Geomorphic and geologic controls of geohazards induced by Nepal's 2015 Gorkha earthquake.

The Gorkha earthquake (magnitude 7.8) on 25 April 2015 and later aftershocks struck South Asia, killing ~9000 people and damaging a large region. Supported by a large campaign of responsive satellite data acquisitions over the earthquake disaster zone, our team undertook a satellite image survey of the earthquakes' induced geohazards in Nepal and China and an assessment of the geomorphic, tectonic, and lithologic controls on quake-induced landslides. Timely analysis and communication aided response and recovery and informed decision-makers. We mapped 4312 coseismic and postseismic landslides. We also surveyed 491 glacier lakes for earthquake damage but found only nine landslide-impacted lakes and no visible satellite evidence of outbursts. Landslide densities correlate with slope, peak ground acceleration, surface downdrop, and specific metamorphic lithologies and large plutonic intrusions.

Physical exercise in patients with severe kidney disease.

Patients with advanced chronic kidney disease (CKD), especially those on long-term dialysis, often suffer from muscle wasting and excessive fatigue. It is known that inactivity, muscle wasting and reduced physical functioning are associated with increased mortality in CKD. Known causes include uraemic myopathy and neuropathy, inactivity, and anaemia. Exercise in patients receiving regular dialysis treatment for end-stage renal disease was first introduced 3 decades ago, but is still only offered in a minority of renal units around the world, despite a significant body of evidence to support its use. Work is needed to increase awareness of the potential benefits of increased physical activity for patients with advanced CKD. This review summarizes the mechanisms of exercise intolerance and debility in advanced CKD patients, the methods used for the estimation of functional capacity, the options currently available for exercise training, and their influence on the well-being of this group of patients.

Impaired system A amino acid transport mimics the catabolic effects of acid in L6 cells.

BACKGROUND: Metabolic acidaemia stimulates protein catabolism in skeletal muscle cells, leading to muscle wasting. As this occurs without decreasing cytosolic pH, the initial signal is unclear. A possible explanation is that extracellular pH acts on solute transporters at the cell surface, inhibiting nutrient influx. DESIGN: Influx through glucose and Pi transporters and System A amino acid transporters into L6 skeletal muscle cells was assessed using 3H-2-deoxyglucose (2-DG), 33Pi and 14C-methylaminoisobutyrate (MeAIB), respectively. Protein degradation (PD) was assessed from 14C efflux from cells prelabelled with 14C-Phe. Branched-chain amino acids and Phe were assayed by selective fluorimetric assays. RESULTS: While acid (pH 7.1) had little immediate effect on 2-DG or 33Pi influx, exposure to pH 7.1 rapidly inhibited MeAIB influx. To determine whether System A inhibition was sufficient to trigger PD, it was blocked at pH 7.5 by a saturating dose (10 mmol L(-1)) of nonmetabolisable substrate (MeAIB). Like acid, this increased PD and decreased total protein. It also mimicked the decreases in protein synthesis, DNA synthesis, glucose transport and glycolysis, and depletion of branched-chain amino acids and Phe, which are induced in L6 by acid. The onset of inhibition of PD by an extracellular Gln load was retarded at pH 7.1, and stimulation of PD by acid was negligible if PD had already been stimulated by Gln depletion. The stimulatory effect of MeAIB on PD was selectively blunted by an excess of Gln, whereas the inhibitory effect of Gln on PD was blocked by excess MeAIB. CONCLUSIONS: The similarity of changes in response to MeAIB and acid implies that these share a common intracellular signalling pathway triggered by inhibition of System A. Even though System A is only a minor contributor to total Gln influx in L6 cells, it is suggested that blockade of System A with acid or MeAIB induces a catabolic state by denying Gln access to a key intracellular regulatory site.

Leucine suppresses acid-induced protein wasting in L6 rat muscle cells.

