Fatigue crack growth rates (d
a/d
N) in under and peak aged Al–Cu–Mg and Al–Cu–Li depend on environmental exposure given by water vapor pressure/loading frequency
(
P
H
2
O
/
f
)
. The exposure ...dependence of d
a/d
N at constant stress intensity range exhibits four regimes, explained based on hydrogen environment embrittlement and three rate-limiting processes that are similar for each alloy and aging condition. Above a threshold environmental exposure (∼0.01
Pa
s), impeded molecular flow governs increasing d
a/d
N at moderate water vapor exposures to 2
Pa
s. At higher exposures, H diffusion limitation and surface reaction saturation reduce the d
a/d
N dependence on
P
H
2
O
/
f
, with plateau response above ∼500
Pa
s. Slip morphology rather than solute or phase reactivity per se controls d
a/d
N for low to moderate exposures, since identical slow growth rates are produced for shearable precipitate or cluster structures that each promote heterogeneous slip-band formation and {1
1
1}-faceted cracking. Alloy design for fatigue crack growth resistance depends on the environmental exposure and strength requirements of the application, as shown by the dramatic difference in d
a/d
N degradation due to peak aging, only for Al–Cu–Mg and only in the low
P
H
2
O
/
f
regime.
Low bone mass is an important complication of primary biliary cirrhosis (PBC), resulting in an increased risk of fractures and reduced mobility. In the present study, we sought to determine the ...frequency of low bone mass in PBC, and its relationship to disease severity and non-invasive markers of bone turnover.
In 36 women with PBC, bone mineral density of the lumbar spine and hip was assessed by dual emission X-ray absorptiometry. Serum and urinary markers of bone turnover were compared with those from age- and sex-matched controls.
Spinal osteopenia (T score, -1.5 to -2.5) was present in 15 of the 36 patients (42%), while six others (16%) had established osteoporosis (T < -2.5). Osteopenia of the femoral neck was found in 17 patients (47%), and osteoporosis in five (14%). The severity of liver disease, as determined by Mayo Clinic R score and histological stage, correlated negatively with both regional bone mineral density and total bone mineral content expressed as a ratio to lean body mass. There was a strong positive correlation between serum levels of the procollagen degradation peptides, PICP and PIIINP (r = 0.65, P < 0.001), and both peptides correlated significantly (P < 0.001) with histological stage and Mayo Clinic R score. Fasting urinary pyridinoline and deoxypyridinoline to creatinine ratios were also significantly raised.
Low bone mass in PBC correlates positively with disease severity, and is associated with a net increase in bone resorption, as assessed by urinary collagen cross-link excretion. These markers of bone turnover may be of value in controlled clinical trials aimed at improving bone mass in PBC.
1 Paracetamol hepatotoxicity has been found to be potentiated by anticonvulsant drugs in animal experiments; isolated case reports in humans sugest that long-term anticonvulsant therapy may also ...adversely influence outcome following overdose.
2 We compared the clinical course, after paracetamol overdose, of 18 patients on long-term anticonvulsant therapy with corresponding features in two published series of paracetamol-induced fulminant hepatic failure from this unit: 297 patients seen between 1973 and 1985 and a further 99 between October 1986 and April 1988.
3 Mortality in those patients who were taking anticonvulsants, but who did not receive N-acetylcysteine, was higher than in either of these series (93.3% vs 64.6% and vs 57.9%, P< 0.025). Although not statistically significant, there were also trends towards more severe coma (grade 3 or 4: 93.3% vs 75.4%, 1986-88), acidosis (pH less than 7.30: 40% vs 22.6%, 1973-85) and coagulopathy (prothrombin time greater than 100 s: 53.3% vs 33.7%, 1973-85). In the small number of patients given N-acetylcysteine, mortality was similar to that in the 1986-88 series (1/3 vs 15/42).
4 We conclude that chronic use of anticonvulsants enhances clinical features of paracetamol toxicity and discuss possible mechanisms by which this could be mediated.
1 In a retrospective study, we stratified 79 patients with paracetamol hepatotoxicity into two groups according to weekly alcohol consumption below (n = 49) or above (n = 30) Royal College of ...Physicians' guidelines of 21 units week -1 for males and 14 for females.
2 Survival was lower (33%) and serum creatinine on admission higher (median 207 μmol) in patients whose alcohol consumption was above recommended guidelines than in those whose drank less than this (65.9% and 138 μmol, P < 0.01 and P = 0.027, respectively). An arterial blood pH < 7.30 on admission was also more common in those patients with a higher alcohol consumption (30% v 12.2%, P = 0.05).
3 In all patients whose alcohol consumption exceeded the guidelines, paracetamol overdose was fatal if associated with a serum creatinine greater than 300 μmol in conjunction with a prothrombin time over 100 s and grade 3 or 4 encephalopathy or a peak prothrombin time over 180 s.
