bluuebunny/crossref_metadata_2025 huggingface dataset:
Review: Improving symptom control in early Parkinson’s disease
Authors: Isaacson Stuart H. , Hauser Robert A.
Published: August 2009

Motor symptoms in Parkinson’s disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control.
Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig
Authors: Ferrer Elisabet , Peinado Víctor Ivo , Díez Marta , Carrasco Josep Lluís , Musri Melina Mara , Martínez Anna , Rodríguez-Roisin Robert , Albert Barberà Joan
Published: August 2009

Background

Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages. The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.

Methods

19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods. Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP. The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of α-actin and desmin. Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically. The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.

Results

Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta. Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure. Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure. Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces. Lung expression of eNOS was decreased in animals exposed to cigarette smoke.

Conclusion

In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS. These changes appear after 3 months of exposure and precede the development of pulmonary emphysema.
Long-range regulation is a major driving force in maintaining genome integrity
Authors: Mongin Emmanuel , Dewar Ken , Blanchette Mathieu
Published: August 2009

Background

The availability of newly sequenced vertebrate genomes, along with more efficient and accurate alignment algorithms, have enabled the expansion of the field of comparative genomics. Large-scale genome rearrangement events modify the order of genes and non-coding conserved regions on chromosomes. While certain large genomic regions have remained intact over much of vertebrate evolution, others appear to be hotspots for genomic breakpoints. The cause of the non-uniformity of breakpoints that occurred during vertebrate evolution is poorly understood.

Results

We describe a machine learning method to distinguish genomic regions where breakpoints would be expected to have deleterious effects (called breakpoint-refractory regions) from those where they are expected to be neutral (called breakpoint-susceptible regions). Our predictor is trained using breakpoints that took place along the human lineage since amniote divergence. Based on our predictions, refractory and susceptible regions have very distinctive features. Refractory regions are significantly enriched for conserved non-coding elements as well as for genes involved in development, whereas susceptible regions are enriched for housekeeping genes, likely to have simpler transcriptional regulation.

Conclusion

We postulate that long-range transcriptional regulation strongly influences chromosome break fixation. In many regions, the fitness cost of altering the spatial association between long-range regulatory regions and their target genes may be so high that rearrangements are not allowed. Consequently, only a limited, identifiable fraction of the genome is susceptible to genome rearrangements.
Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and non-Hispanic whites
Authors: Mattei Josiemer , Parnell Laurence D , Lai Chao-Qiang , Garcia-Bailo Bibiana , Adiconis Xian , Shen Jian , Arnett Donna , Demissie Serkalem , Tucker Katherine L , Ordovas Jose M
Published: August 2009

Background

Variations in gene allele frequencies can contribute to differences in the prevalence of some common complex diseases among populations. Natural selection modulates the balance in allele frequencies across populations. Population differentiation (FST) can evidence environmental selection pressures. Such genetic information is limited in Puerto Ricans, the second largest Hispanic ethnic group in the US, and a group with high prevalence of chronic disease. We determined allele frequencies and population differentiation for 101 single nucleotide polymorphisms (SNPs) in 30 genes involved in major metabolic and disease-relevant pathways in Puerto Ricans (n = 969, ages 45–75 years) and compared them to similarly aged non-Hispanic whites (NHW) (n = 597).

Results

Minor allele frequency (MAF) distributions for 45.5% of the SNPs assessed in Puerto Ricans were significantly different from those of NHW. Puerto Ricans carried risk alleles in higher frequency and protective alleles in lower frequency than NHW. Patterns of population differentiation showed that Puerto Ricans had SNPs with exceptional FST values in intronic, non-synonymous and promoter regions. NHW had exceptional FST values in intronic and promoter region SNPs only.

Conclusion

These observations may serve to explain and broaden studies on the impact of gene polymorphisms on chronic diseases affecting Puerto Ricans.
Genomic diversity of citrate fermentation in Klebsiella pneumoniae
Authors: Chen Ying-Tsong , Liao Tsai-Lien , Wu Keh-Ming , Lauderdale Tsai-Ling , Yan Jing-Jou , Huang I-Wen , Lu Min-Chi , Lai Yi-Chyi , Liu Yen-Ming , Shu Hung-Yu , Wang Jin-Town , Su Ih-Jen , Tsai Shih-Feng
Published: August 2009

Background

It has long been recognized that Klebsiella pneumoniae can grow anaerobically on citrate. Genes responsible for citrate fermentation of K. pneumoniae were known to be located in a 13-kb gene cluster on the chromosome. By whole genome comparison of the available K. pneumoniae sequences (MGH 78578, 342, and NTUH-K2044), however, we discovered that the fermentation gene cluster was present in MGH 78578 and 342, but absent in NTUH-K2044. In the present study, the previously unknown genome diversity of citrate fermentation among K. pneumoniae clinical isolates was investigated.

