Combining CAPRA-S With Tumor IDC/C Features Improves the Prognostication of Biochemical Recurrence in Prostate Cancer Patients

Background: Intraductal carcinoma and cribriform (IDC/C) tumor features are well-established prognosticators of biochemical recurrence (BCR), metastasis, and prostate cancer (PCa)-specific mortality. However, approximately 70% of PCa patients undergoing a radical prostatectomy are IDC/C negative, yet up-to 20% of these patients progress and experience BCR. Thus, tumor histopathologic characteristics such as IDC/C alone are limited in their ability to predict disease progression. Conversely, several nomograms such as Cancer of the Prostate Risk Assessment-Surgery (CAPRA-S) have been developed to aid in the prognostication of BCR, but not yet widely applied in clinical settings. Materials and methods: In this study, we assessed the combined prognostic utility of IDC/C, and CAPRA-S for BCR in 3 PCa patient cohorts. Results: CAPRA-S+IDC/C improved the predictive accuracy of BCR in all 3 cohorts (P < .001). Specifically, among IDC/C negative cases, CAPRA-S improved the prognostication of BCR in low-risk (Cohort 1; P < .001, Cohort 2; P < .001, Cohort 3; P = .003), intermediate (Cohort 1; P < .001, Cohort 2; P = .006, Cohort 3; P = .03) and high-risk (Cohort 1-3; P < .001) patients. Conversely, IDC/C improved the prognostication of BCR among CAPRA-S low-risk (Cohorts 1; P < .001 and Cohort 3; P = .003) patients. Conclusion: Our results suggest the investigation of histopathological IDC/C features in CAPRA-S low-risk patients and conversely, nomogram CAPRA-S among IDC/C negative patients improves the identification of patients likely to experience BCR, which would otherwise be missed through current assessment regimens. These patients can be offered more intensive monitoring and adjuvant therapies upfront to circumvent the development of recurrent cancer or overtreatment at the time of surgery.     

Pharmacological Characterization of Bradykinin Receptors Coupled to Phosphoinositide Turnover in SV40-Immortalized Human Trabecular Meshwork Cells

This study sought to pharmacologically characterize bradykinin receptors on SV40-immortalized human trabecular meshwork (HTM3) cells. Phosphoinositide (PI) turnover studies were conducted using [³H]myo-inositol-labeled HTM3 cells and anion exchange chromatography to quantify [³H]inositol phosphates generated in response to bradykinin (BK) and various BK analogs. The blockade of these responses was studied using two potent and receptor-subtype selective antagonists. BK and T-kinin (Ile-Ser-BK; TK) induced a 4.2–4.4 fold stimulation of PI turnover above base levels at 1–10 μM. Several other peptides unrelated to BK, including angiotensin II, endothelin, cholecystokinin, bombesin and peptide YY tested at 1–10 μMwere essentially inactive. The molar potencies (EC₅₀) of BK, TK and close analogs were: BK=4.5±0.5 nM(n=6), Lys-BK=6.5±0.7 nM(n=3), TK=38.8±6.6 nM(n=8), Met-Lys-BK=41.5±13.4 nM(n=4), Des-Arg⁹-BK=2093±626 nM(n=4). All the latter BK-related peptides>were full agonists. The actions of BK and TK were potently and competitively antagonized by Hoe-140 (molar potency=0.6–1 nM;pA₂n=8.97–9.21,n=3–4) and byD-Arg⁰[Hyp³,-Thi^5,8,-DPhe⁷]-BK (molar potency=251 nM;-log potency, pK_b=6.6), two selective B₂-type BK antagonists. In conclusion, rank order of potency of BK agonists and the blockade of BK- and TK-induced PI turnover by the selective antagonists are consistent with the classification of the BK receptors on HTM3 cells as the B₂-receptor subtype.     

Ultrastructure of the periaqueductal grey matter of the rat: an electron microscopical and horseradish peroxidase study.