4 Chronic alcohol intake above suggested limits is an adverse prognostic feature in cases of severe paracetamol overdose. This effect is partly related to increased nephrotoxicity.
In a case of danazol-induced cholestasis, the anti-cholestatic agent S-adenosylmethionine was given intravenously for 3 weeks and then orally for 6 weeks. This was well tolerated and led to prompt ...resolution of both jaundice and associated renal impairment.
In studies to date seeking associations between human leukocyte antigens (HLA) and primary biliary cirrhosis, no class I association but several different class II associations have been described. ...The aims of this study were to reassess the DR associations in primary biliary cirrhosis and to examine for the first time the role of DQB. DRB genotypes were determined on standard Taq1 restriction‐fragment‐length polymorphism analysis in 159 white northern European patients with the disease and 162 racially matched local controls. Polymerase chain reaction gene amplification and sequence‐specific oligonucleotide analysis were used to determine DQB genotypes in 89 patients and 181 controls. An increased frequency of human leukocyte antigen DR8 was observed in the patient group (11% vs 4%; relative risk = 3.3; p < 0.01). Although we saw an increased frequency of the DQB1*0402 allele (11% vs. 3%; relative risk = 3.5; p < 0.025), this was not significant after correction for multiple testing. The strongest association was with the two‐locus haplotype DR8‐DQB1*0402 (11% vs. 2.2%; relative risk 5.5; p < 0.001). The DRB data reported here confirm the findings of previous studies, although the described association with DR8 is considerably weaker. The weak genetic contribution of human leukocyte antigen in the susceptibility to primary biliary cirrhosis is in contrast to its role in other autoimmune liver diseases.
Because S‐adenosylmethionine promotes synthesis of hepatic glutathione in chronic liver disease and is well tolerated in man, we investigated its use as an antidote to acetaminophen hepatotoxicity in ...two mouse models.
In C57B16 mice, deaths were abolished by S‐adenosylmethionine given within 1 hr of 3.3 mmol/kg body wt acetaminophen (0 of 32 vs. 13 of 49, p < 0.005) and reduced if given 2 to 5 hours after acetaminophen administration (4 of 42 vs. 13 of 49, p < 0.01). Mixed disulfate/tosylate salt of S‐adenosylmethionine abolished mortality in C3H mice given 2 mmol/kg body wt acetaminophen (0 of 24 vs. 4 of 18; p < 0.05). In both mouse models, S‐adenosylmethionine reduced depletion of plasma (median = 20.8 μmol/L vs. 14.6 μmol/L) and liver glutathione (198% vs. 100%; p < 0.05), liver damage and release of AST after acetaminophen administration. Pretreatment with buthionine sulfoximine, which inhibits glutathione synthesis, abolished the beneficial effect of S‐adenosylmethionine on survival and plasma glutathione level.
S‐adenosylmethionine reduces acetaminophen hepatotoxicity by metabolism of the active moiety to glutathione. This benefit may last as long as 5 hr after acetaminophen ingestion. (HEPATOLOGY 1992;15:297‐301).
Liver failure induced by paracetamol Bray, Gary P
BMJ. British medical journal (International ed.),
01/1993, Letnik:
306, Številka:
6871
Journal Article
Recenzirano
Liver failure induced by an overdose of paracetamol is discussed in an editorial. About 160 people in England and Wales die each year from liver failure after an overdose of the drug.
OBJECTIVES: Biliary tract abnormalities are well recognised in AIDS, most frequently related to opportunistic infection with Cryptosporidium, Microsporidium, and cytomegalovirus. We noted a high ...frequency of pancreatic abnormalities associated with biliary tract disease. To define these further we reviewed the clinical and radiological features in these patients. METHODS: Notes and radiographs were available from two centres for 83 HIV positive patients who had undergone endoscopic retrograde cholangiopancreatography for the investigation of cholestatic liver function tests or abdominal pain. RESULTS: 56 patients had AIDS related sclerosing cholangitis (ARSC); 86% of these patients had epigastric or right upper quadrant pain and 52% had hepatomegaly. Of the patients with ARSC, 10 had papillary stenosis alone, 11 had intra- and extrahepatic sclerosing cholangitis alone, and 35 had a combination of the two. Ampullary biopsies performed in 24 patients confirmed an opportunistic infection in 16. In 15 patients, intraluminal polyps were noted on the cholangiogram. Pancreatograms were available in 34 of the 45 patients with papillary stenosis, in which 29 (81%) had associated pancreatic duct dilatation, often with associated features of chronic pancreatitis. In the remaining 27 patients, final diagnoses included drug induced liver disease, acalculous cholecystitis, gall bladder empyema, chronic B virus hepatitis, and alcoholic liver disease. CONCLUSION: Pancreatic abnormalities are commonly seen with ARSC and may be responsible for some of the pain not relieved by biliary sphincterotomy. The most frequent radiographic biliary abnormality is papillary stenosis combined with ductal sclerosis.
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