Toxicology and adverse effects of drugs used for immunosuppression in organ transplantation

The main mechanism causing catabolite repression by glucose and other carbon sources transported by the phosphotransferase system (PTS) in Escherichia coli involves dephosphorylation of enzyme IIA(Glc) as a result of transport and phosphorylation of PTS carbohydrates. Dephosphorylation of enzyme IIA(Glc) leads to 'inducer exclusion': inhibition of transport of a number of non-PTS carbon sources (e.g. lactose, glycerol), and reduced adenylate cyclase activity. In this paper, we show that the non-PTS carbon source glucose 6-phosphate can also cause inducer exclusion. Glucose 6-phosphate was shown to cause inhibition of transport of lactose and the non-metabolizable lactose analogue methyl-beta-D-thiogalactoside (TMG). Inhibition was absent in mutants that lacked enzyme IIA(Glc) or were insensitive to inducer exclusion because enzyme IIA(Glc) could not bind to the lactose carrier. Furthermore, we showed that glucose 6-phosphate caused dephosphorylation of enzyme IIA(Glc). In a mutant insensitive to enzyme IIA(Glc)-mediated inducer exclusion, catabolite repression by glucose 6-phosphate in lactose-induced cells was much weaker than that in the wild-type strain, showing that inducer exclusion is the most important mechanism contributing to catabolite repression in lactose-induced cells. We discuss an expanded model of enzyme IIA(Glc)-mediated catabolite repression which embodies repression by non-PTS carbon sources.     

The Malone antegrade colonic enema enhances the quality of life in children undergoing urological incontinence procedures

PURPOSE: Functional alterations of the gastrointestinal and genitourinary tracts, and physical limitations in children with spina bifida, imperforate anus and spinal cord injury challenge the ability to have independent fecal and urinary continence. Urologists have successfully helped these patients achieve urinary continence. We report our experience with the antegrade colonic enema procedure, which allows select individuals to achieve continence of stool, enhancing quality of life. MATERIALS AND METHODS: Since December 1992, 18 antegrade colonic enema procedures were performed in 12 female and 6 male patients 5 to 31 years old of whom 14 had spina bifida, 2 had imperforate anus and 2 had spinal cord injury. Simultaneous urological continence procedures were performed in 8 patients, including appendicovesicostomy in 4, augmentation cystoplasty in 2 and augmentation cystoplasty plus an ileal Mitrofanoff procedure in 2. Four patients previously underwent urological reconstruction. RESULTS: In 24 months of followup (average 6.6) all patients with a functioning stoma remained continent of stool and 17 were continent of urine. Complications related to the antegrade colonic enema procedure occurred in 4 children (22%) of whom 3 required further surgery. Three patients (17%) had minor stomal stenosis. CONCLUSIONS: The antegrade colonic enema procedure is easily performed and it should be considered for any child with significant physical limitations and/or refractory fecal incontinence before urological continence promoting procedures are done.     

Comparison of hypnosis and distraction in severely ill children undergoing painful medical procedures.

An ethnically diverse sample of high and low hypnotizable children (N?=?27) suffering from cancer or blood disorders and their parents were trained to use both distraction and hypnosis to reduce pain and anxiety. Measures of pain and anxiety were obtained from the children and their parents. Independent raters also judged participants' video-taped distress responses. Data were collected during painful medical procedures, for baseline, distraction, and hypnosis conditions. Supporting E. R. Hilgard's (1977, 1992) neodissociation theory, hypnotizable children showed significantly lower pain, anxiety, and distress scores in response to hypnosis in contrast to low hypnotizable children. Distraction produced significant positive effects for observer-rated distress scores for the low hypnotizable children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A stress inoculation program for parents whose children are undergoing painful medical procedures.

