Anti-apoptotic effect of adipose tissue-derived stromal vascular fraction in denervated rat muscle.

BACKGROUND: Recovery of muscle function after peripheral nerve injury is often poor, and this can be attributed to muscle fiber atrophy and cell death. In the current study, we have investigated the effects of stromal vascular fraction (SVF) on muscle cell apoptosis and its potential to preserve muscle tissue following denervation. METHODS: Rat gastrocnemius muscle was denervated by sciatic nerve transection. At 2 and 4 weeks after injury, muscles were examined histologically and apoptosis was measured using TUNEL assay and PCR array for a range of apoptotic genes. Additionally, an in vitro TNF-α apoptosis model was established using SVF cells co-cultured indirectly with primary rat myoblasts. Annexin V and TUNEL were used together with Western blotting to investigate the signaling pathways. RESULTS: Denervated muscles showed significantly higher TUNEL reactivity at 2 and 4 weeks following nerve injury, and an increased expression of caspase family genes, mitochondria-related apoptotic genes, and tumor necrosis factor family genes. In cultured rat primary myoblasts, Annexin V labeling was significantly increased at 12 h after TNF-α treatment, and this was followed by a significant increase in TUNEL reactivity at 48 h. Western blotting showed that caspase-7 was activated/cleaved as well as the downstream substrate, poly (ADP-ribose) polymerase (PARP). Co-culture of myoblasts with SVF significantly reduced all these measures of apoptosis. Bax and Bcl-2 levels were not changed suggesting that the TNF-α-induced apoptosis occurred via mitochondria-independent pathways. The protective effect of SVF was also shown in vivo; injections of SVF cells into denervated muscle significantly improved the mean fiber area and diameter, as well as reduced the levels of TUNEL reactivity. CONCLUSIONS: This study provides new insights into how adipose tissue-derived cells might provide therapeutic benefits by preserving muscle tissue.

Low plasma thiamine and phosphate in male patients with Parkinson's disease is associated with mild cognitive impairment.

OBJECTIVES: Thiamine deficiency (TD) and phosphate depletion increase the risk for cognitive disturbances. This study investigates whether plasma levels of thiamine (P-THIAM), thiamine-monophosphate (P-TMP), and phosphate (P-PHOS) are associated with mild cognitive decline (MCI) in patients with Parkinson's disease (PD). DESIGN AND STUDY POPULATION: This case-control study includes baseline data from a cohort of newly diagnosed patients identified in the New Parkinsonism in Umeå study (NYPUM) (N = 75) and an age and sex matched control group (n = 24). MEASUREMENTS: Mini Nutritional Assessment (MNA-score) and concentrations of P-THIAM, P-TMP, and P-PHOS at baseline were compared between PD patients with mild cognitive impairment (PD-MCI) and PD patients with normal cognition (PD-NC). Neuropsychological assessments of MCI were performed at time of diagnosis. RESULTS: Compared to patients with NC, patients with MCI had lower levels of P-THIAM and P-TMP as well as lower scores on both the Mini Mental State Examination (MMSE) and MNA-screening test. In addition, patients with MCI were older and had more motor problems. The multiple logistic regressions adjusted for age and sex revealed that higher levels of P-THIAM and the MNA-total score were associated with a lower risk of having MCI. Higher MNA-total score and higher P-THIAM and P-PHOS concentrations decreased the risk of MCI in male patients, but not in female patients. The decreased risk of MCI with higher P-TMP levels was lost after adding age and sex to the model. Bivariate correlations between P-PHOS and P-TMP were shown for the total PD population and controls as well as for males with MCI (r = 0.533; n = 22; p = 0.011), but not for males with NC (r = 0.314; n = 19; p = 0.204). An inverse partial correlation (adjusted for age, sex and UPDRS III) was shown for P-THIAM and MNA-total (r = -0.315,p = 0.009) and -final (part II) (r = -0.395,p = 0.001) score for the PD population (n = 75). CONCLUSIONS: Higher P-THIAM and P-PHOS concentrations and higher MNA-total score were associated with a lower risk of MCI in male PD patients, findings that indicate that nutritional factors may influence cognitive function in males in the early phase of PD.

The adipose tissue stromal vascular fraction secretome enhances the proliferation but inhibits the differentiation of myoblasts.

