Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity.

BACKGROUND AND AIMS: Abdominal obesity (AO) is associated with endothelial function (EF) alteration and increased global cardiovascular (CV) risk. Therapeutic lifestyle changes (TLSC) reduce CV risk, but the impact on EF assessed by peripheral artery tonometry (PAT) is unknown. In this study, we aimed to prospectively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO. METHODS AND RESULTS: 150 patients with AO and moderate CV risk were randomized to groups receiving a one-year intervention of either conventional medical care (control group, CG) or an intensive TLSC program (intervention group, IG). Vascular studies (EF by PAT, intima-media thickness (IMT)) and lifestyle (LS) assessment were performed before and after intervention. The PAT ratio improved in the IG and worsened in the CG. The global CV risk was reduced (P = 0.017) in the IG due to a significant decrease in systolic blood pressure (P < 0.001), increase in HDL cholesterol and ApolipoproteinA1 (P = 0.013). More individuals in the IG than in the CG quit smoking (P = 0.001) and increased their physical activity (P = 0.014). The improvement in at least two LS components was associated with a PAT ratio increase (2.44 IC: 95% 0.99-6.00, P = 0.051). The PAT ratio increase determined less IMT progression (-1.1 IC: 95% 0.91-1.00, P = 0.053). CONCLUSIONS: Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement. The PAT ratio increase is the main determinant of lower IMT progression.

Utilidad de las técnicas de imagen y biomarcadores en la predicción del riesgo cardiovascular en pacientes con enfermedad renal crónica en España: Proyecto NEFRONA* / Usefulness of imaging techniques and novel biomarkers in the prediction of cardiovascular risk in patients with chronic kidney disease in Spain: The NEFRONA project

Justificación: La enfermedad cardiovascular (ECV) es la primera causa de mortalidad en pacientes con enfermedad renal crónica (ERC). La valoración del riesgo cardiovascular a partir de los factores tradicionales es poco útil en esta población debido al fenómeno de «reverse epidemiology» y a la existencia de factores específicos derivados de la uremia. En este trabajo presentamos el protocolo del proyecto NEFRONA, un estudio prospectivo con el objetivo de evaluar la utilidad de técnicas de imagen y biomarcadores en la predicción de la ECV en la ERC. Métodos: A partir de noviembre 2009 se reclutarán 2.661adultos asintomáticos con ERC (estadios 3-5D) procedentes de consultas ambulatorias de nefrología y centros de diálisis distribuidos a lo largo del territorio español. Asimismo, se incluirán843 participantes sin ERC (grupo control). Además, semestralmente se registrará la aparición de acontecimientos cardiovasculares y mortalidad. Un equipo itinerante realizará una ecografía carotíde a para valorar el grosor íntima-media y la presencia de placas, y determinará el índice tobillo-brazo para la clasificación de la enfermedad ateromatosa. Para el estudio de las calcificaciones vasculares se utilizará un score basado en la presencia de calcificaciones en las arterias carótidas, femorales y braquiales, y en las válvulas cardíacas, mediante ecografía. Finalmente, se recogerán muestras de sangre para la determinación de biomarcadores. Discusión: El proyecto NEFRONA nos permitirá evaluar la utilidad de las técnicas de imagen y biomarcadores en la valoración de la enfermedad ateromatosa y su valor predictivo en la población española con ERC (AU)

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease(CKD). Cardiovascular risk assessment in this population is hampered by the failure of traditional risk factors to fully account for the elevated CVD risk, mainly due to the reverse epidemiology effect, and the presence of risk factors specifically related to uremia. Hereby, we present the protocol of a prospective study aimed to assess the predictive value of imaging techniques and biomarkers for CVD in patients with CKD. Methods: From November 2009, 2.661asymptomatic adult patients with stages 3-5D CKD will be recruited from nephrology services and dialysis units throughout Spain. Eighthundred forty-three participants without CKD (control group) will be also recruited. During the follow-up, CVD events and mortality will be recorded from all CKD patients. One trained itinerant team will carry out a carotid ultrasound to assess intima-media thickness and presence of plaques. A composite atherosclerosis score will be constructed based on carotid ultrasound data and ankle-brachialindex. Presence and type of calcifications will be assessed in carotid, femoral and brachial arteries, and in cardiac valves, by ultrasound. Finally, blood samples will be collected from all participants to study biomarkers. Discussion: The NEFRONA study will allow us to examine the usefulness of imaging techniques and biomarkers to assess atherosclerosis development and their predictive value in a Spanish population with CKD (AU)

