Evaluation of biotransformation capacity of transplastomic plants and hairy roots of Nicotiana tabacum expressing human cytochrome P450 2D6.

Cytochrome P450 monooxygenases (CYPs) are important tools for regio- and stereoselective oxidation of target molecules or engineering of metabolic pathways. Functional heterologous expression of eukaryotic CYPs is often problematic due to their dependency on the specific redox partner and the necessity of correct association with the membranes for displaying enzymatic activity. Plant hosts offer advantages of accessibility of reducing partners and a choice of membranes to insert heterologous CYPs. For the evaluation of plant systems for efficient CYP expression, we established transplastomic plants and hairy root cultures of Nicotiana tabacum carrying the gene encoding human CYP2D6 with broad substrate specificity. The levels of CYP2D6 transcript accumulation and enzymatic activity were estimated and compared with the data of CYP2D6 transient expression in N. benthamiana. The relative level of CYP2D6 transcripts in transplastomic plants was 2-3 orders of magnitude higher of that observed after constitutive or transient expression from the nucleus. CYP2D6 expressed in chloroplasts converted exogenous synthetic substrate loratadine without the need for co-expression of the cognate CYP reductase. The loratadine conversion rate in transplastomic plants was comparable to that in N. benthamiana plants transiently expressing a chloroplast targeted CYP2D6 from the nucleus, but was lower than the value reported for transiently expressed CYP2D6 with the native endoplasmic reticulum signal-anchor sequence. Hairy roots showed the lowest substrate conversion rate, but demonstrated the ability to release the product into the culture medium. The obtained results illustrate the potential of plant-based expression systems for exploiting the enzymatic activities of eukaryotic CYPs with broad substrate specificities.

Anorectal dysfunction in adults with spina bifida and associated socio-emotional factors-a retrospective, cross-sectional cohort study.

STUDY DESIGN: Retrospective, cross-sectional study. OBJECTIVES: To investigate prevalence, types, and severity of fecal incontinence (FI) and constipation in adults with spina bifida (SB), in relation to self-perception and help-seeking, and to compare findings to data from a general population reference group. SETTING: University Medical Center Groningen (UMCG), the Netherlands. METHODS: The 294 adults with SB registered at UMCG in 2017 were invited to participate. The Groningen Defecation and Fecal Continence Questionnaire was used to assess functional outcomes for FI and constipation using Rome IV criteria. Vaizey (for FI) and Agachan (for constipation) scores were determined. Socio-demographic factors and self-perception of bowel-related problems were recorded through the questionnaire. Data were compared with an age and sex matched reference group. RESULTS: The completed questionnaires of 112 (38%) responding participants were analyzed. FI and constipation were more prevalent in the study group (35% and 45%, respectively) than in the reference group (8.9% and 22%, respectively). In general, in participants with SB aperta (SBA; n = 75), FI was more severe than in participants with SB occulta (SBO; n = 37). However, severity of FI was higher in SBO participants than in the SBA group after the age of 61. Bowel problems in adults with SB were associated with worse self-perception regarding health. CONCLUSIONS: In adults with SB, anorectal dysfunction is often present and severe. Older persons with SBO experience more severe FI than in early age. Bowel problems should systematically and more adequately be addressed and controlled throughout adulthood in both the spina bifida groups.

Interaction between LRP5 and periostin gene polymorphisms on serum periostin levels and cortical bone microstructure.

