New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone

Typhoid fever is often associated with abnormal liver biochemical tests, but severe hepatic involvement with a clinical feature of acute hepatitis is a rare complication. There have been more than 150 cases of salmonella hepatitis reported from both developed and developing countries. The documented incidence varies widely from less than 1% to 26% patients with enteric fever. The possible associated factors for development of salmonella hepatitis are virulence of the organisms, delayed treatment and poor general health of the patients. The pathogenesis of severe hepatic involvement in salmonella infection may be multifactorial and includes endotoxin, local inflammatory and/or host immune reactions. Clinical jaundice in salmonella hepatitis usually occurs within the first 2 weeks of the febrile illness. Hepatomegaly and moderate elevation of transaminase levels are common findings. Extreme hepatic dysfunction with hepatic encephalopathy is a rare coexisting complication in salmonella hepatitis. A positive culture for salmonella from blood or stool is essential to differentiate salmonella hepatitis from other causes of acute hepatitis. Hepatic pathology is characterized by the presence of typhoid nodules with marked hyperplasia of reticuloendothelial cells. The prognosis is usually good as salmonella hepatitis responds well to a specific antibiotic therapy and juandice resolves with clinical improvement. The clinical course can be severe with a mortality rate as high as 20%, particularly with delayed treatment or in patients with other complications of salmonella infection. As enteric fever is a common infection, the recognition of salmonella hepatitis is of clinical importance.     

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

BACKGROUND: Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. METHODS: Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range <1-60 years) treated with allogeneic blood or marrow transplants for CML between 1989 and 1997, reported to the European Group for Blood and Marrow Transplantation (EBMT), were used to develop and test a simple risk score based on previously reported major pretransplant risk factors: histocompatibility, stage of disease at time of transplantation, age and sex of donor and recipient, and time from diagnosis to transplantation. We analysed probabilities of survival, leukaemia-free survival, transplant-related mortality, and relapse incidence with respect to these risk factors. FINDINGS: At the time of analysis, 1922 (61%) of the 3142 patients were alive-1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA-identical sibling transplants and unrelated transplants for transplants done in 1989-93 and 1994-96. INTERPRETATION: Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.     

Non-MHC-restricted cell-mediated lysis of human oligodendrocytes in vitro: relation with CD56 expression

Oligodendrocytes and their myelin membranes are the apparent target of the autoimmune response that characterizes the human adult central nervous system-demyelinating disease multiple sclerosis. Human oligodendrocytes do not express MHC class II molecules, a requirement for MHC-restricted injury mediated by myelin-reactive CD4+ T cells, the cell type implicated in initiating the disease process. In this study we observed that human adult central nervous system-derived oligodendrocytes can be susceptible to non-MHC-restricted lysis mediated by myelin basic protein-reactive CD4+ T cell lines. Cytotoxicity was significantly greater (37 +/- 4 vs 7 +/- 3%) with cell lines in which a high proportion of cells (mean, 28 +/- 6%) expressed CD56 compared with cytotoxicity mediated by low CD56 cell lines (8 +/- 2%). High CD56 cell lines, when rested in IL-2, lost cytotoxic activity and had reduced expression of CD56 (mean, 5 +/- 2%). CD4+ T cells isolated from short term (3-day) anti-CD3/IL-2-activated mononuclear cell cultures did not express CD56 and were not cytotoxic to oligodendrocytes unless lectin was added. In contrast, an enriched population of non-T cells extracted from the same activated MNC cultures expressed CD56 as well as other NK cell-associated surface molecules and was cytotoxic. These results indicate the potential susceptibility of human oligodendrocytes to non-MHC-restricted injury mediated by both Ag-reactive and nonspecific cellular immune effector cells, with CD56 expression being a common feature of the effector cells.     

Stiffness of trabecular bone of the tibial plateau in patients with rheumatoid arthritis of the knee

