Germ cell cancer and disorders of spermatogenesis: an environmental connection?

Why is there a small peak of germ cell tumours in the postnatal period and a major peak in young age, starting at puberty? And, paradoxically, small risk in old age, although spermatogenesis is a lifelong process? Why is this type of cancer more common in individuals with maldeveloped gonads, including undescended testis, gonadal dysgenesis and androgen insensitivity syndrome? Why has there, during the past 50 years, been a quite dramatic increase in testicular cancer in many developed countries? These are just a few of many questions concerning testicular cancer. However, the recent progress in research in the early stages of testicular cancer (carcinoma in situ testis (CIS)) allows us to begin to answer some of these questions. There is more and more evidence that the CIS cell is a gonocyte with stem cell potential, which explains why an adult man can develop a non-seminoma, which is a neoplastic caricature of embryonic growth. We consider the possibility that CIS cells may loose their stem cell potential with ageing. Along these lines, a seminoma is regarded a gonocytoma where the single gonocytes have little or no stem cell potential. The Sertoli and Leydig cells, which are activated postnatally and during and after puberty, may play a crucial role for both the development of the CIS gonocyte and progression of the neoplasm to invasiveness. The reported increase in testicular cancer is not the only sign that male reproductive health is at risk. There are reports that undescended testis and hypospadias have become more common. Also semen quality has deteriorated, at least in some countries. The epidemiological evidence suggests that environmental factors may play a role. Are the environmental hormone disrupters (e.g. DDT, PCB, nonylphenol, bisphenol A) to be blamed for the apparently synchronised deterioration in these aspects of male reproductive health?     

Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.     

Oxidative autoaggression by phagocytes in human peritonitis

In 60 abdominal exudates from patients with the diagnosis of either acute or persistent (chronic) peritonitis, indicators of phagocyte-derived oxidative systems (myeloperoxidase, chemiluminescence) and proteases (elastase) were measured. These exudates reveal a picture of maximal inflammatory activation. Both types of exudates (30 each) showed a significant influx of inflammatory cells, with the mean leucocyte count being 73,000 microL and 32,000 microL-1 respectively. Local myeloperoxidase concentrations were approximately 1000-fold greater than that of normal plasma. Spontaneous and elicitable chemiluminescence--indicators of phagocyte respiratory burst activity--were dramatically increased. In addition, levels of extracellularly released elastase (from neutrophils) were found to be up to about 1000-fold that of normal plasma values. Although most of the elastase detected in the exudates was complexed with alpha 1-proteinase inhibitor (alpha 1 PI), enzymatically active elastase could be measured in approximately 60% of the samples being investigated. As there was an excess of immunoreactive alpha 1 PI in these exudates, the free elastase activity implies that much of the alpha 1 PI was inactive, presumably subjected to oxidative destruction. Moreover, a trypsin-inhibitory activity to antigen ratio below 1 (mean = 0.81) in 75% of the purulent exudates indicated also partial proteolytic degradation of alpha 1 PI. In contrast, 16 clear exudates (no bacteria, white cell count below 500 microL-1) taken from the non-infected peritoneal cavity of patients undergoing intra-abdominal surgery revealed a similar permeability increase of the peritoneum but did not show relevant oxidative and proteolytic activity or destruction of alpha 1 PI compared with purulent specimens. Thus, only the inflammatory process of peritonitis appears to result in an overwhelming local phagocytic activity that initiates and maintains protease inhibitor consumption and/or inactivation. The tremendous oxidative potential found in purulent exudates may cause destruction in a wide variety of defence systems.     

Regulation of MHC class I heterodimer stability and interaction with TAP by tapasin

Major histocompatibility complex (MHC) class I molecules are heterodimers of a class I heavy chain and beta 2-microglobulin that bind peptides supplied by the MHC region-encoded transporters associated with antigen processing (TAP). Peptide binding by class I heterodimers is necessary for their maturation into stable complexes and is dependent on their physical association with TAP. In human mutant 721.220 cells, however, a novel genetic defect causes the failure of class I heterodimers to associate with TAP. This deficiency correlates with lack of expression of a glycoprotein, tapasin (TAP-associated glycoprotein), which has been found in association with class I heterodimers and TAP. Employing a transcomplementation analysis, we obtained evidence co-localizing the genetic defect of mutant 220 cells and the structural or a regulatory gene controlling the expression of tapasin on the short arm of chromosome 6, which includes the MHC. Expression of tapasin and the normal interaction of class I heterodimers with TAP are concomitantly restored, indicating the probable function of tapasin as a physical link between these complexes. In further support of this model, the absence of tapasin in mutant 220 cells correlates with reduced class I heterodimer stability, suggesting that tapasin may stabilize class I heterodimers and thereby enhance their association with TAP. These results further implicate tapasin in a mechanism that promotes peptide binding by class I heterodimers through their interaction with TAP.     

The natural history of patients with benign prostatic hyperplasia as diagnosed by North American urologists

PURPOSE: We defined outcomes for men with a clinical diagnosis of benign prostatic hyperplasia. MATERIALS AND METHODS: We followed for 4 years 500 candidates for elective prostatectomy treated nonoperatively in 5 North American urology practices. RESULTS: There were 371 survivors with complete data at 4 years. Of 60 men with mild, 245 with moderate and 66 with severe baseline symptoms 10, 24 and 39%, respectively, had undergone surgery; 27, 31 and 27%, respectively, were on pharmacological therapy, and 63, 45 and 33%, respectively, were off active treatment at 4 years. Mild or moderate symptoms were noted at 4 years in 83, 59 and 23% of the patients, respectively, while 17, 41 and 77%, respectively, had severe symptoms or had undergone surgery. CONCLUSIONS: Outcomes for men with a clinical diagnosis of benign prostatic hyperplasia depend on initial symptom severity. However, the course of symptoms also varies among patients even with the same initial symptom severity.     

Interactions between anaesthetics and lipid mixtures. Amines

Variance analysis, an accounting technique, is applied to an eight-component model of hospital costs to determine the contribution each component makes to cost increases. The method is illustrated by application to data on total costs from 1950 to 1973 for all U.S. nongovernmental not-for-profit short-term general hospitals. The costs of a single hospital are analyzed and compared to the group costs. The potential uses and limitations of the method as a planning and research tool are discussed.