Twin studies indicate that genetic factors may explain about 50% of the variation of serum 25-hydroxyvitamin D (25OHD). Polymorphisms of 3 genes, delta-7-sterol-reductase, CYP2R1, and DBP/GC (and ...maybe CYP24A1) combined, can explain about 5% to 10% of the variation in serum 25OHD. These polymorphisms are found in nearly all populations. The variation in serum 25OHD found in different areas and populations in the world is mainly due to environmental and lifestyle factors, not truly dependent on racial differences. One genetic variant of DBP, (GC2), is associated with a modest (∼10%) decrease in serum DBP and 25OHD concentrations for unexplained reasons.
Context. Calcifediol has been proposed as a potential treatment for COVID-19 patients. Objective: To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized ...because of COVID-19. Design: Retrospective, multicenter, open, non-randomized cohort study. Settings: Hospitalized care. Patients: Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain. Intervention: Patients received calcifediol (25-hydroxyvitamin D3) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not. Main Outcome Measure: In-hospital mortality during the first 30 days after admission. Results: A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). Conclusion: Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.
Intensive Insulin Therapy in Critically Ill Patients Van den Berghe, Greet; Wouters, Pieter; Weekers, Frank ...
New England journal of medicine/The New England journal of medicine,
11/2001, Letnik:
345, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Hyperglycemia is common in critically ill patients, but it is not known whether normalization of blood glucose levels with insulin therapy improves the prognosis. This trial compared intensive ...insulin treatment (maintenance of blood glucose levels at 80 to 110 mg per deciliter) with conventional treatment in patients admitted to a surgical intensive care unit. Most of the patients did not have a history of diabetes. Intensive insulin therapy reduced mortality among patients who spent more than five days in the intensive care unit and reduced rates of multiple-organ failure due to sepsis and acute renal failure.
The results of this trial suggest that intensive treatment of modest hyperglycemia may have a substantial effect on the prognosis.
Critically ill patients who require intensive care for more than five days have a 20 percent risk of death and substantial morbidity.
1
Critical-illness polyneuropathy and skeletal-muscle wasting prolong the need for mechanical ventilation.
2
–
5
Moreover, increased susceptibility to severe infections and failure of vital organs amplify the risk of an adverse outcome.
Hyperglycemia associated with insulin resistance
6
–
8
is common in critically ill patients, even those who have not previously had diabetes. It has been reported that pronounced hyperglycemia may lead to complications in such patients,
9
–
13
although data from controlled trials are lacking. In diabetic patients with acute myocardial . . .
Severe vitamin D deficiency can be defined as the dose of vitamin D or serum 25OHD concentrations needed to prevent nutritional rickets or osteomalacia. There is large international consensus that ...these diseases can be prevented by 400 IU of vitamin D/d and 25OHD above 30 nmol/l (12 ng/ml). Vitamin D deficiency can also accelerate the risk of fractures and probably also of falls in elderly subjects but there is no consensus on the required daily doses or minimal 25OHD threshold for these endpoints. The majority of experts consider 800 IU/d and serum 25OHD above 50 nmol/l (20 ng/ml) as sufficient, with a minority opinion aiming for 75 nmol/l or even higher. For other extra-skeletal endpoints, no hard evidence is available to define whether or not this is causally related to vitamin D status. Therefore, for these endpoints no minimal dosage or 25OHD threshold can be defined.
The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious ...potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin–angiotensin–bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.
OBJECTIVESMaintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin ...dose vs. blood glucose control on the observed outcome benefits.
DESIGNA prospective, randomized, controlled trial.
SETTINGA 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital
PATIENTS AND INTERVENTIONA total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80–110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180–200 mg/dL.
MEASUREMENTS AND MAIN RESULTSIt was feasible and safe to achieve and maintain blood glucose levels at <110 mg/dL by using a titration algorithm. Stepwise linear regression analysis identified body mass index, history of diabetes, reason for intensive care unit admission, at-admission hyperglycemia, caloric intake, and time in intensive care unit as independent determinants of insulin requirements, together explaining 36% of its variation. With nutritional intake increasing from a mean of 550 to 1600 calories/day during the first 7 days of intensive care, normoglycemia was reached within 24 hrs, with a mean daily insulin dose of 77 IU and maintained with 94 IU on day 7. Insulin requirements were highest and most variable during the first 6 hrs of intensive care (mean, 7 IU/hr; 10% of patients required >20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2–14) vs. 0.8% of conventionally treated patients on day 11 (2–10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p < .0001), critical illness polyneuropathy (p < .0001), bacteremia (p = .02), and inflammation (p = .0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p = .03). As compared with normoglycemia, an intermediate blood glucose level (110–150 mg/dL) was associated with worse outcome.
CONCLUSIONNormoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose per se, was related to the beneficial effects of intensive insulin therapy.
The choice of a vitamin D–binding protein assay is key in calculating free 25-hydroxyvitamin D levels. The results of this analysis support the use of total 25-hydroxyvitamin D as a marker of vitamin ...D status, regardless of race or GC genotype.
To the Editor:
It is unclear whether circulating free or bioavailable 25-hydroxyvitamin D is a better marker of vitamin D status than is total 25-hydroxyvitamin D, especially in racially diverse populations. Until recently, the only method to compare the levels was to estimate the level of free or bioavailable 25-hydroxyvitamin D from total 25-hydroxyvitamin D, vitamin D–binding protein (also known as gc-globulin, encoded by the
GC
gene), and albumin, with or without the
GC
genotype. Powe et al. reported that levels of vitamin D–binding protein, as measured on a monoclonal enzyme-linked immunosorbent assay (ELISA, R&D Systems), were lower in black . . .
Androgens and Bone Vanderschueren, Dirk; Vandenput, Liesbeth; Boonen, Steven ...
Endocrine reviews,
2004-June, Letnik:
25, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption ...and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs.
Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERα. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERα pathways are involved in androgen action on radial bone growth. ERβ may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males.
In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERα.
The analysis of cytokine profiles helps to clarify functional properties of immune cells, both for research and for clinical diagnosis. The real-time reverse transcription polymerase chain reaction ...(RT-PCR) is becoming widely used to quantify cytokines from cells, body fluids, tissues, or tissue biopsies. Being a very powerful and sensitive method it can be used to quantify mRNA expression levels of cytokines, which are often very low in the tissues under investigation. The method allows for the direct detection of PCR product during the exponential phase of the reaction, combining amplification and detection in one single step. In this review we discuss the principle of real-time RT-PCR, the different methodologies and chemistries available, the assets, and some of the pitfalls. With the TaqMan chemistry and the 7700 Sequence Detection System (Applied Biosystems), validation for a large panel of murine and human cytokines and other factors playing a role in the immune system is discussed in detail. In summary, the real-time RT-PCR technique is very accurate and sensitive, allows a high throughput, and can be performed on very small samples; therefore it is the method of choice for quantification of cytokine profiles in immune cells or inflamed tissues.
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