The neurons of the mesencephalic periaqueductal grey substance (PAG) in the rat are small and medium sized. The cells are frequently located in small clusters, without interdigitating glial elements and may be connected by direct membrane appositions or by gap junctions. The inner zone of the PAG is cell poor. In many cases, the cytoplasm of the cells is filled with extensive rough endoplasmic reticulum, free ribosomes, Golgi apparatus, and large lysosome-like granules. The nuclei show large indentations. The cells have a high nucleus-cytoplasm ratio. The neuropil is very extensive and particularly rich in large numbers of small unmyelinated axons, dendrites, axonal varicosities, and synaptic connections. Myelinated fibres are relatively scarce. The orientation of the fibres was studied in transverse and horizontal sections, in combination with HRP track tracing experiments. It appeared that throughout the PAG most of the fibres were orientated longitudinally. Quantitation showed that most fibres were present in the inner zones of the PAG. Moreover, the diameter of the fibres adjacent to the aqueduct was smaller than that of the fibres in the peripheral parts of the PAG. The thin unmyelinated fibres made extensive synaptic connections within the PAG. Many synaptic varicosities were found in the neuropil of the PAG. There were four types of synaptic varicosities, characterized by different populations of clear and dense-core secretory granules and by the different morphology of the synaptic specializations. In general, the different types of varicosity were homogeneously distributed in the different parts of the PAG. Electron dense secretory granules, when present, were located at some distance from the synaptic junction. Serial sections revealed varicosities which contained only dense-core secretory granules, without synaptic specializations. The dendrites of PAG neurons generally lacked synaptic spines. Many dendrites, particularly those of neurons located in the peripheral parts of the PAG, were directed toward the aqueduct. The present study shows that the PAG is a very complex brain area. The crisscrossing of axons and dendrites with synaptic connections at considerable distances from the cell bodies render it very difficult to unravel the relationships between the possible sources and destinations of ongoing information. This structure complicates the search for relationships between the functional organization and the cytoarchitectural borders in the PAG area.     

A biometrical genetic approach to chromosome analysis inDrosophila: Detection of epistatic interactions in geotaxis

Chromosome analysis has been widely used as a first step in eclucidating the genetic architecture of several behaviors ofDrosophila melanogaster. These chromosome studies have generally used incomplete designs or fairly simple statistical analyses. Here I reanalyze two data sets on geotaxis from Pyle (1978) and Ksander (1966) using a biometrical genetic design. Results from the biometrical genetic reanalysis suggest that individual differences in geotaxis might be due to genes on all three major chromosomes which show extensive epistatic interactions.     

A Bayesian approach to subvoxel tissue classification in NMR microscopic images of trabecular bone

NMR microscopy is currently being used as an investigational tool for the evaluation of micromorphometric parameters of trabecular bone as a possible means to assess its strength. Since, typically, the image voxel size is not significantly smaller than individual trabecular elements, partial volume blurring can be a major complication for accurate tissue classification. In this paper, a Bayesian segmentation technique is reported that achieves improved subvoxel tissue classification. Each voxel is subdivided either into eight subvoxels twice the original resolution, or up to four subvoxels along the transaxial direction and the subvoxels optimally classified as either bone or marrow. Based on a statistical model for partial volume blurring, the likelihood for the number of marrow subvoxels in each voxel can be computed on the basis of its measured signal. To resolve the ambiguity of the location of the marrow subvoxels, a Gibbs distribution is introduced to model the interaction between the subvoxels. Neighboring subvoxel pairs with the same tissue label are encouraged, and pairs with distinct labels are penalized. The segmentation is achieved by maximizing the a posteriori probability of the label image using the block ICM (iterative conditional mode) algorithm. The potential of the proposed technique is demonstrated in real and synthetic NMR microscopic images.     

Variation of prostate-specific antigen expression in different tumour growth patterns present in prostatectomy specimens

Summary A series of 55 randomly chosen radical prostatectomy specimens was analyzed for expression of prostate-specific antigen (PSA) by immunohistochemical techniques. Tissue sections were selected in such a manner that in addition to glandular benign prostatic hyperplasia (BPH), one or more different prostatic tumour growth patterns were present. Four monoclonal antibodies, directed against three different PSA epitopes, and one polyclonal anti-PSA antiserum were used. Expression of PSA was compared with that of prostate-specific acid phosphatase (PAP), recognized by two different polyclonal antisera. A critical dilution aimed at a maximum of staining intensity on BPH tissue sections was chosen for all antibodies. Anti-PSA and anti-PAP antisera stained essentially all BPH samples (over 90%). Irrespective of the nature of the antibodies used, PSA expression was found to be decreased in prostatic carcinoma. A clear cut relationship was found between immunoreactivity for PSA and the degree of differentiation of the tumour area. Under the experimental conditions used the PSA monoclonal antibodies stained only 1 out of 10 undifferentiated carcinomas, whereas 50% to 70% of the well- and moderately-differentiated carcinomas showed immunoreactivity. This correlation was less pronounced with the PAP staining pattern. If the PSA antibody titer was raised the percentage of clearly staining undifferentiated carcinomas could be considerably increased (up to 60%–100%), indicating that PSA expression is not absent, but lowered in most (if not all) undifferentiated carcinomas.     