We investigated the interaction between periostin SNPs and the SNPs of the genes assumed to modulate serum periostin levels and bone microstructure in a cohort of postmenopausal women. We identified an interaction between LRP5 SNP rs648438 and periostin SNP rs9547970 on serum periostin levels and on radial cortical porosity. PURPOSE: The purpose of this study is to investigate the interaction between periostin gene polymorphisms (SNPs) and other genes potentially responsible for modulating serum periostin levels and bone microstructure in a cohort of postmenopausal women. METHODS: In 648 postmenopausal women from the Geneva Retirees Cohort, we analyzed 6 periostin SNPs and another 149 SNPs in 14 genes, namely BMP2, CTNNB1, ESR1, ESR2, LRP5, LRP6, PTH, SPTBN1, SOST, TGFb1, TNFRSF11A, TNFSF11, TNFRSF11B and WNT16. Volumetric BMD and bone microstructure were measured by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. RESULTS: Serum periostin levels were associated with radial cortical porosity, including after adjustment for age, BMI, and years since menopause (p = 0.036). Sixteen SNPs in the ESR1, LRP5, TNFRSF11A, SOST, SPTBN1, TNFRSF11B and TNFSF11 genes were associated with serum periostin levels (p range 0.03-0.001) whereas 26 SNPs in 9 genes were associated with cortical porosity at the radius and/or at the tibia. WNT 16 was the gene with the highest number of SNPs associated with both trabecular and cortical microstructure. The periostin SNP rs9547970 was also associated with cortical porosity (p = 0.04). In particular, SNPs in LRP5, ESR1 and near the TNFRSF11A gene were associated with both cortical porosity and serum periostin levels. Eventually, we identified an interaction between LRP5 SNP rs648438 and periostin SNP rs9547970 on serum periostin levels (interaction p = 0.01) and on radial cortical porosity (interaction p = 0.005). CONCLUSION: These results suggest that periostin expression is genetically modulated, particularly by polymorphisms in the Wnt pathway, and is thereby implicated in the genetic variation of bone microstructure.

The impact of low back pain on health-related quality of life in old age: results from a survey of a large sample of Swiss elders living in the community.

PURPOSE: The present study aims at investigating the effects of low back pain (LBP), i.e., type of symptoms, activity limitations, frequency, duration, and severity on health-related quality of life (HRQoL) in a sample of 707 community-dwelling men and women aged ≥ 65 years living in Switzerland. METHODS: The study is part of a larger survey conducted in Switzerland on a sample of older adults selected randomly from population records, stratified by age and sex. The Standardized Back Pain Definition was used to investigate LBP, and HRQoL was assessed by means of the EQ-5D, including Health Utility Index (HUI) measures. RESULTS: For more than half of the sufferers, pain was chronic, occurred most days or every day and induced activity limitations. One-third of the sufferers reported sciatica symptoms. Individuals reporting every day pain, severe pain and more than 3 years since the last episode without pain lost nearly 10 points of HRQoL. Amongst the dimension of HRQoL, Mobility was the most affected by LBP. CONCLUSIONS: These results provide further insight into the impact of qualitative aspects of LBP and in particular the importance of radiating leg pain and pain frequency and duration. While LBP-related activity limitations had little impact on both self-rated overall health and HUI, radiating leg pain and pain frequency and duration were associated with significantly decreased scores on both dimensions.

Desynchronization does not contribute to intracortical inhibition and facilitation: a paired-pulse paradigm study combined with TST.

The paired-pulse (PP) transcranial magnetic stimulation (TMS) paradigms allow the exploration of the motor cortex physiology. The triple stimulation technique (TST) improves conventional TMS by reducing effects of desynchronization of motor neuron discharges allowing a precise evaluation of the corticospinal conduction. The objective of our study was to explore PP TMS paradigms combined with the TST to study whether the desynchronization contributes to these phenomena and whether the combined TMS-TST protocol could improve the consistency of responses. We investigated the PP paradigms of short intracortical inhibition (SICI) with 2 ms interstimulus interval (ISI) and of intracortical facilitation (ICF) with 10 ms ISI in 22 healthy subjects applying either conventional TMS alone or combined with the TST protocol. The results of the PP paradigms combined with the TST of SICI and ICF do not differ from those with conventional TMS. However, combining the PP paradigm with the TST reduces their variability. These results speak against a contribution of the desynchronization of motor neuron discharges to the PP paradigms of SICI and ICF. Combining the PP TMS paradigm with the TST may improve their consistency, but the interindividual variability remains such that it precludes their utility for clinical practice.NEW & NOTEWORTHY Combining the triple stimulation technique with the paired-pulse stimulation paradigm improves the consistency of short intracortical inhibition and facilitation and could be useful in research, but the interindividual variability precludes their utility for clinical practice. Our findings do not suggest that desynchronization of descending discharges following transcranial magnetic stimulation contributes to short intracortical inhibition or intracortical facilitation.

Association of cortical microinfarcts and cerebral small vessel pathology in the ageing brain.

