Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients.

OBJECTIVE: To investigate prevalence and recovery of olfactory dysfunction (OD) in COVID-19 patients according to the disease severity. METHODS: From 22 March to 3 June 2020, 2581 COVID-19 patients were identified from 18 European hospitals. Epidemiological and clinical data were extracted at baseline and within the 2-month post-infection. RESULTS: The prevalence of OD was significantly higher in mild form (85.9%) compared with moderate-to-critical forms (4.5-6.9%; P = 0.001). Of the 1916 patients with OD, 1363 completed the evaluations (71.1%). A total of 328 patients (24.1%) did not subjectively recover olfaction 60 days after the onset of the dysfunction. The mean duration of self-reported OD was 21.6 ± 17.9 days. Objective olfactory evaluations identified hyposmia/anosmia in 54.7% and 36.6% of mild and moderate-to-critical forms, respectively (P = 0.001). At 60 days and 6 months, 15.3% and 4.7% of anosmic/hyposmic patients did not objectively recover olfaction, respectively. The higher baseline severity of objective olfactory evaluations was strongly predictive of persistent OD (P < 0.001). CONCLUSION: OD is more prevalent in mild COVID-19 forms than in moderate-to-critical forms. OD disappeared in 95% of patients regarding objective olfactory evaluations at 6 months.

Farnesoid X receptor as marker of osteotropism of breast cancers through its role in the osteomimetism of tumor cells.

BACKGROUND: The skeleton is the first and most common distant metastatic site for breast cancer. Such metastases complicate cancer management, inducing considerable morbidities and decreasing patient survival. Osteomimetism is part of the complex process of osteotropism of breast cancer cells. Recent data indicate that Farnesoid X Receptor (FXR) is involved in the transformation and progression of breast cancer. METHODS: The expression of FXR, Runt-related transcription factor 2 (RUNX2) and bone proteins were evaluated on two tumor cell lines (MCF-7 and MDA-MB-231) by immunohistochemistry, immunofluorescence and western blotting and quantified. RESULTS: In a series of 81 breast cancer patients who developed distant metastases, we found a strong correlation between FXR expression in primary breast tumors and the development of bone metastases, especially in patients with histological grade 3 tumors. In in vitro studies, FXR activation by Chenodeoxycholic acid (CDCA) increased the expression of numerous bone proteins. FXR inhibition by lithocholic acid and z-guggulsterone decreased bone protein expression. Short Hairpin RNA (ShRNA) against FXR validated the involvement of FXR in the osteomimetism of breast cancer cells. CONCLUSION: Our experimental results point to a relationship between the expression of FXR in breast cancer cells and the propensity of these tumor cells to develop bone metastases. FXR induces the expression of RUNX2 which itself causes the synthesis of bone proteins by tumor cells.

SNPs at miR-155 binding sites of TYRP1 explain discrepancy between mRNA and protein and refine TYRP1 prognostic value in melanoma.

BACKGROUND: We previously demonstrated an inverse correlation between tyrosinase-related protein 1 (TYRP1) mRNA expression in melanoma metastases and patient survival. However, TYRP1 protein was not detected in half of tissues expressing mRNA and did not correlate with survival. Based on a study reporting that 3' untranslated region (UTR) of TYRP1 mRNA contains two miR-155-5p (named miR-155) binding sites exhibiting single-nucleotide polymorphisms (SNPs) that promote (matched miRNA-mRNA interaction) mRNA decay or not (mismatched), we aimed to investigate the role of miR-155 in the regulation of TYRP1 mRNA expression and protein translation accounting for these SNPs. METHODS: The effect of miR-155 on TYRP1 mRNA/protein expression was evaluated in two melanoma cell lines harbouring matched or mismatched miR-155-TYRP1 mRNA interaction after transfection with pre-miR-155. In parallel, 192 skin and lymph node melanoma metastases were examined for TYRP1 mRNA/protein, miR-155 and SNPs and correlated with patient survival. TYRP1 mRNA, SNPs at its 3'UTR and miR-155 were analysed by RT-qPCR, whereas TYRP1 protein was evaluated by western blot in cell lines and by immunohistochemistry in metastatic tissues. RESULTS: The miR-155 induced a dose-dependent TYRP1 mRNA decay and hampered its translation into protein in the line with the 'match' genotype. In melanoma metastases, TYRP1 mRNA inversely correlated with miR-155 expression but not with TYRP1 protein in the 'match' group, whereas it positively correlated with protein but not with miR-155 in the 'mismatch' group. Consequently, in the latter group, TYRP1 protein inversely correlated with survival. CONCLUSION: Polymorphisms in 3'UTR of TYRP1 mRNA can affect TYRP1 mRNA regulation by miR-155 and its subsequent translation into protein. These SNPs can render TYRP1 mRNA and protein expression nonsusceptible to miR-155 activity and disclose a prognostic value for TYRP1 protein in a subgroup of melanoma patients. These data support the interest in the prognostic value of melanogenic markers and propose TYRP1 to refine prognosis in patients with advanced disease.

