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Background Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms. Methods Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors. Results Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks. Conclusions These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma. © 2014 Society of Biological Psychiatry.

Background: Although phytoestrogens modulated pancreatic tumour growth in experimental studies, it remains unclear whether phytoestrogen intake is associated with pancreatic cancer., Methods: Of 92,278 persons who completed the Diet History Questionnaire in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 346 were diagnosed with pancreatic cancer within a median follow-up of 9.4 years. Cox proportional hazards regression was used to evaluate pancreatic cancer risk in relation to phytoestrogen intake., Results: After adjustment for confounders, intakes of glycitein and formononetin were associated with a reduced risk of pancreatic cancer [highest vs. lowest quartile, hazard ratio (HR) (95% confidence interval (CI)) for glycitein: 0.60 (0.39, 0.92); P for linear trend: 0.01; HR for formononetin: 0.51 (0.37, 0.70); P for linear trend: 0.005]. These associations were stronger and their linear trends across the quartiles of intakes were more statistically significant among ever smokers than never-smokers. A reduced risk was also observed for ever smokers in the highest quartile of total isoflavones or daidzein compared with those in the lowest quartile., Conclusions: Our study suggests that high intakes of total isoflavones and some individual isoflavones were inversely associated with pancreatic cancer risk, but this potential protective effect was confined to ever smokers., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: All methods were conducted in compliance with the relevant ethical guidelines and regulations. The PLCO Cancer Screening Trial was approved by both the institutional review boards of the National Cancer Institute and all participating screening centres Informed consent: Written informed consent was obtained from all participants., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The COVID-19 pandemic affected daily life significantly and had massive consequences for healthcare systems with tremendous regional differences. This retrospective study aimed to investigate whether the pandemic and resulting societal changes impacted the diagnosis of pediatric malignancies in a distinct region. Pediatric cancer cases in Bavaria (2016-2021) and SARS-CoV-2 proceedings during the peak phase of the pandemic (2020-2021) were retrospectively analyzed. All new diagnoses of pediatric malignancies reported from cancer centers in Bavaria were included. Clinical data from pre-pandemic years was compared to diagnoses made during the pandemic. Official SARS-CoV-2 reports were received from the Bavarian Health and Food Safety Authority and data on regional pandemic measures were obtained from the Healthcare Data Platform. With this design, a comprehensive analysis of the pandemic proceedings was performed. We found significantly decreased incidence-rate ratios for pediatric cancer diagnosis during the early spring peak of SARS-CoV-2 as it was observed in May during the pandemic, followed by non-significantly increased metastatic cancer diagnosis two months later. Additionally, the time-to-diagnosis of pediatric malignancies was significantly prolonged during the pandemic, and outpatient contacts were significantly reduced, although the availability of consultations remained the same. From our findings, we may hypothesize that there have been effects on pediatric cancer diagnosis during the COVID-19 pandemic at vulnerable times. Interpretation of changes remains speculative with potential causes from behavior patterns, such as hesitation, concerns, and potential societal changes during phases of public restrictions, rather than overwhelmed medical capacities. Nevertheless, specific awareness is needed to protect this patient population during potential future pandemics.

