Ultrastructural localization of blood group antigen A in normal and neoplastic urothelium

The subcellular distribution of the blood group antigen A in the transitional epithelium of the urinary tract and its neoplastic growths was studied using transmission immuno-electronmicroscopy. Sixty-five tissue specimens from 50 blood group A1 patients were processed according to an immunogold procedure which was optimized for preservation of both antigen and ultrastructure. The reactions were stronger in the glycocalyx of the luminal surfaces and at the interdigitating cytoplasmic processes of the cells. In the intracellular compartment the reactions were associated with tubulovesicular membrane-bound structures and with the Golgi complexes. Secretory products, intra- or extra-cellular, were also positive. The greatest variability was noted in the cell surface reactions, which were positive in 88% of normal but only 41% of neoplastic urothelial specimens. An inverse correlation was found between malignant behaviour and cell surface, but not intracellular, reactions. We conclude that, in transitional cell carcinomas, there is a quantitative defect in the processing of substance A which affects predominantly the cell surface component and may involve either the transport-insertion steps, the plasma membrane-associated glycosyltransferases or internalization of blood group antigen A.     

Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset.

Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.     

Leukemia clusters around nuclear facilities in Britain

He bas been retained for the defense by British Nuclear Fuelsplc in two suits in which leukemia and non-Hodgkin's lymphoma have been alleged to result from radiation exposures due to the operation of the nuclear reprocessing plant at Sellafield. This paper has been sent to the senior authors of the papers reporting clusters of leukemia or other malignancy in the vicinity of nuclear facilities in Britain and their comments invited. Subject to considerations of space and CCC style, these comments will be published as submited.     

Phosphorylation of neurofilament H subunit as related to arrangement of neurofilaments

To find out what causes differences in phosphorylation states in neurofilaments (NF), we selected two types of dendrite, one provided with very few NFs (Purkinje cell) and the other with relatively many (anterior horn cell). We examined these with four monoclonal antibodies selected by the Western blot analysis, two (NE14 and SMI31) recongnizing only phosphorylated, SMI32 recognizing only nonphosphorylated, and N52 recognizing phosphorylation-independent epitopes of NF-H. The immunoperoxidase labeling of dendrites, and also of perikarya, in both neurons was detectable with all four antibodies. After the tissue was treated with Triton X-100, the labeling was still detectable with SMI32 or N52, but undetectable with NE14 and SMI31. The brain homogenate Triton-extracted supernatant after centrifugation at 100,000g for 1 hr showed the staining of NE14, SMI31, and N52 but not that of SMI32. In Purkinje cell dendrite and perikaryon, NFs always appeared singly. In the immunogold labeling, they were labeled only with SMI32 or N52. Labeling by NE14 or SMI31 was distributed throughout the cytoplasm and hardly associated with NFs. In the anterior horn cell dendrite and perikaryon, NFs appeared both single and in bundles. They were predominantly labeled with SMI31 or N52 when they were single, and with NE14, SMI31, or N52 when they were bundled. Even in one NF, portions that appeared single were labeled mostly with SMI32 or N52, while the remainder, to which other NFs approached closely, were labeled mostly with NE14, SMI31, or N52. Thus, when NFs appear singly, NF-H in their projections or cross-bridges with other organelles is not phosphorylated, while when NFs are bundled, NF-H is phosphorylated in crossbridges between NF core filaments. These data may explain why the NF-H is heavily phosphorylated in axons, where NFs are abundant, and not in dendrites and perikarya, where NFs are sparse. Wiley-Liss, Inc.     

Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy

: A rising prostate specific antigen (PSA) following treatment for adenocarcinoma of the prostate indicates eventual clinical failure, but the rate of rise can be quite different from patient to patient, as can the pattern of clinical failure. We sought to determine whether the rate of PSA rise could differentiate future local versus metastatistic failure.

: Two thousand six hundred sixty-seven PSA values from 400 patients treated with radiotherapy for localized adenocarcinoma of the prostate were analyzed with respect to PSA patterns and clinical outcome. Patients had received no hormonal therapy or prostate surgey and had ?4 PSA values post-treatment PSA rate of rise, determined by the slope of the natural log, was classified as gradual (< 0.69 log (ng/ml)/year, or doubling time (DT) > 1 year), moderate (0.69-1.4 log (ng/ml)/year, or DT 6 months-1 year), or rapid [>1.4 log (ng/ml)/year, or DT < 6 months].

: SIxty-one percent of patients had non-rising PSA following treatment; 25% of patients with rising PSA developed clinical failure, and 93% of patients with clinical failure had rising PSA. The rate of rise discerned different clinical failure patterns. Local failure occurred in 23% of patients with moderate rate of rise versus 7% with gradual rise (p = 0.0001). Metastatic disease developed in 46% of those with rapid versus 8% with moderate rise (p < 0.0001). By multivariate analysis, in addition to rate of rise, PSA nadir and rate of decline predicted local failure; those with post-treatment nadir of 1–4 ng/ml were five times more likely to experience local failure than nadir < 1 ng/ml (p = 0.0002). Rapid rate of rise was the most significant independent predictor of metastastic failure.

: The rate of PSA rise following definitive radiotherapy can predict clinical failure patterns, with a rapidly rising PSA indicating metastatic recurrence and moderately rising PSA local recurrence. This information could potentially dirent therapy; if the rise predicts metastatic failure hormonal therapy could be cosidereed, while aggressive salvage therapy may benefit subclinical local recurrence identified by a moderate rate of PSA rise.     