A small angle light scattering device for planar connective tissue microstructural analysis

The planar fibrous connective tissues of the body are composed of a dense extracellular network of collagen and elastin fibers embedded in a ground matrix, and thus can be thought of as biocomposites. Thus, the quantification of fiber architecture is an important step in developing an understanding of the mechanics of planar tissues in health and disease. We have used small angle light scattering (SALS) to map the gross fiber orientation of several soft membrane connective tissues. However, the device and analysis methods used in these studies required extensive manual intervention and were unsuitable for largescale fiber architectural mapping studies. We have developed an improved SALS device that allows for rapid data acquisition, automated high spatial resolution specimen positioning, and new analysis methods suitable for large-scale mapping studies. Extensive validation experiments revealed that the SALS device can accurately measure fiber orientation for up to a tissue thickness of at least 500 μm to an angular resolution of∼1^o and a spatial resolution of±254 μm. To demonstrate the new device’s capabilities, structural measurements from porcine aortic valve leaflets are presented. Results indicate that the new SALS device provides an accurate method for rapid quantification of the gross fiber structure of planar connective tissues.     

The Cutaneous Microcirculation: Ultrastructure and Microanatomical Organization

The cutaneous microcirculation is organized as two horizontal plexuses. One is situated 1–1.5 mm below the skin surface, and the other is at the dermal-subcutaneous junction. Ascending arterioles and descending venules are paired as they connect the two plexuses. From the upper layer, arterial capillaries arise to form the dermal papillary loops that represent the nutritive component of the skin circulation. There are sphincter-like smooth muscle cells at the point where the ascending arterioles divide to form the arteriolar component of the upper horizontal plexus. At the dermal subcutaneous junction, there are collecting veins with 2-cusped valves that are oriented to prevent the retrograde flow of blood. Laser Doppler flowmetry (LDF) has demonstrated vasomotion of red cell flux localized to the sites of ascending arterioles. The simultaneous recording by LDF of red cell flux and the concentration of moving red blood cells from individual sites allows one to construct by computer topographic maps of these two valves. The two maps, based on initial studies using correlative skin biopsy specimens, can define 1-mm³ volumes of skin that are predominantly arteriolar in composition, predominantly venular in composition, or essentially devoid of all microvascular elements. The electron and light microscopic features that define the microvascular segments, when coupled with the ability of LDF to define the predominant microvascular segments under the probe, will allow one to study both the mechanisms of normal physiological states and the pathogenetic mechanisms underlying pathological skin disorders in which the microvasculature plays a predominant role.     

培养细胞整装内质网三维结构的多态性

用高锰酸钾－锇酸固定法制备了５种培养细胞整装内质网标本，并在扫描电镜下对其三维结构进行了观察。观察结果表明内质网是由膜性小管构成的贯穿整个细胞质的管囊网络样膜性区室，并以多种形态深入到细胞伪足及突起中；细胞质中内质网则表现为簇状网络（见于ＧＣＭ３Ｔ３细胞）、多态性多孔扁囊样网络、筛网状网络、条索状网络、大孔条索网状和细孔扁囊样分区网络、不规则管网状和多孔管囊分区网络（见于ＣＶ－１细胞）、细管网络（见于ＣＣＬ１８７和ＣＣＬ２２９细胞）、球囊网络（见于ＣＣＬ１８７和Ａ４３１细胞）和不规则管网状网络（见于Ａ４３１细胞）等。内质网的这种多态性提示它是一种高度可变的结构，其可变性可能与细胞特性、分化程度、细胞功能状态及细胞骨架系统的分布变化等因素有关。     

Housing and house-dust mites

Because the mite-allergen content in homes is highly variable even in the same geographic area, we tried to determine which variables influence mite infestation. We evaluated mite-allergen content in bedding relative to housing conditions and living habits. This cross-sectional study included 108 homes. Housing conditions were assessed by an architect and living habits by a researcher specialized in social and family economics. Group I allergen level was measured on the mattress dust with monoclonal antibodies, and relative humidity (RH) was monitored in the bedroom during a 2-week period. Homes with low RH did have low mite-allergen content. In contrast, homes with intermediate RH levels had very variable mite-allergen content. Using analysis of variance and a logistic regression analysis, we were unable to identify any variable predictive of mite-allergen content. Thus, factors other than relative humidity seem to influence mite infestation. Moreover, the absence of association between mite infestation and ventilation rate might be accounted for by the gentle climate in our area with notable outdoor RH.