BACKGROUND: Metabolic acidosis induces protein wasting in skeletal muscle cells, accompanied by decreased glycolysis and compensatory increased consumption of other metabolic fuels, implying that protein wasting arises from fuel starvation and might be rectified by fuel supplements. Design To test this hypothesis, total protein and protein degradation (release of 14C-phenylalanine) were measured in L6 skeletal muscle cells cultured in Eagle's Minimum Essential Medium at pH 7.1-7.5 for 3 days with metabolic inhibitors or metabolic fuel supplements. RESULTS: Inducing metabolic fuel starvation with inhibitors (1 mmol L(-1) 2-deoxyglucose or 0.1 mmol L(-1) KCN [potassium cyanide]) failed to stimulate protein degradation or net protein wasting under nonacidaemic conditions (pH 7.5). Conversely metabolic fuel supplements (1 mmol L(-1) octanoate, pyruvate or alanine) failed to increase the protein content of the cultures at any pH tested, in spite of significant consumption of the fuels by the cells. Only leucine (1-3 mmol L(-1)) increased protein content and suppressed protein degradation in opposition to the catabolic effect of acidaemia (pH 7.1). Conclusion Leucine exerts a beneficial anabolic effect on cultured skeletal muscle cells in the face of metabolic acidaemia. The failure of other metabolic fuels to do this, and of the metabolic inhibitors to exert a catabolic effect, suggests that leucine acts as a specific modulator of protein turnover and not as a nonspecific source of carbon for oxidation as a fuel.

Effects of acidosis on leptin secretion from 3T3-L1 adipocytes and on serum leptin in the uraemic rat.

Marked hyperleptinaemia and metabolic acidosis are common findings in patients with chronic renal failure. In animal models, both leptin administration and acidosis reduce food intake. However, leptin causes loss of body fat, while acidosis induces muscle wasting. Whether a low pH and leptin production are related has not been studied. Leptin secretion was measured in cultured 3T3-L1 adipocytes exposed to acid or control pH for up to 96 h. In addition, serum leptin was compared between acidotic and bicarbonate-treated uraemic Wistar rats using the remnant model. Leptin levels in the culture medium were decreased at an acid pH of 7.1 compared with a control pH of 7.5 at 96 h (562+/-78 and 831+/-103 pg.48 h(-1). well(-1) respectively; mean+/-S.E.M.; P=0.037). Similarly, serum leptin in uraemic rats was found to be lower in the acidotic group than in the bicarbonate-treated group, although this observation fell just short of statistical significance (1273+/-171 compared with 2059+/-376 pg/ml; P=0.07). In conclusion, acidosis decreases leptin secretion from cultured adipocytes. Accordingly, acidotic uraemic rats seem to exhibit lower serum leptin levels than their bicarbonate-supplemented counterparts. This study is the first report providing a link between acidosis and leptin levels.

Impaired glycolysis and protein catabolism induced by acid in L6 rat muscle cells.

BACKGROUND: In skeletal muscle, metabolic acidosis stimulates protein degradation and oxidation of branched-chain amino acids. This could occur to compensate for impairment of glucose utilization induced by acid. METHODS: To test this hypothesis, glycolysis and protein degradation (release of [14C]-phenylalanine) were measured in L6 skeletal muscle cells cultured in Eagle's minimum essential medium at pH 7.1 or 7.5 for up to 3 days. RESULTS: No marked changes in total DNA or in cell viability were detected, nor was there any significant effect on intracellular pH or the water content of the cells (which is thought to be a key regulator of protein turnover, especially in liver). In spite of this, acid stimulated protein degradation, induced net protein loss from the cultures, inhibited glucose uptake and glycolysis (lactate output) and was associated with increased [1-14C]-leucine oxidation. Effects on protein degradation and glycolysis were gradual, reaching a maximum after 20-30 h. To investigate whether glycolytic flux itself can influence protein degradation, increased glycolysis was simulated by adding glucose (20 mmol L-1) or pyruvate (1 mmol L-1) to the medium. At pH 7.1, neither addition had any effect on protein degradation. CONCLUSION: Although acid-induced protein wasting is associated with impaired glycolysis, no obligatory coupling exists between glycolytic flux and protein degradation.

Inhibition of protein synthesis by acid in L6 skeletal muscle cells: analogies with the acute starvation response.

