Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic ...reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Background
Acute kidney injury (AKI) requiring dialysis in critically ill patients is associated with an in-hospital mortality rate of 50–80 %. Extended daily hemodialysis (EHD) and high volume ...peritoneal dialysis (HVPD) have emerged as alternative modalities.
Methods
A double-center, randomized, controlled trial was conducted comparing EHD versus HVPD for the treatment for AKI in the intensive care unit (ICU). Four hundred and seven patients were randomized and 143 patients were analyzed. Principal outcome measure was hospital mortality, and secondary end points were recovery of renal function and metabolic and fluid control.
Results
There was no difference between the two groups in relation to median ICU stay 11 (5.7–20) vs. 9 (5.7–19), recovery of kidney function (26.9 vs. 29.6 %,
p
= 0.11), need for chronic dialysis (9.7 vs. 6.5 %,
p
= 0.23), and hospital mortality (63.4 vs. 63.9 %,
p
= 0.94). The groups were different in metabolic and fluid control. Blood urea nitrogen (BUN), creatinine, and bicarbonate levels were stabilized faster in EHD group than in HVPD group. Delivered
Kt
/
V
and ultrafiltration were higher in EHD group. Despite randomization, there were significant differences between the groups in some covariates, including age, pre-dialysis BUN, and creatinine levels, biased in favor of the EHD. Using logistic regression to adjust for the imbalances in group assignment, the odds of death associated with HVPD was 1.4 (95 % CI 0.7–2.4,
p
= 0.19). A detailed investigation of the randomization process failed to explain the marked differences in patient assignment.
Conclusions
Despite faster metabolic control and higher dialysis dose and ultrafiltration with EHD, this study provides no evidence of a survival benefit of EHD compared with HVPD. The limitations of this study were that the results were not presented according to the intention to treat and it did not control other supportive management strategies as nutrition support and timing of dialysis initiation that might influence outcomes in AKI.
ABSTRACT
It has been suggested recently that the change in cosmological redshift (the Sandage test of expansion) could be observed in the next generation of large telescopes and ultra‐stable ...spectrographs. In a recent paper, we estimated the change of peculiar velocity, that is the peculiar acceleration, in nearby galaxies and clusters and shown it to be of the same order of magnitude as the typical cosmological signal. Mapping the acceleration field allows for a reconstruction of the galactic gravitational potential without assuming virialization. In this paper, we focus on the peculiar acceleration in our own Galaxy, modelled as a Kuzmin disc and a dark matter spherical halo. We estimate the peculiar acceleration for all known Galactic globular clusters and find some cases with an expected velocity shift in excess of 20 cm s−1 for observations 15 yr apart, well above the typical cosmological acceleration. We then compare the predicted signal for a modified Newtonian dynamics (MOND) model in which the spherical dark matter halo is absent. We find that the signal pattern is qualitatively different, showing that the peculiar acceleration field could be employed to test competing theories of gravity. However, the difference seems too small to be detectable in the near future.
Some inflationary models predict the existence of isocurvature primordial fluctuations, in addition to the well known adiabatic perturbation. Such mixed models are not yet ruled out by available data ...sets. In this paper we explore the possibility of obtaining better constraints on the isocurvature contribution from future astronomical data. We consider the axion and curvaton inflationary scenarios, and use Planck satellite experimental specifications together with the Sloan Digital Sky Survey galaxy survey to forecast for the best parameter error estimation by means of the Fisher information matrix formalism. In particular, we consider how cosmic microwave background (CMB) lensing information can improve this forecast. We found substantial improvements for all the considered cosmological parameters. In the case of isocurvature amplitude this improvement is strongly model-dependent, varying between less than 1% and above 20% around its fiducial value. Furthermore, CMB lensing enables the degeneracy break between the isocurvature amplitude and correlation phase in one of the models. In this sense, CMB lensing information will be crucial in the analysis of future data.
In this study, diabetes mellitus (DM) was induced in Wistar rats during pregnancy and maintained in the postpartum period (PP) and we evaluated systolic blood pressure (SBP), glomerular filtration ...rate (GFR) and renal immunohistochemical and morphometric studies from different groups: G1 (non-pregnant control rats), G2 (non-pregnant diabetic rats), G3 (control mothers) and G4 (diabetic mothers). We found that there were no differences in relation to SBP, but there was a tendency for reduction in GFR from G4 compared with the other groups (G). There was increased total kidney weight/body weight ratio of G4 compared with other G. There were increase in glomerular tuft area in G3 and G4 compared with G1 and G2. G2 and G4 showed even higher percentage of cortical collagen. G3 showed increased glomerular proliferating cells compared with G1 and G2, while in G4 this number was smaller than G3. Cell proliferation was higher in the tubulointerstitial (TBI) compartment from G4. Glomerular and TBI α-smooth muscle actin expression was increased in G4 compared with other G. The glomerular p-p38 expression showed a pattern similar to proliferation cell nuclear antigen, with a reduction of p-p38 in G4 relative to other G. The immunoreactivity of p-JNK was higher in both the glomeruli and TBI compartment in G4 compared with G1, G2 and G3. The DM induced during pregnancy and maintained in the PP resulted in renal structural and functional changes to mothers. In addition, altered mitogen-activated protein kinase expression in association with these changes may play an important role in renal damage observed in the present investigation.
