P53 mutations in hepatocellular carcinoma patients in Egypt

The p53 gene plays a major role in hepatocellular carcinoma (HCC). Acquired mutations may provide clues to etiology, as some carcinogenic agents are associated with specific genetic changes in p53. Our aim was to analyze the spectrum of p53 mutations in tumor tissues from subjects with HCC in Egypt, where there is a rising incidence of HCC due to hepatitis C virus (HCV). We collected tumor tissues from 41 subjects with HCC diagnosed at the National Cancer Institute of Cairo University during 2000-2003. Sequence mutations were analyzed by the Affymetrix GeneChip technique. HCV RNA was detected in the sera of 37 subjects (90%). Only one patient had a current HBV infection. A total of 17 of the 41 subjects (41%) had p53 mutations. Thirteen of these were in exon 7, of which 10 were in codon 249, but only 8 of the 10 were the R249S mutation, previously reported to be associated with aflatoxin exposure. The other three exon 7 mutations were found in codons 232, 242 and 248. A total of three mutations were detected in exon 5 codons 133, 144 and 176. One mutation was detected in exon 8 codon 275. Unlike previous studies, this population is characterized by a high prevalence of chronic HCV infection. The presence of the R249S mutation in exon 7 may indicate that these subjects with HCC have been exposed to aflatoxin (AFB1), and further investigation is in progress to measure AFB1-albumin adducts in the sera of these subjects.     

Intracardiac ultrasound detection of thrombus on transseptal sheath: incidence, treatment, and prevention

BACKGROUND: Transseptal (TS) catheterization is used for left atrial (LA) ablation procedures and a major risk is thromboembolism. The purpose of this study was to assess (1) the value of intracardiac ultrasound (ICUS) monitoring during LA ablation procedures, and (2) a new technique to reduce the risk of thrombus formation. METHODS AND RESULTS: One hundred and eighty consecutive patients underwent TS catheterization under ICUS guidance with two sheaths for atrial fibrillation ablation and one for other LA procedures. Group I included the initial 90 patients in whom TS sheaths were flushed with a standard 2 U/cc concentration of heparin; group II consisted of the next 90 patients in whom sheaths were flushed with 1,000 U/cc concentration. All patients received bolus and infusion of heparin to maintain ACT between 250-300 seconds. ICUS was monitored throughout. In group I, echodense material at the tip of the sheath consistent with thrombus was observed on ICUS in 8 of 90 patients (9%) within 5-15 minutes of entering the LA. In group II, only 1 of 90 patient (1%) demonstrated thrombus (P < 0.001). There were no significant clinical differences in group I patients with and without thrombus. In all nine patients, the clot was removed with vigorous aspiration. No patients suffered a neurological event. CONCLUSION: Thrombus formation on TS sheath, detected by ICUS, may be more common than expected despite adequate anticoagulation. Using a higher concentration of heparin for the TS system before deployment reduced the risk. The thrombus was retrieved with aspiration without the need to abort the procedure.     

Unusual eosinophilic variant of chromophobe cell renal carcinoma--an ultrastructural diagnosis

A case of eosinophilic variant of chromophobe cell renal carcinoma (EVCCRC), an uncommon variety of renal cell carcinoma, occurred in a 72 year old male. The most problematic differential diagnosis was renal oncocytoma, as the two entities share overlapping features on histology, yet differ completely in biological behavior. EVCCRC is a potentially malignant neoplasm whereas renal oncocytoma is totally benign. Staining with Hale's Colloidal Iron using modified Mowry's technique showed granular cytoplasmic positivity. The diagnosis was confirmed by ultrastructural examination of the tumor which revealed unique features of EVCCRC like presence of numerous cytoplasmic microvesicles along with mitochondria displaying tubulo-vesicular cristae. This case delineates the role of electron microscopic examination as the sole means to differentiate EVCCRC from renal oncocytomas.     

Using protein microarray as a diagnostic assay for non-small cell lung cancer

RATIONALE: Phenotypic and genotypic heterogeneity of lung cancer likely precludes the identification of a single predictive marker and suggests the importance of identifying and measuring multiple markers. OBJECTIVES: We describe the use of a fluorescent protein microarray to identify and measure multiple non-small cell lung cancer-associated antibodies and show how simultaneous measurements can be combined into a single diagnostic assay. METHODS: T7 phage cDNA libraries of non-small cell lung cancer were first biopanned with plasma samples from normal subjects and patients with non-small cell lung cancer to enrich the component of tumor-associated proteins, and then applied to microarray slides. Two hundred twelve immunogenic phage-expressed proteins were identified from roughly 4,000 clones, using high-throughput screening with patient plasmas and assayed with 40 cancer and 41 normal plasma samples. Twenty patient and 21 normal plasma samples were randomly chosen and used for statistical determination of the predictive value of each putative marker. Statistical analysis identified antibody reactivity to seven unique phage-expressed proteins that were significantly different (p < 0.01) between patient and normal groups. The remaining 20 patient and 20 normal plasma samples were used as an independent test of the predictive ability of the selected markers. MAIN RESULTS: Measurements of the 5 most predictive phage proteins were combined in a logistic regression model that achieved 90% sensitivity and 95% specificity in prediction of patient samples, whereas leave-one-out statistical analysis achieved 88.9% diagnostic accuracy among all 81 samples. CONCLUSION: Our data indicate that antibody profiling is a promising approach that could achieve high diagnostic accuracy for non-small cell lung cancer.     

