Case-control and case-only designs with genotype and family history data: estimating relative risk, residual familial aggregation, and cumulative risk

In case-control studies of inherited diseases, participating subjects (probands) are often interviewed to collect detailed data about disease history and age-at-onset information in their family members. Genotype data are typically collected from the probands, but not from their relatives. In this article, we introduce an approach that combines case-control analysis of data on the probands with kin-cohort analysis of disease history data on relatives. Assuming a marginally specified multivariate survival model for joint risk of disease among family members, we describe methods for estimating relative risk, cumulative risk, and residual familial aggregation. We also describe a variation of the methodology that can be used for kin-cohort analysis of the family history data from a sample of genotyped cases only. We perform simulation studies to assess performance of the proposed methodologies with correct and mis-specified models for familial aggregation. We illustrate the proposed methodologies by estimating the risk of breast cancer from BRCA1/2 mutations using data from the Washington Ashkenazi Study.     

Characterization of senescence-associated proteases in postharvest broccoli florets.

We characterized the senescence-associated proteases of postharvest broccoli (Brassica oleracea L. var Green King) florets, using class-specific protease inhibitors and gelatin-polyacrylamide gel electrophoresis. Different classes of senescence-associated proteases in broccoli florets were partially characterized for the first time. Protease activity of broccoli florets was depressed by all the inhibitors and showed different inhibition curves during postharvest. The hydrolytic activity of metalloprotease (EC 3.4.24. - ) and serine protease (EC 3.4.21. - ) reached a maximum, 1 day after harvest (DAH), then decreased, while the hydrolytic activity of cysteine protease (EC 3.4.22. - ) and aspartic protease (EC 3.4.23. - ) increased throughout the postharvest senescence based on the calculated inhibition percentage of protease activity. The senescence-associated proteases were separated into seven endoprotease (EP) groups by gelatin-polyacryamide gel electrophoresis and classified into EP1 (metalloprotease), EP2 (metalloprotease and cysteine protease), EP3 (serine protease and aspartic protease), EP4, EP5, EP7 (cysteine protease), and EP6 (serine protease) based on the sensitivity of class-specific protease inhibitors. The proteases EP2, EP3, and EP4 were present throughout the postharvest stages. EP3 was the major EP at all times during senescence; EP4 intensity of activity increased after 2 DAH; EP6 and EP7 clearly increased after 4 DAH. Our results suggest that serine protease activity contributes to early stage (0-1 DAH) and late stage (4-5 DAH) of senescence; metalloprotease activity was involved in the early and intermediate stages (0-3 DAH) of senescence; and cysteine protease and aspartic protease activities participated in the whole process of broccoli senescence.     

Differential role of leptin receptors at the hypothalamic paraventricular nucleus in tonic regulation of food intake and cardiovascular functions

Leptin plays an important role in the central regulation of body weight and arterial pressure via activation of leptin receptors (Ob-Rs) in the hypothalamic area, including the hypothalamic paraventricular nucleus (PVN). The present study was undertaken to investigate whether endogenous leptin in the PVN plays a dual role in the tonic regulation of body weight and arterial pressure. Adult, male normal-weight Sprague-Dawley rats, which were anesthetized and maintained with propofol, were used. A direct bilateral microinjection into the PVN of an antisense oligonucleotide against Ob-R mRNA (ASON1, 50 pmol) significantly increased the daily food intake and body weight gain, effects which lasted for at least 14 days. The same treatment, on the other hand, had no appreciable effect on the basal mean systemic arterial pressure (SAP), heart rate (HR), or power density of the vasomotor components of SAP signals, the experimental index of neurogenic sympathetic vasomotor tone. ASON1 treatment also exerted an insignificant effect on the baroreceptor reflex control of HR. Western blot analysis revealed that a bilateral microinjection into the PVN of ASON1 (50 pmol) significantly decreased the expression of the Ob-R protein in the hypothalamus. The same treatment also attenuated hypertension, tachycardia, and the increase in the power density of the vasomotor components of the SAP signals induced by exogenous bilateral application of leptin (5 or 50 ng) into the PVN. Control application of sense (SON, 50 pmol) or a scrambled antisense Ob-R oligonucleotide (ASON2, 50 pmol) into the bilateral PVN promoted no discernible effect on Ob-R protein expression in the hypothalamus, on daily food intake, or on cardiovascular performance. Our results indicate that whereas the Ob-Rs in the PVN are involved in the tonic regulation of food intake, they might not be actively involved in the tonic regulation of cardiovascular functions.     