AIMS: Cortical microinfarcts (CMI) are frequently observed in the ageing brain independent of cognitive decline, but their aetiology is not fully elucidated. To examine the potential role of different vessel pathologies, including cerebral amyloid angiopathy (CAA), arteriolosclerosis-hyalinosis and thromboembolism in the development of CMI, we examined 80 autopsy cases with more than one CMI on routine neuropathological examination. METHODS: Pial and intracortical vessels around CMI were assessed for their integrity with haematoxylin-eosin staining and antibodies against amyloid-ß protein and fibrinogen using a semiquantitative four-level rating scale (absent to severe) in the hippocampus, and the frontal, temporal and occipital cortex. Four histological categories of changes were defined: CAA, vessel pathology other than CAA, thromboembolism and absence of vessel pathology near CMI. RESULTS: A differential distribution of microvascular pathology was observed depending on brain regions. In the occipital cortex, CAA was commonly associated with CMI. In contrast, in the hippocampus and the frontal cortex, cases without any vascular pathology in pial and intracortical vessels were significantly more frequent. CONCLUSIONS: The aetiology of CMI differs depending on brain location. CAA may play a role principally in the occipital cortex. The large number of intact vessels around the CMI (mainly in the frontal cortex and hippocampus) raises the possibility that pathologies other than structural microangiopathy, including hypoperfusion/arterial hypotension or large vessel atherosclerosis, play a role in the development of microvascular lesions. These results are relevant in the context of aetiopathogenesis of vascular changes associated with conditions like vascular dementia.

Prolonged suppressive antibiotic therapy for prosthetic joint infection in the elderly: a national multicentre cohort study.

During prosthetic joint infection (PJI), optimal surgical management with exchange of the device is sometimes impossible, especially in the elderly population. Thus, prolonged suppressive antibiotic therapy (PSAT) is the only option to prevent acute sepsis, but little is known about this strategy. We aimed to describe the characteristics, outcome and tolerance of PSAT in elderly patients with PJI. We performed a national cross-sectional cohort study of patients >75 years old and treated with PSAT for PJI. We evaluated the occurrence of events, which were defined as: (i) local or systemic progression of the infection (failure), (ii) death and (iii) discontinuation or switch of PSAT. A total of 136 patients were included, with a median age of 83 years [interquartile range (IQR) 81-88]. The predominant pathogen involved was Staphylococcus (62.1%) (Staphylococcus aureus in 41.7%). A single antimicrobial drug was prescribed in 96 cases (70.6%). There were 46 (33.8%) patients with an event: 25 (18%) with an adverse drug reaction leading to definitive discontinuation or switch of PSAT, 8 (5.9%) with progression of sepsis and 13 died (9.6%). Among patients under follow-up, the survival rate without an event at 2 years was 61% [95% confidence interval (CI): 51;74]. In the multivariate Cox analysis, patients with higher World Health Organization (WHO) score had an increased risk of an event [hazard ratio (HR) = 1.5, p = 0.014], whereas patients treated with beta-lactams are associated with less risk of events occurring (HR = 0.5, p = 0.048). In our cohort, PSAT could be an effective and safe option for PJI in the elderly.

Age-associated declines in muscle mass, strength, power, and physical performance: impact on fear of falling and quality of life.

UNLABELLED: This 3-year longitudinal study among older adults showed that declining muscle mass, strength, power, and physical performance are independent contributing factors to increased fear of falling, while declines of muscle mass and physical performance contribute to deterioration of quality of life. Our findings reinforce the importance of preserving muscle health with advancing age. INTRODUCTION: The age-associated loss of skeletal muscle quantity and function are critical determinants of independent physical functioning in later life. Longitudinal studies investigating how decrements in muscle components of sarcopenia impact fear of falling (FoF) and quality of life (QoL) in older adults are lacking. METHODS: Twenty-six healthy older subjects (age, 74.1 ± 3.7; Short Physical Performance Battery (SPPB) score ≥10) and 22 mobility-limited older subjects (age, 77.2 ± 4.4; SPPB score ≤9) underwent evaluations of lower extremity muscle size and composition by computed tomography, strength and power, and physical performance at baseline and after 3-year follow-up. The Falls Efficacy Scale (FES) and Short Form-36 questionnaire (SF-36) were also administered at both timepoints to assess FoF and QoL, respectively. RESULTS: At 3-year follow-up, muscle cross-sectional area (CSA) (p < 0.013) and power decreased (p < 0.001), while intermuscular fat infiltration increased (p < 0.001). These decrements were accompanied with a longer time to complete 400 m by 22 ± 46 s (p < 0.002). Using linear mixed-effects regression models, declines of muscle CSA, strength and power, and SPPB score were associated with increased FES score (p < 0.05 for each model). Reduced physical component summary score of SF-36 over follow-up was independently associated with decreased SPPB score (p < 0.020), muscle CSA (p < 0.046), and increased 400 m walk time (p < 0.003). CONCLUSIONS: In older adults with and without mobility limitations, declining muscle mass, strength, power, and physical performance contribute independently to increase FoF, while declines of muscle mass and physical performance contribute to deterioration of QoL. These findings provide further rationale for developing interventions to improve aging muscle health.

