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Introduction: Sexual Health Inventory for Men (SHIM) is a validated questionnaire that is widely used in urology clinics to evaluate and assess treatment efficacy for erectile dysfunction (ED)., Aim: In this study, we evaluated the benefit of using the SHIM questionnaire as a screening tool for ED in a general urology clinic MATERIAL AND METHODS: We retrospectively reviewed records of patients presenting to our general urology clinic from October 2018 to June 2019. During this period, all new male urology patients who are 40 years of age or older visiting the general urology clinic for any urologic condition received the SHIM questionnaire. We excluded all patients whose chief complaint was ED, Peyronie's disease, and hypogonadism. Patients were then asked if they want treatment for ED, and those patients who did, received a full ED evaluation and treatment. Factors associated with desire for ED treatment were analyzed using logistic regression., Main Outcome Measures: SHIM score, desire for ED treatment, and factors influencing desire for treatment., Results: Three hundred seventy-nine patients received the SHIM questionnaire. Of which, 48 patients (12.7%) declined to fill the questionnaire. We excluded all patients presenting for sexual health issues (67 patients, 17.7%). We included the remaining 264 patients (69.6%). The mean age was 61.7 years (range 40 to 85). Older patients were more likely to want ED treatment and had lower SHIM scores. However, older than the age of 70 years, there was a decline in the number of patients wanting treatment. In a multivariate regression analysis, age between 61 and 70 years and having diabetes mellitus were associated with the desire for ED treatment., Conclusions: The SHIM questionnaire is a useful tool in the general urology clinic. It can serve as an efficient tool to screen for and quantify ED in patients presenting for other urologic issues. Maximum benefit is seen in patients between the age of 51 and 70 years and in patients with diabetes. Alwaal A, Awad M, Boggs N, et al. Sexual Health Inventory for Men Questionnaire as a Screening Method for Erectile Dysfunction in a General Urology Clinic. Sex Med 2020;8:660-663., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) caused by explosive munitions, known as blast TBI, is the signature injury in recent military conflicts in Iraq and Afghanistan. Diagnostic evaluation of TBI, including blast TBI, is based on clinical history, symptoms, and neuropsychological testing, all of which can result in misdiagnosis or underdiagnosis of this condition, particularly in the case of TBI of mild-to-moderate severity. Prognosis is currently determined by TBI severity, recurrence, and type of pathology, and also may be influenced by promptness of clinical intervention when more effective treatments become available. An important task is prevention of repetitive TBI, particularly when the patient is still symptomatic. For these reasons, the establishment of quantitative biological markers can serve to improve diagnosis and preventative or therapeutic management. In this study, we used a shock-tube model of blast TBI to determine whether manganese-enhanced magnetic resonance imaging (MEMRI) can serve as a tool to accurately and quantitatively diagnose mild-to-moderate blast TBI. Mice were subjected to a 30 psig blast and administered a single dose of MnCl2 intraperitoneally. Longitudinal T1-magnetic resonance imaging (MRI) performed at 6, 24, 48, and 72 h and at 14 and 28 days revealed a marked signal enhancement in the brain of mice exposed to blast, compared with sham controls, at nearly all time-points. Interestingly, when mice were protected with a polycarbonate body shield during blast exposure, the marked increase in contrast was prevented. We conclude that manganese uptake can serve as a quantitative biomarker for TBI and that MEMRI is a minimally-invasive quantitative approach that can aid in the accurate diagnosis and management of blast TBI. In addition, the prevention of the increased uptake of manganese by body protection strongly suggests that the exposure of an individual to blast risk could benefit from the design of improved body armor.

Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation-negative controls. We studied 22 familial RDP patients, 3 non-motor-manifesting mutation-positive family members, 29 mutation-negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) and a cognitive battery of memory and learning, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed and similarly for severity of depressive symptoms. A majority of RDP patients had onset of motor symptoms by age 25 and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia-parkinsonism. The affected RDP patients performed more poorly, on average, than mutation-negative controls for all memory and learning, psychomotor speed, attention, and executive function scores (all P ≤ 0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms. Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP., (© 2014 International Parkinson and Movement Disorder Society.)

