Single-Subject Grey Matter Graphs in Alzheimer's Disease

Coordinated patterns of cortical morphology have been described as structural graphs and previous research has demonstrated that properties of such graphs are altered in Alzheimer''s disease (AD). However, it remains unknown how these alterations are related to cognitive deficits in individuals, as such graphs are restricted to group-level analysis. In the present study we investigated this question in single-subject grey matter networks. This new method extracts large-scale structural graphs where nodes represent small cortical regions that are connected by edges when they show statistical similarity. Using this method, unweighted and undirected networks were extracted from T1 weighted structural magnetic resonance imaging scans of 38 AD patients (19 female, average age 72±4 years) and 38 controls (19 females, average age 72±4 years). Group comparisons of standard graph properties were performed after correcting for grey matter volumetric measurements and were correlated to scores of general cognitive functioning. AD networks were characterised by a more random topology as indicated by a decreased small world coefficient (p = 3.53×10⁻⁵), decreased normalized clustering coefficient (p = 7.25×10⁻⁶) and decreased normalized path length (p = 1.91×10⁻⁷). Reduced normalized path length explained significantly (p = 0.004) more variance in measurements of general cognitive decline (32%) in comparison to volumetric measurements (9%). Altered path length of the parahippocampal gyrus, hippocampus, fusiform gyrus and precuneus showed the strongest relationship with cognitive decline. The present results suggest that single-subject grey matter graphs provide a concise quantification of cortical structure that has clinical value, which might be of particular importance for disease prognosis. These findings contribute to a better understanding of structural alterations and cognitive dysfunction in AD.     

Preconditioning 2D Integer Data for Fast Convex Hull Computations

In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s ≤ n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p × q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) ≤ n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) ≤ n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved.     

Atrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials

There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ∼1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ∼18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195–1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.     

A Self-Report Risk Index to Predict Occurrence of Dementia in Three Independent Cohorts of Older Adults: The ANU-ADRI

Background and Aims

The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer''s disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.

Methods

This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.

Results

For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).

Conclusion

A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.     

Effect of Hypohydration on Peripheral and Corticospinal Excitability and Voluntary Activation

We investigated whether altered peripheral and/or corticospinal excitatory output and voluntary activation are implicated in hypohydration-induced reductions in muscle isometric and isokinetic (90°.s⁻¹) strength. Nine male athletes completed two trials (hypohydrated, euhydrated) comprising 90 min cycling at 40°C, with body weight losses replaced in euhydrated trial. Peripheral nerve and transcranial magnetic stimulations were applied during voluntary contractions pre- and 40 min post-exercise to quantify voluntary activation and peripheral (M-wave) and corticospinal (motor evoked potential) evoked responses in m. vastus medialis. Both maximum isometric (−15.3±3.1 vs −5.4±3.5%) and isokinetic eccentric (−24.8±4.6 vs −7.3±7.2%) torque decreased to a greater extent in hypohydrated than euhydrated trials (p<0.05). Half relaxation time of the twitch evoked by peripheral nerve stimulation during maximal contractions increased after exercise in the hypohydrated (21.8±9.3%) but stayed constant in the euhydrated (1.6±10.7%; p = 0.017) condition. M-wave amplitude during maximum voluntary contraction increased after exercise in the heat in hypohydrated (10.7±18.0%) but decreased in euhydrated condition (−17.4±16.9%; p = 0.067). Neither peripheral nor cortical voluntary activation were significantly different between conditions. Motor evoked potential amplitude increased similarly in both conditions (hypohydrated: 25.7±28.5%; euhydrated: 52.9±33.5%) and was accompanied by lengthening of the cortical silent period in euhydrated but not hypohydrated condition (p = 0.019). Different neural strategies seem to be adopted to regulate neural drive in the two conditions, with increases in inhibitory input of either intracortical or corticospinal origin during the euhydrated trial. Such changes were absent in the hypohydrated condition, yet voluntary activation was similar to the euhydrated condition, perhaps due to smaller increases in excitatory drive rather than increased inhibition. Despite this maximal isometric and eccentric strength were impaired in the hypohydrated condition. The increase in peripheral muscle excitability evident in the hypohydrated condition was not sufficient to preserve performance in the face of reduced muscle contractility or impaired excitation-contraction coupling.     

Regional Amyloid Deposition in Amnestic Mild Cognitive Impairment and Alzheimer's Disease Evaluated by [18F]AV-45 Positron Emission Tomography in Chinese Population

Background

To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer''s disease (AD) subjects with [¹⁸F]AV-45 positron emission tomography (PET).

