bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron Deficiency Anemia
Authors: Clark Susan F.
Published: May 2008

The most severe consequence of iron depletion is iron deficiency anemia (IDA), and it is still considered the most common nutrition deficiency worldwide. Although the etiology of IDA is multifaceted, it generally results when the iron demands by the body are not met by iron absorption, regardless of the reason. Individuals with IDA have inadequate intake, impaired absorption or transport, physiologic losses associated with chronological or reproductive age, or chronic blood loss secondary to disease. In adults, IDA can result in a wide variety of adverse outcomes including diminished work or exercise capacity, impaired thermoregulation, immune dysfunction, GI disturbances, and neurocognitive impairment. In addition, IDA concomitant with chronic kidney disease or congestive heart failure can worsen the outcome of both conditions. In this review, the prevalence of IDA related to confounding medical conditions will be described along with its diverse etiologies. Distinguishing IDA from anemia of chronic disease using hematologic measures is reviewed as well. In addition, current diagnostic strategies that are inclusive of clinical presentation, biochemical tests, and differential diagnosis will be outlined, followed by a discussion of treatment modalities and future research recommendations.
Death Resulting From Overzealous Total Parenteral Nutrition: The Refeeding Syndrome Revisited
Authors: Miller Sarah J.
Published: May 2008

Commentary is provided on the pivotal paper by Weinsier and Krumdieck from 1981 describing 2 patients who developed profound and fatal refeeding syndrome following initiation of aggressive total parenteral nutrition. This classic description was among the first to describe the overwhelming cardiovascular and pulmonary manifestations that can accompany parenteral refeeding with carbohydrate in chronically malnourished patients. The syndrome has also been described with oral and enteral nutrition. One of the hallmarks of the syndrome is hypophosphatemia. Since 1981, dosing schemes for addressing hypophosphatemia have been refined. Other manifestations of the syndrome include other electrolyte abnormalities such as hypokalemia and hypomagnesemia, hyperglycemia, fluid and sodium retention, and neurologic and hematologic complications. Case reports of refeeding syndrome continue to be published, particularly in the anorexia nervosa population. Stressed, critically ill patients may be at risk of refeeding following short periods of fasting; hypophosphatemia is commonly encountered in this situation. It behooves the current nutrition support practitioner to keep in mind the types of patients at risk of refeeding syndrome and to approach refeeding of such patients with caution and careful monitoring.
Principles and practice of hormetic treatment of aging and age-related diseases
Authors: Rattan Suresh IS
Published: May 2008

Aging is characterized by stochastic accumulation of molecular damage, progressive failure of maintenance and repair, and consequent onset of age-related diseases. Applying hormesis in aging research and therapy is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. Studies on the beneficial biological effects of repeated mild heat shock on human cells in culture, and other studies on the anti-aging and life-prolonging effects of proxidants, hypergravity, irradiation and ethanol on cells and organisms suggest that hormesis as an antiaging and gerontomodulatory approach has a promising future. Its clinical applications include prevention and treatment of diabetes, cataract, osteoporosis, dementia and some cancers.
Low-dose radioimmuno-therapy of cancer
Authors: Pollycove Myron , Feinendegen Ludwig E
Published: May 2008

Four decades of genomic, cellular, animal and human data have shown that low-dose ionizing radiation stimulates positive genomic and cellular responses associated with effective cancer prevention and therapy and increased life span of mammals and humans. 1—8 Nevertheless, this data is questioned because it seems to contradict the well demonstrated linear relation between ionizing radiation dose and damage to DNA without providing a clear mechanistic explanation of how low-dose radiation could produce such beneficial effects. This apparent contradiction is dispelled by current radiobiology that now includes DNA damage both from ionizing radiation and from endogenous metabolic free radicals, and coupled with the biological response to low-dose radiation. Acceptance of current radiobiology would invalidate long established recommendations and regulations of worldwide radiation safety organizations and so destroy the basis of the very expensive existing system of regulation and remediation. More importantly, current radiobiology would facilitate urgently needed clinical trials of low dose radiation (LDR) cancer therapy.
Hormesis and toxic torts: traditional torts and claims for subclinical harm
Authors: Juni Robin L
Published: May 2008

This article explores the implications of hormesis on toxic tort litigation, in particular litigation regarding claims for medical monitoring or subclinical harm. In considering medical monitoring issues, courts have described medical monitoring both as a remedy and as an independent claim. If medical monitoring is upheld as an indepedent claim — as opposed to a remedy awarded after negligence or another claim is pled and proven — the article explains that the evidentiary showing necessary to succeed on the medical monitoring claim may be less rigorous than would be the case if the issues were considered separately. Because hormesis by definition involves low dose exposures that are more likely to involve subclinical harm, exposure evidence that includes a hormetic effect may well become an issue in medical monitoring cases, and may complicate an already confusing doctrine.
Clinical assessment compared to laboratory screening in acutely poisoned patients
Authors: Heyerdahl F , Hovda KE , Bjornaas MA , Brørs O , Ekeberg O , Jacobsen D
Published: May 2008