Clinical presentation and management of patients with primary hyperparathyroidism of the Swiss Primary Hyperparathyroidism Cohort: a focus on neuro-behavioral and cognitive symptoms.

PURPOSE: To describe the clinical and biochemical profile of patients with primary hyperparathyroidism (PHPT) of the Swiss Hyperparathyroidism Cohort, with a focus on neurobehavioral and cognitive symptoms and on their changes in response to parathyroidectomy. METHODS: From June 2007 to September 2012, 332 patients were enrolled in the Swiss PHPT Cohort Study, a nationwide prospective and non-interventional project collecting clinical, biochemical, and outcome data in newly diagnosed patients. Neuro-behavioral and cognitive status were evaluated annually using the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, and the Clock Drawing tests. Follow-up data were recorded every 6 months. Patients with parathyroidectomy had one follow-up visit 3-6 months' postoperatively. RESULTS: Symptomatic PHPT was present in 43 % of patients. Among asymptomatic patients, 69 % (131/189) had at least one of the US National Institutes for Health criteria for surgery, leaving thus a small number of patients with cognitive dysfunction or neuropsychological symptoms, but without any other indication for surgery. At baseline, a large proportion showed elevated depression and anxiety scores and cognitive dysfunction, but with no association between biochemical manifestations of the disease and test scores. In the 153 (46 %) patients who underwent parathyroidectomy, we observed an improvement in the Mini-Mental State Examination (P = 0.01), anxiety (P = 0.05) and depression (P = 0.05) scores. CONCLUSION: PHPT patients often present elevated depression and anxiety scores and cognitive dysfunction, but rarely as isolated manifestations. These alterations may be relieved upon treatment by parathyroidectomy.

Low back pain and health-related quality of life in community-dwelling older adults.

PURPOSE: Investigation of self-reported of low back pain (LBP) over the last month and associated health-related quality of life (HRQoL) in a sample of a community-dwelling population aged ≥65. METHODS: Cross-sectional study including older adults selected randomly from population records. Data were collected within a sample stratified by age and sex. Physical and psychological healths were investigated using a standardized definition of LBP and the EuroQoL-5D for HRQoL. Analyses were first conducted on the entire sample (N = 3042) and subsequently considering the subsample who reported LBP and a paired sample drawn from the pool of LBP-free respondents. RESULTS: 889 (29 %) respondents reported LBP within the past month, present 'most days' or 'every day' in 52 % and limiting activities in the same proportion. Average pain score was 4.6 (SD 2.2; 0-10 scale). Age was associated with pain frequency and duration, with younger groups more often reporting pain 'some days' and 'dating back <3 months'. Results of regression analyses showed that individuals suffering from LBP had significantly more problems than LBP non-sufferers on all EQ-5D subscales, except self-care: pain/discomfort (OR 5.33; 95 % CI [4.19-6.79]), mobility (OR 2.66; 95 % CI [2.04-3.46]), usual activities (OR 1.92; 95 % CI [1.42-2.60]), anxiety/depression (OR 1.59; 95 % CI [1.23-2.04]) and self-care (OR 1.29; 95 % CI [0.84-1.98]). CONCLUSION: LBP appears to be a more permanent condition in the older groups. LBP may be a part of the definition of a subgroup of elderly at risk of becoming frail in relation with higher levels of functional limitations, psychological difficulties and social restrictions, hence globally impaired HRQoL.

Nasal salmon calcitonin blunts bone microstructure alterations in healthy postmenopausal women.