Modern toxicological evaluations have evolved to consider toxicity as a perturbation of biological pathways or networks. As such, toxicity testing approaches are shifting from common end point evaluations to pathway based approaches, where the degree of perturbation of select biological pathways is monitored. These new approaches are greatly increasing the data available to toxicologists, but methods of analyses to determine the inter-relationships between potentially affected pathways are needed to fully understand the consequences of exposure. An approach to construct dose-response curves that use graph theory to describe network perturbations among three disparate mitogen-activated protein kinase (MAPK) pathways is presented. Mitochondrial stress was induced in human hepatocytes (HepG2) by exposing the cells to increasing doses of the complex I inhibitor, deguelin. The relative phosphorylation responses of proteins involved in the regulation of the stress response were measured. Graph theory was applied to the phosphorylation data to obtain parameters describing the network perturbations at each individual dose tested. The graph theory results depicted the dynamic nature of the relationship between p38, JNK, and ERK1/2 under conditions of mitochondrial stress and revealed shifts in the relationships between these MAPK pathways at low doses. The inter-relationship, or crosstalk, among these 3 traditionally linear MAPK cascades was further probed by coexposing cells to deguelin plus SB202190 (JNK and p38 inhibitor) or deguelin plus SB202474 (JNK inhibitor). The cells exposed to deguelin plus SB202474 resulted in significantly decreased viability, which could be visualized and attributed to the decrease of ERK1/2 network centrality. The approach presented here allows for the construction and visualization of dose-response curves that describe network perturbations induced by chemical stress, which provides an informative and sensitive means of assessing toxicological effects on biological systems.

The pharmaceutical world has greatly benefited from the well-characterized structure-function relationships of toxins with endogenous biomolecules, such as ion-channels, receptors, and signaling molecules. Thus, therapeutics derived from toxins have been aggressively pursued. However, the multifunctional role of various toxins may lead to undesirable off-target effects, hindering their use as therapeutic agents. In this paper, we suggest that previously unsuccessful toxins (due to off-target effects) may be revisited with mixtures by utilizing the pharmacodynamic response to the potential primary therapeutic as a starting point for finding new targets to ameliorate the unintended responses. In this proof of principle study, the pharmacodynamic response of HepG2 cells to a potential primary therapeutic (deguelin, a plant-derived chemopreventive agent) was monitored, and a possible secondary target (p38MAPK) was identified. As a single agent, deguelin decreased cellular viability at higher doses (>10 μM), but inhibited oxygen consumption over a wide dosing range (1.0-100 μM). Our results demonstrate that inhibition of oxygen consumption is related to an increase in p38MAPK phosphorylation, and may only be an undesired side effect of deguelin (i.e., one that does not contribute to the decrease in HepG2 viability). We further show that deguelin's negative effect on oxygen consumption can be diminished while maintaining efficacy when used as a therapeutic mixture with the judiciously selected secondary inhibitor (SB202190, p38MAPK inhibitor). These preliminary findings suggest that an endogenous response-directed mixtures approach, which uses a pharmacodynamic response to a primary therapeutic to determine a secondary target, allows previously unsuccessful toxins to be revisited as therapeutic mixtures., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Background: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized., Methods: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews., Results: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder., Conclusions: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

To develop a deeper understanding of the optical signatures of both biological aerosols and potential interferents, we made field measurements of optical cross sections and compared them to model-based predictions. We measured aerosol cross sections by conducting a hard-target calibration of a light detection and ranging system (LIDAR) based on the Frequency Agile Laser (FAL). The elastic backscatter cross sections are estimated at 19 long-wave infrared (LWIR) wavelengths spanning the range from 9.23 to 10.696 μm. The theoretical modeling of the elastic backscatter cross sections is based on the measured refractive index and size distribution of the aerosols, which are used as inputs into Mie calculations. Both model calculations and experimental measurements show good agreement and also indicate the presence of spectral features based on single particle absorption in the backscatter cross sections that can be used as a basis for discrimination for both standoff and point sensors.

Six married couples (12 adults, mean age 34.8 years) were randomized as couples in a cross-over design to sleep on a queen-size conventional mattress for 2 weeks and a specially-designed pressure-relief mattress for 2 weeks. The pressure-relief mattress was designed to reduce the number of contact points exceeding 30 mm Hg. Actigraphic measurements of sleep and self-reports of sleep and daytime symptoms were collected at baseline for 2 weeks on each couple's home mattress and box springs at home, followed by 2 weeks of data collection on each randomized mattress for a total of 6 weeks of data collection. Pressure maps were created for each participant on each sleeping surface. There were no significant differences between the randomized sleeping surfaces for any measure of actigraphic sleep or self-reported sleep and daytime symptoms. However, poor pressure relief performance of the home mattress was associated with better actigraphic sleep on the randomized pressure-relief mattress. We conclude that while pressure-relief mattresses may not be universally preferred, baseline characteristics of the sleeper and/or their mattress may explain performance and sleeper preferences on future mattress selection., (Copyright © 2011 Elsevier Ltd and The Ergonomics Society. All rights reserved.)

The activity of mitochondrial complex I of the electron transport chain (ETC) is known to be affected by an extraordinarily large number of diverse xenobiotics, and dysfunction at complex I has been associated with a variety of disparate human diseases, including those with potentially environmentally relevant etiologies. However, the risks associated with mixtures of complex I inhibitors have not been fully explored, and this warrants further examination of potentially greater than additive effects that could lead to toxicity. A potential complication for the prediction of mixture effects arises because mammalian mitochondrial complex I has been shown to exist in two distinct dynamic conformations based upon substrate availability. In this study, we tested the accepted models of additivity as applied to mixtures of rotenone, deguelin, and pyridaben, with and without substrate limitation. These compounds represent both natural and synthetic inhibitors of complex I of the ETC, and experimental evidence to date indicates that these inhibitors share a common binding domain with partially overlapping binding sites. Therefore, we hypothesized that prediction of their mixtures effects would follow dose addition. Using human hepatocytes, we analyzed the effects of these mixtures at doses between 0.001 and 100 μM on overall cellular viability. Analysis of the dose-response curves resulting from challenge with all possible binary and ternary mixtures revealed that the appropriate model was not clear. All of the mixtures tested were found to be in agreement with response addition, but only rotenone plus deguelin and the ternary mixture followed dose addition. To determine if conformational regulation via substrate limitation could improve model selection and our predictions, we tested the models of additivity for the binary and ternary mixtures of inhibitors when coexposed with 2-deoxy-d-glucose (2-DG), which limits NADH via upstream inhibition of glycolysis. Coexposure of inhibitors with 2-DG did facilitate model selection: Rotenone plus pyridaben and the ternary mixture were in sole agreement with dose addition, while deguelin plus pyridaben was in sole agreement with response addition. The only ambiguous result was the agreement of both models with the mixture of rotenone plus deguelin with 2-DG, which may be explained by deguelin's well-known affinity for protein kinase B (Akt) in addition to complex I. Thus, our findings indicate that predictive models for mixtures of mitochondrial complex I inhibitors appear to be compound specific, and our research highlights the need to control for dynamic conformational changes to improve our mechanistic understanding of additivity with these inhibitors.

Objectives: Our prior work has shown that there is improvement in self-reported sleep in persons receiving placebo in hypnotic clinical trials. We examined the components of the "placebo response" in a hypnotic clinical trial., Methods: This was an exploratory analysis of a randomized, double-blind clinical trial of eszopiclone versus placebo in the treatment of persons with depression and insomnia who were also receiving fluoxetine at a clinic of a teaching hospital. Sixty adults with both depression and insomnia symptoms, who were free of significant primary sleep disorders, received open-label fluoxetine for 9weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. We examined the respective contributions of three factors associated with the "placebo effect": (1) regression to the mean, (2) expectancy, and (3) social desirability., Results: There was evidence for regression to the mean for the continuous measurement of the Insomnia Severity Index (ISI) and the Hamilton Depression Rating Scale. There was evidence for expectancy in self-reported Wake After Sleep Onset, continuous measurement of ISI, and dichotomous remission/non-remitter measurement of ISI. There was evidence of social desirability affecting self-reported Total Sleep Time., Conclusions: Factors that have been associated with the "placebo effect" are operating in hypnotic clinical trials. However, the role of each factor differs depending upon which self-reported variable is being considered. The findings have implications for clinical trial design in insomnia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia., Methods: Sixty patients aged 41.5±12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI., Results: Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking (p<0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking (p<0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking., Conclusions: The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.

Study Objectives: Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken., Design: Double-blind, randomized, placebo-controlled clinical trial., Setting: Outpatient clinic and sleep laboratory., Patients: 60 depressed, insomniac outpatients., Interventions: One week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime., Measurements: The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis-32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD)., Results: At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 +/- 0.64) than those receiving placebo (1.2 +/- 0.72), p = 0.01. The effect size for DLRF was 0.62, indicating a moderate effect. An advantage for ESZ was also seen in other measures of HRQOL, and most assessments of antidepressant efficacy and sleep. Women reported better end of treatment HRQOL scores than men., Conclusions: ESZ treatment of insomnia in depressed patients is associated with multiple favorable outcomes, including superior improvement in HRQOL, depression severity, and sleep.

Insomnia-pharmacology clinical trials routinely exclude primary sleep disorders, such as obstructive sleep apnea (OSA) and periodic limb movement disorder (PLMD), with a single night of polysomnography (PSG). Given the expense of PSG, we examined whether a thorough clinical screening, combined with actigraphy, would successfully identify OSA and PLMD as part of baseline screening for a clinical trial of insomnia treatment in depressed patients. Of the 73 patients with a complete baseline dataset, 12 screened positive for OSA/PLMD (AHI > 15, or PLMAI > 15), while 61 "passed" the PSG screen. The OSA/PLMD+ patients were older (51.4 +/- 10.2 y) and took more naps (2.6 per week) than the OSA/PLMD- patients (41.3 +/- 12.8 y; and 1.1 naps per week). The combination of age and nap frequency produced a "good" receiver operating characteristic (ROC) model for predicting OSA/PLMD+, with the area under the curve of 0.82. There were no other demographic, sleep diary, or actigraphic variables, which differed between OSA/PLM + or -, and no other variable improved the ROC model. Still, the best model misclassified 16 of 73 persons. We conclude that while age and the presence of napping were helpful in identifying OSA and PLM in a well-screened sample of depressed insomniacs, PSG is required to definitively identify and exclude primary sleep disorders in insomnia clinical trials.

Loss of self-incompatibility (SI) in Arabidopsis thaliana was accompanied by inactivation of genes required for SI, including S-LOCUS RECEPTOR KINASE (SRK) and S-LOCUS CYSTEINE-RICH PROTEIN (SCR), coadapted genes that constitute the SI specificity-determining S haplotype. Arabidopsis accessions are polymorphic for PsiSRK and PsiSCR, but it is unknown if the species harbors structurally different S haplotypes, either representing relics of ancestral functional and structurally heteromorphic S haplotypes or resulting from decay concomitant with or subsequent to the switch to self-fertility. We cloned and sequenced the S haplotype from C24, in which self-fertility is due solely to S locus inactivation, and show that this haplotype was produced by interhaplotypic recombination. The highly divergent organization and sequence of the C24 and Columbia-0 (Col-0) S haplotypes demonstrate that the A. thaliana S locus underwent extensive structural remodeling in conjunction with a relaxation of selective pressures that once preserved the integrity and linkage of coadapted SRK and SCR alleles. Additional evidence for this process was obtained by assaying 70 accessions for the presence of C24- or Col-0-specific sequences. Furthermore, analysis of SRK and SCR polymorphisms in these accessions argues against the occurrence of a selective sweep of a particular allele of SCR, as previously proposed.

The N-terminal decapeptide methyl ester, H-Ala-Asn-Lys-Gly-Phe-Leu-Gla-Gla-Val-Arg-OCH3 (16) of bovine prothrombin fragment 1 has been prepared by standard solution techniques, via a fragment coupling strategy. Hexapeptide Boc-Ala-Asn-Lys epsilon (Boc)-Gly-Phe-Leu-OBzl (9) was obtained by coupling Boc-Ala-Asn-Lys epsilon (Boc)Gly-OH (6) to the trifluoroacetate salt of H-Phe-Leu-OBzl (8). Hydrogenolysis of (9) followed by coupling to HCl. H-Gla gamma (OtBu)2-Gla gamma (OtBu)2-Val-Arg(HCl)-OCH3 (14) gave the fully protected decapeptide (15). Treatment of 15 with 90% trifluoroacetic acid followed by ion exchange chromatography of 15 yielded the methyl ester (16). The decapeptide 16 labeled with 125I using the Bolton-Hunter reagent, did not bind to antibodies specific for the calcium ion-induced conformation of bovine fragment 1.