Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in ...kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.
Aim
Disturbances of renal medullary perfusion and metabolism have been implicated in the pathogenesis of kidney disease and hypertension. Furosemide, a loop diuretic, is widely used to prevent renal ...medullary hypoxia in acute kidney disease by uncoupling sodium metabolism, but its effects on medullary perfusion in humans are unknown. We performed quantitative imaging of both renal perfusion and oxygenation using Magnetic Resonance Imaging (MRI) before and during furosemide. Based on the literature, we hypothesized that furosemide would increase medullary oxygenation, decrease medullary perfusion, but cause minor changes (<10%) in renal artery flow (RAF).
Methods
Interleaved measurements of RAF, oxygenation (T2*) and perfusion by arterial spin labelling in the renal cortex and medulla of 9 healthy subjects were acquired before and after an injection of 20 mg furosemide. They were preceded by measurements made during isometric exercise (5 minutes handgrip bouts), which are known to induce changes in renal hemodynamics, that served as a control for the sensitivity of the hemodynamic MRI measurements. Experiments were repeated on a second day to establish that the measurements and the induced changes were reproducible.
Results
After furosemide, T2* values in the medulla increased by 53% (P < 0.01) while RAF and perfusion remained constant. After hand‐grip exercise, T2* values in renal medulla increased by 22% ± 9% despite a drop in medullary perfusion of 7.2% ± 4.7% and a decrease in renal arterial flow of 17.5% ± 1.7% (P < 0.05). Mean coefficients of variation between repeated measurements for all parameters were 7%.
Conclusion
Furosemide induced the anticipated increase in renal medullary oxygenation, attributable exclusively to a decrease in renal oxygen consumption, since no change of RAF, cortical or medullary perfusion could be demonstrated. All measures and the induced changes were reproducible.
Cells in the human body need oxygen to function and survive, and severe deprivation of oxygen, as occurs in ischaemic heart disease and stroke, is a major cause of mortality. Nevertheless, other ...organisms, such as the fossorial mole rat or diving seals, have acquired the ability to survive in conditions of limited oxygen supply. Hypoxia tolerance also allows the heart to survive chronic oxygen shortage, and ischaemic preconditioning protects tissues against lethal hypoxia. The recent discovery of a new family of oxygen sensors--including prolyl hydroxylase domain-containing proteins 1-3 (PHD1-3)--has yielded exciting novel insights into how cells sense oxygen and keep oxygen supply and consumption in balance. Advances in understanding of the role of these oxygen sensors in hypoxia tolerance, ischaemic preconditioning and inflammation are creating new opportunities for pharmacological interventions for ischaemic and inflammatory diseases.
Endurance training has been shown to be effective in treating adolescents with major depressive disorder (MDD). To integrate endurance training into the therapeutic setting and the adolescents' daily ...lives, the current performance status of the adolescents should be accurately assessed. This study aims to examine adolescents with MDD concerning exhaustion criteria during a cardiopulmonary exercise test (CPET), as well as to compare the values obtained thereon with sex- and age-related control values. The study included a retrospective examination of exhaustion criteria ((i) oxygen consumption (V̇O
2
) plateau, (ii) peak respiratory exchange ratio (RER
peak
) > 1.0, (iii) peak heart rate (HR
peak
) ≥ 95% of the age-predicted maximal HR, and (iv) peak blood lactate concentration (BLC
peak
) > 8.0 mmol⋅L
−1
) during a graded CPET on a cycle ergometer in adolescents with MDD (n = 57). Subsequently, maximal V̇O
2
, peak minute ventilation, V̇O
2
at the first ventilatory threshold, and peak work rate of participants who met at least two of four criteria were compared with published control values using an independent-sample t-test. Thirty-three percent of the total population achieved a V̇O
2
plateau and 75% a RER
peak
> 1.0. The HR and BLC criteria were met by 19% and 22%, respectively. T-test results revealed significant differences between adolescents with MDD and control values for all outcomes. Adolescents with MDD achieved between 56% and 83% of control values.
Conclusions
: The study shows that compared with control values, fewer adolescents with MDD achieve the exhaustion criteria on a CPET and adolescents with MDD have significantly lower cardiorespiratory fitness.
Clinical trial registration
: No. U1111-1145–1854.
What is Known:
• It is already known that endurance training has a positive effect on depressive symptoms.
What is New:
• A relevant proportion of adolescents with major depressive disorder do not achieve their V̇O2max during a graded cardiopulmonary exercise test.
• Adolescents with major depressive disorder have significantly lower cardiorespiratory fitness compared to sex- and age-related control values.
Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential ...for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.