Results

Using a genomic microarray containing probe sequences from multiple K. pneumoniae strains, we investigated genetic diversity among K. pneumoniae clinical isolates and found that a genomic region containing the citrate fermentation genes was not universally present in all strains. We confirmed by PCR analysis that the gene cluster was detectable in about half of the strains tested. To demonstrate the metabolic function of the genomic region, anaerobic growth of K. pneumoniae in artificial urine medium (AUM) was examined for ten strains with different clinical histories and genomic backgrounds, and the citrate fermentation potential was found correlated with the genomic region. PCR detection of the genomic region yielded high positive rates among a variety of clinical isolates collected from urine, blood, wound infection, and pneumonia. Conserved genetic organizations in the vicinity of the citrate fermentation gene clusters among K. pneumoniae, Salmonella enterica, and Escherichia coli suggest that the13-kb genomic region were not independently acquired.

Conclusion

Not all, but nearly half of the K. pneumoniae clinical isolates carry the genes responsible for anaerobic growth on citrate. Genomic variation of citrate fermentation genes in K. pneumoniae may contribute to metabolic diversity and adaptation to variable nutrient conditions in different environments.
Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1
Authors: Jiang Shiwen , Inada Takefumi , Tanaka Masakazu , Furuta Rika A , Shingu Koh , Fujisawa Jun-ichi
Published: August 2009

Background

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T -cell leukemia (ATL) but the expression of HTLV-1 is strongly suppressed in the peripheral blood of infected people. However, such suppression, which may explain the long latency in the development of ATL, is readily reversible, and viral expression resumes quickly with ex vivo culture of infected T -cells. To investigate the mechanism of in vivo -specific transcriptional suppression, we established a mouse model in which mice were intraperitoneally administered syngeneic EL4 T -lymphoma cells transduced with a recombinant retrovirus expressing a GFP-Tax fusion protein, Gax, under the control of the HTLV-1 enhancer (EL4-Gax).

Results

Gax gene transcription was silenced in vivo but quickly up-regulated in ex vivo culture. Analysis of integrated Gax reporter gene demonstrated that neither CpG methylation of the promoter DNA nor histone modification was associated with the reversible suppression. ChIP-analysis of LTR under suppression revealed reduced promoter binding of TFIIB and Pol-II, but no change in the binding of CREB or CBP/p300 to the viral enhancer sequence. However, the expression of TORC2, a co-activator of CREB, decreased substantially in the EL4-Gax cells in vivo, and this returned to normal levels in ex vivo culture. The reduced expression of TORC2 was associated with translocation from the nucleus to the cytoplasm. A knock-down experiment with siRNA confirmed that TORC2 was the major functional protein of the three TORC-family proteins (TORC1, 2, 3) in EL4-Gax cells.

Conclusion

These results suggest that the TORC2 may play an important role in the in vivo -specific transcriptional control of HTLV-1. This study provides a new model for the reversible mechanism that suppresses HTLV-1 expression in vivo without the DNA methylation or hypoacetylated histones that is observed in the primary cells of most HTLV-1 -infected carriers and a substantial number of ATL cases.
Optimal nutrition during the period of mechanical ventilation decreases mortality in critically ill, long-term acute female patients: a prospective observational cohort study
Authors: Strack van Schijndel Rob JM , Weijs Peter JM , Koopmans Rixt H , Sauerwein Hans P , Beishuizen Albertus , Girbes Armand RJ
Published: August 2009

Introduction

Optimal nutrition for intensive care patients has been proposed to be the provision of energy as determined by indirect calorimetry, and protein provision of at least 1.2 g/kg pre-admission weight per day. The evidence supporting these nutritional goals is based on surrogate outcomes and is not yet substantiated by patient oriented, clinically meaningful endpoints. In the present study we evaluated the effects of achieving optimal nutrition in ICU patients during their period of mechanical ventilation on mortality.

