Social Mobility and Tooth Loss: A Systematic Review and Meta-analysis.

This study systematically reviews the evidence of the association between life course social mobility and tooth loss among middle-aged and older people. PubMed, Scopus, Embase, and Web of Science were systematically searched in addition to gray literature and contact with the authors. Data on tooth loss were collated for a 4-category social mobility variable (persistently high, upward or downward mobility, and persistently low) for studies with data on socioeconomic status (SES) before age 12 y and after age 30 y. Several study characteristics were extracted to investigate heterogeneity in a random effect meta-analysis. A total of 1,384 studies were identified and assessed for eligibility by reading titles and abstracts; 21 original articles were included, of which 18 provided sufficient data for a meta-analysis with 40 analytical data sets from 26 countries. In comparison with individuals with persistently high social mobility, the pooled odds ratios (ORs) for the other categories were as follows: upwardly mobile, OR = 1.73 (95% CI, 1.53 to 1.95); downwardly mobile, OR = 2.52 (95% CI, 2.19 to 2.90); and persistently low, OR = 3.96 (95% CI, 3.13 to 5.03). A high degree of heterogeneity was found(I2 > 78%), and subgroup analysis was performed with 17 study-level characteristics; however, none could explain heterogeneity consistently in these 3 social mobility categories. SES in childhood and adulthood is associated with tooth loss, but the high degree of heterogeneity prevented us from forming a robust conclusion on whether upwardly or downwardly mobile SES may be more detrimental. The large variability in effect size among the studies suggests that contextual factors may play an important role in explaining the difference in the effects of low SES in different life stages (PROSPERO CRD42018092427).

Midlife improvements in financial situation are associated with a reduced dementia risk later in life: the CAIDE 30-year study.

OBJECTIVES: Perceived financial strain is associated with various health conditions, but it is unknown whether it is associated with an increased risk for dementia. The goal is to examine the associations between midlife perceptions of financial situation and dementia risk later in life. METHODS: Participants were derived from the Cardiovascular Risk Factors, Aging, and Dementia population-based cohort study (n = 2000) (between 1972 and 1987, baseline mean age 50 years) in Finland. Participants returned for two re-examinations in late life (in 1998 and 2005-2008, mean age 71 and 78 years). In this study, 1442 subjects that participated in at least one re-examination (mean total follow-up 25 years) were included in analyses. Financial strain was measured using two questions in midlife on perceptions of financial situation and perceptions of changes in financial situation. For each question, participants were categorized into three groups reporting improvement, worsening, or stability, with the latter set as the reference group. Analyses were adjusted for potential confounding factors. RESULTS: The group reporting better financial situation had a reduced risk for dementia (fully adjusted model: odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33-0.86). In contrast, the group reporting worse financial situation did not have an increased risk for dementia (OR: 1.04, 95% CI: 0.53-2.02). Analyses on perceptions of current financial situation showed that the groups reporting satisfaction or dissatisfaction with financial situation did not differ in risk for dementia. CONCLUSION: This study is the first to show that midlife improvements in financial situation are associated with a reduced dementia risk later in life. Potential pathways related to stress reduction, improved lifestyle, and potential biological mechanisms are discussed.

Heavy metal content of Swedish municipal wastewater sludge - status and goals.

In 2014, 25% of the sludge produced at Swedish municipal wastewater treatment plants was applied to agricultural land. Even though the Swedish heavy metal limits for sludge to be used in agriculture are amongst the most stringent in the EU, more stringent heavy metal limits are proposed. Most sludge applied to agricultural land is recycled within a certification system, Revaq. Revaq has targets for control at source management and improvement of sludge quality. Statistics based on data collected within the Revaq system was used to differentiate between local and general sources of heavy metals and assess the need to improve sludge quality. The analysis indicates that proposed future national limits on the quality of the sludge can be met by most of the sludge. The improvement needed for about 20% of the sludge is feasible through local control at source management. The levels of cadmium, copper and mercury need to be reduced if these metals are not to limit the amount of sludge that may be applied per unit area of arable land. Finally, the long term Revaq targets for cadmium and silver will be difficult to meet.

