Nonsteroidal anti-inflammatory drug hypersensitivity syndrome: a multicenter study. II. Basophil activation by nonsteroidal anti-inflammatory drugs and its impact on pathogenesis.

BACKGROUND: Patients who are clinically hypersensitive to nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes present basophil activation in vitro, and in 50% of cases a parallel response to release of sulfidoleukotrienes (cellular allergen stimulation test) is observed. These phenomena occur not only in clinically hypersensitive patients, but also in some healthy controls who tolerate NSAIDs. MATERIAL AND METHODS: We studied 16 clinically hypersensitive patients, 22 controls tolerating NSAIDs, and 29 healthy blood donors (clinical NSAID status unknown) using 2 different basophil isolation techniques (buffy coat or plasma leukocytes). RESULTS: In a population of 13 aspirin-tolerant healthy controls and 29 healthy blood donors, basophil activation with aspirin, diclofenac, and naproxen was analyzed at 4 different concentrations. The results in the 2 groups were quite similar in qualitative terms. Choosing a cutoff of 5% and a stimulation index >2, the proportion of positive results increased with the concentration. There were more positive results at all concentrations using the plasma leukocyte technique. CONCLUSIONS: The most important finding of this study is that basophil activation by NSAIDs occurs not only in clinically hypersensitive patients but also, to a very variable extent and on an individual basis, in apparently normal healthy individuals who tolerate NSAIDs. The phenomenon is clearly dose-related, and hypersensitive patients seem to react to lower NSAID concentrations.

Nonsteroidal anti-inflammatory drug hypersensitivity syndrome. A multicenter study. I. Clinical findings and in vitro diagnosis.

BACKGROUND: We present the results obtained from the largest series of in vitro diagnostic tests ever reported in patients with clinically validated hypersensitivity to acetylsalicylic acid (ASA)/nonsteroidal anti-inflammatory drugs (NSAID) compared with various categories of controls tolerating ASA/NSAIDs. This multicenter study, which was performed within the framework of the European Network for Drug Allergy (ENDA) group, showed that the basophil activation test (BAT), particularly when used with the 3 NSAIDs aspirin (ASA), diclofenac (DIC), and naproxen (NAP), allows us to confirm the diagnosis of NSAID hypersensitivity syndrome. The results of the cellular allergen stimulation test (CAST) frequently correlate with those of the BAT, although not always. An unexpected finding was that basophil activation by NSAIDs is not an all-or-nothing phenomenon restricted to clinically hypersensitive patients, but that it also occurs in a dose-related manner in some NSAID-tolerant control individuals.Therefore, NSAID hypersensitivity appears as a shift in the normal pharmacological response to NSAIDs. These findings allow us to formulate a new rational hypothesis about the mechanism of NSAID hypersensitivity syndrome, a mechanism that most authors continue to describe as "unknown." METHODS: We enrolled 152 patients with a history of hypersensitivity to NSAIDs and 136 control participants in 11 different centers between spring 2003 and spring 2006. Flowcytometric BAT was performed. RESULTS: The most noteworthy results of our study were that 57% of 140 patients presented very clear-cut positive BAT results to multiple NSAIDs, and 16% were entirely negative. In about 27% of cases, positive results were obtained with 1 or 2 concentrations of a single NSAID. There is clearly a correlation between the results of BAT and CAST. CONCLUSIONS: BAT seems particularly indicated in patients with a clinical history of NSAID intolerance, and in whom a provocation test is not advisable for ethical, clinical, or other reasons. Clear-cut positive results can be considered as confirming a history of NSAID hypersensitivity, although negative results may not exclude it.

Direct observation of the alpha-epsilon transition in shock-compressed iron via nanosecond x-ray diffraction.

In situ x-ray diffraction studies of iron under shock conditions confirm unambiguously a phase change from the bcc (alpha) to hcp (epsilon) structure. Previous identification of this transition in shock-loaded iron has been inferred from the correlation between shock-wave-profile analyses and static high-pressure x-ray measurements. This correlation is intrinsically limited because dynamic loading can markedly affect the structural modifications of solids. The in situ measurements are consistent with a uniaxial collapse along the [001] direction and shuffling of alternate (110) planes of atoms, and are in good agreement with large-scale nonequilibrium molecular dynamics simulations.

Implementing practice guidelines for diabetes care using problem-based learning. A prospective controlled trial using firm systems.