[Usefulness of imaging techniques and novel biomarkers in the prediction of cardiovascular risk in patients with chronic kidney disease in Spain: the NEFRONA project]. / Utilidad de las técnicas de imagen y biomarcadores en la predicción del riesgo cardiovascular en pacientes con enfermedad renal crónica en España: Proyecto NEFRONA.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Cardiovascular risk assessment in this population is hampered by the failure of traditional risk factors to fully account for the elevated CVD risk, mainly due to the reverse epidemiology effect, and the presence of risk factors specifically related to uremia. Hereby, we present the protocol of a prospective study aimed to assess the predictive value of imaging techniques and biomarkers for CVD in patients with CKD. METHODS: From November 2009, 2.661 asymptomatic adult patients with stages 3-5D CKD will be recruited from nephrology services and dialysis units throughout Spain. Eight hundred forty-three participants without CKD (control group) will be also recruited. During the follow-up, CVD events and mortality will be recorded from all CKD patients. One trained itinerant team will carry out a carotid ultrasound to assess intima-media thickness and presence of plaques. A composite atherosclerosis score will be constructed based on carotid ultrasound data and ankle-brachial index. Presence and type of calcifications will be assessed in carotid, femoral and brachial arteries, and in cardiac valves, by ultrasound. Finally, blood samples will be collected from all participants to study biomarkers. DISCUSSION: The NEFRONA study will allow us to examine the usefulness of imaging techniques and biomarkers to assess atherosclerosis development and their predictive value in a Spanish population with CKD.

Predictive value of ankle brachial index in patients with acute ischaemic stroke.

BACKGROUND: The ankle brachial index (ABI) is a known measure of lower-limb peripheral artery disease (PAD), as well as a marker for other cardiovascular disease events. OBJECTIVE: Our goal was to compare the prevalence of abnormal ABI scores (ABI or=3 (33.8% vs. 7.1%, P = 0.001) and large-artery atherosclerosis (LAA) (43.5% vs. 19.4%, P = 0.015). Multivariate analyses (logistic regression) only identified VRF > 3 as independently associated with low ABI (OR: 6.46; 1.81-23.02; P = 0.004). Abnormal ABI was associated with stroke recurrence (32.1% vs. 13.6%, P = 0.027) and the appearance of any major vascular event (50.0% vs. 17.0%, P < 0.001). In the logistic regression analysis, adjusted for VRF, age, and LAA, ABI remained as an independent predictor of vascular events (HR 3.99; 1.90-8.41 P < 0.001). CONCLUSION: Abnormal ABI was associated with classical risk factors, especially hypertension. The measurement of ABI amongst patients with IS appeared to be useful to identify high-risk patients and plan adequate prevention therapies.

Nonconcordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV-infected patients: relationships with serum markers of oxidation and inflammation.