Rainbow trout (Oncorhynchus mykiss) immune response towards a recombinant vaccine targeting the parasitic ciliate Ichthyophthirius multifiliis.

The protective effect in rainbow trout (Oncorhynchus mykiss) of an experimental subunit vaccine targeting antigens in the parasite Ichthyophthirius multifiliis has been evaluated and compared to effects elicited by a classical parasite homogenate vaccine. Three recombinant parasite proteins (two produced in E. coli and one in insect cells) were combined and injected i.p., and subsequently, protection and antibody responses were analysed. Both the experimental and the benchmark vaccine induced partial but significant protection against I. multifiliis when compared to control fish. Specific antibody responses of vaccinated trout (subunit vaccine) were raised against one neurohypophysial n-terminal domain protein #10 of three recombinant proteins, whereas the benchmark vaccine group showed specific antibody production against all three recombinant proteins. The immunogenic parasite protein #10 may be a potential vaccine candidate supplementing the protective I-antigen in future vaccine trials.

Improved pan-specific prediction of MHC class I peptide binding using a novel receptor clustering data partitioning strategy.

Pan-specific prediction of receptor-ligand interaction is conventionally done using machine-learning methods that integrates information about both receptor and ligand primary sequences. To achieve optimal performance using machine learning, dealing with overfitting and data redundancy is critical. Most often so-called ligand clustering methods have been used to deal with these issues in the context of pan-specific receptor-ligand predictions, and the MHC system the approach has proven highly effective for extrapolating information from a limited set of receptors with well characterized binding motifs, to others with no or very limited experimental characterization. The success of this approach has however proven to depend strongly on the similarity of the query molecule to the molecules with characterized specificity using in the machine-learning process. Here, we outline an alternative strategy with the aim of altering this and construct data sets optimal for training of pan-specific receptor-ligand predictions focusing on receptor similarity rather than ligand similarity. We show that this receptor clustering method consistently in benchmarks covering affinity predictions, MHC ligand and MHC epitope identification perform better than the conventional ligand clustering method on the alleles with remote similarity to the training set.

Adsorption of formic acid on rutile TiO2 (110) revisited: an infrared reflection-absorption spectroscopy and density functional theory study.

Formic acid (HCOOH) adsorption on rutile TiO2 (110) has been studied by s- and p-polarized infrared reflection-absorption spectroscopy (IRRAS) and spin-polarized density functional theory together with Hubbard U contributions (DFT+U) calculations. To compare with IRRAS spectra, the results from the DFT+U calculations were used to simulate IR spectra by employing a three-layer model, where the adsorbate layer was modelled using Lorentz oscillators with calculated dielectric constants. To account for the experimental observations, four possible formate adsorption geometries were calculated, describing both the perfect (110) surface, and surfaces with defects; either O vacancies or hydroxyls. The majority species seen in IRRAS was confirmed to be the bridging bidentate formate species with associated symmetric and asymmetric frequencies of the ν(OCO) modes measured to be at 1359 cm(-1) and 1534 cm(-1), respectively. The in-plane δ(C-H) wagging mode of this species couples to both the tangential and the normal component of the incident p-polarized light, which results in absorption and emission bands at 1374 cm(-1) and 1388 cm(-1). IRRAS spectra measured on surfaces prepared to be either reduced, stoichiometric, or to contain surplus O adatoms, were found to be very similar. By comparisons with computed spectra, it is proposed that in our experiments, formate binds as a minority species to an in-plane Ti5c atom and a hydroxyl, rather than to O vacancy sites, the latter to a large extent being healed even at our UHV conditions. Excellent agreement between calculated and experimental IRRAS spectra is obtained. The results emphasize the importance of protonation and reactive surface hydroxyls - even under UHV conditions - as reactive sites in e.g., catalytic applications.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

CONTEXT: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

A strategy for reducing pollutants at source in order to obtain sustainable agricultural recycling of wastewater sludge.

