Application of genome-wide expression analysis to human health and disease

The application of genome-wide expression analysis to a large-scale, multicentered program in critically ill patients poses a number of theoretical and technical challenges. We describe here an analytical and organizational approach to a systematic evaluation of the variance associated with genome-wide expression analysis specifically tailored to study human disease. We analyzed sources of variance in genome-wide expression analyses performed with commercial oligonucleotide arrays. In addition, variance in gene expression in human blood leukocytes caused by repeated sampling in the same subject, among different healthy subjects, among different leukocyte subpopulations, and the effect of traumatic injury, were also explored. We report that analytical variance caused by sample processing was acceptably small. Blood leukocyte gene expression in the same individual over a 24-h period was remarkably constant. In contrast, genome-wide expression varied significantly among different subjects and leukocyte subpopulations. Expectedly, traumatic injury induced dramatic changes in apparent gene expression that were greater in magnitude than the analytical noise and interindividual variance. We demonstrate that the development of a nation-wide program for gene expression analysis with careful attention to analytical details can reduce the variance in the clinical setting to a level where patterns of gene expression are informative among different healthy human subjects, and can be studied with confidence in human disease.     

The impact of medical illness on executive function

Executive function can be defined as one's ability to plan, initiate, sequence, monitor, and inhibit complex goal-directed behaviors. Although executive impairment is generally associated with dementia, recent studies have suggested that patients with chronic diseases, such as hypertension, chronic obstructive pulmonary disease, and diabetes, may also have executive deficits independent of psychiatric comorbidities. Because executive function is associated with functional outcomes, medication compliance, and the capacity to give informed consent, it is important that it be assessed. However, it is the authors' impression that executive function is not adequately assessed in medical settings, despite the availability of reliable measures. This article reviews the impact of medical illness on executive function and discusses practical diagnostic instruments and treatment strategies. The changes in functional status associated with executive impairment as well as pathophysiology and treatment strategies are also discussed.     

Comparison of Monte Carlo calculations around a Fletcher Suit Delclos ovoid with radiochromic film and normoxic polymer gel dosimetry

The Fletcher Suit Delclos (FSD) ovoids employed in intracavitary brachytherapy (ICB) for cervical cancer contain shields to reduce dose to the bladder and rectum. Many treatment planning systems (TPS) do not include the shields and other ovoid structures in the dose calculation. Instead, TPSs calculate dose by summing the dose contributions from the individual sources and ignoring ovoid structures such as the shields. The goal of this work was to calculate the dose distribution with Monte Carlo around a Selectron FSD ovoid and compare these calculations with radiochromic film (RCF) and normoxic polymer gel dosimetry. Monte Carlo calculations were performed with MCNPX 2.5.c for a single Selectron FSD ovoid with and without shields. RCF measurements were performed in a plane parallel to and displaced laterally 1.25 cm from the long axis of the ovoid. MAGIC gel measurements were performed in a polymethylmethacrylate phantom. RCF and MAGIC gel were irradiated with four 33 microGy m2 h(-1) Cs-137 pellets for a period of 24 h. Results indicated that MCNPX calculated dose to within +/- 2% or 2 mm for 98% of points compared with RCF measurements and to within +/- 3% or 3 mm for 98% of points compared with MAGIC gel measurements. It is concluded that MCNPX 2.5.c can calculate dose accurately in the presence of the ovoid shields, that RCF and MAGIC gel can demonstrate the effect of ovoid shields on the dose distribution and the ovoid shields reduce the dose by as much as 50%.     

Egr-2 and Egr-3 are negative regulators of T cell activation

T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis we have identified here early growth response gene 2 (Egr-2) and Egr-3 as key negative regulators of T cell activation. Overexpression of Egr2 and Egr3 was associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr3(-/-) mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program.     