The efficacy of a stress inoculation intervention program was compared with that of a child-focused intervention program in helping parents cope with their children's painful medical procedures. Ss included 72 parents (79% mothers) of pediatric leukemia patients (aged 3–12 yrs) who were undergoing either bone marrow aspirations (n?=?28) or lumbar punctures (n?=?44). Parents were assessed during a baseline procedure and then were randomly assigned to either a stress inoculation group or a child-focused intervention group. In the child-focused intervention, parents merely observed their child's participation in a cognitive behavior therapy program. Assessment of parents included an observation measure of parent behavior, self-reported measures of anxiety and coping, and physiological measures. Results indicate that parents in the stress inoculation program reported lower anxiety scores and higher positive self-statement scores than did parents in the child-focused intervention. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Puppet modeling technique for children undergoing stressful medical procedures: Tips for clinicians.

Films of puppet models have been found effective in reducing anxiety levels in children facing medical stressors. Unfortunately, films that address the specific medical stressors faced by a given child are not always available. The current work describes how individual clinicians can use puppets as models to alleviate children's anxiety when they face medical stressors. The elements of this technique are presented and discussed with an illustrative case history. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrospective review of the effects of rhDNase in children with cystic fibrosis

Bone densitometry is characterized by high sensitivity and specificity in osteoporosis, and new generations of densitometers enable measurements with improved intra- and inter-assay precision. The clinical potential of bone densitometry is well documented and the technique is widely used in clinical practice. It does not, however, allow for measurement of "true" bone density; instead it measures so called serial density (expressed in g/cm2) which is the distribution of bone mass over the flat projection of the skeleton. Limitations of densitometric techniques can be overcome by applying other methods, i.e. quantitative computed tomography (QCT) and ultrasound (US). QCT enables separate measurements of compact and trabecular bone density (expressed in g/cm3), as well as calculation of Strength-Strain Index (SSI), reflecting the mechanical resistance of bone to fracture. US is a non-invasive technique, providing information of fracture risk and bone tissue quality. Both techniques seem very promising and have been extensively studied recently; they are expected to move from clinical research to clinical practice soon.     

An evaluation of procedures used in staging carcinoma of the cervix

A review of 227 cases of invasive carcinoma of the cervix was undertaken to determine the efficacy of procedures using in the staging of this disease. All patients had a pretreatment chest radiography and intravenous pyelogram. 96.5% had pretreatment cystoscopy, 98.6% had pretreatment proctoscopy, and 92% had a pretreatment barium enema. These patients were retrospectively staged on the findings of physical examination only. Each additional procedure was then evaluated by comparison with the initial staging. Cystoscopy and chest film findings each would have changed the clinical stage in fewer than 1% of cases, barium enema in 1.4%, and proctoscopy in 2.2%. No patient had a positive barium enema without a positive proctoscopy, while two patients had positive proctoscopies with negative barium enemas. The overall yield of positive findings by pretreatment intravenous pyelography was 7.3%. Lymphangiography, although inconsistently done, yielded positive findings in all stages. Chest radiographs, intravenous pyelography, proctoscopy, and lymphangiography are recommended as part of the pretreatment workup of patients with carcinoma of the cervix. Routine barium enema is no longer recommended, and cystoscopy is only recommended in patients with clinical stage IIB disease or greater.     

Factors associated with elevated rates of adverse outcomes after cyclodestructive procedures versus drainage device procedures

