Amyloid β 38, 40, and 42 species in cerebrospinal fluid: More of the same?

Various C-terminally truncated amyloid beta peptides (Abeta) are linked to Alzheimer's disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Abeta38, Abeta40, and Abeta42 were measured by enzyme-linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Abeta42 levels was decreased in patients with AD, whereas CSF Abeta38 and Abeta40 levels were similar in patients with AD and control subjects. All three Abeta peptides were interrelated, particularly CSF Abeta38 and Abeta40. Diagnostic accuracy of CSF Abeta42 concentrations was not improved by applying the ratios of CSF Abeta42 to Abeta38 or Abeta40.     

Presence and localization of T-cell subsets in relation to melanocyte differentiation antigen expression and tumour regression as assessed by immunohistochemistry and molecular analysis of microdissected T cells

Melanoma-associated antigens may be the driving force behind the lymphocytic infiltrates in melanomas and the occurrence of melanoma regression. To investigate the clinical relevance of melanoma differentiation antigens (MDAs) as T-cell targets, the relationship between the presence and localization of T-cell subsets and the expression of MDAs was studied by immunohistochemistry and the diversity of CD8+ T cells in regressive melanomas was assessed using laser-assisted microdissection. While MDA expression as well as T-cell subset distribution, as assessed by immunohistochemical analysis, was heterogeneous within and between lesions, they were histologically independent phenomena. In four lesions studied in detail by PCR analysis of microdissected T cells, a limited T-cell diversity and evidence for clonally expanded tumour infiltrating lymphocytes were found. However, no major differences in T-cell diversity, as assessed by PCR analysis, between peri-and intra-tumoural areas became apparent, this despite the known clinical significance of the specific localization of a T-cell infiltrate. T cells of clonal origin did not show preferential localization to regressive tumour areas. Moreover, clonally related cells were found in two lesions with a non-brisk infiltrate, while in two lesions with a brisk infiltrate (clinically, a good prognostic factor) no evidence for clonally expanded tumour infiltrating lymphocytes was found. These data support the notion that specific immune reactivity and homing of specific cells to the tumour can occur in melanoma patients. However, they also show that the presence of clonally expanded T cells in the tumour is not necessarily associated with an effective anti-tumour immune response and may, for instance, represent regulatory cells. It appears that the clinical impact of an anti-tumour immune response is largely decided at the tumour site, where micro-environmental conditions dictate the functional state of the T cells. Full understanding of these processes can only be achieved by performing more dynamic analyses of the local host-tumour interactions.     

Radical radiotherapy compared with surgery for advanced squamous cell carcinoma of the base of tongue

PURPOSE: This study reports on T3/T4 base of tongue (BOT) tumors treated at the Erasmus MC (Rotterdam) with external beam radiotherapy (EBRT) and brachytherapy (BT). Local control, survival, and functional outcome are compared to results obtained in similar patients treated at the Vrije University Medical Center (VUMC, Amsterdam) by surgery and postoperative RT (PORT). METHODS AND MATERIALS: At Rotterdam 46/2 Gy was given to the primary and bilateral neck, followed by an implant using low-dose-rate (LDR 24-35 Gy; median 27 Gy), or fractionated high-dose-rate (fr. HDR 20-28 Gy; median 24 Gy). A neck dissection (ND) was performed in case of N+ disease. 67% of BOT tumors had a T4 cancer. At Amsterdam surgery (S) followed by PORT 40-70 Gy (median 60 Gy) was performed; 26% BOT tumors were T4. Sex, age and nodal distribution were similar. Actuarial local control and survival were computed. Performance Status Scale (PSS) scores were established. Xerostomis was determined on visual analog scales (VAS). RESULTS: Local failure at 5-years was 37% (Rotterdam) vs. 9% (Amsterdam) (p < 0.01). The overall survival was not significantly different (median 2.5 years vs. 2.9 years, respectively [p = 0.47]). The PSS favored brachytherapy. Both groups were equally affected by xerostomia. CONCLUSIONS: The 5-year local control was 65% with EBRT and BT. This result is strongly affected by 4 patients with residual disease after implantation. The Rotterdam patients had more advanced BOT tumors (67% vs. 26% T4), explaining the higher local failure rate. Given the organ preservation properties of radiotherapy-only and the better PSS scores, the jury is still out on the optimal treatment for BOT tumors.     