Materials and Methods

[¹⁸F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [¹⁸F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed.

Results

The global cortical [¹⁸F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment.

Conclusions

Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [¹⁸F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [¹⁸F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.     

Development of a Screening Algorithm for Alzheimer's Disease Using Categorical Verbal Fluency

We developed a weighted composite score of the categorical verbal fluency test (CVFT) that can more easily and widely screen Alzheimer''s disease (AD) than the mini-mental status examination (MMSE). We administered the CVFT using animal category and MMSE to 423 community-dwelling mild probable AD patients and their age- and gender-matched cognitively normal controls. To enhance the diagnostic accuracy for AD of the CVFT, we obtained a weighted composite score from subindex scores of the CVFT using a logistic regression model: logit (case)  = 1.160+0.474× gender +0.003× age +0.226× education level – 0.089× first-half score – 0.516× switching score -0.303× clustering score +0.534× perseveration score. The area under the receiver operating curve (AUC) for AD of this composite score AD was 0.903 (95% CI = 0.883 – 0.923), and was larger than that of the age-, gender- and education-adjusted total score of the CVFT (p<0.001). In 100 bootstrapped re-samples, the composite score consistently showed better diagnostic accuracy, sensitivity and specificity for AD than the total score. Although AUC for AD of the CVFT composite score was slightly smaller than that of the MMSE (0.930, p = 0.006), the CVFT composite score may be a good alternative to the MMSE for screening AD since it is much briefer, cheaper, and more easily applicable over phone or internet than the MMSE.     

Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies

Background

There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM).

Methods and Findings

We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR = 1.10, 95%CIs: 1.00–1.21; P = 0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR = 1.19, 95%CIs: 1.04–1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR = 1.46, 95%CIs: 1.03–2.08; P = 0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled results suggested that ADT was associated with CVM (HR = 1.17, 95%CIs: 1.04–1.32; P = 0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g. prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR = 1.19, 95%CIs: 1.08–1.30; P<0.001) and CVM (HR = 1.30, 95%CIs: 1.13–1.50; P<0.001) were found in men treated with ADT monotherapy.

Conclusions

ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.     

Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study

Objectives

Possible association between diabetes mellitus (DM) and Alzheimer’s disease (AD) has been controversial. This study used a nationwide population-based dataset to investigate the relationship between DM and subsequent AD incidence.

Methods

Data were collected from Taiwan’s National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74±14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD.

Results

Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.50–2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10–1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06–1.46, p = 0.008), hypertension (HR, 1.30; 95% CI, 1.07–1.59, p = 0.01), previous stroke history (HR, 1.79; 95% CI, 1.28–2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07–1.63, p = 0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04–4.52, p = 0.039).

Conclusion

Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk.     

Prion Protein Is Decreased in Alzheimer's Brain and Inversely Correlates with BACE1 Activity,Amyloid-β Levels and Braak Stage

The cellular prion protein (PrP^C) has been implicated in the development of Alzheimer''s disease (AD). PrP^C decreases amyloid-β (Aβ) production, which is involved in AD pathogenesis, by inhibiting β-secretase (BACE1) activity. Contactin 5 (CNTN5) has also been implicated in the development of AD by a genome-wide association study. Here we measured PrP^C and CNTN5 in frontal cortex samples from 24 sporadic AD and 24 age-matched control brains and correlated the expression of these proteins with markers of AD. PrP^C was decreased in sporadic AD compared to controls (by 49%, p = 0.014) but there was no difference in CNTN5 between sporadic AD and controls (p = 0.217). PrP^C significantly inversely correlated with BACE1 activity (r_s = −0.358, p = 0.006), Aβ load (r_s = −0.456, p = 0.001), soluble Aβ (r_s = −0.283, p = 0.026) and insoluble Aβ (r_s = −0.353, p = 0.007) and PrP^C also significantly inversely correlated with the stage of disease, as indicated by Braak tangle stage (r_s = −0.377, p = 0.007). CNTN5 did not correlate with Aβ load (r_s = 0.040, p = 0.393), soluble Aβ (r_s = 0.113, p = 0.223) or insoluble Aβ (r_s = 0.169, p = 0.125). PrP^C was also measured in frontal cortex samples from 9 Down''s syndrome (DS) and 8 age-matched control brains. In contrast to sporadic AD, there was no difference in PrP^C in the DS brains compared to controls (p = 0.625). These data are consistent with a role for PrP^C in regulating Aβ production and indicate that brain PrP^C level may be important in influencing the onset and progression of sporadic AD.     