In burn patients, vitamin D deficiency has been associated with increased incidence of sepsis and infectious complications. The objective of this study was to assess the impact of vitamin D deficiency in adult burn patients on hospital length of stay (LOS). This was a multicenter retrospective study of adult patients at 7 burn centers admitted over a 3.5-year period, who had a 25-hydroxyvitamin D concentration drawn within the first 7 days of injury. Of 1147 patients screened, 412 were included. Fifty-seven percent were vitamin D deficient. Patients with vitamin D deficiency had longer LOS (18.0 vs 12.0 days, P < .001), acute kidney injury (AKI) requiring renal replacement therapy (7.3 vs 1.7%, P = .009), more days requiring vasopressors (mean 1.24 vs 0.58 days, P = .008), and fewer ventilator-free days of the first 28 days (mean 22.9 vs 25.1, P < .001). Univariable analysis identified burn center, AKI, TBSA, inhalation injury, admission concentration, days until concentration drawn, days until initiating supplementation, and dose as significantly associated with LOS. After controlling for center, TBSA, age, and inhalation injury, vitamin D deficiency was associated with longer LOS. In conclusion, patients with thermal injuries and vitamin D deficiency on admission have increased LOS and worsened clinical outcomes when compared with patients with nondeficient vitamin D concentrations., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Studies focusing on pharmacotherapy interventions to aid patients after thermal injury are a minor focus in burn injury-centered studies and published across a wide array of journals, which challenges those with limited resources to keep their knowledge current. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Twenty-three geographically dispersed, board-certified pharmacists participated in the review. A Medical Subject Heading-based, filtered search returned 2336 manuscripts over the previous 2-year period. After manual review, 98 (4%) manuscripts were determined to have a potential impact on current pharmacotherapy practice. The top 10 scored manuscripts are discussed. Only 17% of those reviewed were assessed to likely have little effect on current practice. The overall impact of the current cohort was higher than previous editions of this review, which is encouraging. There remains a need for investment in well-designed, high-impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background & Aims: It remains unclear why the association between cigarette smoking and lung cancer was substantially stronger in Western countries than in Asian countries. As experimental studies have revealed that fat intake modulates tobacco carcinogen metabolism and the growth of transplanted or carcinogen-induced lung tumors in mice, the present study sought to investigate whether the association between cigarette smoking and lung cancer was modified by intake of total fat and types of fat (saturated, monounsaturated, and polyunsaturated fats) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial., Methods: During a median follow-up of 8.9 years, 1,425 cases of lung cancer were documented from 100,864 participants eligible for the present analysis. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: After adjustment for established or suspected confounders, the strength of the association between cigarette smoking and lung cancer was remarkably larger among individuals with high fat intake. HRs (95% CIs) comparing current with never smokers were 23.0 (13.4, 39.6), 32.7 (20.3, 52.8), and 59.8 (30.2, 118.2) for the tertile 1 (≤13.48 g/day), tertile 2 (13.49-21.89 g/day), and tertile 3 (≥21.90 g/day) of saturate fat intake, respectively. A similar pattern of the non-significant interaction was observed when the accumulated amount of cigarette smoking (1-19, 20-39, and ≥40 vs. 0 pack-years) was entered into the regression models., Conclusions: The present study showed that lung cancer risk associated with both the status and accumulated amount of cigarette smoking was remarkably stronger in individuals with high intakes of fat, particularly saturated fat. However, this interaction was not statistically significant and thus warrants further investigations in other studies., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Vitamin D (25OHD) deficiency is associated with poor outcomes in intensive care populations. The primary objective of this 7-center study was to determine if 25OHD deficiency is associated with infectious outcomes in adult burn patients. Generalized linear mixed modeling was used to control for center effect, percent total body surface area burn (% TBSA), age, and presence of inhalation injury. A total of 1147 patients were initially included (admitted January 2016 through August 2019). After exclusions, 234 (56.8%) in the deficient (25OHD<20 ng/mL) and 178 in the non-deficient group (25OHD ≥ 20 ng/mL) remained, surpassing a priori power requirements. The non-deficient group had their concentration drawn earlier (p < 0.001), were more likely to be male (p = 0.006), Caucasian (p < 0.001), have lower body mass index (p = 0.009), lower % TBSA (p = 0.002), and taking a 25OHD supplement prior to admission (p < 0.001). Deficient patients were more likely to have an infectious outcome (52.1% vs 36.0%, p = 0.002), acute kidney injury with renal replacement therapy (p = 0.009), less ventilator free days in the first 28 days (p < 0.001), and vasopressors (p = 0.01). After controlling for center, % TBSA, age, and inhalation injury the best model also included presence of deficiency (OR 2.425 [CI 1.206-4.876]), days until 25OHD supplement initiation (OR 1.139 [CI 1.035-1.252]), and choice of cholecalciferol over ergocalciferol (OR 2.112 [CI 1.151-3.877]). To the authors' knowledge, this is the first multicenter study to evaluate the relationship between 25OHD and infectious complications in burn patients., Competing Interests: Conflict of Interest The authors have no conflicts relative to this manuscript., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Background: The broad-spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare., Objectives: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics., Methods: Retrospective analysis of isavuconazole plasma concentrations were obtained as part of routine therapeutic drug monitoring (TDM) of ICU patients with invasive aspergillosis or other fungal infections treated with isavuconazole. Plasma levels 0-4 h after last dosing were defined as peak levels (C max ), those 20-28 h after last dosing as trough levels (C min )., Results: Overall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median C max was 2.36 μg/ml (mean 2.43 μg/ml, range 0.41-7.79 μg/ml) and the overall median C min was 1.74 μg/ml (mean 1.77 μg/ml, range 0.24-4.96 μg/ml). In total, 31.7% of the C min values of the total cohort were below the plasma target concentrations of 1 μg/ml, defined as EUCAST antifungal clinical breakpoint for Aspergillus fumigatus. Both peak and trough plasma levels of isavuconazole were significantly lower among patients with a body mass index (BMI) ≥25. In addition, a significant correlation was observed between isavuconazole trough levels and sepsis-related organ failure assessment (SOFA) score., Conclusions: This study shows that isavuconazole plasma concentrations vary in critical ill ICU patients. Significantly lower isavuconazole levels were associated with elevated BMI and higher SOFA score indicating a need of isavuconazole TDM in this specific patient population., (© 2022 The Authors. Mycoses published by Wiley-VCH GmbH.)