Acute poisonings may require identification of the toxic agents. It is impossible for routine laboratories to provide a full spectrum of toxicological analyses, and clinicians should know the reliability of the clinical diagnoses of toxic agents. We performed a 1-year study of hospitalized acute poisonings to determine the agreement between the clinical assessment on admission and serum laboratory tests for eight common toxic agents. Blood samples were drawn in 665 (70%) of the 947 admissions. The total number of laboratory found agents (967) exceeded the clinically suspected (871) by 11%. The agreement between the clinical assessment and laboratory analyses was good for ethanol and paracetamol ( κ = 0.70 for both), whereas only moderate or fair for other agents ( κ 0.22–0.51). Sensitivities of the clinical assessments compared to the laboratory results were better for common than rare agents, and better for higher than lower serum concentrations. The four most common agents (ethanol, benzodiazepines, paracetamol, and opiates) had overall sensitivity of 82% for higher-than-median serum concentrations, whereas the other agents had sensitivities ranging from 14% to 71% for higher-than-median concentrations. The reliability of the clinical diagnoses varied to such an extent that agents, which are important to recognize for specific treatment, should be tested for.
Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta
Authors: Rahi M , Heikkinen T , Hakkola J , Hakala K , Wallerman O , Wadelius M , Wadelius C , Laine K
Published: May 2008

Background: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood–tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. Methods: We have studied the dose–response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression ( n = 44) and the transfer ( n = 16) of saquinavir. Results: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. Conclusions: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp–mediated placental transfer of saquinavir.
Unusual presentations of scorpion envenomation
Authors: Ranu Alpay N , Satar S , Sebe A , Demir M , Topal M
Published: May 2008

Scorpions are nocturnal arthropods that inject their venom through the victims’ skin by stingers. By the envenomation, clinical manifestations in a wide spectrum may occur, including pain at one side and death because of severe cardiopulmonary or neurological abnormalities. Sometimes the victim cannot describe the insect or does not remember even being stung after the event. We present two cases of scorpion envenomation with different and rare clinical situations with a short review of the literature.
Pediatric poisonings in southeast of Turkey: epidemiological and clinical aspects
Authors: Ozdogan H , Davutoglu M , Bosnak M , Tutanc M , Haspolat K
Published: May 2008

Current detailed information about the causes, management, and clinical course of acute childhood poisonings in Turkey is scarce. Therefore, we have conducted a descriptive study of children presenting with acute poisoning to the pediatric emergency department of Dicle University Hospital throughout an 8-month period. Two hundred unselected children with poisoning were evaluated in terms of clinical, epidemiological and socioeconomic aspects. The mean age of patients was 5.7 ± 4.0 years. The majority of the patients ( n = 108, 54%) were aged from 13 months to 4 years ( P < 0.05). In majority of patients (66.5%, n = 133), poisonings were accidental. Intentional poisonings accounted for 3.5% ( n = 7) and food poisoning accounted for 30% ( n = 60) of all cases. The families had more than three children in 129 (97%) of accidentally poisoned and in seven (100%) of intentionally poisoned patients, six were girls and one was a boy. The parents of most patients were uneducated. Furthermore, more than two third of families had low level of income. In all, 171 patients (85.5%) were discharged after an observation period of 24 h. Four patients died. In conclusion, factors such as low educational level of parents, presence of more than three children in the family, and low income increase the incidence of childhood poisonings. The low educational level of girls increases the incidence of intentional poisoning.
Low-dose radiation and its clinical implications: diabetes
Authors: Wang Guan-Jun , Li Xiao-Kun , Sakai Kazuo , Lu Cai
Published: May 2008

Induction of hormesis and adaptive response by low-dose radiation (LDR) has been extensively indicated. Adaptive response induced by LDR was not only resistant to damage caused by a subsequently high-dose radiation, but also cross-resistant to other non-radiation challenges, such as chemicals. Mechanisms by which LDR induces the preventive effect on radiation- or chemical-induced tissue damage include induced or up-regulated expression of protective proteins, such as heat shock proteins and antioxidants. Since oxidative damage to tissues is a major pathogenesis of many human diseases including diabetes, this review will summarize the available data with an emphasis of the preventive effect of LDR on the development of diabetes and the therapeutic effect of LDR on diabetic cardiovascular complications. The available data indicated that pre-exposure of mice to LDR reduced the incidence of alloxan-induced diabetes, and also delayed the onset of hyperglycaemia in diabetes-prone non-obese diabetic mice. Experiments with animals indicated the effectively therapeutic effect of low-intensity or power laser (LIL or LPL) radiation on skin wound healing, which has stimulated clinical use of LIL to cure skin ulcer in diabetic patients. Mechanisms by which LDR prevents diabetes, though are unclear now, may include the induction of pancreatic antioxidants to prevent β cell from oxidative damage and immunomodulation to preserve pancreatic function. For LIL therapeutic effect on diabetic wound healing, mechanisms may include its antioxidant action, immunomodulation, cell proliferation stimulation as well as improvement of systemic and wound-regional microcirculation. Therefore, although only a few studies indicating LDR prevention of the development of diabetes, many studies have demonstrated LDR, specifically LIL, therapeutic effectiveness of diabetic wound healing. These preliminary results are really encouraging for us to further pursue the clinical implication of LDT to diabetes-related areas.
Active Vibration Control of Structures Subject to Parameter Uncertainties and Actuator Delay
Authors: Haiping Du  , Nong Zhang
Published: May 2008

