Isolated central nervous system relapse of non-seminomatous germ cell tumour of the testis. A case report and review of the literature.

Isolated central nervous system (CNS) relapse of non-seminomatous germ cell tumour (NSGCT) of the testis has been reported in only 12 patients previously. We report a patient with an isolated CNS relapse of NSGCT, following a prior systemic relapse. From a review of previous cases, isolated CNS relapse appears to be more common in patients with embryonal cell histology (alone or mixed with other elements) and occurred after a median of 8.5 months following initial presentation. Long-term survival appears possible using multi-modal treatment with whole-brain radiotherapy, surgery and/or chemotherapy. However, the optimal treatment of isolated CNS relapse remains undefined.

Postural renal transplant obstruction: a case report and review of the literature.

A 48-year-old woman underwent cadaveric renal transplantation for end-stage renal failure secondary to polycystic kidney disease. Nine months after transplantation, intermittent renal dysfunction and severe graft hydronephrosis developed despite the presence of a ureteric stent. A Tc-99m MAG3 scan performed with the patient standing showed complete transplant obstruction. Rapid tracer clearance with progressive bladder filling was present when the patient was imaged in the supine position. Ureteric obstruction is the most common urologic complication of renal transplantation. However, postural ureteric obstruction has been described only rarely. This case indicates that posture may affect ureteric patency and highlights this potential pitfall in the evaluation of intermittent graft dysfunction by diuretic renography.

Diagnosis of kidney transplant obstruction using Mag3 diuretic renography.

Kidney transplant obstruction (KTO) following renal transplantation remains an important reversible cause of allograft dysfunction, requiring prompt diagnosis to prevent long-term graft damage. Although ultrasound can accurately diagnose renal transplant hydronephrosis, it cannot be used to assess its functional significance. We prospectively assessed the utility of technetium-99m mercaptoacetyltriglycine (Tc99m MAG3) diuretic renography for the diagnosis of allograft KTO, using standard visual and quantitative parameters, as well as calculated renal output efficiency (OE), which has been postulated to improve diagnostic yield. From a cohort of 45 renal transplant patients, two subgroups were formed. The first group of transplant recipients (n = 21) with stable function and no obstruction was used to derive normal values for Tc99m MAG3 scans. A second group of transplant recipients with acute renal dysfunction in whom KTO was clinically suspected was used to test the diagnostic utility of these derived values (n = 43 scans). KTO was diagnosed independently of the MAG3 scans by a fall in the serum creatinine in response to renal pelvis urinary drainage. OE in 12 renal allografts with KTO was significantly reduced compared with 31 Tc99m MAG3 scans without KTO (59.6 +/- 18.9 vs. 81.6 +/- 5.4%, p < 0.001). In KTO, the mean time of isotope appearance in the bladder (time to bladder [TTB]) was extended compared with unobstructed allografts (7.9 +/- 4.1 vs. 3.6 +/- 1.5 min, p < 0.001). Measurement of OE significantly improved the accuracy of diuretic MAG3 renography in the diagnosis of renal allograft KTO, especially when supplemented by the TTB, parenchymal transit time and shape of the renogram curve. Ureteric obstruction of the kidney transplant can be diagnosed with an OE reduced to < 75% (sensitivity 92%, specificity 87%) and confirmed by isotope hold-up in the pelvicalyceal system. A normal or slowly declining renogram curve effectively excluded KTO (sensitivity of 96%, negative predictive value of 84%). A parenchymal transit time of > 5 min and a TTB of > 7 min both yielded a sensitvity of 92% and a specificity of 81%. In conclusion, MAG3 renography is a clinically useful investigation for the diagnosis of KTO.

Pharmacokinetics and disposition of L-692,429. A novel nonpeptidyl growth hormone secretagogue in preclinical species.

L-692,429 is a novel nonpeptidyl growth hormone secretagogue that has been demonstrated to stimulate growth hormone secretion in rats, dogs, and humans after intravenous administration. We have examined the pharmacokinetics and disposition of L-692,429 in male Sprague-Dawley rats, beagle dogs, and chimpanzees. Plasma clearance (CLp) of L-692,429 in dogs after intravenous dosing was approximately 18 ml/min/kg and was constant between the doses of 0.1 and 0.9 mg/kg. In rats, CLp after intravenous dosing increased from 3 to 12 ml/min/kg in a dose-dependent manner between 0.1 and 5 mg/kg. In chimpanzees, CLp after an intravenous dose of L-692,429 at 0.5 mg/kg was 5.7 ml/min/kg. In vitro binding of L-692,429 to plasma proteins of dogs, chimpanzees, and humans was approximately 87%, 94%, and 93.5%, respectively, and was independent of concentration. In contrast, plasma binding of L-692,429 was concentration-dependent in rats and decreased from 98.5% to 90.6% between 0.01 and 10 micrograms/ml. Metabolism of L-692,429 was minimal in rats, but moderate in dogs, with the major metabolite being a derivative monohydroxylated at the benzolactam moiety. Thus, the faster clearance of L-692,429 in dogs likely is caused by less extensive plasma protein binding and higher metabolic clearance. The nonlinear pharmacokinetics in rats probably is the result of concentration-dependence in plasma binding. The results of these studies suggest that plasma protein binding plays a major role in determining the values of CLp of L-692,429 among the species. After an intravenous dose of [3H]L-692,429 to rats, liver, kidney, lung, and heart had the highest levels of radioactivity at the early time points, but the gastrointestinal tract had increasing concentrations at later time points. Most of the radioactivity was cleared from all tissues by 24 hr, indicating that L-692,429 did not accumulate in tissues. After intravenous dosing of [3H]L-692,429 to rats and dogs, recoveries of total radioactivity in urine and feces corresponded to approximately 10% and 90%, respectively. Greater than 70% of radioactivity was recovered in bile of rats within 24 hr after intravenous dosing of [3H]L-692,429, indicating that biliary excretion was the primary route of elimination. Based on the combined recoveries of the radioactive dose in bile and urine after an oral dose of L-692,429, oral absorption in rats was approximately 3%. The poor absorption may be the result of the zwitterionic nature of this compound.

