bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory mechanism of smooth muscle contraction studied with gelsolin-treated strips of taenia caeci in guinea pig
Authors: Liou Ying-Ming , Watanabe Masaru , Yumoto Masatoshi , Ishiwata Shin'ichi
Published: February 2009

The potential roles of the regulatory proteins actin, tropomyosin (Tm), and caldesmon (CaD), i.e., the components of the thin filament, in smooth muscle have been extensively studied in several types of smooth muscles. However, controversy remains on the putative physiological significance of these proteins. In this study, we intended to determine the functional roles of Tm and CaD in the regulation of smooth muscle contraction by using a reconstitution system of the thin filaments. At appropriate conditions, the thin (actin) filaments within skinned smooth muscle strips of taenia caeci in guinea pigs could be selectively removed by an actin-severing protein, gelsolin, without irreversible damage to the contractile apparatus, and then the thin filaments were reconstituted with purified components of thin filaments, i.e., actin, Tm, and CaD. We found that the structural remodeling of actin filaments or thin filaments was functionally linked to the Ca2+-induced force development and reduction in muscle cross-sectional area (CSA). That is, after the reconstitution of the gelsolin-treated skinned smooth muscle strips with pure actin, the Ca2+-dependent force development was partially restored, but the Ca2+-induced reduction in CSA occurred once. In contrast, the reconstitution with actin, followed by Tm and CaD, restored not only the force generation but also both its Ca2+ sensitivity and the reversible Ca2+-dependent reduction in CSA. We confirmed that both removal of the thin filaments by gelsolin treatment and reconstitution of the actin (thin) filaments with Tm and CaD caused no significant changes in the level of myosin regulatory light chain phosphorylation. We thus conclude that Tm and CaD are necessary for the full regulation of smooth muscle contraction in addition to the other regulatory systems, including the myosin-linked one.
Functional regulation of H+-ATPase-rich cells in zebrafish embryos acclimated to an acidic environment
Authors: Horng Jiun-Lin , Lin Li-Yih , Hwang Pung-Pung
Published: February 2009

It is important to maintain internal pH homeostasis in biological systems. In our previous studies, H+-ATPase-rich (HR) cells were found to be responsible for proton secretion in the skin of zebrafish embryos during development. In this study, zebrafish embryos were exposed to acidic and basic waters to investigate the regulation of HR cell acid secretion during pH disturbances. Our results showed that the function of HR cells on the skin of zebrafish embryos can be upregulated in pH 4 water not only by increasing the cell number but also by enlarging the acid-secreting function of single cells. We also identified an “alveolar-type” apical opening under scanning electron microscopy observations of the apical membrane of HR cells, and the density and size of the alveolar type of apical openings were also increased in pH 4 water. p63 and PCNA immunostaining results also showed that additional HR cells in pH 4 water may be differentiated not only from ionocyte precursor cells but also newly proliferating epithelial stem cells.
Preconditioning stimuli that augment chromaffin cell secretion
Authors: Tapia Laura , García-Eguiagaray Josefina , García Antonio G. , Gandía Luis
Published: February 2009

We have investigated here whether a preconditioned stimulation of nicotinic and muscarinic receptors augmented the catecholamine release responses elicited by supramaximal 3-s pulses of 100 μM acetylcholine (100ACh) or 100 mM K+ (100K+) applied to fast-perifused bovine adrenal chromaffin cells. Threshold concentrations of nicotine (1–3 μM) that caused only a tiny secretion did, however, augment the responses elicited by 100ACh or 100K+ by 2- to 3.5-fold. This effect was suppressed by mecamylamine and by Ca2+ deprivation, was developed with a half-time ( t1/2) of 1 min, and was reversible. The nicotine effect was mimicked by threshold concentrations of ACh, choline, epibatidine, and oxotremorine-M but not by methacholine. Threshold concentrations of K+ caused lesser potentiation of secretion compared with that of threshold nicotine. The data are compatible with an hypothesis implying 1) that continuous low-frequency sympathetic discharge places chromaffin cells at the adrenal gland in a permanent “hypersensitive” state; and 2) this allows an explosive secretion of catecholamines by high-frequency sympathetic discharge during stress.
Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose
Authors: Murphy Beth Ann , Fioramonti Xavier , Jochnowitz Nina , Fakira Kurt , Gagen Karen , Contie Sylvain , Lorsignol Anne , Penicaud Luc , Martin William J. , Routh Vanessa H.
Published: February 2009

Fasting increases neuropeptide Y (NPY) expression, peptide levels, and the excitability of NPY-expressing neurons in the hypothalamic arcuate (ARC) nucleus. A subpopulation of ARC-NPY neurons (∼40%) are glucose-inhibited (GI)-type glucose-sensing neurons. Hence, they depolarize in response to decreased glucose. Because fasting enhances NPY neurotransmission, we propose that during fasting, GI neurons depolarize in response to smaller decreases in glucose. This increased excitation in response to glucose decreases would increase NPY-GI neuronal excitability and enhance NPY neurotransmission. Using an in vitro hypothalamic explant system, we show that fasting enhances NPY release in response to decreased glucose concentration. By measuring relative changes in membrane potential using a membrane potential-sensitive dye, we demonstrate that during fasting, a smaller decrease in glucose depolarizes NPY-GI neurons. Furthermore, incubation in low (0.7 mM) glucose enhanced while leptin (10 nM) blocked depolarization of GI neurons in response to decreased glucose. Fasting, leptin, and glucose-induced changes in NPY-GI neuron glucose sensing were mediated by 5′-AMP-activated protein kinase (AMPK). We conclude that during energy sufficiency, leptin reduces the ability of NPY-GI neurons to sense decreased glucose. However, after a fast, decreased leptin and glucose activate AMPK in NPY-GI neurons. As a result, NPY-GI neurons become depolarized in response to smaller glucose fluctuations. Increased excitation of NPY-GI neurons enhances NPY release. NPY, in turn, shifts energy homeostasis toward increased food intake and decreased energy expenditure to restore energy balance.
Controlled aquaporin-2 expression in the hypertonic environment
Authors: Hasler Udo
Published: February 2009

