There is a paucity of quality evidence regarding the effects of sodium restriction in patients with CKD, particularly in patients with pre-end stage CKD, where controlling modifiable risk factors may ...be especially important for delaying CKD progression and cardiovascular events. We conducted a double-blind placebo-controlled randomized crossover trial assessing the effects of high versus low sodium intake on ambulatory BP, 24-hour protein and albumin excretion, fluid status (body composition monitor), renin and aldosterone levels, and arterial stiffness (pulse wave velocity and augmentation index) in 20 adult patients with hypertensive stage 3-4 CKD as phase 1 of the LowSALT CKD study. Overall, salt restriction resulted in statistically significant and clinically important reductions in BP (mean reduction of systolic/diastolic BP, 10/4 mm Hg; 95% confidence interval, 5 to 15 /1 to 6 mm Hg), extracellular fluid volume, albuminuria, and proteinuria in patients with moderate-to-severe CKD. The magnitude of change was more pronounced than the magnitude reported in patients without CKD, suggesting that patients with CKD are particularly salt sensitive. Although studies with longer intervention times and larger sample sizes are needed to confirm these benefits, this study indicates that sodium restriction should be emphasized in the management of patients with CKD as a means to reduce cardiovascular risk and risk for CKD progression.
We compiled all credible repeated lion surveys and present time series data for 47 lion (Panthera leo) populations. We used a Bayesian state space model to estimate growth rate-λ for each population ...and summed these into three regional sets to provide conservation-relevant estimates of trends since 1990. We found a striking geographical pattern: African lion populations are declining everywhere, except in four southern countries (Botswana, Namibia, South Africa, and Zimbabwe). Population models indicate a 67% chance that lions in West and Central Africa decline by onehalf, while estimating a 37% chance that lions in East Africa also decline by one-half over two decades. We recommend separate regional assessments of the lion in the World Conservation Union (IUCN) Red List of Threatened Species: already recognized as critically endangered in West Africa, our analysis supports listing as regionally endangered in Central and East Africa and least concern in southern Africa. Almost all lion populations that historically exceeded ∼500 individuals are declining, but lion conservation is successful in southern Africa, in part because of the proliferation of reintroduced lions in small, fenced, intensively managed, and funded reserves. If management budgets for wild lands cannot keep pace with mounting levels of threat, the species may rely increasingly on these southern African areas and may no longer be a flagship species of the once vast natural ecosystems across the rest of the continent.
All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide recombinant human PTH(1–34), ...represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive.
Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores ≤ 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity.
Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (≤1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.
Background
Salt intake shows great promise as a modifiable risk factor for reducing heart disease incidence and delaying kidney function decline in people with chronic kidney disease (CKD). However, ...a clear consensus of the benefits of reducing salt in people with CKD is lacking.
Objectives
This review evaluated the benefits and harms of altering dietary salt intake in people with CKD.
Search methods
We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
Selection criteria
We included randomised controlled trials (RCTs) that compared two or more levels of salt intake in people with any stage of CKD.
Data collection and analysis
Two authors independently assessed studies for eligibility and conducted risk of bias evaluation. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Mean effect sizes were calculated using the random‐effects models.
Main results
We included eight studies (24 reports, 258 participants). Because duration of the included studies was too short (1 to 26 weeks) to test the effect of salt restriction on endpoints such as mortality, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were applied. Three studies were parallel RCTs and five were cross‐over studies. Selection bias was low in five studies and unclear in three. Performance and detection biases were low in two studies and unclear in six. Attrition and reporting biases were low in four studies and unclear in four. One study had the potential for high carryover effect; three had high risk of bias from baseline characteristics (change of medication or diet) and two studies were industry funded.
There was a significant reduction in 24 hour sodium excretion associated with low salt interventions (range 52 to 141 mmol) (8 studies, 258 participants: MD ‐105.86 mmol/d, 95% CI ‐119.20 to ‐92.51; I2 = 51%). Reducing salt intake significantly reduced systolic blood pressure (8 studies, 258 participants: MD ‐8.75 mm Hg, 95% CI ‐11.33 to ‐6.16; I2 = 0%) and diastolic blood pressure (8 studies, 258 participants: MD ‐3.70 mm Hg, 95% CI ‐5.09 to ‐2.30; I2 = 0%). One study reported restricting salt intake reduced the risk of oedema by 56%. Salt restriction significantly increased plasma renin activity (2 studies, 71 participants: MD 1.08 ng/mL/h, 95% CI 0.51 to 1.65; I2 = 0%) and serum aldosterone (2 studies, 71 participants: 6.20 ng/dL (95% CI 3.82 to 8.58; I2 = 0%). Antihypertensive medication dosage was significantly reduced with a low salt diet (2 studies, 52 participants): RR 5.48, 95% CI 1.27 to 23.66; I2 = 0%). There was no significant difference in eGFR (2 studies, 68 participants: MD ‐1.14 mL/min/1.73 m2, 95% CI ‐4.38 to 2.11; I2 = 0%), creatinine clearance (3 studies, 85 participants): MD ‐4.60 mL/min, 95% CI ‐11.78 to 2.57; I2 = 0%), serum creatinine (5 studies, 151 participants: MD 5.14 µmol/L, 95% CI ‐8.98 to 19.26; I2 = 59%) or body weight (5 studies, 139 participants: MD ‐1.46 kg; 95% CI ‐4.55 to 1.64; I2 = 0%). There was no significant change in total cholesterol in relation to salt restriction (3 studies, 105 participants: MD ‐0.23 mmol/L, 95% CI ‐0.57 to 0.10; I2 = 0%) or symptomatic hypotension (2 studies, 72 participants: RR 6.60, 95% CI 0.77 to 56.55; I2 = 0%). Salt restriction significantly reduced urinary protein excretion in all studies that reported proteinuria as an outcome, however data could not be meta‐analysed.
