Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.

BACKGROUND: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

Effects of whole blood leukoreduction on platelet function and hemostatic parameters.

AIMS/OBJECTIVES: The aim of this study was to evaluate the hemostatic consequences of whole blood leukoreduction (LR). BACKGROUND: Whole blood is being used for trauma resuscitation in the military, and an increasing number of civilian trauma centres across the nation. The benefits of LR, such as decreased infectious and transfusion-related complications, are well established, but the effects on hemostatic parameters remain a concern. METHODS: Twenty-four units of whole blood were assigned to one of the four groups: non-leukoreduced (NLR), leukoreduced at 1 h and a height of 33 in. (LR-1), leukoreduced at 4 h and a height of 33 in. (LR-4(33)), or leukoreduced at 4 h and a height of 28 in. (LR-4(28)). Viscoelastic parameters, platelet aggregation, cell counts, physiological parameters and thrombin potential were evaluated immediately before and after LR, and on days 1, 7, 14 and 21 following LR. RESULTS: The viscoelastic parameters and thrombin generation potential were unchanged between the groups. Platelet aggregation was reduced in the LR-1 group compared with NLR after 7 days. The LR-4(28) group also showed a trend of reduced platelet aggregation compared with NLR. Aggregation in LR-4(33) was similar to NLR throughout the storage time. Physiological and electrolyte changes over the whole blood storage period were not affected by LR. CONCLUSION: Our study shows that whole blood can be LR at 4 h after collection and a height of 33 in. while maintaining platelet count and without altering platelet function and hemostatic performance.

MIND Diet Associated with Reduced Incidence and Delayed Progression of ParkinsonismA in Old Age.

BACKGROUND: In old age, motor impairments including parkinsonian signs are common, but treatment is lacking for many older adults. In this study, we examined the association of a diet specifically developed to promote brain health, called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), to the incidence and progression of parkinsonism in older adults. METHODS: A total of 706 Memory and Aging Project participants aged 59 -97 years and without parkinsonism at baseline were assessed annually for the presence of four parkinsonian signs using a 26-item modified version of the United Parkinson's Disease Rating Scale. Incident parkinsonism was defined as the first occurrence over 4.6 years of follow-up of two or more parkinsonian signs. The progression of parkinsonism was assessed by change in a global parkinsonian score (range: 0-100). MIND, Mediterranean, and DASH diet pattern scores were computed based on a validated food frequency questionnaire including 144 food items. We employed Cox-Proportional Hazard models and linear mixed models, to examine the associations of baseline diet scores with incident parkinsonism and the annual rate of change in global parkinsonian score, respectively. RESULTS: In models adjusted for age, sex, smoking, total energy intake, BMI and depressive symptoms, higher MIND diet scores were associated with a decreased risk of parkinsonism [(HR=0.89, 95% CI 0.83-0.96)]; and a slower rate of parkinsonism progression [(ß= -0.008; SE=0.0037; p=0.04)]. The Mediterranean diet was marginally associated with reduced parkinsonism progression (ß= -0.002; SE=0.0014; p=0.06). The DASH diet, by contrast, was not associated with either outcome. CONCLUSION: The MIND diet created for brain health may be a associated with decreased risk and slower progression of parkinsonism in older adults.

Mediterranean diet and depressive symptoms among older adults over time.

OBJECTIVE: To examine whether adherence to a Mediterranean-based dietary pattern is predictive of depressive symptoms among older adults. DESIGN: Generalized estimating equation models were used to test the association between a Mediterranean-based dietary pattern and depressive symptoms over time. Models were adjusted for age, sex, race, education, income, widowhood, antidepressant use, total calorie intake, body mass index, smoking, alcohol consumption, number of self-reported medical conditions, cognitive function, and physical disability. SETTING: Chicago, Illinois. PARTICIPANTS: Community-dwelling participants (n=3502) of the Chicago Health and Aging Project aged 65+ years (59% African American) who had no evidence of depression at the baseline. MEASUREMENTS: Adherence to a Mediterranean-based dietary pattern was assessed by the MedDietScore. Dietary evaluation was performed with a food frequency questionnaire at baseline and related to incident depression as measured by the presence of four or more depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale. RESULTS: Over an average follow-up of 7.2 years, greater adherence to a Mediterranean-based diet was associated with a reduced number of newly occurring depressive symptoms (parameter estimate = -0.002, standard error = 0.001; p = 0.04). The annual rate of developing depressive symptoms was 98.6% lower among persons in the highest tertile of a Mediterranean-based dietary pattern compared with persons in the lowest tertile group. CONCLUSION: Our results support the hypothesis that adherence to a diet comprised of vegetables, fruits, whole grains, fish, and legumes may protect against the development of depressive symptoms in older age.