BACKGROUND: Adipose tissue is an excellent source for isolation of stem cells for treating various clinical conditions including injuries to the neuromuscular system. Many previous studies have focused on differentiating these adipose stem cells (ASCs) towards a Schwann cell-like phenotype (dASCs), which can enhance axon regeneration and reduce muscle atrophy. However, the stromal vascular fraction (SVF), from which the ASCs are derived, also exerts broad regenerative potential and might provide a faster route to clinical translation of the cell therapies for treatment of neuromuscular disorders. METHODS: The aim of this study was to establish the effects of SVF cells on the proliferation and differentiation of myoblasts using indirect co-culture experiments. A Growth Factor PCR Array was used to compare the secretomes of SVF and dASCs, and the downstream signaling pathways were investigated. RESULTS: SVF cells, unlike culture-expanded dASCs, expressed and secreted hepatocyte growth factor (HGF) at concentrations sufficient to enhance the proliferation of myoblasts. Pharmacological inhibitor studies revealed that the signal is mediated via ERK1/2 phosphorylation and that the effect is significantly reduced by the addition of 100 pM Norleual, a specific HGF inhibitor. When myoblasts were differentiated into multinucleated myotubes, the SVF cells reduced the expression levels of fast-type myosin heavy chain (MyHC2) suggesting an inhibition of the differentiation process. CONCLUSIONS: In summary, this study shows the importance of HGF as a mediator of the SVF effects on myoblasts and provides further evidence for the importance of the secretome in cell therapy and regenerative medicine applications.

Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials.

BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Intake of vitamin B before onset of Parkinson's disease and atypical parkinsonism and olfactory function at the time of diagnosis.

BACKGROUND/OBJECTIVES: To investigate whether vitamin-B density in the diet 2-8 years before diagnosis is associated with olfactory function at the time of diagnosis. SUBJECTS/METHODS: This prospective nested case-control study included patients with Parkinson's disease (PD), multiple system atrophy and progressive supranuclear paralysis identified between 2004 and 2009 in the county of Västerbotten in northern Sweden. The case database (NYPUM study; Newly Diagnosed Parkinson in Umeå; n=147) was cross-linked to the Northern Sweden Health and Disease Study (NSHDS). Identified patients (n=96) and controls (n=375) were matched for sex, age, year of health survey, sub-cohort and geographical area. Dietary intake was assessed by a food frequency questionnaire, and the brief smell identification test (B-SIT) was used to measure olfactory function at the time of diagnosis. RESULTS: There was no difference in vitamin-B or any other macro- or micro-nutrient densities, energy intake or body mass index (kg/m2; BMI) between patients and controls at baseline at the time of the healthcare survey. A lower thiamin and folate density, amount per 1 megajoule, was reported in patients who scored below median on B-SIT (<7) when compared with that in patients who scored ⩾7 at the time of diagnosis. After adjusting for age, sex and BMI using linear and logistic regressions, an even stronger association was found between thiamin density and olfactory function. CONCLUSIONS: A low thiamin and folate density in the reported diet, 2-8 years before PD diagnosis, was significantly associated with olfactory dysfunction at the time of PD diagnosis.

The influence of negative life events on hippocampal and amygdala volumes in old age: a life-course perspective.

BACKGROUND: Psychosocial stress has been related to changes in the nervous system, with both adaptive and maladaptive consequences. The aim of this study was to examine the relationship of negative events experienced throughout the entire lifespan and hippocampal and amygdala volumes in older adults. METHOD: In 466 non-demented old adults (age range 60-96 years, 58% female), hippocampal and amygdala volumes were segmented using Freesurfer. Negative life events and the age at which these events occurred were assessed by means of a structured questionnaire. Using generalized linear models, hippocampal and amygdala volumes were estimated with life events as independent variables. The statistical analyses were adjusted for age, gender, intracranial volume, lifestyle factors, cardiovascular risk factors, depressive symptoms, and cognitive functioning. RESULTS: Total number of negative life events and of late-life events, but not of early-life, early-adulthood, or middle-adulthood events, was related to larger amygdala volume. There were interactions of early-life events with age and gender. Participants who reported two or more early-life events had significantly smaller amygdala and hippocampal volumes with increasing age. Furthermore, smaller hippocampal volume was found in men who reported two or more early-life events, but not in women. CONCLUSIONS: These results suggest that the effect of negative life events on the brain depends on the time when the events occurred, with the strongest effects observed during the critical time periods of early and late life.

Cardiovascular risk factors and the risk of Parkinson's disease.