The Swedish licensing system for wastewater sludge use in agriculture, REVAQ, sets challenges. These include a maximum nominal accumulation rate of 0.2%/year on farmland, for specified metals, to be reached by 2025. Here a model is suggested, and applied for the Gothenburg regional wastewater treatment plant, Gryaab, to quantify historic sludge quality improvements and necessary future development. Local sampling campaigns covering two decades show a substantial reduction of heavy metals and ecologically harmful organic substances (such as adsorbable organic halogens, nonylphenols, phthalates, naphthalenes and polycyclic aromatic hydrocarbons) from households and society at large. For the metals studied the historic mass flow reduction to sludge varies from 1 to 2%/year for mercury, zinc and copper to 15%/year for silver. Copper needs further reduction, involving water pipes and copper roofing. Silver is rare in soil, and significant reduction from already low levels is needed to reach the accumulation goal. Further reduction of other metals involves addressing storm- and drainage water entering the sewers and the sediments already in the sewers. Fulfilling the goals of REVAQ implies national and local measures affecting public and private stakeholders including property owners, the wastewater collection system, commercial businesses and legislating authorities.

Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.

Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation.

Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. Behavior was assessed 2.5 weeks later in a social interaction paradigm followed by the NOR task. We found that selective cholinergic denervation of neocortex led to a significant reduction in duration of social interaction, specifically active social interaction. Acute administration of PCP (1.0 mg/kg, s.c.) caused a marked decrease of active social interaction, such that there was no longer a difference between intact and denervated animals. Neither cholinergic denervation alone, nor PCP (1.0 mg/kg, s.c.) alone blocked the ability of rats to recognize a novel object. However, when animals lacking cortical cholinergic innervation were challenged by PCP, they were no longer able to recognize a novel object. This study indicates that rats lacking cholinergic innervation of neocortex have impaired social interaction and specifically that the duration of active contact is shortened. Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.

Retention and maternal transfer of brominated dioxins in zebrafish (Danio rerio) and effects on reproduction, aryl hydrocarbon receptor-regulated genes, and ethoxyresorufin-O-deethylase (EROD) activity.

Brominated dioxins have recently been detected in Baltic Sea biota. Due to their similarities to the highly toxic chlorinated dioxins, concern has been raised about their potential biological effects. The present study investigated retention and effects of brominated dioxins in adult zebrafish, as well as maternal transfer and effects on offspring. We exposed adult zebrafish for nine weeks via feed to 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) or to a mixture of brominated dioxins (Baltic Sea mixture), which was designed to reflect relative concentrations found in Baltic Sea biota. We studied spawning success, gonad morphology, hepatic vitellogenin gene expression, and offspring early life-stage development to investigate effects on zebrafish reproduction. Hepatic ethoxyresorufin-O-deethylase (EROD) activity and hepatic expression of a number of aryl hydrocarbon receptor (AHR)-regulated genes were studied to investigate if the brominated dioxins can activate gene transcription through the AHR pathway in zebrafish. In addition, glutathione reductase activity and expression of genes involved in adaptive responses to intracellular stress were studied to investigate potential stress effects of brominated dioxins. After nine weeks of exposure, all brominated dioxins spiked to the feed were detected in female fish and transferred to eggs. Exposure to the Baltic Sea mixture and TBDD clearly induced AHR-regulated genes and EROD activity. Exposure to TBDD reduced spawning success, altered ovarian morphology and reduced hepatic vitellogenin gene expression, which implies that TBDD has a similar effect pattern as the chlorinated analogue. Overall, our results show that dietary exposure to sublethal concentrations of brominated dioxins may impair reproductive physiology in fish and induce AHR-regulated genes.

Minimal eating observation form: reliability and validity.