OBJECTIVES: HIV-infected patients show an increased cardiovascular disease (CVD) risk resulting, essentially, from metabolic disturbances related to chronic infection and antiretroviral treatments. The aims of this study were: (1) to evaluate the agreement between the CVD risk estimated using the Framingham risk score (FRS) and the observed presence of subclinical atherosclerosis in HIV-infected patients; (2) to investigate the relationships between CVD and plasma biomarkers of oxidation and inflammation. METHODS: Atherosclerosis was evaluated in 187 HIV-infected patients by measuring the carotid intima-media thickness (CIMT). CVD risk was estimated using the FRS. We also measured the circulating levels of interleukin-6, monocyte chemoattractant protein-1 (MCP-1) and oxidized low-density lipoprotein (LDL), and paraoxonase-1 activity and concentration. RESULTS: There was a weak, albeit statistically significant, agreement between FRS and CIMT (kappa=0.229, P<0.001). A high proportion of patients with an estimated low risk had subclinical atherosclerosis (n=66; 56.4%). In a multivariate analysis, the presence of subclinical atherosclerosis in this subgroup of patients was associated with age [odds ratio (OR) 1.285; 95% confidence interval (CI) 1.084-1.524; P=0.004], body mass index (OR 0.799; 95% CI 0.642-0.994; P=0.044), MCP-1 (OR 1.027; 95% CI 1.004-1.050; P=0.020) and oxidized LDL (OR 1.026; 95% CI 1.001-1.051; P=0.041). CONCLUSION: FRS underestimated the presence of subclinical atherosclerosis in HIV-infected patients. The increased CVD risk was related, in part, to the chronic oxidative stress and inflammatory status associated with this patient population.

Influence of a monocyte chemoattractant protein 1 mutated allele on the response to protease inhibitor-based antiretroviral therapy.

BACKGROUND: Antiretroviral drug efficacy has been widely studied in relation to viral factors. Mutations in the HIV co-receptors and their natural chemokines, however, may be critical in HIV infection and treatment response. We compared the efficacy of protease inhibitor (PI) treatment among PI-naïve patients grouped according to whether they carried the chemokine CC motif receptor 2 (CCR-2) 64I and monocyte chemoattractant protein 1 (MCP-1)-2518G alleles. METHODS AND RESULTS: HIV-infected patients who were PI-naive were selected for the study (n=164) but there was no restriction on lymphocyte CD4 count or plasma HIV viral load. Follow-up was for the first 24 months of treatment. Clinical and laboratory data were obtained every 3 months. All the participants were genotyped for the MCP-1-2518G, CCR-2 64I, CCR-5Delta32 and stromal derived factor 1 (SDF1) 3'A mutated alleles. The results indicated that patients carrying the mutated allele of MCP-1 had a higher mean CD4 cell count throughout the follow-up period than those with the common allele (P=0.01). Also, patients with the MCP-1 and CCR-2 mutated alleles were more likely to continue to have an undetectable viral load following treatment (P=0.05). CONCLUSION: A better response to PI treatment appears to be conferred by mutations in the host MCP-1 and CCR-2 genes, and may be related to the cellular axis-of-entry used by the retrovirus.

Effects of rosiglitazone on postprandial leukocytes and cytokines in type 2 diabetes.

OBJECTIVE: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. For this purpose, we determined the effects of rosiglitazone (8 mg/d) on postprandial leukocyte counts and pro-inflammatory cytokines (IL-6 and IL-8) in patients with type 2 diabetes. METHODS AND RESULTS: A randomized, 8-week, cross-over, placebo-controlled, double-blind clinical trial was performed in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. During placebo treatment, blood leukocytes increased to a maximum 6-h postprandially, due to significant increases in neutrophils and lymphocytes. Concomitant postprandial increases were observed for IL-6 and IL-8, the major chemokines responsible for leukocyte recruitment. Rosiglitazone reduced the incremental area under the curves (dAUCs) for IL-6 (-63%, p<0.01) and IL-8 (-16%, p<0.05). The dAUC for leukocytes decreased with 37% (p<0.05), due to a specific reduction of neutrophils (-39%, p<0.05). CONCLUSIONS: Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. Since inflammation is a major force driving atherosclerosis, and man lives in a postprandial period most part of the day, a reduced inflammatory response after a meal may delay progression of atherosclerosis. CONDENSED ABSTRACT: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. These effects may contribute to cardiovascular risk reduction.