The Supplementary Motor Area Exerts a Tonic Excitatory Influence on Corticospinal Projections to Phrenic Motoneurons in Awake Humans

Introduction

In humans, cortical mechanisms can interfere with autonomic breathing. Respiratory-related activation of the supplementary motor area (SMA) has been documented during voluntary breathing and in response to inspiratory constraints. The SMA could therefore participate in the increased resting state of the respiratory motor system during wake (i.e. "wakefulness drive to breathe").

Methods

The SMA was conditioned by continuous theta burst magnetic stimulation (cTBS, inhibitory) and 5 Hz conventional rTMS (5 Hz, excitatory). The ensuing effects were described in terms of the diaphragm motor evoked response (DiMEPs) to single-pulse transcranial magnetic stimulation over the motor cortex. DiMEPs were recorded at baseline, and at 3 time-points ("post1", "post2", "post3") up to 15 minutes following conditioning of the SMA.

Results

cTBS reduced the amplitude of DiMEPs from 327.5±159.8 µV at baseline to 243.3±118.7 µV, 217.8±102.9 µV and 240.6±123.9 µV at post 1, post 2 and post 3, respectively (F = 6.341, p = 0.002). 5 Hz conditioning increased the amplitude of DiMEPs from 184.7±96.5 µV at baseline to 270.7±135.4 µV at post 3 (F = 4.844, p = 0.009).

Conclusions

The corticospinal pathway to the diaphragm can be modulated in both directions by conditioning the SMA. This suggests that the baseline respiratory activity of the SMA represents an equipoise from which it is possible to move in either direction. The resting corticofugal outflow from the SMA to phrenic motoneurones that this study evidences could putatively contribute to the wakefulness drive to breathe.     

Effects of 12 Weeks High-Intensity & Reduced-Volume Training in Elite Athletes

It was investigated if high-intensity interval training (HIT) at the expense of total training volume improves performance, maximal oxygen uptake and swimming economy. 41 elite swimmers were randomly allocated to a control (CON) or HIT group. For 12 weeks both groups trained ∼12 h per week. HIT comprised ∼5 h vs. 1 h and total distance was ∼17 km vs. 35 km per week for HIT and CON, respectively. HIT was performed as 6-10×10-30 s maximal effort interspersed by 2–4 minutes of rest. Performance of 100 m all-out freestyle and 200 m freestyle was similar before and after the intervention in both HIT (60.4±4.0 vs. 60.3±4.0 s; n = 13 and 133.2±6.4 vs. 132.6±7.7 s; n = 14) and CON (60.2±3.7 vs. 60.6±3.8 s; n = 15 and 133.5±7.0 vs. 133.3±7.6 s; n = 15). Maximal oxygen uptake during swimming was similar before and after the intervention in both the HIT (4.0±0.9 vs. 3.8±1.0 l O₂×min⁻¹; n = 14) and CON (3.8±0.7 vs. 3.8±0.7 l O₂×min⁻¹; n = 11) group. Oxygen uptake determined at fixed submaximal speed was not significantly affected in either group by the intervention. Body fat % tended to increase (P = 0.09) in the HIT group (15.4±1.6% vs. 16.3±1.6%; P = 0.09; n = 16) and increased (P<0.05) in the CON group (13.9±1.5% vs. 14.9±1.5%; n = 17). A distance reduction of 50% and a more than doubled HIT amount for 12 weeks did neither improve nor compromise performance or physiological capacity in elite swimmers.     

The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers

The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2×10⁻⁴) and ptau (p = 1.8×10⁻³) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7–24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9–13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4–4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.     

De Novo Lipogenesis and Cholesterol Synthesis in Humans with Long-Standing Type 1 Diabetes Are Comparable to Non-Diabetic Individuals

Background

Synthesis of lipid species, including fatty acids (FA) and cholesterol, can contribute to pathological disease. The purpose of this study was to investigate FA and cholesterol synthesis in individuals with type 1 diabetes, a group at elevated risk for vascular disease, using stable isotope analysis.

