Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita

Dyskeratosis congenita (DC) is an inherited bone marrow (BM) failure syndrome associated with mutations in telomerase genes and the acquisition of shortened telomeres in blood cells. To investigate the basis of the compromised hematopoiesis seen in DC, we analyzed cells from granulocyte colony-stimulating factor mobilized peripheral blood (mPB) collections from 5 members of a family with autosomal dominant DC with a hTERC mutation. Premobilization BM samples were hypocellular, and percentages of CD34⁺ cells in marrow and mPB collections were significantly below values for age-matched controls in 4 DC subjects. Directly clonogenic cells, although present at normal frequencies within the CD34⁺ subset, were therefore absolutely decreased. In contrast, even the frequency of long-term culture-initiating cells within the CD34⁺ DC mPB cells was decreased, and the telomere lengths of these cells were also markedly reduced. Nevertheless, the different lineages of mature cells were produced in normal numbers in vitro. These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs.     

Pagetoid reticulosis (Woringer‐Kolopp disease)

Pagetoid reticulosis (Woringer‐Kolopp disease) is a rare subtype of cutaneous CD8‐positive T‐cell lymphoma. A 41‐year‐old man presented with a 7‐year history with a slowly progressive erythematous plaque on his right buttocks. With the working diagnosis of psoriasis, he was treated with topical corticosteroids which produced no improvement. Histological examination showed an epidermotropic T‐cell lymphoma with predominance of CD8‐ vs.CD4‐positive lymphocytes. Based on the clinical picture and the histological findings, we diagnosed pagetoid reticulosis. Excision of the plaque and cream PUVA photo‐chemotherapy produced long‐term remission.     

Visual Functioning Questionnaire: reevaluation of psychometric properties for a group of working-age adults.

PURPOSE: The Visual Functioning Questionnaire (VFQ-25) is one of the most widely used measures of vision-related quality of life. However, the questionnaire does not meet some psychometric quality criteria. The objectives of this study were first to obtain the factor structure of the VFQ-25, and second, to obtain interval scales by Rasch analysis. METHODS: The questionnaire was administered to 129 visually impaired adults (mean age 42.1 years; range 21 to 67 years). First, the items of the VFQ-25 were subjected to an exploratory factor analysis with Promax rotation. Next, we performed a separate Rasch analysis on each factor. We examined step thresholds and goodness of fit statistics of the items. Finally, we examined differential item functioning. RESULTS: Factor analysis indicated four factors: Near Activities, Distance Activities and Mobility, Mental Health and Dependency, and Pain and Discomfort. They accounted for 46.37% of the total variance. Most items showed some degree of disordering. After collapsing response categories, all items showed ordered thresholds. The Near Activities domain showed excellent fit, whereas the Distance Activities and Mobility domain, the Mental Health and Dependency domain, and the Pain and Discomfort domain had an unsatisfactory fit. There were two items showing uniform differential item functioning. CONCLUSIONS: The four-factor structure of the VFQ-25 largely confirms the structure of the questionnaire. However, the results of this study suggest that modifications of the original VFQ-25 structure are necessary.     

Stereoacuity and ocular associations at age 12 years: findings from a population-based study.

PURPOSE: To report the distribution of stereoacuity thresholds and ocular characteristics associated with reduced stereoacuity in a representative sample of 12-year-old Australian children. METHODS: Stereoacuity thresholds were determined using the three quantitative plates of the TNO test in 2343 children, either unaided or with spectacles, if worn. Logarithm of minimum angle of resolution (logMAR) visual acuity was measured. Cycloplegic autorefraction (using cyclopentolate), cover testing, and dilated fundus examination were performed. Reduced stereoacuity was defined as > 120 arcsec. Myopia was defined as spherical equivalent refraction (SER) < or = -0.50 D hyperopia as spherical equivalent refraction > or = +2.0 D, anisometropia as spherical equivalent refraction difference between eyes > or =1.00 D, and astigmatism as cylinder > or = 1.0 D. RESULTS: Stereoacuity was based on unaided visual acuity in 1975 children (84.3%) and on spectacle-corrected visual acuity in 368 children (15.7%); 87 children (3.7%) had reduced stereoacuity. Amblyopia was the most common identifiable cause, accounting for 32%, followed by strabismus (15%) and anisometropia (14%). Presence of anisometropia was significantly associated with reduced stereoacuity; 78.6% of anisometropic children achieved normal stereoacuity versus 98.9% without anisometropia (p < 0.0001). CONCLUSIONS: Reduced stereoacuity was relatively uncommon in a population of 12-year-old Australian children. Its functional and psychosocial impact on individuals and on the whole population remains uncertain.     

Phase 2 reentry in man.