Evolución al año de los pacientes mayores intervenidos de fracturas de cadera. Resultados de un protocolo de tratamiento / One-year outcome in older patients undergoing surgery for hip fractures. Results of a treatment protocol

Introducción: Las fracturas de cadera son unas lesiones de alta incidencia y con grandes costes, cuyo tratamiento muestra una elevada variabilidad en nuestro medio. Objetivo: Analizar los resultados tras un seguimiento de un año. Pacientes y métodos: 200 fracturas del extremo proximal del fémur en pacientes de edad superior a 64 años, tratados entre junio de 1997 y enero de 1999, tras la aplicación de un protocolo de actuación (vía clínica) consensuado y multidisciplinario. Fueron evaluados diferentes parámetros clínicos y epidemiológicos de un modo prospectivo y descriptivo. Resultados: La estancia media fue de 7,7 días y se obtuvo una disminución en el coste medio por proceso de unos 900 euros. La mortalidad al año fue del 24,5 por ciento, relacionándose con factores como la edad avanzada, sexo masculino, diversos antecedentes patológicos, complicaciones médicas postoperatorias y nivel de autonomía. La mortalidad hospitalaria fue del 5 por ciento. Conclusión: La aplicación de una vía clínica permite obtener resultados hospitalarios e índices de mortalidad al año similares a los de otras series publicadas, si bien permite importantes mejoras en parámetros tales como la estancia media, el coste medio hospitalario por proceso y la autonomía precoz del paciente (AU)

[Emergency valvular replacement in infective endocarditis: hospital and long term clinical course. Analysis of 45 patients]. / Sustitución valvular urgente en la endocarditis infecciosa: evolución hospitalaria y a largo plazo. Análisis de 45 pacientes.

BACKGROUND: To define the evolution of patients with infective endocarditis who require urgent valve replacement in our environment. PATIENTS AND METHODS: We followed 45 consecutive cases of infective endocarditis that require valve replacement during their hospitalization. 32 patients had native valve infective endocarditis, 7 early prosthesis valve endocarditis and 6 late prosthesis valve endocarditis. Patients were followed for a long-term period, clinical and echocardiographycally. RESULTS: In 39 cases valve replacement was performed before ending antibiotic therapy. The main indications for surgery were refractory heart failure (24 patients) and shock (11 patients). The mortality rate was 24%: 19% in native valve infective endocarditis, 43% in early prosthetic valve endocarditis and 33% in late prosthesis valve endocarditis. The first cause of death was septic shock (46%). We followed 31 over 34 survivors for a mean time 65 (DS 49) months. We found two relapses and six deaths (1 sudden death, 2 endocarditis) and 72% of patients presented class I NYHA. We detected 17% prosthetic leaks (34% in the prosthetic valve endocarditis group). CONCLUSIONS: The need of urgent valve replacement in the context of infective endocarditis is associated with a high mortality rate, and should be considered a serious condition. Long term prognosis is, however, acceptable, although 17% of patients had prosthesis leak, specially those with prosthetic valve endocarditis.

Exposición mercurial y estado de salud del personal que labora en el Servicio de Odontología del IPASME Barquisimeto / Mercury exposure and health status of the personnel working at the Dental Service of the IPASME Barquisimeto