This article presents a robust H∞ controller design approach for active vibration attenuation of structures considering parameter uncertainties and time delay in control input. The parameter uncertainties dealt with belong to the polytopic type, and are assumed to be variations of the structural stiffnesses and damping coefficients. The time delay is an uncertain time-invariant with known constant bound. In terms of the feasibility of certain delay-dependent matrix inequalities, both state feedback and static output feedback controllers can be designed. To overcome the bilinear matrix inequality problems involved in the delay-dependent conditions, a genetic algorithm is used to find feasible solutions, after which use is made of the solvability of linear matrix inequalities. The performance of the presented approach is demonstrated by numerical simulations on the vibration control of a building structure subjected to seismic excitation. It is confirmed that the controllers designed by this method can effectively attenuate the structural vibration and ensure system stability even when there are parameter uncertainties and actuator delay.
Design of Mechanical Band-Pass Filters for Energy Scavenging: Multi-Degree-of-Freedom Models
Authors: Shahruz S.M.
Published: May 2008

In this article, a model of a mechanical band-pass filter to be used in energy scavengers is studied. The filter is an ensemble of cantilever beams where at the tip of each beam a mass, known as the proof mass, is mounted. A beam with a proof mass at its tip is called a beam-mass system. The dynamics of a beam-mass system can be represented by its corresponding generalized single-degree-of-freedom (SDoF) system. Using this model, dimensions of the beams and masses of the proof masses of beam-mass systems can be determined, so that an ensemble of such systems would function as a band-pass filter. To verify the adequacy of the SDoF model in representing the dynamics of the infinite-dimensional beam-mass system, a two-degree-of-freedom (TDoF) model of this system is developed. This model affirms that, as far as the energy scavenging is concerned, the SDoF model adequately represents the dynamics of the infinite-dimensional beam-mass system. Consequently, in designing mechanical band-pass filters, it is sufficient to use the SDoF models of the beam-mass systems.
The Amsterdam Studies of Acute Psychiatry I (ASAP-I); A prospective cohort study of determinants and outcome of coercive versus voluntary treatment interventions in a metropolitan area
Authors: van der Post Louk , Schoevers Robert , Koppelmans Vincent , Visch Irene , Bernardt Clemens , Mulder Niels , Beekman Aartjan , de Haan Lieuwe , Dekker Jack
Published: May 2008

Background

The overall number of involuntary admissions is increasing in many European countries. Patients with severe mental illnesses more often progress to stages in which acute, coercive treatment is warranted. The number of studies that have examined this development and possible consequences in terms of optimizing health care delivery in emergency psychiatry is small and have a number of methodological shortcomings. The current study seeks to examine factors associated with compulsory admissions in the Amsterdam region, taking into account a comprehensive model with four groups of predictors: patient vulnerability, social support, responsiveness of the health care system and treatment adherence.

Methods/Design

This paper describes the design of the Amsterdam Study of Acute Psychiatry-I (ASAP-I). The study is a prospective cohort study, with one and two-year follow-up, comparing patients with and without forced admission by means of a selected nested case-control design. An estimated total number of 4,600 patients, aged 18 years and over, consecutively coming into contact with the Psychiatric Emergency Service Amsterdam (PESA) are included in the study. From this cohort, a randomly selected group of 125 involuntary admitted subjects and 125 subjects receiving non-coercive treatment are selected for further evaluation and comparison.

First, socio-demographic, psychopathological and network characteristics, and prior use of health services will be described for all patients who come into contact with PESA. Second, the in-depth study of compulsory versus voluntary patients will examine which patient characteristics are associated with acute compulsory admission, also taking into account social network and healthcare variables. The third focus of the study is on the associations between patient vulnerability, social support, healthcare characteristics and treatment adherence in a two-year follow-up for patients with or without involuntarily admittance at the index consultation.

Discussion

The current study seeks to establish a picture of the determinants of acute compulsory admissions in the Netherlands and tries to gain a better understanding of the association with the course of illness and patient's perception of services and treatment adherence. The final aim is to find specific patient and health care factors that can be influenced by adjusting treatment programs in order to reduce the number of involuntary admissions.
The effect of voluntary fasting and dehydration on flicker-induced retinal vascular dilation in a healthy individual: a case report
Authors: Heitmar Rebekka , Gherghel Doina , Armstrong Richard , Cubbidge Robert , Hosking Sarah
Published: May 2008

Introduction

Dynamic retinal vessel analysis represents a well-established method for the assessment of vascular reactivity during both normal conditions and after various provocations. We present a case where the subject showed abnormal retinal vessel reactivity after fasting voluntarily for 20 hours.