Impaired protein synthesis (PS) occurs in skeletal muscle during acute starvation. Even though it is well established that uraemic metabolic acidosis (MA) stimulates protein degradation (PD) and is a major contributor to skeletal muscle wasting in chronic renal failure, the accompanying effects of MA on PS are much less clear. Previous work has shown that, in cultured L6 skeletal muscle cells, PD and leucine oxidation are stimulated by acid. The aim of the present study was to determine whether acid (like acute starvation) can also inhibit PS. PS (14C-phenylalanine incorporation) was measured in L6 cells in MEM + 2% serum at acid pH (7.1) or control pH (7.5). After 24 h, acid inhibited PS (7.7 +/- 0.2 vs. 8.9 +/- 0.1 nmol Phe/4 h/35-mm culture well in controls, p = 0.01) and this was maintained at 72 h. In vitro this could arise because acid only inhibits the rapid PS occurring in dividing cells. However, when division was abolished with 10(-5) mol/l cytosine arabinoside, PS inhibition by acid still occurred (6.9 +/- 0.1 vs. 8.3 +/- 0.2 at control pH, p < 0.05). Acid also had no effect on the specific radioactivity of cellular phenylalanine, suggesting that the impaired PS was not a consequence of inadequate labelling of this pool. Elevated PD and impaired PS together led to loss of 7% of the total protein in only 28 h (-21 +/- 3 microg/well, p = 0.004). This combination of impaired PS with increased PD and increased leucine oxidation in response to acid resembles the response of skeletal muscle to acute starvation. These superficial similarities between the starvation state and MA suggest that fundamental metabolic signals may occur which are common to both states.

Renal effects of metabolic acidosis in the normal rat.

Metabolic acidosis causes renal growth and proteinuria, and may contribute to the progression of CRF. This study assessed the effects of HCI-induced acidosis on the structure and function of normal kidneys. Acidosis was induced in 12 rats by dietary HCl. After 2 weeks, acidotic animals had higher kidney/body weight ratios (0.47 +/- 0.10 vs. 0.35 +/- 0.10 g%, p < 0.001) and higher kidney protein content (123 +/- 3 vs. 111 +/- 4 mg/kidney, p < 0.05) than controls, but tubular nuclear densities were lower, suggesting tubular hypertrophy. Acidotic animals developed tubular proteinuria (16.4 +/- 2.6 mg/day after 2 weeks of acidosis vs. 2.9 +/- 0.3 mg/day at baseline; p < 0.001), and the pattern of immunohistochemical staining for Tamm-Horsfall protein suggested tubular injury. These data suggest that a tubulotoxic effect of metabolic acidosis may contribute to the progression of CRF.

Amino acid profiles and muscle protein composition in rats with a reduced renal mass in the fed state.

In severe chronic renal failure (CRF) with associated metabolic acidosis, abnormalities in protein metabolism and amino acid (AA) profiles in the fed state are well described. To evaluate the effect of early uraemia and the influence of acid-base status on protein metabolism and AA profiles, three groups of pair-fed rats were studied: group I - rats with 1+ 1/2 nephrectomy; group II - rats with 1+ 1/2 nephrectomy receiving NaHCO3 supplementation, and group III - sham-operated rats with NaHCO3 supplementation. After 4 weeks, serum creatinine values were similar in groups I and II (111 +/- 5 and 119 +/- 4 mumol/l) and higher than in group III (51 +/- 5 mumol/l, p < 0.0001); HCO-3 was reduced only in group I (22.4 +/- 0.8 mmol/l) compared to group II (28.3 +/- 0.6 mmol/l, p < 0.001) and group III (28.2 +/- 1.3 mmol/l, p < 0.001). In the uraemic animals (groups I and II) arterial AA profiles showed increased levels of phenylalanine, glycine, glutamate, proline and alanine. The marked increase of threonine in group I was corrected by NaHCO3 supplementation in group II. The total nonessential AA were higher both in group I (1,832 +/- 53 mumol/l, p < 0.05) and group II (1,788 +/- 103 mumol/l, p < 0.05) than in group III (1,542 +/- 54 mumol/l). These results are similar to those described in the fed state of uraemic patients. Intracellular AA changes were detected, especially in group II namely increased glycine and a decrease in threonine and serine levels. No signs of malnutrition or changes in alkali-soluble protein (ASP) or ASP/DNA ratio in liver and muscle were observed. These results show that AA abnormalities in the fed state occur early in the course of CRF, and that the marked increase of threonine is corrected by NaHCO3 supplementation. These data suggest that either an impaired utilization of the ingested proteins might occur before the appearance of major alterations in endogenous protein metabolism or acid-base status might alter AA metabolic rate per se.

Metabolic acidosis is a potent stimulus for cellular inorganic phosphate generation in uraemia.

