Experience with 2 years' intervention to progressively reduce salt supply to kitchens in elderly care facilities-challenges and further research: post hoc analysis of the DECIDE-Salt randomized clinical trial.

BACKGROUND: Progressive reduction of sodium intake is an attractive approach for addressing excessive salt intake, but evidence for this strategy in real practice is limited. We aimed to determine the feasibility, effectiveness, and safety of a progressive sodium intake reduction intervention in real-world setting. METHODS: We randomized 48 residential elderly care facilities in China, with 1612 participants aged 55 years and older, to either progressive reduction (PR, 24 facilities) or no reduction (NR, 24 facilities) of the supply of study salt to the kitchens of these facilities for 2 years. The primary efficacy outcome was systolic blood pressure (SBP) at any scheduled follow-up visit. Secondary efficacy outcomes included diastolic blood pressure (DBP) at any scheduled follow-up visit, and major adverse cardiovascular events (comprising non-fatal stroke, non-fatal myocardial infarction, hospitalized non-fatal heart failure, or vascular death) and total mortality. The perception of food saltiness, the addition of out-of-study salt in meals, and 24-h urinary sodium excretion were used as process indicators. RESULTS: Pre-specified analysis per randomization found no effect of the intervention on the 2-year overall mean systolic and diastolic blood pressure (SBP, DBP) and any other outcomes. However, post hoc analysis showed that the intervention effect on blood pressure varied over multiple follow-up visits (p for interaction < 0.046) and presented favorable differences at the 24-month visit (SBP = - 3.0 mmHg, 95%CI = - 5.6, - 0.5; p = 0.020; DBP = - 2.0 mmHg, 95%CI - 3.4, - 0.63; p = 0.004). The effect on 24-h sodium was non-significant (- 8.4 mmol, 95%CI = - 21.8 to 4.9, p = 0.216), though fewer participants with NR than with PR reported food tasting bland (odds ratio 0.46; 95%CI 0.29 to 0.73; p = 0.001). Reporting of bland food taste and other process measures indicated that intervention delivery and adherence were not fully achieved as designed. CONCLUSIONS: The experience of this real-world study demonstrated that achieving acceptability and sustainability of the progressive sodium intake reduction strategy among older adults was challenging, but it has shown potential for effectiveness in these and potentially other residential settings if the lessons of DECIDE-Salt are applied in further studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03290716).

Salt substitution and salt-supply restriction for lowering blood pressure in elderly care facilities: a cluster-randomized trial.

There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (-7.1 mmHg, 95% confidence interval (CI) -10.5 to -3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure. Salt substitute also lowered diastolic blood pressure (-1.9 mmHg, 95% CI -3.6 to -0.2) and resulted in fewer cardiovascular events (hazard ratio (HR) 0.60, 95% CI 0.38-0.96), but had no effect on total mortality (HR 0.84, 95% CI 0.63-1.13). From a safety standpoint, salt substitute increased mean serum potassium and led to more frequent biochemical hyperkalemia, but was not associated with adverse clinical outcomes. In contrast, salt restriction had no effect on any study outcome. The results of this trial indicate that use of salt substitute, but not efforts to restrict salt supply, may achieve blood pressure lowering and deliver health benefits to residents of elderly care facilities in China. Clinicaltrials.gov registration: NCT03290716.

Cost-effectiveness analysis of tenofovir/emtricitabine and abacavir/lamivudine in combination with efavirenz or atazanavir/ritonavir for treatment-naïve adults with HIV-1 infection in the UK, based on the AIDS Clinical Trials Group 5202 clinical trial.

OBJECTIVES: The aim of the study was to assess the cost-effectiveness of the four regimens studied in the AIDS Clinical Trials Group (ACTG) 5202 clinical trial, tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) in combination with efavirenz (EFV) or atazanavir/ritonavir (ATV/r), for treatment-naïve adults with HIV-1 infection in the UK. METHODS: A Markov model with six health states based on CD4 cell count ranges was developed to predict long-term costs and health outcomes for individuals on first-line therapy. Head-to-head efficacy data comparing TDF/FTC + EFV, TDF/FTC + ATV/r, ABC/3TC + EFV, and ABC/3TC + ATV/r were obtained from ACTG 5202 for up to 192 weeks. Antiretroviral drug costs were based on current list prices. Other medical costs (2013 UK pounds sterling), utility values, and mortality rates were obtained from published sources. Base-case, sensitivity, and subgroup analyses (by baseline viral load) were conducted. RESULTS: Individuals using TDF/FTC-based regimens were predicted to remain on first-line therapy longer and accrue more quality-adjusted life-years (QALYs) than individuals using ABC/3TC-based regimens. At a willingness-to-pay threshold of £30 000 per QALY gained, TDF/FTC-based regimens were predicted to be cost-effective compared with ABC/3TC-based regimens, with incremental cost-effectiveness ratios of £23 355 for TDF/FTC + EFV vs. ABC/3TC + EFV and £23 785 for TDF/FTC + ATV/r vs. ABC/3TC + ATV/r. Results were generally robust in subgroup, sensitivity, and scenario analyses. CONCLUSIONS: In an analysis of the regimens studied in ACTG 5202 for treatment-naïve adults with HIV-1 infection in the UK, TDF/FTC-based regimens yielded more favourable health outcomes and were generally predicted to be cost-effective compared with ABC/3TC-based regimens. These results confirm that TDF/FTC-based regimens are not only clinically effective but also cost-effective.

