Vitamin D binding protein, but not vitamin D or vitamin D-related peptides, is associated with septic shock mortality / La proteína transportadora de vitamina D, pero no la vitamina D ni los péptidos derivados de ella se asocia con la mortalidad de los pacientes en shock séptico

BACKGROUND: The aim of this study was to assess the prognostic value of vitamin D, vitamin D binding protein (VDBP) and vitamin D-related peptides in septic shock patients in relation to hospital mortality. METHODS: This is a single-center, prospective, observational study that included all consecutive patients meeting criteria for septic shock who were admitted to the ICU. VDBP, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, cathelicidin and beta-defensin levels were determined in blood samples obtained on admission to the ICU. RESULTS: Seventy-five patients were studied. The best area under the curve (AUC) for prediction of in-hospital mortality was for VDBP (0.78), with a negative predictive value of 85.45% for the optimal cut-off point. VDBP was also the only variable that had a statistically significant association with a higher risk of in-hospital mortality, regardless of other assessed variables and pre-determined confounders: adjusted odds ratio of 5.20 (95% confidence interval: 1.21-22.36). When restricted to patients with vitamin D insufficiency (n = 54), the AUC was 0.77, and the adjusted OR 12.22 (95% CI: 1.46-102.14; p = 0.021) for in-hospital mortality. CONCLUSIONS: VDBP levels showed a statistically significant association with in-hospital mortality, supporting the clinical utility of VDBP as a good prognostic marker in septic shock patients. Vitamin D and vitamin D-related peptides are not associated with in-hospital mortality. These results should be confirmed in a multicentre study with a larger sample size

INTRODUCCIÓN: El objeto de este estudio fue evaluar el valor pronóstico de la vitamina D, la proteína transportadora de la vitamina D (PTVD) y de los péptidos derivados de la vitamina D en relación a la mortalidad hospitalaria de los pacientes en shock séptico. MÉTODOS: Se trata de un estudio prospectivo unicéntrico observacional que incluyo consecutivamente a todos los pacientes que ingresan en la UCI en shock séptico. Los valores de la PTVD, 25-hydroxy vitamina D, 1,25-dihydroxy vitamina D, catelicidina y beta-defensina se cuantificaron en muestras sanguíneas extraídas en el momento del ingreso en la UCI. RESULTADOS: Se incluyeron un total de 75 pacientes. La mejor área bajo la curva (AUC) para la predicción de mortalidad hospitalaria fue para la PTVD (0,78), con un valor predictivo negativo del 85,45% para el punto de corte óptimo. La PTVD fue además la única variable asociada estadísticamente con un mayor riesgo de mortalidad hospitalaria independientemente de las otras variables evaluadas y de los factores de confusión prestablecidos: odds ratio ajustada 5,20 (intervalo de confianza [IC] 95%: 1,21-22,36). Cuando el estudio se focalizó en los pacientes con insuficiencia de vitamina D (N = 54), el AUC fue de 0,77 y la odds ratio ajustada de 12,22 (IC 95%: 1,46-102,14; p = 0,021) en relación a la mortalidad hospitalaria. CONCLUSIONES: Los valores sanguíneos de la PTVD se asociaron de forma estadísticamente significativa con la mortalidad hospitalaria, apoyando la potencial utilidad clínica de la PTVD como un buen marcador pronóstico en los pacientes en shock séptico. La vitamina D y los péptidos derivados de ella no relacionaron con la mortalidad hospitalaria. Estos resultados deben ser confirmados en un estudio multicéntrico con mayor número de pacientes

Vitamin D binding protein, but not vitamin D or vitamin D-related peptides, is associated with septic shock mortality.