Temporal dynamics of age-related differences in auditory incidental verbal learning

Auditory response profiles for a group of ten healthy young and ten healthy elderly subjects, evoked by implicit memory and delayed verbal recognition tasks, were evaluated to determine if effects of stimulus repetition could be identified in the superior temporal gyrus (STG) and prefrontal cortical regions. We hypothesized that effects of stimulus repetition should occur both early in time and at early levels of the nervous system (STG) followed by later effects in prefrontal regions. Magnetoencephalographic (MEG) responses were recorded using a whole-head MEG system and automated, multi-start analysis methods were applied to the data in order to characterize the temporal response profiles from distributed but focal, cortical regions engaged in memory-related tasks. The findings revealed a main effect of age for early activity ( approximately 50 ms) in STG which appeared to be nonspecific for Old/New words and an Age x Task interaction for late activity ( approximately 100-800 ms) in STG which was specific to Old/New words. Although the behavioral performance measures did not reveal traditional effects of response priming, the MEG measures did reveal a reduction in amplitude with stimulus repetition in young subjects. The elderly did not reveal a reduction in amplitude concomitant with stimulus repetition for either the global attributes of words or for specific Old/New words. Long duration effects of stimulus repetition noted in the present study raise the possibility that results from sensory gating, mismatch negativity and P300 paradigms may represent a continuum of stimulus repetition effects. Two of these paradigms evoke greater enhancement to novel or infrequent stimuli, or rather, greater reduction of amplitude with repetition.     

Pathological aging of the vascular endothelium: are endothelial progenitor cells the sentinels of the cardiovascular system?

Aging is associated with vascular endothelial dysfunction, which ultimately leads to atherosclerosis. On the other hand, it is clear that in young patients with risk factors for cardiovascular diseases (CVD), endothelial dysfunction is an early marker of the ongoing atherogenic process. It is therefore tempting to speculate that risk factors for CVD accelerate the aging process. The aging of an endothelial cell (EC) is not chronological but rather dependent on its replication rate. ECs have a finite number of divisions and enter replicative senescence after exhaustion of this potential. Telomere attrition is believed to be responsible for this phenomenon. Upon reaching a critical minimal telomere length, ECs enter a nondividing state of replicative senescence. Recently, endothelial progenitor cells originating from the bone marrow have been isolated from the circulation. They integrate into the endothelial layer of the vessel and contribute to healing, ischemic repair and angiogenesis. A completely new field of investigation is now open. Are endothelial progenitor cells sensitive to the aging process? Do they prevent endothelial dysfunction? Are they the ultimate shield against the damages induced by risk factors for CVD? There are no definite answers to these questions, but the potential of these cells is tremendous and understanding their physiology is essential.     

Proliferative activity of myeloma cells determined by Ki-67 antibody: biological and clinical significance

In this study we analyzed proliferative activity of myeloma cells and a possible correlation with selected clinical data, histological features and survival in 59 patients with newly diagnosed multiple myeloma (27 females and 32 males, mean age 62 years). Imunohistochemical method was applied using Ki-67 antibody on B5-fixed and paraffin-embedded bone marrow specimens to evaluate growth fraction of myeloma cells. Clinical staging was done according to the Durie-Salmon classification (4 patients had stage I disease, 16 patients stage II and 39 patients stage III). The number of Ki-67+ myeloma cells ranged from 1% to 36% (mean value 7%). In 39 of 59 patients (66.1%) number of Ki-67+ cells was less than 10% (cases with low proliferative index). Ki-67 expression significantly correlated with the clinical stage, beta2-microglobulin level, plasma cell morphology, volume of myeloma infiltration and the extent of osteolytic lesions. Patients with increased proliferative index (Ki-67+ cells > or = 10%) showed a significantly shorter survival compared to those with low proliferative index (14 months vs. 36 months, p = 0.023). However, this difference was not shown in multivariate analysis, particularly due to the high correlation between proliferative activity and plasma cell morphology and the volume of myeloma infiltration.     

Lichenoid drug eruption probably associated with rofecoxib

OBJECTIVE: To report a case of lichenoid drug eruption (LDE) probably induced by rofecoxib. CASE SUMMARY: A 73-year-old woman was prescribed rofecoxib 25 mg/day for rheumatoid arthritis in addition to other medications on which the patient had been stabilized. Six months after initiation of rofecoxib, linear plaques over the infra-orbital and bitemporal areas of both eyes were observed. Several itchy violaceous papules also developed on her right wrist and dorsum of the left foot. She also had a hyperpigmented macule on her right buccal mucosa. As the skin rash was localized and the patient was initially unwilling to undergo skin biopsy, rofecoxib was continued and a topical steroid was started. One month later, the patient was seen in the dermatology clinic, and the improvement of her skin reaction was significant. A skin biopsy performed during this visit was consistent with LDE. On the next day, her rheumatologist decided to discontinue the offending drug, rofecoxib. Two months later, all skin lesions had completely resolved. No rechallenge with rofecoxib was attempted. DISCUSSION: LDE is a rare skin reaction that can be associated with several drugs. Rofecoxib, a cyclooxygenase-2 inhibitor, has never before been reported to cause LDE. An objective causality assessment indicates that rofecoxib was the probable cause of the skin reaction. CONCLUSIONS: As of this writing, to our knowledge, this is the first case report in the English literature in which rofecoxib had led to the development of LDE.     

Classification and pathogenensis of spondyloarthropathies

The classification and pathogenesis of spondyloarthropathies are presented.