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AbstractObjectivesTo compare the discriminative capabilities for the manifestation of sarcopenia or physical frailty between serum creatinine- and cystatin C-derived indices among community-dwelling older adults. DesignCross-sectional study. SettingPrimary Care and Community. ParticipantsWe utilized a subset of data from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, which was initiated in 2015 to gather comprehensive information on various health-related parameters among community-dwelling older individuals (age ≥65 years). MeasurementsFive serum creatinine–cystatin C based indices including the Sarcopenia Index, the serum creatinine/cystatin C ratio, the disparity between serum cystatin-C-based and creatinine-based estimated GFR, the total body muscle mass index (TBMM), and the prediction equation for skeletal muscle mass index (pSMI) were employed. Sarcopenia and physical frailty were identified based on the Asian Working Group for Sarcopenia criteria and the revised Japanese version of the Cardiovascular Health Study criteria, respectively. The receiver operating characteristic (ROC) and logistic regression analyses were performed to assess the discriminative abilities of these tools. ResultsIn the analysis of 954 participants, 52 (5.5%) were identified with sarcopenia and 35 (3.7%) with physical frailty. Regarding sarcopenia discrimination, TBMM and pSMI both exhibited area under the curve (AUC) values exceeding 0.8 for both men and women. Concerning the identification of physical frailty, AUC values ranged from 0.61 to 0.77 for males and 0.50 to 0.69 for females. In the multivariate logistic regression analyses, only TBMM and pSMI consistently displayed associations with sarcopenia, irrespective of sex (P<0.001, respectively). On the other hand, no consistent associations were observed between the indices and physical frailty. ConclusionsThis study provides a robust association of a serum creatinine- and cystatin C-derived indices, especially TBMM and pSMI, with sarcopenia among community-dwelling older adults. Conversely, the application of these indices for the screening of physical frailty has its constraints, necessitating further investigation.

Abnormal amplification of centrosomes is the major cause of mitotic defects and chromosome instability in cancer cells. Centrosomes duplicate once in each cell cycle, and abrogation of the regulatory mechanism underlying centrosome duplication leads to centrosome amplification. p53 tumor suppressor protein is involved in the regulation of centrosome duplication: loss of p53 as well as expression of certain p53 mutants result in deregulated centrosome duplication and centrosome amplification. p53 at least in part depends on its transactivation function to control centrosome duplication, primarily via upregulation of p21 cyclin-dependent kinase (CDK) inhibitor, which prevents untimely activation of CDK2/cyclin E, a key initiator of centrosome duplication. However, numerous studies have shown the presence of p53 at centrosomes, yet the role of the centrosomally localized p53 in the regulation of centrosome duplication had been enigmatic. Here, we comparatively examined wild-type p53 and p53 mutants that are transactivation(+)/centrosome-binding(−), transactivation(−)/centrosome-binding(+) and transactivation(−)/centrosome-binding(−) for their abilities to control centrosome duplication. We found that the transactivation(+)/centrosome-binding(−) and transactivation(−)/centrosome-binding(+) mutants suppress centrosome duplication only partially compared with wild-type p53. Moreover, the transactivation(−)/centrosome-binding(−) mutant almost completely lost the ability to suppress centrosome duplication. These observations provide direct evidence for the centrosomally localized p53 to participate in the regulation of centrosome duplication in a manner independent of its transactivation function in addition to its transactivation-dependent regulation of centrosome duplication.

Cervical nodal metastasis is a key prognostic factor in patients with papillary thyroid carcinoma. The role of lymph nodes in papillary thyroid carcinoma management and prognosis remains controversial. Level IIb lymph nodes obtained from 44 patients with papillary thyroid carcinoma were histopathologically examined retrospectively. Specimens were classified as ipsilateral or contralateral. The number of dissected nodes and prevalence of level IIb metastasis were compared according to pre-operative clinical nodal stage. In the node-negative neck, the prevalence of contralateral and ipsilateral IIb nodes was 0 out of 20 and 0 out of 3, respectively. In the node-positive neck, the prevalence of contralateral and ipsilateral IIb nodes was 1 out of 13 (7.70 per cent) and 3 out of 41 (7.32 per cent), respectively. Clinically determined and pathologically confirmed level IIb node negativity were significantly associated. Thirty-four patients (77.3 per cent) developed accessory nerve complications from level IIb dissection. Level IIb neck dissection for papillary thyroid carcinoma may be required if pre-operative examination reveals multilevel, level IIa or suspicious level IIb metastasis.

Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability.

Background and aims:Chromosomal instability (CIN) is recognised as a hallmark of cancer and is caused by a spindle assembly checkpoint disorder or chromosome mis-segregation during mitosis. Although the recent identification of human shugoshin (hSgo1), an important player in proper chromosome segregation, has suggested the involvement of hSgo1 in colorectal tumourigenesis, little is known about how it is involved. The aim of this study was to obtain information about the status of hSgo1 in human colorectal cancer.Method and results:Among the 46 colorectal cancer cases, hSgo1 mRNA expression was decreased in the tumour tissue in comparison with the corresponding normal tissue (p = 0.032). Human Sgo1-downregulated tumours (tumour to normal mucosa ratio<0.5) had preferential location on the left side large bowel rather than on the right side (p = 0.012), and a higher variation of centromere numbers revealed by fluorescence in situ hybridisation (FISH). To assess the effects of hSgo1 downregulation, hSgo1 knockdown was performed by transfecting the diploid HCT116 cell line with a short hairpin RNA expression vector. hSgo1 knockdown cells proliferated slowly because of both G2/M arrest and apoptosis (p<0.001), and markers of CIN in the form of aneuploidy (p<0.001) and micronuclei (p<0.005) were later observed in hSgo1 knockdown cells. Increased centrosome amplification (p<0.05), the presence of binucleated cells and mitotic catastrophes were also noted in hSgo1 knockdown cells.Conclusions:These findings suggest that hSgo1-downregulated colorectal cancers have a clinicopathological character of CIN, and hSgo1 downregulation leads to CIN in colorectal cancer cells.

This study aimed to evaluate the relationship between timed up-and-go (TUG) test time and changes in frailty status in a longitudinal cohort study of rural Japanese older adults. This prospective cohort study included 545 community-dwelling older adults. Initial and 2-year follow-up surveys were conducted. We compared the number of the Japanese version of the Cardiovascular Health Study components during the follow-up period and classified the participants into three groups: the favorable change, unchanged as prefrail, and unfavorable change groups. Associations between changes in frailty status and TUG time in the first survey were examined. The predictive ability of the TUG test was determined using the receiver operating characteristic (ROC) curve. The favorable change group comprised 315 individuals (57.8%), the unchanged as prefrail group 105 (19.2%), and the unfavorable change group 125 (22.9%). TUG time was associated with the favorable and unfavorable changes after adjustment for covariates (OR 0.79, 95% CI 0.68-0.92, =0.001 and OR 1.27, 95% CI 1.09-1.49, =0.002). The ROC curve of TUG time as a predictor of unfavorable changes showed an area under the curve of 0.59. A cut-off point of TUG was calculated as 6.3 s with 49.6% sensitivity and 66.0% specificity. TUG time in the first survey was significantly associated with changes in frailty status 2 years later. However, its predictive value as a stand-alone test is limited and has the potential to predict future changes in the frailty status in older adults in combination with other tests.