Indication of dynamic neurovascular coupling from inconsistency between EEG and fMRI indices across sleep–wake states

Sleep and Biological Rhythms - Neurovascular coupling (NVC), the transient regional hyperemia following the evoked neuronal responses, is the basis of blood oxygenation level-dependent techniques...     

Expression of Cell Competition Markers at the Interface between p53 Signature and Normal Epithelium in the Human Fallopian Tube

There is a growing body of evidence regarding cell competition between normal and mutant mammalian cells, which suggest that it may play a defensive role in the early phase of carcinogenesis. In vitro study in the past has shown that overexpression of vimentin in normal epithelial cells at the contact surface with transformed cells is essential for the cell competition involved in epithelial defense against cancer. In this study, we attempted to examine cell competition in human tissue in vivo by investigating surgically resected human fallopian tubes that contain p53 signatures and serous tubal intraepithelial lesions (STILs), a linear expansion of p53-immunopositive/TP53 mutant tubal epithelial cells that are considered as precursors of pelvic high grade serous carcinoma. Immunofluorescence double staining for p53 and the cell competition marker vimentin was performed in 21 sections of human fallopian tube tissue containing 17 p53 signatures and 4 STILs. The intensities of vimentin expression at the interface between p53-positive cells at the end of the p53 signature/STIL and adjacent p53-negative normal tubal epithelial cells were compared with the background tubal epithelium. As a result, the average vimentin intensity at the interfaces relative to the background intensity was 1.076 (95% CI, 0.9412 – 1.211 for p53 signature and 0.9790 (95% CI, 0.7206 – 1.237) for STIL. Thus, it can be concluded that overexpression of the cell competition marker vimentin are not observed in human tissue with TP53 alterations.     

Prolonged Cerebral Circulation Time Is the Best Parameter for Predicting Vasospasm during Initial CT Perfusion in Subarachnoid Hemorrhagic Patients

Purpose

We sought to imitate angiographic cerebral circulation time (CCT) and create a similar index from baseline CT perfusion (CTP) to better predict vasospasm in patients with subarachnoid hemorrhage (SAH).

Methods

Forty-one SAH patients with available DSA and CTP were retrospectively included. The vasospasm group was comprised of patients with deterioration in conscious functioning and newly developed luminal narrowing; remaining cases were classified as the control group. The angiography CCT (XA-CCT) was defined as the difference in TTP (time to peak) between the selected arterial ROIs and the superior sagittal sinus (SSS). Four arterial ROIs were selected to generate four corresponding XA-CCTs: the right and left anterior cerebral arteries (XA-CCT_RA2 and XA-CCT_LA2) and right- and left-middle cerebral arteries (XA-CCT_RM2 and XA-CCT_LM2). The CCTs from CTP (CT-CCT) were defined as the differences in TTP from the corresponding arterial ROIs and the SSS. Correlations of the different CCTs were calculated and diagnostic accuracy in predicting vasospasm was evaluated.

Results

Intra-class correlations ranged from 0.96 to 0.98. The correlations of XA-CCT_RA2, XA-CCT_RM2, XA-CCT_LA2, and XA-CCT_LM2 with the corresponding CT-CCTs were 0.64, 0.65, 0.53, and 0.68, respectively. All CCTs were significantly prolonged in the vasospasm group (5.8–6.4 s) except for XA-CCT_LA2. CT-CCT_A2 of 5.62 was the optimal cut-off value for detecting vasospasm with a sensitivity of 84.2% and specificity 82.4%

Conclusion

CT-CCTs can be used to interpret cerebral flow without deconvolution algorithms, and outperform both MTT and TTP in predicting vasospasm risk. This finding may help facilitate management of patients with SAH.     

The first Praesiricidae (Hymenoptera) from Northeast China

A new subfamily Rudisiricinae Gao, Rasnitsyn, Ren & Shih, n. subfam. and a new genus Rudisiricius Gao, Rasnitsyn, Ren & Shih, n. gen. with three new species R. belli Gao, Rasnitsyn, Ren & Shih n. sp., R. crassinodus Gao, Rasnitsyn, Ren & Shih, n. sp., and R. celsus Gao, Rasnitsyn, Ren & Shih, n. sp. are described and illustrated from the family Praesiricidae. The type specimens were collected from the Late Jurassic to Early Cretaceous Yixian Formation, northeastern China. The new subfamily also includes Aulidontes Rasnitsyn from the Upper Jurassic of Karatau in Kazakhstan. This is the first record of Praesiricidae in China. These well-preserved nearly-complete new fossils reported here provide additional material and structure characters about this family, which helps filling some gap in the evolution of Lower Hymenoptera.