Stiffness of subchondral proximal tibial trabecular bone is a factor in the stability of prostheses implanted into that bone. The stiffness of trabecular bone in osteoarthritis (OA) has been documented. Trabecular bone in rheumatoid arthritis (RA) is osteopenic in numerous sites and morphologically abnormal in the proximal tibia. Reliable data on proximal tibial bone in RA are lacking, although 1 study failed to identify abnormalities. The purposes of this study were (1) to document the stiffness of the proximal tibial cancellous bone in patients with RA, (2) to determine the effect of angular deformity on bone stiffness in rheumatoid patients, and (3) to compare RA stiffness values with those in published reports for OA. Fifteen tibial plateau were obtained from patients with RA during surgery. Each plateau was horizontally seated in a mold and covered with cement. The plateau was divided into 6 regions, which were used to facilitate comparison between specimens and the existing literature. Indentation tests were conducted with a 4-mm-diameter cylindrical indentor controlled by an MTS machine. The indentor descended at a rate of 2 mm/min to a maximum depth of 1.0 mm; load and displacement data were digitally recorded. Stiffness was calculated from the slope of the linear region of the curve using best-fit linear regression. Where varus deformity was present, stiffness in the medial plateau was higher overall than for the other compartment; whereas in the case of valgus deformity, stiffness of the lateral side was significantly higher (P < .05 for each observation). In comparison to older normal specimens, both the medial compartment of the varus RA specimens (P < .01) and the posterolateral compartment of the valgus RA specimens (P < .01) had significantly lower stiffness. Comparison with OA specimens showed that in varus RA, the posteromedial region had significantly lower stiffness than in varus OA at the same site (P < .01). In valgus RA, the lateral region had significantly lower stiffness than in valgus OA at the same site (P < .01). The mean stiffness ratio of the valgus RA was significantly (P < .01) altered from normal, and for the varus RA, it was significantly (P < .01) different from normal posteriorly. The stiffness ratios for the varus RA were significantly (P < .01) different from those for varus OA; there was no difference between valgus RA and valgus OA. It is concluded that RA affected bone has significantly lower stiffness than normal and osteoarthritic bone. The loaded plateau is stiffer than the unloaded plateau in angular deformity, but is still less stiff than normal bone and osteoarthritic plateaus with corresponding deformities.     

Current management of bladder exstrophy

This article describes in detail the modern management of the patient born with classic bladder exstrophy. Also, new techniques of prenatal diagnosis and pelvic fixation to secure the initial or secondary closure are discussed. Last, management of the failed closure and the bladder not suitable for closure are described and outlined. A successful initial closure of the infant born with bladder exstrophy is the single most important determinant in the eventual development of continence in the exstrophy patient.     

Premedication with oral midazolam in children--an assessment of psychomotor function, anxiolysis, sedation and pharmacokinetics

We studied 30 children, aged 4 to 12 years, undergoing elective circumcision, premedicated with midazolam 0.5 mg.kg-1 and atropine 0.02 mg.kg-1 by mouth. A modified postbox test and the coding component of the Wechsler intelligence scale (WISC-R) was used to assess the preoperative effect of premedication on psychomotor function. Mood and sedation were also scored and related to serum midazolam concentrations. The children showed a significant decline in psychomotor performance 30 and 60 minutes after premedication when compared with their best unmedicated performance recorded the previous evening. This decline in psychomotor performance was only weakly associated with serum midazolam concentrations (r = 0.1). The postbox toy ratio is a suitable measurement of psychomotor performance in children because of its simplicity and ease of use in the clinical environment, although it may suffer the "test-retest" limitations of similar types of assessment. The sedative and anxiolytic effects of midazolam provide a quiet environment for a smooth induction of anaesthesia.     

Personality profile in adult female fragile X carriers: assessed with the Minnesota Multiphasic Personality Profile (MMPI)

To assess if the higher incidence of psychiatric morbidity in fragile X carriers is related to a particular pathological personality profile, we obtained a Minnesota Multiphasic Personality Profile from 11 normally intelligent (female) fragile X carriers. The sample mean for the clinical and validity scales all fell within the normal range. Although no pathological profile was found, some unexpected results emerged: low scores for the scales "schizophrenia" and "social introversion" and a so-called faking-good profile on the validity scales. This combination suggests that the subjects might not be aware of some personality characteristics in these areas. Implications for further research are discussed.     

Renal proliferative and phenotypic changes in rats with two-kidney, one-clip Goldblatt hypertension

Previous research in this laboratory has shown that preweaning and postweaning juvenile meadow voles, Microtus pennsylvanicus, can acquire a spatial task, the Morris water-maze task. The present study examined the influence of age of juvenile acquisition ("before weaning" (BW; Day 10 and 15 after birth) and "after weaning" (AW; Day 20 and 25 after birth)) of a spatial task on subsequent re-acquisition of the same hidden-platform spatial water-maze task. This study also compared sex differences and litter sex-ratio effects on reacquisition performance. Fifteen litters of adults were re-tested in the same water maze 6 weeks after being initially tested as juveniles. All analyses were conducted using a covariate that removed the group differences in the original task performance. Adult voles from female-biased litters, that had previously learned the task at an older juvenile age (AW), reacquired the same task faster than adults that had previously learned the task at a younger juvenile age (BW). In the adult BW group there was also a significant litter sex-ratio effect such that voles born into a female-biased litter re-acquired the task more slowly than did voles born into a male-biased litter. There were no significant sex or litter sex-ratio effects on spatial learning in the AW group. These results show that adult meadow voles can require a spatial task more quickly if they initially learned the task at an older juvenile age, suggestive of a period of infantile amnesia. In addition, these results indicate that the litter sex-ratio can affect adult spatial performance, suggesting that the relative amount of androgens in utero may influence the development of sexually-dimorphic spatial ability in adulthood.