Cognitive reserve, presynaptic proteins and dementia in the elderly.

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination.

OBJECTIVE: To investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally. METHODS: In 121 community-dwelling participants of the Chicago Health and Aging Project, serum markers of vitamin B12 status were related to summary measures of neuropsychological tests of 5 cognitive domains and brain MRI measures obtained on average 4.6 years later among 121 older adults. RESULTS: Concentrations of all vitamin B12-related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume. CONCLUSIONS: Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.

Experience of laparoscopic incisional hernia repair in kidney and/or pancreas transplant recipients.

Despite the wide popularity of laparoscopic incisional hernia repair (LIHR) in the nontransplant population, there are very few reports of LIHR available in abdominal organ transplant patients and none exclusively on kidney and/or pancreas (KP) transplant patients. We retrospectively reviewed a consecutive series of LIHR in KP transplant recipients performed over a period of 4 years and compared the results with LIHR in non-transplant patients during the same period. A total of 36 transplant patients were compared with 62 nontransplant patients. There were five patients converted to the open procedure in the transplant and four in nontransplant patients (p-NS). There were three seromas and one patient had a bowel perforation in the transplant group versus eight seromas, one bowel perforation and one small bowel obstruction noted in the nontransplant group. One patient in each group had a mesh infection requiring explant. Patients were followed up for a mean period of 2.2 years in the transplant group and 3 years in the nontransplant group. Overall there were five recurrences in the transplant group and four in the nontransplant group (p = NS). These results suggest that that LIHR is a safe and effective alternative to open repair.

The role of nutrition in Alzheimer's disease: epidemiological evidence.

The prevalence of Alzheimer's disease (AD) increases exponentially with age but there is limited knowledge of the modifiable risk factors for AD. However, there is growing evidence for possible dietary risk factors in the development of AD and cognitive decline with age, such as antioxidant nutrients, fish, dietary fats, and B-vitamins. Numerous animal and laboratory studies have shown that antioxidant nutrients can protect the brain from oxidative and inflammatory damage, but there are limited data available from epidemiological studies. There is more substantial epidemiological evidence from a number of recent studies that demonstrate a protective role of omega-3 fatty acids, such as docosahexaenoic acid, in AD and cognitive decline. This review will focus on epidemiological evidence investigating the relationship between nutrition and AD, focusing particularly on the roles of dietary fats and antioxidants.

Enhanced 'Reading the Mind in the Eyes' in borderline personality disorder compared to healthy controls.

BACKGROUND: Borderline personality disorder (BPD) is partly characterized by chronic instability in interpersonal relationships, which exacerbates other symptom dimensions of the disorder and can interfere with treatment engagement. Facial emotion recognition paradigms have been used to investigate the bases of interpersonal impairments in BPD, yielding mixed results. We sought to clarify and extend past findings by using the Reading the Mind in the Eyes Test (RMET), a measure of the capacity to discriminate the mental state of others from expressions in the eye region of the face. METHOD: Thirty individuals diagnosed with BPD were compared to 25 healthy controls (HCs) on RMET performance. Participants were also assessed for depression severity, emotional state at the time of assessment, history of childhood abuse, and other Axis I and personality disorders (PDs). RESULTS: The BPD group performed significantly better than the HC group on the RMET, particularly for the Total Score and Neutral emotional valences. Effect sizes were in the large range for the Total Score and for Neutral RMET performance. The results could not be accounted for by demographics, co-occurring Axis I or II conditions, medication status, abuse history, or emotional state. However, depression severity partially mediated the relationship between RMET and BPD status. CONCLUSIONS: Mental state discrimination based on the eye region of the face is enhanced in BPD. An enhanced sensitivity to the mental states of others may be a basis for the social impairments in BPD.

Body mass index and cognitive decline in a biracial community population.

