Differential bud activation by a net positive root signal explains branching phenotype in prostrate clonal herbs: a model.

Regulation of branching within perennial prostrate clonal herbs differs from the annual orthotropic species, Arabidopsis and pea, as the dominant signal transported from roots is a branching promoter, not an inhibitor. Trifolium repens, an exemplar of such prostrate species, was used to investigate the interaction between roots and branch development. This study tests whether or not current knowledge when synthesized into a predictive model is sufficient to simulate the branching pattern developing on the shoot distal to a basal root. The major concepts underpinning the model are: (i) bud outgrowth (activation) is stimulated in a dose-dependent manner by branching promoter signals from roots, (ii) the distribution of this net root stimulus (NRS) is uniform throughout the shoot system distal to the basal root but declines geometrically in intensity upon continued enlargement of this shoot system, and (iii) each bud has an outgrowth potential, equal to the activation level of the apical bud in which it forms, that moderates its response to NRS. The validity of these concepts was further tested by running simulations of the branching of a phylogenetically-distanced prostrate perennial monocotyledonous species, Tradescantia fluminensis. For both species the model reasonably accounted for the observed pattern of branching. The outgrowth potential of buds plays an important role in limiting the number of hierarchies of branching that can develop on a plant. In conclusion, for both species, the model accounted for the major factors involved in the correlative regulation of branching and is possibly also pertinent for all prostrate clonal species.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

A grid overlay framework for analysis of medical images and its application to the measurement of stroke lesions.

OBJECTIVES: To create and evaluate an interactive software tool for measuring imaging data in situations where hand-drawn region-of-interest measurements are unfeasible, for example, when the structure of interest is patchy with ill-defined boundaries. METHODS: An interactive grid overlay software tool was implemented that enabled coding of voxels dependent on their imaging appearance with a series of user-defined classes. The Grid Analysis Tool (GAT) was designed to automatically extract quantitative imaging data, grouping the results by tissue class. Inter- and intra-observer reproducibility was evaluated by six observers of various backgrounds in a study of acute stroke patients. RESULTS: The software tool enabled a more detailed classification of the stroke lesion than would be possible with a region-of-interest approach. However, inter-observer coefficients of variation (CVs) were relatively high, reaching 70% in "possibly abnormal" tissue and around 15-20% in normal appearing tissues, while intra-observer CVs were no more than 13% in "possibly abnormal" tissue and generally less than 1% in normal-appearing tissues. CONCLUSIONS: The grid-overlay method overcomes some of the limitations of conventional Region Of Interest (ROI) approaches, providing a viable alternative for segmenting patchy lesions with ill-defined boundaries, but care is required to ensure acceptable reproducibility if the method is applied by multiple observers. KEY POINTS: Computer software developed to overcome limitations of conventional regions of interest measurements • This software is suitable for patchy lesions with ill-defined borders • Allows a more detailed assessment of imaging data.

Existing branches correlatively inhibit further branching in Trifolium repens: possible mechanisms.

In Trifolium repens removal of any number of existing branches distal to a nodal root stimulates development of axillary buds further along the stem such that the complement of branches distal to a nodal root remains constant. This study aimed to assess possible mechanisms by which existing branches correlatively inhibit the outgrowth of axillary buds distal to them. Treatments were applied to basal branches to evaluate the roles of three postulated inhibitory mechanisms: (I) the transport of a phloem-mobile inhibitory feedback signal from branches into the main stem; (II) the polar flow of auxin from branches into the main stem acting to limit further branch development; or (III) the basal branches functioning as sinks for a net root-derived stimulatory signal (NRS). Results showed that transport of auxin, or of a non-auxin phloem-mobile signal, from basal branches did not influence regulation of correlative inhibition and were consistent with the possibility that the intra-plant distribution of NRS could be involved in the correlative inhibition of distal buds by basal branches. This study supports existing evidence that regulation of branching in T. repens is dominated by a root-derived stimulatory signal, initially distributed via the xylem, the characterization of which will progress the generic understanding of branching regulation.

Predominant time scales in fission processes in reactions of S, Ti and Ni with W: zeptosecond versus attosecond.

The inhibition of fusion by quasifission is crucial in limiting the formation of superheavy elements in collisions of heavy nuclei. Time scales of ∼10(-18) s inferred for fissionlike events from recent crystal blocking measurements were interpreted to show either that quasifission itself is slower than previously believed, or that the fraction of slow fusion-fission is higher than expected. New measurements of mass-angle distributions for (48)Ti and (64)Ni bombarding W targets show that in these reactions quasifission is the dominant process, typically occurring before the system formed after contact has made a single rotation, corresponding to time scales of ≤10(-20) s.

Low energy proton beam induces efficient cell killing in A549 lung adenocarcinoma cells.