Con el objeto de investigar la exposición mercurial y estado de salud del personal que labora en el Servicio de Odontología de la Unidad de IPAS-ME Barquisimeto, se realizó un estudio de corte transversal, utilizándose una muestra de cuarenta y siete trabajadores del Servicio de Odontología, lo cual representa un 92 por ciento del total de la población. Para investigar la exposición del metal mercurio en la orina recolectada en 24 horas, se realizaron análisis de laboratorio, además de exámenes complementarios: Hematología completa, Glicemia y pruebas renales y examen físico. Entre los resultados más relevantes se encontró que la población estudiada presentó niveles aceptables de Hg en orina, un 62 por ciento el nivel básico (0,6 mcg/lts), un 17 por ciento cifras entre 07-14 mcgs/lts, un 19 por ciento cifras entre 15.29mcgs/lts, un 2 por ciento en el nivel de intoxicación preclínica no encontrándose valores iguales o mayor a 50 mcgs/lts, el cual se considera como el índice de contaminación mercurial. Cabe destacar que los resultados de valores mercuriales en los ambientes del Servicio de Odontología se ubicaron por debajo de 0,05 mg/m3 de aire, concentración máxima permitida en ambiente de trabajo en Venezuela, por lo tanto se concluye que no existe exposición a la contaminación mercurial en el personal que labora en el Servicio de Odontología de la Unidad IPAS-ME Barquisimeto. Se espera que con los resultados obtenidos se elaboren y apliquien programas preventivos sobre la contaminación mercurial, con la finalidad de evitar el inicio del proceso de enfermedad debido a la falta de información sobre las normas de higiene mercurial

The development of a prognostic score for patients with parotid carcinoma.

BACKGROUND: Understanding of prognostic factors in parotid carcinoma has grown considerably. In particular, clinical tumor staging and histologic classification have been found to be prognostically important. Univariate and multivariate analyses have indicated that other variables, such as age, pain, skin invasion, and facial nerve impairment, are important predictors as well. In an actual patient, some of these factors are present and others are absent. However, a clinical tool incorporating this information, resulting in an individualized prognosis based on the combined effects of present adverse prognostic factors, has never been devised. METHODS: Of a cohort of 168 patients, 151 were evaluated to assess the prognostic value of clinical and pathologic factors in a multivariate proportional hazards analysis. Follow-up ranged from 1 to 278 months (median, 37 months). The end point was tumor recurrence. Identified prognostic factors and their hazard ratios were combined into prognostic scores. RESULTS: Clinical T classification, clinical N classification, pain, age at diagnosis, skin invasion, facial nerve dysfunction, perineural growth, and positive surgical margins acted as major factors predicting recurrence. A prognostic score (PS), generated by the weighted combination of the factors present in the individual patient, placed the patient in one of four subgroups with markedly different prognoses. In the subgroups based on the preoperative prognostic score, 5-year recurrence free percentages ranged from 92% (in the group PS1=1) to 23% (in PS1=4). In the subgroups based on the postoperative prognostic score, which took into account the histologic details of the resected specimen, 5-year recurrence free percentages ranged from 95% (in the group PS2=1) to 42% (in PS2=4). CONCLUSIONS: The proposed subgrouping, which is based on the combined effects of key prognostic preoperative and postoperative factors, provides a practical prognostic grouping system for the clinician treating patients with parotid carcinoma.

Prognostic factors for long term results of the treatment of patients with malignant submandibular gland tumors.

BACKGROUND: Concerning malignant submandibular gland tumors, a rare disease entity, there are few recent reports of long term treatment results and of prognostic factors modifying these results. METHODS: The clinical data of 43 patients with malignant submandibular gland tumors who were treated at the Netherlands Cancer Institute between 1973 and 1994 were reviewed to evaluate treatment results and to control described prognostic factors. The median follow-up for patients alive at the end of follow-up was 143 months. Only univariate analyses were performed. RESULTS: The crude 5- and 10-year survival rates were 50% and 36%, respectively; the 5- and 10-year disease specific survival (DSS) rates were 61% and 51%, respectively; and the 5- and 10-year recurrence free percentages were 57% and 52%, respectively. Factors predicting crude survival were age at diagnosis (P = 0.0006), International Union Against Cancer/American Joint Committee on Cancer (UICC/ AJCC) TNM classification and its regrouping into tumor stage (P = 0.001), and clinical skin invasion (P = 0.005). In surgically treated patients, soft tissue invasion (P = 0.005), metastatic lymph nodes (P = 0.006), and perineural growth (P = 0.01) were prognostic for survival. Factors predicting DSS were the UICC/AJCC TNM classification and regrouping into tumor stage (P = 0.002). In surgical patients, perineural growth (P = 0.0008) conferred a lower DSS. Factors predicting tumor recurrence were the UICC/AJCC TNM classification and its regrouping into tumor stage (P = 0.009). In surgical patients, perineural growth (P = 0.003) predicts tumor recurrence. CONCLUSIONS: Of patients with submandibular gland carcinoma treated according to a stable treatment protocol in a European tertiary referral center, 52% were tumor free 10 years later. Patients exhibiting the described adverse prognostic factors are likely to benefit from added radiotherapy.