Acute renal injury (AKI) interferes greatly with nutritional status, affecting the metabolism of all macronutrients and increased mortality rates in hospitalized patients. Our objective was to ...evaluate the association of nutritional parameters (albumin, cholesterol, caloric and protein intake and nitrogen balance (NB)) with mortality in patients with AKI.
This is a prospective observational study that evaluated 595 consecutive patients over the age of 18 years with AKI, requiring enteral or parenteral feeding. At the time of the patient's enrollment, demographic and laboratorial data, caloric and protein supply and NB were recorded on the first day of referral to the nephrologist. All patients were followed throughout the hospital stay and mortality rate was also recorded.
The medium age of patients with AKI was 64 (54-75) years, 64.5% male, 62% admitted to intensive care unit (ICU), 52% on dialysis and the majority (48%) were at stage 3 by AKIN. Length of stay and hospital mortality were 18 (10-31) days and 46%, respectively. Superior age, AKI severity, lower body weight and body mass index (BMI), higher need for dialysis, ICU admission and shorter hospital stay were associated with higher mortality. At logistic regression, caloric (OR: 0.946; CI:95%: 0.901-0.994; p:0.029) and protein intake (OR: 0.947; CI:95%: 0.988-0.992; p = 0.028) and serum albumin (OR: 0.545; CI:95%: 0.401-0741; p < 0.001) were associated with hospital mortality. Cholesterol (OR: 0.995; CI:95%: 0.991-1.000; p = 0.052) was not associated with increased mortality in the adjusted analysis. Analysis of the receiver operating characteristic (ROC) curve showed that calorie intake < 12 kcal/kg (AUC: 0.745; CI:95%: 0.684-0.765; p < 0.001) and protein intake < 0.5 g/kg (AUC: 0.726; CI:95%: 0.686-0.767; p < 0.001) were predictors of hospital mortality, as well as a negative NB < -6.47 g N/day (AUC: 0.745; CI:95%: 0.704-0.786; p < 0.001).
In conclusion, low caloric and protein intake, negative NB and low albumin value are conditions associated with higher hospital mortality in patients with AKI.
Surviving acute kidney (AKI) patients have a higher late mortality compared with those admitted without AKI. The negative impact of malnutrition on the early outcome of AKI patients has recently been ...confirmed by various studies. However, its impact after hospital discharge has not been studied. The objective of the study was to determine the role of anthropometric measurements and handgrip strength as predictors of mortality 180 days after discharge.
Eighty-two survivors AKI patients who were older than 18 y old and followed by AKI team were prospectively evaluated. Patient's characteristics were recorded, anthropometric measurements were taken, handgrip strength (HGS) was measured, subjective global assessment and bioimpedance were applied and blood samples were collected during hospitalization at first and last nephrologist evaluation and in after hospital discharge at 1 month, 3 and 6 months. Multivariable logistic regression was used to adjust confounding and selection bias.
Age was 62.3 ± 14.7 years, prevalence of hospitalization in medical wards of 71.6%, index of severity of AKI (ATN-ISS) was 28% and late mortality rates was 25.6%. Risk factors associated with late mortality were the number of comorbidities (HR = 1.79, 95% CI = 1.45-2.46, p = 0.04), cancer (HR = 1.89, 95 CI% = 1.48-3.16, p = 0.01), sepsis (HR = 1.47, 95% CI = 1.18-2.38, p = 0.03), no recovery of renal function at hospital discharge (HR = 1.46, 95% CI = 1.02-2.16, p = 0.03), malnutrition at first evaluation (HR = 1.58, 95% CI = 1.14-2.94, p = 001), the HGS value at the moment of last evaluation by nephrologist (HR = 1.81, 95% CI = 1.17-2.31, p = 0.04) and gain weigh < 1 kg between the moment at first evaluation by nephrologist and one month after hospital discharge (HR = 1.95, 95 CI% = 1.29-3.3, p = 0.02).
HGS and gain weight were identified as predictors of late mortality. Simple and ease methods can be applied in AKI patients during and after hospitalization to diagnose nutritionally patients who are at higher risk for poor prognosis and, consequently intervention measures can be performed to improve survival in long-term.
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