OBJECTIVE: To identify factors associated with an increased risk of adverse outcomes after cyclodestructive or drainage device procedures. DESIGN: Retrospective, cohort analysis. PARTICIPANTS: A total of 5570 Medicare patients who were older than 65 years of age and who underwent cyclodestructive or drainage device procedures in 1994 participated. INTERVENTION: The authors identified cyclodestructive and drainage device procedures from claims to the Health Care Finance Administration (HCFA) by International Classification of Diseases (ICD-9) procedure codes, Current Procedural Terminology procedure codes, and HCFA Common Procedural Classification System codes. The authors analyzed adverse outcome rates using hierarchical logistic regression. Race, age group, gender, length of observed follow-up, state in which surgery took place, ocular procedures performed before and at the same time as the index surgery, and ocular diagnosis were included as covariates in the model. MAIN OUTCOME MEASURES: The authors defined an adverse outcome as the occurrence after the index surgery of at least one of the following: repeat cyclodestructive or drainage device procedure, retinal hole-tear repair, retinal detachment repair, surgery for endophthalmitis, vitrectomy, enucleation, evisceration, surgery for ocular hypotony, and/or extrusion or revision of drainage device. Adverse outcomes were also defined without the inclusion of repeat cyclodestructive or drainage device procedures. RESULTS: When repeat cyclodestructive or drainage device procedures were not included in the definition of an adverse outcome, eyes with a drainage device procedure were 3.8 times more likely to have an adverse outcome than eyes with a cyclodestructive procedure (odds ratio [OR], 3.8; 95% confidence interval [CI], 3.07, 4.67). Subjects with concurrent corneal transplant had increased odds of an adverse outcome compared to subjects without a concurrent corneal transplant (OR, 2.00; 95% CI, 1.27, 3.15). When the definition of an adverse outcome included repeat cyclodestructive or drainage device procedures, the odds of an adverse outcome were similar for both cyclodestructive and drainage device procedures (OR, 0.94; 95% CI, 0.79, 1.13). CONCLUSIONS: Cyclodestructive procedures need to be repeated more frequently than drainage device procedures. However, if the patient has a drainage device procedure, then that patient is more likely to have other types of adverse ophthalmic events than if he or she had a cyclodestructive procedure. Because the average follow-up of subjects in this study is 5 months (range, 0-12 months), outcomes that might take longer to manifest themselves would be excluded from this study.     

Thoracoscopic anterior spinal procedures in children

METHODS: From February 1996 through July 1997, 20 patients were determined to be appropriate for a thoracoscopic approach for the anterior portion of their spinal surgery. Ages ranged from 8 to 17 years of age and weight from 20 to 70 kg. The diagnosis included severe idiopathic and neurogenic scoliosis or kyphosis (n = 20) and congenital hemivertebra (n = 4). The procedures performed included diskectomy and anterior release from two to nine vertebral levels, hemivertebrectomy, and epiphysiodesis. Four patients also had an open lumbar exposure and all had a posterior fusion. RESULTS: All procedures were completed successfully endoscopically. Surgical times for the thoracoscopic portion of the procedure averaged 106 minutes and total procedure times were comparable with the standard open technique. Three patients were extubated at the end of the procedure with the majority extubated on postoperative day 1. Average intensive care unit stay was 1.8 days, and chest tubes were removed between postoperative day 1 and 5 (average, 2.2 days). In follow-up, surgical correction was deemed to be acceptable and equivalent to open techniques in all cases. CONCLUSION: This technique has proven to be safe and effective in children and appears to be associated with less pain and morbidity as evidenced by earlier extubation and chest tube removal and shorter ICU stay.     

Coping by children undergoing stressful medical procedures: Some conceptual, methodological, and therapeutic issues.

Because coping is postulated to change across persons, time, and stressors, the study of coping is inherently complex. These complexities are magnified in children's coping because a child's ability to effectively appraise a stressor and the coping resources that are available is dependent on the child's rapidly shifting developmental level. A small set of recent pediatric psychology studies describes children's active, informative-seeking coping versus avoidant or information-denying coping as an example of current trends in research on children's coping. Review of these studies highlights the need for tighter, more complete conceptualizations and improved methodologies. There are many therapeutic implications of this research, not the least of which is the problem of how (or even if) avoidant children should be prepared for medical procedures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Primary and secondary control among children undergoing medical procedures: Adjustment as a function of coping style.

The literature suggests that optimal adjustment to relatively uncontrollable stressors may require adjusting oneself to the stressors rather than trying to alter them. This possibility was explored for low-controllability stressors (e.g., painful medical procedures) associated with leukemia. Children's reports of coping strategies and goals were classified as primary control coping (attempts to alter objective conditions), secondary control coping (attempts to adjust oneself to objective conditions), or relinquished control (no attempt to cope). Secondary control coping was positively associated with (1) general behavioral adjustment assessed by the Child Behavior Checklist and (2) illness specific adjustment assessed by children's own distress ratings and by behavioral observations during painful procedures. All significant group differences showed better adjustment among secondary control children than among the primary or relinquished groups. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Viability of M. leprae while undergoing laboratory procedures