Methods

Individuals with type 1 diabetes (n = 9) and age-, sex-, and BMI-matched non-diabetic subjects (n = 9) were recruited. On testing day, meals were provided to standardize food intake and elicit typical feeding responses. Blood samples were analyzed at fasting (0 and 24 h) and postprandial (2, 4, 6, and 8 hours after breakfast) time points. FA was isolated from VLDL to estimate hepatic FA synthesis, whereas free cholesterol (FC) and cholesteryl ester (CE) was isolated from plasma and VLDL to estimate whole-body and hepatic cholesterol synthesis, respectively. Lipid synthesis was measured using deuterium incorporation and isotope ratio mass spectrometry.

Results

Fasting total hepatic lipogenesis (3.91±0.90% vs. 5.30±1.22%; P = 0.41) was not significantly different between diabetic and control groups, respectively, nor was synthesis of myristic (28.60±4.90% vs. 26.66±4.57%; P = 0.76), palmitic (12.52±2.75% vs. 13.71±2.64%; P = 0.65), palmitoleic (3.86±0.91% vs. 4.80±1.22%; P = 0.65), stearic (5.55±1.04% vs. 6.96±0.97%; P = 0.29), and oleic acid (1.45±0.28% vs. 2.10±0.51%; P = 0.21). Postprandial lipogenesis was also not different between groups (P = 0.38). Similarly, fasting synthesis of whole-body FC (8.2±1.3% vs. 7.3±0.8%/day; P = 0.88) and CE (1.9±0.4% vs. 2.0±0.3%/day; P = 0.96) and hepatic FC (8.2±2.0% vs. 8.1±0.8%/day; P = 0.72) was not significantly different between diabetic and control subjects.

Conclusions

Despite long-standing disease, lipogenesis and cholesterol synthesis was not different in individuals with type 1 diabetes compared to healthy non-diabetic humans.     

Meta-Analysis of Randomised Clinical Trials Comparing Idarubicin + Cytarabine with Daunorubicin + Cytarabine as the Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukaemia

Background

To determine whether the use of idarubicin+cytarabine (IA) is more effective than the use of daunorubicin+cytarabine (DA) as induction chemotherapy for patients with newly diagnosed acute myeloid leukaemia.

Methods

A computer-based search was performed. Randomised trials comparing IA with DA as induction therapy for newly diagnosed AML were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival, event-free survival and overall survival); the secondary endpoint was complete remission.

Results

Ten trials with 4,060 patients were eligible for this meta-analysis. Our pooled results suggest that IA is associated with a significant advantage in CR (RR = 1·23; 95% CI = 1·07–1·41, p = 0.004), EFS (HR = 0·64; 95% CI = 0·45–0·91, p = 0.013), and OS (HR = 0·88; 95% CI = 0·81–0·95, p = 0.02) but not in DFS (HR = 0·90; 95% CI = 0·80–1·00, p = 0.06). In the subgroup analysis, age had a significant interaction with OS and CR benefits.

Conclusion

Our analysis indicated that IA could improve the duration of overall survival compared to DA as induction therapy for young patients with newly diagnosed AML. Further study is needed to determine whether IA can produce clinical benefits in selected genetic or molecular subgroups of young AML patients.     

Pacing-Induced Regional Differences in Adenosine Receptors mRNA Expression in a Swine Model of Dilated Cardiomyopathy

The adenosinergic system is essential in the mediation of intrinsic protection and myocardial resistance to insult; it may be considered a cardioprotective molecule and adenosine receptors (ARs) represent potential therapeutic targets in the setting of heart failure (HF). The aim of the study was to test whether differences exist between mRNA expression of ARs in the anterior left ventricle (LV) wall (pacing site: PS) compared to the infero septal wall (opposite region: OS) in an experimental model of dilated cardiomyopathy. Cardiac tissue was collected from LV PS and OS of adult male minipigs with pacing-induced HF (n = 10) and from a control group (C, n = 4). ARs and TNF–α mRNA expression was measured by Real Time-PCR and the results were normalized with the three most stably expressed genes (GAPDH, HPRT1, TBP). Immunohistochemistry analysis was also performed. After 3 weeks of pacing higher levels of expression for each analyzed AR were observed in PS except for A₁R (A₁R: C = 0.6±0.2, PS = 0.1±0.04, OS = 0.04±0.01, p<0.0001 C vs. PS and OS respectively; A_2AR: C = 1.04±0.59, PS = 2.62±0.79, OS = 2.99±0.79; A_2BR: C = 1.2±0.1, PS = 5.59±2.3, OS = 1.59±0.46; A₃R: C = 0.76±0.18, PS = 8.40±3.38, OS = 4.40±0.83). Significant contractile impairment and myocardial hypoperfusion were observed at PS after three weeks of pacing as compared to OS. TNF-α mRNA expression resulted similar in PS (6.3±2.4) and in OS (5.9±2.7) although higher than in control group (3.4±1.5). ARs expression was mainly detected in cardiomyocytes. This study provided new information on ARs local changes in the setting of LV dysfunction and on the role of these receptors in relation to pacing-induced abnormalities of myocardial perfusion and contraction. These results suggest a possible therapeutic role of adenosine in patients with HF and dyssynchronous LV contraction.     