A new monoclonal antibody which binds to the cytoplasm of large cell lymphomas.

We reported a new monoclonal antibody, designated FUB-1, reacting with normal and neoplastic large lymphoid cells. FUB-1 was produced using a Burkitt's lymphoma cell line (HBL-5) as an immunogen. Its immunoglobulin subtype was IgM. The determinant was not on the surface but in the cytoplasm. Western blotting analysis revealed that the molecular weight of the antigen was 52,000 dalton. In the normal lymphoid tissue, FUB-1 reacted with large lymphoid cells, but not with small or medium-sized lymphoid cells or plasma cells. In addition, the FUB-1 antigen was not found in resting cells in the peripheral blood (PB), but it was induced on mononuclear cells of PB by addition of PWM or PMA. In the B-cell lymphomas tested, FUB-1 reacted with small cleaved cell lymphomas (3/12), large cell lymphomas (7/10), Burkitt's lymphomas (4/4) and immunoblastic lymphomas (2/2), but not with small cell lymphomas (0/3) or intermediate lymphocytic lymphomas (0/8). These findings indicate that the FUB-1 antigen appears to be expressed on normal lymphoid cells during blastoid transformation and on neoplastic large lymphoid cells. FUB-1 also reacted with normal glandular epithelium and various adenocarcinomas. FUB-1 may be useful to investigate the mechanism of in vitro blastoid transformation or activation of lymphoid cells.     

Significance of the BTA Test in Bladder Cancer: A Multicenter Trial

Background :
The BTA test is a latex agglutination assay for the qualitative detection in the urine of analytes that are associated with bladder tumor. We compared the results of the BTA test with those of voided urine cytology (VUC) in patients with bladder cancer.
Methods :
A multicenter trial was performed at 6 institutions. A total of 132 patients with histologically diagnosed bladder cancer were enrolled. Urine samples were split for BTA and VUC testing.
Results :
The sensitivities of the BTA test and VUC were 57.6% and 37.9%, respectively; this difference was significant ( P < 0.001). The BTA test had much higher sensitivity for small, solitary, superficial tumors than did VUC.
Conclusion :
The BTA test is simple to perform, gives rapid results, and is far more sensitive than VUC for detection of bladder cancer. The BTA test has the potential to become an additional tool for detecting bladder cancer.     

The relationship of proliferating cell density at the invasive tumour front with prognostic and risk factors in human oral squamous cell carcinoma

BACKGROUND: We hypothesise that the density of proliferating cells at the invasive tumour front (ITF) has a positive relationship with prognostic and risk factors in human oral squamous cell carcinoma (SCC). METHODS: Tissues from 47 human oral SCC specimens were collected and stained with a monoclonal antibody directed against the Ki-67 antigen using a horseradish peroxidase based two-step immunostaining method. Counting was performed on two parallel sections at the ITF using an image analyser. The Ki-67 labelling index (LI) was determined by measuring the number of nuclei/mm(2) of epithelium. RESULTS: Our results show that the density of proliferating cells is related to clinical staging, with advanced stage of disease having a significantly higher Ki-67 LI compared with early stage of disease (2111 +/- 905 vs. 1908 +/- 913; P = 0.03). Importantly, this study shows that tumours that have metastasised have a significantly higher Ki-67 LI than tumours where distant metastasis was not detected (3257 +/- 650 vs. 1966 +/- 881; P < 0.0001). CONCLUSIONS: Cell proliferation, as measured by the Ki-67 LI at the ITF, has a positive relationship with clinical staging, tumour thickness, smoking status of the patient and alcohol consumption. Further, we suggest that a multicenter study with a large cohort of patients is indicated to fully elucidate whether cell proliferation at the ITF is directly related to patient survival.     

Absence of donor-type major histocompatibility complex class I antigen-bearing microglia in the rat central nervous system of radiation bone marrow chimeras

Localization of bone marrow-originated cells in the central nervous system (CNS) of the rat was investigated by using bone marrow chimeras. In order to do this, Lewis rats which carry major histocompatibility complex (MHC) class I antigens haplotype 1 (RT1.Al) were reconstituted with (Lew X PVG)F1 (RT1.Al/c) bone marrow cells after lethal irradiation. Transferred bone marrow cells were detected by immunohistochemical staining using a monoclonal antibody, OX27, specific for haplotype c of rat MHC class I antigens (RT1.Ac). The spleen and thymus of chimeric rats were fully reconstituted with transferred F1 cells 4 weeks after bone marrow transplantation. At this stage, mononuclear cells in the subarachnoid space of the CNS expressed OX27 antigen indicating that they were of bone marrow origin. A few OX27-positive blood cells were scattered in the CNS parenchyma 4-12 weeks after reconstitution. Ramified microglia, however, remained OX27-negative. Bone marrow-derived microglia were not observed throughout the period of examination until 24 weeks. In addition, experimental allergic encephalomyelitis (EAE) was induced in chimeric rats in order to augment the expression of MHC class I antigens on microglia. Even under this condition, no OX27-positive microglia were observed. Taken together, ramified microglia might be of neuroectodermal origin and there is little possibility that the microglia are derived from the bone marrow. However, if the ramified microglia are derived from blood cells, the microglia may be expected to have characteristic cell kinetics from the following points: (1) the precursor cells of the microglia may enter the CNS only at the perinatal stage; and (2) even under the condition in which lymphocytes and macrophages enter the CNS as observed in EAE, the precursor cells of the microglia are not supplied from the blood.