OBJECTIVE: To examine whether a higher body mass index (BMI) in older adults is associated with greater cognitive decline. METHODS: A longitudinal study was conducted from 1993 to 2003 with an average follow-up of 6.4 years of a biracial community population on the south side of Chicago. Participants were 3,885 community-dwelling adults aged 65 and older who participated in at least two assessments. A composite measure of global cognitive function was used which was derived from the average of standardized scores from four cognitive tests. RESULTS: There was a significant curvilinear association between BMI and cognitive function scores at baseline for both black (= -0.0014, p = 0.001) and non-black subjects (= -0.0011, p = 0.002). In a mixed model adjusted for age, sex, race, and education, higher BMI was associated with less cognitive decline in both black (= 0.0013, p = 0.009) and non-black subjects (= 0.0021, p = 0.006). Adjusting for comorbid illnesses did not change these findings substantially. However, the associations were much smaller and no longer significant among participants with no cognitive decline at baseline as measured by a Mini-Mental State Examination score of greater than 24. CONCLUSIONS: The findings suggest that greater body mass index in old age is not predictive of cognitive decline in a cognitively unimpaired community population.

IANA task force on nutrition and cognitive decline with aging.

Cognitive impairment can be influenced by a number of factors. The potential effect of nutrition has become a topic of increasing scientific and public interest. In particular, there are arguments that nutrients (food and/or supplements) such as vitamins, trace minerals, lipids, can affect the risk of cognitive decline and dementia, especially in frail elderly people at risk of deficiencies. Our objective in this paper is to review data relating diet to risk of cognitive decline and dementia, especially Alzheimer's disease (AD). We chose to focus our statements on homocysteine-related vitamins (B-vitamins), antioxidant nutrients (vitamins E and C, carotenoids, flavonoids, enzymatic cofactors) and dietary lipids. Results of epidemiological studies may sometimes appeared conflicting; however, certain associations are frequently found. High intake of saturated and trans-unsaturated (hydrogenated) fats were positively associated with increased risk of AD, whereas intake of polyunsaturated and monounsaturated fats were protective against cognitive decline in the elderly in prospective studies. Fish consumption has been associated with lower risk of AD in longitudinal cohort studies. Moreover, epidemiologic data suggest a protective role of the B-vitamins, especially vitamins B9 and B12, on cognitive decline and dementia. Finally, the results on antioxidant nutrients may suggest the importance of having a balanced combination of several antioxidant nutrients to exert a significant effect on the prevention of cognitive decline and dementia, while taking into account the potential adverse effects of these nutrients. There is no lack of attractive hypotheses to support research on the relationships between nutrition and cognitive decline. It is important to stress the need to develop further prospective studies of sufficiently long duration, including subjects whose diet is monitored at a sufficiently early stage or at least before disease or cognitive decline exist. Meta analyses should be developed, and on the basis of their results the most appropriate interventional studies can be planned. These studies must control for the greatest number of known confounding factors and take into account the impact of the standard social determinants of food habits, such as the regional cultures, social status, and educational level.

Cognitive ability is associated with suspected reporting errors on food frequency questionnaires.

OBJECTIVE: To examine potential for bias in reported total energy intake on a Food Frequency Questionnaire (FFQ) among older adults. DESIGN: Longitudinal cohort study. SUBJECTS/SETTING: 2,706 Community-dwelling Black and White older adults, aged 70-79 years, enrolled in the Health, Aging, and Body Composition study. Multivariate logistic regression analyses were conducted with potential errors on reported total energy intake on the Food Frequency Questionnaire (FFQ) as the outcome variable and with cognitive ability, measured by the Modified Mini Mental State Exam (3MS) as the primary independent variable. The regression model controlled for site, race, gender, age, body size, and physical activity. Separate models were fit using 3MS as a continuous variable and for multiple 3MS cutpoints. All models revealed similar findings. RESULTS: Cognitive ability was inversely associated with potential errors in reporting total energy intake, whereby a five-point increase in 3MS scores was associated with a 14% decreased likelihood of reporting errors (Odds Ratio=0.86, 95% Confidence Interval: 0.77, 0.95). Additionally, compared to White women, White men were 2 times more likely, and Black women and Black men were 3 times more likely, to have errors in reporting total energy intake. CONCLUSION: This study provides evidence that for older adults, lower cognition scores are associated with increased potential errors in reporting total energy intake. APPLICATIONS: Dietary reporting from older adults may be inaccurate due to cognitive deficits. A brief assessment of cognitive function may assist clinicians in dietary evaluations and recommendation and may benefit studies using FFQ data where the measure of cognitive function could be utilized to stratify data analyses and conduct sensitivity analyses.