BACKGROUND/OBJECTIVES: The objective of this study was to investigate whether serum triglycerides (S-TG), cholesterol, blood pressure and waist/height ratio are risk factors for Parkinson's disease (PD). SUBJECTS AND METHODS: A population-based sample within the Northern Sweden Health and Disease Study (NSHDS) was used in this study (n=101 790 subjects). Cases with PD were identified prospectively in a community-based study of idiopathic Parkinsonism in the period 2004-2009 in the county of Västerbotten in northern Sweden. The case database obtained was crosslinked to the NSHDS. Eighty-four of 147 patients with PD had visited the primary health care 2-8 years before diagnosis for participation in the NSHDS. For each case, four referents from the NSHDS population were selected, matched for sex, age, year of health survey, subcohort and geographic area. RESULTS: Cases had lower mean S-TG levels (P=0.007). After stratification for sex, the lower S-TG remained significant for men (P=0.006) but not for women (P=0.450), and these were confirmed by the conditional logistic regression for all cases, none adjusted (hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.42, 0.99) and after adjusting for age, body mass index (BMI) and physical activity (HR: 0.61; 95% CI: 0.39, 0.96). Systolic blood pressure (SBP) was negatively associated with PD risk after adjustments for age, BMI and physical activity (HR: 0.98; 95% CI: 0.97-0.99). Smoking and former smoking were associated with a reduced risk for PD. CONCLUSIONS: We found lower S-TG and SBP 2-8 years before a diagnosis of PD. Smoking was confirmed to be negatively associated with PD, whereas recreational activity indicates a risk for women.

COBRA: A prospective multimodal imaging study of dopamine, brain structure and function, and cognition.

Cognitive decline is a characteristic feature of normal human aging. Previous work has demonstrated marked interindividual variability in onset and rate of decline. Such variability has been linked to factors such as maintenance of functional and structural brain integrity, genetics, and lifestyle. Still, few, if any, studies have combined a longitudinal design with repeated multimodal imaging and a comprehensive assessment of cognition as well as genetic and lifestyle factors. The present paper introduces the Cognition, Brain, and Aging (COBRA) study, in which cognitive performance and brain structure and function are measured in a cohort of 181 older adults aged 64 to 68 years at baseline. Participants will be followed longitudinally over a 10-year period, resulting in a total of three equally spaced measurement occasions. The measurement protocol at each occasion comprises a comprehensive set of behavioral and imaging measures. Cognitive performance is evaluated via computerized testing of working memory, episodic memory, perceptual speed, motor speed, implicit sequence learning, and vocabulary. Brain imaging is performed using positron emission tomography with [(11)C]-raclopride to assess dopamine D2/D3 receptor availability. Structural magnetic resonance imaging (MRI) is used for assessment of white and gray-matter integrity and cerebrovascular perfusion, and functional MRI maps brain activation during rest and active task conditions. Lifestyle descriptives are collected, and blood samples are obtained and stored for future evaluation. Here, we present selected results from the baseline assessment along with a discussion of sample characteristics and methodological considerations that determined the design of the study. This article is part of a Special Issue entitled SI: Memory & Aging.

Vascular hippocampal plasticity after aerobic exercise in older adults.

Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.

Generic tacrolimus in solid organ transplantation.

The availability of a wide range of immunosuppressive therapies has revolutionized the management of patients who have undergone solid organ transplantation (SOT). However, the cost of immunosuppressive drugs remains high. This situation has led to the development of generic equivalents, which are similar in quality, safety, and efficacy to their approved innovator drugs. There are data available for three generic brands, tacrolimus (Intas), tacrolimus (PharOS), and tacrolimus (Sandoz). Bioequivalence has been demonstrated for generic tacrolimus (Sandoz) within a narrow therapeutic range to its innovator tacrolimus drug (Prograf) in both healthy volunteers and kidney transplant patients. Clinical experience with this generic tacrolimus formulation has also been established in both de novo and conversion patients who have undergone kidney and liver transplantation, as well as in conversion of other SOT patients, including lung and heart recipients.

Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? A population-based study.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors (VRFs) or the APOE-ε4 allele. METHODS: This population-based study included 492 participants (age ≥60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter (GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. RESULTS: More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-ε4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-ε4 had no influential effect. CONCLUSION: The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-ε4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility.

Cognitive deficits in unipolar old-age depression: a population-based study.