BACKGROUND: The aim of this study was to assess the prognostic value of vitamin D, vitamin D binding protein (VDBP) and vitamin D-related peptides in septic shock patients in relation to hospital mortality. METHODS: This is a single-center, prospective, observational study that included all consecutive patients meeting criteria for septic shock who were admitted to the ICU. VDBP, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, cathelicidin and beta-defensin levels were determined in blood samples obtained on admission to the ICU. RESULTS: Seventy-five patients were studied. The best area under the curve (AUC) for prediction of in-hospital mortality was for VDBP (0.78), with a negative predictive value of 85.45% for the optimal cut-off point. VDBP was also the only variable that had a statistically significant association with a higher risk of in-hospital mortality, regardless of other assessed variables and pre-determined confounders: adjusted odds ratio of 5.20 (95% confidence interval: 1.21-22.36). When restricted to patients with vitamin D insufficiency (n=54), the AUC was 0.77, and the adjusted OR 12.22 (95% CI: 1.46-102.14; p=0.021) for in-hospital mortality. CONCLUSIONS: VDBP levels showed a statistically significant association with in-hospital mortality, supporting the clinical utility of VDBP as a good prognostic marker in septic shock patients. Vitamin D and vitamin D-related peptides are not associated with in-hospital mortality. These results should be confirmed in a multicentre study with a larger sample size.

Influence of interleukin 10 promoter polymorphisms in polymyalgia rheumatica: disease susceptibility and functional consequences.

OBJECTIVES: To investigate the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to, and disease phenotype, in patients with polymyalgia rheumatica (PMR). METHODS: A total number of 168 with PMR and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. The levels of circulating IL10 and the production of IL10 by PBMCs after in vitro stimulation were studied by Cytometric Bead Array. RESULTS: No significant differences were observed in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. No significant differences between PMR patients with low ESR (<40 mm/hr) and classic PMR (>40 mm/hr) were found. Furthermore, we did not observe any influence of circulating IL10 with the intensity of the acute phase response. In both, PMR patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. CONCLUSIONS: These results do not support the impact of IL10 variants in susceptibility or clinical phenotype of PMR patients. In this aged population no functional association was found between IL10 gene variants and IL10 production.

Cytokine gene considerations in giant cell arteritis: IL10 promoter polymorphisms and a review of the literature.

Polymorphisms of cytokine genes have been investigated as susceptibility markers of giant cell arteritis (GCA). Here, we have reviewed the evidence to date and especially addressed the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to and disease phenotype in GCA. A total number of 71 patients with GCA and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. As previous studies in GCA showed inconsistent results, a meta-analysis of the existing studies was also conducted by using both fixed and random-effects models. The levels of circulating IL10 and the production of IL10 by peripheral blood mononuclear cells after in vitro stimulation were studied by Cytometric Bead Array. Data showed no significant differences in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. However, the meta-analysis found a significant association of IL10 -592C/A polymorphism with susceptibility to GCA (odds ratio 2.205 (95% confidence interval 1.074-4.524); p = 0.031). In both patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. In conclusion, although our cohort results do not support the impact of IL10 variants in susceptibility or clinical phenotype of GCA patients, the meta-analysis revealed a significant association of -592C/A polymorphism with susceptibility to GCA. In this population, no functional association was found between IL10 gene variants and IL10 production.

Homocysteine and cognition in first-episode psychosis patients.

In the last years, there has been growing evidence linking elevated homocysteine levels with cognitive dysfunction in several neurological and neuropsychiatric diseases. The aim of the present study was to investigate the potential relationship between elevated homocysteine levels and cognitive deficits in first-episode psychosis patients. Plasma levels and cognitive performance of 139 patients and 99 healthy volunteers were compared. Patients were classified as elevated homocysteine (>90 percentile for controls) and normal and compared on 22 cognitive outcome measures grouped into cognitive domains known to be impaired in schizophrenia. Patients had a statistically significant increase in plasmatic homocysteine levels. In addition, they presented with significantly increased cognitive deficits. However, no relationship between homocysteine levels and cognitive impairment was detected. These results suggest the need for further studies to clarify the role of homocysteine in the etiology and prognosis of psychosis.

Age and low levels of circulating vitamin D are associated with impaired innate immune function.