The aim of the current study was to determine the signaling differences between gamma- and proton beam-irradiations. A549 lung adenocarcinoma cells were irradiated with 2 Gy proton beam or gamma-radiation. Proton beam was found to be more cytotoxic than gamma-radiation. Proton beam-irradiated cells showed phosphorylation of H2AX, ATM, Chk2, and p53. The mechanism of excessive cell killing in proton beam-irradiated cells was found to be upregulation of Bax and downregulation of Bcl-2. The noteworthy finding of this study is the biphasic activation of the sensor proteins, ATM, and DNA-PK and no activation of ATR by proton irradiation.

Axillary bud outgrowth potential is determined by parent apical bud activity.

Axillary buds within a plant shoot system are known to differ in their ability to respond to treatments favouring their development. This ability is referred to as their outgrowth potential. Using two species of prostrate nodally-rooting herbs, dicotyledonous Trifolium repens and monocotyledonous Tradescantia fluminensis, grown throughout in a strictly vegetative state, this study tested two hypotheses. Hypothesis 1: that each axillary bud exhibits an outgrowth potential that is directly related to the growth rate of its parent apical bud, and Hypothesis 2: that the growth rate attained by an axillary bud depends upon both its outgrowth potential and the local supply of stimulatory root-derived signal (NRS) available to it. Activation levels (growth rates) of apical buds were varied by differential exposure to nodal roots and the outgrowth responses of axillary buds recently emerged from them were then measured under standardized conditions of NRS supply. Hypothesis 1 was shown to be correct for both species. Hypothesis 2, tested only in T. repens, was supported by results showing that an axillary bud's outgrowth potential and the NRS supply to it each independently influenced its growth rate, there being no significant interaction between the two. These results emphasize the significant role the physiological state/activity of apical buds has on the outgrowth potential of axillary buds formed within them. The fact that similar relationships were observed on axillary buds on stems of differing developmental maturity and branching hierarchy, and in two taxonomically diverse species, suggests they might be widespread among morphologically similar species.

Regulation of shoot branching patterns by the basal root system: towards a predictive model.

This study aimed to underpin the development of a generic predictive model of the regulation of shoot branching by roots in nodally rooting perennial prostrate-stemmed species using knowledge gained from physiological studies of Trifolium repens. Experiment 1 demonstrated that the net stimulatory influence from the basal rooted region of the plant on growth of newly emerging axillary buds on the primary stem decreased as their phytomeric distance from the basal root system increased. Experiment 2 found that at any one time the distribution of net root stimulus (NRS) to the apical bud on the primary stem and all lateral branches was fairly uniform within a single plant. Thus, although NRS availability was uniform throughout the shoot system at any point in time, it progressively decreased as shoot apical buds grew away from the basal root system. Based on these findings, a preliminary predictive model of the physiological regulation of branching pattern was developed. This model can explain the decline in growth rate of buds on a primary stem as it grows away from its basal root system but not the rapid progressive decline in secondary branch development on successive lateral branches. Thus knowledge of NRS availability to emerging buds is not, by itself, a sufficient basis from which to construct a predictive model. In addition, it seems that the ability of an emerging bud to become activated in response to its local NRS availability is, at least in part, directly influenced by the activation level of its parent apical bud. The experimental testing of this hypothesis, required for continued development of the model, is proceeding.

Do patients with p16-positive oropharyngeal squamous cell carcinoma get more bone metastasis than p16-negative patients?

BACKGROUND: Oropharyngeal squamous cell carcinoma is thought to rarely metastasise to bone. This study hypothesised that in p16-positive disease there is a significant incidence of bony metastasis. METHODS: This was an ambispective cohort review. All patients with oropharyngeal squamous cell carcinoma diagnosed and treated at one centre were included. RESULTS: A total of 180 consecutive patients were identified over 5 years. Fifteen patients were excluded because of lack of p16 status, none of whom had bony metastasis. The final analysis included 165 patients: 48 (29.09 per cent) in the p16-negative group and 117 (70.91 per cent) in the p16-positive group. Ten patients (8.55 per cent) in the p16-positive group developed bony metastasis, compared with zero in the p16-negative group; this difference was statistically significant (p = 0.036). CONCLUSION: Expression of p16 was associated with an increased incidence in bony metastasis in this cohort. This is the first study to explore this specific question.

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Simple Single-Pass Technique for Ultrathin Descemet Stripping Automated Endothelial Keratoplasty: A Pilot Study.

