Analysis of CDKN1A polymorphisms: markers of cancer susceptibility?

The CDKN1A (TP21) gene encodes a 21-kD protein that is a critical downstream mediator of wild-type TP53 and an important regulator of the cell cycle. Failure in the function of this gene would be expected to result in abnormal cell proliferation and transformation. Tumor-associated mutations of the coding region of the TP21 are rare. On the other hand, some TP21 polymorphisms have been identified and characterized by single base substitutions. In the present study, we investigated the potential role of TP21 gene polymorphisms in skin, head, and neck tumorigenesis. A total of 261 samples were examined by polymerase chain reaction single-strand conformational analysis, and one mutation at codon 31 and four polymorphisms in exons 2 (codon 55) and 3 [nucleotide (nt)590] and in promoter region (nt2298) were identified. In conclusion, this investigation confirmed the rarity of mutations in this gene, arguing against a role for TP21 mutations in skin, head, and neck cancers. Also, our results show significant differences in nt2298 allele frequencies between normal individuals and skin malignant tumors (P < 0.05). The results suggest that this polymorphism affects TP21 transactivator binding and may be important during the pathogenesis of skin cancer.     

IgVH gene analysis suggests that peritoneal B cells do not contribute to the gut immune system in man

The contribution of peritoneal B cells to the intestinal lamina propria plasma cell population is well documented in mice, but unknown in humans. We have analyzed immunoglobulin (Ig) genes of human peritoneal B cells, because such genes show distinctive characteristics in mucosal B cells, particularly highly mutated variable regions. Here, we report the characteristics of variable region genes used by IgM, IgA and IgG in peritoneal cells. We focused on the properties of IgV(H)4-34 to allow comparisons of like-with-like between different isotypes and cells from different immune compartments. We observed that the IgM genes were mostly unmutated, and that the mutated subset had less mutations than would be expected in a mucosal B cell population. Likewise, the IgV(H)4-34 genes used by IgA and IgG from peritoneal B cells had significantly lower numbers of mutations than observed in the mucosal counterparts. Other trends observed, while not reaching statistical significance, followed the trend of peripheral B cells. The peritoneal B cell population had more IgA1 than IgA2 sequences, and there was no dominance of J(H)4 in the IgA from peritoneum or spleen, in contrast to the mucosal sequences. Overall, this study suggested that human peritoneal B cell are either peripheral or mixed in origin; they are unlikely to represent an inductive compartment for the mucosal B cell system.     

Data on the clinical aspects and therapy of primary gastrointestinal lymphomas

Fifteen cases of primary gastrointestinal lymphoma diagnosed over 8 years are reviewed. In the period 1980 to 1982 there was a cumulative appearance of GI lymphomas, nine out of 15 cases were diagnosed in that period. According to its localization, lymphoma occurred in 12 cases in the stomach, and in 3 in the small intestines and the colon. One case of gastric lymphoma was Hodgkin type, the others were non-Hodgkin types. The clinical symptoms were not characteristic of lymphoma. The age of the patients was, on the average, ten years lower than the mean age of carcinoma patients. Preoperative diagnosis by gastric biopsy was successful in four cases. In patients with lymphoma of the colon not subjects to surgery, colonoscopy verified the origin of lymphoma. Exact clinical classification in the majority of cases was made intraoperatively. In the non-operated cases, sonography and lymphography were performed. In general, operation was attempted, but patients in stage II, in very poor condition, were possibly not operated. The possibility and indications of the "second look" operation are discussed. Histological typing was made according to the Kiel classification. In the literature, in the most controversial question of therapy, individual consideration of the cases is recommended. Based on our experience, in devising therapy or therapeutic strategy as well as concerning prognosis, the degree of malignancy according to histological type, clinical stage and anatomical localization seem to be the most decisive factors. In exceptionally malignant cases a protocol with doxorubicine + bleomycin + teniposide and prednisolone was applied.     

Activation of mucosal Vβ3+ T cells and tissue damage in human small intestine by the bacterial superantigen,Staphylococcus aureus enterotoxin B

Staphylococcus aureus enterotoxin B (SEB) was added to explants of fetal human intestine in organ culture or administered into the lumen of fetal small intestine prior to culture. Both routes produced a massive increase in lamina propria T cells expressing Vβ33, and to a lesser extent, those expressing Vβ5 and Vβ12. SEB-activated lamina propria T cells produced interleukin-2 and interferon-Y and T cell activation was accompanied by tissue damage, which was inhibited by FK506.     