UNLABELLED: In healthy postmenopausal women, nasal salmon calcitonin blunted distal radius and tibia bone microstructure degradation. INTRODUCTION: Nasal salmon calcitonin (NSC) has been reported to lower vertebral fracture risk by 33%, but to modestly increase spine areal bone mineral density (aBMD) by 1.5%. Thus, NSC may also influence bone microstructure, another known determinant of bone strength. METHODS: In a randomized, double-blind, placebo-controlled trial, we investigated the effects of 200 IU/day NSC on distal radius and tibia bone microstructure (by high-resolution 3-dimensional peripheral quantitative computerized tomography), aBMD (by dual-energy X-ray absorptiometry), and serum bone turnover markers in healthy postmenopausal women. RESULTS: Mean age was 57.6 ± 0.8 (±SEM) and 57.4 ± 0.7 in NSC (n = 45) and placebo groups (n = 45), respectively. Mean femoral neck T-score was in the osteopenic range; prevalent vertebral fracture was 4% in each group. There was no observed between-group difference in the primary outcome distal radius BV/TV (-2.8 ± 0.6% vs. -4.3 ± 1.0%, NS). By 2 years, the decrease in distal radius total density vs. baseline was 4.4 ± 0.7% in controls and 2.1 ± 0.6% in NSC-receiving patients (p < 0.05). Distal radius and tibia cortical thickness decreased by 3.7 ± 1.0 and 2.4 ± 0.5% in placebo (p < 0.05 vs. baseline for both), respectively, but not in the NSC group. Distal radius total density and cortical thickness changes were lower in NSC group than in placebo (p < 0.05 for both) in the subgroup with baseline C-terminal telopeptides (CTX) above the median. By 6 and 12 months, serum CTX decreased by 17.3 ± 6.2 and 19.1 ± 6.6% (both p < 0.05 vs. baseline), respectively, in NSC, but remained stable in controls (NS vs. baseline). There was no difference in aBMD. NSC was well tolerated, with less arthralgia than the placebo group (14 vs. 26, p < 0.05). CONCLUSION: Nasal salmon calcitonin blunted the degradation of distal radius and tibia bone microstructure in healthy postmenopausal women.

Prior ankle fractures in postmenopausal women are associated with low areal bone mineral density and bone microstructure alterations.

UNLABELLED: In a cross-sectional analysis in postmenopausal women, prior ankle fractures were associated with lower areal bone mineral density (BMD) and trabecular bone alterations compared to no fracture history. Compared to women with forearm fractures, microstructure alterations were of lower magnitude. These data suggest that ankle fractures are another manifestation of bone fragility. INTRODUCTION: Whether ankle fractures represent fragility fractures associated with low areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) and/or bone microstructure alterations remains unclear, in contrast to the well-recognised association between forearm fractures and osteoporosis. The objective of this study was to investigate aBMD, vBMD and bone microstructure in postmenopausal women with prior ankle fracture in adulthood, compared with women without prior fracture or with women with prior forearm fractures, considered as typically of osteoporotic origin. METHODS: In a cross-sectional analysis in the Geneva Retirees Cohort study, 63 women with ankle fracture and 59 with forearm fracture were compared to 433 women without fracture (mean age, 65 ± 1 years). aBMD was measured by dual-energy X-ray absorptiometry; distal radius and tibia vBMD and bone microstructure were measured by high-resolution peripheral quantitative computed tomography. RESULTS: Compared with women without fracture, those with ankle fractures had lower aBMD, radius vBMD (-7.9%), trabecular density (-10.7%), number (-7.3%) and thickness (-4.6%) and higher trabecular spacing (+14.5%) (P < 0.05 for all). Tibia trabecular variables were also altered. For 1 standard deviation decrease in total hip aBMD or radius trabecular density, odds ratios for ankle fractures were 2.2 and 1.6, respectively, vs 2.2 and 2.7 for forearm fracture, respectively (P ≤ 0.001 for all). Compared to women with forearm fractures, those with ankle fractures had similar spine and hip aBMD, but microstructure alterations of lower magnitude. CONCLUSION: Women with ankle fractures have lower aBMD and vBMD and trabecular bone alterations, suggesting that ankle fractures are another manifestation of bone fragility.

Improvement in executive subfunctions following cerebrospinal fluid tap test identifies idiopathic normal pressure hydrocephalus from its mimics.