A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery

In this randomized, controlled, dose-ranging study, we evaluated the analgesic efficacy of a novel single-dose extended-release epidural morphine (Depodur) in patients undergoing lower abdominal surgery. Five-hundred-forty-one patients were randomly assigned to one of six epidural treatments administered approximately 30 min before surgery. The 6 treatments were 5 mg of standard epidural morphine sulfate (MS) (active comparator); 5 mg of single-dose extended-release epidural morphine (EREM) (dose control); and 10, 15, 20, and 25 mg of single-dose EREM. The main study objective was to assess the efficacy of single-dose EREM 10, 15, 20, or 25 mg versus single-dose EREM 5 mg for the management of postoperative pain. This was done by plotting a linear dose-response relationship to assess postoperative IV patient-controlled analgesia (PCA) fentanyl consumption for breakthrough pain for 48 h after surgery. Secondary safety and efficacy analyses compared the 10-, 15-, 20-, and 25-mg single-dose EREM groups with the 5-mg single-dose EREM group and compared each single-dose EREM group with 5 mg of MS. As shown by the dose-response relationship, there was a dose-related reduction in the use of postoperative IV fentanyl through 48 h (estimated slope, -22.2; P = 0.0002). Patients treated with 10, 20, and 25 mg of single-dose EREM used significantly less IV fentanyl (mean +/- sd: 995 +/- 987 microg, P = 0.0446; 972 +/- 982 microg, P = 0.0221; and 683 +/- 620 microg, P < 0.0001, respectively) through 48 h after surgery compared with the 5-mg single-dose EREM group (1218 +/- 894 microg). At 48 h postdose, significantly more single-dose EREM patients (13%) than MS patients (2%) had required no IV fentanyl (P < 0.01). Although all treatment groups had access to PCA fentanyl and there was more frequent PCA fentanyl use in the MS group, patients in the single-dose EREM 15, 20, and 25 mg groups reported significantly lower pain-intensity scores and greater satisfaction with their pain relief. Overall, single-dose EREM was well tolerated, with 97% of adverse events rated as mild to moderate. As expected, the adverse events reported were consistent with those of other epidural opioids (i.e., nausea, vomiting, pruritus, and hypotension). In conclusion, this controlled study demonstrated that single-dose EREM can provide up to 48 h of postoperative analgesia, but supplementation for breakthrough pain is still required in most patients. Within the context of this study, the side effect profile of single-dose EREM was acceptable and predictable.     

The effect of prostaglandin e1 on responses of smooth muscle to catechol amines, angiotensin and vasopressin

Reduction of the pressor responses to adrenaline in the rabbit following administration of prostaglandin E₁ has been confirmed. The effect is, however, nonspecific since noradrenaline, angiotensin and vasopressin are also antagonized. Analogous responses were observed in blood flow experiments on the cat hind limb but not on the rabbit isolated auricles or the rabbit isolated duodenum. Contractions of the cat nictitating membrane produced by sympathetic preganglionic stimulation or by adrenaline were not decreased following injection of prostaglandin E₁ but the relaxation period was shorter. Contractions of the rabbit vas deferens induced in vivo by adrenaline were smaller after prostaglandin E₁ and this effect tended to be long-lasting.     

Acute coronal plane scaphoid fracture and scapholunate dissociation from an axial load: a case report

Coronal fractures of the scaphoid are rare and can be difficult to diagnose. Axial load injuries that result in a complete coronal fracture of the scaphoid associated with an acute scapholunate dissociation are exceedingly rare. In our patient the radiographic finding of wide scapholunate dissociation was obvious; however, the coronal scaphoid fracture was not recognized initially nor suspected. During surgery the coronal scaphoid fracture was identified, reduced anatomically, and fixed with a compression screw. The scapholunate ligament also was repaired. A good result was obtained with return to sports with extension of 60 degrees and flexion of 70 degrees , grip strength equal to that of the uninjured wrist, and no radiographic problems (arthrosis, avascular necrosis, nonunion).