Tyrosinase-related protein 1 mRNA expression in lymph node metastases predicts overall survival in high-risk melanoma patients.

BACKGROUND: Clinical outcome of high-risk melanoma patients is not reliably predicted from histopathological analyses of primary tumours and is often adjusted during disease progression. Our study aimed at extending our previous findings in skin metastases to evaluate the prognostic value of tyrosinase-related protein 1 (TYRP1) in lymph node metastases of stages III and IV melanoma patients. METHODS: TYRP1 mRNA expression in 104 lymph node metastases was quantified by real-time PCR and normalised to S100 calcium-binding protein B (S100B) mRNA expression to correct for tumour load. TYRP1/S100B ratios were calculated and median was used as cutoff value. TYRP1/S100B mRNA values were correlated to clinical follow-up and histopathological characteristics of the primary lesion. RESULTS: A high TYRP1/S100B mRNA ratio significantly correlated with reduced disease-free (DFS) and overall survival (OS; Cox regression analysis, P=0.005 and 0.01, respectively), increased Breslow thickness (Spearman's rho test, P<0.001) and the presence of ulceration (Mann-Whitney test, P=0.02) of the primaries. Moreover, high TYRP1/S100B was of better prognostic value (lower P-value) for OS than Breslow thickness and ulceration. Finally, it was well conserved during disease progression with respect to high/low TYRP1 groups. CONCLUSION: High TYRP1/S100B mRNA expression in lymph node metastases from melanoma patients is associated with unfavourable clinical outcome. Its evaluation in lymph node metastases may refine initial prognosis for metastatic patients, may define prognosis for those with unknown or non-evaluable primary lesions and may allow different management of the two groups of patients.

TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome.

BACKGROUND: Clinical outcome of patients with high-risk melanoma cannot be reliably predicted on the basis of classical histopathological examination. Our study aimed to determine in melanoma metastases a gene expression profile associated with patient survival, and to identify and validate marker(s) of poor clinical outcome. METHODS: Skin and lymph node metastases from melanoma patients (training population) were used to identify candidate prognostic marker(s) based on DNA microarray analysis. Additional skin metastases (validation population) were used to assess the prognostic value of the first ranked gene by real-time PCR. RESULTS: We performed microarray analysis in the training population and generated a list of 278 probe sets associated with a shorter survival. We used the first ranked gene, tyrosinase-related protein 1 (TYRP1), further measured its expression in the validation population by real-time PCR and found it to be significantly correlated with distant metastasis-free survival (DMFS), overall survival (OS) and Breslow thickness. We also found that it was fairly well conserved in the course of the disease regardless of the delay to metastasis occurrence. Finally, although Tyrp1 protein (immunohistochemistry (IHC)) was only detected in about half of the samples, we showed that its expression also correlated with Breslow thickness. CONCLUSION: Our data indicate that TYRP1 mRNA expression level, at least in skin metastases, is a prognostic marker for melanoma, and is particularly useful when prognostic pathology parameters at the primary lesion are lacking. Its conserved expression further supports its use as a target for therapy.

Increased Dickkopf-1 expression in breast cancer bone metastases.

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.

Lupus-like phototriggering in a young woman with benign summer light eruption.

We report the case of a young woman with a single history of benign summer light eruption (BSLE) who developed delayed onset annular lupus-like lesions triggered by a polychromatic phototest, 6 weeks after the irradiation. BSLE of French authors is an idiopathic photodermatosis that corresponds to the minor form of polymorphic light eruption (PLE) of Anglo-Saxon authors. This patient may develop a true lupus erythematosus in the future as indicated by this lupus-like phototriggering and in view of the high prevalence of PLE in lupus patients.

Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.

Tamoxifen is the standard first-line endocrine therapy for breast cancer, but recent data indicate that it is likely to be replaced by the effective aromatase inhibitors (AIs), in both the metastatic and adjuvant settings. Aromatase inhibitors induce complete oestrogen deprivation that leads to clinically significant bone loss. Several ongoing or planned trials combine AIs with bisphosphonates, even more so that recent data reveal that clodronate may reduce the incidence of bone metastases and prolong survival in the adjuvant setting. Bisphosphonates can inhibit breast cancer cell growth in vitro, but they have never been studied in steroid-free medium (SFM), an in vitro environment that mimics the effects of AIs in vivo. Quite surprisingly, in SFM, clodronate stimulated MCF-7 cell growth in a time- and dose-dependent manner by up to two-fold (crystal violet staining assay), whereas it had no mitogenic activity in complete medium. The bisphosphonate similarly increased the proliferation of IBEP-2 cells, which also express a functional oestrogen receptor (ER), while it weakly inhibited the growth of the ER-negative MDA-MB-231 cells. Expectedly, 17beta-oestradiol stimulated the growth of MCF-7 and IBEP-2 cells cultured in SFM, and had no effect on MDA-MB-231 cells. Moreover, partial (4-OH-tamoxifen) and pure antioestrogens (fulvestrant, ICI 182,780), in combination with clodronate, completely suppressed the mitogenic effect of the bisphosphonate, suggesting that it was mediated by an activation of ER. In accordance with this view, clodronate induced ER downregulation, weakly increased progesterone receptor expression, and stimulated the transcription of an oestrogen-responsive reporter gene. In conclusion, we report a previously unknown stimulatory effect of clodronate on MCF-7 cells grown in SFM, in vitro conditions that are potentially relevant to the use of AIs for breast cancer. Moreover, our data suggest that ER is involved in these effects of clodronate on cancer cell growth.

Extracellular calcium downregulates estrogen receptor alpha and increases its transcriptional activity through calcium-sensing receptor in breast cancer cells.

Skeleton is the most common organ targeted by breast cancer cells, especially from estrogen receptor alpha (ER)-positive neoplasms. Metastatic cells can stimulate directly or indirectly osteoclast-mediated bone resorption. Tumor-induced osteolysis is often extensive and leads to the release of large quantities of calcium. Metastatic cancer cells can be thus exposed to high calcium concentrations (40 mM has been reported at the resorption site). However, the effects of Ca2+ on breast cancer cells have been minimally examined. We showed that 20-mM extracellular Ca2+ induced a downregulation of ER protein in MCF-7 cells and caused ER-mediated transactivation of a reporter gene by 55 +/- 10% (mean +/- SD) in MVLN cells (MCF-7 cells stably transfected with ERE and luciferase reporter gene). Moreover, 3 mM Ca2+ increased progesterone receptor (PgR) expression by 45 +/- 8%. Mg2+ tested at up to 20 mM did not exert any effects, while 17beta-estradiol downregulated ER, transactivated the reporter gene, and enhanced PgR expression. The pure antiestrogen ICI 182,780 was able to abrogate the transactivation of the reporter gene and the increase in PgR levels induced by Ca2+, indicating that Ca2+ may exert a weak and specific estrogenic effect in MCF-7 cells. Ca2+ effects on ER probably start at the cell membrane level since a large Ca2+ influx caused by the ionophore A23187 failed to activate ER. We have thus studied the involvement of the membrane calcium-sensing receptor (CaR) that is known to be expressed notably in MCF-7 cells. We first tested the effects of a specific activator of CaR. Exposure to 10(-4) M calcimimetic NPS R-467 mirrored the changes observed with extracellular Ca2+ by inducing a marked decrease in ER protein levels, increasing the transcriptional activity of ER (67 +/- 12%) and stimulating PgR expression (41 +/- 4%). As expected, the NPS S-467 isomer was less effective. Furthermore, a highly selective CaR antagonist partly suppressed the downregulation of ER as well as transactivation of the reporter gene induced by Ca(2+). Our results suggest that the effects of extracellular Ca2+ on ER expression and activity are mediated, at least in part, by the CaR. In summary, calcium released during the process of metastatic bone destruction could modulate the functions of the estrogen receptor, a key receptor involved in breast cancer cells growth and function, and thus participate in the pathogenesis of tumor-induced osteolysis.

