibrositis occurring in association with rheumatoid arthritis (RAFIB) and in 76 control patients with rheumatoid arthritis. Groups were similar in tests of life stresses: Family Inventory of Life Events, Multidimensional Health Locus of Control, and self-motivation. Only 28% of PF and 25% of RAFIB had Minnesota Multiphasic Personality Inventory profiles classified as "normal" compared with 51-60% of controls. Both PF and RAFIB had elevated "neurotic" scales (hypochondriasis, depression, hysteria), but only PF patients had statistically significant elevations in the pychopathic deviancy, psychasthenia and paranoia scales. When the Arthritis Impact Measurement Scales were used, PF but not RAFIB patients demonstrated statistically significant elevations on the anxiety and depression scales.

Human blood serum was found to contain two enzymes which hydrolyze various phosphate diester and phosphonate ester bonds. The enzymes were isolated by butanol extraction, ammonium sulfate precipitation, column chromatography and gel electrophoresis. Zymograms showed that one of these enzymes is serum alkaline phosphatase and the other is a 'true' phosphodiesterase I. Serums of 25 persons showed no polymorphisms for either activity. Alkaline phosphatase hydrolyzes phenolic thymidine 5'-nucleotide esters readily, but phenylphosphonate esters very poorly. Serum phosphodiesterase I prefers phenylphosphonate esters to nucleotide diesters, and has no detectable monoesterase activity.

Pregnant T-O mice were exposed to 50 ATA He-O2 pressure for 4 days at different stages of gestation: 4-7, 6-9, and 9-12 days gestation. Controls were exposed to 1 atmosphere absolute (ATA) air. After the exposure period, pregnancy continued until 18 days gestation when the mice were killed and autopsied. Data were collected relating to the litters and placentas (Litter size, percent resorptions, placental weight, fetal-to-placental ratio) and fetuses (weight, crown-rump length, sex, skeletal abnormalities) and analyzed using analysis of variance. Results showed a small but significant increase in the percent resorptions in the pressure group and also a decrease in crown-rump length and placental weight. None of these changes were related to the stage of gestation in which the mice were exposed. No teratogenic effects of pressure were seen. We conclude that exposure to 50 ATA He-O2 during pregnancy in mice produces a small nonselective effect on fetal growth and development but does not affect any specific event taking place during these stages of embryogenesis.

Six of the substrates currently used for the detection and quantitation of phosphodiesterase I (PDE I) were examined. Michaelis-Menten kinetic analysis of the hydrolysis of each of these by venom and bovine intestinal PDE I was performed to allow a comparison of the sensitivity of detection for each substrate. The results confirm that phenolic esters of phenylphosphonate are hydrolyzed 2- to 4-fold more rapidly than are the same esters of thymidine 5'-phosphate when both are present in saturating concentrations. The identification of the bovine intestinal enzyme as a PDE I is verified by its extensive similarity to the paradigmatical PDE I from rattlesnake venom. A new definition for PDE I activity is proposed which takes into account its ability to hydrolyze several types of substrates.

Affinity-purified insulin receptor was photoaffinity labeled with a cleavable radioactive insulin photoprobe. Exhaustive digestion of the labeled alpha-subunit with endoproteinase Glu-C produced a major radioactive fragment of 23 kDa as a part of the putative insulin-binding domain. This fragment could contain either residues 205-316 or 518-633 of the alpha-subunit. Rat hepatoma cells and Chinese hamster ovary cells were transfected with cDNA encoding a human insulin receptor mutant with a deletion of the cysteine-rich region spanning amino acid residues 124-319. Insulin binding by these cells was not increased in spite of high numbers of the mutant insulin receptors being expressed. A panel of monoclonal antibodies which was specific for the receptor alpha-subunit and inhibited insulin binding immunoprecipitated the photolabeled 23-kDa receptor fragment but not the receptor mutant. A synthetic peptide containing residues 243-251 was specifically bound by agarose-insulin beads. We therefore suggest that the 23-kDa fragment contains residues 205-316, and that insulin binding occurs, in part, in the cysteine-rich region of the alpha-subunit.

Prior studies have detected biochemical and immunological differences between insulin receptors in plasma membranes and isolated nuclei. To further investigate these receptors, they were solubilized in Triton X-100 and partially purified by wheat germ agglutinin-agarose chromatography. In these preparations, the nuclear and plasma membrane receptors had very similar pH optima (pH 8.0) and reactivities to a group of polyclonal antireceptor antibodies. Further, both membrane preparations had identical binding activities when labeled insulin was competed for by unlabeled insulin (50% inhibition at 800 pM). Next, nuclear and plasma membranes were solubilized and purified to homogeneity by wheat germ agglutinin-agarose and insulin-agarose chromatography. In both receptors, labeled insulin was covalently cross-linked to a protein of 130 kilodaltons representing the insulin receptor alpha subunit. When preparations of both receptors were incubated with insulin and then adenosine 5'-[gamma-32P]triphosphate, a protein of 95 kilodaltons representing the insulin receptor beta subunit was phosphorylated in a dose-dependent manner. These studies indicate, therefore, that solubilized plasma membrane and nuclear insulin receptors have similar structures and biochemical properties, and they suggest that they are the same (or very similar) proteins.

The 4-methylumbelliferyl analog of p-nitrophenyl phenylphosphonate was prepared and its cleavage by different phosphohydrolases was studied. The new compound, 4-methylumbelliferyl phenylphosphonate, is hydrolyzed by purified phosphodiesterase I (EC 3.1.4.1) from snake venom or bovine intestinal mucosa. This fact has been exploited to develop a zymogram method which allows the detection of these phosphohydrolases on gels, even when the enzymes are present in small amounts in crude extracts. This method is superior to chromogenic methods evolving p-nitrophenol in that it is far more sensitive and is superior to the 4-methylumbelliferyl thymidine 5'-phosphate method in that the substrate is easier to prepare and can be isolated in large quantity.

Although its potential is great, the use of aquatic insects in determining submersion intervals at death-scene investigations has not been exploited in the past. Aquatic environments have no known true specific indicator species, as do terrestrial habitats. However, aquatic environmental studies show that organisms may colonize a substrate dependent on factors such as size, position, exposure to current, water temperature, current speed, water depth, the presence of algal communities, or detritus. Certain aquatic insects such as the chironomid midges (Diptera, Chironomidae), and the caddisflies (Trichoptera), are capable of colonizing immersed bodies; and with the known biology of a specific species of insect for a certain geographic area, time intervals of submersion can be established.