OBJECTIVES: Eating difficulties are common for patients in hospitals (82% have one or more). Eating difficulties predict undernourishment, need for assistance when eating, length of hospital stay and level of care after hospital stay. Eating difficulties have through factor analysis (FA) been found to belong to three dimensions (ingestion, deglutition and energy). The present study investigates inter-observer reliability. Other questions at issue are if the findings from the previous FA can be confirmed, if adjustments need to be done and if the Minimal Eating Form (MEOF) can serve as an assessment model for identification of eating difficulties. Previously found associations between eating difficulties and outcomes as well as measures taken to improve oral intake were also investigated. DESIGN: Inter-observer study and cross-sectional observational study. SETTINGS: Hospitals and special accommodations (SAs). PARTICIPANTS AND MEASUREMENTS: Inter-observer study: Observers made standardized assessments of eating, independently and at the same time, on a sample of 50 patients with stroke. Survey study: 2600 (88%) out of 2945 persons agreed to participate in a survey of eating and nutrition. All SAs within six municipalities and six hospitals were involved. Nursing students, clinical tutors and staff performed the assessments, supported by the researchers. RESULTS: The average agreement between observers of eating difficulties was 89% (Kappa coefficient 0.70). In the survey study, the mean age of persons (n=1726) living in SAs was 85 years (SD 8) and 69% were women, while the corresponding figures for patients (n=874) in hospitals were 69 years (SD 18) and 53% women. Low Body Mass Index (BMI) was found in 27%, unintentional weight loss in 23% and need of eating assistance in 38% of the persons. Protein- and energy- (PE-) enriched food was given to 4%, adapted consistency of food to 23% and food supplements to 16% of the persons. The new FA confirmed the previous one and minor adjustments of the model were made. Having ingestion difficulties was the strongest predictor of need for eating assistance (OR 14.5). Deglutition difficulties strongly predicted serving of adapted consistency of food (OR 7.3). Poor energy levels and reduced appetite predicted weight loss (OR 6.0), BMI below limits (OR 2.5), supplements (OR 5.3) and PE-enriched food (OR 3.4). CONCLUSIONS: The MEOF has satisfying validity and reliability. The earlier model of eating difficulties was confirmed (MEOF-I), and the model was slightly adjusted to a new model, MEOF-II. Providing eating assistance seems effective in preventing malnutrition (weight loss and BMI below limits), and is mainly provided to persons with ingestion difficulties. Difficulties with energy intake and appetite are not associated with eating assistance; indicating that those persons might need support of some other kind. This support can include providing PE-enriched food and supplements, but seems however insufficiently or inadequately delivered, as low energy and appetite problems are also associated with both weight loss and low BMI. Findings from other studies are confirmed.

Rain events and their effect on effluent quality studied at a full scale activated sludge treatment plant.

The effect of rain events on effluent quality dynamics was studied at a full scale activated sludge wastewater treatment plant which has a process solution incorporating pre-denitrification in activated sludge with post-nitrification in trickling filters. The incoming wastewater flow varies significantly due to a combined sewer system. Changed flow conditions have an impact on the whole treatment process since the recirculation to the trickling filters is set by the hydraulic limitations of the secondary settlers. Apart from causing different hydraulic conditions in the plant, increased flow due to rain or snow-melting, changes the properties of the incoming wastewater which affects process performance and effluent quality, especially the particle removal efficiency. A comprehensive set of on-line and laboratory data were collected and analysed to assess the impact of rain events on the plant performance.

Short circuiting in a denitrifying activated sludge tank.

The presence of a short circuit flow in a denitrifying activated sludge tank was identified and modelled. Tracer tests with pulse addition of lithium salt were used to investigate the hydraulics of the tank. The lithium concentration in the effluent was detected and residence time distribution (RTD) curves were generated. Hydraulic models based on completely stirred tank reactors (CSTRs) in series were generated from the RTD curves and the models were compared. The short circuit problem was successfully described using the Martin model, where the inflow is divided into two strands. Each strand was modelled as a number of CSTRs in series. At a normal flow the results of the model show that the tank has 12.8% dead volume, 85.8% main volume and 1.3% short circuiting volume. The inflow was divided into 91.9% entering the main volume and 8.1% entering the short circuiting volume. The mean velocity of the short circuiting stream was estimated to 0.4 m/s. At maximum flow the short circuiting stream was even larger and handled 24.3% of the flow. The short circuiting stream was identified in the upper part of the tank due to the position of the inlet and the outlet. The configuration of a tank including the use of baffles, the geometry of the inlet and mixer configuration should be considered carefully if short circuiting is to be avoided.