Suture Pull-Through Insertion Techniques for Descemet Stripping Automated Endothelial Keratoplasty in Chinese Phakic Eyes: Outcomes and Complications

Purpose

To investigate the outcomes and complications of suture pull-through insertion techniques for Descemet stripping automated endothelial keratoplasty (DSAEK) in Chinese phakic eyes.

Patients and Methods

Retrospective case series. Included in the study were all Chinese patients with phakic eyes who underwent DSAEK at Peking University Third Hospital from August 2008 to August 2011. All ocular diseases of the patients were recorded. Distance visual acuity (DVA), near visual acuity (NVA), intraocular pressure (IOP), anterior chamber depth (ACD), central corneal thickness (CCT), and corneal endothelial cell density (ECD) were compared prior to and 12 months after DSAEK. The DSAEK success rate, endothelial cell loss (ECL), complications, and prognosis were analyzed. All patients had at least 12 months of follow up.

Results

Twenty-one eyes of 16 patients were included (11 males and 5 females). Ages ranged from 2 to 47 years with an average age of 29.8 years. The average follow up was 15.4 months (ranging from 12 to 36 months). Diagnoses included 7 eyes (4 patients) with corneal endothelial dystrophy and 14 eyes (12 patients) with bullous keratopathy. Presurgical DVA and NVA (LogMAR) were 1.7±0.7 and 1.2±0.4; postsurgical DVA and NVA were 0.8±0.6 and 0.7±0.5; Z = −3.517, −2.764; P<0.001 and P = 0.006 respectively. Presurgical IOP was 15.8±3.7 mm Hg; postsurgical IOP was 15.2±2.6 mm Hg; Z = −0.505, P = 0.614. Presurgical ACD was 3.00±0.74 mm; postsurgical ACD was 2.72±0.59 mm; Z = −0.524, P = 0.600. Donor ECD was 2992±163 cells/mm², ECD was 1836±412 cells/mm² with a 12-month postsurgical ECL of 39%. Success rate was 86%. Surgery complications included pupillary block-induced hypertension in 5 eyes (24%), graft detachment in 3 eyes (14%), and graft dislocation in 1 eye (5%).

Conclusions

DSAEK on Chinese phakic eyes can significantly improve DVA and NVA by preserving the patient’s own crystalline lens. DSAEK is an optional surgery for patients who need to preserve accommodative function. More attention should be given to postsurgical pupillary block-induced hypertension.     

Acoustic Radiation Force Impulse Imaging for Noninvasive Evaluation of Renal Parenchyma Elasticity: Preliminary Findings

Objective

To evaluate the diagnostic value of acoustic radiation force impulse (ARFI) to test the elasticity of renal parenchyma by measuring the shear wave velocity (SWV) which might be used to detect chronic kidney disease (CKD).

Methods

327 healthy volunteers and 64 CKD patients were enrolled in the study. The potential influencing factors and measurement reproducibility were evaluated in the healthy volunteers. Correlations between SWV and laboratory tests were analyzed in CKD patients.?Receiver-operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance of ARFI.