Keeping abreast with current literature can be challenging, especially for practitioners caring for patients sustaining thermal or inhalation injury. Practitioners caring for patients with thermal injuries publish in a wide variety of journals, which further increases the complexity for those with resource limitations. Pharmacotherapy research continues to be a minority focus in primary literature. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Sixteen geographically dispersed, board-certified pharmacists participated in the review. A MeSH-based, filtered search returned 1536 manuscripts over the previous 2-year period. After manual review and exclusions, only 98 (6.4%) manuscripts were determined to have a potential impact on current pharmacotherapy practices and included in the review. A summary of the 10 articles that scored highest are included in the review. Nearly half of the reviewed manuscripts were assessed to lack a significant impact on current practice. Despite an increase in published literature over the previous 2-year review, the focus and quality remain unchanged. There remains a need for investment in well-designed, high impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Water therapies as hydrotherapy, balneotherapy or aqua therapy are often used in the relief of disease- and treatment-associated symptoms of cancer patients. Yet, a systematic review for the evidence of water therapy including all cancer entities has not been conducted to date., Purpose: Oncological patients often suffer from symptoms which in patients with other diseases are successfully treated with water therapy. We want to gather more information about the benefits and risks of water therapy for cancer patients., Method: In May 2020, a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and PubMed) to find studies concerning the use, effectiveness and potential harm of water therapy on cancer patients., Results: Of 3165 search results, 10 publications concerning 12 studies with 430 patients were included in this systematic review. The patients treated with water therapy were mainly diagnosed with breast cancer. The therapy concepts included aqua lymphatic therapy, aquatic exercises, foot bathes and whole-body bathes. Outcomes were state of lymphedema, quality of life, fatigue, BMI, vital parameters, anxiety and pain. The quality of the studies was assessed with the AMSTAR2-instrument, the SIGN-checklist and the IHE-Instruments. The studies had moderate quality and reported heterogeneous results. Some studies reported significantly improved quality of life, extent of lymphedema, neck and shoulder pain, fatigue and BMI while other studies did not find any changes concerning these endpoints., Conclusion: Due to the very heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of water therapy on cancer patients is not possible., (© 2022. The Author(s).)

Genetically encoded fluorescent sugar sensors are valuable tools for the discovery of transporters and for quantitative monitoring of sugar steady-state levels in intact tissues. Genetically encoded Förster resonance energy-transfer sensors for glucose have been designed and optimized extensively, and a full series of affinity mutants is available for in vivo studies. However, to date, only a single improved sucrose sensor FLIPsuc-90μΔ1 with K m for sucrose of ∼90 μM was available. This sucrose sensor was engineered on the basis of an Agrobacterium tumefaciens sugar-binding protein. Here, we took a two-step approach to first improve the dynamic range of the FLIPsuc sensor and then expand the detection range from micro- to millimolar sucrose concentrations by mutating a key residue in the binding site. The resulting series of sucrose sensors may enable investigation of sucrose transporter candidates and comprehensive in vivo analyses of sucrose concentration in plants. Since FLIPsuc-90μ also detects trehalose in animal cells, the new series of sensors will likely be suitable for investigating trehalose transport and monitor trehalose steady-state levels in vivo.

