Higher dementia incidence in older adults with type 2 diabetes and large reduction in HbA1c

BACKGROUND: although type 2 diabetes increases risk of dementia by 2-fold, whether optimizing glycemic level in late life can reduce risk of dementia remains uncertain. We examined if achieving the glycemic goal recommended by the American Diabetes Association (ADA) within a year was associated with lower risk of dementia in 6 years. METHODS: in this population-based observational study, we examined 2246 community-living dementia-free Chinese older adults with type 2 diabetes who attended the Elderly Health Centres in Hong Kong at baseline and followed their HbA1c level and cognitive status for 6 years. In line with the ADA recommendation, we defined the glycemic goal as HbA1c < 7.5%. The study outcome was incident dementia in 6 years, diagnosed according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) or Clinical Dementia Rating of 1-3. RESULTS: those with HbA1c ≥ 7.5% at baseline and HbA1c < 7.5% in 1 year were associated with higher rather than lower incidence of dementia, independent of severe hypoglycemia, glycemic variability and other health factors. Sensitivity analyses showed that a relative reduction of ≥10%, but not 5-10%, in HbA1c within a year was associated with higher incidence of dementia in those with high (≥8%) and moderate (6.5-7.9%) HbA1c at baseline. CONCLUSION: a large reduction in HbA1c could be a potential predictor and possibly a risk factor for dementia in older adults with type 2 diabetes. Our findings suggest that optimizing or intensifying glycemic control in this population requires caution

Risk of incident dementia varies with different onset and courses of depression

Background: This study aims to examine if risk of dementia differs between adult- and late-onset depression. Methods: 16,608 community-living dementia-free older adults were followed for 6 years to the outcome of incident dementia. Depression was diagnosed according to international diagnostic guidelines. Depression in adulthood or late life was categorized using age 65 as cutoff. Hazard ratio for dementia was estimated using Cox regression analysis. Results: People with depression in adulthood only did not have higher dementia incidence, suggesting those in remission from adult-onset depression are not at greater risk of dementia. Conversely, having depression in both adulthood and late life was associated with higher dementia risk, and improvement in depression in late life was associated with lower risk, suggesting persistent or recurrent lifetime depression is a risk factor for dementia. Those with depression in late life only were not associated with higher dementia risk after controlling for the longitudinal changes in depressive symptoms, consistent with late-onset depression being a prodrome of dementia. Limitations: Reverse causation is a potential limitation. This was minimized by careful ascertainment of depression and dementia cases, exclusion of individuals with suspected dementia at baseline and those who developed dementia within 3 years after baseline, and controlling for various important confounders. Conclusions: Risk of incident dementia varies with presence and resolution of depression at different ages. Further studies are needed to test whether treating adult-onset depression may prevent dementia. Older adults with a history of depression present for an extended time should be monitored for cognitive decline

Physical health and lifestyle predictors for significant cognitive impairment in community-dwelling Chinese older adults in Hong Kong

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Association between vascular risk factors and incident significant cognitive impairment in Chinese older people in Hong Kong in a six-year study

Objective: This study aimed to examine the association between vascular risk factors, namely hypertension, diabetes mellitus and hypercholesterolemia, and incident significant cognitive impairment in community-dwelling Chinese older people in Hong Kong. Methods: Community-dwelling Chinese older people aged 65 years and above who attended Nam Shan Elderly Health Centre in 2005 with no history of dementia or stroke constituted the baseline sample. Retrospective data retrieval for the presence of vascular risk factors at baseline was conducted. Annual clinical assessment on cognition was offered in the 6-year study period. Significant cognitive impairment was defined by presence of dementia in accordance with DSM-IV-TR, scoring below the cut-off point on the Cantonese version of the Mini-Mental State Examination, and / or a global Clinical Dementia Rating score of 1-3. Results: A total of 1925 subjects were recruited into our study; 161 (8.4%) subjects developed significant cognitive impairment in the 6-year study period. Subjects with incident significant cognitive impairment was older (75 vs. 73 years; Mann-Whitney U test, p < 0.001) with lower education attainment (30.4% vs. 23.9% of illiteracy; χ2 test, p = 0.06). However, there was no statistically significant difference in the point prevalence of pre-existing hypertension (χ2 test, p = 0.68), diabetes mellitus (χ2 test, p = 0.21), and hypercholesterolemia (χ2 test, p = 0.31) between subjects who developed significant cognitive impairment and those who remained cognitively stable. Interestingly, baseline pulse pressure, but not systolic or diastolic blood pressure, was found to be higher among subjects with incident significant cognitive impairment (70 mm Hg vs. 66 mm Hg; Mann-Whitney U test, p = 0.03). Conclusions: This study did not have evidence to show that hypertension, diabetes mellitus, and hypercholesterolemia were associated with incident significant cognitive impairment in the Chinese older people in Hong Kong. Further studies are needed to examine the role of pulse pressure in contributing to cognitive decline in late life.published_or_final_versio