BACKGROUND: Ventricular extrasystoles are characterized by a fixed coupling interval to the last QRST complex preceding it. OBJECTIVES: We hypothesized that this QRST complex differed from QRST complexes of other sinus beats not followed by ventricular extrasystoles. Further, we investigated whether phase 2 reentry, demonstrated in animal experiments to initiate ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation, also plays a role in humans. METHODS: We examined 18 patients with ventricular extrasystoles and/or ventricular tachycardia by signal averaging of the ECG (group A) or by single-beat analysis of intracardiac electrograms (group B). Group A consisted of six patients without structural heart disease and one patient with the Brugada syndrome. Six of the seven patients had right ventricular outflow tract ventricular extrasystoles. Group B consisted of 11 patients undergoing radiofrequency ablation. Eight of the 11 patients had right ventricular outflow tract extrasystoles. RESULTS: In six of the seven patients in group A, we demonstrated significant ST-elevation and/or T-wave changes in the sinus beat preceding ventricular extrasystoles compared with the second last sinus beat in one or more of the three orthogonal leads X, Y, and Z. In 9 of the 11 patients in group B, single-beat analysis of unipolar and bipolar electrograms recorded close to successful ablation sites demonstrated similar changes, that is, ST-elevation (median peak voltage gradient 150 muV, range 0-1,700) and T-wave changes in the sinus beat prior to ventricular ectopy. In addition, J-point elevation was demonstrated in several cases. In total, significant changes were demonstrated in 15 of the 18 patients studied (83%). CONCLUSION: J-point elevation, ST-elevation, and T-wave changes documented in the last sinus beat prior to ventricular extrasystoles are in agreement with phase 2 reentry, suggesting that this may be the responsible mechanism for ventricular extrasystoles and ventricular tachycardia/fibrillation. The phenomenon has been demonstrated in only animal experiments to date.     

Pneumolysin potentiates oxidative inactivation of alpha-1-proteinase inhibitor by activated human neutrophils

This study was designed to investigate the effects of the Streptococcus pneumoniae-derived, pro-inflammatory toxin, pneumolysin (8.37 and 41.75 ng/ml), on the oxidative inactivation of alpha-1-protease inhibitor (API) by chemoattractant-activated human neutrophils in vitro. The elastase inhibitory capacity (EIC) of API in supernatants from unstimulated neutrophils, neutrophils treated with pneumolysin only, or with the chemoattractant FMLP (1 microM) only, or the combination of the toxin with FMLP was measured by a colorimetric procedure based on the activity of added porcine elastase. The EIC of API was unaffected by exposure to pneumolysin only, unstimulated neutrophils, or neutrophils treated with pneumolysin only. However, exposure to FMLP-activated neutrophils resulted in a reduction of the EIC of API, which was significantly (P<0.05) augmented by pneumolysin (mean reductions of 16%, 43% and 83% for FMLP only and in combination with 8.37 and 41.75 ng/ml pneumolysin, respectively), and was attenuated by wortmannin (1 microM), an inhibitor of NADPH oxidase, the oxidant-scavenger methionine (100 microM), and depletion of Ca2+ from the cell-suspending medium. These pro-proteolytic interactions of pneumolysin with chemoattractant-activated neutrophils may contribute to the invasiveness of the pneumococcus.     

Immunostaining of p53 protein in ovarian carcinoma: correlation with histopathological data and clinical outcome

Objective: The objective of this study was to analyze the incidence of immunohistochemically detectable p53 protein accumulation in epithelial ovarian carcinomas and to correlate these data with the clinical outcome so as to clarify further the role of p53 mutations in prognosis with these patients.Methods: Tumor tissues from 179 patients with epithelial ovarian carcinoma were used for immuno-histochemical analysis with monoclonal antibody DO1 and BP 53-12-1 on formalin-fixed, paraffin-embedded tissue.Results: A total of 78 cases (44%) showed positive nuclear p53 staining. The p53-positive cases were found in all histological types of epithelial ovarian tumors. p53 staining was found in tumors of all stages with a higher percentage of positive cases in stage IV ovarian carcinomas (not significant). Poorly differentiated carcinomas showed a significantly higher percentage of p53 protein expression than did highly differentiated tumors (P=0.0002). Clinical follow-up of up to 14 years (median 25 months) showed a slightly but not significantly shortened disease-free and overall survival time for patients with p53-positive epithelial ovarian carcinomas.Conclusions: We conclude from our data that p53 expression in ovarian carcinoma is associated with poor differentiation but not with the disease being in an advanced stage. There was a tendency for shortened disease-free and overall survival for patients with p53-positive tumors.     

The Effect of Pain on Major Cognitive Impairment in Older Adults

Older adults frequently report pain; cross-sectional studies have shown that pain is associated with worse cognitive function. However, longitudinal studies are lacking. We prospectively studied 441 participants without dementia, including 285 with pain, aged 65 years and older, enrolled in the Central Control of Mobility in Aging study, a prospective cohort study. We analyzed the longitudinal association between pain (measured with the Medical Outcomes Study pain severity scale) and major cognitive impairment (measured with the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test Delta) using Cox regression analysis adjusted for age, gender, ethnicity, and education. Over a mean follow-up of 2.75 years (standard deviation?=?1.94), there was no difference in the risk of developing cognitive impairment between participants with pain and participants without pain. However, among those with pain, risk for developing major memory impairment was higher among those with high levels of pain than those with low levels of pain (adjusted hazard ratio?=?3.47, 95% confidence interval?=?1.42–8.46). The association with pain and incident impairments in attention or executive function was not significant. We did not find that pain is associated with incident cognitive impairment in general, but among older adults with pain, a high level of pain is associated with increased risk of developing incident memory impairment.