Phenology of Honey Bee Swarm Departure in New Jersey, United States.

Departure of swarms from honey bee (Apis mellifera Linnaeus (Hymenoptera: Apidae)) nests is an important reproductive event for wild honey bee colonies and economically costly in managed bee colonies. The seasonal timing of swarm departure varies regionally and annually, creating challenges for honey bee management and emphasizing the potential for swarming behavior to be affected by plant-pollinator phenological mismatch. In this study, we first document variability in the timing of swarm departure across the large and heterogeneous geographical area of New Jersey over 4 years using 689 swarm-cluster observations. Second, hypothesizing that honey bee colonies adaptively tune the timing of swarm departure to match floral food-resource availability, we predicted that growing degree-days could be used to account for regional and annual variability. To test this idea, we used local weather records to determine the growing degree-day on which each swarm cluster was observed and tested for differences among climate regions and years. The state-wide mean swarm cluster date was May 15 (± 0.6 d), with moderate but significant differences among the state's five climate regions and between years. Use of degree-day information suggests that local heat accumulation can account for some climate-region differences in swarm-departure timing. Annual variation existed on a scale of only several days and was not accounted for by growing degree-days, suggesting little adaptive tuning of swarm-departure timing with respect to local heat accumulation.

NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT.

The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities.

What is the need for additional bladder surgery after bladder augmentation in childhood?

PURPOSE: Bladder augmentation has revolutionized the care of children with a neuropathic bladder but it remains a major surgical procedure. However, the need for subsequent bladder surgery has not been well defined in a large series with long-term followup. MATERIALS AND METHODS: We retrospectively reviewed the records of the first 500 bladder augmentations performed from 1978 to 2003 at our institution. Charts were reviewed for complications requiring additional surgery, including malignancy, bladder perforation, repeat augmentation, bowel obstruction and bladder calculi. Mean and median followup was 13.3 years. RESULTS: Complications occurred in 169 patients (34%) resulting in a total of 254 surgeries. The cumulative risk of further surgery at the bladder level was 0.04 operations per patient per year of augmentation. Three patients (0.6%) had transitional cell carcinoma, of whom all presented with metastatic disease and died. Bladder perforation occurred in 43 patients (8.6%) with a total of 53 events. Of the patients 16 (3.2%) required laparotomy for bowel obstruction and 47 (9.4%) required repeat augmentation. Bladder stones were treated in 75 patients (15%), who required a total of 125 surgeries. CONCLUSIONS: Bladder augmentation provides immeasurable improvements in quality of life but it requires lifelong dedication from the patient, family and health care providers. While the requirements for additional surgery are not trivial, 66% of our patients have not required any further surgery in the augmented bladder.

Hallucinations, cognitive decline, and death in Alzheimer's disease.

The relation of psychotic symptoms to cognitive decline and mortality in Alzheimer's disease (AD) was examined during a mean of 2.2 years in 478 persons selected from clinical settings. Psychotic symptoms were ascertained at baseline and cognition was assessed semiannually with nine tests from which a global measure was formed. In analyses that controlled for age, sex, race, and education, hallucinations (29.6%), especially visual ones, were associated with more rapid global cognitive decline and increased mortality, even after controlling for baseline level of cognition and use of antipsychotic medication, and the association with mortality increased with higher level of education. Delusions and misperceptions were not strongly related to cognitive decline or mortality. The results suggest that hallucinations in Alzheimer's disease, particularly visual ones, are associated with more rapid progression.

Influence of behavioral symptoms on rates of institutionalization for persons with Alzheimer's disease.

BACKGROUND: Recent studies indicate that behavioral symptoms may play a key role in decisions to institutionalize persons with Alzheimer's disease (AD), but the specific types of behavior that contribute to this increased risk have not been reliably identified. The relationship between behavioral symptoms and time to institutionalization was evaluated in a 4-year longitudinal study. METHOD: A total of 410 persons with the clinical diagnosis of AD completed annual clinical evaluations to assess cognitive impairment, functional limitations, delusions, hallucinations, depressive symptoms and physical aggression. Participation rates among survivors exceeded 90% for four follow-up evaluations with complete ascertainment of mortality and institutionalization. Time to institutionalization was evaluated using proportional hazards regression models in relation to time-varying clinical features. RESULTS: In multivariate models, adjusted for demographic and social variables, four clinical features emerged as the predominant predictors of institutionalization: cognitive impairment level, physical aggression, hallucinations and depressive symptoms. These associations were virtually unchanged in analyses controlling for mortality. CONCLUSIONS: Specific behavioral symptoms are important independent risk factors for institutionalization in persons with AD. Because behavioral symptoms are susceptible to therapy, efforts to modify or prevent these symptoms deserve careful consideration as a means to delay institutionalization for persons with this disease.