Patients recovering from COVID-19 often report symptoms of exhaustion, fatigue and dyspnoea and present with exercise intolerance persisting for months post-infection. Numerous studies investigated ...these sequelae and their possible underlying mechanisms using cardiopulmonary exercise testing. We aimed to provide an in-depth discussion as well as an overview of the contribution of selected organ systems to exercise intolerance based on the Wasserman gears. The gears represent the pulmonary system, cardiovascular system, and periphery/musculature and mitochondria. Thirty-two studies that examined adult patients post-COVID-19 via cardiopulmonary exercise testing were included. In 22 of 26 studies reporting cardiorespiratory fitness (herein defined as peak oxygen uptake—
V
O
2peak
),
V
O
2peak
was < 90% of predicted value in patients.
V
O
2peak
was notably below normal even in the long-term. Given the available evidence, the contribution of respiratory function to low
V
O
2peak
seems to be only minor except for lung diffusion capacity. The prevalence of low lung diffusion capacity was high in the included studies. The cardiovascular system might contribute to low
V
O
2peak
via subnormal cardiac output due to chronotropic incompetence and reduced stroke volume, especially in the first months post-infection. Chronotropic incompetence was similarly present in the moderate- and long-term follow-up. However, contrary findings exist. Peripheral factors such as muscle mass, strength and perfusion, mitochondrial function, or arteriovenous oxygen difference may also contribute to low
V
O
2peak
. More data are required, however. The findings of this review do not support deconditioning as the primary mechanism of low
V
O
2peak
post-COVID-19. Post-COVID-19 sequelae are multifaceted and require individual diagnosis and treatment.
Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially ...growing Mycobacterium tuberculosis (Mtb) cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in Mtb cultures. This effect was concentrationand time-dependent, relying on increased oxygen consumption that triggered enhanced production of reactive oxygen species. In infected murine macrophages, the addition of N-acetylcysteine to isoniazid treatment potentiated the killing of Mtb. Furthermore, we demonstrate that the addition of small thiols to Mtb drug treatment shifted the menaquinol/menaquinone balance toward a reduced state that stimulates Mtb respiration and converts persister cells to metabolically active cells. This prevention of both persister cell formation and drug resistance leads ultimately to mycobacterial cell death. Strategies to enhance respiration and initiate oxidative damage should improve tuberculosis chemotherapies.
Climate warming is predicted to negatively impact fish populations through impairment of oxygen transport systems when temperatures exceed those which are optimal for aerobic scope (AS). This concept ...of oxygen- and capacity-limited thermal tolerance (OCLTT) is rapidly gaining popularity within climate change research and has been applied to several fish species. Here, we evaluated the relevance of aerobic performance of juvenile barramundi (Lates calcarifer) in the context of thermal preference and tolerance by (1) measuring standard and maximum metabolic rates (SMR and MMR, respectively) and AS of fish acclimated to 29°C and acutely exposed to temperatures from 23 to 38°C, (2) allowing the fish to behaviourally select a preferred temperature between 29 and 38°C, and (3) quantifying alterations to AS after 5 weeks of acclimation to 29 and 38°C. SMR and MMR both increased continuously with temperature in acutely exposed fish, but the increase was greater for MMR such that AS was highest at 38°C, a temperature approaching the upper lethal limit (40-41°C). Despite 38°C eliciting maximum AS, when given the opportunity the fish selected a median temperature of 31.7 ± 0.5°C and spent only 10 ± 3% of their time at temperatures >36°C. Following acclimation to 38°C, AS measured at 38°C was decreased to the same level as 29°C-acclimated fish measured at 29°C, suggesting that AS may be dynamically modulated independent of temperature to accommodate the requirements of daily life. Together, these results reveal limited power of the OCLTT hypothesis in predicting optimal temperatures and effects of climate warming on juvenile barramundi.
Skin‐to‐skin care for procedural pain in neonates Johnston, Celeste; Campbell‐Yeo, Marsha; Disher, Timothy ...
Cochrane database of systematic reviews,
02/2017, Letnik:
2017, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Background
Skin‐to‐skin care (SSC), often referred to as 'kangaroo care' (KC) due to its similarity with marsupial behaviour of ventral maternal‐infant contact, is one non‐pharmacological ...intervention for pain control in infants.
Objectives
The primary objectives were to determine the effect of SSC alone on pain from medical or nursing procedures in neonates compared to no intervention, sucrose or other analgesics, or additions to simple SSC such as rocking; and to determine the effects of the amount of SSC (duration in minutes), method of administration (e.g. who provided the SSC) of SSC in reducing pain from medical or nursing procedures in neonates
The secondary objectives were to determine the safety of SSC care for relieving procedural pain in infants; and to compare the SSC effect in different postmenstrual age subgroups of infants.