BACKGROUND AND PURPOSE: Patients with idiopathic normal pressure hydrocephalus (iNPH) present cognitive deficits that overlap with other neurological conditions such as Parkinson's disease or vascular dementia, therefore mimicking iNPH. This prospective study aimed to compare cognitive performances between iNPH and iNPH mimics before and after cerebrospinal fluid (CSF) tapping. METHODS: A total of 57 patients with suspicion of iNPH (75.84 ± 6.42 years; 39% female) were included in this study (37 iNPH and 20 iNPH mimics). Neuropsychological assessments were performed before and 24 h after CSF tapping of 40 ml. Multivariate logistic regressions were used to examine the association between iNPH and cognitive functions, adjusted for age, education, baseline cognitive assessment and disease duration. RESULTS: Both groups presented the same baseline cognitive performances. After CSF tapping, iNPH patients improved their semantic (P = 0.001) and phonemic verbal fluencies (P = 0.001), whereas iNPH mimics presented similar performances to before CSF tapping. The phonemic verbal fluency (odds ratio 1.43, 95% confidence interval 1.05; 1.96) and the Color Trails Test (odds ratio 0.10, 95% confidence interval 0.01; 0.76) improvements were the two discriminative cognitive tests that identified iNPH from iNPH mimics. CONCLUSION: Improvement in executive subfunctions after CSF tapping identified iNPH patients from other neurological conditions that mimic iNPH. These findings respond to clinical issues encountered on a daily basis and would improve the diagnostic process of iNPH.

Vitamin D and white matter abnormalities in older adults: a cross-sectional neuroimaging study.

BACKGROUND AND PURPOSE: Morphological brain changes related to hypovitaminosis D have been poorly studied. In particular, the age-related decrease in vitamin D concentrations may explain the onset of white matter abnormalities (WMA) in older adults. Our objectives were (i) to investigate whether there was an association between serum 25-hydroxyvitamin D (25OHD) concentration and the grade of WMA in older adults and (ii) to determine whether the location of WMA was associated with 25OHD concentration. METHODS: One hundred and thirty-three Caucasian older community-dwellers with no clinical hydrocephalus (mean 71.6 ± 5.6 years; 43.6% female) received a blood test and a magnetic resonance imaging scan of the brain. The grades of total, periventricular and deep WMA were scored using semiquantitative visual rating scales from T2-weighted fluid-attenuated inversion recovery images. The association of WMA with as-measured and deseasonalized 25OHD concentrations was evaluated with the following covariates: age, gender, body mass index, use of anti-vascular drugs, number of comorbidities, impaired mobility, education level, Mini-Mental State Examination score, medial temporal lobe atrophy, serum concentrations of calcium, thyroid-stimulating hormone and vitamin B12, and estimated glomerular filtration rate. RESULTS: Both as-measured and deseasonalized serum 25OHD concentrations were found to be inversely associated with the grade of total WMA (adjusted ß = -0.32, P = 0.027), specifically with periventricular WMA (adjusted ß = -0.15, P = 0.009) but not with deep WMA (adjusted ß = -0.12, P = 0.090). Similarly, participants with 25OHD concentration <75 nM had on average a 33% higher grade of periventricular WMA than those with 25OHD ≥75 nM (P = 0.024). No difference in average grade was found for deep WMA (P = 0.949). CONCLUSIONS: Lower serum 25OHD concentration was associated with higher grade of WMA, particularly periventricular WMA. These findings provide a scientific basis for vitamin D replacement trials.

The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.

AIMS: Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid ß protein (Aß) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer's disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a 1-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva. MATERIALS AND METHODS: Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal and occipital cortex, using an antibody against Aß, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established. RESULTS: CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters. CONCLUSION: The present data show that CAA plays a role in the development of microvascular lesions in the ageing brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contribute importantly to the pathogenesis of microvascular changes.

Effect of a multifactorial fall-and-fracture risk assessment and management program on gait and balance performances and disability in hospitalized older adults: a controlled study.