Authors' conclusions
We found a critical evidence gap in long‐term effects of salt restriction in people with CKD that meant we were unable to determine the direct effects of sodium restriction on primary endpoints such as mortality and progression to end‐stage kidney disease (ESKD). We found that salt reduction in people with CKD reduced blood pressure considerably and consistently reduced proteinuria. If such reductions could be maintained long‐term, this effect may translate to clinically significant reductions in ESKD incidence and cardiovascular events. Research into the long‐term effects of sodium‐restricted diet for people with CKD is warranted, as is investigation into adherence to a low salt diet.
Conservation of large carnivores, such as the African lion, requires preservation of extensive core habitat areas, linkages between them, and mitigation of human-wildlife conflict. However, there are ...few rigorous examples of efforts that prioritized conservation actions for all three of these critical components. We used an empirically optimized resistance surface to calculate resistant kernel and factorial least cost path predictions of population connectivity and conflict risk for lions across the Kavango-Zambezi Transfrontier Conservation Area (KAZA) and surrounding landscape. We mapped and ranked the relative importance of (1) lion dispersal areas outside National Parks, (2) corridors between the key areas, and (3) areas of highest human-lion conflict risk. Spatial prioritization of conservation actions is critical given extensive land use redesignations that are reducing the extent and increasing the fragmentation of lion populations. While our example focuses on lions in southern Africa, it provides a general approach for rigorous, empirically based comprehensive conservation planning based on spatial prioritization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The scarcity of embryonic/foetal material as a resource for direct study means that there is still limited understanding of human retina development. Here, we present an integrated transcriptome ...analysis combined with immunohistochemistry in human eye and retinal samples from 4 to 19 post-conception weeks. This analysis reveals three developmental windows with specific gene expression patterns that informed the sequential emergence of retinal cell types and enabled identification of stage-specific cellular and biological processes, and transcriptional regulators. Each stage is characterised by a specific set of alternatively spliced transcripts that code for proteins involved in the formation of the photoreceptor connecting cilium, pre-mRNA splicing and epigenetic modifiers. Importantly, our data show that the transition from foetal to adult retina is characterised by a large increase in the percentage of mutually exclusive exons that code for proteins involved in photoreceptor maintenance. The circular RNA population is also defined and shown to increase during retinal development. Collectively, these data increase our understanding of human retinal development and the pre-mRNA splicing process, and help to identify new candidate disease genes.
Background
Evidence indicates that reducing dietary salt may reduce the incidence of heart disease and delay decline in kidney function in people with chronic kidney disease (CKD). This is an update ...of a review first published in 2015.
Objectives
To evaluate the benefits and harms of altering dietary salt for adults with CKD.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 6 October 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
Randomised controlled trials comparing two or more levels of salt intake in adults with any stage of CKD.
Data collection and analysis
Two authors independently assessed studies for eligibility, conducted risk of bias evaluation and evaluated confidence in the evidence using GRADE. Results were summarised using random effects models as risk ratios (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).
Main results
We included 21 studies (1197 randomised participants), 12 in the earlier stages of CKD (779 randomised participants), seven in dialysis (363 randomised participants) and two in post‐transplant (55 randomised participants). Selection bias was low in seven studies, high in one and unclear in 13. Performance and detection biases were low in four studies, high in two, and unclear in 15. Attrition and reporting biases were low in 10 studies, high in three and unclear in eight.
Because duration of the included studies was too short (1 to 36 weeks) to test the effect of salt restriction on endpoints such as death, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were examined.
Reducing salt by mean ‐73.51 mmol/day (95% CI ‐92.76 to ‐54.27), equivalent to 4.2 g or 1690 mg sodium/day, reduced systolic/diastolic blood pressure by ‐6.91/‐3.91 mm Hg (95% CI ‐8.82 to ‐4.99/‐4.80 to ‐3.02; 19 studies, 1405 participants; high certainty evidence). Albuminuria was reduced by 36% (95% CI 26 to 44) in six studies, five of which were carried out in people in the earlier stages of CKD (MD ‐0.44, 95% CI ‐0.58 to ‐0.30; 501 participants; high certainty evidence). The evidence is very uncertain about the effect of lower salt intake on weight, as the weight change observed (‐1.32 kg, 95% CI ‐1.94 to ‐0.70; 12 studies, 759 participants) may have been due to fluid volume, lean tissue, or body fat. Lower salt intake may reduce extracellular fluid volume in the earlier stages of CKD (‐0.87 L, 95% CI ‐1.17 to ‐0.58; 3 studies; 187 participants; low certainty evidence). The evidence is very uncertain about the effect of lower salt intake on reduction in antihypertensive dose (RR 2.45, 95% CI 0.98 to 6.08; 8 studies; 754 participants). Lower salt intake may lead to symptomatic hypotension (RR 6.70, 95% CI 2.40 to 18.69; 6 studies; 678 participants; moderate certainty evidence). Data were sparse for other types of adverse events.