OBJECTIVE: A controlled trial with 15-month follow-up was conducted in two outpatient clinics to study the effects of using the problem-based learning technique to implement a diabetes clinical practice guideline. RESEARCH DESIGN AND METHODS: A total of 144 patients with type 2 diabetes aged 25-65 years in two internal medicine outpatient clinics were enrolled in the study. African-Americans and Hispanics made up > 75% of the patients. Doctors and staff in one of the clinics were trained in the use of a clinical practice guideline based on Staged Diabetes Management. A problem-based learning educational program was instituted to reach consensus on a stepped intensification scheme for glycemic control and to determine the standards of care used in the clinic. HbA1c was obtained at baseline and at 9 and 15 months after enrollment. RESULTS: At 9 months, there was a mean -0.90% within-subject change in HbA1c in the intervention group, with no significant changes in the control group. The 15-month mean within-subject change in HbA1c of -0.62% in the intervention group was also significant. Among intervention patients, those with the poorest glycemic control at baseline realized the greatest benefit in improvement of HbA1c. The intervention group also exhibited significant changes in physician adherence with American Diabetes Association standards of care. CONCLUSIONS: Clinical practice guidelines are an effective way of improving the processes and outcomes of care for patients with diabetes. Problem-based learning is a useful strategy to gain physician support for clinical practice guidelines. More intensive interventions are needed to maintain treatment gains.

Pain reduction in breast augmentation using methocarbamol.

Submuscular placement of breast implants produces significant postoperative pain and discomfort. The standard use of narcotics alone does not optimize pain reduction. Methocarbamol was used intraoperatively and postoperatively in 62 patients undergoing manipulation of the pectoralis major associated with breast implant surgery. Significant pain relief was achieved.

Explantation and mastopexy: the vertical mammaplasty technique to optimize breast shape.

Twenty-seven patients who requested removal of their breast implants underwent simultaneous explantation and mastopexy. The time from implantation to explantation ranged from 4 to 26 years. Follow-up after surgery ranged from 5 months to 3 years. The mastopexy procedure used is a modification of the vertical mammaplasty. The final form of the breast is dependent on parenchymal reshaping rather than the pattern shape of the skin brassiere. The technique produced satisfactory breast shape and projection while limiting the extent of skin scarring. Minimal complications were noted, and patient satisfaction remains high.

A comparison of attributions, health beliefs, and negative emotions as predictors of fluid adherence in renal dialysis patients: a prospective analysis.

Excessive fluid intake in hemodialysis patients can lead to serious cardiovascular complications. However, previous studies have not investigated factors that affect fluid adherence over time. The influence of three sets of factors--attributions, health beliefs, and negative emotions--was examined to determine their influence on changes in fluid adherence over time. We assessed patient's fluid-intake changes across two time periods, as well as their absolute level. The results indicated that attributions, while predicting absolute fluid adherence, did not predict changes in fluid adherence. On the other hand, health beliefs predicted changes in fluid adherence but not absolute levels. Negative emotions predicted neither absolute nor changes in fluid adherence. It is suggested that attributions are more responsible for maintenance and control of stable fluid adherence levels, while health beliefs are more responsible for motivational factors related to changes in fluid adherence over time.

Weight reduction and fluid intake in an obese and fluid noncompliant ESRD patient.

This case study describes the application of a behavioral weight reduction program to an obese ESRD patient who was also fluid noncompliant. The major purpose of the study was to determine whether the behavioral weight reduction program could be successfully applied to a hemodialysis patient, and if so, what effect reduced caloric intake would have on fluid intake. Based on animal and human studies showing a strong relation between eating and drinking, it was expected that body weight reduction would be accompanied by reduced fluid intake. On the other hand, an alternative psychological hypothesis suggested that increased fluid intake might be substituted for reduced food intake. The results of the weight reduction program indicated that a successful weight reduction of 42 lbs was maintained over an 18-month follow-up period. However, fluid intake increased during periods when caloric intake was reduced. Overall, the results indicated that behavioral weight reduction programs can be successfully applied to weight reduction in obese hemodialysis patients but that ways to avoid increased fluid intake need to be carefully addressed by such programs.

Kegel exercises and childhood incontinence: a new role for an old treatment.

Kegel exercises were used to treat urinary incontinence in 79 children. An average of less than 2 hours of professional time was required. Incontinence was eliminated in 60% of the patients; children who had both day and night wetting tended to show simultaneous improvements in both problems. Research is needed to test the hypothesis that Kegel exercises eliminate involuntary contractions of the detrusor muscle.

Sexual harassment of female doctors by patients.