The corticomedullary osmolality gradient is the driving force for water reabsorption occurring in the kidney. In the collecting duct, this gradient allows luminal water to move across aquaporin (AQP) water channels, thereby increasing urine concentration. However, this same gradient exposes renal cells to great osmotic challenges. These cells must constantly adapt to fluctuations of environmental osmolality that challenge cell volume and incite functional change. This implies profound alterations of cell phenotype regarding water permeability. AQP2 is an essential component of the urine concentration mechanism whose controlled expression dictates apical water permeability of collecting duct principal cells. This review focuses on changes of AQP2 abundance and trafficking in hypertonicity-challenged cells. Intracellular mechanisms governing these events are discussed and the biological relevance of altered AQP2 expression by hypertonicity is outlined.
Influence of dietary creatine supplementation on muscle phosphocreatine kinetics during knee-extensor exercise in humans
Authors: Jones Andrew M. , Wilkerson Daryl P. , Fulford Jonathan
Published: February 2009

We hypothesized that increasing skeletal muscle total creatine (Cr) content through dietary Cr supplementation would result in slower muscle phosphocreatine concentration ([PCr]) kinetics, as assessed using31P magnetic resonance spectroscopy, following the onset and offset of both moderate-intensity (Mod) and heavy-intensity (Hvy) exercise. Seven healthy males (age 29 ± 6 yr, mean ± SD) completed a series of square-wave transitions to Mod and Hvy knee extensor exercise inside the bore of a 1.5-T superconducting magnet both before and after a 5-day period of Cr loading (4× 5 g/day of creatine monohydrate). Cr supplementation resulted in an ∼8% increase in the resting muscle [PCr]-to-[ATP] ratio (4.66 ± 0.27 vs. 5.04 ± 0.22; P < 0.05), consistent with a significant increase in muscle total Cr content consequent to the intervention. The time constant for muscle [PCr] kinetics was increased following Cr loading for Mod exercise (control: 15 ± 8 vs. Cr: 25 ± 9 s; P < 0.05) and subsequent recovery (control: 14 ± 8 vs. Cr: 27 ± 8 s; P < 0.05) and for Hvy exercise (control: 54 ± 18 vs. Cr: 72 ± 30 s; P < 0.05), but not for subsequent recovery (control: 41 ± 11 vs. Cr: 44 ± 6 s). The magnitude of the increase in [PCr] following Cr loading was correlated ( P < 0.05) with the extent of the slowing of the [PCr] kinetics for the moderate off-transient ( r = 0.92) and the heavy on-transient ( r = 0.71). These data demonstrate, for the first time in humans, that an increase in muscle [PCr] results in a slowing of [PCr] dynamics in exercise and subsequent recovery.
Multiple sweet receptors and transduction pathways revealed in knockout mice by temperature dependence and gurmarin sensitivity
Authors: Ohkuri Tadahiro , Yasumatsu Keiko , Horio Nao , Jyotaki Masafumi , Margolskee Robert F. , Ninomiya Yuzo
Published: February 2009

Sweet taste transduction involves taste receptor type 1, member 2 (T1R2), taste receptor type 1, member 3 (T1R3), gustducin, and TRPM5. Because knockout (KO) mice lacking T1R3, gustducin's Gα subunit (Gαgust), or TRPM5 exhibited greatly reduced, but not abolished responses of the chorda tympani (CT) nerve to sweet compounds, it is likely that multiple sweet transduction pathways exist. That gurmarin (Gur), a sweet taste inhibitor, inhibits some but not all mouse CT responses to sweet compounds supports the existence of multiple sweet pathways. Here, we investigated Gur inhibition of CT responses to sweet compounds as a function of temperature in KO mice lacking T1R3, Gαgust, or TRPM5. In T1R3-KO mice, responses to sucrose and glucose were Gur sensitive (GS) and displayed a temperature-dependent increase (TDI). In Gαgust-KO mice, responses to sucrose and glucose were Gur-insensitive (GI) and showed a TDI. In TRPM5-KO mice, responses to glucose were GS and showed a TDI. All three KO mice exhibited no detectable responses to SC45647, and their responses to saccharin displayed neither GS nor a TDI. For all three KO mice, the lingual application of pronase, another sweet response inhibitor, almost fully abolished responses to sucrose and glucose but did not affect responses to saccharin. These results provide evidence for 1) the existence of multiple transduction pathways underlying responses to sugars: a T1R3-independent GS pathway for sucrose and glucose, and a TRPM5-independent temperature sensitive GS pathway for glucose; 2) the requirement for Gαgust in GS sweet taste responses; and 3) the existence of a sweet independent pathway for saccharin, in mouse taste cells on the anterior tongue.
Influence of thermal balance on cold-induced vasodilation
Authors: Flouris Andreas D. , Cheung Stephen S.
Published: February 2009