Education and the course of cognitive decline in Alzheimer disease.

OBJECTIVE: To test the hypothesis that higher level of education is related to more rapid cognitive decline in Alzheimer disease (AD). METHODS: Participants are older persons with clinically diagnosed AD recruited from health care facilities in the Chicago area. At 6-month intervals for up to 4 years, they underwent uniform structured clinical evaluations that included administration of nine cognitive performance tests from which a composite measure of global cognition was derived. Analyses are based on 494 persons with follow-up data (89.3% of those eligible). In mixed models that allowed for linear and nonlinear decline, the authors first accounted for the effects of age on cognition and then tested the relation of education to rate of cognitive decline. RESULTS: Global cognitive decline had linear and nonlinear components, resulting in a gradually accelerating course of decline. Age was related to linear but not nonlinear decline, with more rapid decline observed in younger compared with older persons. Higher educational level was related to more rapid global cognitive decline, as hypothesized, with education related to the nonlinear but not the linear component of decline. CONCLUSION: Higher educational attainment is associated with a slightly accelerated rate of cognitive decline in Alzheimer disease.

Premorbid proneness to distress and episodic memory impairment in Alzheimer's disease.

BACKGROUND: Chronic stress has been associated with impaired episodic memory, but the association of premorbidly experienced distress with memory function in Alzheimer's disease is unknown. OBJECTIVE: To investigate the link between proneness to distress and Alzheimer's disease. METHODS: Participants were 363 persons with clinically diagnosed Alzheimer's disease. At baseline, a knowledgeable informant rated each person's premorbid personality (that is, before dementia onset) along five dimensions, one of which was the tendency to experience psychological distress. Participants underwent structured clinical evaluations at baseline and then annually for up to four years. Each evaluation included 17 cognitive tests from which previously established measures of episodic memory, visuoconstruction, repetition, and naming were derived. RESULTS: In a series of random effects models adjusted for age, sex, and education, premorbid distress proneness was associated with baseline impairment in episodic memory but not with impairment in other cognitive domains, or with change in any cognitive domain. No other trait was related to baseline function or rate of decline in any cognitive domain. CONCLUSIONS: The results suggest that premorbid proneness to experience psychological distress is related to level of impairment in episodic memory in persons with Alzheimer's disease, but neither distress proneness nor other personality traits are related to disease progression.

Rate of cognitive decline and mortality in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with increased mortality, but survival in those with the disease varies widely. It is uncertain how much of the variation in survival is due to individual differences in rate of disease progression. METHODS: During a 4-year period, 354 persons with AD underwent annual clinical evaluations that included administration of 17 cognitive function tests, from which global and specific measures of cognitive function were derived. A growth curve approach was used to assess individual rates of cognitive decline and proportional hazards models adjusted for age, sex, and education to examine the associations of baseline level of cognition and rate of cognitive decline with mortality. RESULTS: During the 4-year study period, 242 persons survived and 112 died. At baseline, the global measure of cognition ranged from -1.68 to 1.36 (mean = 0.03, SD = 0.57), with higher scores indicating better function. Baseline level of cognition was not related to mortality (p = 0.12). Global cognition declined an average of 0.56 unit/year, with substantial heterogeneity (SD = 0.41). To determine mortality risk, persons were divided into quartiles based on rate of cognitive decline and survival contrasted in the quartile with the least decline with survival in each remaining quartile, adjusting for baseline level of cognition. Compared with those with the least decline, risk of death was increased more than threefold in the subgroup with mild decline, more than fivefold in those with moderately rapid decline, and more than eightfold in those with the most rapid decline. Similar results were found after controlling for baseline health and disability and in analyses using specific cognitive function measures. CONCLUSION: Mortality in AD is strongly associated with rate of cognitive decline.

DNA-PKcs is critical for telomere capping.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is critical for DNA repair via the nonhomologous end joining pathway. Previously, it was reported that bone marrow cells and spontaneously transformed fibroblasts from SCID (severe combined immunodeficiency) mice have defects in telomere maintenance. The genetically defective SCID mouse arose spontaneously from its parental strain CB17. One known genomic alteration in SCID mice is a truncation of the extreme carboxyl terminus of DNA-PKcs, but other as yet unidentified alterations may also exist. We have used a defined system, the DNA-PKcs knockout mouse, to investigate specifically the role DNA-PKcs specifically plays in telomere maintenance. We report that primary mouse embryonic fibroblasts (MEFs) and primary cultured kidney cells from 6-8 month-old DNA-PKcs-deficient mice accumulate a large number of telomere fusions, yet still retain wild-type telomere length. Thus, the phenotype of this defect separates the two-telomere related phenotypes, capping, and length maintenance. DNA-PKcs-deficient MEFs also exhibit elevated levels of chromosome fragments and breaks, which correlate with increased telomere fusions. Based on the high levels of telomere fusions observed in DNA-PKcs deficient cells, we conclude that DNA-PKcs plays an important capping role at the mammalian telomere.