Cámara de retina no midriática: estudio de coste-efectividad en la detección temprana de la retinopatía diabética / Non mydriatic retinal camera: cost-effectiveness study for early detection of diabetic retinopathy

FUNDAMENTO Y OBJETIVO: Realizar un análisis de coste-efectividad (ACE) de la aplicación de la fotografía de fondo de ojo con cámara de retina no midriática (Ffo-CNM) en el diagnóstico temprano de la retinopatía diabética, comparado con la oftalmoscopia con dilatación pupilar. PACIENTES Y MÉTODO: Se incluyó a los pacientes diabéticos mayores de 14 años atendidos en tres áreas básicas de salud (n = 1.495). Para la medida de efectividad se utilizaron los casos verdaderos positivos detectados (VPD) y casos correctamente diagnosticados. La medida de coste fue el coste total por paciente. El ACE se definió como coste esperado por caso VPD y como coste esperado por caso correctamente diagnosticado. Los resultados se sometieron a un análisis de sensibilidad de las variables clave del estudio. RESULTADOS: La Ffo-CNM presentó una sensibilidad del 90,91 por ciento (intervalo de confianza [IC del 95 por ciento] 69,4-98,4 por ciento), una especificidad del 78,21 por ciento (IC del 95 por ciento, 67,1-86,4 por ciento), un valor predictivo positivo del 54,05 por ciento (IC del 95 por ciento, 37,1-70,2 por ciento) y un valor predictivo negativo del 96,83 por ciento (IC del 95 por ciento, 88,0-99,4 por ciento). La efectividad, definida como caso VPD, fue del 15,4 por ciento para la oftalmoscopia y del 19,5 por ciento para la Ffo-CNM y, definida como caso correctamente diagnosticado, fue del 70 y el 79,8 por ciento, respectivamente. En cuanto a la razón coste-efectividad, para el sistema sanitario, el coste por caso VPD fue de 52,62 euros para la oftalmoscopia y de 28,44 euros para la FfoCNM, y el coste por caso correctamente diagnosticado fue de 11,58 y 6,95 euros, respectivamente; para la sociedad el coste por caso VPD fue de 100,13 euros para la oftalmoscopia y de 34,54 euros para la Ffo-CNM, y el coste por caso correctamente diagnosticado fue de 22,03 y de 8,44 euros, respectivamente. CONCLUSIONES: Si se decidiese la implantación de un programa de detección temprana de retinopatía diabética dirigido a toda la población diabética, la opción de hacerlo utilizando la FfoCNM sería la más eficiente (AU)

Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886.

Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Transcriptional regulation of intracellular IL-1 receptor antagonist gene by IL-1 alpha in primary mouse keratinocytes.

The inflammatory cytokine IL-1alpha mediates inflammatory reactions in skin and up-regulates the expression of other proinflammatory genes. We previously found that IL-1alpha also increases steady state mRNA levels for intracellular IL-1 receptor antagonist (icIL-1Ra) in primary mouse keratinocytes; however, the mechanism for this was unknown. Here we show that increased expression in primary keratinocytes is due to increased rates of transcription. To study the transcriptional regulation of icIL-1Ra expression induced by IL-1alpha, we functionally characterized 4.5 kb of the 5'-flanking region of the human icIL-1Ra gene. Deletion analysis showed that regulatory elements were contained in the -598- and -288-bp region upstream of the transcription start site. Then we investigated cis- and trans-acting factors required for icIL-1Ra expression and found that a NF-IL-6 site and a NF-kappaB site in the icIL-1Ra promoter were responsible for IL-1alpha-induced icIL-1Ra expression. Moreover, gel shift assays and cotransfection experiments showed that CCAAT/enhancer-binding proteins alpha, beta, and p65 bind to the NF-IL-6 site and NF-kappaB site, respectively, and functionally trans-activate the icIL-1Ra promoter. Finally, mutational analysis confirmed that these elements were both essential for maximal transcription induced by IL-1alpha.

Role of intracellular interleukin-1 receptor antagonist in skin carcinogenesis.

Interleukin 1 (IL-1) is a major mediator of inflammation and exerts pleiotropic effects on many systems. To elucidate the role of its endogenous inhibitor, intracellular IL-1 receptor antagonist (icIL-1Ra), in mouse skin, we produced an icIL-1Ra-overexpressing skin carcinoma cell line (icIL-1Ra-JWF2). Altered expression of icIL-1Ra did not change IL-1alpha mRNA levels in these transfected cells. In icIL-1Ra-JWF2 cells, however, cyclooxygenase-2 mRNA levels were dramatically reduced and shown to be transcriptionally regulated by icIL-1Ra. To determine the effect of icIL-1Ra on cell proliferation, cell counts were done 24 h after plating equal numbers of cells. Cells from three icIL-1Ra-JWF2 clones showed significantly reduced growth rates compared with parental JWF2 cells. We subcutaneously injected five independent clones of icIL-1Ra-JWF2 cells into nude mice and measured the tumor doubling time by weekly measurements of tumor volume. IcIL-1Ra appeared to significantly slow the growth of tumors in vivo. Collectively these observations suggest that IL-1Ra has antiproliferative effects in murine skin carcinoma cells.