This study investigated in vivo the influence of age and vitamin D status on innate immune function in HC. Serum 25OHD was measured in 71 HC. TLR expression on various subpopulations of PBMCs, as well as TLR function by stimulating PBMCs with specific ligands, was assessed by flow cytometry. Circulating cathelicidin levels were determined by ELISA. Serum 25OHD levels decreased with age, and there was a significant inverse correlation between 25OHD levels and age. There was a negative correlation between serum 25OHD levels and MFI expression of TLR7 on B cells, T cells, and monocytes. TLR7 function, addressed by in vitro stimulation with a specific agonist, was significantly correlated with serum 25OHD levels, and this was especially a result of the results in HC older than 60 years. MFI expression of TLR5 on T cells and TLR2 on monocytes was also negatively correlated with serum 25OHD levels. TLR1 (monocytes) and TLR2 (monocytes) expression was positively correlated with age. Furthermore, TLR4 and TLR8 function was negatively correlated with age. Circulating cathelicidin levels decreased with age and were positively correlated with 25OHD levels. Aging is accompanied by changes in expression and function of several TLRs. Serum 25OHD levels decrease with age and are also associated with a change in expression and defective function of certain TLRs, especially those involved in viral response.

Toll-like receptor 4 gene polymorphisms in polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVES: Coding variants in TLR4 gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (Asp299Gly and Thr399Ile) of TLR4 contribute to the genetic background of polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we have attempted to correlate the functional consequences of these polymorphisms. METHODS: 164 patients with PMR, 93 with EORA and 126 unrelated age-matched controls were genotyped. The TLR4 genotypes were determined using allele-specific primers and restriction fragment length polymorphism analysis. Association of genotypes and alleles with disease susceptibility and disease phenotypes were studied. TLR4 expression was assessed on PBMCs by flow cytometry and TLR4 function was assessed by stimulating PBMCs in vitro with LPS. RESULTS: No significant difference in allele frequency or genotype between patients with elderly-onset inflammatory conditions and controls was observed. The Thr399Ile CC genotype was associated with a higher cumulative dose of corticosteroids in patients with PMR (p=0.031). We found no association with TLR4 expression on B cells, T cells or monocytes or a distinct phenotype of TLR4 response with the Asp299Gly or Thr399Ile genotypes. CONCLUSIONS: These results do not support the association of these TLR4 variants with two age-related inflammatory conditions. The value of determining Thr399Ile genotypes for disease prognosis in PMR should be confirmed in different populations.

Lack of association between Toll-like receptor 4 gene polymorphisms and giant cell arteritis.

OBJECTIVE: Coding variants in Toll-like receptor 4 (TLR4) have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (+896 A/G and +1196 C/T) are associated with susceptibility and clinical features of GCA. We also attempted to correlate the functional consequences of these polymorphisms. METHODS: A total of 72 patients with GCA and 126 age-matched controls were genotyped using allele-specific PCR and restriction fragment length polymorphism analysis. TLR4 expression was studied on peripheral blood mononuclear cells by flow cytometry and TLR4 function was assessed by stimulating monocytes in vitro with a specific ligand. RESULTS: There was no significant difference in allele frequency or genotype of TLR4 (+896 A/G and +1196 C/T) between GCA patients and controls. The clinical characteristics of these patients were unrelated to the presence of these polymorphisms. Furthermore, we did not observe an association with TLR4 expression or a distinct phenotype of TLR4 response with the +896 A/G and +1196 C/T genotypes. CONCLUSION: Our results do not support the association of these TLR4 variants with GCA. Studies including a larger number of patients and patient populations from different geographical origin are needed.

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand system in the early post-operative period of liver transplantation.