Premorbid reading activity and patterns of cognitive decline in Alzheimer disease.

BACKGROUND: Educational and occupational attainment have been associated with progression of Alzheimer disease in some studies. One hypothesis about this association is that education and occupation are markers for lifelong participation in cognitively stimulating activities like reading. OBJECTIVE: To assess the relation of premorbid reading activity with patterns of cognitive decline in Alzheimer disease. METHODS: During a 4-year period, 410 persons with Alzheimer disease had annual clinical evaluations, which included administration of 17 cognitive function tests from which global, verbal, and nonverbal summary measures were derived. At baseline, a knowledgeable informant was questioned about the affected person's reading frequency and access to reading materials before dementia onset. RESULTS: A composite measure of premorbid reading activity was developed. It had moderately high internal consistency and was positively correlated with education and baseline level of cognitive function. In analyses that controlled for baseline cognitive function, education, and other demographic variables, higher level of premorbid reading activity was associated with more rapid decline on the global cognitive and verbal measures but not on the nonverbal measure. CONCLUSIONS: These results suggest that both the extent and nature of premorbid cognitive experiences may affect how Alzheimer disease pathology is clinically expressed.

Ku acts in a unique way at the mammalian telomere to prevent end joining.

Telomeres are specialized DNA/protein structures that act as protective caps to prevent end fusion events and to distinguish the chromosome ends from double-strand breaks. We report that TRF1 and Ku form a complex at the telomere. The Ku and TRF1 complex is a specific high-affinity interaction, as demonstrated by several in vitro methods, and exists in human cells as determined by coimmunoprecipitation experiments. Ku does not bind telomeric DNA directly but localizes to telomeric repeats via its interaction with TRF1. Primary mouse embryonic fibroblasts that are deficient for Ku80 accumulated a large percentage of telomere fusions, establishing that Ku plays a critical role in telomere capping in mammalian cells. We propose that Ku localizes to internal regions of the telomere via a high-affinity interaction with TRF1. Therefore, Ku acts in a unique way at the telomere to prevent end joining.

Decline of language among women and men with Alzheimer's disease.

Previous research raises the possibility that gender differences occur in language function in Alzheimer's disease, but this hypothesis has not been evaluated systematically in longitudinal studies. The authors examined the association of gender with rate of decline in language and other cognitive functions among 410 persons with Alzheimer's disease. Participants were recruited from a dementia clinic and followed for up to 5 annual evaluations. Follow-up participation among survivors exceeded 90%. Decline in a composite score based on 8 language tests was evaluated in random effects models with age, education, and race controlled. Annual decline was 0.71 standard units (95% confidence interval [CI] = 0.62-0.79) for women and 0.74 units (95% CI = 0.61-0.86) for men, not a significant difference. Decline on the individual language tests and on composite measures of memory, perception, and global cognition also indicated no significant association with gender. These results suggest that Alzheimer's disease affects language and other cognitive functions similarly in women and men.

Hallucinations, delusions, and cognitive decline in Alzheimer's disease.

OBJECTIVES: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline. METHODS: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses. RESULTS: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations. CONCLUSION: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease.

Progression of parkinsonism and loss of cognitive function in Alzheimer disease.

OBJECTIVE: To assess the relation between parkinsonism and cognitive function in Alzheimer disease from cross-sectional and longitudinal perspectives. DESIGN: Prospective cohort study with annual clinical evaluations during a 4-year period. SETTING: Alzheimer disease clinic in an urban medical center. PARTICIPANTS: Four hundred ten persons with clinically diagnosed Alzheimer disease. MAIN OUTCOME MEASURES: Global and specific measures of cognitive function and parkinsonism. RESULTS: Higher levels of parkinsonism at baseline were reliably associated with lower levels of cognitive function at baseline and with more rapid cognitive decline during the 4-year study period. However, the associations were small, with baseline parkinsonism accounting for less than 10% of the variation either in baseline cognitive function or in the rate of cognitive decline. By contrast, rates of change in parkinsonism and cognitive function were strongly correlated, with 70% or more shared variance in the rates of change in many models. The association was observed with diverse measures of cognition and parkinsonism and was not explained by demographic variables or use of neuroleptic medications. CONCLUSION: In Alzheimer disease, progressive worsening of parkinsonism is more strongly associated with cognitive decline than previously recognized. Arch Neurol. 2000.

