Test-bolus injection for optimization of arterial phase imaging during contrast-enhanced hepatic MR imaging

Contrast enhancement during the dynamic MR imaging is important for the detection and characterization of focal liver lesions. The purpose of this study was to determine whether or not a timing examination with a injection of a 1.0-mL bolus of gadopentetate dimeglumine into the antecubital vein followed by rapid dynamic scanning and measurement of signal intensity of the aorta could help to obtain proper arterial-dominant phase images for the characterization of focal hepatic lesions during subsequent multiphase dynamic MR imaging. The imaging delay to acquisition of the first gadolinium-enhanced image for multiphase dynamic MR imaging was set to equal the time to peak aortic enhancement during the test examination. The first contrast-enhanced images of 80 patients with 160 focal liver lesions (hepatocellular carcinoma, n = 79; cavernous hemangioma, n = 51; metastatic tumor, n = 30) were then retrospectively reviewed. Peak aortic enhancement occurred between 10 and 28 seconds (mean, 16.5 seconds +/- 3.1) after starting the infusion of contrast material in 80 patients during the test-examination. Depending on the findings of intrahepatic vascular enhancement on the full-scale dynamic images, hepatic arterial phase (n = 11, 14%) or sinusoid phase (n = 65, 81%) imaging was obtained during the first gadolinium-enhanced acquisition in 76 (95%) of 80 patients. Three different lesions were well characterized and easily distinguished from each other (p < .0001) on the first-phase images depending on their enhancement pattern. In the majority of patients, timing examination with test-bolus injection was helpful in obtaining qualified images for the characterization of various focal lesions.     

Additive effect of TRAIL and p53 gene transfer on apoptosis of human lung cancer cell lines

TRAIL is a cytokine that can induce tumor-specific apoptosis through its specific death receptors (DR4 and DR5) and p53 has been proven to increase the expression of death receptors. To examine their interaction in tumor suppression, p53 and TRAIL genes were inserted in recombinant adenovirus vectors and transferred simultaneously into non-small cell lung cancer cell lines (NCI-H157, NCI-H358, NCI-H460 and A549). Western blot assay demonstrated production of TRAIL protein in NCI-H157 and A549 cell lines. Increased expressions of DR4 and DR5 of NCI-H157 and DR4 of A549 after p53 overexpression were confirmed by flow cytometry. p53 or TRAIL gene transfer increased sub-G1 fraction in cell cycle analysis and inhibited the tumor growth dose-dependently and the degree was potentiated by co-transfer. But isobologram analysis indicated an additive effect. Together, these data indicate that p53 and TRAIL interact additively on tumor apoptosis despite theoretical synergism.     

Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa-/- (Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Hexb-/- mice is associated with apoptosis occurring throughout the CNS, while Hexa-/- mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.      

The role of recombination signal sequences in the preferential joining by deletion in DH-JH recombination and in the ordered rearrangement of the IgH locus

The bias favoring deletion over inversion in DH-JH rearrangement has been known for years, but the underlying mechanism has yet to be fully defined. It has been suggested that the ratio of deletion/inversion is determined by the combined effect of two factors: (i) the relative strengths of 5' and 3' recombination signal sequences (RSS) of a DH segment, and (ii) the efficiency with which the deletional product (one joint) forms relative to the inversional product (two joints). In this study, we analyzed for the first time the effect of factor 1 alone on the biased 3' RSS utilization in DH-JH joining by using deletional plasmids in an extrachromosomal substrate V(D)J recombination assay. It was found that the 3' RSS and associated coding end (12 bp) mediate recombination more efficiently than the 5' RSS/coding end DH-JH plasmids. These results demonstrate that the effect of the RSS/coding end alone can account, at least partially, for the predominant deletion in DH-JH recombination. The potential effect of the relative strength of RSS and associated coding end on the ordered rearrangement of DH-JH followed by VH to DH-JH was also assessed. When recombination frequencies of D-->J (3' DH to J3) were compared with frequencies of V-- >D (VHPJ14 to 3' DH or VHOX2 to 3' DH), it was found that V-->D joining was, if anything, more efficient than D-->J joining. Therefore, if all three segments were accessible, RSS/coding end effects would not contribute to the ordered rearrangement of the IgH locus.      

Mechanisms of enhanced prevalence of asthma and atopy in developed countries

Atopy — a T helper 2 cell driven hypersensitivity to innocuous antigens (allergens) which causes most cases of asthma — is of complex genetic and environmental origins. There is compelling epidemiological evidence for a rise in atopic disease in ‘westernised’ communities. The changing pattern of microbial exposure in early childhood is suggested to be the principal candidate mechanism for this rise.     

The incidence and clinical implications of hypersensitivity to papain in an allergic population, confirmed by blinded oral challenge

Five hundred allergy clinic patients were prick skin tested with papain, 1 mg/mL, in addition to usual local aeroallergens. Five of 475 subjects with seasonal allergic disease had positive skin tests to both papain and local pollens. None of the 25 individuals with negative skin test to pollens had skin reactivity to papain. The five subjects with positive skin tests to papain underwent double-blind placebo-papain challenges. All papain challenges were positive. Placebo challenges were negative. Papain-induced symptoms included palatal itching, watering itchy eyes, sneezing, rhinorrhea, abdominal cramps, diarrhea, and diaphoresis. Circulating papain-specific IgE was detected in all the papain-sensitive individuals, but not in control subjects. Confirmed papain sensitivity occurred in 1.05% of allergic subjects. In the papain-sensitive patients, cross-reacting antibodies with chymopapain were found. The small number of non-allergic subjects did not show any papain or chymopapain sensitivity in vitro.     

Radiologic findings of Mirizzi syndrome with emphasis on MRI

We have reported a case of Mirizzi syndrome preoperatively diagnosed using MR cholangiopancreatography. MRCP and T2-weighted image using a single-shot fast spin-echo sequence accurately depicted all components of Mirizzi syndrome, including impacted stone in the neck of the gallbladder compressing the common hepatic duct and wall-thickening of the gallbladder without any evidence of malignancy. The combination of MRCP and T2-weighted image can be counted on to replace conventional modalities of diagnosing Mirizzi syndrome without any loss of diagnostic accuracy.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.