Enteric-coated mycophenolate sodium in de novo pediatric renal transplant patients

Data on the use of enteric-coated mycophenolic acid (EC-MPS) in pediatric transplantation cases are scarce. We undertook a 12-month, multicenter, open-label pilot study in which 16 de novo renal transplant patients aged 5–16 years received EC-MPS with cyclosporine A microemulsion (CsA-ME), steroids, and anti-interleukin-2 receptor antibody induction. The mean dose of EC-MPS was 916 ± 93 mg/m² per day during weeks 1–2, 810 ± 193 mg/m² per day during months 3–6, and 827 ± 153 mg/m² per day during months 6–12. The mean CsA C₂ level exceeded target range up to month 6 post-transplant. Efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) occurred in two patients: one patient with primary non-function underwent nephrectomy, and one patient experienced biopsy-proven acute rejection (Grade 1B, day 344) following EC-MPS dose reduction. There were no deaths. Creatinine clearance (Schwartz) was 103 ± 30 mL/min per 1.73 m² at month 6 and 100 ± 16 mL/min per 1.73 m² at month 12. The majority of adverse events were mild or moderate (101/126, 80.2%). In this pilot study, EC-MPS 450 mg/m² administered twice daily with CsA, steroids, and interleukin-2 antibody induction resulted in a low rate of rejection with good renal function in a pediatric population. However, a larger, controlled trial is required to confirm these results.     

Immune function during and after 60 min of moderate exercise wearing protective clothing

INTRODUCTION: As exercise while wearing protective clothing exacerbates body heat storage compared to exercise in the heat, and as exercise alters immune responses, it appeared worthwhile to examine immune and stress responses while wearing protective clothing during moderate exercise. METHODS: Eight subjects completed two bouts of exercise at 45% Vo2(max) in a thermoneutral environment: once while wearing shorts only (Control trial, CON) and again while wearing protective clothing (PRO). Venous blood samples were taken to analyze TNF-alpha mRNA by RT-PCR in LPS stimulated blood, plasma catecholamines, and cortisol. Blood cell count was analyzed by flow cytometry. Rectal temperature (T(re)) was monitored continuously. RESULTS: Exercise with PRO resulted in significantly greater increases in T(re) (39.2 +/- 0.2 degrees C in PRO vs. 38.0 +/- 0.1 degrees C in CON) and plasma epinephrine and norepinephrine (+70% and 150%, respectively). Plasma cortisol increased only at the end of PRO exercise (+33%). Leukocyte and lymphocyte cell count was 14% and 18% higher, respectively, but there were no significant changes in T cytotoxic and NK cell counts compared to the CON trial. Only T helper lymphocyte count was lower (-29%). During both exercise trials, T helper lymphocytes were significantly decreased at the end of exercise and recovery. With or without protective clothing, exercise was associated with an inhibition of TNF- alpha expression in stimulated monocytes (approximately -50% at min 20 and 40, and approximately -30% at min 60). DISCUSSION: Protective clothing wearing induces significant thermal challenge during exercise. The inhibition of TNF-alpha appears to be mediated primarily by exercise and not the added thermal load associated with protective clothing.     

Cross-sectional study of pain and disability at knee replacement surgery for osteoarthritis in 299 patients

ObjectiveTo evaluate pain and disability at the time of knee replacement surgery for osteoarthritis.MethodsIn this multicenter cross-sectional study, 299 patients at 12 orthopedic surgery centers in Lyon, France were evaluated on the day before knee replacement surgery. Pain severity was assessed on a visual analog scale (VAS) and function using the Lequesne index and the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC).ResultsThere were 207 women and 92 men with a mean age of 73 years. Mean (±SD) VAS pain score upon walking was 55.8 ± 24 mm. Compared to patients with very severe disability (Lequesne index > 12), those with mild-to-severe disability (Lequesne index ≤ 12) were more likely to be older than 70 years (odds ratio [OR], 2.85; 95% confidence interval [95%CI], 1.25–5) and male (OR, 2.5; 95%CI, 1.3–5); they were less likely to have a body mass index > 27 kg/m² (OR, 2.2; 95%CI, 1.3–3.3) and to engage in sporting activities (OR, 3.3; 95%CI, 1.4–10).ConclusionPatients about to undergo knee replacement surgery had high levels of pain and disability, with little variation across centers. Nevertheless, the severity of pain and disability may depend in part on age, gender, body mass index, and sporting activities, which probably influence the decision to perform knee replacement surgery.     