1. During metabolic acidosis, significant fluxes of inorganic phosphate (Pi) may occur from cellular to extracellular fluid. In this study Pi was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma Pi (hyperphosphataemia) and cellular organic phosphate concentrations. 2. Before dialysis, the ratio of cellular to extracellular Pi concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2. 3. An increase in cellular Pi similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro. 4. The total Pi content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of Pi from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of Pi into plasma. 5. In addition, the increase in the steady-state cellular Pi concentration on adding a constant extracellular Pi load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane Pi gradient also contribute to the rise in cellular Pi observed at low pH. 6. At normal plasma Pi concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular Pi was increased by adding Pi to the plasma in vitro. 7. Metabolic acidosis is therefore a potent stimulus for Pi generation in erythrocytes, and this Pi may serve to stimulate glycolysis which is normally inhibited by low pH.

Growth of proximal tubular cells in the presence of albumin and proteinuric urine.

The degree of interstitial scarring and proteinuria both correlate with renal function in progressive renal disease. Cellular hypertrophy and hyperplasia have been shown to occur under different experimental conditions. This study investigated the effect of protein on the growth of OK cells. Bovine serum albumin (BSA)- and fatty-acid-free BSA (FFBSA)-stimulated proliferation of OK cells and hypertrophy occurred when the cells were incubated with 10 mg/ml of BSA or FFBSA. Incubation with proteinuric urine from nephrotic rats resulted in much greater proliferation. Hence protein can alter proximal tubular cell growth in culture and the mixture of proteins in proteinuric urine has a greater effect than can be explained by albumin alone. These findings may be of significance in the progression of renal disease and indicate the potential importance of urinary proteins other than albumin in modulating tubular cell growth.

Hypertrophy of proximal tubular epithelial cells induced by low pH in vitro is independent of ammoniagenesis.

Metabolic acidosis can lead to tubular hypertrophy in vivo. This is thought to arise from stimulation of renal production of ammonia, a known hypertrophic agent. To examine this effect in vitro, confluent opossum (OK) proximal tubular epithelial cells were cultured at acidic pH (7.21 +/- 0.02) or at control pH (7.37 +/- 0.01) for 4 days. Protein content was 9% higher at acidic pH whereas DNA content was unaffected. The resulting increase in mean cell size (protein/DNA ratio) was 10% but correlated inversely with the mass of cells in control wells, varying from +48% at low cell mass to -14% at high cell mass. In contrast, low pH decreased 3H-thymidine incorporation by 9%. However, ammonia production was unaffected. These changes in protein/DNA ratio and 3H-thymidine incorporation cannot therefore be attributed to acid-induced ammoniagenesis and imply that low pH exerts a more direct effect on tubular cell growth than previously envisaged.

Regulation of intracellular creatine in erythrocytes and myoblasts: influence of uraemia and inhibition of Na,K-ATPase.

The regulation of intracellular creatine concentration in mammalian cells is poorly understood, but is thought to depend upon active sodium-linked uptake of creatine from extracellular fluid. In normal human erythrocytes, creatine influx into washed cells was inhibited by 40 per cent in the absence of extracellular sodium. In washed cells from uraemic patients, sodium-independent creatine influx was normal, whereas the sodium-dependent component of creatine influx was 3.3 times higher than normal, possibly reflecting the reduced mean age of uraemic erythrocytes. In spite of this, the intracellular creatine concentration was no higher than normal in uraemic erythrocytes, implying that some factor in uraemic plasma in vivo inhibits sodium-dependent creatine influx. Both in normal and uraemic erythrocytes, the creatine concentration was 10 times that in plasma, and the concentration in the cells showed no detectable dependence on that in plasma, suggesting that the intracellular creatine concentration is controlled by an active saturable process. Active sodium-dependent accumulation of creatine was also demonstrated in L6 rat myoblasts and was inhibited when transport was measured in the presence of 10(-4) M ouabain or digoxin, implying that uptake was driven by the transmembrane sodium gradient. However, when creatine influx was measured immediately after ouabain or digoxin had been washed away, it was higher than in control cells, suggesting that Na,K-ATPase and/or sodium-linked creatine transport are up-regulated when treated with inhibitors of Na,K-ATPase.

Plasma amino acid profile in the elderly with increasing uraemia.

