Immunodetection of apoptosis-regulating proteins in lymphomas from patients with and without human immunodeficiency virus infection.

The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV-associated Hodgkin's disease samples were positive for all markers. For the HIV-related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl-1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs.     

Tissue injury and repair in the rat kidney after exposure to cisplatin or carboplatin

Cisplatin (cis-diamminedichloroplatinum II) has emerged as an anticancer drug of considerable value for the chemotherapy of several human neoplasms. However, this agent often causes renal toxicity, which appears to be the dose-limiting untoward effect. The present animal study was undertaken to compare, with regard to kidney injury and renal tissue repair, cisplatin and carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II), a platinum derivative more recently introduced in clinics. Female Sprague-Dawley rats (four animals per group) were treated ip with cisplatin (4 or 8 mg/kg, delivered in four consecutive daily injections) or carboplatin (40 mg/kg given in one injection) and terminated 4, 7, and 21 days after drug administration. One hour prior to sacrifice, each animal received ip 200 microCi of [3H]thymidine for the measurement of DNA synthesis and cell proliferation (frequency of S-phase cells in renal tissue, determined by histoautoradiography). Cisplatin, particularly at 8 mg/kg, caused severe tubular injury (acute tubular necrosis) culminating in a long-lasting cystic tubular dilatation in the outer stripe of outer medulla. Tubular damage was followed by a sharp proliferative response, indicative of tubular regeneration. However, the proliferative activity was still above basal level at the end of the observation period, suggesting that the tissue repair process had not reached completeness 3 weeks after cisplatin administration. In contrast, carboplatin only induced focal tubular necrosis in proximal tubules. Distal and collecting tubules also showed ultrastructural evidence of hydropic degeneration after exposure to the latter drug. Renal tubular injury associated with carboplatin was followed by a mild proliferative response. From this study, we can infer that carboplatin is less nephrotoxic than cisplatin, but still causes histopathological alterations in renal tissue. Furthermore, the lesser nephrotoxicity of carboplatin has a primary origin and is not due to a more efficient tissue repair reaction.     

An open,randomized single-centre study to compare the efficacy and convenience of follitropin beta administered by a pen device with follitropin alpha administered by a conventional syringe in women undergoing ovarian stimulation for IVF/ICSI

BACKGROUND: A pen device, similar to an insulin pen, has been recently marketed for the administration of follitropin beta in cartridges. A randomized controlled trial was performed to compare the efficacy and convenience of this pen device delivering follitropin beta with a conventional syringe delivering follitropin alpha. METHODS: A total of 200 patients needing IVF/ICSI treatment and willing to self-inject were enrolled in the study. All subjects had ovarian stimulation according to a long protocol and were randomized to the pen or the conventional syringe group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to fill in a daily local tolerance book after each injection. On the day of hCG the patients scored a Visual Analogue Scale (VAS) for pain and convenience. RESULTS: The average duration, total dose of recombinant FSH and number of cumulus oocyte complexes retrieved were 10.8/12.0 days (P = 0.001), 1880/2226 IU (P < 0.001) and 15.2/13.1 respectively in the pen device and conventional syringe groups; the presence of pain after the daily injection was significantly higher in the conventional syringe group (P = 0.027); the visual analogue scale score was similar for pain but significantly more convenient for the pen device (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the pen device and conventional syringe groups. CONCLUSIONS: Self-injection with the pen device is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration.     