Case presentation

A healthy, 21-year-old man who fasted voluntarily for 20 hours exhibited abnormal retinal vascular reactivity (dilation and constriction) after flicker provocation as measured using the Dynamic Retinal Vessel Analyser (Imedos, Jena, Germany).

Conclusion

The abnormal vascular reactivity induced by fasting was significant; abnormal levels of important nutrients due to fasting and dehydration could play a role through altering the concentration of vasoactive substances such as nitric oxide. This hypothesis needs further investigation.
Monogenic Diabetes in the Young, Pharmacogenetics and Relevance to Multifactorial Forms of Type 2 Diabetes
Authors: Vaxillaire Martine , Froguel Philippe
Published: May 2008

Most valuable breakthroughs in the genetics of type 2 diabetes for the past two decades have arisen from candidate gene studies and familial linkage analysis of maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes typically occurring before 25 years of age caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but presents genetic, metabolic and clinical heterogeneity. MODY can result from mutations in at least six different genes encoding the glucose sensor enzyme glucokinase and transcription factors that participate in a regulatory network essential for adult β-cell function. Additional genes have been described in other discrete phenotypes or syndromic forms of diabetes. Whereas common variants in the MODY genes contribute very modestly to type 2 diabetes susceptibility in adults, major findings emerging from the advent of genome-wide association studies will deliver an increasing number of genes and new pathways for the pathological events of the disease.
Transdermal delivery enhancement of haloperidol from gel formulations by 1,8-cineole
Authors: Elgorashi Abubakr S , Heard Charles M , Niazy Esmail M , Noureldin Osman H , Pugh W John
Published: May 2008

The feasibility of using 10% 1,8-cineole as an enhancer for transdermal delivery of haloperidol has been examined. In-vitro transdermal delivery across full-thickness human, rabbit and hairless mouse skins was measured from three polymer gel systems, hypromellose (hydroxypropylmethylcellulose), Carbomer (Carbopol) 940 and macrogol (polyethylene glycol) using Franz cells. Values for the permeability coefficient kp, calculated as the product (Kh)×(D/h2) where these two factors were obtained from curve fitting of the non-steady-state equation over 24 h, were similar from the three formulations. The value of kp from hypromellose was significantly enhanced by cineole by factors of 6.2 (4.6–8.1), 5.6 (5.0–6.2) and 3.0 (2.6–3.4) for human, rabbit and mouse, respectively (mean and 95% confidence intervals). Enhancement ratios for K: 13.3 (8.3–20), 3.1 (2.5–3.9) and 2.0 (1.5–2.6), were higher than those for D: 0.47 (0.41–0.55), 1.8 (1.6–2.1) and 1.5 (1.3–1.8). This suggested that the barrier function of the skin lipids was marginally affected and the main effect was to increase the thermodynamic activity of the drug in the barrier. The enhancement achieved in human skin suggested that delivery could be safely enhanced by terpenoids.
Characterization of primary sensory neurons mediating static and dynamic allodynia in rat chronic constriction injury model
Authors: Yamamoto Wataru , Sugiura Akemi , Nakazato-Imasato Etsuko , Kita Yasuhiro
Published: May 2008

Mechanical allodynia, such as static and dynamic allodynia, is a prominent feature of neuropathic pain syndromes. The aim of this study is to characterize primary sensory neurons mediating the mechanical allodynia in a rat chronic constriction injury (CCI) model with a combination of pharmacological and histological investigations. N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a selective and competitive antagonist of the vanilloid receptor 1 (TRPV1), and resiniferatoxin, which causes desensitization of TRPV1-expressing fibres, suppressed static allodynia but not dynamic allodynia in CCI rats. Immunohistochemical studies of TRPV1 and NF200, an A-fibre marker 200 kDa neurofilament, in dorsal root ganglion neurons demonstrated that each 48% of the positive-stained neurons were immunoreactive only for TRPV1 or NF200. The other 4% of stained neurons were double-positive for TRPV1 and NF200. Of the TRPV1-positive neurons, more than 99% were small- (diameter <25 μm) and medium- (25–45 μm) sized. In contrast, 97% of NF200 single-labelled neurons were medium- and large- (>45 μm) sized. These findings suggest that two types of mechanical allodynia are transmitted by different primary sensory neurons: static allodynia is mediated by TRPV1 positive small- and medium-sized neurons and dynamic allodynia might be signalled by TRPV1-negative medium- and large-sized neurons.
Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis
Authors: Okumura Takako , Murata Yoko , Taniguchi Kana , Murase Akio , Nii Aisuke
Published: May 2008