We examined the effect of thermal balance perturbation on cold-induced vasodilation through a dynamic A-B-A-B design applying heat ( condition A) and cold ( condition B) to the body's core, while the hand is exposed to a stable cold stimulus. Fifteen healthy adults (8 men, 7 women) volunteered. Applications of heat and cold were achieved through water immersions in two tanks maintained at 42 and 12°C water temperature, respectively, in an A-B-A-B fashion. Throughout the experiment, the participants’ right hand up to the ulnar styloid process was placed inside a temperature-controlled box set at 0°C air temperature. Results demonstrated that cold-induced vasodilation occurred only during condition B and at times when body heat content was decreasing but rectal temperature had not yet dropped to baseline levels. Following the occurrence of all cold-induced vasodilation events, rectal temperature was reduced, and the phenomenon ceased when rectal temperature fell below baseline. Heart rate variability data obtained before and during cold-induced vasodilation demonstrated a shift of autonomic interaction toward parasympathetic dominance, which, however, was attributed to a sympathetic withdrawal. Receiver operating characteristics curve analyses demonstrated that the cold-induced vasodilation onset cutoff points for rectal temperature change and finger temperature were 0.62 and 16.76°C, respectively. It is concluded that cold-induced vasodilation is a centrally originating phenomenon caused by sympathetic vasoconstrictor withdrawal. It is dependent on excess heat, and it may be triggered by excess heat with the purpose of preserving thermal balance.
Responses of Neurons in Chinchilla Auditory Cortex to Frequency-Modulated Tones
Authors: Brown Trecia A. , Harrison Robert V.
Published: February 2009

Frequency-modulated (FM) stimuli have been used to explore the behavior of neurons in the auditory cortex of several animal models; however, the properties of FM-sensitive auditory cortical neurons in the chinchilla are still unknown. Single-unit responses to FM stimulation were obtained from the auditory cortex of anesthetized adult chinchillas ( Chinchilla laniger). Upward and downward linear FM sweeps spanning frequencies from 0.1 to 20 kHz were presented at speeds of 0.05 to 0.82 kHz/ms. Results indicated that >90% of sampled neurons were responsive to FM sweeps. The population preference was for upward FM sweeps and for medium to fast speeds (≥0.3 kHz/ms). Few units (3%) were selective for downward FM sweeps, whereas <22% of units preferred slow speeds (≤0.1 kHz/ms). Velocity preference and direction sensitivity were positively correlated for upward sweeps only ( r = 0.40, P = 0.0021, t-test). Three types of firing rate patterns were observed in the FM response peristimulus time histograms: a single peak at sweep onset/offset (“onset”) and a single peak (“late”) or multiple peaks (“burst”) during the sweep. “Late” units expressed the highest mean values for direction sensitivity and speed selectivity; “onset” units were selective only for direction and “burst” units were not selective for either direction or speed. The robust responsiveness of these neurons to FM sweeps suggests a functional role for FM detection such as the identification of FM sweeps present in vocalizations of other organisms within the chinchilla's natural environment.
Immunoendocrine Alterations during Human Tuberculosis as an Integrated View of Disease Pathology
Authors: Bottasso Oscar , Bay María Luisa , Besedovsky Hugo , del Rey Adriana
Published: February 2009

Tuberculosis (TB) is a chronic infectious disease accompanied by excessive and/or prolonged cytokine production, which might affect the immunoendocrine communication and favor the establishment of an adverse state with important alterations in essential biological functions. Studies in blood from TB patients showed increased levels of interferon γ (IFN-γ), interleukin 10 (IL-10), and IL-6, accompanied by a modest increase in the levels of cortisol, prolactin, and thyroid hormones and markedly augmented concentrations of growth hormone. Conversely, testosterone and dehydroepiandrosterone (DHEA) levels were profoundly decreased, resulting in an increased cortisol/DHEA ratio. The finding that culture supernatants from Mycobacterium-tuberculosis-stimulated peripheral blood mononuclear cells (PBMCs) of TB patients inhibit DHEA secretion by a human adrenal cell line indicates that immune cells from these patients can directly affect the synthesis of this hormone. Supporting the existence of bidirectional interactions, in vitro treatment of PBMCs from TB patients with physiological concentrations of cortisol inhibited mycobacterial antigen-driven lymphoproliferation and IFN-γ production, whereas DHEA suppressed transforming growth factor β production from cases with progressive disease. Further analysis showed that plasma DHEA levels correlated positively with the in vitroproduction of IFN-γ by mycobacterial-stimulated PBMCs, and the cortisol/DHEA ratio was inversely correlated with IFN-γ production. Lastly, it was also shown that the immunoendocrine imbalance in TB patients was associated with weight loss, which in turn correlated with the impairment on their specific in vitro cellular immune responses. These immunoendocrine interactions may play a detrimental role during TB, in terms of the development of protective immune responses, control of tissue damage and metabolic disorders, being implicated in disease aggravation and the ‘classic’ TB consumption.
Beta-Androstenes and Resistance to Viral and Bacterial Infections
Authors: Loria Roger M.
Published: February 2009

This report illustrates that the β-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis.
The Impact of Infectious Diseases upon Neuroendocrine Circuits
Authors: Pérez Ana Rosa , Bottasso Oscar , Savino Wilson
Published: February 2009