Parents' attachment histories and children's externalizing and internalizing behaviors: exploring family systems models of linkage.

Twenty-seven mothers and 27 fathers were given the Adult Attachment Interview (M. Main & R. Goldwyn, in press) when their children were 3.5 years old. Continuous ratings of narrative coherence, probable experience quality (parents perceived as loving), and state of mind (current anger at parents) were entered as latent variables in partial least squares structural equation models that included observational measures of marital quality and parenting style. Models that include fathers' attachment histories predicted more variance in kindergarten teachers' descriptions of children's externalizing behavior, whereas models that include mothers' attachment histories predicted more variance in children's internalizing behavior. Marital data added predictive power to the equations. Discussion is focused on the importance of integrating attachment and family systems approaches, and of parents' gender and marital quality, in understanding specific links between parents' attachment histories and their young children's externalizing and internalizing behaviors.

Adult attachment and adult child-older parent relationships.

Adult attachment status, concurrent and early relationships with parents, and depressive symptoms were assessed in 53 adults. Individuals with consistent reports of relationships--positive or negative--were most coherent in their narratives. Depressive symptoms were associated with negativity in both recalled and current relationships with parents, but were not correlated with coherence of narratives. Clinical implications of the findings are discussed.

Child-mother attachment of six-year-olds and social competence at school.

89 children and their mothers participated in a study examining the association between attachment and peer social competence. During the summer following kindergarten, quality of attachment was assessed from reunion episodes following a 1-hour separation. In the fall, measures of sociometric status, peer behavior nominations, and peer liking ratings were collected. Teachers completed liking ratings and ratings of behavior problems and competence. Consistent with longitudinal studies of infant attachment and peer relations, insecurely attached boys were less well liked by peers and teachers, were perceived as more aggressive by classmates, and were rated by teachers as less competent and as having more behavior problems than were their secure counterparts. No such associations emerged for girls. Possible explanations for unanticipated differences in the pattern of results for boys and girls are discussed.

Minimal role for the spleen in antibody responses of C57BR/cdj mice to pneumococcal polysaccharide antigens.

The role of the spleen in antibody production and in susceptibility to pneumococcal infections remains poorly understood. Recently we showed that in A/J mice high antibody responses to polysaccharide antigens depend upon dosage, antigenic structure, interval between immunization and assay and the presence of the spleen. To investigate the possibility of alternative patterns of response, intact and splenectomized (Sx) C57BR/cdj mice were assayed for antibody responses to two structurally different pneumococcal polysaccharides, type 3 (SIII) and type 14 (SXIV). After 50 or 100 ng of SIII, intact C57BR/cdj mice produced uniformly low antibody responses that were further suppressed by splenectomy, but after 1,000 ng of SIII, C57BR/cdj mice, regardless of whether they were intact or Sx, produced antibody responses as high as those of intact A/J mice. Following SXIV, a spleen-dependent antigen, C57BR/cdj mice produced consistently lower antibody responses than A/J mice. Antibody responses to 500 or 5,000 ng of SXIV were totally obliterated in Sx C57BR/cdj mice; but unlike A/J mice, responses to 10,000 ng were similar regardless of whether C57BR/cdj mice were intact or Sx. The inability of intact C57BR/cdj mice to produce elevated responses to SIII or SXIV suggests that C57BR/cdj mice may lack the subset of spleen cells necessary for a vigorous response to these antigens. The data suggest that these mice could provide useful animal models for studying host variability in antibody responses to pneumococcal polysaccharides.

Immunoregulatory role of the spleen in antibody responses to pneumococcal polysaccharide antigens.