PURPOSE: To assess intraoperative and postoperative graft thickness (GT) after donor deturgescence for ultrathin Descemet stripping automated endothelial keratoplasty and to evaluate visual outcomes, endothelial cell density, and patient satisfaction at 1 year. METHODS: Prospective interventional case series of patients with Fuchs endothelial dystrophy, Fuchs endothelial dystrophy and cataract, and pseudophakic bullous keratopathy (n = 12 grafts). The donor cornea was allowed to thin out by simple evaporation on an artificial anterior chamber, to the required precut thickness, before a single microkeratome pass. GT after microkeratome cut, at 1 week, 1, 3, 6, and 12, months was measured. Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity, Pelli-Robson contrast sensitivity, endothelial cell density, and score on the visual function questionnaire (VFQ-25) were assessed. RESULTS: Mean intraoperative postmicrokeratome cut GT was 78.9 ± 33.3 µm. Mean GT at 1 week, 1, 3, 6, and 12 months was 70.7, 70.9, 62.8, 66.5, and 58.9 µm, respectively. Mean initial donor corneal thickness was 647 ± 67 µm, and mean precut thickness was 526 ± 4.5 µm (mean thinning time: 17 min). Best-corrected visual acuity at 1 week, 1, 3, 6, and 12 months was 68.8, 76.9, 76.3, 76.9, and 78.6 letters with 9-letter gain at 12 months (P = 0.02). Mean endothelial cell loss at 3, 6, and 12 months was 36.8% ± 6.75%, 37.2% ± 8%, and 37.9% ± 9.75% loss, respectively. At 1 year, 83.3% of patients achieved ≥20/40 (6/12) and 66.7% of patients achieved ≥20/32 (6/9.5). VFQ-25 testing showed an improvement in the visual function. CONCLUSIONS: This pilot study demonstrates a simple graft deturgescence technique that reproducibly creates ultrathin grafts without donor wastage.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Gonadal dysfunction in diabetic men with organic impotence.

Previous studies of the relationship of gonadal function to impotence in men with diabetes mellitus have yielded conflicting results. Pituitary-testicular function was studied in 28 impotent diabetic men and 15 normal men. Impotence was documented by clinical history and subdivided into categories of primary organic (n = 16), primary psychogenic (n = 7), and unclassified (n = 5) on the basis of nocturnal penile tumescence (NPT) testing, psychological testing, and penile vascular studies. All NPT parameters were diminished (P less than or equal to 0.001) in the impotent diabetic men compared to values in the normal men. Endocrine studies revealed increased urinary LH (P less than or equal to 0.05) and diminished serum free testosterone levels in the diabetic men with primary organic impotence. These changes were not found in normal men or diabetic men with primary psychogenic impotence. Six months of treatment in a home blood glucose-monitoring program resulted in significant improvement in metabolic control but no improvement in pituitary-testicular function, NPT, or sexual performance in the primary organic impotent group. Eight patients with primary organic impotence and no evidence of penile vascular disease had significant improvement (P less than or equal to 0.01) in NPT results as well as subjective improvement in sexual function after 6 months of parenteral testosterone administration. These studies suggest that primary gonadal dysfunction may be related to organic impotence in diabetes, and improvement in selected patients can occur with androgen therapy.

Sources of variation in energy intake by men and women as determined from one year's daily dietary records.

Data from a year-long study conducted by the US Department of Agriculture's Beltsville Human Nutrition Research Center were used to identify sources of variation in daily energy intakes. A specific hypothesis was that an inverse relationship exists between past body weight and future energy intake whereas a direct relationship exists between past energy intake and future weight. Daily energy intakes of 29 male (n = 13) and female (n = 16) adult subjects were related through linear-regression analysis to sex (+ for males), age (-), height (+), weight (- for past and present measurements, + for future measurement), data collection method (- for duplicate plate), day of week (+ for Friday and Saturday), and month (+ for May, July, August, December, and January). These relationships were statistically significant (p less than 0.05). The results confirmed the hypothesis and were in general agreement with previously published studies that used larger samples but fewer days of data.

Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease.

The presence of the APOE epsilon 4 allele encoding apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset Alzheimer's disease (AD). However, the molecular and cellular mechanisms by which APOE epsilon 4 renders AD risk are unclear. In this report, we present genetic evidence that an apoE receptor, LRP, may be associated with the expression of late-onset AD. Using a biallelic genetic marker in exon 3 of LRP, late-onset AD cases markedly differed from the control subjects in the distribution of LRP genotypes, and this difference was highly accentuated among AD cases with positive family history of senile dementia. Furthermore, the numbers of neutritic plaques were significantly altered as a consequence of different LRP genotypes in postmortem AD cases. Taken together, our results implicate the pathophysiology of LRP in the expression of late-onset AD.

ApoE and CYP2D6 polymorphism with and without parkinsonism-dementia complex in the people of Chamorro, guam.

