Complicaciones hemorrágicas de la nefrolitotomía percutánea: valor del tratamiento endovascular precoz / Hemorrhagic complicationes after percutaneous nephrolithotomy: The importance of an early endovascular management

Introducción y objetivos: La hemorragia secundaria a la fístula arteriovenosa (FAV) o al pseudoaneurisma (PA) es una complicación poco frecuente de la nefrolitotomía percutánea (NLPC). El objetivo de este estudio es evaluar las complicaciones hemorrágicas (CH) tras la NLPC y los resultados del tratamiento endovascular.Materiales y métodosEntre mayo de 2009 y diciembre de 2019 se realizaron en nuestro centro 1.335 NLPC por litiasis renal. Analizamos la incidencia de CH tempranas y tardías, el tratamiento administrado, la necesidad de embolización posterior y los datos clínicos y analíticos de los pacientes.ResultadosUn total de 59 (4,4%) pacientes presentaron CH, y todos fueron tratados con arteriografía y embolización selectiva (AES) para controlar el sangrado. Se observó hematoma perirrenal en 38 pacientes (64%).En cuanto a los hallazgos angiográficos, hubo 32 (54%) PA, 8 (14%) FAV, 4 (7%) extravasaciones por laceración vascular y 15 (25%) PA combinadas con FAV. En un caso, fueron necesarios 3 procedimientos para controlar la hemorragia. En 30 pacientes (51%) no se requirió transfusión de sangre, mientras que en 29 (49%) se transfundió una media de 1,3 unidades. La mediana de seguimiento fue de 24±21 meses.El intervalo de tiempo medio entre la NLPC y la AES fue de 7,3±4,9 días. Un total de 24 (41%) pacientes reingresaron tras el alta debido a una CH tardía que requería AES. La demora entre el reingreso y la AES fue de 4,8±4,6horas de media.ConclusiónLas CH tempranas y tardías tras la NLPC pueden ser mayores. El tratamiento con AES tras la detección precoz es un método efectivo y mínimamente invasivo que evita múltiples transfusiones de sangre, en muchos casos insuficientes. (AU)

Introduction and objectives: Hemorrhage due to arteriovenous fistula (AVF) or pseudoaneurysm (PA) is a rare complication after percutaneous nephrolithotomy (PCNL). The objective of this study is to evaluate hemorrhagic complications (HC) after PCNL and the results of their endovascular treatment.Materials and methodsBetween May 2009 and December 2019, 1335 PCNL were performed in our center for kidney stone disease. We analyzed the incidence of early and late HC, their management, the need for subsequent embolization, as well as clinical and analytical data of these patients.ResultsA total of 59 (4.4%) patients presented HC. Bleeding was managed with arteriography and selective embolization (ASE). Perirenal hematoma was seen in 38 patients (64%).Regarding angiographic findings, there were 32 (54%) PA, 8 (14%) AVF, 4 (7%) extravasations due to vascular laceration and 15 (25%) PA combined with AVF. In one case, 3 procedures were required to control the bleeding. In 30 patients (51%) blood transfusions were not necessary, while in 29 (49%), a mean of 1.3 units were transfused. Median follow-up was 24±21 months.Mean time interval between PCNL and ASE was 7.3±4.9 days. A total of 24 (41%) patients were readmitted after discharge due to late HC requiring ASE. Delay between readmission and ASE was 4.8±4.6hours in average.ConclusionEarly and late HC after PCNL can be severe. Rapid identification and treatment with ASE is an effective and minimally invasive and avoids multiple blood transfusions which in many cases constitute an insufficient treatment. (AU)

Hemorrhagic complicationes after percutaneous nephrolithotomy: The importance of an early endovascular management.

