Temporal sequence of mammary intraductal proliferations, ductal carcinomas in situ and adenocarcinomas induced by 1-methyl-1- nitrosourea in rats

An experimental model for mammary carcinogenesis has been described in which intraductal proliferations, ductal carcinomas in situ and adenocarcinomas can be readily detected and the frequency of their occurrence quantified. The objective of the experiment reported in this study was to determine the latency period between carcinogen administration and the occurrence of each of these types of lesion. A total of 150 female Sprague-Dawley rats were injected i.p. with 50 mg 1- methyl-1-nitrosourea (MNU)/kg body wt at 21 days of age. Groups of 30 rats each were killed at 7, 14, 21, 28 and 35 days post-carcinogen. Mammary intraductal proliferations were the first detected lesions and were observed in 20% of the animals at 14 days following carcinogen administration. At 21 days post-carcinogen ductal carcinomas in situ and adenocarcinomas were observed. The number of each type of lesion increased with time post-carcinogen, but the temporal pattern of occurrence was different among lesion types. The pattern of lesion occurrence was consistent with intraductal proliferations being a precursor lesion for ductal carcinomas in situ and adenocarcinomas. Furthermore, the data imply that ductal carcinomas in situ represent one pathway of morphological progression by which intraductal proliferations evolve into invasive carcinomas, but that this lesion type, as currently defined histologically, may not be an obligatory intermediate in morphologic progression. These findings are consistent with emerging evidence of multiple but distinct pathogenetic pathways leading to mammary carcinomas that display different morphological patterns and biological activities.      

Wilms' tumor and gonadal dysgenesis in a child with the 2q37.1 deletion syndrome

Here we report Wilms' tumor, gonadal dysgenesis and a bifid uterus in an 18-month-old female with a terminal deletion of the long arm of chromosome 2 [46, XX, del(2)(q37.1)]. Since Wilms' tumor has been previously reported in the 2q37 deletion syndrome, the present observation raises the question of whether a tumor susceptibility gene maps to chromosome 2q37 and suggests giving consideration to the possible occurrence of Wilms' tumor in the course of disease.     

Stromal growth factor production in irradiated lectin exposed long-term murine bone marrow cultures

Hematopoietic regulatory factors produced by adherent (stromal) cells in long-term murine bone marrow cultures have been investigated. Using an in situ double layer agar overlay system, we demonstrated that exposure of the stromal cells to 1,100-rad irradiation increased their activities in stimulating colony formation of FDC-P1, an interleukin 3 (IL 3)-responsive cell line. The colony-stimulating activities (CSAs) of the irradiated stroma also stimulated normal marrow cells to form granulocyte-macrophage, megakaryocyte, and mixed lineage colonies. Addition of the lectin pokeweed mitogen to the irradiated stroma increased the level of CSAs. The FDC-P1 CSA of the irradiated stroma was inhibited by antibodies directed against murine granulocyte- macrophage colony stimulating factor (GM-CSF) but not by those against murine IL 3. Stromal-derived CSA for marrow cells was also partially blocked by anti-GM-CSF antibodies, probably reflecting the presence of other CSAs such as CSF-1. This latter growth factor has been found to be present in conditioned media from Dexter stroma, but levels are not increased after irradiation or lectin exposure. Partially purified GM- CSF, like IL 3, stimulated FDC-P1 proliferation and granulocyte, macrophage, and megakaryocyte colony formation. These results indicate that the major terminal differentiating hormone elicited by irradiation or lectin exposure of murine marrow stromal cells is GM-CSF. This growth factor, along with CSF-1, can account for the differentiated progeny produced in this system: macrophages, granulocytes, and megakaryocytes.     

Purified interleukin-3 and erythropoietin support the terminal differentiation of hemopoietic progenitors in serum-free culture

We studied the effect of purified interleukin-3 (IL-3) and erythropoietin on colony formation by hemopoietic progenitors in serum- free cultures of spleen cells from 5-fluorouracil (5-FU)-treated mice. In the presence of IL-3 alone, most of the multilineage (three or more lineages) colonies did not contain erythroid cells. However, in the presence of IL-3 and erythropoietin, most of the multilineage colonies contained various numbers of erythroid cells. Replating experiments suggest that IL-3 maintains the growth of the progenitor cells, which could differentiate into erythroid cells. Erythropoietin facilitated the terminal differentiation and amplification of erythroid cells, although it did not sustain the growth of multipotential stem cells. Single-cell transfer experiments demonstrate that IL-3 supported the late stages of differentiation of neutrophils, macrophages, eosinophils, and megakaryocytes in the absence of lineage-specific factors. Therefore, IL-3 supports the differentiation of multilineage hemopoietic progenitors, and the terminal differentiation of most hemopoietic lineages, with the exception of the erythroid lineage.     