Prostaglandin E2 (PGE2) produced by cyclooxygenase (COX) is a potent pro-inflammatory mediator. We have recently discovered CJ-023,423, a highly selective antagonist of EP4 receptors, one of the PGE2 receptors. This agent is suitable for exploring the effects of blocking EP4 receptors following oral administration in rats. In this study, CJ-023,423 was used in rats with adjuvant-induced arthritis (AIA) to investigate the role of the EP4 receptor in chronic inflammation and bone destruction. These effects were compared with those of rofecoxib, a selective COX-2 inhibitor. CJ-023,423 had significant inhibitory effects on paw swelling, inflammatory biomarkers, synovial inflammation and bone destruction in AIA rats. In particular, the inhibitory effect on paw swelling in AIA rats was comparable to that of rofecoxib. These results suggest that PGE2 acting via the EP4 receptor is involved in the development of chronic inflammation and bone destruction, particularly with respect to oedema in AIA rats. This is the first study to confirm the in-vivo effects of EP4 receptor blockade on inflammation and bone destruction in AIA rats with a small-molecule compound.
Protective effect of the endothelin antagonist CPU0213 against isoprenaline-induced heart failure by suppressing abnormal expression of leptin, calcineurin and SERCA2a in rats
Authors: Xu Ming , Ji Hui , Dai De-Zai , Tang Xiao-Yun , Dai Yin
Published: May 2008

Heart failure (HF) may be produced by sustained β-adrenoceptor stimulation by causing changes in the expression of endothelin-1 (ET-1), the leptin system, calcineurin and sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) underlying cardiac dysfunction. The aim of this study was to verify whether isoprenaline (ISO)-induced HF is attributed to changes in the above molecular markers, and whether the dual ET-receptor antagonist CPU0213 could reverse the cardiac dysfunction caused by ISO treatment, focusing on these molecular markers. HF was induced in rats by administration of ISO (2 mgkg−1 s.c.) for 10 days. CPU0213 (30 mgkg−1 s.c.) and propranolol (4 mgkg−1 s.c.) were administered on days 7–10. HF developed after 10 days' ISO administration and was manifest as impaired cardiac performance, increased heart weight index, oxidative stress, elevated serum enzymes, and disordered expression of the endothelin system, leptin system, calcineurin and SERCA2a. All these abnormalities were significantly reversed by CPU0213, and the effectiveness of this ET-receptor antagonist was comparable to that of propranolol. Thus, antagonism of ET receptors by CPU0213 normalizes these changes in molecular markers, alleviating HF.
The induction of atherogenic dyslipidaemia in poloxamer 407-treated mice is not mediated through PPARα
Authors: Johnston Thomas P , Waxman David J
Published: May 2008

The copolymer surfactant poloxamer 407 (P-407) has been used to induce a dose-controlled dyslipidaemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentration-dependent reduction in cholesterol efflux to apolipoprotein A1 (apoA1) due to down-regulation of the ATP-binding cassette transporter A1 (ABCA1). Peroxisome proliferator-activated receptor alpha (PPARα) can increase expression of liver X receptor alpha (LXRα) in macrophages and thereby promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1. This study investigated point(s) along this signalling pathway at which P-407 might act to inhibit cholesterol efflux from macrophages. A transactivation assay was used to evaluate whether P-407 could either activate PPARα or block the activation of PPARα by an established PPARα agonist. P-407 was also evaluated for its potential to alter plasma lipid concentrations following its administration to both normal C57BL/6 and PPARα-deficient mice. P-407 was unable to modulate PPARα activity, as determined in cell-based transactivation assays. Moreover, P-407-induced dyslipidaemia occurred at the same rate and to the same extent in PPARα-deficient mice as was observed in C57BL/6 mice, suggesting no role for PPARα in P-407-mediated dyslipidaemia. Although PPARs are known to mediate the transcriptional regulation of the two major apolipoproteins associated with HDL (apoA1 and apoA2), P-407 treatment resulted in a similar decrease (∼30%) in the plasma concentration of apoA1 in both control and PPARα-deficient mice. Since our previous work demonstrated that P-407 was unable to abrogate the capacity of a known LXRα agonist to increase cholesterol efflux from macrophages, P-407 is likely to exert its effect, either directly or indirectly, on ABCA1, rather than on LXRα. On the basis of these findings it is concluded that PPARα does not mediate the P-407-dependent reduction in apoA1-facilitated cholesterol efflux from macrophages.
Dose-dependent effect of oregano (Origanum vulgare L.) on lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis
Authors: Srihari Thummala , Sengottuvelan Murugan , Nalini Namasivayam
Published: May 2008