BACKGROUND: The precise mechanism that leads to accelerated bone resorption in the early post-transplant period remains unclear. Recent data suggest that osteoprotegerin (OPG) and its ligand receptor activator of nuclear factor-kappaB ligand (RANKL) constitute a novel cytokine system that can influence the function of both bone and immune cells. The aim of our study was to assess OPG and RANKL concentrations in the early post-operative period of liver transplantation. METHODS: Serum OPG and RANKL levels were measured in 30 patients who underwent liver transplantation at 1, 7 and 14 d post-operatively. These values were compared with 22 age- and sex-matched healthy controls. Plasma sodium, creatinine, aspartate-aminotransferase, alanine-amino transferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time, tacrolimus and cyclosporine levels were measured in each patient. RESULTS: We found a significant increase in OPG levels in the early post-operative period compared with the control group: day 1 (10.42 pmol/L, range 3.80-17.50 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001), day 7 (6.90 pmol/L, range 3.00-15.30 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001) and day 14 (5.76 pmol/L, range 2.60-10.70 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.001). Similarly, serum RANKL levels were significantly higher than in the control group in this period, day 1 (0.123 pmol/L, range 0.010-0.420 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.02), day 7 (0.236 pmol/L, range 0.010-0.720 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.0004) and day 14 (0.137 pmol/L, range 0.010-0.520 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.007). No correlation was found between OPG levels and RANKL, ischemic times, liver function tests, albumin, sodium or creatinine concentrations and tacrolimus or cyclosporine levels. CONCLUSIONS: A significant amount of OPG and RANKL is released in the early post-transplant period of liver transplantation. This might be explained by an activation of the immune system caused by the allograft. Therefore, the RANKL/OPG system may be involved in the pathophysiological evolution of transplantation osteoporosis.

[Electrolyte disorders following colonic cleansing for imaging studies]. / Alteraciones electrolíticas inducidas por la preparación para los estudios de imagen del colon.

BACKGROUND AND OBJECTIVE: An adequate bowel cleansing is needed prior to radiologic and endoscopic procedures. However, it may have a number of adverse effects, including abnormalities of calcium-phosphorus homeostasis. PATIENTS AND METHOD: This was an observational prospective study in a hospital practice setting. We included consecutive inpatients (n = 47) subjected to a barium enema or colon endoscopy. Prior cleansing was done as indicated by the attending physician by using a low-salt oral poliethylenglicol (PEG) solution, oral sodium phosphate or a phosphate-containing enema. RESULTS: PEG solution frequently caused mild increases in serum sodium, and decreases in serum potassium. Oral phosphate caused a significant increase in serum phosphorus and parathormone concentrations, whereas it decreased serum calcium. Mild hyperphosphatemia was found in 57% of cases, and hypocalcemia in 36%. Phosphate enema also increased serum phosphate, causing mild hyperphosphatemia (33% cases). Although in the whole subgroup of enema-treated patients there were no significant changes in serum calcium, mild hypocalcemia was found in 27% cases. CONCLUSIONS: Bowel cleansing procedures, particularly those using oral phosphate salts, frequently induce hyperphosphatemia and other abnormalities in serum electrolytes. Although usually transitory and without overt clinical consequences, clinicians should be aware of this potential risk, especially in elderly patients and those with impaired renal function.

Alteraciones electrolíticas inducidas por la preparación para los estudios de imagen del colon / Electrolyte disorders following colonic cleansing for imaging studies