Effect of low dose irradiation on estrogen receptor level in MCF-7 breast cancer cells.

Exposure of MCF-7 cells to single and/or repeated low gamma-ray doses (0.5 to 8 Gy) resulted in a decrease in the capacity of these cells to concentrate tritiated estradiol ([3H]E2) (reduction of the number of binding sites). The decrease in the [3H]E2-binding capacity was higher than the survival rate, indicating that it could not be ascribed to cell death. Moreover, such low irradiation doses failed to similarly affect the specific incorporation of [3H]ORG 2058, even when the progesterone receptor was induced by E2, a finding that rejects the hypothesis of a nonspecific effect on all steroid hormone receptors. This loss of [3H]E2 binding was reflected by the elimination of the estrogen receptor alpha (ER) when the latter was assessed by immunocytochemistry. However, additional immunochemical studies (Western blot data) performed on cell extracts under denaturing conditions failed to show any similar elimination of the ER peptide, suggesting that the loss of E2-binding capacity would be relevant to subtle changes in the ER structure and/or ER-associated proteins. The loss of binding capacity, produced by a 3-Gy irradiation, failed to decrease the sensitivity of the cells to E2, since progesterone receptor induction and growth stimulation were maintained. Insufficient ER diminution may explain this observation.

Fixed solar urticaria to visible light successfully treated with fexofenadine.

Fixed solar urticaria (FSU) represents an uncommon form of urticaria related mostly to radiation from the ultraviolet (UVB, UVA) and visible spectrum. The exact pathomechanism has so far remained unknown. A 52-year-old woman with a 3-year history of urticated eruptions limited to certain skin areas is presented. Photobiological testing revealed positive reactions limited to the visible light range. The induced lesions appeared only in originally affected skin sites. The particular distribution of whealing supports the concept of specific alteration of mast cells in well defined areas. The clinical findings and the results of phototesting lead to the diagnosis of FSU to visible light. It is recommended to carry out phototesting in patients with FSU in the originally affected skin areas, usually covered and protected by the patient, to avoid false-negative results. Fexofenadine given in the conventional dosage can prevent recurrences and represents a successful treatment measure when dealing with this peculiar form of solar urticaria.

[Photoaggravated contact allergy and contact photoallergy caused by ketoprofen: 19 cases]. / Allergies de contact photoaggravées et photoallergies de contact au kétoprofène: 19 cas.

INTRODUCTION: Between September 1994 and September 1999, we observed 19 cases of photoaggraved contact allergy or contact photoallergy to ketoprofen (non steroidal anti-inflammatory derived from arylpropionic acid). We present a clinical and photobiological retrospective study of these 19 cases with investigation of cross-reactivity between benzophenone-containing molecules. PATIENTS AND METHODS: On clinical level, we investigated the type of eruption, the delay of appearance, the initial area of eruption and areas of diffusion. Phototesting included patchtests and photopatchtests performed with the gel containing ketoprofen (17 patients), ketoprofen 2 p. 100 petrolatum (14 patients), fenofibrate 10 p. 100 petrolatum and 10 p. 100 water (15 patients), 3 benzophenones (19 patients): oxybenzone 10 p. 100 petrolatum, mexenone 2 p. 100 petrolatum, sulisobenzone 10 p. 100 petrolatum and the other arylpropionic derivatives (4 patients). Three identical series were applied: one was irradiated with 3/4 polychromatic minimal erythematosus dose, a second was irradiated with UVA 13 J/cm2 until January 1997, then 5 J/cm2, the third series was not irradiated (control series). RESULTS: Patients were 9 men and 10 women with an average age of 41.2 years. The type of eruption was an eczema. The delay of appearance of the eruption was one day to 3 months. For 10 patients, the delay was between 4 and 18 days. The eruption was localized to the application area in 1 case, to the application area then to the same contralateral area in 3 cases, to the application area then to all photoexposed areas in 13 cases, to the application area then to the photoexposed areas and then to non-sun-exposed areas in 2 cases. Evolution showed prolonged photosensitivity in 3 cases after withdrawal of the contact and the contact photoallergy to ketoprofen was severe. Gel-containing ketoprofen photopatchtests showed 9 photoaggravated contact allergy, 6 contact photoallergy and 2 contact allergy. Ketoprofen photopatchtests showed 12 contact photoallergy and 2 photoaggraved contact allergy. Tiaprofenic acid photopatchtests were positive in all performed cases (4/4), but photopatchtests with the other arylpropionic derivatives, without benzophenone structure, were negative. Fenofibrate photopatchtests were always positive (15/15). Benzophenones photopatchtests only showed 4 cases of contact photoallergy to oxybenzone (4/19). In 68 p. 100 of cases, patients presented a contact allergy or photoallergy to fragrances. CONCLUSIONS: This study shows the actual frequency of contact allergy and contact photoallergy to ketoprofen with a higher frequency of contact photoallergy. Thus, photopatchtesting is essential. In cases of contact photoallergy to ketoprofen, ketoprofen, tiaprofenic acid but not the other arylpropionic derivatives, fenofibrate and benzophenones have to be withdrawn.