Colon cancer is a major cause of morbidity and mortality in developed and developing countries. Diet and dietary constituents play a major role in the aetiology of colon cancer. We have investigated the effect of an aqueous extract of oregano (Origanum vulgare. L.) on lipid peroxidation and anti-oxidant status in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. We aimed to identify the important antioxidants present in Indian oregano using RP-HPLC. DMH (20 mgkg−1) was administered subcutaneously once a week for the first four weeks and then discontinued. Oregano was supplemented every day orally at a dose of 20, 40 or 60 mgkg−1 to different groups of rats for 15 weeks. After this time the rats were killed and the colons were examined visually and evaluated biochemically. The levels of lipid peroxidation products, such as thiobarbituric acid reactive substances and conjugated dienes were significantly higher in the liver whereas in caecum and colon the levels were lower in DMH-treated animals as compared with control rats. The levels of the anti-oxidants superoxide dismutase, catalase, reduced glutathione, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were decreased in DMH-treated rats, but were significantly reversed on oregano supplementation. Oregano supplementation (40 mgkg−1) had a modulatory role on tissue lipid peroxidation and antioxidant profile in colon cancer-bearing rats, which suggested a possible anti-cancer property of oregano.
A new model for hemoglobin ingestion and transport by the human malaria parasite Plasmodium falciparum
Authors: Lazarus Michelle D. , Schneider Timothy G. , Taraschi Theodore F.
Published: May 2008

The current model for hemoglobin ingestion and transport by intraerythrocytic Plasmodium falciparum malaria parasites shares similarities with endocytosis. However, the model is largely hypothetical, and the mechanisms responsible for the ingestion and transport of host cell hemoglobin to the lysosome-like food vacuole (FV) of the parasite are poorly understood. Because actin dynamics play key roles in vesicle formation and transport in endocytosis, we used the actin-perturbing agents jasplakinolide and cytochalasin D to investigate the role of parasite actin in hemoglobin ingestion and transport to the FV. In addition, we tested the current hemoglobin trafficking model through extensive analysis of serial thin sections of parasitized erythrocytes (PE) by electron microscopy. We find that actin dynamics play multiple, important roles in the hemoglobin transport pathway, and that hemoglobin delivery to the FV via the cytostomes might be required for parasite survival. Evidence is provided for a new model, in which hemoglobin transport to the FV occurs by a vesicle-independent process.
yuri gagarinis required for actin, tubulin and basal body functions inDrosophilaspermatogenesis
Authors: Texada Michael J. , Simonette Rebecca A. , Johnson Cassidy B. , Deery William J. , Beckingham Kathleen M.
Published: May 2008

Males of the genus Drosophila produce sperm of remarkable length. Investigation of giant sperm production in Drosophila melanogaster has demonstrated that specialized actin and microtubule structures play key roles. The gene yuri gagarin (yuri) encodes a novel protein previously identified through its role in gravitaxis. A male-sterile mutation of yuri has revealed roles for Yuri in the functions of the actin and tubulin structures of spermatogenesis. Yuri is a component of the motile actin cones that individualize the spermatids and is essential for their formation. Furthermore, Yuri is required for actin accumulation in the dense complex, a microtubule-rich structure on the sperm nuclei thought to strengthen the nuclei during elongation. In the yuri mutant, late clusters of syncytial nuclei are deformed and disorganized. The basal bodies are also mispositioned on the nuclei, and the association of a specialized structure, the centriolar adjunct (CA), with the basal body is lost. Some of these nuclear defects might underlie a further unexpected abnormality: sperm nuclei occasionally locate to the wrong ends of the spermatid cysts. The structure of the axonemes that grow out from the basal bodies is affected in the yuri mutant, suggesting a possible role for the CA in axoneme formation.
Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei
Authors: Grasser Florian , Neusser Michaela , Fiegler Heike , Thormeyer Tobias , Cremer Marion , Carter Nigel P. , Cremer Thomas , Müller Stefan
Published: May 2008

Using published high-resolution data on S-phase replication timing, we determined the three-dimensional (3D) nuclear arrangement of 33 very-early-replicating and 31 very-late-replicating loci. We analyzed diploid human, non-human primate and rearranged tumor cells by 3D fluorescence in situ hybridization with the aim of investigating the impact of chromosomal structural changes on the nuclear organization of these loci. Overall, their topology was found to be largely conserved between cell types, species and in tumor cells. Early-replicating loci were localized in the nuclear interior, whereas late-replicating loci showed a broader distribution with a higher preference for the periphery than for late-BrdU-incorporation foci. However, differences in the spatial arrangement of early and late loci of chromosome 2, as compared with those from chromosome 5, 7 and 17, argue against replication timing as a major driving force for the 3D radial genome organization in human lymphoblastoid cell nuclei. Instead, genomic properties, and local gene density in particular, were identified as the decisive parameters. Further detailed comparisons of chromosome 7 loci in primate and tumor cells suggest that the inversions analyzed influence nuclear topology to a greater extent than the translocations, thus pointing to geometrical constraints in the 3D conformation of a chromosome territory.
Acetyl Chloride-Mediated Synthesis of trans-2-[(Diethoxyphosphorylamino)alkyl]-4-aryl-5,5-dimethyl-1,3,2λ5-dioxaphosphorinane-2-oxide
Authors: Miao Zhiwei , Zhang Jianfeng , Cui Zhanwei , Chen Ruyu
Published: May 2008