Authors' conclusions
We found high certainty evidence that salt reduction reduced blood pressure in people with CKD, and albuminuria in people with earlier stage CKD in the short‐term. If such reductions could be maintained long‐term, this effect may translate to clinically significant reductions in CKD progression and cardiovascular events. Research into the long‐term effects of sodium‐restricted diet for people with CKD is warranted.
Background
SMAD4 is a tumour suppressor gene that is mutated in a variety of cancers. SMAD4 nonstop mutations, which convert stop codons to sense codons that extend transcription, have been ...identified in genomic databases but have not been characterised in human pathology samples. The frequency of SMAD4 nonstop mutations and the consequences of nonstop mutations on SMAD4 protein expression are unknown.
Methods
We retrospectively analysed our cancer sequencing database of 38,002 tumour specimens and evaluated the spectrum of SMAD4 mutations. SMAD4 protein expression was evaluated by immunohistochemistry in tumours with SMAD4 nonstop mutations.
Results
In total, 1956 SMAD4 mutations were identified in 1822 tumours. SMAD4 mutations were most common in tumours of the gastrointestinal tract and included nonsense variants (n = 344), frameshift indels (n = 258), splice site variants (n = 104), and missense variants at codon R361 (n = 245). In a subset of cases with immunohistochemistry, SMAD4 expression was lost in 23 of 25 tumours (92%) with protein truncating variants and in 7 of 27 tumours (26%) with missense variants. Four cases harboured SMAD4 nonstop mutations. SMAD4 nonstop mutations were identified in two pancreatic adenocarcinomas, one colonic adenocarcinoma, and one non‐small cell lung carcinoma. Immunohistochemistry demonstrated loss of SMAD4 protein expression in each of the four tumours with SMAD4 nonstop mutations.
Conclusion
SMAD4 nonstop mutations are associated with loss of SMAD4 protein expression in multiple tumour types. SMAD4 nonstop mutations should be clinically interpreted as pathogenic loss of function alterations when identified in cancer sequencing panels.
Herpes Virus Genome, The Pressure Is On Bauer, David W; Huffman, Jamie B; Homa, Fred L ...
Journal of the American Chemical Society,
07/2013, Letnik:
135, Številka:
30
Journal Article
Recenzirano
Odprti dostop
Herpes simplex virus type 1 (HSV-1) packages its micrometers-long double-stranded DNA genome into a nanometer-scale protein shell, termed the capsid. Upon confinement within the capsid, neighboring ...DNA strands experience repulsive electrostatic and hydration forces as well as bending stress associated with the tight curvature required of packaged DNA. By osmotically suppressing DNA release from HSV-1 capsids, we provide the first experimental evidence of a high internal pressure of tens of atmospheres within a eukaryotic human virus, resulting from the confined genome. Furthermore, the ejection is progressively suppressed by increasing external osmotic pressures, which reveals that internal pressure is capable of powering ejection of the entire genome from the viral capsid. Despite billions of years of evolution separating eukaryotic viruses and bacteriophages, pressure-driven DNA ejection has been conserved. This suggests it is a key mechanism for viral infection and thus presents a new target for antiviral therapies.
Despite Xinomavro (
L.) being a well-known noble red grape variety of northern Greece, little is known about its ''bouquet'' typicity. Volatile compounds of Xinomavro wines produced using a common ...vinification protocol were analyzed by gas chromatography-mass spectrometry and sensory descriptive analysis was carried out with a trained panel. Wines were characterized by the presence of fatty acids, ethyl and acetate esters, and alcohols, with contributions from terpenes and a volatile phenol. The most active aroma compounds were determined to be 3-methylbutyl acetate, β-damascenone, ethyl esters of octanoic and hexanoic acids, and eugenol. Those compounds positively correlated with fruity and spicy odor descriptors, with the wines being mostly characterized by five typical aroma terms: strawberry, berry fruit, spices, tomato, and green bell pepper. Partial least squares regression (PLSR) analysis was used to visualize relationship between the orthonasal sensory attributes and the volatile aroma compounds with calculated OAVs > 1. Key aroma-active volatiles in the wines were identified using GC-MS/olfactometry, providing a list of 40 compounds, among which 13 presented a modified detection frequency > 70%. This study is the first of its kind and provided strong indications regarding the aroma compounds defining the sensory characteristics of Xinomavro wines.
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