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.     

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.      

Evolution of influenza polymerase: nucleotide sequence of the PB2 gene of A/Chile/1/83 (H1N1)

Summary The complete nucleotide sequence of the PB2 gene of influenza virus A/Chile/1/83 (H1N1) is presented. Sequence comparison between A/Chile PB2 protein and the known PB2 sequences of the influenza strains A/WSN/33 (H1N1), A/PR/8/34 (H1N1), A/NT/60/68 (H3N2), A/Kiev/59/79 (H1N1), A/FPV/Rostock/34 (H7N1), and B/Ann Arbor/1/66 indicates extensive amino acid homology for the influenza A virus PB2 proteins. Small clusters of basic amino acids are conserved in all PB2 proteins including the influenza B PB2 protein which has only 39% sequence homology overall to the PB2 polypeptides of type A influenza viruses. The evolutionary rate of 5.7 × 10^–3 nucleotide substitutions per site per year and 0.25% amino acid changes per year between the A/Chile/1/83 and A/NT/60/68 PB2 appears to be higher than that calculated earlier for A/NT, A/PR/8 and A/WSN. An unusually high degree of sequence change between A/Chile/1/83 and A/Kiev/59/79 PB2 polymerase was revealed and this is discussed in terms of its probable origin.     

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.      

Cognitive functioning in female patients with 21-hydroxylase deficiency

The cognitive functioning of 27 female patients with congenital adrenal hyperplasia (CAH) (aged 11–41 yrs) and 13 of their healthy sisters (13–31 yrs) was compared using short versions of age-appropriate Wechsler scales. In contrast to other studies, neither a higher than average IQ level for CAH patients (mean: 99.0) nor for their sisters (97.7) was found. Unexpectedly, and in contrast to other reports, the subgroup of salt-wasting (SW) patients>16 yrs (N=6; mean score: 111.5) differed from their sisters as well as from simple-virilizing (SV) patients in full IQ (p<0.05) and subtest scorings for Information, Similarities, and Picture Completion (p<0.05–<0.10). SW patients displayed more masculine behaviour (vs. SV patients and sisters) which, in turn, was related to differential prenatal hormonal influences. No clear-cut relationships between IQ/cognitive (subtest) findings and gender-role behaviour were found.

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Zusammenfassung 27 Patientinnen mit dem Adrenogenitalen Syndrom (AGS) (11–41 J.) und 13 ihrer Schwestern (13–31 J.) wurden hinsichtlich intellektueller Funktionen verglichen (Kurzformen von HAWIK, HAWIE). Im Unterschied zu den meisten früheren Untersuchungen wurden weder für Patientinnen (mean: 99.0) noch für Kontrollen (97.7) über dem Durchschnitt liegende IQ-Werte gefunden. Im Gegensatz zur Literatur unterschied sich die Teilgruppe der Salzverlust-Patientinnen (SW)>16 J. (N=6, mean: 111.5) von den Schwestern und den Patientinnen mit einfachem AGS (SV) im Gesamt-IQ (p<0.05) und in den Untertests Allgemeines Wissen, Gemeinsamkeiten und Bilderergänzen (p<0.05–<0.10). SW-Patientinnen hatten signifikant männlichere Verhaltensmuster gezeigt (vs. SV-Patientinnen und Schwestern), die auf differentielle Hormoneffekte pränatal bezogen worden waren. Es fanden sich aber keine klaren Zusammenhänge zwischen IQ-bzw. Untertest-Resultaten und Ergebnissen für Geschlechtsrollenverhalten.

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Résumé Le fonctionnement cognitif de 21 patientes avec une hyperplasie congénitale surrénale (âgée de 11 à 41 ans) et de 13 de leurs soeurs saines (13–31 ans) a été comparé au moyen de versions raccourcies de l'échelle de Wechsler appropriée à l'âge. En contraste avec d'autres études, il n'a été retrouvé un Q.I. plus haut que la moyenne ni pour les patientes (moyenne 99.0) ni pour leurs soeurs (moyenne 97.7). De façon inattendue, et en contraste avec d'autres études, le sous-groupe de patientes déprivées en sel (SW)>16 ans (N=6), moyenne score: 111.5) différait de leurs soeurs aussi bien en tant que patientes présentant des signes de virilsation (SV) pour le Q.I. complet (p<0.05) et les scores aux subtests d'information, de similarité et de complément d'images (p<0.05–0.10). Les patientes déprivées en sel (SW) montraient un comportement plus masculin (vs. SV et leurs soeurs) qui en retour était relié aux influences hormonales prénatales différentes. Il n'y avait pas de relation de différences nettes entre les résultats aux sous-tests cognitifs du Q.I. et le comportement de genre.

     

Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.