Fundamento y objetivo: La limpieza intestinal es imprescindible para que los estudios de imagen del colon sean eficaces. Sin embargo, no está exenta de riesgos. En particular, recientemente se ha llamado la atención sobre la posibilidad de que ocasione alteraciones del metabolismo fosfocálcico. Este estudio se ha diseñado para evaluar sistemáticamente estas alteraciones en pacientes hospitalizados. Pacientes y método: Se ha realizado un estudio observacional prospectivo en un entorno de práctica hospitalaria habitual. Se incluyó en él a los pacientes hospitalizados consecutivos que iban a ser sometidos a un estudio endoscópico o radiológico del colon (n = 47). La preparación previa se llevó a cabo, según el criterio del médico a cargo del paciente, con uno de los 3 preparados siguientes: solución de polietilenglicol (PEG) con baja concentración de sales, fosfato sódico por vía oral (Fosfosoda®) o fosfato sódico en enemas. Resultados: La solución de PEG indujo frecuentemente hipernatremia e hipopotasemia ligeras, sin alterar la homeostasia fosfocálcica. El fosfato sódico oral provocó además un aumento significativo de la fosfatemias y un descenso de la calcemia, con un incremento compensador de la hormona paratiroidea. El 57% de los pacientes presentó valores de fósforo por encima del intervalo de referencia, mientras el 36% presentó calcemias inferiores al límite normal. El fosfato sódico en enemas no provocó cambios en las concentraciones de sodio y potasio, pero también aumentó significativamente la fosfatemia y la hormona paratiroidea. En un 33% de los casos provocó hiperfosfatemia. Aunque los cambios globales de la calcemia no fueron estadísticamente significativos, en un 27% de los pacientes que recibió enemas la concentración de calcio se redujo por debajo del límite inferior de la normalidad. Conclusiones: Las preparaciones de limpieza intestinal, en particular las basadas en el fosfato oral, se asocian frecuentemente a alteraciones electrolíticas. Aunque en general son autolimitadas y sin repercusión clínica, estas complicaciones deben tenerse en cuenta en pacientes de riesgo, como los ancianos y los que presentan insuficiencia renal

Background and objective: An adequate bowel cleansing is needed prior to radiologic and endoscopic procedures. However, it may have a number of adverse effects, including abnormalities of calcium-phosphorus homeostasis. Patients and method: This was an observational prospective study in a hospital practice setting. We included consecutive inpatients (n = 47) subjected to a barium enema or colon endoscopy. Prior cleansing was done as indicated by the attending physician by using a low-salt oral poliethylenglicol (PEG) solution, oral sodium phosphate or a phosphate-containing enema. Results: PEG solution frequently caused mild increases in serum sodium, and decreases in serum potassium. Oral phosphate caused a significant increase in serum phosphorus and parathormone concentrations, whereas it decreased serum calcium. Mild hyperphosphatemia was found in 57% of cases, and hypocalcemia in 36%. Phosphate enema also increased serum phosphate, causing mild hyperphosphatemia (33% cases). Although in the whole subgroup of enema-treated patients there were no significant changes in serum calcium, mild hypocalcemia was found in 27% cases. Conclusions: Bowel cleansing procedures, particularly those using oral phosphate salts, frequently induce hyperphosphatemia and other abnormalities in serum electrolytes. Although usually transitory and without overt clinical consequences, clinicians should be aware of this potential risk, especially in elderly patients and those with impaired renal function

Osteoprotegerin and RANKL in alcoholic liver cirrhosis.

BACKGROUND/AIMS: The mechanisms leading to osteoporosis in alcoholic liver disease remain poorly understood. Recently identified soluble circulating osteoprotegerin (OPG), is the osteoclastogenesis inhibitory factor. It acts as a decoy receptor for osteoclast activating factor, receptor activator of nuclear factor-kappaB ligand (RANKL), and impairs osteoclast function. The aim of our study was to investigate the OPG/RANKL system in alcoholic cirrhotic patients and their correlation with biochemical marker of bone turnover. PATIENTS AND METHODS: Serum OPG, RANKL, osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX-I), bone alkaline phosphatase activity (bALP), and urinary hydroxyproline were measured in 30 patients with alcoholic cirrhosis, and in 20 age- and sex-matched healthy controls. RESULTS: OPG levels were significantly increased in patients with alcoholic cirrhosis compared with healthy subjects (5.9 pmol/l, range 2.7-9.0 vs 4.1 pmol/l, range 1.2-6.6; P < 0.001). RANKL levels were significantly higher in patients with cirrhosis (0.48 pmol/l, range 0.01-1.34) than in healthy subjects (0.11 pmol/l, range 0.01-0.90). There was a positive correlation between serum OPG and RANKL (r = 0.37; P < 0.001), bALP (r = 0.66; P < 0.001) and urinary hydroxyproline (r = 0.51; P < 0.05) but not with OC and CTX-I. CONCLUSIONS: OPG might partly represent a compensating mechanism to the negative balance of bone remodelling in patients with alcoholic cirrhosis.