Evidence of an estrogen receptor form devoid of estrogen binding ability in MCF-7 cells.

In MCF-7 breast cancer cells, hydroxytamoxifen (OH-Tam) up-regulates the estrogen receptor (ER) in a form unable to bind [(3)H]estradiol (E(2)). We show here that this property is not restricted to this antiestrogen. [(3)H]E(2) binding assays (whole cell assays, DCC assays on cell extracts) and enzyme immunoassays (Abbott) performed in parallel, establish the permanent presence of such unusual ERs in the absence of any exposure of the cells to a ligand. E(2) and the pure antiestrogen RU 58 668, which down-regulate ER, also decrease [(3)H]E(2) binding. In control cells, these ERs represent about the half of the whole receptor population; they also display a tendency to stabilize within the cell nucleus. Loss of E(2) binding ability appears irreversible, since we failed to label receptor accumulated under OH-Tam with [(3)H]E(2) or [(3)H]tamoxifen aziridine (TAZ). Cycloheximide (CHX), which blocks E(2)-induced down regulation of ER, failed to stabilize [(3)H]E(2) binding (whole cell assay) after an [(3)H]E(2) pulse (1 h), confirming that regulation of E(2) binding and peptide level are related to different regulatory mechanisms. Loss of binding ability could not be ascribed to any ER cleavage as demonstrated by Western blotting with a panel of ER antibodies raised against its various domains (67 kDa ER solely detected). We propose that loss of E(2) binding ability is related to the aging process of the receptor, i.e. it is progressively converted to a form devoted to degradation after it has accomplished its physiological role. Ligands may favor (E(2), RU 58 668) or impede (OH-Tam) this elimination process.

Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis.

Iodinated oestradiol-labeled oestrogen receptor (ER) isoforms devoid of amino-terminal ABC domains represent about two-thirds of the whole receptor population detected in cytosol samples from human breast cancers. This high frequency could not be ascribed to the expression of truncated mRNAs, or to the proteolysis of the native ER peptide at the time of homogenization or assay, suggesting an intracellular proteolysis. Free amino-terminal and ligand-binding domains maintained together within oligomeric structure(s); increase of ionic strength separated them. The amino-terminal region was consistently detected in the cell nucleus by specific immunohistochemistry leading to the concept of a potential intranuclear association between ER cleavage products and/or other regulatory proteins.

Prolonged photosensitivity following contact photoallergy to ketoprofen.

We report the third case of prolonged photosensitivity secondary to contact photoallergy to topical ketoprofen, a 2-arylpropionic acid derivative. The patient suffered from persistent photosensitivity for more than 1 year after the withdrawal of ketoprofen with recurrent eruptions on sun-exposed skin areas. This photosensitivity was associated with a persistent decrease in polychromatic and UVA minimal erythemal doses. Photobiological testing revealed cross-reactivity with fenofibrate and benzophenones. Photoallergy to ketoprofen is due to the benzophenone structure or to the very similar thiophene phenylketone of tiaprofenic acid, but not to the arylpropionic function. Thus, fenofibrate, tiaprofenic acid and benzophenones should be avoided by patients with a positive history of photocontact dermatitis to ketoprofen.

Characterization of a cell line established from diethylstilbestrol-induced renal tumors in Syrian hamsters.

