bcl-2 protein expression in astrocytomas in relation to patient survival and p53 gene status

bcl-2 protein expression was characterized in a series of 58 astrocytomas from 21 pediatric and 37 adult patients. As part of a continuing attempt to define relevant prognostic factors which may predict clinical outcome, we have determined the impact of bcl-2 accumulation in malignant astrocytes on the length of patient survival. Aberrant overexpression of bcl-2 protein in tumor cells was detected in 57% (12 of 21) of pediatric and 73% (27 of 37) of the adult cases. Among pediatric patients, the median survival in months showed no relationship with the incidence of bcl-2-positive tumors. Among the adult patients, a favorable prognostic indicator was low-tumor grade (P = 0.05). bcl-2-positive tumors occurred with similar frequencies in WHO grades III and IV of malignancy. When bcl-2 expression in tumor cells was tested as a variable to predict for patient survival, the 6 patients without bcl-2 expression among 23 adult patients with grade IV tumors had a shorter median survival. The same 58 tumors had been previously analyzed for alterations of p53: 4 pediatric and 16 adult tumors had p53 gene mutations. There was no significant difference in median survival related to p53 gene status. There was no relationship between bcl-2 expression and p53 gene status: approximately equal numbers of tumors with either wild-type or mutant p53 were bcl-2 negative or bcl-2 positive. bcl-2 expression is high (40–100%) among other tumors of the central nervous system which also show low malignant potential. Up-regulation of bcl-2 in malignant astrocytes or constitutive expression in some tumor types may be a factor leading to a more favorable clinical outcome. Received: 27 January 1997 / Revised: 21 March 1997 / Accepted: 28 March 1997     

Recurrent urinary tract infection in girls. Group with lower tract findings and a benign course

A group of girls is described with recurrent urinary tract infections characterized by predominantly lower tract symptoms. Clinical, laboratory, and radiography findings during the period of follow-up are presented. Infection persisted in most patients over several years. Response to medical and surgical treatment was unsatisfactory. The mean interval between the initial and most recent radiological study was 6 1/2 years. No case of renal parenchymal scarring was seen.     

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

Background

Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses.

Methods

Autologous DCs were generated from 10 patients (HLA-0201) with advanced cancer by culturing CD14+ blood monocytes in the presence of GM-CSF and IL-4 supplemented with TNF-α [DCT] or TNF-α and IFN-α [DCTI]. The capacity of the DCs to induce functional CD8+ T cell responses to hTERT HLA-0201 restricted nonapeptides was assessed by MHC tetramer binding and peptide-specific cytotoxicity. Each DC preparation (DCT or DCTI) was pulsed with only one type of hTERT peptide (p540 or p865) and both preparations were injected into separate lymph node draining regions every 2–3 weeks. This vaccination design enabled comparison of efficacy between DCT and DCTI in generating hTERT peptide specific CD8+ T cells and comparison of class I hTERT peptide (p540 or p865)-loaded DCT with or without class II cognate help (p766 and p672) in 6 patients. T regulatory cells were evaluated in 8 patients.

Results

(i) DCTIs and DCTs, pulsed with hTERT peptides, were comparable (p = 0.45, t-test) in inducing peptide-specific CD8+ T cell responses. (ii) Class II cognate help, significantly enhanced (p < 0.05, t-test) peptide-specific CD8+T cell responses, compared with class I pulsed DCs alone. (iii) Clinical responders had significantly lower (p < 0.05, Mann-Whitney U test) T regs, compared with non-responders. 4/16 patients experienced partial but transient clinical responses during vaccination. Vaccination was well tolerated with minimal toxicity.

Conclusion

Addition of IFN-α to ex vivo monocyte-derived DCs, did not significantly enhance peptide-specific T cell responses in vivo, compared with TNF-α alone. Class II cognate help significantly augments peptide-specific T cell responses. Clinically favourable responses were seen in patients with low levels of circulating T regs.     