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy

Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.     

The educational impact of ACGME limits on resident and fellow duty hours: a pre-post survey study.

PURPOSE: To assess the educational impact of Accreditation Council for Graduate Medical Education resident work-hour limits implemented in July 2003. METHOD: All trainees in all 76 accredited programs at two large teaching hospitals were surveyed between May and June 2003 (before work-hour reductions) and then between May and June 2004 (after work-hour reductions) about hours, education, and fatigue. Based on changes in weekly duty hours, 13 programs experiencing substantial reduction in hours were classified into a reduced-hours group. Differences in assessments of educational endpoints before and after policy implementation by trainees in the reduced-hours group were compared with those in other programs to control for potential temporal trends, using two-way ANOVA with interaction. RESULTS: The number of respondents was 1,770 (60% response rate). The reduced-hours group reported a significant decrease in time spent directly caring for patients (from 48.5 to 42.3 mean h/wk, P = 0.03), but the volume of important clinical experiences, including procedures, was preserved, as was the sense of clinical preparedness. On 22 questions related to educational quality and adequacy, only three differences in differences were significant, with the reduced-hours group reporting a relative increase in opportunities for research, decrease in quality of faculty teaching, and decrease in educational satisfaction. The percentage of trainees reporting frequent negative effects of fatigue dropped more in the reduced-hours programs than in the other programs (P < 0.05). CONCLUSION: This study shows that it may be possible to reduce residents' hours--and the perceived adverse impact of fatigue--while generally preserving the self-assessed quality, quantity, and outcomes of graduate medical education.     

Familial testicular cancer: interest in genetic testing among high-risk family members.

PURPOSE: This study is part of an ongoing National Cancer Institute multidisciplinary, etiologically-focused, cross-sectional study of Familial Testicular Cancer (FTC). The current report targets interest in clinical genetic testing for susceptibility to FTC. METHODS: Demographics, knowledge, health beliefs, and psychological and social factors were evaluated as covariates related to interest in genetic testing. RESULTS: The majority (66%) of 229 participants (64 affected men, 66 unaffected men, and 99 women) from 47 multiple-case FTC families expressed interest in having a genetic test within 6 months, should such a test become available. Interest was similar among the three subgroups mentioned above. Worries about insurance discrimination based on genetic test results were associated with a significantly lower interest in testing. Alternatively, participants were more likely to be interested in genetic testing if they were younger and had higher levels of family support, a physician's recommendation supporting testing, cancer distress, and a need for information to inform the health care of their children. CONCLUSIONS: This study reveals social and relationship factors that FTC survivors and their relatives considered important when contemplating the use of new genetic technologies. This is the first study describing hypothetical interest in genetic testing for familial testicular cancer.     

Examining Trichophyton tonsurans genotype and biochemical phenotype as determinants of disease severity in tinea capitis.

Trichophyton tonsurans infections occur in various host populations, on various body sites and with varying degrees of inflammation. This investigation was undertaken to determine whether fungal factors could explain the degree of severity in clinical symptomatology among infected children. Otherwise healthy children (n=54) presenting with tinea capitis were enrolled in this study. A thorough history was performed, the extent and severity of infection graded and a fungal specimen collected from each child. Strain type was determined by genotyping for 11 sequence variations in the rDNA and ALP1 loci. Secreted protease activity was quantitated after 5 days of growth in aqueous medium. Forty participants were evaluable. Infection duration ranged from 1 day to 3 years and clinical severity score (CSS) from 4-19. Seventeen unique fungal genotypes were present. Keratinase, collagenase and elastase activity varied 32.7-fold, 64.9-fold and 303.3-fold, respectively. A significant association was observed between genotype and disease severity with the rDNA sequence variations accounting for over 50% of the variation observed in CSS (r2=0.539; P<0.001). Phylogenetic analyses appear to suggest that the ancestral strain types of T. tonsurans cause more severe disease. These observations are consistent with reports that recently diverge anthropophilies are associated with diminished inflammatory involvement.