Progression of parkinsonian signs in Alzheimer's disease.

OBJECTIVE: To describe the progression of parkinsonian signs in persons with AD. BACKGROUND: Parkinsonian signs are common in AD and appear to be related to morbidity and mortality. However, little is known about individual patterns of progression of parkinsonian signs. METHODS: A cohort of 410 people with clinically diagnosed AD underwent annual clinical evaluations over a 4-year period, with over 90% of survivors participating in follow-up. The entire motor portion of the Unified Parkinson's Disease Rating Scale (UPDRS) was administered at each evaluation. Previously established measures of four parkinsonian signs were derived from the UPDRS. Scores ranged from 0 to 100 and represented the percent obtained of the total possible item score. RESULTS: A growth curve approach was used to estimate individual paths of change. Rates of change in bradykinesia (4.5% increase per year), rigidity (6.0% increase per year), and gait disorder/postural reflex impairment (8.9% increase per year) were substantial and positively correlated (median r = 0.69). Change in tremor was minimal, mostly confined to postural tremor, and weakly correlated with change in other signs (median r = 0.16). The rate of progression in each sign was highly variable across individuals and not strongly related to demographic factors or use of neuroleptic medications. CONCLUSIONS: Parkinsonian signs other than tremor progress rapidly in AD but at widely differing rates.

Person-specific paths of cognitive decline in Alzheimer's disease and their relation to age.

Change in global and specific measures of cognitive function was studied in a cohort of 410 persons with Alzheimer's disease. Persons completed up to 5 annual evaluations; follow-up participation among survivors exceeded 90%. Average annual decline was 0.57 standard score units (95% confidence interval [CI]: -0.51 to -0.62) on a composite measure based on 17 individual tests and 3.26 points (95% CI: -3.06 to 3.46) on the Mini-Mental State Examination, but substantial heterogeneity was apparent. On both global and specific measures, rate of cognitive decline was reduced in older persons compared with younger persons. A similar effect was observed for estimated age of disease onset. The effect of age was approximately linear and was not attributable to education, sex, race, other conditions that impair cognition, or mortality. The results indicate that person-specific paths of cognitive decline in Alzheimer's disease vary substantially and suggest that in clinical settings some of this variability is related to age.

Ku is associated with the telomere in mammals.

Telomeres are specialized DNA/protein complexes that comprise the ends of eukaryotic chromosomes. The highly expressed Ku heterodimer, composed of 70 and 80 K(d) subunits (Ku70 and Ku80), is the high-affinity DNA binding component of the DNA-dependent protein kinase. Ku is critical for nonhomologous DNA double-stranded break repair and site-specific recombination of V(D)J gene segments. Ku also plays an important role in telomere maintenance in yeast. Herein, we report, using an in vivo crosslinking method, that human and hamster telomeric DNAs specifically coimmunoprecipitate with human Ku80 after crosslinking. Localization of Ku to the telomere does not depend on the DNA-dependent protein kinase catalytic component. These findings suggest a direct link between Ku and the telomere in mammalian cells.

Heat shielding: A novel method of colonial thermoregulation in honey bees.

Honey bees, Apis mellifera, maintain constant colony temperatures throughout the year. Honey bees fan their wings to cool the colony, and often spread fluid in conjunction with this behavior to induce evaporative cooling. We present an additional, previously undescribed mechanism used by the honey bee to maintain constant colony temperature in response to localized temperature increases. Worker bees shield the comb from external heat sources by positioning themselves on hot interior regions of the hive's walls. Although honey comb and brood comb were both shielded, the temperature-sensitive brood received a greater number of heat shielders and was thus better protected from overheating. Heat shielding appears to be a context-dependent adaptive behavior performed by worker bees who would previously have been considered "unemployed.

Cognitive activity in older persons from a geographically defined population.

Patterns of cognitive activity, and their relation to cognitive function, were examined in a geographically defined, biracial population of persons aged 65 years and older. Persons (N = 6,162) were given cognitive performance tests and interviewed about their participation in common cognitive activities, like reading a newspaper. Overall, more frequent participation in cognitive activities was associated with younger age, more education, higher family income, female gender, and White race; participation in activities judged to be more cognitively intense was not strongly related to age, but was associated with more education, higher family income, male gender, and White race. Substantial heterogeneity in activity patterns remained after accounting for demographic factors, however. In an analysis controlling for demographic variables, level of cognitive function on performance tests was positively related to composite measures of the frequency and intensity of cognitive activity. Longitudinal studies are needed to assess the relation of cognitive activity patterns to stability and change in cognitive function in older persons.