Dietary phylloquinone intake as a potential marker for a heart-healthy dietary pattern in the Framingham Offspring cohort

Abstract Associations were evaluated among self-reported dietary intakes of phylloquinone (vitamin K-1), lifestyle characteristics, and intermediary markers of cardiovascular disease risk in a population-based cohort of men and women. Dietary phylloquinone intakes were assessed by food frequency questionnaire in 1,338 men and 1,603 women (mean age, 54 years) participating in the Framingham Heart Study. Cross-sectional associations with lifestyle characteristics and lipid profiles, including total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, and triglyceride concentrations, were estimated across increasing quintile categories of phylloquinone intakes. Participants in the highest quintile category of phylloquinone intake consumed more fruit, vegetables, fish, dietary fiber, and dietary supplements ( P <.001), and consumed less meat and less saturated fat ( P <.001). Higher phylloquinone intakes were also associated with lower triglyceride concentrations ( P <.001). In conclusion, a high phylloquinone intake may be a marker for an overall heart-healthy dietary pattern.     

Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families

Germline mutations in succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary paragangliomas and phaeochromocytomas. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting. However, SDHD shows biallelic expression in brain, kidney and lymphoid tissues (Baysal et al., 2000). Moreover, consistent loss of the wild-type (wt) maternal allele in SDHD-linked tumours suggests expression of the maternal SDHD allele in normal paraganglia. Here we demonstrate exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and phaeochromocytomas, suggesting that combined loss of the wt SDHD allele and maternal 11p region is essential for tumorigenesis. We hypothesize that this is driven by selective loss of one or more imprinted genes in the 11p15 region. In paternally, but not in maternally derived SDHD mutation carriers, this can be achieved by a single event, that is, non-disjunctional loss of the maternal chromosome 11. Thus, the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.     

Noninvasive mapping of left ventricular electromechanical asynchrony by three-dimensional echocardiography and semi-automatic contour detection

A system for analyzing left ventricular (LV) electromechanical asynchrony based on transesophageal 3-dimensional echocardiography (3-DE) and semi-automatic endocardial contour detection is described. Eighteen consecutive patients underwent 3-DE. Using TomTec 4DLV software, a 3-dimensional endocardial surface was reconstructed throughout the cardiac cycle. Matlab software generated color-coded polar maps, displaying regional LV displacement and its timing. At the segmental level, Bland-Altmann assessment showed intraobserver variability of LV displacement of 0.1 +/- 3.0 mm and timing of -5.6 +/- 160 ms (bias +/- 2 SD) for all segments and -1.6 +/- 94 ms for the nonapical segments. The combination of 3-DE and semi-automatic contour detection is feasible and provides unique information for assessing regional LV endocardial displacement and electromechanical asynchrony.     

Human single-chain antibodies reactive with native chondroitin sulfate detect chondroitin sulfate alterations in melanoma and psoriasis

Chondroitin sulfate (CS) belongs to the group of glycosaminoglycans (GAGs), which are linear polysaccharides, located in the extracellular matrix and on the cell surface. To study the structure and distribution of CS in human skin and skin disorders, we have selected antibodies using phage display technique against CS. Four unique human anti-CS single-chain antibodies were selected: IO3D9, IO3H10, IO3H12, and IO4C2. We determined their amino acid sequence and evaluated their CS reactivity using ELISA and immunohistochemistry. Antibodies were reactive with CS, but not with other GAGs except for IO4C2, which was also reactive with heparin. Antibody IO3D9 showed a strong reactivity with highly sulfated CS (CSE). All antibodies displayed a different staining pattern in rat kidney, indicating the recognition of unique CS epitopes. In normal skin, the papillary dermis but not the reticular dermis was strongly stained. Antibody IO3H12 also stained basal keratinocytes. We applied these antibodies to study CS expression and localization in melanoma and psoriasis. A strong immunoreactivity with the extracellular matrix of melanoma metastases could be observed for all four antibodies, while in atypical nevi a less extensive reactivity with only the papillary dermis was observed. In psoriatic lesions, CS could be observed in the papillary dermis and in the reticular dermis, whereas the specific location in the papillary dermis found in normal skin was completely lost. In conclusion, human phage-display-derived anti-CS antibodies have been selected, characterized, and applied to detect CS alterations in skin conditions. Altered CS composition was detected in melanoma and psoriasis.