Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year.While in many cases cerebral ischemic in jury can be limited by effectivw resuscitation or thrombolytic treatment,the injured neurons wither in a process known as delayed neuronal death(DND).Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered.Of particular interest are two groups of signal proteins that participate in apoptosis-cyclin dependent kinases(CDKs) and p53-among a myriad of signaling events after an ischemic insult.Recent investigations have shown that CDKs,a family of enzymes initially known for their role in cell cycle regulation,are activated in injured neurons in DND.As for p53,new reports suggest that its up-regulation may represent a failed attempt to rescue in jured neurons,although its up-regulation was previously considered an indication of apoptosis.These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage.In this review,the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre-clinical data to explore CDK inhibition as a potential neuroprotective target.Finally,using CDK inhibition as an example,this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic in jury.     

Urinary oxalate and glycolate excretion in healthy infants and children

The molar ratios of oxalate and glycolate over creatinine were determined in single urine samples of 26 infants and 27 children aged 1–5 years. In 135 children aged 5–16 years, two urine specimens were collected, one before breakfast and one at noon. Oxalate was determined by oxalate oxidase, and glycolate was measured by a colorimetric method (improved chromatotropic acid-sulphuric acid assay after prior purification by cation and anion exchanger). Both ratios (expressed in mmol/mol creatinine and analysed on a log-normal basis) were highest in infants 0–6 months old [mean oxalate 147 (95% confidence interval: 60–360), mean glycolate 175 (72–425)]. The mean oxalate ratio was 72 mmol/mol (29–174) at the age of 7–24 months, 44 (19–101) at the age of 2–5 years and 22 (12–40) in adolescents aged 16 years. Molar glycolate ratios were higher, but disclosed the same pattern. Oxalate and glycolate ratios in fasting urines did not differ significantly from those in noon samples (except glycolate in the oldest age group). Oxalate ratios correlated well with glycolate ratios in children up to 5 years of age only. Random urine samples are thus suitable for screening. However, interpretation of data requires use of age-specific reference values that are based on comparable methods.     

Lymphoreticular cells in invasive carcinoma of the uterine cervix: an immunohistological study.

In the present study the immunohistology of the cellular stromal reaction of invasive squamous cell carcinoma of the cervix is investigated. Tumor tissue from 10 patients with invasive squamous cell carcinoma of the uterine cervix (stages Ib-IIb, according to FIGO) was immunostained by the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method. The monoclonal antibodies OKT3, OKT4, OKT8, TO15, Ki-M1, and Ki-M6 were applied. The cells in the stroma and the tumor foci were evaluated separately. In all cases, the overwhelming majority of lymphoreticular cells were found in the stroma and the tumor-cell complexes contained relatively low numbers of these cells. While B-lymphocytes were present only in low numbers or were virtually absent from the lymphoreticular infiltrates, cells of the mononuclear-phagocyte system were found to be another prominent constituent of the tumor's cellular stromal reaction.     

Regulation of the release of neuronally localized corticosterone in rat forebrain areas by catecholamines

The influence of intralimbic and intrahypothalamic application of catecholamine-related compounds on the release of neuronally localized corticosterone in the central amygdala, ventral hippocampus and medial hypothalamus was investigated under in vivo and in vitro conditions. It is reported that agonists and antagonists of the alpha-adrenergic system did not affect the release of corticosterone in the brain areas studied. In contrast, the beta-adrenoreceptor agonist isoprenaline markedly enhanced the release of corticosterone. This response is prevented in the presence of the beta-adrenoreceptor antagonist propranolol. The data reveal that limbic and hypothalamic beta-adrenoreceptors play a role in the regulation of corticosterone release and suggest a functional interaction between catecholaminergic and corticosterone releasing neurons in forebrain areas.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.      

Temporal relationship between noradrenaline release in the central amygdala and plasma noradrenaline secretion in rats and tree shrews

In pentobarbital anesthetized Wistar rats and tree shrews (Tupaia belangeri) the hypothalamus, the hippocampus and the amygdala were simultaneously superfused through push-pull cannulae with artificial cerebrospinal fluid. Blood samples were withdrawn in order to make an attempt to correlate release rates of noradrenaline (NA), adrenaline and dopamine in the above-mentioned areas with plasma catecholamine levels. A strong, positive correlation was found between NA release in central amygdala and NA concentrations in peripheral blood suggesting a functional relationship between noradrenergic systems in discrete brain areas and the activity of the peripheral sympathetic nervous system.     

Founder effect in spinal and bulbar muscular atrophy (SBMA)

We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.