INTRODUCTION AND OBJECTIVES: Hemorrhage due to arteriovenous fistula (AVF) or pseudoaneurysm (PA) is a rare complication after percutaneous nephrolithotomy (PCNL). The objective of this study is to evaluate hemorrhagic complications (HC) after PCNL and the results of their endovascular treatment. MATERIALS AND METHODS: Between May 2009 and December 2019, 1335 PCNL were performed in our center for kidney stone disease. We analyzed the incidence of early and late HC, their management, the need for subsequent embolization, as well as clinical and analytical data of these patients. RESULTS: A total of 59 (4.4%) patients presented HC. Bleeding was managed with arteriography and selective embolization (ASE). Perirenal hematoma was seen in 38 patients (64%). Regarding angiographic findings, there were 32 (54%) PA, 8 (14%) AVF, 4 (7%) extravasations due to vascular laceration and 15 (25%) PA combined with AVF. In one case, 3 procedures were required to control the bleeding. In 30 patients (51%) blood transfusions were not necessary, while in 29 (49%), a mean of 1.3 units were transfused. Median follow-up was 24 ±â€¯21 months. Mean time interval between PCNL and ASE was 7.3 ±â€¯4.9 days. A total of 24 (41%) patients were readmitted after discharge due to late HC requiring ASE. Delay between readmission and ASE was 4.8 ±â€¯4.6 h in average. CONCLUSION: Early and late HC after PCNL can be severe. Rapid identification and treatment with ASE is an effective and minimally invasive and avoids multiple blood transfusions which in many cases constitute an insufficient treatment.

Hemorrhagic complicationes after percutaneous nephrolithotomy: The importance of an early endovascular management. / Complicaciones hemorrágicas de la nefrolitotomía percutánea: valor del tratamiento endovascular precoz.

INTRODUCTION AND OBJECTIVES: Hemorrhage due to arteriovenous fistula (AVF) or pseudoaneurysm (PA) is a rare complication after percutaneous nephrolithotomy (PCNL). The objective of this study is to evaluate hemorrhagic complications (HC) after PCNL and the results of their endovascular treatment. MATERIALS AND METHODS: Between May 2009 and December 2019, 1335 PCNL were performed in our center for kidney stone disease. We analyzed the incidence of early and late HC, their management, the need for subsequent embolization, as well as clinical and analytical data of these patients. RESULTS: A total of 59 (4.4%) patients presented HC. Bleeding was managed with arteriography and selective embolization (ASE). Perirenal hematoma was seen in 38 patients (64%). Regarding angiographic findings, there were 32 (54%) PA, 8 (14%) AVF, 4 (7%) extravasations due to vascular laceration and 15 (25%) PA combined with AVF. In one case, 3 procedures were required to control the bleeding. In 30 patients (51%) blood transfusions were not necessary, while in 29 (49%), a mean of 1.3 units were transfused. Median follow-up was 24±21 months. Mean time interval between PCNL and ASE was 7.3±4.9 days. A total of 24 (41%) patients were readmitted after discharge due to late HC requiring ASE. Delay between readmission and ASE was 4.8±4.6hours in average. CONCLUSION: Early and late HC after PCNL can be severe. Rapid identification and treatment with ASE is an effective and minimally invasive and avoids multiple blood transfusions which in many cases constitute an insufficient treatment.

Positive margins after partial nephrectomy in renal cell carcinoma: Oncological outcomes of conservative management after long-term follow-up. / Márgenes positivos tras nefrectomía parcial en carcinoma de células renales: seguimiento a largo plazo y resultados oncológicos con manejo conservador.

INTRODUCTION: Partial nephrectomy (PN) is the standard treatment for small and localized kidney tumours (cT1). One of the controversial aspects regarding this technique is the management of affected/positive resection margins. We present the long-term oncological results in patients with PSM after PN managed conservatively. MATERIAL AND METHODS: There were 207 PN performed in our centre between 1990 and 2011. 17 patients presented PSM. 2 patients were excluded from the study due to completion nephrectomy afterwards. Follow-up was was done with abdominal contrast-enhanced computed tomography every 6 months for the first 2 years and subsequently, once a year. Cancer-specific survival and disease-free survival were calculated with the Kaplan-Meier method. RESULTS: The median age was 62 years (RIQ: 55-71) and the mean tumour size was 34.8 (10-77) mm. Histopathological results were: 6 (40%) clear cell RCC, 4 (26.7%) papillary, 3 (20%) chromophobe and 2 (13.3%) oncocytic. The pathologic stages were: 11 (73.3%) pT1a, 1 (6.7%) pT1b and 3 (20%) pT3a. The median follow-up was 84 months (IQR 72-120). 2 patients had metastatic recurrence and this was the cause of death. The first one had recurrence at 112 months and the second one at 59. 5-year CSS and RFS were 87.5% and 93.3% respectively. CONCLUSIONS: In our experience, patients with PSM after PN can be managed conservatively with satisfactory long-term oncological outcomes.