During infectious diseases, neuroendocrine and immune networks act in concert, facilitating host response. It is known that infections cause profound immune changes, but the impact upon immunoendocrine circuits has been less studied. Disorders in the hypothalamic-pituitary-adrenal (HPA) axis were frequently observed associated with infections, and these changes often occur in parallel to alterations in the systemic cytokine network. Explanations for the infection-associated immunoendocrine disturbances include several and not mutually exclusive possibilities. Changes in cytokine levels can enhance or suppress the HPA axis, by acting at the hypothalamus-pituitary unit and/or at the adrenal glands. In situ inflammatory reactions or structural changes like vascular alterations or an enhanced extracellular matrix deposition in the endocrine microenvironment may also lead to a transient HPA dysfunction. Lastly, a microbe-related effect by means of pathogen infiltration or exploitation of the host’s hormonal microenvironment may be involved as well. A better understanding of the relevance of immunoendocrine communication during infectious diseases, and how disturbances in the flux of information lead to neuroendocrine immune-related disorders will provide important insights into mechanisms underlying the disease pathology.
Sex Hormones and Modulation of Immunity against Leishmaniasis
Authors: Snider Heidi , Lezama-Davila Claudio , Alexander James , Satoskar Abhay R.
Published: February 2009

Sex-associated hormones such as estradiol, testosterone and progesterone have all been shown to modulate immune responses, which can result in differential disease outcomes between males and females, as well as between pregnant and nonpregnant females. Most parasitic diseases, including leishmaniasis, usually result in more severe disease in males compared with females. This review highlights our current knowledge concerning the role of sex hormones in modulating leishmaniasis in both clinical settings and experimental disease models.
Challenges in the Determination of Early Predictors of Cerebral Malaria: Lessons from the Human Disease and the Experimental Murine Models
Authors: Martins Yuri Chaves , Carvalho Leonardo José de Moura , Daniel-Ribeiro Cláudio Tadeu
Published: February 2009

Cerebral malaria (CM) is a life-threatening complication of malaria caused by Plasmodium falciparum, and it claims around two million lives a year, mainly those of children in sub-Saharan Africa. A number of works, particularly in murine models of CM, showed that several mediators are involved in the development of the disease, including monocytes, T lymphocytes, cytokines, chemokines, platelets, nitric oxide scavengers and heme, among others, but a comprehensive understanding of the pathogenesis of this complication is still lacking. This overview critically analyzes and discusses the definition, clinical features, neurocognitive outcomes and pathogenesis of human CM. We focused on the relationship between clinical and laboratory features and the diagnosis and prognosis of the complication showing indicators of poor prognosis and emphasizing the need of establishing predictive scores to estimate, on admission, the likelihood of any malarial patient to develop neurological complications. The potential development of a mathematical model for early prediction of CM through neurological assessment using the SHIRPA protocol in Plasmodium berghei ANKA-infected susceptible mice is shown. High positive predictive values (>89%) on days 5 and 6 of infection, observed for some generated SHIRPA scores, indicate the possibility of early detection of mice with a high probability of developing CM.
Controversies in the Management of Colorectal Liver Metastases: Role of PET and PET/CT
Authors: Wiering Bastiaan , Vogel Wouter V. , Ruers Theo J.M. , Oyen Wim J.G.
Published: February 2009

Positron emission tomography (PET) using [F-18]-2-deoxy-2-fluoro-D-glucose (FDG) has emerged as a promising diagnostic modality in recurrent colorectal cancer. Data in the literature show that the addition of FDG-PET changes patient management in up to 30% of patients with potentially resectable liver metastases, mainly by detecting previously unknown extrahepatic disease. Furthermore, FDG-PET is useful in the follow-up of patients who underwent surgical procedures of the liver, since it is sensitive in detecting residual or relapse malignancy in scarred liver tissue following both resection and local ablative techniques. For follow-up during systemic therapy, early FDG-PET appears predictive for response to therapy. FDG-PET, computerized tomography and magnetic resonance imaging are complementary techniques in staging and restaging patients with advanced colorectal cancer. A combination of FDG-PET and CT scanning characteristics seems promising, and integrated PET/ CT is becoming more widely available, although the exact clinical value and efficacy is not yet fully established. In addition, assessment of these modalities in joint reading sessions with radiologist, nuclear medicine physician, medical and surgical oncologists significantly impacts upon patient management. This review evaluates the potential of FDG-PET and combined PET/CT in patients with colorectal liver metastases and discusses potential future possibilities.
Chemotherapy prior to Hepatic Resection for Colorectal Liver Metastases: Helpful until Harmful?
Authors: Abdalla Eddie K. , Vauthey Jean-Nicolas
Published: February 2009