Altered expression of interleukin-1 receptor antagonist in different stages of mouse skin carcinogenesis.

Interleukin-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of interleukin-1. The expression of IL-1Ra and interleukin-1alpha (IL-1alpha) was measured in murine epidermis after treatment with tumor promoters and in tumor cell lines. A single treatment with three different tumor promoters (12-O-tetradecanoylphorbol-13-acetate (TPA), anthralin, and thapsigargin) induced IL-1Ra mRNA with different kinetics in mouse skin. The expression of IL-1Ra mRNA also was induced by TPA and IL-1alpha in a dose-related and time-dependent manner in cultured mouse keratinocytes. Expression of IL-1Ra mRNA peaked 6 h after treatment. Both IL-1Ra and IL-1alpha protein and IL-1Ra and IL-1alpha mRNA were measured in various keratinocyte tumor cell lines (C50, MT1/2, HEL30, JWF2, CH72, and BPCC2). The expression of IL-1alpha was increased in papilloma and squamous cell carcinoma cell lines. IL-1Ra protein also was increased in nontumorigenic and papilloma cell lines; however, the expression was dramatically reduced in some carcinoma cell lines. Finally, we detected IL-1alpha and IL-1Ra protein in mouse skin tumors by western blot analysis, and localization was assessed by immunohistochemical analysis. Positive staining for both IL-1alpha and IL-1Ra was observed in the cytoplasm and was most prominent in the suprabasal layer. Although IL-1Ra protein increased in papillomas and carcinomas, IL-1alpha protein was not significantly increased above basal level in most tumors.

Effect of spray-dried yogurt and lactic acid bacteria on the initiation and promotion stages of chemically induced skin carcinogenesis in mice.

The effects of dietary spray-dried yogurt powder product (YPP) and two strains of lactic acid bacteria on the initiation and promotion stages of carcinogenesis were investigated using the 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model. In two independent studies, Sencar mice were fed a diet containing 86%, 43%, or 0% YPP or the 0% YPP diet supplemented with viable cultures of Lactobacillus acidophilus or bifidobacteria. Animals were initiated with a single topical application of DMBA (10 nmol). Promotion began three weeks later with twice weekly treatment of TPA (1 microgram/200 microliters acetone). During the initiation study (Study 1) the experimental diets were fed for four weeks before and one week after DMBA treatment. All mice were then switched to the AIN-76 diet. For the promotion study (Study 2) the experimental diets were begun one week after initiation and fed during the remainder of the study. Gross appearance of tumors was assessed weekly. No statistically significant differences in body weight or food disappearance were observed among the diet groups during the studies. For Studies 1 and 2, final histologically verified papilloma incidence and multiplicity and carcinoma incidence were not statistically different. These data suggest that different levels of YPP or lactic acid bacteria fed during the initiation or promotion stage of carcinogenesis do not significantly affect chemically induced skin tumor development.

Situación en Chile de algunos tumores del tracto gastrointestinal: consideraciones nutricionales / Gastrointestinal tumors state in Chile: nutritional factors

La importancia de los factores ambientales, especialmente los dietéticos, en la génesis de los principales cánceres del tracto gastrointestinal, es de preocupación en la actualidad. El objetivo de este estudio fue verificar la evolución de la mortalidad por cáncer gástrico, de colon y vesícula, su distribución etárea, sexo y regiones geográficas, como primera etapa en la identificación de factores nutricionales que pudieran determinar estos tumores en población chilena. Con la información oficial se construyeron series temporales desde 1977 hasta 1989 y se compararon diferencias regionales entre las tasas del último trienio de la década de los 70 y el de los 80. La tasa de mortalidad por cáncer gástrico disminuyó hasta 1986, manteniéndose estable desde entonces. Es más prevalente en el sexo masculino, en los mayores de 45 años y en las regiones de mayor producción agrícola. El cáncer de colon ha mantenido tasas prácticamente constantes durante el período observado, tiene mayores tasas de mortalidad en mujeres, especialmente sobre los 65 años. Su distribución geográfica es homogénea, con excepción de las Regiones de Valparaíso y Magallanes que presentan mayores tasas. Las tasas de mortalidad por cáncer de vesícula ha presentado un aumento en el tiempo, es mayor en el sexo femenino y en los mayores de 65 años. Se ha verificado un aumento mayor de sus tasas en las mismas regiones donde el cáncer gástrico tiene mayor mortalidad. Se proponen hipótesis nutricionales sobre estas diferencias y se sugieren líneas de investigaciones futuras