Staying current and evaluating literature related to pharmacotherapy in burn or inhalation injury can be difficult as burn care teams are multidisciplinary and pertinent content can be spread across a plethora of journals. The goal of this review is to critically evaluate recently published pharmacotherapy-pertinent literature, assist practitioners staying current, and better identify potential future research targets. Twelve board-certified clinical pharmacists with experience caring for patients with burn and inhalation injuries reviewed and graded scientific literature published in 2017 and 2018. An MeSH-based search revealed 1158 articles related to burns, which were published during the 2-year period. One-hundred fifty one were determined to be potentially related to pharmacotherapy. After exclusions, only 82 (7%) remained for scoring, and the top 10 comprehensively presented. More than half of the reviewed manuscripts were assessed as lacking a significant impact on pharmacotherapy. There is a need for higher impact literature to support pharmacotherapy-pertinent treatment of such complex patients., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Oxandrolone has proven benefits in thermal burn injury and has become a standard of care. Transaminitis is the most frequent side effect of oxandrolone use, although no risk factors have been identified that increase the risk of transaminitis. The objective was to evaluate the frequency of transaminitis while on oxandrolone and to identify risk factors leading to an increased risk of transaminitis in adult burn patients. This multicenter retrospective risk factor analysis compared two patient groups with and without occurrence of transaminitis, which was detected by an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 mg/dL. Secondary outcomes included percentage increase from baseline for AST/ALT, length of stay, and mortality. After univariable analysis, a multivariable logistic regression analysis was performed to detect possible risk factors leading to transaminitis. A total of 309 patients were included, with transaminitis occurring in 128 patients (41.4%) after 13 (interquartile range [IQR] 8-23) days on oxandrolone. After multivariable analysis, age (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.84-0.99 for a 5-year increase in age), intravenous vasopressor use (OR 1.85; 95% CI 1.05-3.27), and amiodarone use (OR 2.51; 95% CI 1.09-5.77) were independent predictors of transaminitis, controlling for TBSA%. Transaminitis was not significantly associated with length of stay or mortality after adjusting for age and TBSA%. We conclude that patients who are younger and have concurrent amiodarone or vasopressor use have the highest risk of developing oxandrolone induced transaminitis and should be monitored closely., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Vitamin K inhibits prostate cancer cells, and an altered expression of vitamin K-dependent proteins in prostate tumors has been linked to their aggressiveness and progression. However, little is known about the effect of vitamin K intake on prostate cancer in human populations., Objectives: We evaluated the associations of dietary intake of phylloquinone (vitamin K-1), menaquinones (vitamin K-2), and total vitamin K with the development of prostate cancer among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial., Design: Dietary intake of vitamin K was assessed with the Dietary Questionnaire (DQX) at baseline and the Dietary History Questionnaire (DHQ) at the third anniversary of randomization by using high-performance liquid chromatography-based food-composition data obtained from the USDA and published studies. During a median follow-up of 11.8 y, 2978 cases of prostate cancer (including 490 advanced cases) were identified from the 28,356 men who completed DQX. Similarly, 2973 cases of prostate cancer (including 647 advanced cases) were documented from the 48,090 men who completed DHQ. Cox proportional hazards regression was used to estimate prostate cancer risk in relation to the dietary intake of vitamin K., Results: After adjustment for confounders, dietary intakes of phylloquinone, menaquinones, and total vitamin K, assessed with either the DQX or DHQ, were not significantly associated with the risk of advanced, nonadvanced, and total prostate cancer. These results remained virtually the same when vitamin K intake was modeled as a categorical (divided into quintiles) or continuous (per IQR increase) variable or after outliers of total vitamin K intake (defined as a value that falls above the sum of third quartile and twice the IQR) were excluded., Conclusions: The present study does not suggest that vitamin K intake influences the occurrence of total and advanced prostate cancer in the general US population.