Memory function during propofol and alfentanil anesthesia: predictive value of individual differences

BACKGROUND: Conscious recall and implicit memory have been shown to depend on hypnotic state as measured by electroencephalographic (EEG) bispectral index (BIS). A third expression of memory (unconscious-controlled memory) was recently observed after moderate to light sedation (BIS, 70-80). The present study investigated memory function during deep sedation (BIS, 60-70). As memory effects are small, the authors studied potential predictors of individual differences in memory performance. METHODS: Memory function and speed of information processing were assessed in 56 outpatients before surgery. During propofol anesthesia supplemented with alfentanil, patients heard a series of words while anesthesia was titrated to BIS, 60-70. In between words, response to command was assessed using the Isolated Forearm Technique. The authors tested memory with a word stem completion task and process dissociation procedure to distinguish explicit from implicit effects. RESULTS: Mean (+/- SD) BIS during word presentation was 64.0 +/- 3. Patients with conscious recall of verbal commands (n = 9) did not recall or recognize presented words. Even so, the process dissociation procedure revealed evidence of memory by a significantly higher hit rate in the inclusion condition (0.26) than in the exclusion condition (0.12). Patients without conscious recall showed no evidence of memory for presented words. Hit scores correlated significantly with scores in the preoperative memory test (r = 0.35). CONCLUSIONS: The authors found evidence of weak explicit memory function during anesthesia titrated to BIS, 60-70. The observations strongly suggest that postoperative memory relates to awareness during anesthesia, but the nature of this relation remains unclear. Memory seems more likely in patients with good preoperative memory performance.     

The influence of rotator cuff disease on the results of shoulder arthroplasty for primary osteoarthritis: results of a multicenter study

BACKGROUND: Rotator cuff disease is uncommon in primary glenohumeral osteoarthritis. Consequently, the prognostic implications of rotator cuff disease in patients undergoing prosthetic replacement for the treatment of primary glenohumeral osteoarthritis are uncertain. The purpose of this study was to report the effects of the condition of the supraspinatus tendon and the rotator cuff musculature on the results of shoulder arthroplasty in the treatment of primary osteoarthritis. METHODS: Five hundred and fifty-five shoulders in 514 patients who had an arthroplasty for the treatment of primary glenohumeral osteoarthritis as part of a multicenter study were evaluated. Forty-one shoulders had a partial-thickness tear of the supraspinatus, and forty-two had a full-thickness tear. Ninety shoulders had moderate (stage-2) fatty degeneration of the infraspinatus, and nineteen had severe (stage-3 or 4) degeneration. Eighty-four shoulders had moderate fatty degeneration of the subscapularis, and fifteen had severe degeneration. The influence of the condition of the supraspinatus tendon and the infraspinatus and subscapularis musculature on the postoperative outcome was evaluated with respect to the scores according to the system of Constant and Murley, active mobility, subjective satisfaction, radiographic result, and rate of complications. RESULTS: The shoulders were evaluated at a mean of 43.1 months postoperatively. With the numbers available, supraspinatus tears were not found to influence the postoperative outcome with respect to the total Constant score, active mobility, subjective satisfaction, radiographic result, or rate of complications. Additionally, the treatment of these tears did not markedly influence the outcome parameters. Conversely, both shoulders with moderate fatty degeneration and those with severe degeneration of the infraspinatus were associated with poorer results than those with no degeneration with respect to the total Constant score (p < 0.0005), active external rotation (p < 0.0005), active forward flexion (p = 0.001), and subjective satisfaction (p = 0.031). Similar although less dramatic results were seen with fatty degeneration of the subscapularis. CONCLUSIONS: This study demonstrates that minimally retracted or nonretracted rotator cuff tears that are limited to the supraspinatus tendon do not appreciably affect most shoulder-specific outcome parameters in shoulder arthroplasty performed for the treatment of primary osteoarthritis. Conversely, fatty degeneration of the infraspinatus and, less importantly, subscapularis musculature adversely affects many of these parameters.     

Inhibition of 11beta-hydroxysteroid dehydrogenase enzymatic activities by glycyrrhetinic acid in vivo supports direct glucocorticoid-mediated suppression of steroidogenesis in Leydig cells