Antibody responses to two structurally different pneumococcal polysaccharides, type 3 (SIII) and type 14 (SXIV), were examined in intact and splenectomized (Sx) A/J mice to determine whether the role of the spleen in immune responses to these antigens varies with respect to the dosage, the antigenic structure, or the interval between immunization and assay. Antibody responses to SIII and SXIV, measured over a 4-week period by radioimmunoassay, differed in antigenic load requirements, kinetics, and extent of dependence upon the spleen. Intact mice given 50 or 100 ng of SIII produced peak antibody responses on day 5, which tapered off by days 14 and 21. Intact mice given SXIV required doses 100 times greater than those of SIII to stimulate high levels of antibody response; antibody responses increased on day 5 and remained elevated through day 28. In Sx mice given 50 or 100 ng of SIII, the peak antibody response on day 5 was obliterated, but extrasplenic sources produced low levels of antibody which peaked by day 14. In Sx mice given SXIV, all anti-SXIV responses were abrogated regardless of the dose or day of assay. Differences between the anti-SIII and anti-SXIV responses in dependence upon the spleen were probably due to structural differences between the two antigens and to the localization of each to different sites in the reticuloendothelial system. These results attest to the importance of the spleen in antibacterial resistance. They show that, even in the presence of extrasplenic antibody synthesis, the spleen is required for early antibody production, the timing of which is critical for the effective clearance of bacteria.

Genetic variation in androgen regulation of ornithine decarboxylase gene expression in inbred strains of mice.

Previous studies have indicated that androgen regulation of certain gene products in murine kidney is genetically controlled. In the present work, the expression of renal ornithine decarboxylase (ODC) gene(s) was used as a biological marker to study androgen responsiveness of eight inbred strains of mice (A/J, C57BR/cdJ, 129/J, C57L/J, BALB/cJ, SM/J, RF/J, and C57BL/6J). Kidneys of untreated females from these strains did not have significantly different basal ODC activities or ODC mRNA concentrations. However, renal enzyme concentrations in intact male mice exhibited marked strain-dependent variation; three strains (RF/J, SM/J, and C57BR/cdJ) had 5- to 20-fold higher activities than the other five strains. Renal ODC mRNA content showed similar genetic variability in the male mice; animals with highest enzyme activity had higher mRNA levels than those with low activity. These results could not be explained by differences in either serum testosterone levels or renal nuclear androgen receptor content, suggesting that the animals were differentially sensitive to endogenous androgens. To evaluate further the androgen regulation of ODC gene expression, female mice were treated with testosterone-releasing implants for 5-7 days. The two strains (A/J and C57BL/6J) that had low enzyme activity in response to endogenous testosterone in male mice also showed blunted responses to exogenous androgen administration, as measured by the induction of ODC and its mRNA. The relative distribution of the two mRNA species coding for ODC (2.2 and 2.7 kb in size) exhibited strain-dependent variation that did not, however, correlate with the androgen responsiveness. Studies of the mRNA levels in reciprocal F1 hybrids of C57BR/cdJ and C57BL/6J mice suggested that androgen sensitivity of ODC gene expression, at least in these crosses, was inherited in an autosomal dominant manner.

Low immune responses in high androgen responder C57BR/cdj males.

Previous studies have shown that male mice of strains with high target organ responsiveness to androgen, the C57L/J and RF/J, have lower plasma immunoglobulin levels and weaker antibody responses to protein and polysaccharide antigens than mice of low androgen responder (LAR) strains, the A/J and 129/J. In the current report, the relationship between high androgen responsiveness and low immune performance has been investigated in another strain, the C57BR/cdj. Compared to LAR A/J males, C57BR/cdj males had significantly higher target organ responses to androgen as measured by both seminal vesicle bioassay and haematocrit. High androgen responder (HAR C57BR/cdj males were lower than A/J's in PFC responses to sheep red blood cells (SRBC), lipopolysaccharide (LPS) induced spleen cell proliferation and polyclonal B cell activation. HAR C57BR/cdj males were not significantly different from C57BR/cdj females or A/J mice in proliferative responses to concanavalin A (Con A) or phytohaemagglutinin (PHA). These results are compatible with our previous findings in other HAR strains and suggest that the consistently low in vivo immune responses of HAR males may be due to B cell weakness or T suppressor dysregulation.

Differences in survival among germfree mice following transfer to a conventional colony.

Sex and strain differences in survival were studied in 7-9 month old germfree mice following transfer to a conventional colony. One outbred and three inbred strains were observed. All outbred CD-1 mice survived transfer and in 4 months increased their weight by 50%. The majority of inbred mice survived 7 months after transfer. Sex differences in survival were evident throughout the experimental period and were most marked 7 months after transfer. An unexpected new finding was the viability of the male sex in germfree mice after transfer. Possible explanations are considered.

Rapid, safe and simple method for grafting whole thymus in the mouse.

A rapid, safe and simple method is presented for obtaining and grafting whole neonatal thymuses in mice. No anesthesia, sutures or incisions are required for implantation. The grafting technique involves no special skills except the ability to inject mice subcutaneously. Thymuses grafted by the method described show normal architecture, survive lethal irradiation and bone marrow reconstitution, repopulate thymic dependent areas of peripheral lymphoid organs and restore normal inflammatory cell responses to thymic deprived mice.