Results

The SWV of healthy volunteers correlated significantly to age (r = −0.22, P<0.001, n = 327) and differed significantly between men and women (2.06±0.48 m/s vs. 2.2±0.52 m/s, P = 0.018, n = 327). However, it did not correlate significantly to height, weight, body mass index, waistline, kidney dimension and the depth for SWV measurement (n = 30). Inter- and intraobserver agreement expressed as intraclass coefficient correlation were 0.64 (95% CI: 0.13 to 0.82, P = 0.011) and 0.6 (95% CI: 0.31 to 0.81, P = 0.001) (n = 40). The mean SWV in healthy volunteers was 2.15±0.51 m/s, while was 1.81±0.43 m/s, 1.79±0.29 m/s, 1.81±0.44 m/s, 1.64±0.55 m/s, and 1.36±0.17 m/s for stage 1, 2, 3, 4 and 5 in CKD patients respectively. The SWV was significantly higher for healthy volunteers compared with each stage in CKD patients. ARFI could not predict the different stages of CKD except stage 5. In CKD patients, SWV correlated to e-GFR (r = 0.3, P = 0.018), to urea nitrogen (r =  −0.3, P = 0.016), and to creatinine (r =  −0.41, P = 0.001). ROC analyses indicated that the area under the ROC curve was 0.752 (95% CI: 0.704 to 0.797) (P<0.001). The cut-off value for predicting CKD was 1.88 m/s (sensitivity 71.87% and specificity 69.69%).

Conclusion

ARFI may be a potentially useful tool in detecting CKD.     

Analysis of Quality of Clinical Practice Guidelines for Otorhinolaryngology in China

Objective

To evaluate the quality of clinical practice guidelines (CPGs) for otorhinolaryngology in China.

Materials and Methods

A systematic search of relevant literature databases (CBM, WANFANG, VIP, CNKI, China Guideline Clearinghouse) published between 1978 and March 2012 was undertaken to identify and select CPGs related to otorhinolaryngology. Four independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Their degree of agreement was evaluated using the intraclass correlation coefficient (ICC).

Result

From 170 citations, 21 relevant guidelines were included. The overall agreement among reviewers was moderate (ICC = 0.87; 95% confidence interval [CI], 0.78–0.91). The scores for each of the AGREE domains were the following: “scope and purpose” (mean ± standard error [SE] = 45.4±4.4; ICC = 0.92), “stakeholder involvement” (mean ± SE = 30.4±3.1; ICC = 0.81), “rigor of development” (mean ± SE = 20.9±2.8; ICC = 0.87), “clarity of presentation” (mean ± SE = 48.8±3.7; ICC = 0.80), “applicability” (mean ± SE = 12.6±1.7; ICC = 0.72), and “editorial independence” (mean ± SE = 6.2±0.8; ICC = 0.76). Three guidelines (14%) mentioned updates, and the average update frequency was 7 years. None used the GRADE system.

Conclusion

The quality of otorhinolaryngology guidelines in China is low. Greater efforts are needed to provide high-quality guidelines that serve as a useful and reliable tool for clinical decision-making in this field.     

Fatty Acid- and Cholesterol Transporter Protein Expression along the Human Intestinal Tract

Background

Protein distribution profiles along the human intestinal tract of transporters involved in the absorption of cholesterol and long-chain fatty acids (LCFA) have been scarcely evaluated.

Methodology/Principal Findings

In post-mortem samples from 11 subjects, intestinal transporter distribution profiles were determined via Western Blot. Differences in transporter protein levels were statistically tested using ANOVA and Tukey''s Post Hoc comparisons. Levels in all segments were expressed relative to those in duodenum. Except for ABCG5 and FATP4, levels (mean±SEM) were the highest in the ileum. For ABCA1, ileal levels (1.80±0.26) differed significantly from those in duodenum (P = 0.049) and proximal colon (0.92±0.14; P = 0.029). ABCG8 levels in ileum (1.91±0.30) differed from those in duodenum (P = 0.041) and distal colon (0.84±0.22; P = 0.010) and jejunum (1.64±0.26) tended to be higher than distal colon (0.84±0.22; P = 0.087). Ileal NPC1L1 levels (2.56±0.51) differed from duodenum levels (P = 0.019) and from distal colon (1.09±0.22; P = 0.030). There was also a trend (P = 0.098) for higher jejunal (2.23±0.37) than duodenal NPC1L1 levels. The levels of ABCG5 did not correlate with those of ABCG8. FAT/CD36 levels in ileum (2.03±0.42) differed from those in duodenum (P = 0.017), and proximal and distal colon (0.89±0.13 and 0.97±0.15 respectively; P = 0.011 and P = 0.014). FABPpm levels in ileum (1.04±0.13) differed from proximal (0.64±0.07; P = 0.026) and distal colon (0.66±0.09; P = 0.037).

Conclusions/Significance

The distribution profiles showed a bell-shape pattern along the GI-tract with the highest levels in ileum for ABCA1, ABCG8, NPC1L1, FATCD36 and FABPm, suggesting a prominent role for ileum in transporter-mediated uptake of cholesterol and LCFAs.