AIMS: Potassium channel openers (KCOs) are of potential therapeutic value. Little is known about the effect of these drugs on human conduit arteries used as coronary bypass grafts. The purpose of this study was to determine the effect of the KCO aprikalim (RP52891) on human arteries used as coronary bypass grafts with emphasis on the possible difference in the inhibitory effect on depolarizing agent-mediated rather than receptor-mediated contraction. METHODS: Human internal mammary artery segments (IMA, n = 88) taken from 28 patients were studied. Concentration-relaxation curves for aprikalim were established in IMA precontracted with three vasoconstrictors (K+, U46619, and phenylephrine). In IMA rings incubated with aprikalim (1 or 30 microM) for 10 min concentration-contraction curves for the three vasoconstrictors were constructed. RESULTS: Aprikalim-induced relaxation was less in K+ (37.3 +/- 6.4%) than in U46619 (80.2 +/- 7.7%, P=0.002), or phenylephrine (67.5 +/- 7.0%, P=0.038) -precontracted IMA. The EC50 for K+-(-5.40 +/- 0.12 log M) was significantly higher than that for phenylephrine (-6.43 +/- 0.30 log M, P=0.007) but not significant compared with that for U46619 (-5.81 +/- 0.11, P>0.05). Pretreatment with aprikalim depressed the contraction by phenylephrine from 140.6 +/- 27.6% to 49.3 +/- 14.1% (P=0.002) and shifted the EC50 11.0-fold higher in rings treated with 1 microM aprikalim (P=0.007). Treatment of aprikalim did not significantly reduce the K+ and U46619-induced contraction (P>0.05) but shifted the concentration-contraction curves rightward (2.8-fold higher for K+, P<0.05 and 2.2-fold higher for U46619, P<0.05). CONCLUSIONS: This study demonstrates that aprikalim has vasorelaxant effects in human conduit arteries used as coronary artery bypass grafts contracted by a variety of vasoconstrictors and this effect is vasoconstrictor-selective with greater potency for alpha1-adrenoceptor agonists than for depolarizing agent K+. These findings provide information on the possible use of this KCO in various clinical settings.     

Dose-related adverse effects of anticonvulsants

The serum concentration at which a given drug has full efficacy in delivering seizure control bears no predictable relationship to the concentration at which adverse effects will appear. In theory, the threshold for adverse effects should be considerably higher than that for efficacy. For each agent this obviously happens most of the time, or the anticonvulsant would not be on the market, but there are also patients in whom this relationship is reversed. The adverse effects of this class of drugs are discussed from three points of view: the adverse effect type, the kinetic factors that so frequently determine the presence of adverse effects, and the specific characteristics of each drug. Some less well recognized adverse effects syndromes that are not strictly dose related are considered. The importance of adverse effects in therapeutic monitoring is then addressed, and some strategies for maximising efficacy without the burden of long term functional impairment or distress are discussed. The usefulness of monotherapy is stressed with due attention to rational choice of second drugs, when necessary, based on mechanisms of antiepileptic action and adverse effects profiles. While most of these symptoms evolve gradually, there are times when acute, drastic, and even life threatening clinical overdose situations present themselves. Special attention is given to these scenarios, drawing on the drug profiles and clinical pharmacokinetics that define these events to propose methods of coping with the problems efficiently and effectively.     

A review of tibial lengthening procedures

Eight patients had tibial lengthening procedures according to Anderson's method. The necessity of early determination of callus formation and bone grafting, if necessary, is emphasized. The potential morbidity in this procedure is great and the parents must be made fully aware of them. As Anderson states, it is a procedure that should be reserved for the child between 8 and 12 years old with a predictable discrepancy between 4 and 15 cm. We believe it is a useful procedure in problems of unequal length of the lower limbs but should not be used whem simpler procedures such as femoral shortening or epiphyseal arrest are indicated.     

Hemostasis in children undergoing liver transplantation

Faculty workload determination formulas are a means by which program directors can justify their time and that of other faculty. This article is written to assist faculty in this necessary yet time-consuming endeavor. A table of calculations (time/activity ratio) for determination of committed hours, examples of actual workload determination, and a worksheet are provided.