Reactive airways dysfunction syndrome (RADS) following exposure to toxic gases of a swine confinement building.

We describe the case of a 58 year old male, who developed a reactive airways dysfunction syndrome (RADS) after exposure to a high level of toxic gases in a swine confinement building. This previously healthy, nonatopic man developed moderate, partially reversible, airway obstruction and increased responsiveness within a month after the toxic exposure. The circumstances of the incident and the concomitant death of two sows make it likely that hydrogen sulphide was the causative agent. To our knowledge, this is the first case of reactive airways dysfunction syndrome reported from swine confinement buildings and, therefore, should raise awareness of this potential risk in that work environment.

Myxoma of the paranasal sinuses.

Myxomas of the paranasal sinuses are rare but well described in the literature. They may be related to dental malformations or missing teeth, but may also occur without any such abnormalities. Their local aggressiveness and ability to erode bone should not be underestimated, and they should be totally removed whenever possible. A case of myxoma of the sinuses is described, in which recurrence followed several local removals. The patient was only cured by radical maxillectomy. The operation is described, and the literature on the subject reviewed.

Participation of the SOS system in producing deletions in E. coli plasmids.

The participation of the SOS response in the deletion of palindromic and non-palindromic inserts of about 66 and 100 bp cloned within the EcoR1 site of the chloramphenicol acetyl transferase (cat) gene of plasmid pBR325 was tested after introducing the derived plasmids into strains containing different combinations of lexA, recA and umuC alleles and the auxotrophic mutation trpE65. This allowed for a comparison of deletion frequency in the plasmids, measured as the reversion of chloramphenicol sensitivity to resistance (Cms-->Cmr), to point-mutation frequency measured from the reversion of trpE65 to tryptophan independence (Trp(-)-->Trp+). We found that the spontaneous deletion frequency of palindromic inserts was increased by the overproduction of activated RecA* and UmuC+ in lexA (Def) backgrounds but the deletion of the non-palindromic inserts was unaltered. Overproduction of RecA+ had no significant effect on deletion incidence but it did increase Trp(-)-->Trp+ reversions. The SOS stimulation of palindrome deletions paralleled the SOS mutator effect of certain recA and umuC alleles on Trp(-)-->Trp+ reversions, suggesting that some form of SOS processing was responsible for the observed increases. The results further suggest that the SOS effect on deletions depends on the distinction between palindromy vs. non-palindromy, rather than on the sizes or sequences of the inserts or those of the terminal homologies bracketing them.

Transthyretin is an inhibitor of monocyte and endothelial cell interleukin-1 production.

Human serum was found to contain an inhibitor of constitutive interleukin-1 (IL-1) production by human umbilical vein endothelial cells (ECs). Purification of the serum activity by anion exchange chromatography, molecular sieve HPLC, and hydroxyl apatite chromatography yielded material 82% pure with a molecular weight of 17 kDa by SDS-PAGE. Amino acid sequencing revealed the purified inhibitor to be transthyretin (TTR), a liver-derived protein. There was a 42.6% reduction in the production of spontaneous IL-1 activity in EC supernatants after coculture with 10 micrograms/ml TTR. TTR was subsequently found by ELISA to inhibit LPS-stimulated IL-1 production by cells of the human monocytic leukemia line THP-1 by 47.1 +/- 9.4%, whereas a less striking but still significant inhibition of monocyte-derived IL-1 beta production was also observed. Inhibition of IL-1 secretion correlated with increased IL-1 mRNA synthesis in both THP-1 cells and monocytes. Furthermore, TTR was associated with increased intracellular concentrations of IL-1 beta. These data suggest that TTR functions by inhibiting processing of newly synthesized peptide for secretion. This novel inhibitory effect of TTR on the production of IL-1 activity suggests a previously unrecognized endogenous antiinflammatory mediator.