Previous studies have suggested that glucocorticoid (GC) can directly affect testicular testosterone (T) biosynthesis by Leydig cells through a receptor-mediated mechanism. Interconversion of corticosterone (CORT), the active form in rodents, and 11-dehydroCORT, the biologically inert 11-keto form, is catalyzed by 11betaHSD1. This enzyme thus controls the intracellular concentration of active GC. We have postulated that elevated CORT levels resulting from stress exceed the Leydig cell's capacity for metabolic inactivation of CORT, resulting in suppressed T production. The present study tested whether inhibition of 11betaHSD1 in vivo, by the administration of glycyrrhetinic acid (GA), increases intracellular active GC concentration and thereby affects serum T concentration and Leydig cell T production. Adult Sprague-Dawley rats were treated with vehicle (corn oil), CORT, GA, or GA + CORT. Serum luteinizing hormone (LH), CORT, and T levels were measured, as were the steroidogenic capacities of purified Leydig cells. Twofold elevations of CORT were achieved by the administration of either CORT or GA alone, but in both cases there was no effect on serum T levels. However, when CORT and GA were administered in combination, serum CORT levels increased 3.5-fold (to 420 +/- 34 ng/mL) and serum T levels were reduced significantly (to 0.72 +/- 0.07 ng/mL; control, 2.12 +/- 0.23 ng/mL). Serum levels of LH were not affected by CORT, GA, or GA + CORT. Consistent with the reduced serum T levels following GA + CORT, steroidogenic enzyme expression and capacities were significantly reduced compared to control. These data support a role for 11betaHSD1 in modulating intracellular CORT concentrations and, in turn, for a direct effect of GC on Leydig cells in response to stress.     

Use of anti-HBc positive allografts in adult liver transplantation: toward a safer way to expand the donor pool

The use of livers from anti-hepatitis B core (HBc) positive donors can alleviate donor shortage. Nineteen of 367 (6%) adults receiving anti-HBc positive allografts [three were hepatitis B antigen (HBsAg) negative, hepatitis B antibody (HBsAb) positive; four were HBsAg positive and 12 were not exposed to hepatitis B viral (HBV) infection] were retrospectively reviewed. In HBsAg negative recipients, immunoprophylaxis (IP) was guided by viral serology and immunohistochemistry (IH) of day 0 and day 7 liver biopsies. If IH was negative, IP was stopped. None of three HBsAg negative, HBsAb positive recipients infected; one (replicating) of four HBsAg positive recipients reinfected and seven of eight (87.5%) HBsAg, HBsAb negative recipients, who did not receive long-term IP, infected after a median time of 2 years (range 1-5); one patient died of liver failure. Four HBsAg, HBsAb negative recipients, receiving life-long IP, remained infection free. Anti-HBc positive donor livers must be directed selectively first to HBsAg positive recipients, next to recipients having HBV antibodies and finally to HBV-naive recipients. Identification of both donor and recipient risk factors for HBV infection before transplantation allows indiscriminate use of antiviral prophylaxis. The necessity for IP therapy should be guided by HBV-DNA testing of donor liver tissue and serum. IH of early liver biopsies is an unreliable marker for predicting antiviral treatment requirements.     

Compound heterozygosity for unstable hemoglobin Genova and beta(o)-thalassemia associated with early onset of thalassemia major syndrome

We described the case of an infant with compound heterozygozity for a b0-thalassemic mutation and Hemoglobin (Hb) Genova, an unstable Hb variant. He has required regular transfusions as early as the second month of life and since then, behaves like a thalassemia major patient. This association leads to the most severe clinical course involving an unstable variant, reported so far.     

Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium

Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), the most abundant circulating estrogen conjugates. The identity of the conjugated estrogens formed by all known overexpressed UGTs (n = 16) was analyzed by comparison with retention time and mass fragmentation of authentic standards by HPLC tandem mass spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, and 2B7, were found to glucuronidate estradiol (E(2)) and estrone (E(1)), their hydroxyls (OH), and their methoxy derivatives (MeO). Addition of glucuronic acid was catalyzed by specific UGTs at positions 2, 3, and 4 of the estrogens, whereas only E(2) was conjugated at position 17 by UGT2B7. Kinetic parameters indicate that the conjugation of E(2) at position 3 was predominantly catalyzed by 1A1, 1A3, and 1A8 and by 1A8 for E(1). Conjugation of 2-OHE(1)/E(2) and 2- and 4-MeOE(1)/E(2) was selective at position 3, mostly catalyzed by 1A1 and 1A8. Of all UGTs, UGT2B7 demonstrated the highest catalytic activities for estrogens and at least 10- to 50-fold higher activity for the conjugation of genotoxic 4-hydroxycatecholestrogens at position 4, compared with the conjugation of E(2), E(1), and 2-hydroxycatecholestrogens. Its presence was further shown in the endometrium by RT-PCR and immunohistochemistry, localizing in the same cells expressing CYP1B1, involved locally in the formation of 4-hydroxycatecholestrogens. Data show that several UGT enzymes detected in the endometrium are involved in the glucuronidation of E(2) and its 2-OH, 4-OH, and 2-MeO metabolites that exert various biological effects in the tissue.