A non-covalent peptide-based strategy for siRNA delivery.

The major obstacle to clinical development of siRNAs (short interfering RNAs), like for most of the nucleic-acid-based strategies, is their poor cellular uptake and bioavailability. Although several viral and non-viral strategies have been proposed to improve siRNA delivery, their applications in vivo remain a major challenge. We have developed a new strategy, based on a short amphipathic peptide, MPG, that is able to form stable nanoparticles with siRNA. MPG-based particles enter the cell independently of the endosomal pathway and can efficiently deliver siRNA in a fully biologically active form into a variety of cell lines and in vivo. This short review will discuss the mechanism and the potency of the MPG strategy for siRNA delivery both in vitro and in vivo.

Associations of vegetable and fruit consumption with age-related cognitive change.

OBJECTIVE: To examine the association between rates of cognitive change and dietary consumption of fruits and vegetables among older persons. METHODS: The authors conducted a prospective cohort study of 3,718 participants, aged 65 years and older of the Chicago Health and Aging Project. Participants completed a food frequency questionnaire and were administered at least two of three cognitive assessments at baseline, 3-year, and 6-year follow-ups. Cognitive function was measured using the average z-score of four tests: the East Boston Tests of immediate memory and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: The mean cognitive score at baseline for the analyzed cohort was 0.18 (range: -3.5 to 1.6), and the overall mean change in score per year was a decline of 0.04 standardized units. In mixed effects models adjusted for age, sex, race, and education, compared with the rate of cognitive decline among persons in the lowest quintile of vegetable intake (median of 0.9 servings/day), the rate for persons in the fourth quintile (median, 2.8 servings/day) was slower by 0.019 standardized units per year (p = 0.01), a 40% decrease, and by 0.018 standardized units per year (p = 0.02) for the fifth quintile (median, 4.1 servings/day), or a 38% decrease in rates. The association remained significant (p for linear trend = 0.02) with further control of cardiovascular-related conditions and risk factors. Fruit consumption was not associated with cognitive change. CONCLUSION: High vegetable but not fruit consumption may be associated with slower rate of cognitive decline with older age.

Cell-penetrating peptides: tools for intracellular delivery of therapeutics.

The main problem of therapeutic efficiency lies in the crossing of cellular membranes. Therefore, significant effort is being made to develop agents which can cross these barriers and deliver therapeutic agents into cellular compartments. In recent years, a large amount of data on the use of peptides as delivery agents has accumulated. Several groups have published the first positive results using peptides for the delivery of therapeutic agents in relevant animal models. These peptides, called cell-penetrating peptides (CPPs), are short peptides (fewer than 30 residues) with a net positive charge and acting in a receptor- and energy-independent manner. Here, we give an extensive review of peptide-mediated delivery systems and discuss their applications, with particular focus on the mechanisms leading to cellular internalization.

Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline.

BACKGROUND: Dementia can be caused by severe niacin insufficiency, but it is unknown whether variation in intake of niacin in the usual diet is linked to neurodegenerative decline. We examined whether dietary intake of niacin was associated with incident Alzheimer's disease (AD) and cognitive decline in a large, prospective study. METHODS: This study was conducted in 1993-2002 in a geographically defined Chicago community of 6158 residents aged 65 years and older. Nutrient intake was determined by food frequency questionnaire. Four cognitive tests were administered to all study participants at 3 year intervals in a 6 year follow up. A total of 3718 participants had dietary data and at least two cognitive assessments for analyses of cognitive change over a median 5.5 years. Clinical evaluations were performed on a stratified random sample of 815 participants initially unaffected by AD, and 131 participants were diagnosed with 4 year incident AD by standardised criteria. RESULTS: Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (beta = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (beta = 0.023 SU/year; p = 0.02), or those with fewer than 12 years' education (beta = 0.035 SU/year; p = 0.002) CONCLUSION: Dietary niacin may protect against AD and age related cognitive decline.

Blood pressure and late-life cognitive function change: a biracial longitudinal population study.