Methods

This was a prospective observational cohort study in a mixed medical-surgical, 28-bed ICU in an academic hospital. 243 sequential mixed medical-surgical patients were enrolled on day 3–5 after admission if they had an expected stay of at least another 5–7 days. They underwent indirect calorimetry as part of routine care. Nutrition was guided by the result of indirect calorimetry and we aimed to provide at least 1.2 g of protein/kg/day. Cumulative balances were calculated for the period of mechanical ventilation. Outcome parameters were ICU, 28-day and hospital mortality.

Results

In women, when corrected for weight, height, Apache II score, diagnosis category, and hyperglycaemic index, patients who reached their nutritional goals compared to those who did not, showed a hazard ratio (HR) of 0.199 for ICU mortality (CI 0.048–0.831; P = 0.027), a HR of 0.079 for 28 day mortality (CI 0.013–0.467; P = 0.005) and a HR of 0.328 for hospital mortality (CI 0.113–0.952; P = 0.04). Achievement of energy goals whilst not reaching protein goals, did not affect ICU mortality; the HR for 28 day mortality was 0.120 (CI 0.027–0.528; P = 0.005) and 0.318 for hospital mortality (CI 0.107–0.945; P = 0.039). No difference in outcome related to optimal feeding was found for men.

Conclusions

Optimal nutritional therapy improves ICU, 28-day and hospital survival in female ICU patients. Female patients reaching both energy and protein goals have better outcomes than those reaching only the energy goal. In the present study men did not benefit from optimal nutrition.
“Call for Prices”: Strategic Implications of Raising Consumers' Costs
Authors: Desai Preyas S. , Krishnamoorthy Anand , Sainam Preethika
Published: August 2009

Many consumer durable retailers often do not advertise their prices and instead ask consumers to call them for prices. It is easy to see that this practice increases the consumers' cost of learning the prices of products they are considering, yet firms commonly use such practices. Not advertising prices may reduce the firm's advertising costs, but the strategic effects of doing so are not clear. Our objective is to examine the strategic effects of this practice. In particular, how does making price discovery more difficult for consumers affect competing retailers' price, service decisions, and profits?

We develop a model in which a manufacturer sells its product through a high-service retailer and a low-service retailer. Consumers can purchase the retail service at the high-end retailer and purchase the product at the competing low-end retailer. Therefore, the high-end retailer faces a free-riding problem. A retailer first chooses its optimal service levels. Then, it chooses its optimal price levels. Finally, a retailer decides whether to advertise its prices. The model results in four structures: (1) both retailers advertise prices, (2) only the low-service retailer advertises price, (3) only the high-service retailer advertises price, and (4) neither retailer advertises price.

We find that when a retailer does not advertise its price and makes price discovery more difficult for consumers, the competition between the retailers is less intense. However, the retailer is forced to charge a lower price. In addition, if the competing retailer does advertise its prices, then the competing retailer enjoys higher profit margins. We identify conditions under which each of the above four structures is an equilibrium and show that a low-service retailer not advertising its price is a more likely outcome than a high-service retailer doing so. We then solve the manufacturer's problem and find that there are several instances when a retailer's advertising decisions are different from what the manufacturer would want. We describe the nature of this channel coordination problem and identify some solutions.
Investigating Consumer Purchase Behavior in Related Technology Product Categories
Authors: Sriram S. , Chintagunta Pradeep K. , Agarwal Manoj K.
Published: August 2009

We present a framework of durable goods purchasing behavior in related technology product categories that incorporates the following aspects unique to technology product purchases. First, it accounts for consumers' anticipation of declining prices (or increasing quality) over time. Second, the durable nature of technology products implies that even if two categories are related as complements, consumers may stagger their purchases over several periods. Third, the forward-looking consumer decision process, as well as the durable nature of technology products, implies that a consumer's purchase in one category will depend on the anticipated price and quality trajectories of all categories. As a potential aid to future researchers, we also lay out the data requirements for empirically estimating the parameters of our model and the consequences of not having various elements of these data on our ability to estimate the parameters. The data available for our empirical analysis are household-level information on category-level first-time adoption decisions in three categories—personal computers, digital cameras, and printers. Our results reveal a strong complementary relationship between the three categories. Policy simulations based on a temporary price decrease in any one category provide interesting insights into how consumers would modify their adoption behavior over time and also across categories as a consequence of the price decrease.
The Price Precision Effect: Evidence from Laboratory and Market Data
Authors: Thomas Manoj , Simon Daniel H. , Kadiyali Vrinda
Published: August 2009