N-Phosphoramino-protected six-membered cyclic α-aminophosphonates trans-2-[(diethoxyphosphorylamino)alkyl]-4-aryl-5,5-dimethyl-1,3,2λ5-dioxaphosphorinane-2-oxide 4a–4l were synthesized with the help of acetyl chloride. 31P NMR was used to trace the reaction process. A possible reaction mechanism was proposed and the stereochemistry of the title compounds was studied. In order to confirm the structure of 4, products 4f and 4k were recrystallized and determined by X-ray diffraction analysis.
Treatment Pathway and Patterns of Clozapine Prescribing for Schizophrenia in New Zealand
Authors: Wheeler Amanda J
Published: May 2008

Objective:

To describe the treatment pathway and patterns of clozapine use in patients with schizophrenia, including coprescribed psychotropic medications, and compare the extent of coprescribing of clozapine with that of non-clozapine schizophrenia treatment in community montal health services in the Auckland and Northland regions of New Zealand.

Methods:

A retrospective chart review was conducted for adult outpatients receiving care from community mental health services on October 31, 2004. Data collected for all patients prescribed an antipsychotic included demographics (sex, age, ethnicity); principal diagnosis (Diagnostic and Statistical Manual of Mental Disorders, 4th edition); comorbid conditions; duration of mental illness; psychiatric admissions; and treatment information (psychotropic medications, with dose and route of administration). If clozapine had been started after the introduction of full government prescription subsidy (February 1999), additional data, including year of initiation and prior antipsychotic history, were collected. Analysis included all outpatients with a diagnosis of schizophrenia (including schizoaffective disorder).

Results:

Antipsychotics were prescribed for 2796 schizophrenia patients; 32.8% were prescribed clozapine, with a mean dose of 372 mg/day and an average duration of illness of 9.7 years before starting clozapine. Patients who had started treatment after clozapine was funded by the government (59.3%) had received a median of 3 antipsychotic drugs prior to starting clozapine; most of the treatment regimens included 1 second-generation antipsychotic (91.2%). Clozapine patients were less likely to be coprescribed another antipsychotic compared with non-clozapine patients (11.7% vs 17.6%; p conclusions: Outpatients with treatment-resistant schizophrenia were prescribed clozapine at expected rates; however, treatment was delayed longer than recommended. There is some evidence that access to clozapine for treatment-resistant schizophrenia has improved, possibly as the result of the introduction of government subsidy, guideline dissemination, or increasing experience of clinicians with use of clozapine. In this real-world environment, the number of concomitant psychotropic medications for outpatients with schizophrenia was found to be low; when used concomitantly with clozapine, they were most commonly used to manage adverse effects.
Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin
Authors: Anderson Shawn D , Gums John G
Published: May 2008

Objective:

To summarize and evaluate the literature concerning ceftobiprole.

Data Sources:

Literature identification was conducted through MEDLINE (1966–February 2008) and International Pharmaceutical Abstracts (1970–February 2008) using the terms ceftobiprole, medocaril, BAL 5788, RO-5788, BAL 9141, RO 63-9141, pynolidinone cephalosporin. MRSA, complicated skin and skin-structure infections (cSSSIs), community-acquired pneumonia, and nosocomial pneumonia. Additional publications were identified through a review of articles and abstracts from infectious disease meetings.

Study Selection and Data Extraction:

All articles in English were evaluated and all pertinent information was included.

Data Synthesis:

Ceftobiprole medocaril is an extended-spectrum cephalosporin with activity against methicillin-reslstant Staphylococcus spp., vancomycin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa. Inactivity includes extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae and Enterococcus faecium. Preliminary data suggest that ceftobiprole may be effective with a 1-hour infusion of 500 mg every 12 hours for gram-positive infections and 500 mg every 8 hours with a 2-hour infusion for polymicrobial infections. Two clinical trials support these dosing regimens for cSSSIs. Ceftobiprole was noninferior to vancomycin in suspected gram-positive cSSSIs, with cure rates of 93.3% and 93.5%, respectively. Furthermore, ceftobiprole was noninferior to vancomycin and ceftazidime in polymicrobial cSSSIs (cure rates 90.5% vs 90.2%, respectively). Although the total number of adverse effects was similar to those of the comparator, more patients in the ceftobiprole group experienced nausea, vomiting, and dysgeusia.