Renal expression of Na+-phosphate cotransporter mRNA and protein: Effect of the Gy mutation and low phosphate diet

The X-linked Gy mutation is closely linked, but not allelic, to Hyp and is characterized by rickets, hypophosphatemia, decreased renal tubular maximum for phosphate (Pi) reabsorption (Tm_P) and a specific reduction in renal brush-border membrane (BBM) Na⁺-Pi cotransport. Gy mice, like their normal littermates, respond to a low-Pi diet with an increase in BBM Na⁺-Pi cotransport, but fail to show an adaptive increase in Tm_p. Using an antibody raised against the NH₂ terminal peptide of the rat renal-specific Na⁺-Pi cotransporter (NaPi-2) and a NaPi-2 cDNA probe, we examined the effect of the Gy mutation and low-Pi diet (0.03% Pi) on NaPi-2 protein and mRNA abundance. The reduction in BBM Na⁺-Pi cotransport in Gy mice (51 ± 5% of normal, P < 0.05) was associated with a decrease in NaPi-2 protein (46 ± 12% of normal, P < 0.05) and mRNA abundance (76 ± 5%, P < 0.05). The low-Pi diet elicited a two- to three-fold increase in Na⁺-Pi cotransport in both normal and Gy mice that was accompanied by a large increase in NaPi-2 protein (10.2-fold in normal and 16.9-fold in Gy mice) and a modest increase in NaPi-2 mRNA (1.3-fold in both mouse strains, P < 0.05). The present data demonstrate that (1) the renal defect in BBM Pi transport in Gy mice can be ascribed to a deficit in NaPi-2 protein and mRNA abundance, (2) both normal and Gy mice respond to low Pi with an adaptive increase in NaPi-2 protein that exceeds the increase in Na⁺-Pi cotransport activity and NaPi-2 mRNA, (3) the adaptive increase in NaPi-2 protein and mRNA are not sufficient for the overall increase in Tm_P following Pi restriction. Received: 27 October 1995 / Received after revision: 4 December 1995 / Accepted: 6 December 1995     

MUC1 expression is correlated with nuclear grade and tumor progression in pT1 renal clear cell carcinoma

We studied, by immunohistochemical analysis, the expression of MUC1 and epithelial membrane antigen in 44 stage pT1 renal cell carcinomas (RCCs). Six patients had a metastatic evolution. The percentage of stained cells was determined for each tumor. All tumors and normal adjacent renal parenchyma were stained. In normal kidney, distal convoluted tubules and collecting ducts stained strongly with an apical distribution. In tumors, there was a significant statistical correlation of the MUC1 expression level with the nuclear grade and with tumor progression. High-grade tumors had more stained cells than did low-grade tumors. Metastatic tumors also were more stained than nonmetastatic lesions. By using the Kaplan-Meier method and the log-rank test, we observed that patients with fewer than 10% of stained cells had no metastatic evolution. In contrast, patients with 70% or more stained cells had significantly lower metastasis-free survival rates. We conclude that MUC1 is expressed in RCC and is associated with tumor progression in pT1 RCC.     

Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review

Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published. In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed. The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.     

Autosome and Sex Chromosome Diversity Among the African Pygmy Mice, Subgenus Nannomys (Murinae; Mus)

The African pygmy mice, subgenus Nannomys, constitute the most speciose lineage of the genus Mus with 19 recognized species. Although morphologically very similar, they exhibit considerable chromosomal diversity which is here confirmed and extended by the G-banding analysis of 65 mice from West and South Africa. On the basis of their karyotype and distribution area, the specimens were assigned to at least five species. Extensive differentiation both within and between species was observed that involved almost exclusively Robertsonian translocations, 23 of which are newly described. Two of the rearrangements were sex chromosome-autosome translocations, associated in some cases with partial deletions of the X or Y chromosomes. Several authors have predicted that the highly deleterious effect of this rearrangement would be reduced if the sex and autosomal segments were insulated by a block of centromeric heterochromatin. The C-banding analyses performed showed that among the species carrying X-autosome translocations, one followed the expected pattern, while the other did not. In this case, functional isolation of the sex and autosome compartments must involve other repetitive sequences or genomic traits that require further molecular characterization. Such studies will provide insight into the causes and consequences of the high diversity of sex chromosome rearrangements in this subgenus.     

Growth hormone deficiency in Costello syndrome

We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.