We examine two questions: Does the roundness or precision of prices bias magnitude judgments? If so, do these biased judgments affect buyer behavior? Results from five studies suggest that buyers underestimate the magnitudes of precise prices. We term this the precision effect. The first three studies are laboratory experiments designed to test the existence of the precision effect and examine the underlying psychological processes. In Study 1, we find that precise prices are judged to be smaller than round prices of similar magnitudes. For example, participants in this experiment incorrectly judged $395,425 to be smaller than $395,000. In Study 2, we show that precision is more likely to affect magnitude judgments under conditions of uncertainty. Study 3 demonstrates that manipulating prior experience with the pattern of roundness and precision in numbers can moderate the precision effect. Studies 4 and 5 examine whether the precision effect influences buyers' willingness to pay for negotiated purchases (e.g., houses). In Study 4, we conduct an experiment on a nationally representative sample of homeowners to demonstrate that participants are willing to pay more for houses when the sellers use precise (e.g., $364,578) instead of comparable round (e.g., $365,000) prices. In Study 5, we analyze data from residential real estate transactions in two separate markets and find that buyers pay higher sale prices when list prices are more precise. These empirical results enrich our understanding of the psychological processes that underlie price magnitude judgments and have substantive implications for buyer and seller behavior.
The Race for Sponsored Links: Bidding Patterns for Search Advertising
Authors: Katona Zsolt , Sarvary Miklos
Published: August 2009

Paid placements on search engines reached sales of nearly $11 billion in the United States last year and represent the most rapidly growing form of online advertising today. In its classic form, a search engine sets up an auction for each search word in which competing websites bid for their sponsored links to be displayed next to the search results. We model this advertising market, focusing on two of its key characteristics: (1) the interaction between the list of search results and the list of sponsored links on the search page and (2) the inherent differences in attractiveness between sites. We find that both of these special aspects of search advertising have a significant effect on sites' bidding behavior and the equilibrium prices of sponsored links. Often, sites that are not among the most popular ones obtain the sponsored links, especially if the marginal return of sites on clicks is quickly decreasing and if consumers do not trust sponsored links. In three extensions, we also explore (1) heterogeneous valuations across bidding sites, (2) the endogenous choice of the number of sponsored links that the search engine sells, and (3) a dynamic model where websites' bidding behavior is a function of their previous positions on the sponsored list. Our results shed light on the seemingly random order of sites on search engines' list of sponsored links and their variation over time. They also provide normative insights for both buyers and sellers of search advertising.
Serotonin Transporter Availability in the Amygdala and Bed Nucleus of the Stria Terminalis Predicts Anxious Temperament and Brain Glucose Metabolic Activity
Authors: Oler Jonathan A. , Fox Andrew S. , Shelton Steven E. , Christian Bradley T. , Murali Dhanabalan , Oakes Terrence R. , Davidson Richard J. , Kalin Ned H.
Published: August 2009

The serotonin transporter (5-HTT) plays a critical role in regulating serotonergic neurotransmission and is implicated in the pathophysiology of anxiety and affective disorders. Positron emission tomography scans using [11C]DASB [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] to measure 5-HTT availability (an index of receptor density and binding) were performed in 34 rhesus monkeys in which the relationship between regional brain glucose metabolism and anxious temperament was previously established. 5-HTT availability in the amygdalohippocampal area and bed nucleus of the stria terminalis correlated positively with individual differences in a behavioral and neuroendocrine composite of anxious temperament. 5-HTT availability also correlated positively with stress-induced metabolic activity within these regions. Collectively, these findings suggest that serotonergic modulation of neuronal excitability in the neural circuitry associated with anxiety mediates the developmental risk for affect-related psychopathology.
Neuronal Circuit Remodeling in the Contralateral Cortical Hemisphere during Functional Recovery from Cerebral Infarction
Authors: Takatsuru Yusuke , Fukumoto Dai , Yoshitomo Miki , Nemoto Tomomi , Tsukada Hideo , Nabekura Junichi
Published: August 2009

Recent advances in functional imaging of human brain activity in stroke patients, e.g., functional magnetic resonance imaging, have revealed that cortical hemisphere contralateral to the infarction plays an important role in the recovery process. However, underlying mechanisms occurring in contralateral hemisphere during functional recovery have not been elucidated. We experimentally induced a complete infarction of somatosensory cortex in right hemisphere of mice and examined the neuronal changes in contralateral (left) somatosensory cortex during recovery. Both basal and ipsilateral somatosensory stimuli-evoked neuronal activity in left (intact) hemisphere transiently increased 2 d after stroke, followed by an increase in the turnover rate of usually stable mushroom-type synaptic spines at 1 week, observed by using two-photon imagingin vivo. At 4 weeks after stroke, when functional recovery had occurred, a new pattern of electrical circuit activity in response to somatosensory stimuli was established in intact ipsilateral hemisphere. Thus, the left somatosensory cortex can compensate for the loss of the right somatosensory cortex by remodeling neuronal circuits and establishing new sensory processing. This finding could contribute to establish the effective clinical treatments targeted on the intact hemisphere for the recovery of impaired functions and to achieve better quality of life of patients.
TrkB Modulates Fear Learning and Amygdalar Synaptic Plasticity by Specific Docking Sites
Authors: Musumeci Gabriele , Sciarretta Carla , Rodríguez-Moreno Antonio , Al Banchaabouchi Mumna , Negrete-Díaz Vicente , Costanzi Marco , Berno Valeria , Egorov Alexei V. , von Bohlen und Halbach Oliver , Cestari Vincenzo , Delgado-García José M. , Minichiello Liliana
Published: August 2009

Understanding the modulation of the neural circuitry of fear is clearly one of the most important aims in neurobiology. Protein phosphorylation in response to external stimuli is considered a major mechanism underlying dynamic changes in neural circuitry. TrkB (Ntrk2) neurotrophin receptor tyrosine kinase potently modulates synaptic plasticity and activates signal transduction pathways mainly through two phosphorylation sites [Y515/Shc site; Y816/PLCγ (phospholipase Cγ) site]. To identify the molecular pathways required for fear learning and amygdalar synaptic plasticity downstream of TrkB, we used highly defined genetic mouse models carrying single point mutations at one of these two sites (Y515F or Y816F) to examine the physiological relevance of pathways activated through these sites for pavlovian fear conditioning (FC), as well as for synaptic plasticity as measured by field recordings obtained from neurons of different amygdala nuclei. We show that a Y816F point mutation impairs acquisition of FC, amygdalar synaptic plasticity, and CaMKII signaling at synapses. In contrast, a Y515F point mutation affects consolidation but not acquisition of FC to tone, and also alters AKT signaling. Thus, TrkB receptors modulate specific phases of fear learning and amygdalar synaptic plasticity through two main phosphorylation docking sites.
Attention Improves Object Representation in Visual Cortical Field Potentials
Authors: Rotermund David , Taylor Katja , Ernst Udo A. , Kreiter Andreas K. , Pawelzik Klaus R.
Published: August 2009

Selective attention improves perception and modulates neuronal responses, but how attention-dependent changes of cortical activity improve the processing of attended objects is an open question. Changes in total signal strength or enhancements in signal-to-noise ratio have been proposed as putative mechanisms. However, it is still not clear whether, and to what extent, these processes contribute to the large perceptual improvements. We studied the ability to discriminate states of activity in visual cortex evoked by differently shaped objects depending on selective attention in monkeys. We found that gamma-band activity from V4 and V1 contains a high amount of information about stimulus shape, which increases for V4 recordings considerably with attention in successful trials, but not in case of behavioral errors. This effect resulted from enhanced differences between the stimulus-specific distributions of power spectral amplitudes. It could be explained neither by enhancements of signal-to-noise ratios, nor by changes in total signal power. Instead our results indicate that attention causes underlying cortical network states to become more distinct for different stimuli, providing a new neurophysiological explanation for improvements of behavioral performance by attention. The absence of the enhancement in discriminability in trials with behavioral errors demonstrates the relevance of this novel neural mechanism for perception.
Enigmatic Central Canal Contacting Cells: Immature Neurons in “Standby Mode”?
Authors: Marichal Nicolás , García Gabriela , Radmilovich Milka , Trujillo-Cenóz Omar , Russo Raúl E.
Published: August 2009

The region that surrounds the central canal of the spinal cord derives from the neural tube and retains a substantial degree of plasticity. In turtles, this region is a neurogenic niche where newborn neurons coexist with precursors, a fact that may be related with the endogenous repair capabilities of low vertebrates. Immunohistochemical evidence suggests that the ependyma of the mammalian spinal cord may contain cells with similar properties, but their actual nature remains unsolved. Here, we combined immunohistochemistry for cell-specific markers with patch-clamp recordings to test the hypothesis that the ependyma of neonatal rats contains immature neurons similar to those in low vertebrates. We found that a subclass of cells expressed HuC/D neuronal proteins, doublecortin, and PSA-NCAM (polysialylated neural cell adhesion molecule) but did not express NeuN (anti-neuronal nuclei). These immature neurons displayed electrophysiological properties ranging from slow Ca2+-mediated responses to fast repetitive Na+spikes, suggesting different stages of maturation. These cells originated in the embryo, because we found colocalization of neuronal markers with 5-bromo-2′-deoxyuridine when injected during embryonic day 7–17 but not in postnatal day 0–5. Our findings represent the first evidence that the ependyma of the rat spinal cord contains cells with molecular and functional features similar to immature neurons in adult neurogenic niches. The fact that these cells retain the expression of molecules that participate in migration and neuronal differentiation raises the possibility that the ependyma of the rat spinal cord is a reservoir of immature neurons in “standby mode,” which under some circumstances (e.g., injury) may complete their maturation to integrate spinal circuits.
Rural‐Urban Differences in Environmental Concern in Canada
Authors: Huddart‐Kennedy Emily , Beckley Thomas M. , McFarlane Bonita L. , Nadeau Solange
Published: August 2009

Abstract Distinctions between rural and urban populations are well documented in environmental sociology literature. Rural and urban places may exert different influences on participation in environmentally supportive behavior (ESB) as well as on other forms of environmental concern (EC). The influence of these distinct geographies may be due to present circumstances or because of childhood socialization in these places. Using data from a national survey in Canada (n=51 664), we use cognitive (basic values, environmental worldview, and environmental attitude) and behavioral indicators (public and private sphere) of EC to explore differences among rural and urban populations and we include analyses accounting for place of socialization. We extend the conventional private sphere category of ESB by including stewardship behaviors. Results showed few differences between rural and urban residents on indicators of EC. Rural residents, however, scored higher on altruistic values, placed a higher priority on the environment, and reported higher participation in recycling and stewardship behaviors. Analysis that included place of socialization showed differences on environmental worldview, basic values, and some ESB. In terms of ESB, we conclude that residence and place of socialization may be less of a factor than opportunity and highlight the importance of providing services and facilities. We recommend future research on residence and ESB include a variety of behaviors that reflect opportunities for both rural and urban residents.
Adult GH deficiency throughout lifetime
Authors: Thomas Julia D J , Monson John P
Published: August 2009

It is now accepted that adults with severe GH deficiency (GHD) demonstrate impaired physical and psychological well-being and may benefit from replacement with recombinant human GH. Post-marketing surveillance surveys, such as the Pfizer International Metabolic Database (KIMS), were initially set-up to provide safety data on long-term treatment but have the added benefit of providing ongoing observational data on the effect of GH replacement on body composition, lipid and glucose status, hypertension, bone density and quality of life. These data demonstrate that although GHD has clinical impact at all ages, the individual consequences of this condition may take on greater significance at different stages in life. At all ages, accurate, safe diagnosis and appropriate GH dosing are necessary to provide the individual with the best possible outcome.
Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?
Authors: Brabant G , Poll E M , Jönsson P , Polydorou D , Kreitschmann-Andermahr I
Published: August 2009

Previous work has examined potential links between the etiology of GH deficiency (GHD) and the baseline characteristics of the patients including biochemical and psychometric parameters. Using an update of the KIMS pharmaco-epidemiological database (Pfizer International Metabolic Database), we addressed the question how well such results can be generalized and whether regional differences may play a role. From 30 different countries, 13 167 GH-deficient patients were included in KIMS at the data close in December 2008. In order to explore country-specific differences of baseline characteristics documented in KIMS, separate analyses of baseline characteristics of adult-onset GHD patients (n=7708) were performed for the six largest contributing European countries and the United States. This analysis revealed striking regional variations in the pathogenesis of the disease, clinical characteristics such as body mass index, and in the classical features of the metabolic syndrome such as blood pressure or lipid status between countries. Moreover, the approach to endocrine function testing was widely different between countries, as well as the distribution of etiologies of GHD. These data suggest that a complex relation between biochemical and clinical signs of GHD exists, and that the spectrum of adult GHD syndrome is influenced by regional diagnostic and clinical particularities.
Safety aspects of GH replacement
Authors: Svensson Johan , Bengtsson Bengt-Åke
Published: August 2009

In adults, GH replacement therapy will often be maintained for decades. Owing to the long duration of GH replacement in many adults, it is essential to establish the long-term safety aspects of the treatment. In this review, studies that have investigated the safety profile of long-term GH replacement will be reviewed with an emphasis on studies based on data from the Pfizer International Metabolic Database (KIMS). These studies show that long-term GH replacement in adults is safe and that long-term GH replacement may even improve cardiovascular mortality and morbidity in GH-deficient adults.
ACROSTUDY: the first 5 years
Authors: Trainer Peter J
Published: August 2009

ACROSTUDY is an observational registry intended to collect safety and efficacy data on pegvisomant therapy. A total of 792 patients have been enrolled, of whom 83% had commenced pegvisomant prior to recruitment. The mean follow-up is 1.66 years with the mean duration of pegvisomant therapy 3.31 years representing 2625 patient years of treatment. About 90% of patients were on once daily pegvisomant, and 67% were on monotherapy. Disappointingly, IGF1 was normalised in <70% of patients; furthermore, in 80% of patients with an elevated IGF1, the daily dose of pegvisomant was 20 mg or less. A total of 56 serious adverse events (AEs) were reported, of which 13 were related to pegvisomant. A total of 276 AEs were reported, of which 56 were considered related to pegvisomant. The AEs most frequently attributed to pegvisomant were disturbed liver function tests and injection site reactions. Magnetic resonance imaging (MRI) was available in 684 patients. A total of 411 patients had at least one MRI on pegvisomant compared with a baseline. In 31 patients, a decrease in tumour size has been reported, of whom 20 had previously received radiotherapy. An increase in tumour size has been reported and confirmed in 22 patients. In 11 patients, there was contradictory data on tumour size, while, in six patients, central review of the films failed to confirm increase in tumour size. In conclusion, the safety data are generally reassuring, while the IGF1 normalisation rate is disappointing, which probably reflects a failure of dose titration. Further effort is needed to understand the reasons for the failure of dose titration.
Which patients with acromegaly are treated with pegvisomant? An overview of methodology and baseline data in ACROSTUDY
Authors: Brue Thierry , Castinetti Frederic , Lundgren Frida , Koltowska-Häggström Maria , Petrossians Patrick , _ _
Published: August 2009

Context

Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound.

Patients and methods

This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories.

Results

Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml.

Conclusion

Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.
The German ACROSTUDY: past and present
Authors: Buchfelder M , Schlaffer S , Droste M , Mann K , Saller B , Brübach K , Stalla G K , Strasburger C J , _ _
Published: August 2009

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible.

As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging.

Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients.

In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.
Dendritic Amplification of Stereoselectivity of a Prolinamide‐Catalyzed Direct Aldol Reaction
Authors: Mitsui Kazuhiko , Parquette Jon R.
Published: August 2009

Isomeric “compact” and “expanded” dendrimers functionalized with L‐prolinamide catalytic units at the periphery were compared as catalysts to monomer controls in the organocatalytic direct aldol condensation. A positive dendritic effect that amplifies the stereoselectivity of the direct aldol condensation was observed for dendrimers 3 and 4, compared with lower molecular weight catalysts L‐prolinani‐lide 1 and G1 dendron 2. The difference in the compactness between 3 and 4 appears to have less impact on the stereoselectivity than the preorganized multivalency of the dendritic catalysts.
Structure–Activity Relationship Studies in Single‐Site Esterase Peptide Dendrimers
Authors: Javor Sacha , Reymond Jean‐Louis
Published: August 2009

We recently reported on peptide dendrimers with a single catalytic site at the dendrimer core catalyzing the hydrolysis of acetoxy‐ and butyryloxy‐pyrene trisulfonate 1a/b in aqueous buffer with Michaelis–Menten kinetics. Substrate binding is mediated by a pair of protonated arginine or histidine residues in the first generation branch, and esterolysis is performed by the imidazole side‐chain of a histidine residue in the core acting as a general base or nucleophile. Herein we report on a structure–activity relationship study searching for an optimal combination between amino acid sequence and catalytic machinery. Installation of histidine residues onto the aromatic dendrimer framework “R” leads to 10‐fold higher rate acceleration up to kcat/kuncat = 1.5 * 103 at pH 5.5 with dendrimers RG3H (AcYT)8 (BWG)4 (BHS)2BHS and RMG3H (AcYT)8(BWG)4(BHSG)2BHS (one‐letter codes for L‐amino acids; Ac = acetyl, B = L‐2,3‐diaminopropionic acid branching point, C‐terminus is amide ‐CONH2). These dendrimers reach the compactness of a native folded protein.
Synthesis and Characterization of Anionic Triazine Dendrimers with a Labile Disulfide Core
Authors: Zhang Wen , Lalwani Sanjiv , Chouai Abdellatif , Simanek Eric E.
Published: August 2009

Anionic dendrimers based on melamine with disulfide bonds at the core were prepared to investigate the solubility of these architectures, the ability of these molecules to solubilize pyrene as a model drug, and the ability of these architectures to undergo thiol‐disulfide exchange. The ability to solubilize pyrene is directly correlated with molecular weight of the dendrimer—aggregation of dendrons does not occur. Thiol‐disulfide exchange occurs rapidly using dithiothreitol as the reductant to yield dendrimers with thiol cores that can undergo oxidation in air to yield the original dendrimer.
Self‐Assembling Dendronized Dendrimers
Authors: Percec Virgil , Imam Mohammad R. , Peterca Mihai , Cho Wook‐Dong , Heiney Paul A.
Published: August 2009

The amine groups from the periphery of poly(propylenimine) dendrimers [DAB‐(NH2)n] (n = 4 and 8) were reacted with the carboxylic groups of five different first and second generation self‐assembling dendrons. The amidation was mediated by the peptide bond forming reagent 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT)/N‐methylmorpholine (NMM). All the resulting dendronized dendrimers self‐assemble into helical pyramidal columns that self‐organize into columnar hexagonal and columnar rectangular 2D lattices and in supramolecular spheres that self‐organize into 3D Pm3n and P42/mnm tetragonal lattices. The structural and retrostructural analysis of the supramolecular dendrimers by X‐ray diffraction experiments demonstrated that supramolecular dendritic spheres are assembled from various spherical fragments, including conical and half‐sphere in which the DAB dendrimer is confined to their apex. Dendritic‐crown is the most frequently encountered conformation of the dendronized dendrimers that is responsible for the assembly of helical pyramidal columns.
Solution and Thin‐Film Aggregation Studies of Octasubstituted Dendritic Phthalocyanines
Authors: Kernag Casey A. , Mcgrath Dominic V.
Published: August 2009

The synthesis and solution and thin‐film characterization of eight octasubstituted dendritic phthalocyanines (Pcs) and their zinc complexes are reported. The Pc chromophore was substituted in the 2,3,9,10,16,17,23,24‐positions with three generations of benzylaryl ether dendrons with either a benzyl (3a‐3c) or 3,5‐di‐t‐butylbenzyl periphery (3d‐3f). Visible spectra in solution (CH2Cl2‐EtOH mixtures, toluene, THF, dioxane, acetone, and EtOAc) indicated a varying degree of chromophore aggregation that depended on solvent, dendrimer generation, and whether the Pc was metallated. Variable‐concentration visible spectroscopic studies were analyzed using a nonlinear least‐squares fitting procedure giving Kd values. These values further quantitated the observations that the t‐butyl‐substituted den‐drimers 3d‐3f were all less prone to aggregation in solution than the unsubstituted dendrimers 3a‐3c, with a monotonic decrease in Kd across the series 3a → 3b → 3c → 3d → 3e → 3f. Second‐generation t‐butyl‐substituted dendrimer 3f showed little to no aggregation in all solvents studied. Thin‐film studies indicated that the largest members of the two dendrimer groups, third‐generation 3c and second‐generation 3f, were largely monomeric as evidenced by split Q‐bands, similar to that seen in dilute CH2Cl2 solution when deposited via spin‐coating onto glass slides. The metallated zinc Pcs 4a‐4f all exhibited significantly less tendency toward aggregation in both solution and thin‐films than their unmetallated analogues.
Polymetallic Carbosilane Dendrimers Containing N,N'‐Iminopyridine Chelating Ligands: Applications in Catalysis
Authors: Martínez‐Olid Francisco , Benito José M. , Flores Juan C. , de Jesús Ernesto
Published: August 2009

This overview covers the most relevant results obtained by our group in the last few years concerning the synthesis and catalytic applications of metal complexes anchored to the surface of carbosilane dendrimers functionalized with iminopyridine ligands. Nickel dibromide complexes activated with methylaluminoxane (MAO) have been studied for the polymerization of ethylene, whereas cat‐ionic palladium(ii) derivatives have been applied to the copolymerization of carbon monoxide and tert‐butylstyrene. In addition, palladium dendrimers have been tested in the Heck reaction between methyl acrylate and iodotoluene. Correlations between the catalyst activities or reaction products (product distributions, polymer molecular weights, etc.) and the dendrimer generation are discussed and tentative explanations for these correlations provided.