Conclusions:

The activity of ceftobiprole and limited clinical data suggest that it may be useful as empiric monotherapy for cSSSI and in combination with other antimicrobials in lower respiratory tract infections for which Phase 3 clinical trials are currently exploring. Although not shown in vitro, ceftobiprole may induce resistance due to its broad spectrum of activity. Approval is expected for the treatment of cSSSI.
Vibrissal Responses of Thalamic Cells That Project to the Septal Columns of the Barrel Cortex and to the Second Somatosensory Area
Authors: Bokor Hajnalka , Acsády László , Deschênes Martin
Published: May 2008

The rodent somatosensory cortex contains barrel-related and septa-related circuits representing two separate streams of vibrissa information processing that differ in their response patterns and anatomical connections. Whereas barrel-related circuits process lemniscal inputs that transit through the thalamic barreloids, septa-related circuits process paralemniscal inputs and inputs that are relayed through the ventral lateral part of the ventral posterior medial nucleus (VPMvl). Septa-projecting thalamic afferents also target the secondary somatosensory cortical area. Although a number of studies have examined response properties in the lemniscal pathway, and demonstrated that barreloids receive feedback from specific sets of corticothalamic and reticular thalamic neurons, such information is currently lacking for the VPMvl. In the present study, we show that in sharp contrast to the relay cells of the barreloids VPMvl neurons exhibit large multiwhisker receptive fields that are independent of input from the principal trigeminal nucleus. Results also suggest that the topography of receptive fields and response properties in VPMvl rely on converging input from neurons of the interpolaris trigeminal nucleus. Tracer injection and single-cell labeling further reveal that the VPMvl receives input from specific populations of reticular thalamic and corticothalamic neurons. Together, these results confirm the status of the VPMvl as a thalamic relay of an independent parallel pathway of vibrissa information processing. They further indicate that a sensory pathway does not merely consist on a three-neuron chain that links the vibrissae to the cerebral cortex, but that it also involves specific sets of topographically related corticothalamic and reticular thalamic projections.
Foxg1Is Required for Development of the Vertebrate Olfactory System
Authors: Duggan Cynthia D. , DeMaria Shannon , Baudhuin Ariane , Stafford David , Ngai John
Published: May 2008

Illuminating the molecular identity and regulation of early progenitor cells in the olfactory sensory epithelium represents an important challenge in the field of neural development. We show in both mouse and zebrafish that the winged helix transcription factorFoxg1is expressed in an early progenitor population of the olfactory placode. In the mouse,Foxg1is first expressed throughout the olfactory placode but later becomes restricted to the ventrolateral olfactory epithelium. The essential role ofFoxg1in olfactory development is demonstrated by the strikingly severe phenotype ofFoxg1knock-out mice: older embryos have no recognizable olfactory structures, including epithelium, bulb, or vomeronasal organs. Initially, a small number of olfactory progenitors are specified but show defects in both proliferation and differentiation. Similarly, antisense RNA knockdown ofFoxg1expression in the zebrafish shows a reduction in the number of neurons and mitotic cells in olfactory rosettes, mirroring the phenotype seen in the mouseFoxg1null mutant. Using mosaic analysis in the zebrafish, we show thatFoxg1is required cell-autonomously for the production of mature olfactory receptor neurons. Therefore, we identified an evolutionarily conserved requirement forFoxg1in the development of the vertebrate olfactory system.
Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination
Authors: Binder Michele D. , Cate Holly S. , Prieto Anne L. , Kemper Dennis , Butzkueven Helmut , Gresle Melissa M. , Cipriani Tania , Jokubaitis Vilija G. , Carmeliet Peter , Kilpatrick Trevor J.
Published: May 2008

The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles ofAxl,Mer, andGas6mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression ofTyro3decreased, correlating with the loss of oligodendrocytes. Gas6 both promotedin vitrosurvival of oligodendrocytes (39.3 ± 3.1 vs 11.8 ± 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor α mRNA expression was reduced ∼48%). In Gas6−/−mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-π (glutathioneS-transferase-π)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6−/−mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6−/−mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.
Conditions for Propagating Synchronous Spiking and Asynchronous Firing Rates in a Cortical Network Model
Authors: Kumar Arvind , Rotter Stefan , Aertsen Ad
Published: May 2008

Isolated feedforward networks (FFNs) of spiking neurons have been studied extensively for their ability to propagate transient synchrony and asynchronous firing rates, in the presence of activity independent synaptic background noise (Diesmann et al., 1999; van Rossum et al., 2002). In a biologically realistic scenario, however, the FFN should be embedded in a recurrent network, such that the activity in the FFN and the network activity may dynamically interact. Previously, transient synchrony propagating in an FFN was found to destabilize the dynamics of the embedding network (Mehring et al., 2003). Here, we show that by modeling synapses as conductance transients, rather than current sources, it is possible to embed and propagate transient synchrony in the FFN, without destabilizing the background network dynamics. However, the network activity has a strong impact on the type of activity that can be propagated in the embedded FFN. Global synchrony and high firing rates in the embedding network prohibit the propagation of both, synchronous and asynchronous spiking activity. In contrast, asynchronous low-rate network states support the propagation of both, synchronous spiking and asynchronous, but only low firing rates. In either case, spiking activity tends to synchronize as it propagates, challenging the feasibility to transmit information in asynchronous firing rates. Finally, asynchronous network activity allows to embed more than one FFN, with the amount of cross talk depending on the degree of overlap in the FFNs. This opens the possibility of computational mechanisms using transient synchrony among the activities in multiple FFNs.