Optimum drilled flange moment resisting connections for seismic regions

Extensive damage in welded unreinforced flange (WUF) connections in previous earthquakes has led to the idea of using reduced beam section (RBS) connections to prevent brittle failure modes in welded joints. Using a similar concept, drilled flange (DF) moment resisting connections are established by a series of holes drilling on the top and the bottom flanges of the beam to create an intentional weak area to shift nonlinear deformations. DF connections are very easy-to-construct and they can also prevent the premature local buckling modes in the reduced section of RBS connections. This study aims to improve the performance of DF connections to make them viable alternatives to RBS connections for ductile steel frames in seismic regions. A wide range of experimentally validated non-linear FE models are used to investigate the effects of different design parameters such as drilled flange hole locations, hole configurations, panel zone shear strength ratio and doubler plate thickness. The results indicate that there is an optimum location and configuration for the drilled flange holes, which can reduce by up to 40% the maximum Equivalent Plastic Strain and Rupture Index of DF connections. It is shown that using strong panel zones can also improve the seismic performance of DF connections by reducing stress concentrations at the CJP groove weld lines. The results of this study are used to develop optimum design solutions for DF connections, which should prove useful in practical applications

Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma

Patients with metastatic nasopharyngeal carcinoma have variable survival outcomes. We previously designed a scoring system to better prognosticate these patients. Here, we report results on validation of this new prognostic index score in a separate cohort of patients. Clinical features and laboratory parameters were examined in 172 patients with univariate and multivariate analyses and a numerical score was derived for each independent prognostic variable. Significant independent prognostic variables and their scores assigned included poor performance status (score 5), haemoglobin <12 g dl−1 (score 4) and disease-free interval (DFI) (DFI⩽6 months (score 10) or metastases at initial diagnosis (score 1)). Maximum score was 19 and patients stratified into three prognostic groups: good, 0–3; intermediate, 4–8; poor, ⩾9. When applied to a separate cohort of 120 patients, 59 patients were good, 43 intermediate and 18 poor prognosis, with median survivals of 19.6 (95% CI 16.1, 23.1), 14.3 (95% CI 12.3, 16.2) and 7.9 (95% CI 6.6, 9.2) months, respectively. (logrank test: P=0.003). We have validated a new prognostic score with factors readily available in the clinics. This simple score will prove useful as a method to prognosticate and stratify patients as well as to promote consistent reporting among clinical trials

State-of-the-art management of nasopharyngeal carcinoma: current and future directions

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer. Approximately 70% of patients with newly diagnosed NPC present with locally advanced disease. Phase III clinical trials support the addition of chemotherapy to radiotherapy for the initial treatment of these patients. Once metastatic disease develops, practices become varied. Further experience needs to be gained with both targeted therapies and immunotherapy to gauge whether they will improve treatment outcomes in NPC

Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines

INTRODUCTION: The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells. METHODS: The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot. RESULTS: 5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7. CONCLUSION: In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast cancers, the schedule Dox→Pacl→48-h washout→5-FU was highly active and schedule-dependent and has recently been used to plan a phase I/II clinical protocol

Aging Predisposes Oocytes to Meiotic Nondisjunction When the Cohesin Subunit SMC1 Is Reduced

In humans, meiotic chromosome segregation errors increase dramatically as women age, but the molecular defects responsible are largely unknown. Cohesion along the arms of meiotic sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I. One attractive hypothesis to explain age-dependent nondisjunction (NDJ) is that loss of cohesion over time causes recombinant homologues to dissociate prematurely and segregate randomly during the first meiotic division. Using Drosophila as a model system, we have tested this hypothesis and observe a significant increase in meiosis I NDJ in experimentally aged Drosophila oocytes when the cohesin protein SMC1 is reduced. Our finding that missegregation of recombinant homologues increases with age supports the model that chiasmata are destabilized by gradual loss of cohesion over time. Moreover, the stage at which Drosophila oocytes are most vulnerable to age-related defects is analogous to that at which human oocytes remain arrested for decades. Our data provide the first demonstration in any organism that, when meiotic cohesion begins intact, the aging process can weaken it sufficiently and cause missegregation of recombinant chromosomes. One major advantage of these studies is that we have reduced but not eliminated the SMC1 subunit. Therefore, we have been able to investigate how aging affects normal meiotic cohesion. Our findings that recombinant chromosomes are at highest risk for loss of chiasmata during diplotene argue that human oocytes are most vulnerable to age-induced loss of meiotic cohesion at the stage at which they remain arrested for several years