Background: Improved efficacy of chemotherapy for treatment of colorectal liver metastases (CLM) has renewed interest in the use of systemic treatment as part of a ‘potentially curative’ treatment plan for patients with CLM. Controversy exists regarding potential hepatotoxicity of therapy delivered before liver resection. Methods: Medline reports of pathologic changes in liver and tumor, specific chemotherapy types and clinical outcomes were examined. Results: Hepatic steatosis without inflammation (simple steatosis) may occur with chemotherapy treatment, but hepatic resection can be performed safely even in patients with severe (>30%) steatosis. Steatohepatitis is associated with irinotecan therapy and an increased risk for liver failure and death after hepatic resection. Hepatic sinusoidal obstruction can occur with oxaliplatin treatment and appears to increase in severity with prolonged treatment (>6 cycles). Bevacizumab can be used safely when discontinued >5 weeks before liver resection. Importantly, bevacizumab decreases the incidence and severity of sinusoidal injury with oxaliplatin therapy. Pathologic response is improved with the addition of bevacizumab and is evolving as an independent predictor of long-term survival. Conclusions: Chemotherapy-related liver injuries are regimen-specific. Targeted therapy combined with cytotoxic therapy is safe and most effective. With the use of limited chemotherapy combining appropriately selected agents, the risk of surgical complications can be minimized and the overall effect and benefits of treatment optimized.
‘Liver First’ Approach in the Treatment of Colorectal Cancer with Synchronous Liver Metastases
Authors: Mentha Gilles , Roth Arnaud D. , Terraz Sylvain , Giostra Emiliano , Gervaz Pascal , Andres Axel , Morel Philippe , Rubbia-Brandt Laura , Majno Pietro E.
Published: February 2009

Background: In patients with synchronous colorectal liver metastases, an approach reversing the traditional therapeutic order – i.e. starting with chemotherapy first, doing the liver surgery second, and performing the colorectal surgery last – is theoretically appealing as it avoids the risk of metastatic progression during treatment of the primary tumor. The present series updates on a previously reported pilot experience. Patients and Methods: 35 patients with advanced synchronous colorectal metastases and nonobstructive colorectal tumors were treated with the reversed approach. Data were collected in a prospective database. Results: The median number of metastases was 6, the median size of the largest metastasis was 6 cm. Five patients could not complete the program (one death from sepsis during chemotherapy, 3 cases of progressive disease under treatment, and one case of vanishing liver metastases). The remaining 30 patients responded and underwent R0 liver resections with no major complications. One patient needed a Hartmann’s procedure for obstruction after a first-step hepatectomy, and 1 patient had a rectal anastomotic leak. Median survival was 44 months. Overall survival rates of the 30 patients who completed the program at 1, 2, 3, 4 and 5 years were 100, 89, 60, 44 and 31%. Conclusions: The reverse approach appeared feasible and safe, with operability and survival rates better than expected for patients with similar severity. Potential problems, in particular regrowth of vanishing metastases and primary tumors, chemotherapy-associated liver damage, and large bowel obstruction, can be minimized by careful multidisciplinary selection, planning and execution.
Trends in Pharmacogenomic Epidemiology: 2001–2007
Authors: Guessous I. , Gwinn M. , Yu W. , Yeh J. , Clyne M. , Khoury M.J.
Published: February 2009

Background: Pharmacogenomic epidemiology (PGxE) assesses the range of responses to pharmacologic agents in relation to genetic variation in population groups. We analyzed publication trends to describe the emerging field of PGxE. Methods: We analyzed PGxE literature published from 2001 to 2007 by using the HuGE Navigator, a curated database of abstracts on human genome epidemiology extracted from PubMed. We summarized trends by gene and study design and, for the 4 most cited genes, by associated health outcomes and drugs. Results: In all, 1,855 PGxE articles were indexed from 2001 through 2007, with annual publications increasing more than 15-fold during this period. Observational studies outnumbered clinical trials by a ratio of 10 to 1 (1,660 vs. 178). Just 4 genes together accounted for nearly one-fifth of all publications: ABCB1, CYP2C9, CYP2C19, and CYP2D6. For these 4 genes, the most frequently cited therapeutic category was antineoplastic agent, followed by anticoagulant, antiulcer, and antidepressant. Warfarin was the single most frequently cited drug. Conclusions: The field of PGxE is growing rapidly, encompassing a large spectrum of diseases and drugs important in clinical practice. Systematic tracking and synthesis of the published literature in PGxE can help identify promising applications and guide translation research.
The Potential of a Placebo/Nocebo Effect in Pharmacogenetics
Authors: Haga S.B. , Warner L.R. , O’Daniel J.
Published: February 2009

Pharmacogenetic testing holds great promise to improve health outcomes and reduce adverse drug responses through enhanced selection of therapeutic agents. Since drug responses can be manipulated by verbal suggestions, it is of particular interest to understand the potential impact of pharmacogenetic test results on drug response. Placebo and nocebo-like effects may be possible due to the suggestive nature of pharmacogenetic information that a drug will or will not likely lead to improved health outcomes. For example, pharmacogenetic testing could provide further reassurance to patients that a given drug will be effective and/or cause minimal side effects. However, pharmacogenetic information could adversely affect drug response through negative expectations that a drug will be less than optimally effective or cause an adverse response, known as a nocebo-like effect. Therefore, a patient’s perceived value of testing, their understanding of the test results, and the manner in which they are communicated may influence therapeutic outcome. As such, physicians should consider the potential effect of pharmacogenetic test results on therapeutic outcome when communicating results to patients. Studies are needed to investigate the impact of pharmacogenetic information of therapeutic outcome.
Pharmacogenomics and the Challenge of Health Disparities
Authors: Lee S.S.
Published: February 2009

