Shifting from Declines to Improvements: Associations between a Meaningful Walking Speed Change and Cognitive Evolution over Three Years in Older Adults

Background

Although the close relationship between mobility and cognitive declines is well-known, literature has very little questioned whether improvement in walking speed over time could be associated with improvements in cognitive functions. The objective of this study was to examine the associations between a clinically meaningful improvement in walking speed and global and specific cognitive changes in older adults. Design: Prospective cohort study.

Setting

Multidomain Alzheimer Preventive Trial (MAPT) study.

Participants

Three-hundred participants from the control group of the MAPT study (mean age 74.8 ± 4.2; 57% women).

Measurements

The 4-m usual walking speed, global cognition, memory, executive functions, and processing speed measures were collected at baseline, and at 6, 12, 24 and 36 months. Participants were categorized into three groups according to their walking speed change over the three-year study: 1/ Non-Improvers (participants not presenting an increase ≥0.05m/sec on walking speed; n=138); 2/ Improvers (increase ≥0.05m/sec; n=40); Cyclic (≥0.05m/sec improvement at some time points without maintaining it through the whole period; n=122).

Results

Adjusted mixed-effect linear regressions revealed that walking speed improvers did not significantly differ from participants who never or temporarily improved their walking speed on all of global and specific cognitive functions over three years. Nevertheless, a sensitivity analysis (excluding participants with a nonclinical walking speed improvement) indicated specific cognitive trajectories per group associated with better episodic memory scores for Improvers compared to non-improvers (β=2.41, 95% CI=.12 - 4.71; p=.039).

Conclusion

This study found that the overtime trajectories of cognitive functions did not differ as a function of clinically meaningful walking speed changes in older adults. Nevertheless, secondary analyses provided new insights on the relationship between walking speed and specific cognitive functions. The novelty of this approach (switching from declines to improvements) should be considered in future large-scale, observational longitudinal studies.

     

MSCT labelling for pre-operative planning in cardiac resynchronization therapy.

The objective of this paper is twofold: (i) to show how multislice computed tomography (MSCT) data sets bring the information required for cardiac resynchronisation therapy (CRT) planning; (ii) to demonstrate the feasibility of 3D navigation into the veins where left ventricular leads have to be placed. The former has been achieved by exploring and labelling the cardiac structures of concern, the latter has been performed by using the concept of virtual navigation with high resolution surface detection and estimation algorithms.     

Azathioprine induction of tumors with microsatellite instability: Risk evaluation using a mouse model

Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2^wt mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2^+/− mice were found more tolerant than Msh2^wt mice to the cytotoxicity of Aza. In Msh2^+/− mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2^wt mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.     

Careful Selection and Close Monitoring of Low-Risk Prostate Cancer Patients on Active Surveillance Minimizes the Need for Treatment

Background

With the advent of prostate-specific antigen (PSA) screening and the increase in the number of transrectal ultrasound–guided biopsy cores, there has been a dramatic rise in the incidence of low-risk prostate cancer (LRPC). Because >97% of men with LRPC are likely to die of something other than prostate cancer, it is critical that patients give thought to whether early curative treatment is the only option at diagnosis.

Objective

To identify a group of men with LRPC who may not require initial treatment and monitor them on our active surveillance (AS) protocol, to determine the percentage treated and the outcome and to analyze the quality-of-life data.

Design, setting, and participants

We defined patients eligible for AS as Gleason ≤6, PSA ≤10, and two or fewer biopsy cores with ≤20% tumor in each core.

Measurements

Kaplan Meier analysis was used to predict the 5-year treatment free survival. Logistic regression determined the predictors of treatment. Data on sexual function, continence, and outcome were obtained and analyzed.

Results and limitations

The AS cohort consisted of 230 patients with a mean age of 63.4 yr; 86% remained on AS for a mean follow-up of 44 mo. Thirty-two of the 230 patients (14%) were treated for a mean follow-up of 33 mo. Twelve had a total prostatectomy (TP). The pathologic stage of these patients was similar to initially treated TP patients with LRPC. Fourteen underwent radiation therapy, and six underwent androgen-deprivation therapy. Fifty percent of patients had no tumor on the first rebiopsy, and only 5% of these patients were subsequently treated. PSA doubling time and clinical stage were not predictors of treatment. No patient progressed after treatment. Among the AS patients, 30% had incontinence, yet <15% were bothered by it. As measured by the Sexual Health Inventory for Men, 49% of patients had, at a minimum, moderate (≤16) erectile dysfunction.