BACKGROUND: Sexual harassment within the doctor-patient relationship is typically discussed in terms of male doctors harassing female patients. We investigated the sexual harassment of female doctors by patients. METHODS: Surveys were mailed to a random sample of 599 of the 1064 licensed female family physicians in Ontario, Canada. Respondents were asked about their experiences of sexual harassment by either male or female patients and about the nature and frequency of harassing behavior. Suggestions for prevention were requested. RESULTS: Seventy percent (422) of the questionnaires were completed and returned. More than 75 percent of the respondents reported some sexual harassment by patient at some time during their careers. Physicians had been harassed most often in their own offices and by their own patients. However, in settings such as emergency rooms and clinics, unknown patients presented a proportionately higher risk. The physicians' perceptions of the seriousness of the problem varied with the frequency and severity of the incidents. CONCLUSIONS: Sexual harassment of female doctors appears to occur frequently, and it is therefore an important topic to address in medical school and professional development.

Comparison of rapid versus slow tissue expansion on skin-flap viability.

The effect of rapid versus slow tissue expansion on random-pattern skin-flap survival lengths was evaluated in two groups of pigs. Each group (group 1--slow; group 2--rapid) was further evaluated for the effect that delay (A), delay plus expansion (B), expansion only (C), and acute flap elevation (D) had on flap length viability. Intergroup and intragroup comparisons were made. In the slowly expanded group, significantly greater flap length viabilities were demonstrated in the slow expansion flaps as compared with the delay plus expander flaps and the delayed flaps, respectively. In the rapidly expanded group, the flap length viabilities of flaps C, B, and A were statistically equal. However, the flap length viability of the rapidly expanded flaps was statistically equal to that of the slowly expanded flaps (C1 = C2). The effect tissue expansion has on improving flap length viability as compared with the delay phenomenon may be related to the combination of a delay effect plus increased nutrient flow density that slow expansion produces. This combined metabolic enhancement is preserved with rapid tissue expansion.

Role of stress in the etiology and treatment of diabetes mellitus.

Stress has long been suspected as having major effects on metabolic activity. The effects of stress on glucose metabolism are mediated by a variety of "counter-regulatory" hormones that are released in response to stress and that result in elevated blood glucose levels and decreased insulin action. This energy mobilizing effect is of adaptive importance in a healthy organism. However, in diabetes, because of a relative or absolute lack of insulin, stress-induced increases in blood glucose cannot be adequately metabolized. Thus, stress is a potential contributor to chronic hyperglycemia in diabetes, although its exact role is unclear. Although there is some suggestion from retrospective human studies that stress can precipitate type I diabetes, animal studies are contradictory with different stressors either having facilitatory or inhibitory effects upon the development of the disease. Human investigations in patients with established diabetes are equally confusing with some showing that stress can stimulate hyperglycemia, hypoglycemia or have no effect at all on glycemic status. There is more consistent evidence supporting the role of stress in animal models of type II diabetes. However, human studies on the role of stress on the course of established type II diabetes are few. Intervention studies suggest that behavioral or pharmacologic intervention to manage stress may contribute significantly to diabetes treatment, but more long-term research is needed. It is concluded that further research is needed to establish the importance of behavioral factors in the etiology and management of diabetes, and several areas of methodologic improvement are suggested.

Stress and diabetes mellitus.

Stress is a potential contributor to chronic hyperglycemia in diabetes. Stress has long been shown to have major effects on metabolic activity. Energy mobilization is a primary result of the fight or flight response. Stress stimulates the release of various hormones, which can result in elevated blood glucose levels. Although this is of adaptive importance in a healthy organism, in diabetes, as a result of the relative or absolute lack of insulin, stress-induced increases in glucose cannot be metabolized properly. Furthermore, regulation of these stress hormones may be abnormal in diabetes. However, evidence characterizing the effects of stress in type I diabetes is contradictory. Although some retrospective human studies have suggested that stress can precipitate type I diabetes, animal studies have shown that stressors of various kinds can precipitate--or prevent--various experimental models of the disease. Human studies have shown that stress can stimulate hyperglycemia, hypoglycemia, or have no affect at all on glycemic status in established diabetes. Much of this confusion may be attributable to the presence of autonomic neuropathy, common in type I diabetes. In contrast, more consistent evidence supports the role of stress in type II diabetes. Although human studies on the role of stress in the onset and course of type II diabetes are few, a large body of animal study supports the notion that stress reliably produces hyperglycemia in this form of the disease. Furthermore, there is mounting evidence of autonomic contributions to the pathophysiology of this condition in both animals and humans.

Gasoline-induced contact burns.

Gasoline contact may cause significant full-thickness burn injuries. Systemic complications may result from the absorption of hydrocarbons through the skin. Regional neuromuscular absorption may produce transient or even permanent impairment. It is vital that the physician be aware of the possible full-thickness injuries and complications that may result from cutaneous exposure to gasoline.

Fluid noncompliance and symptomatology in end-stage renal disease: cognitive and emotional variables.