Lumbar Spinal Stenosis Severity by CT or MRI Does Not Predict Response to Epidural Corticosteroid versus Lidocaine Injections.

BACKGROUND AND PURPOSE: Epidural steroid injections may offer little-to-no short-term benefit in the overall population of patients with symptomatic spinal stenosis compared with lidocaine alone. We investigated whether imaging could identify subgroups of patients who might benefit most. MATERIALS AND METHODS: A secondary analysis of the Lumbar Epidural Steroid Injections for Spinal Stenosis prospective, double-blind trial was performed, and patients were randomized to receive an epidural injection of lidocaine with or without corticosteroids. Patients (n = 350) were evaluated for qualitative and quantitative MR imaging or CT measures of lumbar spinal stenosis. The primary clinical end points were the Roland-Morris Disability Questionnaire and the leg pain numeric rating scale at 3 weeks following injection. ANCOVA was used to assess the significance of interaction terms between imaging measures of spinal stenosis and injectate type on clinical improvement. RESULTS: There was no difference in the improvement of disability or leg pain scores at 3 weeks between patients injected with epidural lidocaine alone compared with corticosteroid and lidocaine when accounting for the primary imaging measures of qualitative spinal stenosis assessment (interaction coefficients for disability score, -0.1; 95% CI, -1.3 to 1.2; P = .90; and for the leg pain score, 0.1; 95% CI, -0.6 to 0.8; P = .81) or the quantitative minimum thecal sac cross-sectional area (interaction coefficients for disability score, 0.01; 95% CI, -0.01 to 0.03; P = .40; and for the leg pain score, 0.01; 95% CI, -0.01 to 0.03; P = .33). CONCLUSIONS: Imaging measures of spinal stenosis are not associated with differential clinical responses following epidural corticosteroid injection.

[Submental transcutaneous electrical stimulation for obstructive sleep apnea]. / Transkutane, submentale Elektrostimulationstherapie bei obstruktiver Schlafapnoe.

BACKGROUND: Transcutaneous electrical stimulation while asleep has been used to treat obstructive sleep apnea (OSA), although without convincing results. Modern strategies consist of electrical muscle training for a number of weeks during wakefulness rather than stimulation during sleep. OBJECTIVE: The purpose of this study was to assess the practicability, safety, and efficacy of a new device, SilentOne (Imperpuls, Chemnitz, Germany). PATIENTS AND METHODS: Fifteen patients with various degrees of OSA used transcutaneous submental electrical stimulation therapy for 4-5 weeks every day, day and night. A patient's diary recorded practicability and potential adverse events. Respiratory parameters were recorded by fully attended polysomnography in the sleep lab. Daytime sleepiness and snoring were assessed by questionnaires. RESULTS: The apnea-hypopnea-index decreased from 29.2 before to 21.2 after therapy (P<0.05). Daytime sleepiness improved significantly (P<0.01) as did snoring (P<0.005). CONCLUSIONS. Transcutaneous electrical stimulation therapy using SilentOne proved to be safe, easy to use, and potent. However, therapy showed a limited cure rate.

Revision of deep brain stimulator for tremor. Technical note.

The treatment of essential tremor with thalamic deep brain stimulation (DBS) is considered to be more effective and to cause less morbidity than treatment with thalamotomy. Nonetheless, implantation of an indwelling electrode, connectors, and a generator is associated with specific types of morbidity. The authors describe three patients who required revision of their DBS systems due to lead breakage. The connector between the DBS electrode and the extension wire, which connects to the subclavicular pulse generator, was originally placed subcutaneously in the cervical region to decrease the risk of erosion through the scalp and to improve cosmesis. Three patients presented with fractured DBS electrodes that were located in the cervical region near the connector, necessitating reoperation with stereotactic retargeting and placement of a new intracranial electrode. At reoperation, the connectors were placed subgaleally over the parietal region. Management of these cases has led to modifications in the operative procedure designed to improve the durability of DBS systems. The authors recommend that surgeons avoid placing the connection between the DBS electrode and the extension wire in the cervical region because patient movement can cause microfractures in the electrode. Such microfractures require intracranial revision, which may be associated with a higher risk of morbidity than the initial operation. The authors also recommend considering prophylactic relocation of the connectors from the cervical area to the subgaleal parietal region to decrease the risk of future DBS electrode fracture, which would necessitate a more lengthy procedure to revise the intracranial electrode.