Mechanisms of ENaC regulation and clinical implications

The epithelial Na+ channel (ENaC) transports Na+ across tight epithelia, including the distal nephron. Different paradigms of ENaC regulation include extrinsic and intrinsic factors that affect the expression, single-channel properties, and intracellular trafficking of the channel. In particular, recent discoveries highlight new findings regarding proteolytic processing, ubiquitination, and recycling of the channel. Understanding the regulation of this channel is critical to the understanding of various clinical phenomena, including normal physiology and several diseases of kidney and lung epithelia, such as blood pressure (BP) control, edema, and airway fluid clearance. Significant progress has been achieved in this active field of research. Although ENaC is classically thought to be a mediator of BP and volume status through Na+ reabsorption in the distal nephron, several studies in animal models highlight important roles for ENaC in lung pathophysiology, including in cystic fibrosis. The purpose of this review is to highlight the various modes and mechanisms of ENaC regulation, with a focus on more recent studies and their clinical implications.     

Simulation fails to replicate stress in trainees performing a technical procedure in the clinical environment

Introduction: Simulation-based training (SBT) has become an increasingly important method by which doctors learn. Stress has an impact upon learning, performance, technical, and non-technical skills. However, there are currently no studies that compare stress in the clinical and simulated environment. We aimed to compare objective (heart rate variability, HRV) and subjective (state trait anxiety inventory, STAI) measures of stress theatre with a simulated environment.

Methods: HRV recordings were obtained from eight anesthetic trainees performing an uncomplicated rapid sequence induction at pre-determined procedural steps using a wireless Polar RS800CX monitor © in an emergency theatre setting. This was repeated in the simulated environment. Participants completed an STAI before and after the procedure.

Results: Eight trainees completed the study. The theatre environment caused an increase in objective stress vs baseline (p?=?.004). There was no significant difference between average objective stress levels across all time points (p?=?.20) between environments. However, there was a significant interaction between the variables of objective stress and environment (p?=?.045). There was no significant difference in subjective stress (p?=?.27) between environments.

Discussion: Simulation was unable to accurately replicate the stress of the technical procedure. This is the first study that compares the stress during SBT with the theatre environment and has implications for the assessment of simulated environments for use in examinations, rating of technical and non-technical skills, and stress management training.     

Progressive pulmonary calcification in a child after orthotopic liver transplantation

We present a case of progressive pulmonary calcification associated with prolonged respiratory insufficiency in a 2-year-old boy with a history of orthotopic liver transplantation. This case demonstrates the potentially progressive nature of pulmonary calcification and that it can present with respiratory insufficiency at a later period after transplantation than previously thought. We describe radiological findings and discuss established as well as plausible pathological mechanisms contributing to the development of calcifications in these patients.     

Neuron-specific enolase and retinoblastoma. Clinicopathologic correlations

Neuron-specific enolase (a glycolytic, ubiquitous, intracellular enzyme) has recently been reported to be detectable in the aqueous humor of eyes containing retinoblastoma. Aqueous humor from 17 patients with histologically proven retinoblastoma was assayed for the presence of neuron-specific enolase (NSE). NSE was detectable in 17 out of 17 patients with levels between 619 and 60,000 ng/ml. A multitude of clinocopathological parameters were examined for statistically significant correlations with levels of aqueous humor NSE. This investigation demonstrated that only two parameters, the presence of tumor invasion into the anterior chamber, and inflammation significantly correlated with aqueous NSE levels. Histological parameters which did not correlate with aqueous NSE levels included tumor necrosis, calcification, Flexner-Wintersteiner rosettes, exophytic/endophytic tumor type, tumor extent relative to the equator, and optic nerve/choroidal invasion. Clinical parameters which showed no correlation included patient sex (M/F), enucleation age, presentation age, family history, laterality, prior treatment, and presence of metastatic disease. Neuron-specific enolase is present in the anterior chamber of eyes enucleated for retinoblastoma, but additional testing is necessary to determine the normal levels of neuron-specific enolase in children's eyes and the levels in eyes with lesions simulating retinoblastoma.