Fluid noncompliance in patients with end-stage renal disease (ESRD) is a widespread problem with severe consequences for health. In addition, ESRD patients report considerable stress in relation to their illness and dialysis treatment. The present study examined the role of cognitive and emotional variables in fluid noncompliance, symptomatology, and stress. Fifty hemodialysis patients were assessed (a) on the cognitive variables of locus of control, self-evaluations of their past compliance, and self-efficacy to resist fluid intake and (b) on the emotional variables of depression, anger, and anxiety. Results showed that cognitive variables accounted for fluid noncompliance and predicted future adherence. Patients high in negative emotions complied equally as well as patients low in negative emotions but were found to report substantially more symptomatology and distress associated with their treatment. The implications of these findings for treatment of ESRD patients and future research are discussed.

Cementoma--presentation predicates approach.

Cementomas are benign jaw tumors that originate from periodontal ligament elements. Four classifications of cementomas are described: periapical fibrous dysplasia, benign cementoblastoma, cementifying fibroma, and florid osseous dysplasia. Usual treatment regimens vary from observation to limited surgical resection based upon tumor type and clinical characteristics. We present an unusual case report of an extensive cementifying fibroma that required mandibular and inferior alveolar nerve resection followed by osseous and neural reconstruction.

Large diameter therapeutic penetrating keratoplasties.

Fourteen penetrating keratoplasties were done on ten patients using 9.5 mm or larger diameter grafts. The causes for large grafts were perforation or impending perforation of large descemetoceles due to bacterial ulceration in five eyes, herpes simplex viral keratouveitis in three eyes, severe keratoconjunctivitis sicca with ulceration in four eyes, alkali burn and Mooren's ulcer in one eye each. The average duration of graft clarity was 67.2 days (range 14 days to 6 months). The best spectacle corrected visual acuity range was from l.p. to 20/40. Two patients had recurrent ulceration requiring two large diameter regrafts each. The average period of clarity in these repeated grafts was 26 days. A small graft placed inside of the failed large graft remained clear in 50% of the six eyes which were done for visual restoration. A large diameter penetrating keratoplasty may salvage an eye that might have otherwise been lost and in a few cases provide the opportunity for useful vision.

The tensiometric properties of expanded guinea pig skin.

Our purpose in this study was to evaluate the tensile properties of expanded skin. In five guinea pigs, 29-cc ovoid tissue expanders were placed and sequentially expanded every 4 days until maximum volume was achieved. Five control and five expanded skins were harvested. Using an Instron tensile testing apparatus, skins were evaluated for stress-strain, maximum stiffness, and tensile strength, and the results were statistically compared. Centrally located expanded specimens demonstrated significantly weaker stress-strain values: 9.51 in.lb/in3 for expanded versus 30.11 in.lb/in3 for control (p less than 0.001). Maximum stiffness was similarly reduced: 4.56 lb/mm2 for expanded vs. 12.98 lb/mm2 for control (p less than 0.001). This is a 67.4 and 64.9 percent reduction, respectively, for the stress-strain and maximum stiffness. No statistically significant difference was seen in peripherally located expanded specimens relative to the controls: stress-strain expanded, 28.7 in.lb/in3 (p greater than 0.5); maximum stiffness expanded, 12.84 lb/mm2 (p greater than 0.5). Expanded skin demonstrated an average 35 percent reduction in tensile strength. We conclude that the tensile properties of expanded skin are significantly less than unexpanded skin and are a function of the degree of expansion.

Left ventricular function before and after reaching the anaerobic threshold.

Simultaneous pulmonary gas exchange analysis and exercise radionuclide angiography were performed in 24 normal patients (14 supine and ten upright). Left ventricular (LV) volumes and ejection fraction (EF) were measured at rest, anaerobic threshold (point of nonlinear increase in ventilation relative to oxygen uptake), and peak exercise. The anaerobic threshold occurred at a similar heart rate for supine vs upright exercise, 78 percent and 77 percent of peak heart rate, respectively. The anaerobic threshold occurred at a similar workload for supine vs upright exercise, 60 percent and 56 percent of peak workload, respectively. The anaerobic threshold also occurred at a similar oxygen uptake for supine vs upright exercise, 69 percent vs 69 percent of peak oxygen uptake, respectively. For both exercise modes, mean LVEF increased (p less than 0.01) by a similar amount (.06 vs .07) from rest to anaerobic threshold, but there was no further increase from anaerobic threshold to peak exercise. The mechanism of the increase was a reduction in end-systolic volume with little or no change in end-diastolic volume. This increase was not seen in patients with rest LVEF in the high normal range (greater than 0.68). Therefore, for both supine and upright exercise, the major augmentation in LVEF occurs at earlier stages of exercise, prior to the anaerobic threshold. After the anaerobic threshold, the LVEF response may be highly variable, and a uniform increase is not necessarily expected even in normal subjects.