DESOXYCORTICOSTERONE ACETATE : THE POTENTIATION OF ITS ACTIVITY BY SODIUM CHLORIDE

1. Desoxycorticosterone acetate (DCA) and NaCl, in the dosage employed in normal rats, caused renal and cardiac hypertrophy, characteristic changes in the renal tubular epithelium, atrophic changes in the subcapsular zone of the adrenal cortex, and serum electrolyte changes characterized by a rise in sodium and fall in potassium. 2. In rats rendered nephritic with a rabbit anti-rat-kidney serum, the same regimen caused similar changes. In addition, DCA given concurrently with NaCl greatly intensified the nephritic process and gave rise to striking arterial hypertension. 3. A diet, virtually sodium-free, administered to normal and nephritic rats receiving daily injections of DCA abolished or reduced to a minimum the effects of this steroid; i.e., a liberal ingestion of NaCl was essential for the potentiation of the action of DCA. 4. The addition of KCl to the drinking water of rats receiving DCA and NaCl tended to correct the depression of the level of potassium in the serum, but had no effect upon the hypertension in nephritic animals nor upon the anatomical lesions. 5. The mechanism by which the sodium ion potentiates the activity of DCA has not been established.     

Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance.

OBJECTIVE: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors ('statins'). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. METHODS: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients' representation of the doctor-patient interaction and physicians' attribution, when patients report perceived ADRs. RESULTS: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10(-8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. CONCLUSIONS: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs.     

Nitrogen metabolite repression in Hansenula polymorpha: the nmr1-1 mutation

In Hansenula polymorpha, the expression of the nitrate assimilation metabolism is subjected to re-pression-derepression mechanisms triggered by reduced nitrogen compounds such as ammonium. To further our knowledge on the genetics of these regulatory mechanisms, a screening strategy for the isolation of mutants exhibiting nitrate reductase activities in the presence of reduced nitrogen compounds was set up. This strategy makes use of a nitrate+ methylamine mutant to isolate suppressors of its characteristic phenotype--the inability to grow on a nitrate plus methylamine medium. A total of 21 regulatory mutants were isolated with this strategy and grouped into five complementation classes. One of these mutants harbours the recessive mutation nmr1-1, which determines the derepression of the nitrate assimilation metabolism in media containing nitrate plus a repressing nitrogen source (ammonium, methylamine, glutamate, urea or aspartate). Therefore, nitrate reductase activities are detected in the presence of reduced nitrogen sources, as long as nitrate is also in the medium. Our data indicate that the processes of repression-derepression and induction are controlled by elements which are distinct. Furthermore, they indicate that Nmrlp is involved in repressing circuits which control not only the nitrate-utilisation pathway, but also other pathways which are necessary for the utilisation of nitrogen sources alternative to ammonium. Of considerable interest is the fact that our nmr1-1 mutant is derepressed in glutamate but not in glutamine. Since the phenotype of this mutant seems to exclude a glutamine synthetase defect, we suggest that glutamate (or a derivative of this compound) might be involved in signalling nitrogen metabolite repression in H. polymorpha. Thus, in H. polymorpha, a glutamine-dependent circuit may co-exist with a glutamine-independent circuit.     

Combined cytotoxic activity of an infectious,but non‐replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells

Malignant melanoma is an aggressive tumour of the skin with increasing incidence, frequent metastasis and poor prognosis. At the same time, it is an immunogenic type of cancer with spontaneous regressions. Most recently, the tumoricidal effect of plasmacytoid dendritic cells (pDC) and their capacity to overcome the immunosuppressive tumour microenvironment are being investigated. In this respect, we studied the effect of the infectious, but replication‐deficient, herpes simplex virus 1 (HSV‐1) d106S vaccine strain, which lacks essential immediate early genes, in pDC co‐cultures with 11 melanoma cell lines. We observed a strong cytotoxic activity, inducing apoptotic and necrotic cell death in most melanoma cell lines. The cytotoxic activity of HSV‐1 d106S plus pDC was comparable to the levels of cytotoxicity induced by natural killer cells, but required only a fraction of cells with effector : target ratios of 1 : 20 (P < 0·05). The suppressive activity of cell‐free supernatants derived from virus‐stimulated pDC was significantly neutralized using antibodies against the interferon‐α receptor (P < 0·05). In addition to type I interferons, TRAIL and granzyme B contributed to the inhibitory effect of HSV‐1 d106S plus pDC to a minor extent. UV‐irradiated viral stocks were significantly less active than infectious particles, both in the absence and presence of pDC (P < 0·05), indicating that residual activity of HSV‐1 d106S is a major component and sensitizes the tumour cells to interferon‐producing pDC. Three leukaemic cell lines were also susceptible to this treatment, suggesting a general anti‐tumour effect. In conclusion, the potential of HSV‐1 d106S for therapeutic vaccination should be further evaluated in patients suffering from different malignancies.     

Bone marrow fibroblasts overexpress miR-27b and miR-214 in step with multiple myeloma progression,dependent on tumour cell-derived exosomes

Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR-27b-3p and miR-214-3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR-27b-3p and miR-214-3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti-apoptotic factor MCL1, suggesting that miR-27b-3p and miR-214-3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR-27b-3p and miR-214-3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell-derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR-27b-3p and miR-214-3p in MGUS fibroblasts co-cultured with myeloma cell-derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS-to-myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.