Cell cycle arrest of human gingival fibroblasts and periodontal ligament cells by Actinobacillus actinomycetemcomitans: involvement of the cytolethal distending toxin.

The cytolethal distending toxin (Cdt) is produced by several Gram-negative bacterial species and causes growth arrest and morphological alterations in mammalian cells. Actinobacillus actinomycetemcomitans, which is involved in the pathogenesis of localized aggressive periodontitis, also produces a Cdt that affects periodontal connective tissue cells. The aim of this study was to investigate in which phase of the cell cycle these cells are arrested and enlarged when challenged with A. actinomycetemcomitans, and to evaluate the involvement of its Cdt. Human gingival fibroblasts and periodontal ligament cells were challenged with A. actinomycetemcomitans extract, or with purified Cdt, and cell cycle analysis was performed by propidium iodide staining and flow cytometry. Cells exposed to an A. actinomycetemcomitans wild-type strain, or to purified Cdt, were arrested in both G1 and G2/M phases, and appeared enlarged compared to the corresponding controls. The cellular enlargement occurred in both G1 and G2/M arrested cells. In contrast, cells exposed to an A. actinomycetemcomitans cdt-knockout mutant strain showed cell cycle phase distribution and size similar to the controls. In conclusion, A. actinomycetemcomitans causes a combined G1 and G2/M growth arrest and enlargement in periodontal connective tissue cells, which is attributed to its Cdt.

Reducing the total discharge from a large WWTP by separate treatment of primary effluent overflow.

At many large wastewater treatment plants (WWTPs) the increased hydraulic load, caused by combined sewer systems during storm events, results in primary effluent overflow when the capacity of further treatment is exceeded. Due to stringent effluent standards, regulating the total discharge from the WWTPs, the Rya WWTP in Göteborg and the Sjölunda WWTP in Malmö will have to reduce the impact of primary effluent overflow. Separate, high rate, precipitation processes operated only during high flow conditions have been investigated in pilot units at the two WWTPs. Precipitation in existing primary settlers operated at a surface loading of 3.75 m/h removed phosphorus to 0.35 mg/l. The Actiflo process was also shown to remove suspended solids and phosphorus well. BOD was reduced by 50-60%. With such processes the overall effluent concentrations from the plants can be reduced significantly. Key upgrading features are small footprints, short start up time and high efficiency.

Loss of cortical acetylcholine enhances amphetamine-induced locomotor activity.

Cholinergic disturbances have been implicated in schizophrenia. In a recent study we found that intracerebroventricular (i.c.v.) delivery of the immunotoxin 192 IgG-saporin, that effectively destroys cholinergic projections from the basal forebrain to hippocampus and cortex cerebri, leads to a marked facilitation of amphetamine-induced locomotor activity in adult rats. The aim of the present experiments was to evaluate the contribution of the septohippocampal versus the basalocortical cholinergic projections for the amphetamine hyper-response seen previously in i.c.v. 192 IgG-saporin injected rats. Since i.c.v. delivery of 192 IgG-saporin also destroys a population of Purkinje neurons in cerebellum, this cell loss needs to be taken into consideration as well. Cortex cerebri and hippocampus were selectively cholinergically denervated by intraparenchymal injections of 192 IgG-saporin into nucleus basalis magnocellularis and the medial septum/diagonal band of Broca, respectively. Selective loss of Purkinje cells in cerebellum was achieved by i.c.v. delivery of OX7 saporin. Possible effects of these three lesions on spontaneous and amphetamine-induced locomotor activity were assessed in locomotor activity cages. We find that selective cholinergic denervation of cortex cerebri, but not denervation of hippocampus or damage to cerebellum can elicit dopaminergic hyper-reactivity similar to that seen in previous i.c.v. 192 IgG-saporin experiments. Our data are compatible with the hypothesis that disturbances of cholinergic neurotransmission in cortex cerebri may be causally involved in forms of schizophrenia.

Excess breast cancer risk and the role of parity, age at first childbirth and exposure to radiation in infancy.

Exposure to ionizing radiation is a known risk factor for breast cancer and the fertility pattern is a recognized modifier of breast cancer risk. The aim of this study was to elucidate the interaction between these 2 factors. This study is based on a Swedish cohort of 17 202 women who had been irradiated for skin haemangiomas in infancy between 1920 and 1965. The mean age at treatment was 6 months and the median breast dose was 0.05 Gy (range 0-35.8 Gy). Follow-up information on vital status, parity, age at first childbirth and breast cancer incidence was retrieved through record linkage with national population registers for the period 1958-1995. Analyses of excess relative risk (ERR) models were performed using Poisson regression methods. In this cohort, the fertility pattern differed from that in the Swedish population, with significantly fewer childbirths overall and before 25 years of age but more childbirth after that age. There were 307 breast cancers in the cohort and the standardized incidence ratio (SIR) was 1.22 (95% CI 1.09-1.36). A linear dose-response model with stratification for fertility pattern and menopausal status resulted in the best fit of the data. ERR/Gy was 0.33 (95% CI 0.17-0.53). In absolute terms this means an excess of 2.1 and 5.4 cases per Gy per 10(4) breast-years in the age groups 40-49 and 50-59 years respectively. The fertility pattern influenced the breast cancer risk in this irradiated population in a similar way to that observed in other studies. SIR at dose = 0 was highest, 2.31, among postmenopausal nulliparous women (95% CI 1.48-3.40, n = 62). SIR at dose = 0 was lowest in pre- or postmenopausal women with a first childbirth before 25 years of age; 0.89 (0.71-1.09) and 0.88 (0.58-1.25) respectively. Thus, in addition to the dose-effect response in the cohort, part of the breast cancer excess could be explained by a different fertility pattern. The estimates of ERR/Gy for the various categories of age at first childbirth, number of children, menopausal status and ovarian dose were very similar, contradicting any interaction effects on the scale of relative risk.

Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits.

The physiological interrelationships between cognitive impairments, neurotransmitter loss, amyloid processing and energy metabolism changes in AD, cholinergic dementia and Down's syndrome are largely unknown to date. This report contains novel studies into the association between cognitive function and cerebral metabolism after long-term selective CNS cholinergic neuronal and synaptic loss in a rodent model. We measured local cerebral rates of glucose utilization ((14)C-2-deoxyglucose) throughout the brains of awake rats 4.5 months after bilateral intraventricular injections of a cholinotoxic antibody directed against the low-affinity NGF receptor (p75 NGF) associated with cholinergic neurons (192 IgG-saporin). Permanent cholinergic synapse loss was demonstrated by [(3)H]-vesamicol in vitro autoradiography defining presynaptic vesicular acetylcholine (ACh) transport sites. While other metabolic studies have defined acute and transient glucose use changes after relatively nonspecific lesions of anatomical regions containing cholinergic neurons, our results show sustained reductions in glucose utilization in brain regions impacted by cholinergic synapse loss, including frontal cortical and hippocampal regions, relative to glucose use levels in control rats. In the same animals, impaired cognitive spatial performance in a Morris water maze was correlated with reduced glucose use rates in the cortex and hippocampus at this time point, which is consistent with increased postmortem cortical and hippocampal amyloid precursor protein (APP) levels (45, 46). These results are consistent with the view of cholinergic influence over metabolism, APP processing, and cognition in the cortex and hippocampus.