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 use of magnetic resonance imaging and spectroscopy in the assessment of patients with head and neck and other superficial human malignancies

The proper demarcation of diseased tissue is important for radiation therapy planning and treatment. The volume to be irradiated is usually identified on radiographs or on x-ray computed tomography (CT) sections. Magnetic resonance (MR)-derived images of the proton T2 relaxation times in small pixel elements, typically 0.5 mm2 or less, provide significantly sharper differentiation between normal and diseased tissue. The T2 values in tissue depend on the tissue composition, histologic condition, and physiologic environment within the tumor. Furthermore, for many tumors the histogram of T2 values has a clear biphasic distribution suggesting that T2 maps may be useful for the identification of necrotic or hypoxic regions within tumors. The distribution of T2 values within the tumor bed shows the general pattern that the T2 values are elevated with a range greater than that seen in normal muscle. Elevated T2 values are not by themselves diagnostic of malignancy; however, they demonstrate the heterogeneity of the microenvironment present within a tumor. The spatial distribution of T2 values is being explored as a method for computer assistance in the delineation of the target volume for treatment planning. In addition, MR P-31 spectroscopic examinations were performed on 30 patients with squamous cell carcinomas of the head and neck. Although hampered by muscle contamination in some P-31 spectra obtained with surface coil profile localization techniques, significant trends can still be appreciated in our data. These trends include the following: (1) the P-31 spectra from malignant tissue have well-resolved spectral lines in the upfield region that correspond to Pi, phosphomonoester (PME), and phosphodiester (PDE) not usually seen in normal muscle; (2) the PDE/B-ATP and PME/B-ATP ratios are greater than unity in all cases; and (3) most of the tumors have higher PME peaks than PDE peaks. The P-31 spectra from patients treated with ionizing radiation changed during and after therapy. Some of the changes could be associated with alteration of the tumor metabolic activity or synthesis and breakdown of lipoproteins. These studies suggest that magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies may be useful for both radiotherapy treatment planning and the noninvasive monitoring of patients both before and during treatment.     

Central nodal necrosis and extracapsular neoplastic spread in cervical lymph nodes: MR imaging versus CT.

Computed tomographic (CT) scans and magnetic resonance (MR) images obtained in 24 patients with cervical lymphadenopathy were retrospectively and blindly evaluated by two readers for the presence of central nodal necrosis (CNN) and extracapsular nodal spread (ENS). The CT studies were all enhanced, and the MR images were obtained with short repetition time (TR)/echo time (TE), long TR/double echo, and enhanced short TR/TE fat-suppressed sequences. Each MR imaging sequence was interpreted separately and then collectively. Sixty lymph nodes were identified with CT. Sensitivity for CNN was 16%-67% with the unenhanced MR pulse sequences, 50% with enhanced sequences, and 83%-100% with CT. The most accurate reading of MR images for CNN was with the unenhanced T1-weighted and T2-weighted images (86%-87%); the accuracy of CT was 91%-96%. The accuracy of MR imaging for detecting ENS was maximal with T1-weighted images (78%-90%). Gadolinium-enhanced, fat-suppressed images did not improve accuracy in evaluating CNN or ENS. CT is currently more accurate than unenhanced or enhanced MR imaging in detecting CNN or ENS.     

Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene.

Recent studies show that 1) the p53 tumor suppressor protein is overexpressed by rheumatoid arthritis (RA) synovium and fibroblast-like synoviocytes (FLS) and 2) somatic mutations previously identified in human tumors are present in RA synovium and FLS. We have hypothesized that abnormalities in p53 can contribute to chronic destructive RA synovitis. To understand the functional consequences of p53 abnormalities in FLS, RA and normal FLS expressing wild-type p53 were transduced with a retroviral vector encoding the human papilloma virus 18 E6 gene, which inactivates endogenous p53 protein. Three RA and one normal FLS lines were infected with recombinant retrovirus encoding the neomycin resistance gene (neo) or E6+neo. FLS proliferation, apoptosis, and invasion was studied in E6, neo, and uninfected parental strains (PS). The growth rate for E6 was significantly increased with a sixfold increase in cell number after 7 days compared with a twofold to threefold increase in neo and PS. When FLS were treated with cytokines, proliferative response of E6, neo, and PS to interleukin-1 and transforming growth factor-beta were similar. However, response to platelet-derived growth factor was significantly greater in E6 FLS compared with neo or PS. Apoptosis was studied by incubating FLS with sodium nitroprusside as a source of nitric oxide or hydrogen peroxide for 8 hours and examining DNA fragmentation and E6 cells were significantly less susceptible to cell death. In addition, E6 FLS were more invasive into cartilage extracts than neo or PS using an in vitro cell invasion assay. These data suggest that p53 is a critical regulator of FLS proliferation, apoptosis, and invasiveness. Abnormalities of p53 function might contribute to synovial lining expansion and joint destruction in RA.     

The Chiari-I malformation

We have described the important clinical features and aspects of the Chiari-I malformations, with particular emphasis on Chiari-I malformation. Previously thought to be a rare finding with only minor significance, Chiari-I malformation is an important cause of a variety of symptoms, and will be diagnosed even more frequently as the use of MRI increases. The clinician must consider Chiari-I malformation in any patient with unexplained sensorineural hearing loss, headache, vertigo, ataxia, dysequilibrium, dysphagia or other cranial nerve symptom, especially if accompanied by more classic symptoms of this disorder, such as cervical pain or weakness.     

Erythrokeratodermia Variabilis Present at Birth: Case Report and Review of the Literature

Abstract: A healthy boy had the distinctive lesions of erythrokeratodermia variabilis (EKV) at birth. Twenty-eight patients described in the literature had EKV that presented in childhood. Nine of the 28 were said to have had a rash since birth, but none were distinctive of EKV. To our knowledge this is the first well-documented case describing a child born with the skin manifestations of EKV. We conclude that patients with EKV are infrequently born with a rash, and that only very rarely when the rash is present is it suggestive of the disorder.