Expression of 92-kDa type IV collagenase correlates with angiogenic markers and poor survival in head and neck squamous cell carcinoma.

MMP-9, which degrades extracellular matrix, is believed to play a crucial role in tumor invasion and metastasis. Angiogenesis is also perceived as an important step in tumor growth and metastasis. The aim of this study was to investigate the expression of MMP-9 in tumor samples of HNSCC patients and to study a possible correlation to angiogenic markers. Cryostat sections of 52 HNSCC tumors were immunostained for MMP-9, bFGF and VEGF using a standard streptavidin-biotin complex procedure for light microscopic investigation. Microvessel density (MVD) was determined by staining of endothelial cells immunohistochemically using anti-vWF monoclonal antibody. MMP-9 positive staining was detected in 27/52 (52%) of the tumors. MMP-9 immunoreactivity did not correlate with the main clinicopathological characteristics of the patients (localisation, T-stage, N-stage, histological grading), but correlated with worse survival of the patients. MMP-9 negative tumors showed a significant lower mean MVD per microscopic field than MMP-9 positive tumors (p<0. 001). There was a significant association of MMP-9 and VEGF expression (p<0.05). The presence of MMP-9 in HNSCC cancer and the positive correlation with MVD and VEGF expression supports the theory that MMP-9 functions as a regulator of tumor angiogenesis supporting endothelial cell invasion. MMP-9 and VEGF might act co-operatively in the process of neovascularization in human head and neck cancer.

Serum levels of matrix metalloproteinase-2 and -9 in patients with head and neck squamous cell carcinoma.

BACKGROUND: Matrix Metalloproteinases (MMPs) have been implicated as playing an important role in cancer invasion and metastasis. MMPs have been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). MATERIAL AND METHODS: We investigated the circulating level of MMP-2 (gelatinase A or 72-kD type IV collagenase) and MMP-9 (gelatinase B or 92-kD type IV collagenase) in sera from patients with various head and neck squamous cell carcinomas (n = 86) as well as from healthy normal controls (n = 47). Serum MMP concentrations were determined as serum immunoreactivity by using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the t-test and Kruskal-Wallis test were performed. RESULTS: The majority of the patients with HNSCC were found to have high concentrations of serum MMP-9. The levels of MMP-9 in the sera of patients with cancer ranged from 39 to 1547 ng/ml (mean, 417 ng/ml). In contrast, the MMP-9 serum levels in 47 healthy individuals ranged from 30 to 537 ng/ml (mean, 189 ng/ml), MMP-9 serum concentration being significantly higher in HNSCC patients (p = 0.001). MMP-9 serum concentrations of patients with advanced stage HNSCC were significantly higher (p = 0.0449) compared to patients with early stage cancer. No significant difference of MMP-2 serum levels was seen when comparing HNSCC patients and normal controls. CONCLUSION: The present data indicate that the elevation of serum levels of MMP-9, but not MMP-2, may be a useful marker for clinical monitoring of HNSCC patients.

Serum levels of vascular endothelial growth factor in patients with head and neck cancer.

Angiogenesis is now considered to be crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to be correlated with metastasis and aggressiveness. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen, which is induced by hypoxia and is angiogenic in vivo. VEGF has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). We investigated the circulating level of VEGF in sera from patients with various head and neck squamous cell carcinomas (n = 71) as well as from healthy normal controls (n = 47). Serum VEGF concentrations were determined as serum immunoreactivity by using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the Wilcoxon 2-sample test and Kruskal-Wallis test were performed. The majority of the patients with HNSCC were found to have high concentrations of serum VEGE The levels of VEGF in the sera of patients with cancer ranged from below the detection limit to 937.1 pg/ml (mean, 144.5 pg/ml). In contrast, the VEGF serum levels in 47 healthy individuals ranged from below the detection limit to 168.1 pg/ml (mean, 32.7 pg/ml), VEGF serum concentration being significantly higher in HNSCC patients (P = < 0.001). These findings indicate that a positive angiogenesis regulator such as VEGF might function as an endocrine growth factor, particularly for solid HNSCC tumors and may be a useful marker for clinical monitoring.

Vascular endothelial growth factor expression correlates with p53 mutation and angiogenesis in squamous cell carcinoma of the head and neck.