Recent studies have demonstrated that cyclooxygenase-2 (COX-2) is an essential mediator of the cardioprotective effects of the late phase of ischemic preconditioning (PC) in rabbits. The goal of this study was to determine whether COX-2 also plays an essential role in late PC in the mouse. B6129F2/J mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion. Administration of the COX-2 selective inhibitor, NS-398, 30 min prior to the 30-min occlusion (5 mg/kg i.p.) had no appreciable effect on infarct size compared with untreated controls (58.8 +/- 2.1%, vs. 58.8 +/- 4.3% of the risk region, respectively). When mice were preconditioned with six cycles of 4-min coronary occlusion/4-min reperfusion 24 h prior to the 30-min occlusion, infarct size was markedly reduced (19.3 +/- 3.4%), indicating a late PC effect. The protective effect of late PC was completely abrogated by administration of NS-398 30 min before the 30-min coronary occlusion (67.7 +/- 3.0%), but not by administration of vehicle alone (23.6 +/- 3.7%). These results indicate that COX-2 mediates the late phase of ischemic PC in the mouse and imply that the role of this enzyme in cardioprotection is not species-specific.

Background Sodium picosulfate (SP)/magnesium citrate (MC) and polyethylene glycol (PEG) plus ascorbic acid are recommended by Western guidelines as laxative solutions for bowel preparation. Clinically, SP/MC has a slower post-dose defaecation response than PEG and is perceived as less cleansing; therefore, it is not currently used for major bowel cancer screening preparation. The standard formulation for bowel preparation is PEG; however, a large dose is required, and it has a distinctive flavour that is considered unpleasant. SP/MC requires a small dose and ensures fluid intake because it is administered in another beverage. Therefore, clinical trials have shown that SP/MC is superior to PEG in terms of acceptability. We aim to compare the novel bowel cleansing method (test group) comprising SP/MC with elobixibat hydrate and the standard bowel cleansing method comprising PEG plus ascorbic acid (standard group) for patients preparing for outpatient colonoscopy. Methods This phase III, multicentre, single-blind, noninferiority, randomised, controlled, trial has not yet been completed. Patients aged 40–69 years will be included as participants. Patients with a history of abdominal or pelvic surgery, constipation, inflammatory bowel disease, or severe organ dysfunction will be excluded. The target number of research participants is 540 (standard group, 270 cases; test group, 270 cases). The primary endpoint is the degree of bowel cleansing (Boston Bowel Preparation Scale [BBPS] score ≥ 6). The secondary endpoints are patient acceptability, adverse events, polyp/adenoma detection rate, number of polyps/adenomas detected, degree of bowel cleansing according to the BBPS (BBPS score ≥ 8), degree of bowel cleansing according to the Aronchik scale, and bowel cleansing time. Discussion This trial aims to develop a “patient-first” colon cleansing regimen without the risk of inadequate bowel preparation by using both elobixibat hydrate and SP/MC. Trial registration Japan Registry of Clinical Trials (jRCT; no. s041210067; 9 September 2021; https://jrct.niph.go.jp/ ), protocol version 1.5 (May 1, 2023).

Recently, isotemporal substitution has been developed to substitute activity time for an equivalent amount of another activity. This study employed this method to demonstrate the effects of replacing sedentary behavior (SB) time with an equivalent amount of light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) on the risk for different severities of frailty. A total of 886 older adults (average age 73.6 years, female 70%) participated in this cross-sectional study. Frailty status was assessed according to the cardiovascular health study criteria. Wrist-worn accelerometers were used to measure SB, LPA, and MVPA. Isotemporal substitution models were applied to show the estimated effects of substituting 30 min of SB with an equal amount of time spent in LPA or MVPA on the risk for pre-frailty and frailty. The physical activity level and SB were not associated with the incidence of pre-frailty. However, a 16% (OR: 0.84; 95% CI: 0.78-0.90) and 42% (OR: 0.58; 95% CI: 0.37-0.92) decrease in frailty risk was noted when SB was substituted with LPA and MVPA, respectively, in the crude model. In the adjusted model, the significant effect was sustained for LPA (OR: 0.86; 95% CI: 0.80-0.92) but not for MVPA (OR: 0.74; 95% CI: 0.47-1.17). This study indicates that replacing 30 min of SB with an equivalent amount of LPA decreases the risk for frailty in older adults. Moreover, increasing LPA seems more feasible than increasing MVPA in older adults, with substantial benefit.