Parkinsonism-dementia complex (PDC), a neurodegenerative disorder in the Chamorro, Guam population, has been epidemiologically ascribed to the ingestion of the neurotoxin cycasin. This disease is characterized neuropathologically by the presence of abundant neurofibrillary tangles (NFTs). We analyzed a genetic risk factor of Alzheimer's disease (AD), apolipoprotein E, hypothesized to be linked to NFT formation, and a genetic risk factor of Parkinson's disease (PD), CYP2D6 mutation, linked to slower metabolism of exogenous toxins, in Chamorro, Guam individuals with and without PDC. The representation of the G-to-C mutation in exon 9 of the CYP2D6 gene was higher in Chamorro and Filipino than in Caucasian individuals, but this mutant allele had similar high frequencies in both PDC patients and healthy Chamorro individuals. We found no alleles of these genes associated with AD or PD to be overrepresented among those with PDC.

Alzheimer's disease can be accurately diagnosed in very mildly impaired individuals.

BACKGROUND: The growing propensity to diagnose AD in individuals with very mild cognitive impairment increases the danger of false-positive diagnostic errors. Unfortunately, there is little systematically acquired information about the accuracy of the AD diagnosis in very mildly impaired patients. OBJECTIVE: To determine the accuracy of the diagnosis of AD in very mildly impaired patients and to identify objective measures that effectively distinguish these patients from elderly normal controls (NC). METHODS: Consecutive patients with Mini-Mental State Examination scores of > or = 24 who received a clinical diagnosis of AD were evaluated annually for at least 3 years. The initial diagnosis was verified or refuted by autopsy or by information obtained in subsequent evaluations. Initial neuropsychological test scores of verified AD patients were compared with those of NC subjects to identify effective diagnostic measures. RESULTS: The diagnosis of AD was confirmed in 98 of 110 (89%) very mildly impaired patients (33/36 by autopsy, 65/74 by disease progression). The diagnosis was inaccurate in 12 patients (11%): Seven were subsequently diagnosed with other neurologic disorders, and five were ultimately found to be normal. Neuropsychological measures of delayed recall, verbal fluency, and global cognitive status (i.e., Mattis Dementia Rating Scale) provided excellent sensitivity (> or = 96%) and specificity (> or = 93%) for differentiating between very mildly impaired AD patients and NC subjects. CONCLUSIONS: When comprehensive assessment procedures are employed, AD can be diagnosed with reasonably high accuracy in very mildly impaired individuals. However, the dementia evaluation should be repeated after approximately 1 year to ensure the accuracy of the initial diagnosis.

A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study.

BACKGROUND: Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD. METHODS: We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale. RESULTS: A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group. CONCLUSION: A low-dose regimen of prednisone is not useful in the treatment of AD.

Effects of apolipoprotein E on dementia and aging in the Shanghai Survey of Dementia.

We investigated the status of the apolipoprotein E allele in 538 participants in the incidence phase of the ongoing Shanghai Survey of Dementia, including 103 demented subjects, 72 with mild cognitive impairment and 363 cognitively normal. The apo E epsilon 4 allele was present in 10.2% of control subjects and the allelic frequency did not change between ages 60 to 96 years. The apo E epsilon 4 allelic frequency was increased both in those wiht Alzheimer's disease (AD) (25.4%) and those with vascular dementia (VaD) (22.2%), but not in those with other dementing illnesses or the cognitively impaired. All of the subjects homozygous for apo E epsilon 4 were demented, three were diagnosed as having AD, and three met NINDS/AIREN criteria for VaD. The increased apo E epsilon 4 allelic frequency in clinically diagnosed VaD patients suggests that some of the infarcts are secondary to congophilic angiopathy. The adjusted odds ratio of developing AD in this community-derived study for persons with at least one apo E epsilon 4 allele was 4.1 (95% CI: 2.2, 7.7). Thus, the apo E epsilon 4 risk of developing AD in this Chinese cohort is similar to that in western community studies.

Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease.

OBJECTIVE: To examine the genetic association of CYP2D6 locus with Lewy body variant (LBV) and Parkinson's disease (PD). METHODS: Allelic association was studied in patients with pure AD, LBV, and PD by using the CYP2D microsatellite, the (dG-dT)n dinucleotide repeat (n=16 to 27) located between CYP2D8P and CYP2D7 genes, and the CYP2D6 B and D mutations. RESULTS: We found overrepresentation of the alleles longer than 21 repeat (the long-type alleles) in LBV (allele frequency, 0.313) (odds ratio=1.99, p=0.019 by chi2 test) and in PD (0.298) (odds ratio=1.86, p=0.037), but not in pure AD (0.196), compared with the age-matched control (0.186). Strong association was noted of the long-type alleles with the CYP2D6 B mutation (odds ratio=88.50, p < 0.001 by Fisher's exact test), but not with the D mutation or the deletion of CYP2D6 gene. CONCLUSIONS: The CYP2D locus is closely associated with LBV and PD. The CYP2D6 B mutation may be involved in pathogenesis of LBV and PD in a dominant-negative manner, or in the linkage disequilibrium of the CYP2D microsatellite to another pathogenic gene locus.