Characterizing the protective component of the alphabeta T cell response to transplantable squamous cell carcinoma

There is increasing promise that cellular immune response may be manipulated to combat cancer; however, it is also clear that the immune response to cutaneous malignancy comprises different T cell activities that variably inhibit or promote tumor development. Thus, a better understanding of each of these activities is crucial to more effective clinical manipulation. To better characterize the protective anti-tumor effects of alphabeta T cells, we examined the growth of the transplantable squamous cell carcinoma (SCC) line, PDV, which is markedly inhibited in immunocompetent versusalphabeta T cell-deficient mice. We show that the protective response is composed of CD8(+) and interferon-gamma (IFNgamma)-producing CD4(+) cells, and that the most overt effects of these components on tumor growth in situ are to provoke overt focal necroses and to decrease the stromal bed. Tumors growing in the presence of any of these components also show reduced expression of Rae-1, a ligand for the activating NK receptor, NKG2D. Collectively, these data illustrate which components of the alphabeta T cell response against SCC have protective potential, and indicate which aspects of tumor physiology may be most susceptible to their activities.     

G protein beta3 subunit 825T genotype is not associated with differing outcome in pediatric renal transplant recipients

Recent studies have identified a novel polymorphism (C825T) of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3), associated with enhanced activation of G proteins, which appears to be more common in hypertensive patients. The donor GNB3 825TT genotype was associated with reduced kidney allograft survival in adults. We examined (in 100 Caucasian pediatric renal transplant recipients) whether the GNB3 (C825T) polymorphism was associated with disease progression and outcome after renal transplantation. The slope of 1/creatinine was determined by linear regression analysis of a median of 12 points before and after renal transplantation, and the population was divided into two groups of equal size, before and after transplantation, according to the slope. The observed frequencies were 57 for the CC, 33 for the CT, and 10 for the TT haplotype. For comparison, 738 consecutive newborn babies with the same ethnic background were typed in the same hospital. Allele frequencies were statistically not significantly different (chi-square test, p = 0.1327). When dividing the pediatric renal transplant recipients into two groups with regard to the slope of 1/creatinine, both before and after renal transplantation, the observed proportions were CC 26, CT 17, and TT 7 in the group with the poorer slope and CC 31, CT 16, and TT 3 in the group with the better slope before renal transplantation (not significant [NS], chi-square test, p = 0.1777). The observed proportions after renal transplantation were CC 26, CT 16, and TT 8 in the group with the poorer slope and CC 31, CT 15, and TT 4 in the group with the better slope, respectively (NS, chi-square test, p = 0.167). Allograft survival was not associated with the T allele. In conclusion, in a sizeable number of pediatric renal transplant recipients the GNB3 C825T polymorphism was found not to be a genetic risk factor for end-stage kidney disease. In addition, kidney graft function and survival was also found not to be associated with a recipient GNB3 C825T polymorphism.     

Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children

Current data indicate that pharmacokinetic (PK) monitoring of cyclosporin microemulsion (CsA) should be performed using the 2-h concentration (C2), that tacrolimus (Tac) is commonly monitored using the trough level, and mycophenolate mofetil (MMF) should be monitored using the 1-h (C1), 2-h (C2) and 6-h (C6) concentrations. The three differing time-point requirements are cumbersome, and we aimed to develop universal guidelines for all three drugs using a large number of full PK profiles in children. One-hundred and twenty two stable pediatric patients, receiving either CsA (165 PK profiles, 69 patients, 24 with concomitant MMF) or Tac (122 PK profiles, 53 patients, 18 with MMF) were analyzed retrospectively. Pearson r for the CsA C2 was 0.90 [95% confidence interval(CI): 0.86-0.92], for Tac C2 r was 0.86 (95% CI: 0.80-0.90), and for MPA C2 r was 0.77 (95% CI: 0.68-0.83), respectively. For MPA, at least three time-points are required to accurately estimate the area under the concentration-time curve (AUC), and C1, C2 and C6 serve as best markers. Excellent AUC estimations could be obtained from a limited sampling strategy from C1, C2 and C6 or C0, C1, C2 and C4 with clinically acceptable errors for all three drugs. The AUC can be estimated with great precision by using an identical approach for all three drugs. Target AUCs for a given time-point after transplantation remain to be established.     

Operative Verfahren der Mund-, Kiefer- und Gesichtschirurgie an nach Thiel fixierten Körperspenden

Methods: This study investigates whether human cadavers embalmed according to Thiel can be used for research and education in oral-maxillo-facial surgery. Different surgical approaches were tested on such cadavers. The usability of the specimen was judged jointly by anatomists and surgeons. Color, structure, and consistency of the different tissues were comparable to vital conditions. Thiel’s embalming technique applied to human cadavers provides an optimal basis for research and for basic and postgraduate medical education.     

Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), shows substantial interindividual and intraindividual variability. It was recently shown that in vitro calcineurin inhibitors alter the bioavailability of MPA by dose-dependent inhibition of MPA glucuronidation. The authors retrospectively analyzed full 10-point profiles for both MPA and cyclosporine (CyA) in 23 pediatric patients receiving MMF and cyclosporine microemulsion (Neoral; Novartis Pharmaceuticals Canada; Dorval, Quebec, Canada). Mycophenolic acid was measured using a commercially available EMIT (Novartis Pharmaceuticals, Canada) assay. As the majority of patients were treated with low doses of cyclosporine after adding MMF, the area under the concentration-time curve (AUC) for cyclosporine showed a wide scatter ranging from 296 to 6400 ng x h/mL. The mean cyclosporine dose was 100 +/- 76 mg/m2 per day (range: 28 to 331). There was no correlation between MPA AUC and MPA dose, and there was substantial interindividual variation. However, there was a significant negative correlation between dose-normalized MPA AUC and cyclosporine AUC ( r2 = 0.23, p < 0.0220). When dividing the MPA profiles into two groups (11 and 12 patients) with a CyA AUC less than or greater than 1600 ng x h/mL, there was a significantly higher 8-hour concentration in the patients with the lower CyA AUC, secondary to a higher second peak. The data demonstrate that the cyclosporine AUC is a determining factor for the MPA AUC and that MPA dose should be reduced when cyclosporine dose is reduced to achieve the same MPA AUC. The significantly higher peak in the group with a lower CyA profile supports the concept of a dose-dependent cyclosporine-induced inhibition of MPA glucuronidation.     

Interindividual reproducibility in perioperative rotational alignment of femoral components in knee prosthetic surgery using the transepicondylar axis

Femoral component malalignment is one of the main causes of persisting anterior knee pain after knee replacement. This study examined interindividual reproducibility in perioperative definition of the transepicondylar axis (TEA) as a reference for measuring the rotational alignment of the femoral component. Eight surgeons experienced in knee prosthetic surgery marked on Thiel-embalmed cadaver specimens the reference points that they would normally use to define the TEA during knee replacement. These were digitized by a video system, and all the spots defined by the surgeon were translated into a reference picture, allowing a digital analysis of the distances between all the spots marked. The maximal distance between the spots that the participants had marked as relevant for the TEA was 13.8 mm at the lateral and 22.3 mm at the medial epicondyle. Projecting all spots marked into one picture resulted in an area of 116 mm2 on the lateral and 102 mm2 on the medial epicondyle. The median range of the fault between two different participants was 6.4 mm on the lateral side (range 13.2 mm) and 9.7 mm on the medial (range 21.6 mm). Because the rotational alignment of the femoral component is extremely relevant for successful implantation of total knee prosthesis, the interindividual discrepancy in defining the TEA as reference is rather high. As this reference line is commonly used, the perioperative variance and the resulting rotational discrepancy of the femoral component must be considered.     

Straight ileoanal anastomosis and ileal pouch-anal anastomosis in the surgical management of idiopathic ulcerative colitis and familial polyposis coli in children: follow-up and comparative analysis

We compared the postoperative course in children and teenagers who underwent subtotal colectomy, mucosal proctectomy, and either straight ileoanal anastomosis (group 1, n = 8) or ileal pouch-anal anastomosis (group 2, n = 10) for the surgical treatment of idiopathic ulcerative colitis (n = 15) and familial polyposis coli (n = 3). Two of eight children in group 1 developed intractable diarrhea that persisted despite revision of the anastomosis to include an ileal pouch; therefore, ileostomies were necessary in both cases. One patient in group 2 had a diverting ileostomy as a result of abscess formation at the site of the ileoanal anastomosis. Despite a longer period of postoperative follow-up (48.9 +/- 11.8 months), the remaining six patients in group 1 had a significantly greater number of bowel movements each day (7.8 +/- 6.5) as compared with the nine patients in group 2 who had 4.8 +/- 2.6 stools each day (p less than 0.05) at a mean follow-up of 15.7 +/- 9.0 months. A proportion of children in both groups had a poor postoperative functional outcome as determined by fecal incontinence (2 of 6 in group 1, 6 of 9 in group 2), perianal dermatitis (2 of 6, 4 of 9), and therapy with the antidiarrheal agent loperamide (4 of 6, 2 of 9). Increased school attendance (5 of 6, 7 of 7) and improvement in level of participation in social activities (5 of 6, 7 of 7) as compared with the 6-month period prior to surgery occurred, however, for most of the children with ulcerative colitis in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lysolecithin concentration in pancreatic tissue during therapy with phospholipase A2-inhibitors in acute necrotizing pancreatitis

Summary Four hours after hemorrhagic necrotizing pancreatitis was induced in experimental animals the concentration of lysolecithin in pancreatic tissue rose (p=0.0025). Parenteral administration of unspecific inhibitors of phospholipase A₂, such as chlorpromazine, gabexat mesilat and CaNa₂ EDTA, can neither inhibit elevation of the enzyme nor influence the course of the disease.