OBJECTIVE: To examine the relation of blood pressure (BP) to subsequent decline in cognitive function among persons age 65 or over. METHODS: All persons age 65 or over in a geographically defined community were invited to participate in a longitudinal study of problems of the elderly. Interviews were conducted in the participants' homes and included two BP measures and four tests of cognitive function. Follow-up interviews 3 and 6 years after baseline repeated the cognitive function tests. These analyses included 4,284 individuals who had baseline and at least one follow-up measure of cognitive function. The average of z scores of the individual cognitive function tests was used as a global measure of cognitive function. RESULTS: In random effects analyses controlling for age, sex, education, and race, there was no significant linear association of either systolic or diastolic BP with 6-year change in global cognitive function score. There was no significant curvilinear association with systolic BP. In tests for a curvilinear association with diastolic BP, there was a suggestion of increased decline among those with low or high diastolic BP (p = 0.03 for the quadratic diastolic term). At baseline, 50% of participants took some type of medication affecting BP. CONCLUSION: In this community population where BP treatment was common, there was no association of either high systolic or high diastolic BP at the beginning of the observation interval with 6-year cognitive decline.

Dietary fat intake and 6-year cognitive change in an older biracial community population.

OBJECTIVE: To examine whether consumption of different types of fat is associated with age-related change in cognition. METHODS: The authors related fat consumption to 6-year change in cognitive function among 2,560 participants of the Chicago Health and Aging Project, ages 65 and older, with no history of heart attack, stroke, or diabetes at baseline. Fat intake was measured by food frequency questionnaire. Cognitive function was measured at baseline and 3-year and 6-year follow-ups, using the average z score of four cognitive tests: the East Boston Tests of Immediate and Delayed Recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: In separate mixed models adjusted for demographic and cardiovascular risk factors and intakes of antioxidant nutrients and other dietary fats, higher intakes of saturated fat (p for trend = 0.04) and trans-unsaturated fat (p for trend = 0.07) were linearly associated with greater decline in cognitive score over 6 years. These associations became stronger in analyses that eliminated persons whose fat intake changed in recent years or whose baseline cognitive scores were in the lowest 15%. Inverse associations with cognitive decline were observed in these latter restricted analyses for high intake of monounsaturated fat and a high ratio of polyunsaturated to saturated fat intake. Intakes of total fat, vegetable and animal fats, and cholesterol were not associated with cognitive change. CONCLUSION: A diet high in saturated or trans-unsaturated fat or low in nonhydrogenated unsaturated fats may be associated with cognitive decline among older persons.

Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression.

The design of potent systems for the delivery of charged and noncharged molecules that target genes of interest remains a challenge. We describe a novel technology that combines a new generation of peptide nucleic acids (PNAs), or HypNA-pPNAs, with a new noncovalent peptide-based delivery system, Pep-2, which promotes efficient delivery of PNAs into several cell lines. We have validated the potential of this technology by showing that Pep2-mediated delivery of an antisense HypNA-pPNA chimera directed specifically against cyclin B1 induces rapid and robust downregulation of its protein levels and efficiently blocks cell cycle progression of several cell lines, as well as proliferation of cells derived from a breast cancer. Pep-2-based delivery system was shown to be 100-fold more efficient in delivering HypNA-pPNAs than classical cationic lipid-based methods. Whereas Pep-2 is essential for improving the bioavailability of PNAs and HypNA-pPNAs, the latter contribute significantly to the efficiency and specificity of the biological response. We have found that Pep-2/HypNA-pPNA strategy promotes potent antisense effects, which are approximately 25-fold greater than with classical antisense oligonucleotide directed specifically against the same cyclin B1 target. Taken together, these data demonstrate that peptide-mediated delivery of HypNA-pPNAs constitutes a very promising technology for therapeutic applications.

Noncompliance after kidney transplantation: a systematic review.

We performed a systematic review of the literature on medical noncompliance after kidney transplantation in the cyclosporine era. We wished to define commonalities that may help the clinician identify patients for early intervention. We found that patients who were at a higher risk of noncompliance after kidney transplants were younger, female, unmarried, and non-Caucasians. Patients who were recipients of living donor transplants and had been transplanted for a longer time with a history of a previous transplant were also at risk of noncompliance. We also found that patients displaying emotional problems, such as anxiety, hostility, depression, distress, lack of coping, and avoidant behaviors, were also at risk for noncompliance after kidney transplantation.