Hydrophobin coated boehmite nanoparticles have been used to establish tooth-paste like, homogenous emulsions. The surface-modified nanoparticles were simply obtained by mixing aqueous solutions of cationic boehmite particles with the anionic hydrophobin H Star Protein B® (HPB). Surface tension measurements clearly show that 1 wt.% boehmite binds up to 1 wt.% HPB. The strong interaction and aggregation of hydrophobin coated boehmite nanoparticles was proven by Cryo-TEM measurements, too. Interestingly, the combined use of 0.5 wt.% HPB and 0.5 wt.% boehmite as emulsifying agents resulted in very stable, homogenous, high internal phase emulsions (65 wt.% oil) that are stable over months. The established emulsions have also been characterized by rheological measurements. Storage moduli of more than 1000 Pa are characteristic for their high gel-like properties. Furthermore, light microscopy showed an average droplet size close to 1 μm with low polydispersity. Cryo-SEM confirmed that the hydrophobin coated nanoparticles are located at the interface of the oil droplets and therefore stabilize the emulsion systems., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Concern for children exposed to elemental mercury prompted the Agency for Toxic Substances and Disease Registry and the Centers for Disease Control and Prevention to review the sources of elemental mercury exposures in children, describe the location and proportion of children affected, and make recommendations on how to prevent these exposures. In this review, we excluded mercury exposures from coal-burning facilities, dental amalgams, fish consumption, medical waste incinerators, or thimerosal-containing vaccines. We reviewed federal, state, and regional programs with data on mercury releases along with published reports of children exposed to elemental mercury in the United States. We selected all mercury-related events that were documented to expose (or potentially expose) children. Primary exposure locations were at home, at school, and at others such as industrial property not adequately remediated or medical facilities. Exposure to small spills from broken thermometers was the most common scenario; however, reports of such exposures are declining. The information reviewed suggests that most releases do not lead to demonstrable harm if the exposure period is short and the mercury is properly cleaned up. Primary prevention should include health education and policy initiatives.

Objective: Concern for children exposed to elemental mercury prompted the Agency for Toxic Substances and Disease Registry and the Centers for Disease Control and Prevention to review the sources of elemental mercury exposures in children, describe the location and proportion of children affected, and make recommendations on how to prevent these exposures. In this review, we excluded mercury exposures from coal-burning facilities, dental amalgams, fish consumption, medical waste incinerators, or thimerosal-containing vaccines., Data Sources: We reviewed federal, state, and regional programs with information on mercury releases along with published reports of children exposed to elemental mercury in the United States. We selected all mercury-related events that were documented to expose (or potentially expose) children. We then explored event characteristics (i.e., the exposure source, location)., Data Synthesis: Primary exposure locations were at home, at school, and at other locations such as industrial property not adequately remediated or medical facilities. Exposure to small spills from broken thermometers was the most common scenario; however, reports of such exposures are declining., Discussion and Conclusions: Childhood exposures to elemental mercury often result from inappropriate handling or cleanup of spilled mercury. The information reviewed suggests that most releases do not lead to demonstrable harm if the exposure period is short and the mercury is properly cleaned up., Recommendations: Primary prevention should include health education and policy initiatives. For larger spills, better coordination among existing surveillance systems would assist in understanding the risk factors and in developing effective prevention efforts.

Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes., Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol., Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment., Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207)., Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

The Mre11 complex functions in double-strand break (DSB) repair, meiotic recombination, and DNA damage checkpoint pathways. Sae2 deficiency has opposing effects on the Mre11 complex. On one hand, it appears to impair Mre11 nuclease function in DNA repair and meiotic DSB processing, and on the other, Sae2 deficiency activates Mre11-complex-dependent DNA-damage-signaling via the Tel1-Mre11 complex (TM) pathway. We demonstrate that SAE2 overexpression blocks the TM pathway, suggesting that Sae2 antagonizes Mre11-complex checkpoint functions. To understand how Sae2 regulates the Mre11 complex, we screened for sae2 alleles that behaved as the null with respect to Mre11-complex checkpoint functions, but left nuclease function intact. Phenotypic characterization of these sae2 alleles suggests that Sae2 functions as a multimer and influences the substrate specificity of the Mre11 nuclease. We show that Sae2 oligomerizes independently of DNA damage and that oligomerization is required for its regulatory influence on the Mre11 nuclease and checkpoint functions.