ABF1 is a phosphoprotein and plays a role in carbon source control of COX6 transcription in Saccharomyces cerevisiae.

Previously, we have shown that the Saccharomyces cerevisiae DNA-binding protein ABF1 exists in at least two different electrophoretic forms (K. S. Sweder, P. R. Rhode, and J. L. Campbell, J. Biol. Chem. 263: 17270-17277, 1988). In this report, we show that these forms represent different states of phosphorylation of ABF1 and that at least four different phosphorylation states can be resolved electrophoretically. The ratios of these states to one another differ according to growth conditions and carbon source. Phosphorylation of ABF1 is therefore a regulated process. In nitrogen-starved cells or in cells grown on nonfermentable carbon sources (e.g., lactate), phosphorylated forms predominate, while in cells grown on fermentable carbon sources (e.g., glucose), dephosphorylated forms are enriched. The phosphorylation pattern is affected by mutations in the SNF1-SSN6 pathway, which is involved in glucose repression-depression. Whereas a functional SNF1 gene, which encodes a protein kinase, is not required for the phosphorylation of ABF1, a functional SSN6 gene is required for itsd ephosphorylation. The phosphorylation patterns that we have observed correlate with the regulation of a specific target gene, COX6, which encodes subunit VI of cytochrome c oxidase. Transcription of COX6 is repressed by growth in medium containing a fermentable carbon source and is derepressed by growth in medium containing a nonfermentable carbon source. COX6 repression-derepression is under the control of the SNF1-SSN6 pathway. This carbon source regulation is exerted through domain 1, a region of the upstream activation sequence UAS6 that binds ABF1 (J. D. Trawick, N. Kraut, F. Simon, and R. O. Poyton, Mol. Cell Biol. 12:2302-2314, 1992). We show that the greater the phosphorylation of ABF1, the greater the transcription of COX6. Furthermore, the ABF1-containing protein-DNA complexes formed at domain 1 differ according to the phosphorylation state of ABF1 and the carbon source on which the cells were grown. From these findings, we propose that the phosphorylation of ABF1 is involved in glucose repression-derepression of COX6 transcription.

Interaction of recombinant monocyte-derived interleukin 1 receptor antagonist with rheumatoid synovial cells.

Interleukin 1 receptor antagonist (IL-1ra) is a newly described cytokine that is produced by human monocytes cultured on adherent immunoglobulin G (IgG). These studies have characterized the binding of IL-1ra to receptors on human rheumatoid synovial cells in comparison to binding of IL-1 alpha. The human synovial cells bound 35S-IL-1ra with a Kd of 213 pM and a Ki of 134 pM. 125I-IL-1 alpha bound to the synovial cells with similar values, showing a Kd of 205 pM and a Ki of 58 pM. Cross-inhibition studies were performed to examine whether IL-1ra and IL-1 alpha interacted with the same receptors and in an identical fashion. At the highest concentrations of inhibitory proteins, the binding of each ligand was inhibited 100% by the same or opposite ligand. This result indicated that IL-1ra and IL-1 alpha bound to the same receptors and not to overlapping subsets of receptors. In addition, the binding of 35S-IL-1ra was inhibited in an identical fashion by equimolar amounts of IL-1ra or IL-1 alpha. However, twofold or greater amounts of IL-1ra in comparison to IL-1 alpha were required to offer comparable inhibition of binding of 125I-IL-1 alpha. These results suggest that IL-1ra and IL-1 alpha bind with equal avidity to IL-1 receptors but may not bind identically. Additional experiments are necessary to establish whether these two ligands may bind to different regions of the extracellular portion of the IL-1 receptor.