BACKGROUND: There is substantial variability in the degree of cognitive impairment among older depressed persons. Inconsistencies in previous findings may be due to differences in clinical and demographic characteristics across study samples. We assessed the influence of unipolar depression and severity of depression on cognitive performance in a population-based sample of elderly persons aged ⩾60 years. METHOD: Eighty-nine persons fulfilled ICD-10 criteria for unipolar depression (mild, n = 48; moderate, n = 38; severe, n = 3) after thorough screening for dementia (DSM-IV criteria), psychiatric co-morbidities and antidepressant pharmacotherapy. Participants (n = 2486) were administered an extensive cognitive test battery. RESULTS: Moderate/severe unipolar depression was associated with poorer performance on tasks assessing processing speed, attention, executive function, verbal fluency, episodic memory and vocabulary. Mild depression was associated with poorer performance in processing speed, and few differences between mild and moderate/severe depression were observed. No association between depression and short-term memory, general knowledge or spatial ability was observed. Increasing age did not exacerbate the depression-related cognitive deficits, and the deficits remained largely unchanged after excluding persons in a preclinical phase of dementia. Furthermore, depression-related cognitive deficits were not associated with other pharmacological treatments that may affect cognitive performance. CONCLUSIONS: Cognitive deficits in unipolar old-age depression involve a range of domains and the cognitive deficits seem to follow the spectrum of depression severity. The finding that mild depression was also associated with poorer cognitive functioning underscores the importance of detecting mild depression in elderly persons.

Initial experience with hypothermic machine perfusion of kidneys from deceased donors in the Uppsala region in Sweden.

BACKGROUND: Simple cold storage (CS) is the gold standard for organ preservation. Recently, evidence has been presented suggesting compared with CS hypothermic machine perfusion (HMP) improves the quality and outcome of kidneys for transplantation. Uppsala has used the LifePort Kidney Transporter to preserve deceased donor kidneys. We evaluated our first single-center 52 cases retrospectively. METHODS: Deceased donor kidneys preserved with HMP between July 2010 and July 2012 (n = 52) were compared with a matched historical cohort of organs preserved by CS between January 2009 and July 2012 (n = 87). We evaluated delayed graft function (DGF), creatinine level at hospital discharge, length of hospital stay, incidence of acute rejection episodes during the first year after transplantation, and graft survival. RESULTS: Both groups included approximately 69% expanded criteria donors (ECD). Median cold ischemia time (CIT) was 12.8 hours in the HMP group and 11.7 hours in the CS group. The incidence of DGF was 11.5% with HMP and 20.7% with CS. Compared with CS, HMP significantly reduced the occurrence of DGF from 21.4% to 0% using standard criteria kidneys (P = .046), whereas the use of HMP did not impact the occurrence of DGF with ECD kidneys. The creatinine level at hospital discharge was lower after HMP than after CS (P = .047). No difference in graft survival was observed between the groups. CONCLUSIONS: Machine perfusion resulted in a lower occurrence of DGF using kidneys from standard criteria donors with a lower creatinine at hospital discharge among the cohort with reasonably low CIT. Using machine perfusion seems to be safe; no adverse surgical events occurred during the study period.

Alpha-2 adrenergic stimulation triggers Achilles tenocyte hypercellularity: Comparison between two model systems.

The histopathology of tendons with painful tendinopathy is often tendinosis, a fibrosis-like condition of unclear pathogenesis characterized by tissue changes including hypercellularity. The primary tendon cells (tenocytes) have been shown to express adrenoreceptors (mainly alpha-2A) as well as markers of catecholamine production, particularly in tendinosis. It is known that adrenergic stimulation can induce proliferation in other cells. The present study investigated the effects of an exogenously administered alpha-2 adrenergic agonist in an established in vivo Achilles tendinosis model (rabbit) and also in an in vitro human tendon cell culture model. The catecholamine producing enzyme tyrosine hydroxylase and the alpha-2A-adrenoreceptor (α2A AR) were expressed by tenocytes, and alpha-2 adrenergic stimulation had a proliferative effect on these cells, in both models. The proliferation was inhibited by administration of an α2A AR antagonist, and the in vitro model further showed that the proliferative alpha-2A effect was mediated via a mitogenic cell signaling pathway involving phosphorylation of extracellular-signal-regulated kinases 1 and 2. The results indicate that catecholamines produced by tenocytes in tendinosis might contribute to the proliferative nature of the pathology through stimulation of the α2A AR, pointing to a novel target for future therapies. The study furthermore shows that animal models are not necessarily required for all aspects of this research.

Medial temporal lobe is vulnerable to vascular risk factors in men: a population-based study.

BACKGROUND AND PURPOSE: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. METHODS: This cross-sectional study consists of 523 participants (age ≥60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. RESULTS: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex (P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. CONCLUSIONS: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors.

Endogenous substance P production in the Achilles tendon increases with loading in an in vivo model of tendinopathy-peptidergic elevation preceding tendinosis-like tissue changes.