This paper examines emerging technologies and recent research on population differences in pharmacogenomics and the perspectives of scientists, community advocates, policymakers, and social critics on the use of race as a proxy for genetic variation. The discussion focuses on how recent developments in genomic science impact social understandings of racial difference and the public health goal to eliminate ongoing health disparities among racially identified groups. This paper examines how factors such as governmental policies – requiring the use of racial and ethnic categories in genetic research and increasing interest in identifying untapped racial market niches by the pharmaceutical and biotechnology industries – and weak governmental oversight of race-based therapeutics converge to create an ‘infrastructure of racialization’ that may alter the vision of personalized medicine that has been so highly anticipated. This paper argues that significant public investment in pharmacogenomics requires careful consideration of the emerging discourse that tethers racial justice to notions of racial biology and discusses the social and ethical implications for the pendulum shift towards a geneticization of race in drug development.
Will Pharmacogenomics Disrupt the U.S. Health Care System? No
Authors: Garrison L.P.
Published: February 2009

There is a widely held view that the scientific breakthroughs represented by pharmacogenomics and other new biomarkers portend a new ‘personalized medicine’ that will disrupt and revolutionize the U.S. health care system. This paper explores this hypothesis, arguing that while this exciting new science will enhance our understanding of human biology and our ability to develop new measures against disease over the long term, there is little reason to expect it to undermine or fundamentally alter the current U.S. health care system. This system is under attack from other, broader societal forces and will necessarily change; however, the argument made here is that the current system can easily cope with the changes that pharmacogenomics will bring and that it is unlikely to be disruptive to the current system because (1) it will probably unfold gradually and incrementally over a time span of decades and (2) our drug development and health care system – from development to delivery – has demonstrated sufficient flexibility to adapt to these kinds of incremental changes. Nonetheless, the sustainability of the projected growth in health spending is in question. Profound reforms are likely, but improved knowledge of our human biology will more likely be a constructive factor as we adapt to these changes.
Researchers’ Perceptions of the Ethical Implications of Pharmacogenomics Research with Children
Authors: Avard D. , Silverstein T. , Sillon G. , Joly Y.
Published: February 2009

Background: This paper presents the results of an exploratory qualitative study that assesses Canadian pediatric researchers’ perceptions of a pre-selected group of ethical issues raised by pharmacogenomics research with children. Methods: As a pilot study, we conducted semi-structured telephone interviews with Canadian pediatric pharmacogenomic researchers. The interviews were guided by the following themes: (1) benefits and risks of inclusion, (2) the consent/assent process, and (3) the return of research results. Results: Issues about assent, consent, risks and benefits, as well as the communication of results were addressed by the respondents. Some issues, such as the unique vulnerability of children, the long term privacy concerns associated with biobanking, additional core elements that need to be discussed and included in the consent/assent forms, as well as the challenges of communicating research results in a pediatric research were not explicitly identified by the respondents. Conclusion: Further consideration should be given to address the ethical challenges of including children in pharmacogenomics research. This exploratory study indicates that further guidance is needed if children are to be protected and yet benefit from such research.
Factor XII 46C → T Gene Polymorphism in Chilean Subjects with Coronary Artery Disease and Controls
Authors: Caamaño José , Jaramillo Priscilla C. , Lanas Cecilia , Lanas Fernando , Salazar Luis A.
Published: February 2009

Objective: To investigate the possible association between factor XII (F12) gene variant and the presence of coronary artery disease (CAD) in Chilean subjects. Methods: A total of 112 unrelated patients with a diagnosis of CAD confirmed by angiography (33–74 years old) and 107 healthy controls (30–68 years old) were included in this study. PCR-RFLP was used to evaluate the 46C → T polymorphism of the F12 gene. Results: The genotype distribution for the 46C → T variant of the F12 gene in CAD patients (CC: 41%, CT: 39%, TT: 20%) and controls (CC: 38%, CT: 48%, TT: 14%) was comparable (p = 0.365). Similarly, the allelic frequency was equivalent (p = 0.833). The odds ratio for CAD associated with the mutated 46T allele was 1.06 (95% CI = 0.72–1.56) confirming the absence of an association. Conclusion: This study showed that the F12 46C → T gene polymorphism is not related to CAD in the studied population. However, this study is limited by its sample size and the use of controls not matched by age and sex.
Richter’s Syndrome: A Case Report
Authors: Olaniyi J.A. , Ibijola A.A.
Published: February 2009

Objective: To report a case of Richter’s syndrome found in one of the teaching hospitals in Nigeria in the context of sparse earlier reports of Richter’s syndrome in western Africa. Clinical Presentation and Intervention: A 52-year-old male had been diagnosed earlier as having chronic lymphocytic leukaemia (CLL) and treated for 6 months with chlorambucil, although compliance was poor and the patient eventually stopped treatment. He presented to our hospital 18 months later with clinical features in keeping with Richter’s syndrome. The blood and bone marrow smear review, together with fine-needle aspiration cytology of the masses, showed diffuse large cells of non-Hodgkin lymphoma consistent with the Richter’s syndrome stage of CLL. There was significant improvement in response to the first 4 cycles of CHOP chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone) instituted, but then there were features of relapse. Conclusion: The case report serves to increase awareness and improve the index of suspicion about the terminal phase of CLL and low-grade lymphoma. It equally emphasizes the great need to strengthen further the laboratory diagnosis of haematological malignancies in developing countries.
A Case of Boerhaave’s Syndrome Presenting after a Trial of Non-Invasive Ventilation
Authors: Patel M.S. , Chakraborty P.U.
Published: February 2009