UNLABELLED: This controlled intervention study in hospitalized oldest old adults showed that a multifactorial fall-and-fracture risk assessment and management program, applied in a dedicated geriatric hospital unit, was effective in improving fall-related physical and functional performances and the level of independence in activities of daily living in high-risk patients. INTRODUCTION: Hospitalization affords a major opportunity for interdisciplinary cooperation to manage fall-and-fracture risk factors in older adults. This study aimed at assessing the effects on physical performances and the level of independence in activities of daily living (ADL) of a multifactorial fall-and-fracture risk assessment and management program applied in a geriatric hospital setting. METHODS: A controlled intervention study was conducted among 122 geriatric inpatients (mean ± SD age, 84 ± 7 years) admitted with a fall-related diagnosis. Among them, 92 were admitted to a dedicated unit and enrolled into a multifactorial intervention program, including intensive targeted exercise. Thirty patients who received standard usual care in a general geriatric unit formed the control group. Primary outcomes included gait and balance performances and the level of independence in ADL measured 12 ± 6 days apart. Secondary outcomes included length of stay, incidence of in-hospital falls, hospital readmission, and mortality rates. RESULTS: Compared to the usual care group, the intervention group had significant improvements in Timed Up and Go (adjusted mean difference [AMD] = -3.7s; 95 % CI = -6.8 to -0.7; P = 0.017), Tinetti (AMD = -1.4; 95 % CI = -2.1 to -0.8; P < 0.001), and Functional Independence Measure (AMD = 6.5; 95 %CI = 0.7-12.3; P = 0.027) test performances, as well as in several gait parameters (P < 0.05). Furthermore, this program favorably impacted adverse outcomes including hospital readmission (hazard ratio = 0.3; 95 % CI = 0.1-0.9; P = 0.02). CONCLUSIONS: A multifactorial fall-and-fracture risk-based intervention program, applied in a dedicated geriatric hospital unit, was effective and more beneficial than usual care in improving physical parameters related to the risk of fall and disability among high-risk oldest old patients.

Alterations of bone microstructure and strength in end-stage renal failure.

UNLABELLED: End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. INTRODUCTION: Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. METHODS: We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 ± 12.6 years) and 33 age-matched healthy controls. RESULTS: Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with "Kidney Disease: Improving Global Outcomes" working group PTH level categories (r = 0.36, p < 0.04). BMI correlated positively with trabecular number (r = 0.4, p < 0.02) and negatively with trabecular spacing (r = -0.37, p < 0.03) and trabecular network heterogeneity (r = -0.4, p < 0.02). Biomechanics positively correlated with BMI and negatively with BALP. CONCLUSION: Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR-pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patients.

Derivation and validation of a Short Form of the Mini-Mental State Examination for the screening of dementia in older adults with a memory complaint.

BACKGROUND AND PURPOSE: To validate a Short Form of the Mini-Mental State Examination (SMMSE) as a screening test for dementia in older ambulatory individuals followed in a memory clinic for a memory complaint. METHODS: A total of 202 cognitively healthy individuals, 100 individuals with a mild cognitive impairment and 304 demented individuals sent for a memory complaint by their primary care physician to a memory clinic were prospectively included in this cross-sectional study. They were randomized into derivation (n = 303) and validation (n = 303) groups. The SMMSE score was built from six memory items of MMSE, with a score ranging from 0 to 6 (i.e. best performance). RESULTS: The receiver operating characteristic curve showed an area under the curve of 0.98 for the derivation group and 0.97 for the validation group without differences between curves (P = 0.254). The cut-off between the sensitivity and the specificity of the SMMSE score for clinically diagnosed dementia was ≤4. The performance of the SMMSE for the diagnosis of dementia was high in the derivation and validation groups: sensitivity at 93.1% and 93.8%, specificity at 93.8% and 90.5%, positive predictive value at 94.3% and 90.1%, negative predictive value at 92.5% and 94.0%, likelihood ratio of positive test at 14.9 and 9.8 and of negative test at 0.07 and 0.07, respectively. CONCLUSIONS: The Short Form of the Mini-Mental State Examination was a good screening test for dementia in older individuals followed in a memory clinic for a memory complaint. The next step should be the confirmation of its discriminative value in older primary care patients.

Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.

AIMS: Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analysed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. METHODS: We analysed microvessel diameters in the dorsal and subgenual parts of the ACC in eight patients with schizophrenia, 10 patients with sporadic bipolar disorder, eight patients with sporadic major depression, and seven age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal-Wallis group comparisons with Bonferroni correction as well as multivariate regression models. RESULTS: Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable with controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. CONCLUSIONS: Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings is discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders.