bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of diabetes mellitus on bladder uroepithelial cells
Authors: Hanna-Mitchell Ann T. , Ruiz Giovanni W. , Daneshgari Firouz , Liu Guiming , Apodaca Gerard , Birder Lori A.
Published: November 2012

Diabetic bladder dysfunction (DBD), a prevalent complication of diabetes mellitus (DM), is characterized by a broad spectrum of symptoms including urinary urgency, frequency, and incontinence. As DBD is commonly diagnosed late, it is important to understand the chronic impact of DM on bladder tissues. While changes in bladder smooth muscle and innervation have been reported in diabetic patients, the impact of DM on the specialized epithelial lining of the urinary bladder, the urothelium (UT), is largely unknown. Quantitative polymerase chain reaction analysis and electron microscopy were used to evaluate UT gene expression and cell morphology 3, 9, and 20 wk following streptozotocin (STZ) induction of DM in female Sprague-Dawley rats compared with age-matched control tissue. Desquamation of superficial (umbrella) cells was noted at 9 wk DM, indicating a possible breach in barrier function. One causative factor may be metabolic burden due to chronic hyperglycemia, suggested by upregulation of the polyol pathway and glucose transport genes in DM UT. While superficial UT repopulation occurred by 20 wk DM, the phenotype was different, with significant upregulation of receptors associated with UT mechanosensation (transient receptor potential vanilloid subfamily member 1; TRPV1) and UT autocrine/paracrine signaling (acetylcholine receptors AChR-M2 and -M3, purinergic receptors P2X2and P2X3). Compromised barrier function and alterations in UT mechanosensitivity and cell signaling could contribute to bladder instability, hyperactivity, and altered bladder sensation by modulating activity of afferent nerve endings, which appose the urothelium. Our results show that DM impacts urothelial homeostasis and may contribute to the underlying mechanisms of DBD.
Effects of short-term dietary nitrate supplementation on blood pressure, O2uptake kinetics, and muscle and cognitive function in older adults
Authors: Kelly James , Fulford Jonathan , Vanhatalo Anni , Blackwell Jamie R. , French Olivia , Bailey Stephen J. , Gilchrist Mark , Winyard Paul G. , Jones Andrew M.
Published: November 2012

Dietary nitrate (NO3−) supplementation has been shown to reduce resting blood pressure and alter the physiological response to exercise in young adults. We investigated whether these effects might also be evident in older adults. In a double-blind, randomized, crossover study, 12 healthy, older (60–70 yr) adults supplemented their diet for 3 days with either nitrate-rich concentrated beetroot juice (BR; 2 × 70 ml/day, ∼9.6 mmol/day NO3−) or a nitrate-depleted beetroot juice placebo (PL; 2 × 70 ml/day, ∼0.01 mmol/day NO3−). Before and after the intervention periods, resting blood pressure and plasma [nitrite] were measured, and subjects completed a battery of physiological and cognitive tests. Nitrate supplementation significantly increased plasma [nitrite] and reduced resting systolic (BR: 115 ± 9 vs. PL: 120 ± 6 mmHg; P < 0.05) and diastolic (BR: 70 ± 5 vs. PL: 73 ± 5 mmHg; P < 0.05) blood pressure. Nitrate supplementation resulted in a speeding of the V̇o2mean response time (BR: 25 ± 7 vs. PL: 28 ± 7 s; P < 0.05) in the transition from standing rest to treadmill walking, although in contrast to our hypothesis, the O2cost of exercise remained unchanged. Functional capacity (6-min walk test), the muscle metabolic response to low-intensity exercise, brain metabolite concentrations, and cognitive function were also not altered. Dietary nitrate supplementation reduced resting blood pressure and improved V̇o2kinetics during treadmill walking in healthy older adults but did not improve walking or cognitive performance. These results may have implications for the enhancement of cardiovascular health in older age.
Decrease in the red cell cofactor 2,3-diphosphoglycerate increases hemoglobin oxygen affinity in the hibernating brown bearUrsus arctos
Authors: Revsbech Inge G. , Malte Hans , Fröbert Ole , Evans Alina , Blanc Stéphane , Josefsson Johan , Fago Angela
Published: November 2012

During winter hibernation, brown bears ( Ursus arctos) reduce basal O2consumption rate to ∼25% compared with the active state, while body temperature decreases moderately (to ∼30°C), suggesting a temperature-independent component in their metabolic depression. To establish whether changes in O2consumption during hibernation correlate with changes in blood O2affinity, we took blood samples from the same six individuals of hibernating and nonhibernating free-ranging brown bears during winter and summer, respectively. A single hemoglobin (Hb) component was detected in all samples, indicating no switch in Hb synthesis. O2binding curves measured on red blood cell lysates at 30°C and 37°C showed a less temperature-sensitive O2affinity than in other vertebrates. Furthermore, hemolysates from hibernating bears consistently showed lower cooperativity and higher O2affinity than their summer counterparts, regardless of the temperature. We found that this increase in O2affinity was associated with a significant decrease in the red cell Hb-cofactor 2,3-diphosphoglycerate (DPG) during hibernation to approximately half of the summer value. Experiments performed on purified Hb, to which DPG had been added to match summer and winter levels, confirmed that the low DPG content was the cause of the left shift in the Hb-O2equilibrium curve during hibernation. Levels of plasma lactate indicated that glycolysis is not upregulated during hibernation and that metabolism is essentially aerobic. Calculations show that the increase in Hb-O2affinity and decrease in cooperativity resulting from decreased red cell DPG may be crucial in maintaining a fairly constant tissue oxygen tension during hibernation in vivo.
Coding of the long-term value of multiple future rewards in the primate striatum
Authors: Yamada Hiroshi , Inokawa Hitoshi , Matsumoto Naoyuki , Ueda Yasumasa , Enomoto Kazuki , Kimura Minoru
Published: November 2012

Decisions maximizing benefits involve a tradeoff between the quantity of a reward and the cost of elapsed time until an animal receives it. The estimation of long-term reward values is critical to attain the most desirable outcomes over a certain period of time. Reinforcement learning theories have established algorithms to estimate the long-term reward values of multiple future rewards in which the values of future rewards are discounted as a function of how many steps of choices are necessary to achieve them. Here, we report that presumed striatal projection neurons represent the long-term values of multiple future rewards estimated by a standard reinforcement learning model while monkeys are engaged in a series of trial-and-error choices and adaptive decisions for multiple rewards. We found that the magnitude of activity of a subset of neurons was positively correlated with the long-term reward values, and that of another subset of neurons was negatively correlated throughout the entire decision-making process in individual trials: from the start of the task trial, estimation of the values and their comparison among alternatives, choice execution, and evaluation of the received rewards. An idiosyncratic finding was that neurons showing negative correlations represented reward values in the near future (high discounting), while neurons showing positive correlations represented reward values not only in the near future, but also in the far future (low discounting). These findings provide a new insight that long-term value signals are embedded in two subsets of striatal neurons as high and low discounting of multiple future rewards.
Directed functional connectivity matures with motor learning in a cortical pattern generator
Authors: Day Nancy F. , Terleski Kyle L. , Nykamp Duane Q. , Nick Teresa A.
Published: November 2012

Sequential motor skills may be encoded by feedforward networks that consist of groups of neurons that fire in sequence ( Abeles 1991 ; Long et al. 2010 ). However, there has been no evidence of an anatomic map of activation sequence in motor control circuits, which would be potentially detectable as directed functional connectivity of coactive neuron groups. The proposed pattern generator for birdsong, the HVC ( Long and Fee 2008 ; Vu et al. 1994 ), contains axons that are preferentially oriented in the rostrocaudal axis ( Nottebohm et al. 1982 ; Stauffer et al. 2012 ). We used four-tetrode recordings to assess the activity of ensembles of single neurons along the rostrocaudal HVC axis in anesthetized zebra finches. We found an axial, polarized neural network in which sequential activity is directionally organized along the rostrocaudal axis in adult males, who produce a stereotyped song. Principal neurons fired in rostrocaudal order and with interneurons that were rostral to them, suggesting that groups of excitatory neurons fire at the leading edge of travelling waves of inhibition. Consistent with the synchronization of neurons by caudally travelling waves of inhibition, the activity of interneurons was more coherent in the orthogonal mediolateral axis than in the rostrocaudal axis. If directed functional connectivity within the HVC is important for stereotyped, learned song, then it may be lacking in juveniles, which sing a highly variable song. Indeed, we found little evidence for network directionality in juveniles. These data indicate that a functionally directed network within the HVC matures during sensorimotor learning and may underlie vocal patterning.
Responses to loud auditory stimuli indicate that movement-related activation builds up in anticipation of action
Authors: Marinovic Welber , de Rugy Aymar , Lipp Ottmar V. , Tresilian James R.
Published: November 2012

Previous research using a loud acoustic stimulus (LAS) to investigate motor preparation in reaction time (RT) tasks indicates that responses can be triggered well in advance of the presentation of an imperative stimulus (IS). This is intriguing given that high levels of response preparation cannot be maintained for long periods (≈ 200 ms). In the experiments reported here we sought to assess whether response-related activation increases gradually over time in simple RT tasks. In experiment 1, a LAS was presented at different times just prior to the presentation of the IS to probe the level of activation for the motor response. In experiment 2, the same LAS was presented at different times after the presentation of the IS. The results provide evidence that response-related activation does increase gradually in anticipation of the IS, but it remains stable for a short time after this event. The data display a pattern consistent with the response being triggering by the LAS, rather than a reaction to the IS.
Tumor Burden Modeling Versus Progression-Free Survival for Phase II Decision Making
Authors: Kaiser Lee D.
Published: November 2012

Randomized Phase II oncology trial endpoints for decision making include both progression-free survival (PFS) and change in tumor burden as measured by the sum of longest diameters (SLD) of the target lesions. In addition to observed SLD changes, tumor shrinkage and growth parameters can be estimated from the patient-specific SLD profile over time. The ability of these SLD analyses to identify an active drug is contrasted with that of a PFS analysis through the simulation of Phase II trials via resampling from each of 6 large, Phase II and III trials, 5 of which were positive and one negative. From each simulated Phase II trial, a P value was obtained from 4 analyses—a log-rank test on PFS, a Wilcoxon rank-sum test on the minimum observed percentage change from baseline in SLD, and 2 nonlinear, mixed-effects model analyses of the SLD profiles. All 4 analyses led to approximately uniformly distributed P values in the negative trial. The PFS analysis was the best or nearly the best analysis in the other 5 trials. In only one of the positive studies did the modeling analysis outperform the analysis of the minimum SLD. In conclusion, for the decision to start a Phase III trial based on the results of a randomized Phase II trial of an oncology drug, PFS appears to be a better endpoint than does SLD, whether analyzed through simple SLD endpoints, such as the minimum percentage change from baseline, or through the modeling of the SLD time course to estimate tumor dynamics. Clin Cancer Res; 19(2); 314–9. ©2012 AACR.
Breast Cancer Treatment with Imiquimod: Applying an Old Lotion to a New Disease
Authors: Kohrt Holbrook
Published: November 2012

Over the prior two decades, imiquimod, a toll-like receptor 7 agonist, has been applied to nearly 50 clinical settings. Because of its immunomodulatory role, the topical cream today, for the first time, is being applied to cutaneous breast cancer in preclinical models and in a phase II clinical trial. Clin Cancer Res; 18(24); 6571–3. ©2012 AACR.
Radiation Survivors: Understanding and Exploiting the Phenotype following Fractionated Radiation Therapy
Authors: Makinde Adeola Y. , John-Aryankalayil Molykutty , Palayoor Sanjeewani T. , Cerna David , Coleman C. Norman
Published: November 2012

Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors, focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing the cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145, and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multifraction (MF) radiation of 0.5, 1, and/or 2 Gy fraction to 10 Gy total dose, and a single dose of 5 and 10 Gy. The resulting changes in mRNA, miRNA, and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell-cycle arrest, TGF-β, survival, and apoptotic signal transduction. The radiation-induced stress response will set forth a unique platform for exploiting the effects of radiation therapy as “focused biology” for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome. Mol Cancer Res; 11(1); 5–12. ©2012 AACR.
Football Gambling Three Arm-Controlled Study: Gamblers, Amateurs and Laypersons
Authors: Huberfeld Ronen , Gersner Roman , Rosenberg Oded , Kotler Moshe , Dannon Pinhas N.
Published: November 2012

Background: Football (soccer) betting, as a strategic form of betting, became one of the favorite wagers for pathological gamblers. Previous studies demonstrated the psychological and biological significance of the ‘illusion of control’ (personal control) and ‘near miss’ results in gambling. In our study, we explored whether knowledge and expertise of pathological sports gamblers can ensure a successful bet. Sample and Methods: Participants were divided into three groups of individuals – pathological gamblers, amateurs and laypersons – and were asked to predict in advance the general result and the exact result of football matches in the European Champions League Round of 16. Results: The 165 participants included 53 pathological sports gamblers (52 males and 1 female), 78 laypersons (45 females and 33 males) and 34 amateurs (all males). After a thorough statistical analysis, we found no significant differences between the groups, no matter what kind of previous knowledge they had acquired. Conclusion: This study demonstrates that the ‘illusion of control’ of pathological gamblers, attained by knowledge of the game and its latest data and information (especially in a strategic gamble as football betting), has no factual background. Moreover, our study demonstrates without a doubt that there is no significant difference between the male pathological sports gamblers group and the male/female laypersons group.
Can Heroin-Dependent Individuals Benefit from a Methadone Maintenance Treatment Program before They Drop Out against Medical Advice? A 12-Month Follow-Up Study
Authors: Wang Peng-Wei , Wu Hung-Chi , Lin Huang-Chi , Yen Chia-Nan , Yeh Yi-Chun , Chung Kuan-Sheng , Chang Hsun-Cheng , Yen Cheng-Fang
Published: November 2012

Aim: Little is known about whether heroin-dependent individuals receiving methadone maintenance treatment (MMT) who were discharged involuntarily and against medical advice (DAMA) get benefits before they left. The aims of this 12-month follow-up study were to examine whether the effects of MMT on depressive symptoms, heroin dependence and quality of life (QOL) are different among the non-DAMA group, the DAMA group, and the involuntarily discharged group, as well as the time effect of receiving MMT on changes in these three outcome indicators. Method: A total of 266 individuals receiving MMT were divided into the non-DAMA group, the DAMA group, and the involuntarily discharged group. Participants were interviewed at baseline and at 3, 6, 9, and 12 months of treatment for levels of depressive symptoms, heroin dependence and QOL. Results: The levels of depressive symptoms, heroin dependence and QOL in all three groups improved after receiving MMT for 3 months and the improvement was maintained during the MMT period. There were no significant differences in the three outcome indicators among the three groups. Conclusion: The results support the concept that heroin-dependent individuals benefit from MMT, even if they do not want to stay in the program or drop out involuntarily.
Screening Questionnaires for Problem Drinking in Adolescents: Performance of AUDIT, AUDIT-C, CRAFFT and POSIT
Authors: Rumpf Hans-Jürgen , Wohlert Tim , Freyer-Adam Jennis , Grothues Janina , Bischof Gallus
Published: November 2012

Background/Aims: Only rather few data on the validity of screening questionnaires to detect problem drinking in adolescents exist. The aim of this study was to compare the performance of the Alcohol Use Disorders Identification Test (AUDIT), its short form AUDIT-C, the Substance Module of the Problem Oriented Screening Instrument for Teenagers (POSIT), and CRAFFT (acronym for car, relax, alone, forget, family, and friends). Methods: The questionnaires were filled in by 9th and 10th graders from two comprehensive schools. All students received an interview using the alcohol section of the Composite International Diagnostic Interview. Alcohol abuse and alcohol dependence according to DSM-IV as well as episodic heavy drinking served as criteria to validate the screening instruments. Results: All 9th and 10th graders (n = 225) of both schools participated. No significant differences were found for areas under the receiver operating characteristic curves ranging from 0.810 to 0.872. Cronbach’s alpha was satisfactory (0.77–0.80) but poor for CRAFFT (0.64). Different cut-offs are discussed. Conclusions: Considering validity as well as reliability, AUDIT, AUDIT-C and POSIT performed well; however, the POSIT is quite lengthy. AUDIT-C showed good psychometric properties and has clear advantages because of its brevity.
Serum Total Immunoglobulin E Is a Surrogate of Atopy in Adult-Onset Asthma: A Longitudinal Study
Authors: Carsin Anne-Elie , Zock Jan-Paul , Jarvis Deborah , Basagaña Xavier , Heinrich Joachim , Toren Kjell , Janson Christer , Anto Josep Maria , Sunyer Jordi
Published: November 2012

Background: Studies have shown that serum total immunoglobulin E (IgE) levels are higher in asthmatics. However, the role of the serum total IgE level, independently from atopy, in adult asthma is not understood. We studied the associations between serum total IgE, the number of sensitizations and the sum of specific IgEs and new-onset asthma using longitudinal data from the European Community Respiratory Health Survey. Methods: Serum total and specific IgE to 4 common inhalant allergens were measured at baseline in 9,175 participants, with a follow-up of 9 years. Individuals with asthma history and/or asthma symptoms were excluded. Atopy was defined as the presence of at least one specific IgE ≥0.35 kU/l. Total and specific IgEs were regressed against new-onset asthma using multivariate logistic regression with a random intercept for the study centre. Results: Two hundred and ninety-seven participants had developed asthma during follow-up (incidence rate 5.7 per 1,000 person-years). A 10% higher level of total IgE was associated with a 12% increased risk of new-onset asthma (p = 0.005). However, after adjustment for the number of positive specific IgEs [odds ratio (OR) for multiple sensitization 1.74, 95% confidence interval (CI) 1.05–2.88] and the sum of allergen-specific IgEs (OR 1.18, 95% CI 1.00–1.40), the association between total IgE and asthma disappeared (OR 1.00, 95% CI 0.91–1.10). Seventeen percent of new-onset asthma cases could be attributed to atopy, and this estimate was not largely modified when the total IgE level was simultaneously taken into account. Conclusions: After taking into account the number and intensity of 4 specific IgEs, the serum total IgE level was not associated with new-onset asthma in adults.
Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model
Authors: Weidenfeld Joseph , Siegal Tali , Ovadia Haim
Published: November 2012

Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI.
Delayed Central Nervous System Irradiation Effects in Rats – Part 2: Aggravation of Experimental Autoimmune Encephalomyelitis
Authors: Ovadia Haim , Siegal Tali , Weidenfeld Joseph
Published: November 2012

Background: Central nervous system (CNS) irradiation has detrimental effects which become evident within hours to few days and after a long latency of months and years. However, the delayed effect of irradiation on neuroimmune diseases has not been thoroughly examined. Objectives: We evaluated the delayed effects of irradiation on the course of experimental autoimmune encephalomyelitis (EAE), which is used as a model for neuroimmune inflammation and multiple sclerosis. Methods: Adult male rats were exposed to a dose of 15 Gy given to the thoracolumbar spinal cord. Six months later, EAE was induced by inoculation of rat spinal cord homogenate in complete Freund’s adjuvant (CFA). The disease was evaluated by clinical, histopathological and immunological parameters. Results: Irradiated rats developed clinical signs of EAE earlier than the control group and their disease was much more severe. Unlike the control group, all rats in the EAE-irradiated group died within 5 days after the onset of clinical signs. Sections taken from irradiated rats showed diffuse and large hemorrhagic infiltrates of lymphocytes and granulocytes. In contrast, control rats displayed fewer infiltrates, which were less prominent and not hemorrhagic. Conclusions: CNS irradiation has a delayed effect that caused a marked aggravation of the clinical and pathological signs of EAE. The severity of the disease may be a consequence of the effect of irradiation on the CNS vascular bed and impaired blood-brain barrier.
The Discovery of Vitamin K and Its Clinical Applications
Authors: Ferland Guylaine
Published: November 2012

Vitamin K was discovered fortuitously in 1929 as part of experiments on sterol metabolism and was immediately associated with blood coagulation. In the decade that followed, the principal K vitamers, phylloquinone and the menaquinones, were isolated and fully characterized. In the early 1940s, the first vitamin K antagonists were discovered and crystallized with one of its derivatives, warfarin, still being widely used in today’s clinical setting. However, major progress in our understanding of the mechanisms of action of vitamin K came in the 1970s with the discovery of γ-carboxyglutamic acid (Gla), a new amino acid common to all vitamin K proteins. This discovery not only provided the basis to understanding earlier findings about prothrombin but later led to the discovery of vitamin K-dependent proteins (VKDPs) not involved in hemostasis. The 1970s also saw an important breakthrough with respect to our understanding of the vitamin K cycle and marked the discovery of the first bone VKDP, osteocalcin. Important studies relating to the role of vitamin K in sphingolipid synthesis were also underway at that time and would pave the way to further work 15 years later. The decades that followed saw the discovery of additional VKDPs showing wide tissue distribution and functional scope, the latest members having been identified in 2008. The 1990s and 2000s were also marked by important epidemiological and intervention studies that focused on the translational impact of recent vitamin K discoveries, notably with respect to bone and cardiovascular health. This short review presents an overview of the history of vitamin K and of its recent developments.
The Discovery and Characterization of Riboflavin
Authors: Northrop-Clewes Christine A. , Thurnham David I.
Published: November 2012

The first observation of a pigment in milk with yellow-green fluorescence can be traced to the English chemist Alexander Wynter Blyth in 1872, but it was not until the early 1930s that the substance was characterized as riboflavin. Interest in accessory food factors began in the latter half of the 19th century with the discovery of the first vitamin, thiamin. Thiamin was water soluble and given the name vitamin B1. However, researchers realized that there were one or more additional water-soluble factors and these were called the vitamin B-2 complex. The search to identify these accessory food factors in milk, whole wheat, yeast, and liver began in the early 1900s. As there is no classical nutritional disease attributable to riboflavin deficiency, it was the growth-stimulating properties of the food extracts given to young rats that provided the tool with which to investigate and eventually extract riboflavin. Riboflavin was the second vitamin to be isolated and the first from the vitamin B-2 complex; the essential nature of the vitamin as a food constituent for man was shown in 1939.
A History of the Isolation and Identification of Folic Acid (Folate)
Authors: Rosenberg Irwin H.
Published: November 2012

In the 1930s, Lucy Wills identified a ‘new hemopoietic factor’ in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, ‘Wills’ factor’. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin Bc (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid – in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills’ factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present.
The Discovery of Niacin, Biotin, and Pantothenic Acid
Authors: Lanska Douglas J.
Published: November 2012

The aim was to describe the discovery of niacin, biotin, and pantothenic acid. By the 1920s, it became apparent that ‘water-soluble B’ (vitamin B) is not a single substance. In particular, fresh yeast could prevent both beriberi and pellagra, but the ‘antipolyneuritis factor’ in yeast is thermolabile, while the antipellagra factor is heat stable, suggesting that there are at least two water-soluble vitamins. Various terms were proposed for these water-soluble factors, but vitamins B1 and B2 were most widely used to refer to the thermolabile and heat-stable factors, respectively. Although vitamin B1 proved to be a single chemical substance (thiamin), vitamin B2 was ultimately found to be a complex of several chemically unrelated heat-stable factors, including niacin, biotin, and pantothenic acid. Recognition that niacin is a vitamin in the early 20th century resulted from efforts to understand and treat a widespread human disease – pellagra. American epidemiologist and US Public Health Service officer Joseph Goldberger (1874–1929) had been instrumental to elucidating the nutritional basis for pellagra. Goldberger conducted a classic series of observational and experimental studies in humans, combined with an extensive series of experiments with an animal model of the condition (black tongue in dogs). In contrast, recognition that biotin and pantothenic acid are vitamins occurred somewhat later as a result of efforts to understand microbial growth factors. The metabolic roles in humans of these latter substances were ultimately elucidated by human experiments using particular toxins and by studies of rare inborn errors of metabolism. Symptomatic nutritional deficiencies of biotin and pantothenic acid were, and continue to be, rare.
A Brief History of Choline
Authors: Zeisel Steven H.
Published: November 2012

In 1850, Theodore Gobley, working in Paris, described a substance, ‘lecithine’, which he named after the Greek ‘lekithos’ for egg yolk. Adolph Strecker noted in 1862 that when lecithin from bile was heated, it generated a new nitrogenous chemical that he named ‘choline’. Three years later, Oscar Liebreich identified a new substance, ‘neurine’, in the brain. After a period of confusion, neurine and choline were found to be the same molecule, and the name choline was adapted. Lecithin was eventually characterized chemically as being phosphatidylcholine. In 1954, Eugene Kennedy described the cytidine 5-dihphosphocholine pathway by which choline is incorporated into phosphatidylcholine. A second route, the phosphatidylethanolamine-N-methyltransferase pathway, was identified by Jon Bremer and David Greenberg in 1960. The role of choline as part of the neurotransmitter acetylcholine was established by Otto Loewi and Henry Dale. Working in the 1930s at the University of Toronto, Charles Best showed that choline prevented fatty liver in dogs and rats. The importance of choline as an essential nutrient for human health was determined in the 1990s through controlled feeding studies in humans. Recently, an understanding of the role of genetic variation in setting the dietary requirement for choline in people is being unraveled.
Nobel Laureates in the History of the Vitamins
Authors: Souganidis Ellie
Published: November 2012

Research on vitamins has advanced considerably over the past 100 years with numerous advancements in the fields of biochemistry, medicine, and nutrition. The purpose of this article is to present the history of vitamins using Nobel Prizes as a framework for each vitamin-related discovery. The Nobel Prize Presentation Speech and Nobel Lecture were reviewed for each Nobel Laureate who received an award for vitamin-related research. The original scientific work of a number of awardees was also utilized as a primary source of the history. Nobel Prizes were awarded primarily for the identification, isolation, and synthesis of vitamins. Additional awards recognized the role of specific vitamins in disease processes. The awarding of over 10 Nobel Prizes in Chemistry, Physiology or Medicine in the last century has recognized the seminal work of numerous scientists and physicians and showcased multiple important advancements in vitamins research.
On the ‘Discovery’ of Vitamin A
Authors: Semba Richard D.
Published: November 2012

Vitamin A is essential for normal growth, reproduction, immunity, and vision. The characterization of vitamin A spanned a period of about 130 years. During this long, incremental process, there is no single event that can be called the ‘discovery’ of vitamin A. The physiologist François Magendie conducted nutritional deprivation experiments with dogs in 1816 that resulted in corneal ulcers and high mortality – a finding similar to the common clinical situation in poorly fed, abandoned infants in Paris. In the 1880s, Nicolai Lunin showed that there was an unknown substance in milk that was essential for nutrition. Carl Socin suggested that an unknown substance for growth in egg yolk was fat soluble. Frederick Gowland Hopkins proposed in 1906 that there were ‘unsuspected dietetic factors’ that were necessary for life. In 1911, Wilhelm Stepp demonstrated that this essential substance in milk was fat soluble. The following year, Hopkins showed that there were ‘accessory factors’ present in ‘astonishingly small amounts’ in milk that supported life. Contrary to the dogma that all fats had similar nutritional value, in 1913, Elmer McCollum and Marguerite Davis at Wisconsin and Thomas Osborne and Lafayette Mendel at Yale showed butter and egg yolk were not equivalent to lard and olive oil in supporting the growth and survival of rats. The growth-supporting ‘accessory factor’ became known as ‘fat-soluble A’ in 1918 and then ‘vitamin A’ in 1920. Paul Karrer described the chemical structure of vitamin A in 1932. Harry Holmes and Ruth Corbet isolated and crystallized vitamin A in 1937. Methods for the synthesis of vitamin A came with the work of David Adriaan van Dorp and Jozef Ferdinand Arens in 1946 and Otto Isler and colleagues in 1947. Further work on the role of vitamin A in immunity and child survival continued until through the 1990s.
Long-Term Changes of Central Ocular Motor Signs in Patients with Vestibular Migraine
Authors: Neugebauer Hermann , Adrion Christine , Glaser Miriam , Strupp Michael
Published: November 2012

Background: A high percentage of patients with vestibular migraine (VM) were reported to have central ocular motor dysfunctions (COMD) in the symptom-free interval. Since VM is a chronic disorder, it is of interest if COMD worsen over time. Methods: Thirty VM patients and 11 control patients participated in an 8-year-long observational study with follow-up. All patients underwent standardized neuro-ophthalmological and neuro-otological examinations at the initial presentation and at follow-up. The primary outcome measure was change in COMD at follow-up. Results: In general, COMD in the symptom-free interval were subtle, consisting of a saccadic horizontal and/or vertical pursuit. At follow-up, significantly more patients with VM had COMD (p = 0.015). The prevalence of COMD increased from 20 to 63% in VM patients. Further, the presence of COMD at follow-up had a positive predictive value of 90.5% for the diagnosis of VM. Successful treatment with prophylactic migraine medication seems to prevent the development and worsening of COMD (p = 0.008). Conclusion: Mild COMD occur in a large percentage of VM patients during the course of the disease. The presence of COMD is predictive of VM in patients with recurrent attacks of vertigo. Prophylactic migraine medication seems to attenuate the development and progression of COMD.
Hemodynamic Responses to Rapid Saline Loading
Authors: Fujimoto Naoki , Borlaug Barry A. , Lewis Gregory D. , Hastings Jeffrey L. , Shafer Keri M. , Bhella Paul S. , Carrick-Ranson Graeme , Levine Benjamin D.
Published: November 2012

Background—

Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown.

Methods and Results—

Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100–200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L
−1
·m
2
) than the other 3 groups (
P
≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L
−1
·m
2
) than healthy young and older subjects (
P
≤0.005).

Conclusions—

Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.
A general framework for the manufacturing workstation design optimization: a combined ergonomic and operational approach
Authors: del Rio Vilas David , Longo Francesco , Monteil Nadia Rego
Published: November 2012

A general framework for the effective design, or re-design, of manufacturing workstations under a combined ergonomic and operational optimization approach is presented. This general framework must be regarded as a method for facilitating and supporting engineers and researchers in the design of manufacturing workstations. The three key elements forming this general framework are presented and discussed. Finally to provide evidence on the relevance of the proposed general framework, two original case studies, developed by the authors in cooperation with two real manufacturing systems (one located in Italy and one in Spain), are presented. This paper will provide useful insights and guidelines to engineers, researchers and practitioners involved in manufacturing workstations design.
Book reading mediation, SES, home literacy environment, and children’s literacy: Evidence from Arabic-speaking families
Authors: Korat Ofra , Arafat Safieh H. , Aram Dorit , Klein Pnina
Published: November 2012

This article investigates the contribution of maternal mediation in storybook reading, socioeconomic status (SES), and home literacy environment (HLE) to children’s literacy level in kindergarten and first grade in Israeli Arabic-speaking families. A total of 109 kindergarten children and their mothers participated. Children’s literacy level was assessed in kindergarten. Mothers and children were videotaped at home in a book reading activity, and HLE data were gathered from the mothers. One year later, the children’s literacy level was assessed in first grade. Results show that mothers often used paraphrasing in the reading activities and dealt less with the written language. Correlations were found between SES and children’s literacy measures in oral and written language in kindergarten and in first grade. Significant positive relationships were found between HLE and children’s literacy level in kindergarten and first grade. No relationship was found between maternal mediation and children’s spoken and written language skills in either age group. Regression analysis showed that HLE was the best contributor variable to children’s literacy level, followed by family SES level, with no contribution of maternal mediation. Implications of the relationships between children’s literacy development, SES, HLE, and parental mediation in Arabic-speaking families for researchers and educational practitioners are discussed.
Health-Related Quality of Life, Disease Severity, and Anticipated Trajectory of Diabetes
Authors: Scollan-Koliopoulos Melissa , Bleich David , Rapp Kenneth J. , Wong Patrick , Hofmann Cynthia J. , Raghuwanshi Maya
Published: November 2012

Purpose

Adults hospitalized with diabetes are likely to have multiple comorbid conditions contributing to suboptimal health-related quality of life. The purpose of this study was to survey urban, very low-income, hospitalized adults with diabetes about disease severity, anticipated disease trajectory, and self-rated health-related quality of life.

Methods

Data were collected using the Brief Illness Perception Questionnaire, the 36-item Short Form Health Survey (SF-36), the comparative risk perception questionnaire, and glycosylated hemoglobin. Severity was defined by glycosylated hemoglobin level and current microvascular complications from diabetes.

Findings

Those with more severe disease who also anticipated the development of additional diabetes-related complications were likely to have suboptimal physical and mental functioning. The perception of diabetes as a health threat concurrent with having non-diabetes-related comorbid chronic conditions contributed uniquely to explaining scores in health-related quality of life.

Conclusion

Hospitalized adults with diabetes represent a population affected by chronic disease demands that contribute to suboptimal physical and mental functioning. Suboptimal quality of life may contribute to severity of diabetes and to a perception of having a threatening disease trajectory. Hospitalization provides an opportunity for clinicians to intervene in mental and physical functioning by assessing for threatening illness perceptions and employing interventions to promote acceptance of functional limitations.
Secondary School Administrators’ Attitudes Toward Confidentiality in School Counseling
Authors: O’Connell William P.
Published: November 2012

The school counseling literature emphasizes the importance of confidentiality in the counseling relationship. In some circumstances, school policy may require disclosure of content discussed in counseling unrelated to threat of harm to self or others. This pilot study investigated secondary school principals’ attitudes toward the practice of confidentiality in schools. Analysis of the survey data revealed that the sample of principals supported the practice of confidentiality in school counseling in the absence of threat of harm to self or others.
Influences on the decision to prescribe or administer anticholinergic drugs to treat death rattle: A focus group study
Authors: Hirsch Christine A , Marriott John F , Faull Christina M
Published: November 2012

Background:

The evidence supporting pharmacological treatment of death rattle is poor; yet, anticholinergic drugs feature in end-of-life care pathways and guidelines worldwide as a treatment option.

Aim:

This qualitative arm of a wider study aimed to explore important issues which health-care professionals associated with decision-making to prescribe or administer anticholinergics at the end of life.

Design:

After purposive sampling, five focus groups were conducted. Discussions were audiotaped and transcribed verbatim.

Setting:

Thirty medical and nursing personnel working in inpatient and community settings from two specialist palliative care units in the United Kingdom took part in the study.

Results:

Thematic analysis of transcripts from audiotapes revealed perceived pressures to prescribe and/or administer anticholinergics from colleagues and carers, and drugs were often prescribed or administered in order to be seen to ‘do something’, although the benefit in terms of therapeutic response was considered minimal. Familiarity with drug regimens and dosing was often based on personal experience. The monitoring of side effects of anticholinergics at the end of life was recognised as problematic and had little influence on prescribing and administration. There was also an indication that patients and carers in the community were more likely to receive timely verbal preparation and explanation around death rattle than those cared for in an inpatient setting.

Conclusion:

The study raises questions about the routine inclusion of anticholinergic treatment in UK end of life care pathways for the treatment of death rattle.
Exploring Clinical and Personality Characteristics of Adult Male Internet-Only Child Pornography Offenders
Authors: Magaletta Philip R. , Faust Erik , Bickart William , McLearen Alix M.
Published: November 2012

Despite the dramatic increase in the number of convicted child pornography offenders, little is known about their potential clinical needs. The few studies that do explore this subgroup of sex offenders suggest clinical heterogeneity compared with other sex offender subgroups. However, research designs used in many studies have limited generalizability, have examined primarily treated or treatment samples, and have not included comparisons with nontreatment, community samples of men. The current study addresses such limitations by using nontreatment samples and multiple comparison groups to examine mean scales score differences on a commonly used clinical and personality assessment, the Personality Assessment Inventory (PAI). The sample, drawn from an admissions cohort of federal offenders, those Internet-only Child Pornography Offenders (ICPOs; n = 35) and those with a history of child molesting exclusively (child molesters, n = 26). They were compared with each other and the male normative sample from the PAI. Results indicate that interpersonal deficits and depression featured most prominently in the profiles of the ICPOs. Consistent with prior research, they also obtained lower scores on aggression and dominance compared with the child molesters and the male normative sample. Implications for future research, training, and clinical practice with incarcerated ICPOs are offered.