Objective: To highlight the case of a patient with acute respiratory failure, whose diagnosis of Boerhaave’s syndrome only became apparent after a trial of non-invasive ventilation. Clinical Presentation and Intervention: A 68-year-old female presented with a clinical picture of community-acquired pneumonia and exacerbation of asthma that was supported by radiological evidence of a large left-sided pleural effusion. Within 20 h, she deteriorated and progressed to severe type 2 respiratory failure. After initiation of first non-invasive and then invasive ventilation, a tension pneumothorax developed. An emergency decompression of the chest revealed gastric contents in the left hemithorax. A diagnosis of Boerhaave’s syndrome was made. Subsequent management included a thoracotomy, defunctioning oesophagectomy, and gastrostomy with ventilatory and inotropic support. However, despite best efforts, the severe systemic inflammatory response resulted in death 3 weeks after initial presentation. Conclusion: It is important to have an open diagnostic mind with a thorough review of investigations and therapy as a patient deteriorates. This case illustrates the importance of considering the remote possibility of oesophageal rupture prior to commencing non-invasive ventilation, especially with regard to chest radiograph features.
Bilateral Polyorchidism Associated with Intraabdominal Cryptorchidism: A Case Report
Authors: Veloudis George , Pallas Nikolaos , Zografidis Andreas , Gourgiotis Stavros , Villias Constantinos
Published: February 2009

Objective: The aim of this study was to present a rare congenital anomaly of polyorchidism and to review the current management. Clinical Presentation and Intervention: We report the case of a 19-year-old man who was referred for the treatment of an indirect left inguinal hernia. The ultrasound demonstrated a testis on the right side with an additional mass. The preoperative laboratory studies were normal. At surgery, a solid mass consistent with an ectopic testis was removed. The histological evaluation showed the presence of a fourth testis without malignancy, confirming the diagnosis of bilateral, double testes associated with intraabdominal cryptorchidism, which was removed for histology. The postoperative endocrinological evaluation revealed hypergonadotrophic hypogonadism. The patient was followed up conservatively. Conclusion: Polyorchidism should be included in the differential diagnosis of a solid extratesticular mass, and its management should be conservative.
Rubinstein Taybi Syndrome with Hepatic Hemangioma
Authors: Sahiner U.M. , Senel S. , Erkek N. , Karacan C. , Yoney A.
Published: February 2009

Objective: It was the aim of our study to present a case of Rubinstein Taybi syndome (RTS) associated with hepatic hemangioma. Clinical Presentation and Intervention: A 6.5-year-old boy was diagnosed with RTS. He had large areas of cutaneous capillary hemangiomas. Radiological examination revealed a hepatic hemangioma. A multidisciplinary follow-up program was commenced and hepatic ultrasound examinations were performed periodically. No progression and complication have since occurred. Conclusion: This case shows an association between RTS and hepatic hemangioma, and hence, we recommend regular hepatic ultrasound examination when RTS is suspected or diagnosed.
Detection of Antigens Reactive to IgE and IgA during Wheat Seed Maturation and in Different Wheat Cultivars
Authors: Constantin Claudia , Touraev Alisher , Heberle-Bors Erwin , Quirce Santiago , Huber Wolf Dietrich , Valenta Rudolf
Published: February 2009

Background: Dietary intake of wheat causes hypersensitivity reactions in patients suffering from IgE-mediated food allergy and coeliac disease. Aim: To study the expression of IgE- and IgA-reactive antigens during wheat seed maturation and in different wheat cultivars. Methods: Summer wheat was grown in a glasshouse and seeds were harvested at defined maturation stages. Mature seeds were obtained from 13 different defined cultivars. Protein extracts were prepared from different maturation stages and cultivars with a standardized procedure based on seed weight and analysed by IgE and IgA immunoblotting using sera from clinically defined patients suffering from wheat allergy or coeliac disease. Results: With a few exceptions the expression of IgE- and IgA-reactive wheat antigens increased during wheat seed maturation. Wheat cultivars could be identified in which the expression of certain IgE- and IgA-reactive components was strongly reduced or not detectable. Conclusions: The expression of IgE- and IgA-reactive antigens depends on wheat seed maturation and varies in different wheat cultivars.
Probiotic Escherichia coli Nissle 1917 Suppresses Allergen-Induced Th2 Responses in the Airways
Authors: Bickert Thomas , Trujillo-Vargas Claudia M. , Duechs Matthias , Wohlleben Gisela , Polte Tobias , Hansen Gesine , Oelschlaeger Tobias A. , Erb Klaus J.
Published: February 2009

Background: Recent clinical trials, epidemiological studies and animal experiments have suggested that probiotics may help suppress the development of allergic responses. Objective: To investigate whether the application of the probiotic Escherichia coli strain Nissle 1917 (EcN) protects mice from developing ovalbumin (OVA)-specific T helper-2 responses in the airways. Methods: OVA-specific Th2 responses were induced by 2 intraperitoneal (i.p.) injections with OVA/alum followed by 1 intranasal (i.n.) challenge with OVA. EcN was given orally during the entire sensitization and challenge period, together with OVA/alum during the i.p. sensitizations, or i.n. before or during the airway challenge with OVA. Results: We found that when the bacteria were given together with OVA/alum airway eosinophilia, airway hyper-reactivity, goblet cell metaplasia and IL-5 levels in the bronchoalveolar lavage and mediastinal lymph node cell cultures were reduced. This effect was associated with increased numbers of IFN-γ producing T helper-1 cells and IFN-γ levels in the airways and strongly increased OVA-specific IgG2a titers in the serum. The suppressive effect on airway eosinophilia was dependent on IFN-γ but not TLR-4. Applying EcN i.n. or orally did not reduce the development of allergen-specific Th2 responses. Conclusions: Our results suggest that EcN can inhibit the development of allergic responses when the bacteria are present at the site of Th2 cell priming and that this immunomodulatory effect is due to a shift from Th2 to Th1 response. The data support the hypothesis that probiotics may help reduce allergic responses and that EcN may also be used as adjuvant therapy to induce allergen-specific Th1 responses.
Immediate Post-Operative Adjustable Suture Strabismus Surgery Using a Target-Controlled Infusion of Propofol-Remifentanil
Authors: Tatham Andrew , Amaya Luis
Published: February 2009