Vascular endothelial growth factor (VEGF) has potent angiogenic activity and has been identified in a wide variety of malignancies, including head and neck squamous cell carcinoma (HNSCC). The tumour-suppressor gene p53 has been thought to regulate VEGF. Cryostat sections of 33 head and neck squamous cell carcinomas (HNSCC) were immunostained for VEGF using a standard streptavidin-biotin complex procedure. To evaluate angiogenesis, microvascular density was counted by staining endothelial cells immunohistochemically using anti-vWF monoclonal antibody. The p53 gene status was analysed using a PCR-SSCP analysis and direct sequencing. VEGF positive staining was detected in 18 (55%) out of 33 tumours. VEGF immunoreactivity did not correlate with the main clinicopathological characteristics of the patients (localization, T-stage, N-status, histological grading). Statistical analysis gave a clear correlation between the tumour vascularity and the VEGF protein expression (p = 0.0036). VEGF negative tumours showed a lower mean number of microvessels per microscopic field (60.3 +/- 15.5) than VEGF positive tumours (79.6 +/- 22.9). P53 mutations were identified in 12 (36.4%) of 33 tumours. The association of p53 mutations and VEGF expression level was significant (0.027). The higher microvessel density in VEGF positive tumours supports the importance of VEGF for tumour angiogenesis in HNSCC. Our results support the hypothesis of a p53 regulation on the angiogenic process through a VEGF up-regulation.

[Coexpression of VEGF and bFGF is associated with increased vascular density in head and neck carcinomas]. / Ko-Expression von VEGF und bFGF ist assoziiert mit einer erhöhten Gefässdichte in Kopf-Hals-Karzinomen.

BACKGROUND: Angiogenesis is crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to correlate with metastasis and aggressiveness. Vascular endothelial growth factor (VEGF) and basic Fibroblast Growth Factor (bFGF) are known to have potent angiogenic activity. Their expression has been identified in a wide variety of malignancies including head and neck squamous cell carcinoma (HNSCC). Aim of our study was to investigate the role of co-expression of VEGF and bFGF for angiogenesis in HNSCC. MATERIAL AND METHODS: Cryostat sections of 51 primary HNSCC were immunostained for VEGF and bFGF using a standard streptavidin-biotin complex procedure. To evaluate angiogenesis, endothelial cells were stained immunohistochemically using anti-vWF polyclonal antibody. Microvessels were quantified by counting vessels in a x200 field in the most vascular area of the tumor. RESULTS: 25/51 (49%) of the investigated carcinomas showed co-expression of both factors (VEGF+/bFGF+), while 6/51 (11.7%) carcinomas only expressed VEGF and 13/51 (25.5%) carcinomas expressed bFGF. 7/51 (13.7%) tumors showed no expression of these factors (VEGF-/bFGF-). Carcinomas with a co-expression of VEGF and bFGF showed a significantly increased mean microvessel density (88.3 +/- 24.4) compared to tumors expressing only VEGF (77 +/- 16.8) or bFGF (71.1 +/- 15.8) (p = 0.022) or tumors with no expression of both factors (51.1 +/- 13.4) (p < 0.001). The association of VEGF and bFGF expression level was not significant (p = 0.178). CONCLUSIONS: The positive correlation of the co-expression of angiogenic VEGF and bFGF with increased microvessel density underlines the importance of both factors for tumor angiogenesis in HNSCC. VEGF and bFGF might act cooperatively in the process of neovascularization in human head and neck cancer.

Optic nerve glia secrete a low-molecular-weight factor that stimulates retinal ganglion cells to regenerate axons in goldfish.

The ability of lower vertebrates to regenerate an injured optic nerve has been widely studied as a model for understanding neural development and plasticity. We have recently shown that, in goldfish, the optic nerve contains two molecules that stimulate retinal ganglion cells to regenerate their axons in culture: a low-molecular-weight factor that is active even at low concentrations (axogenesis factor-1) and a somewhat less active polypeptide of molecular weight 10,000-15,000 (axogenesis factor-2). Both are distinct from other molecules described previously in this system. The present study pursues the biological source and functional significance of axogenesis factor-1. Earlier studies have shown that cultured goldfish glia provide a highly favorable environment for fish or rat retinal ganglion cells to extend axons. We report that the glia in these cultures secrete high levels of a factor that is identical to axogenesis factor-1 in its chromatographic properties and biological activity, along with a larger molecule that may coincide with axogenesis factor-2. Axogenesis factor-1 derived from either goldfish glial cultures or optic nerve fragments is a hydrophilic molecule with an estimated molecular weight of 700-800. Prior studies have reported that goldfish retinal fragments, when explanted in organ culture, only extend axons if the ganglion cells had been "primed" to begin regenerating in vivo for one to two weeks. However, axogenesis factor-1 caused the same degree of outgrowth irrespective of whether ganglion cells had been induced to regenerate new axons in vivo. Moreover, ganglion cells primed to begin regenerating in vivo continued to extend axons in culture only when axogenesis factor-1 was present. In summary, this study shows that glial cells of the goldfish optic nerve secrete a low-molecular-weight factor that initiates axonal regeneration from retinal ganglion cells.

