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.     

The progression of deafferentation as a retrograde reaction to hypoglossal nerve injury

Summary This study examined the fate of axon terminals of one of the major sources of hypoglossal afferents, the spinal V nucleus, after XIIth nerve resection in adult Sprague-Dawley rats. In order to anterogradely label trigemino-hypoglossal projections, small quantities of horse radish peroxidase were pressure-injected into the ipsilateral dorsal (mandibular) portion of the spinal V nucleus two days before the animals were killed. Survival periods ranged from 5 to 33 days after nerve injury (dpo). Axonal injury produced relative changes in the association of labelled axon terminals to structures in the hypoglossal nucleus on the injured side. The proportion of horse radish peroxidase-labelled spinal V nucleus terminals with spherical vesicles (S-terminals) that were unapposed to hypoglossal somata or dendrites increased rapidly and reached maximal levels by 11 dpo. By contrast, the isolation of labelled terminals with pleomorphic/flattened vesicles (P/F-terminals) from postsynaptic structures began later, advanced at a slower rate and did not attain maximal levels until 20 dpo. S-terminals not apposed to neuronal cell parts increased at a rate of 2.2 times greater than unapposed P/F-terminals. In addition, at peak levels, the proportion of labelled S-terminals that were detached from somata and dendrites was significantly greater than unapposed, labelled P/F-terminals. Axotomy did not alter the caliber of the labelled axon terminals. However, by 29 days after axotomy, the average diameter of dendrites remaining in contact with SPVN terminals was 1/3 the diameter of dendrites of uninjured neurons apposed to labelled axon terminals. These findings provide the morphological correlate for physiological and pharmacological evidence that the effectiveness of excitatory and inhibitory synapses are down-regulated in a coordinated manner after hypoglossal nerve injury.     

Relationship among level of distraction, evoked potentials, spinal cord ischemia and integrity, and clinical status in animals

Somatosensory evoked potentials (SEPs) and neurogenic-motor evoked potentials (NMEPs) were recorded after overdistraction of the spinal cord at T5-T6, T12-L1, or L3-L4. Measures of spinal cord perfusion and clinical status were also administered. Results indicated that stiffer spinal segments allowed less distraction than more flexible segments. SEPs and NMEPs were lost quickly after overdistraction in stiff segments and slowly in more flexible segments. However, SEPs were less sensitive than NMEPs to effects from overdistraction. Spinal cord perfusion and integrity were consistent with reduced perfusion and structural damage after overdistraction in stiff segments; extremely reduced perfusion but no structural changes in more flexible segments. The application of these results to the clinical situation was provided.     

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.      

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.      

Parents' and patients' preferences and concerns in idiopathic adolescent scoliosis: a cross-sectional preoperative analysis

STUDY DESIGN: A multicenter cross-sectional study of parents' and patient's concerns and preferences regarding surgery for idiopathic scoliosis. OBJECTIVES: The purpose of this study was to analyze independently both the parents' and patients' assessments of upcoming surgery for idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: No group has recently reported querying patients and their parents regarding expectations, preferences, reasons, and concerns about and for surgical treatment of adolescent idiopathic scoliosis. METHODS: Ninety-one sets of parents and patients were separately asked to complete questionnaires regarding the patients' upcoming idiopathic scoliosis surgery. Patients' ages ranged from 9 to 18 years, and data were collected from four centers and seven surgeons (all active members of the Scoliosis Research Society) from April through December 1998. Thirty-nine questions covered concerns (n = 6), reasons for surgery (n = 14), expectations (n = 9), assessment of life as is (n = 5), and scar preference (n = 5). RESULTS: The greatest concern about the surgery expressed by both parents and patients was neurologic deficit. The least concern for both was location and appearance of the scar. The highest expectation and main reason for having the surgery was to reduce future pain and disability as an adult. Families would be either somewhat or very dissatisfied to spend the rest of life "as is." CONCLUSION: Although parents and patients had similar ratings and concerns, the parents' concerns were higher, and expectations were greater than the patients'.     

The effect of variation in arm position on sagittal spinal alignment

STUDY DESIGN: A prospective radiographic analysis of sagittal alignment in patients with and without previous spinal fusion. OBJECTIVES: To evaluate the effect of variation of arm position on the segmental, regional, and global sagittal radiographic spinal alignment. In addition, to determine whether spinal fusion has any influence on the effect of variation in arm position on the sagittal spinal alignment. SUMMARY OF BACKGROUND DATA: Importance of segmental, regional, and global sagittal alignment has been widely promoted. However, no mention has been made of arm positioning during a lateral spinal radiograph and the resultant effects it may have on sagittal alignment and balance. METHODS: Prospective evaluation of 40 consecutive patients with and 40 consecutive patients without a previous spinal fusion was performed. The patients had lateral long cassette radiographs performed in a standardized fashion with the first radiograph obtained with the patient's arms raised horizontally forward at 90 degrees of flexion at the shoulder, and the second radiograph obtained with arms raised horizontally forward at 30 degrees of flexion at the shoulder. Standard segmental, regional, and global sagittal alignments were measured and statistically compared. RESULTS: In comparing group 1 (patients with spinal fusion) to group 2 (patients without spinal fusion), there was no statistically significant difference in segmental and regional sagittal alignments. However, positioning the arms at 90 degrees versus 30 degrees resulted in a negative shift of the sagittal vertical axis (SVA) in patients that was statistically significant (P = 0.038) for those with (-6 mm at 90 degrees vs +4 mm at 30 degrees ), but not (P = 0.119) for those patients without (-8 mm at 90 degrees vs -4mm at 30 degrees ) a previous spinal fusion. CONCLUSIONS: Based on the findings in this study, the authors recommend positioning the arms at 30 degrees of forward flexion from the vertical when obtaining a long cassette lateral radiograph of the entire spine.