Conclusions

If guidelines for AS are narrowly defined to include only patients with Gleason 6, tumor volume ≤20% in one or two biopsy cores, and PSA levels ≤10, few patients are likely to require treatment. Progression-free survival of those treated is likely to be equivalent to patients with similar clinical findings treated at diagnosis.     

Two-year outcome of a combination of weight loss therapies for type 2 diabetes

OBJECTIVE: To evaluate the effects over 2 years of a weight loss program combining several weight loss strategies on weight loss and diabetes control in overweight subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 59 overweight or obese individuals with type 2 diabetes were randomly assigned to either a combination therapy weight loss program for 2 years (C therapy) or a standard therapy weight loss program for 1 year followed by a combination therapy weight loss program in the 2nd year (S/C therapy). C therapy combined the use of meal replacement products, repetitive intermittent low-calorie-diet weeks, and pharmacologic therapy with sibutramine. Outcome measures included changes in weight, glycemic control, plasma lipids, blood pressure, and body composition over 2 years. RESULTS: A total of 48 participants (23 in the C therapy group and 25 in the S/C therapy group) completed 2 years of study. After 2 years, the C therapy group had weight loss of 4.6 +/- 1.2 kg (P < 0.001) and a decrease in HbA(1c) of 0.5 +/- 0.3% (P = 0.08) from baseline. At 2 years, the C therapy group had significant reductions in BMI, fat mass, lean body mass, and systolic blood pressure. The S/C therapy group showed changes in weight and HbA(1c) in year 2 of the study that were similar to those demonstrated by the C therapy group in year 1. CONCLUSIONS: This combination weight loss program resulted in significant weight loss and improved diabetes control over a 2-year period in overweight subjects with type 2 diabetes.     

Anionic polymers for decreased toxicity and enhanced in vivo delivery of siRNA complexed with cationic liposomes

We recently reported a cationic lipid-based vector of siRNA, termed siRNA lipoplex that was very efficient in specific gene silencing, both in cell culture and in mouse disease models. To be more efficient, this vector included the addition of a plasmid DNA as an anionic “cargo.” Although this plasmid DNA was devoid of any eukaryotic expression cassette, we decided to replace it by an anionic polymer that would be more acceptable for clinical applications. We identified seven anionic polymers, regarded as non-toxic, biodegradable, of various characteristics and nature. The addition of polymers to siRNA lipoplexes led to the formation of particles with similar characteristics to crude siRNA lipoplexes, decreased cellular toxicity and variable in vitro gene silencing efficiency depending on the type of polymer used. Upon i.v. injection in mice, siRNA lipoplexes prepared with the best polymer, polyglutamate, led to significantly increased recovery of siRNA in liver and lung compared with lipoplexes without polymer.     

Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors

Inhalation of radon is closely associated with an increased risk of lung cancers. While the involvement of Ink4a in lung tumor development has been widely described, the tumor suppressor gene has not been studied in radon-induced lung tumors. In this study, loss of heterozygosity (LOH) analysis of the Cdkn2a locus, common to the Ink4a and Arf genes, was performed on 33 radon-induced rat lung tumors and showed a DNA loss in 50% of cases. The analysis of p16(Ink4a) protein expression by immunohistochemistry revealed that 50% of the tumors were negative for this protein. Looking for the origin of this lack of expression, we observed a low frequency of homozygous deletion (6%), a lack of mutation, an absence of correlation between promoter methylation and Ink4a mRNA expression and no correlation between LOH and protein expression. However, a tendency for an inverse correlation between p16(Ink4a) and pRb protein expression was observed. The expressions of p19Arf, Mmd2 and Mdm4 were not deregulated and only 14% of the tumors were mutated for Tp53. These results indicated that Ink4a/Cdk4/Rb1 pathway deregulation, more than Arf/Mdm2/Tp53 pathway, has a major role in the development of these tumors through p16(Ink4a) deregulation. However, all known mechanisms of inactivation of the pathway do not play a recurrent role in these tumors and the actual origin of the lack of p16(Ink4a) protein expression remains to be established.