Tinidazole in treatment of amoebic liver abscess in children

Tinidazole as a single drug therapy given in a single dose daily for 5 or 3 days was put to rigorous test in malnourished children. Of 25 children with amoebic liver abscess, 23 were cured. The 2 remaining cases required surgical drainage followed by other amoebicides, one subsequently dying from complicating bronchopneumonia.     

Molecular internalization of a region of myelin basic protein

The conformation of myelin encephalitogenic or basic protein (BP) was investigated with a double-antibody radioimmunoassay by studying the reaction of BP or its fragments with antibodies produced in two rabbits against peptide 43-88 linked to rabbit serum albumin. Both antisera reacted well with peptide 43-88 but showed little or no reaction with BP. Absorption of these antisera with a BP-immunoadsorbent did not remove the antibody activity against peptide 43-88. Within the region of peptide 43- 88 it was shown that peptides 68-88 and 79-88 gave an equivalent or better reaction than peptide 43-88, whereas peptides 43-67 and 64-73 had very little reactivity. In the BP fragments containing region 43-88, peptide 1-88 showed the best reactivity, peptide 20-166 showed minimal reactivity, while peptide 1-115 showed none. These data document the internal position of at least a portion of peptide 43-88 and all of residues 79-88 in the BP molecule. The much greater reactivity of peptide 1-88 as compared to peptide 1-115 suggests that the region or a portion of the region of BP containing residues 89- 115 participates in the conformational alignment of BP restricting access to peptide 79-88. After absorption with BP, neither of the antisera prepared to peptide 43-88 reacted with PNS myelin in fixed tissue sections but continued to react with CNS myelin in similarly treated sections. The present findings demonstrate the need to consider the role of shielded antigenic determinants in the investigation of antigens or of immune responses.     

Prediction of treatment response in psoriasis with measurement of serum levels of adalimumab,etanercept, and antidrug antibodies: a pilot study

BackgroundA substantial proportion of patients with psoriasis do not respond or lose initial response to tumour necrosis factor antagonists. This may partly be attributable to development of an immunogenic antibody response which causes subtherapeutic drug levels because of the clearance of drug-antidrug complexes. The aim of this study was to investigate the association between serum drug (adalimumab and etanercept) levels, antidrug antibodies, and clinical response in a cohort of psoriasis patients.MethodsIn a single-centre cohort of 56 adults with psoriasis initiated on adalimumab or etanercept between 2009 and 2011, drug and antidrug antibody levels were measured with a commercially available ELISA at the patients’ routine clinic reviews (4, 12, and 24 weeks of treatment and the last available observation). Responders were defined as having a 75% reduction in psoriasis area and severity index from baseline (PASI 75) within 6 months of treatment, or physician's global score of clear or nearly clear. Non-responders were defined as not achieving a 50% reduction in PASI from baseline (PASI 50) within 6 months or having a loss of PASI 50 treatment response.FindingsAfter 4 weeks of therapy, adalimumab levels were significantly higher in responders than in non-responders (median 5·00 μg/mL [IQR 4·30–5·00] vs 0·12 μg/mL [0·10–1·79], p=0·003) and these higher levels were sustained at 12 and 24 weeks. Anti-adalimumab antibodies were detected in 25% of non-responders (2/8 patients, mean follow-up 22·5 weeks) and not in any responders (n=23, mean follow-up 26·1 weeks). There was no significant association between etanercept levels and clinical response at 4 weeks (median 2·94 μg/mL [IQR 0·78–3·68] vs 1·40 [0·82–2·12], p=0·317), and no anti-etanercept antibodies were detected.InterpretationAdalimumab drug level monitoring at 4 weeks may be useful in predicting treatment response, in contrast to etanercept drug levels. The majority of adalimumab non-responders did not have antidrug antibodies; however, lack of serum trough levels and assay limitations may have underestimated their prevalence. Larger studies are required to investigate other factors contributing to low drug levels and to assess the usefulness of these drug and antidrug assays in personalising therapy in psoriasis.FundingNational Institute for Health Research.