Purpose: To determine the outcome of immediate suture adjustment in adjustable suture strabismus surgery using a general anaesthetic technique. Methods: Adjustable suture strabismus surgery was performed in 69 patients using a target-controlled infusion of propofol-remifentanil. Sutures were adjusted immediately following surgery and patient satisfaction and ocular alignment were assessed at 3 months postoperatively. Results: Preoperatively, 71% (49/69) of patients were divergent (group 1) and 29% (20/69) were convergent (group 2). Following surgery, the mean deviation in group 1 was 3.5 ± 13.08Δ exodeviation for near and 0.8 ± 10.66Δ exodeviation for distance. The mean postoperative deviation in group 2 was 2.6 ± 9.1Δ esodeviation for near and 2 ± 9.0Δ esodeviation for distance. Overall, 80% (45/69) were within 10Δ of orthotropia. Conclusions: Single-stage adjustable suture strabismus surgery produces good results and is well suited to day case surgery.
Self-Evaluation of Voice as a Treatment Outcome Measure
Authors: Laukkanen Anne-Maria , Leppänen Kirsti , Ilomäki Irma
Published: February 2009

This study addressed two self-evaluation questionnaires in investigating the effects of voice hygiene lecture (VHL, 3 h) and additional voice training (VT) or Voice Massage™ (VM; both 5 h) in 90 female teachers. The subjects assessed their voice quality, ease of phonation and tiredness of throat before and after a working day at the beginning and end of the school term using a visual analogue scale (VAS) (Questionnaire 1). At the end of the term, the degree of positive influence of the interventions was reported on VAS, and the type of influence was indicated by choosing one or more of three alternatives (voice quality, audibility and endurance) or by writing a free comment (Questionnaire 2). Questionnaire 1 was pretested and found to be reliable and valid for self-evaluation of voice. At the end of term, the VM and VT groups reported more positive influence of the interventions than did the VHL group. The reported influence did not correlate with working-day-related changes in sensations. Increased difficulty of phonation and tiredness of throat was found in the VHL group at the end of the term. However, the groups did not differ significantly from each other. The challenges of self-evaluations as outcome measures are discussed.
Patterns of Presentation and Outcomes of Patients with Acute Coronary Syndromes
Authors: Ndrepepa Gjin , Mehilli Julinda , Schulz Stefanie , Iijima Raisuke , Keta Dritan , Byrne Robert A. , Pache Jürgen , Seyfarth Melchior , Schömig Albert , Kastrati Adnan
Published: February 2009

Objectives: We undertook this study to assess the relationship between presentation pattern and mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention. Methods: This registry included 10,455 patients with ACS, of whom 2,853 patients had ST-segment elevation myocardial infarction(STEMI), 3,060 patients had non-ST-segment elevation myocardial infarction (NSTEMI) and 4,542 patients had unstable angina. The primary outcome was 1-year mortality. Results: At 1 year there were 976 deaths, 390 (13.7%) among STEMI patients, 366 (12.0%) among NSTEMI patients and 220 (4.8%) among patients with unstable angina (OR = 1.17, 95% CI 1.01–1.35 for STEMI vs. NSTEMI; OR = 3.00, 95% CI 2.56–3.51 for STEMI vs. unstable angina, and OR = 2.58, 95% CI 2.20–3.04 for NSTEMI vs. unstable angina). In the Cox proportional hazards model ACS form was an independent correlate of 1-year mortality (HR = 0.90, 95% CI 0.73–1.13 for STEMI vs. NSTEMI; HR = 1.56, 95% CI 1.13–2.14 for STEMI vs. unstable angina; HR = 1.72, 95% CI 1.30–2.29 for NSTEMI vs. unstable angina). Conclusions: The presentation pattern affects 1-year mortality in patients with ACS, with unadjusted mortality being highest in patients with STEMI and lowest in patients with unstable angina.
Focus on Microalbuminuria to Improve Cardiac and Renal Protection
Authors: de Jong Paul E. , Gansevoort Ron T.
Published: February 2009

With the recent attention to diagnose earlier stages of chronic kidney diseases (CKD), most attention focuses on screening for an impaired estimated glomerular filtration rate (eGFR), i.e. CKD stages 3–5. Less attention is given to the impact of the urinary leakage of albumin. Its presence is not taken into account in the definition of stages 3–5, but only required to diagnose stages 1 and 2. As in stages 1 and 2 CKD, eGFR is not or only modestly impaired, these stages are generally considered to have a relatively better prognosis. In this review, we will show evidence that screening for albuminuria may be of great benefit, not only as an argument to start treatment to prevent progressive renal function loss, but also to prevent cardiovascular events.