This article describes HKT-1097, a new cell line established from renal tumors induced by the protracted administration of diethylstilbestrol (DES) to male Syrian golden hamsters. Cell culture was initiated from tumor samples obtained from two 14-mo.-old animals which had undergone exposure to DES for a period of 11 mo. The HKT-1097 cell line was characterized between Passages 16 and 22 with respect to cell morphology, growth properties, karyology, and the presence of estrogen receptors. Moreover, immunostaining with a panel of antisera was performed to identify the cytological profile of the cell line and establish a parallel with tumor tissue in vivo. HKT-1097 cells are fibroblastoid; their most distinctive feature is that they exhibit strikingly long processes. The HKT-1097 cell line grows as a monolayer with a tendency toward a less stringent density-dependent inhibition of growth. The modal chromosome number is 44, but more than 50% of the cells are aneuploid, suggesting a substantial degree of karyotype instability. HKT-1097 cells express estrogen receptors. They contain immunoreactive vimentin and desmin, but appear negative upon cytokeratin immunostaining. In addition, these cells express glial fibrillary acidic protein and other markers of the neuroectodermal lineage, but lack neurofilament protein. Insofar as the same lineage markers have been demonstrated in DES-induced Syrian hamster kidney tumors (SHKT), we conclude that HKT-1097 cells retain some of the original tumor cell phenotype. The current observations suggest that estrogen-induced SHKT derive from the renal interstitium and point to an involvement of neuroectodermal cells in the development of these neoplasms.

Sunscreen sensitization: a 5-year study.

The purpose of this study was to evaluate the prevalence of sunscreen contact allergy and/or contact photoallergy in 370 patients with suspected photodermatitis. Patch and photopatch tests were performed using the French Society of Photodermatology (SFPD) standard series. A total of 57 cases of contact allergy and/or photocontact allergy to sunscreens were diagnosed (15.4%). Amongst these, 27 reactions were related to oxybenzone and 14 to isopropyl dibenzoylmethane. These results, obtained from January 1990 to December 1994, confirm that, given the high frequency of photosensitization cases, a large part of the battery of photopatch tests should be dedicated to sunblocks.

Sublethal alterations and sustained cell proliferation associated with the diethylstilbestrol-induced renal carcinogenesis in male Syrian golden hamsters.

The current study was initiated to explore the sublethal alterations and the tissue damage occurring in the hamster kidney during diethylstilbestrol-induced renal carcinogenesis. A total of 49 male Syrian golden hamsters (35 treated and 13 control animals) was utilized in the experimental procedure. Chronic exposure to diethylstilbestrol was achieved by s.c. insertion of implants containing 25 mg diethylstilbestrol. For long-term observation, adequate blood level of diethylstilbestrol was insured by renewing the implant every 2 months. Experimental groups (n = 4 to 9) were terminated 1, 2, 4, 6, 9 and 11 months after initial implantation for morphological examination of the kidney. Diethylstilbestrol carcinogenicity in this experimental model was confirmed by the observation that most animals undergoing drug exposure for 6 months or more exhibited renal neoplasms. The most striking nonneoplastic morphological abnormality disclosed by histological and cytological examination consisted in the accumulation of granular inclusions in proximal tubule cells. In renal tissue, the extent of cell proliferation determined by PCNA labeling progressively increased along with the duration of diethylstilbestrol exposure and suggested a sustained proliferative response in altered proximal tubules. The present data suggest that an impairment of functional tubular regeneration could promote, as well as the estrogen genotoxic effect, the tumorigenicity of diethylstilbestrol in the kidney of male hamsters.

Lipid peroxidation after cold storage and normothermic reperfusion: the effect of trimetazidine.

Ischemia reperfusion injury is still a leading cause of early graft dysfunction after transplantation. Trimetazidine (TMZ) has been postulated to be protective against renal damage from oxygen free radicals. The aim of this study was to assess the effect TMZ during cold storage (CS) and normothermic reperfusion in an isolated perfused pig kidney model. Three groups were studied: control group, immediately perfused (G0), 48 h CS in Euro-Collins solution (G1), and 48 h CS in Euro-Collins solution plus TMZ (G2). Glomerular filtration rate (GFR) and fractional sodium reabsorption (FRNa+) were calculated during reperfusion from urine and perfusate samples. Lipid peroxidation was determined by the renal tissue level of Schiff bases (SB) and malondialdehyde (MDA) after reperfusion. A histological evaluation was performed after reperfusion. Renal function was significantly improved and lipid peroxidation reduced after preservation in Euro-Collins solution plus TMZ. Functional data were closely related to histological damage. In conclusion, TMZ is a useful protective agent against renal damage induced by CS.