Abnormalities in plasma amino acid profiles have been reported in severe uraemia and dialysis patients and may be a consequence of altered protein metabolism in the presence of metabolic acidosis. We studied plasma amino acid profiles in 7 control subjects [GFR 92.7 +/- (SEM) 14.5 ml/min/1.73 m2] and 7 elderly patients with renal failure (GFR 16.5 +/- 1.3 ml/min/1.73 m2). Uraemic patients had significantly reduced plasma levels of valine, tyrosine, phenylalanine, tryptophan and elevated histidine compared to controls. There was no correlation between arterial pH or bicarbonate and plasma amino acid levels.

Effects of acid loading on serum amino acid profiles and muscle composition in normal fed rats.

1. Impaired body growth, loss of lean body mass and negative nitrogen balance are common findings in chronic renal failure. Enhanced endogenous protein catabolism in skeletal muscle induced by co-existent metabolic acidosis seems to be an important aetiological factor. 2. In uraemic patients abnormalities in blood amino acid profiles are present after a protein meal, suggesting impaired metabolism of ingested proteins. 3. This study demonstrates that acidosis induces changes in arterial amino acid profiles in fed non-uraemic rats. These included increased levels of threonine, histidine, proline, serine and glycine, and decreased levels of tryptophan. These changes are similar to those found in uraemic patients after a protein meal, suggesting a pathogenic role of acidosis in the impairment of exogenous protein metabolism. 4. Intracellular amino acid levels in the muscle tissue partly reflect the changes in the extracellular level. 5. Acidotic animals had a decreased body weight gain and a reduced alkali-soluble protein/DNA ratio in muscle cells compared with controls. 6. In conclusion, the results show that acidosis per se modifies the circulating amino acid profile in fed rats, resulting in a pattern similar to the post-prandial amino acid changes described in uraemic patients. These abnormalities occur together with impaired growth of skeletal muscle cells.

Calciotropic hormones raise the chemically detectable [Pi] in UMR 106-06 osteoblast-like cells.

Uptake of orthophosphate (Pi) by osteoblast-like cells is known to be stimulated by parathyroid hormone (PTH), but effects on intracellular [Pi] have not been investigated. Here we show in rat osteoblast-like cells (UMR 106-06) that PTH (10(-11) to 10(-7) M) increases both 32Pi uptake and cellular [Pi] by up to 50 per cent. 1,25 Dihydroxyvitamin D3 (1,25D) (10(-12) to 10(-6) M) and salmon calcitonin (CT) (10(-12) to 10(-6) g ml-1) also increased cellular [Pi] (by up to 60 per cent), but the percentage increases in total cellular 32Pi uptake were smaller. The effects of 1,25D were transient (observable at 80 min and 6 h but not 24 h), and were also observed with 24,25 dihydroxy- and 25 hydroxyvitamin D3. Transient degradation of organic phosphorus pools to Pi might contribute to this increased [Pi]. These pools remain to be identified but were not shown to be phospholipids. Foetal bovine serum also affected cellular [Pi]. Care is therefore needed in distinguishing direct hormonal effects on cellular [Pi] from indirect effects arising from changes in the rate of cell growth.

Regulation of the phosphate (Pi) concentration in UMR 106 osteoblast-like cells: effect of Pi, Na+ and K+.

Osteoblast-like cells possess Na-dependent transporters which accumulate orthophosphate (Pi) from the extracellular medium. This may be important in bone formation. Here we describe parallel measurements of Pi uptake and cellular [Pi] in such cells from the rat (UMR 106-01 and UMR 106-06) and human (OB), and in non-osteoblastic human fibroblasts (Detroit 532 (DET)). In UMR 106-01, cellular [Pi] was weakly dependent on extracellular [Pi] and higher than expected from passive transport alone. [32Pi]-uptake was inhibited by Na deprivation, but paradoxically increased on K deprivation. With Na, 87 per cent of cellular 32P was found in organic phosphorus pools after only 5 min. Na deprivation also decreased cellular [Pi], in both UMR 106-01 and DET, but the decrease was smaller than that in [32Pi]-uptake. Ouabain decreased [32Pi]-uptake and cellular [Pi] in DET, but not in UMR 106-01. Regulation of cellular [Pi] is therefore at least partly dependent on Na/Pi co-transport, but this does not seem to be an exclusive property of osteoblasts.