Search methods
For this update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1); MEDLINE via PubMed (1966 to 25 February 2016); Embase (1980 to 25 February 2016); and CINAHL (1982 to 25 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi‐randomized trials.
Selection criteria
Studies with randomisation or quasi‐randomisation, double‐ or single‐blinded, involving term infants (≥ 37 completed weeks' postmenstrual age (PMA) to a maximum of 44 weeks' PMA and preterm infants (< 37 completed weeks PMA) receiving SSC for painful procedures conducted by healthcare professionals.
Data collection and analysis
The main outcome measures were physiological or behavioural pain indicators and composite pain scores. A mean difference (MD) with 95% confidence interval (CI) using a fixed‐effect model was reported for continuous outcome measures. We included variations on type of tissue‐damaging procedure, provider of care, and duration of SSC.
Main results
Twenty‐five studies (n = 2001 infants) were included. Nineteen studies (n = 1065) used heel lance as the painful procedure, one study combined venepuncture and heel stick (n = 50), three used intramuscular injection (n = 776), one used 'vaccination' (n = 60), and one used tape removal (n = 50). The studies were generally strong and had low or uncertain risk of bias. Blinding of the intervention was not possible, making them subject to high risk, depending on the method of scoring outcomes.
Seventeen studies (n = 810) compared SSC to a no‐treatment control. Although 15 studies measured heart rate during painful procedures, data from only five studies (n = 161) could be combined for a mean difference (MD) of −10.78 beats per minute (95% CI −13.63 to −7.93) favouring SSC. Meta‐analysis of four studies (n = 120) showed no difference in heart rate following the painful procedure (MD 0.08, 95% CI −4.39 to 4.55). Two studies (n = 38) reported heart rate variability with no significant differences. Two studies (n = 101) in a meta‐analysis on oxygen saturation at 30 and 60 seconds following the painful procedure did not show a difference. Duration of crying meta‐analysis was performed on four studies (n = 133): two (n = 33) investigated response to heel lance (MD = −34.16, 95% CI −42.86 to −25.45), and two (n = 100) following IM injection (MD = −8.83, 95% CI −14.63 to −3.02), favouring SSC. Five studies, one consisting of two substudies (n = 267), used the Premature Infant Pain Profile (PIPP) as a primary outcome, which favoured SCC at 30 seconds (MD −3.21, 95% CI −3.94 to −2.47), at 60 seconds (3 studies; n = 156) (MD −1.64, 95% CI −2.86 to −0.43), and at 90 seconds (n = 156) (MD −1.28, 95% CI −2.53 to −0.04); but at 120 seconds there was no difference (n = 156) (MD 0.07, 95% CI −1.11 to 1.25). No studies on return of heart rate to baseline level, cortisol levels, and facial actions could be combined for meta‐analysis findings.
Eight studies compared SSC to another intervention with or without a no‐treatment control. Two cross‐over studies (n = 80) compared mother versus other provider (father, another female) on PIPP scores at 30, 60, 90, and 120 seconds with no significant difference. When SSC was compared to other interventions, there were not enough similar studies to pool results in an analysis. One study compared SSC (n = 640) with and without dextrose and found that the combination was most effective and that SSC alone was more effective than dextrose alone. Similarly, in another study SSC was more effective than oral glucose for heart rate (n = 95). SSC either in combination with breastfeeding or alone was favoured over a no‐treatment control, but not different to breastfeeding. One study compared SSC alone and in combination with both sucrose and breastfeeding on heart rate (HR), NIPS scores, and crying time (n = 127). The combinations were more effective than SSC alone for NIPS and crying. Expressed breast milk was compared to SSC in one study (n = 50) and found both equally effective on PIPP scores. There were not enough participants with similar outcomes and painful procedures to compare age groups or duration of SSC. No adverse events were reported in any of the studies.
Authors' conclusions
SSC appears to be effective as measured by composite pain indicators with both physiological and behavioural indicators and, independently, using heart rate and crying time; and safe for a single painful procedure. Purely behavioural indicators tended to favour SSC but with facial actions there is greater possibility of observers not being blinded. Physiological indicators were mixed although the common measure of heart rate favoured SSC. Two studies compared mother‐providers to others, with non‐significant results. There was more heterogeneity in the studies with behavioural or composite outcomes. There is a need for replication studies that use similar, clearly defined outcomes. Studies examining optimal duration of SSC, gestational age groups, repeated use, and long‐term effects of SSC are needed. Of interest would be to study synergistic effects of SSC with other interventions.
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