Two factors secreted by the goldfish optic nerve induce retinal ganglion cells to regenerate axons in culture.

Unlike mammals, lower vertebrates can regenerate an injured optic nerve and other pathways of the CNS throughout life. We report here that in dissociated cell culture, goldfish retinal ganglion cells regenerate their axons in response to two factors derived from the sheath cells of the optic nerve. Axogenesis factor 1 (AF-1) is a small peptide (700-900 Da) that is inactivated by treatment with proteinase K but heat stable. A second factor, AF-2, is a polypeptide of ca 12 kDa. In the absence of these factors, dissociated retinal cells remained viable in serum-free, defined media for at least a week but showed little outgrowth, as visualized using the vital dye 5,6-carboxyfluorescein diacetate (5,6-CFDA). The addition of AF-1 induced up to 25% of cells in culture to extend processes > 75 microns in length by 6 d; AF-2 had a lesser but highly significant effect. To verify that neurite outgrowth was from retinal ganglion cells per se, we applied the lipophilic dye 4-Di-10-ASP to the optic tectum and allowed it to diffuse up the optic nerve for several days before culturing the retina. A far greater percentage of cells containing the dye showed axonal outgrowth than was observed from the overall cell population, indicating that ganglion cells are selective targets of the factors. The effects of AF-1 or AF-2 were not secondary to enhanced viability, since neither overall cell survival nor the number of retinal ganglion cells remaining in culture after 6 d was affected by the presence of the factors. The activity of AF-1 and AF-2 was not mimicked by several defined factors tested over a broad concentration range, for example, NGF, BDNF, NT-3, CNTF, taurine, retinoic acid, acidic or basic fibroblast growth factors. The concentration of AF-1 is considerably higher in CM than in optic nerve homogenates, suggesting that it is actively secreted; AF-2 has a similar concentration intra- and extracellularly. Insofar as AF-1 and AF-2 derive from cells of the optic nerve and act upon retinal ganglion cells, they are likely to be important in inducing optic nerve regeneration in vivo.

Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts.

IL-6 is a multi-functional cytokine that plays an important role in normal biologic homeostasis and disease pathogenesis. Retinoids are vitamin A analogs that regulate the function of a wide variety of inflammatory and structural cells. To further understand the biology of retinoids and IL-6 we determined whether all-trans-retinoic acid (RA) and other retinoids regulate lung fibroblast IL-6 production. RA did not stimulate fibroblast IL-6 production. Instead, it inhibited the production of IL-6 by IL-1-stimulated cells. This effect was dose-dependent with an IC50 of 10(-7) M RA and significant inhibition being noted with doses of RA as low as 10(-8) M. These inhibitory effects could not be explained by cytotoxicity or a shift in the kinetics of IL-6 production. They also did not appear to involve alterations in the early events in IL-1-induced IL-6 production, because RA inhibited IL-6 production even when added 6 h after IL-1 and RA did not inhibit IL-1 binding to cell surface IL-1 receptors. RA inhibition of IL-6 protein production was associated with a comparable decrease in IL-6 mRNA accumulation and gene transcription. 13-cis-retinoic acid, retinol, retinaldehyde, all-trans etretin, Ro 13-6298, and 9-cis retinoic acid also inhibited IL-1-induced IL-6 production. However, 4-hydroxyphenyl retinamide and etretinate did not share this property. The inhibitory effects of these analogues may be mediated by nuclear retinoic acid receptors as mRNA encoding RAR-alpha, RAR-gamma, and RXR-alpha were present, and RAR-beta was induced by RA in human lung fibroblasts. These studies demonstrate that RA and other retinoid analogs inhibit IL-1-induced IL-6 production and that this effect is analog-specific and, at least partially, transcriptionally mediated.