OBJECTIVES: To quantify the intratendinous levels of substance P (SP) at different stages of overload in an established model for Achilles tendinopathy (rabbit). Also, to study the distribution of the SP-receptor, the NK-1R, and the source of SP, in the tendon. METHODS: Animals were subjected to the overuse protocol for 1, 3 or 6 weeks. One additional group served as unexercised controls. Immunoassay (EIA), immunohistochemistry (IHC), and in situ hybridisation (ISH) were performed. RESULTS: EIA revealed increased SP-levels in the Achilles tendon of the exercised limb in all the experimental groups as compared to in the controls (statistically significant; p=0.01). A similar trend in the unexercised Achilles tendon was observed but was not statistically significant (p=0.14). IHC and in ISH illustrated reactions of both SP and NK-1R mainly in blood vessel walls, but the receptor was also found on tenocytes. CONCLUSIONS: Achilles tendon SP-levels are elevated already after 1 week of loading. This shows that increased SP-production precedes tendinosis, as tendinosis-like changes occur only after a minimum of 3 weeks of exercise, as shown in a recent study using this model. We propose that central neuronal mechanism may be involved as similar trends were observed in the contralateral Achilles tendon.

Microstructure of frontoparietal connections predicts cortical responsivity and working memory performance.

We investigated how the microstructure of relevant white matter connections is associated with cortical responsivity and working memory (WM) performance by collecting diffusion tensor imaging and verbal WM functional magnetic resonance imaging data from 29 young adults. We measured cortical responsivity within the frontoparietal WM network as the difference in blood oxygenation level-dependent (BOLD) signal between 3-back and 1-back conditions. Fractional anisotropy served as an index of the integrity of the superior longitudinal fasciculi (SLF), which connect frontal and posterior regions. We found that SLF integrity is associated with better 3-back performance and greater task-related BOLD responsivity. In addition, BOLD responsivity in right premotor cortex reliably mediated the effects of SLF integrity on 3-back performance but did not uniquely predict 3-back performance after controlling for individual differences in SLF integrity. Our results suggest that task-related adjustments of local gray matter processing are conditioned by the properties of anatomical connections between relevant cortical regions. We suggest that the microarchitecture of white matter tracts influences the speed of signal transduction along axons. This in turn may affect signal summation at neural dendrites, action potential firing, and the resulting BOLD signal change and responsivity.

The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia: a cohort study of a community dwelling elderly population.

OBJECTIVE: To investigate the symptom of low mood as a predictor of mild cognitive impairment (MCI) and its progression to dementia, taking into account: (i) MCI severity, (ii) time of assessment and (iii) interaction with other factors. METHODS: 764 cognitively healthy elderly subjects living in the community, from the Kungsholmen Project. Participants were assessed by direct interview to detect low mood. Subjects were then followed for 6 years to identify those who developed MCI. People with incident MCI were followed for a further 3 years to assess progression to dementia. RESULTS: People with low mood at baseline had a 2.7-fold (95% CI 1.9 to 3.7) increased risk of developing MCI at follow-up. The association was stronger for amnestic MCI (aMCI: HR 5.8; 95% CI 3.1 to 10.9) compared with global cognitive impairment (other cognitive impairment no dementia, oCIND: HR 2.2; 95% CI 1.5 to 3.3). ApoE-ε4 interacted with low mood in a synergistic fashion, increasing the risk of aMCI, while no interaction with psychiatric, vascular, frailty related or psychosocial factors was observed. Low mood at baseline, as opposed to low mood co-occurring with MCI, was associated with a 5.3-fold (95% CI 1.2 to 23.3) increased risk of progression to dementia in aMCI. In contrast, no association was found in oCIND. CONCLUSION: Low mood was more strongly associated with aMCI than with global cognitive impairment. Progression towards dementia was predicted only by low mood manifest in the prodromal stage of MCI. These findings indicate that low mood is particularly prominent in the very early stages of cognitive decline.

Conversion from calcineurin inhibitor to either mycophenolate mofetil or sirolimus improves renal function in liver transplant recipients with chronic kidney disease: results of a prospective randomized trial.

BACKGROUND: Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function. PATIENTS AND METHODS: In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m(2)) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm > versus <30 mL/min/1.73 m(2). The 25 patients were enrolled for MMF (n = 13) or SRL (n = 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n = 12) and SRL (n = 10). RESULTS: Mean GFRm for the whole cohort (n = 25) was 31+/-8 mL/min/1.73 m(2) at baseline. After 3 months the GFRm (n = 23) increased to 40+/-10 mL/min/1.73 m(2) (P = .0001) and at 1 year 42 +/- 11 mL/min/1.73 m(2) (n = 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n = 8) with baseline GFRm <30 mL showed a 63% (P = .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes. CONCLUSION: CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study.

This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation.