bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposal of a Holistic Model to Support Local-Level Evidence-Based Practice
Authors: Shahtahmasebi Said , Villa Luis , Nielsen Helen , Graham-Smith Hilary
Published: August 2011

In response to a central drive for evidence-based practice, there have been many research support schemes, setups, and other practices concentrating on facilitating access to external research, such as the Centre for Evidence Based Healthcare Aotearoa, the Cochrane Collaboration, and the York Centre for Reviews and Dissemination. Very little attention has been paid to supporting internal research in terms of local evidence and internal research capabilities. The whole evidence-based practice movement has alienated internal decision makers and, thus, very little progress has been made in the context of evidence informing local policy formation. Health and social policies are made centrally based on dubious claims and often evidence is sought after implementation. For example, on record, most health care practitioners appear to agree with the causal link between depression and mental illness (sometimes qualified with other social factors) with suicide; off the record, even some psychiatrists doubt that such a link is applicable to the population as a whole. Therefore, be it through misplaced loyalty or a lack of support for internal researchers/decision makers, local evidence informing local decision making may have been ignored in favour of external evidence. In this paper, we present a practical holistic model to support local evidence-based decision making. This approach is more relevant in light of a new approach to primary health care of “local knowledge” complementing external evidence. One possible outcome would be to network with other regional programmes around the world to share information and identify “best” practices, such as the “Stop Youth Suicide Campaign”(www.stopyouthsuicide.com).
Effects of Furrow Irrigation on the Growth, Production, and Water Use Efficiency of Direct Sowing Rice
Authors: He Chunlin
Published: August 2011

Rice farming is the major crop production in Asia and is predicted to increase significantly in the near future in order to meet the demands for the increasing human population. Traditional irrigation methods used in rice farming often result in great water loss. New water-saving methods are urgently needed to reduce water consumption. Three field and pot experiments were conducted to evaluate the furrow irrigation (FI) system to improve water use efficiency (WUE) and production of direct sowing rice in southern China. Compared to the conventional irrigation (CI) system (continuous flooding irrigation), for every square hectometer of rice field, the FI system reduced water use by 3130 m3, or 48.1%, and increased grain production by 13.9% for an early cultivar. For a late cultivar, the FI system reduced water use by 2655 m3, or 40.6%, and an increase of grain production by 12.1%. The improved WUE in the FI system is attributed to (1) a significant reduction of irrigation rate, seepage, evaporation, and evapotranspiration; (2) a significant reduction in the reduced materials, such as ferrous ion (Fe2+), and therefore an increase in the vitality of the root system, evident by the increases in the number of white roots by 32.62%, and decreases in the number of black roots by 20.04% and yellow roots by 12.58%; the use of the FI system may also reduce humidity of the rice field and enhance gas transport in the soil and light penetration, which led to reduced rice diseases and increased leaf vitality; and (3) increases in tiller and effective spikes by 11.53% and the weight per thousand grains by 1.0 g. These findings suggest that the shallow FI system is a promising means for rice farming in areas with increasing water shortages.
Kalirin-7 is a Key Player in the Formation of Excitatory Synapses in Hippocampal Neurons
Authors: Ma Xin-Ming
Published: August 2011

Kalirin-7 (Kal7), a major isoform of Kalirin in the adult rodent hippocampus, is exclusively localized to the postsynaptic side of mature excitatory synapses in hippocampal neurons. Kal7 interacts with multiple PDZ domain—containing proteins through its unique PDZ binding motif. Overexpression of Kal7 increases spine density and spine size, whereas reduction of endogenous Kal7 expression by small hairpin RNA (shRNA) causes a decrease in synapse number and spine density in cultured hippocampal neurons. Hippocampal CA1 pyramidal neurons of Kal7 knockout (Kal7KO) mice show decreased spine density, spine length, synapse number, and postsynaptic density (PSD) size in their apical dendrites; are deficient in long-term potentiation (LTP); and exhibit decreased frequency of spontaneous excitatory postsynaptic current (sEPSC). Kal7 plays a key role in estrogen-mediated spine/synapse formation in hippocampal neurons. Kal7 is also an essential determinant of dendritic spine formation following chronic cocaine treatment. Kal7 plays a key role in excitatory synapse formation and function.
TRP Channels in Human Prostate
Authors: Van Haute Carl , De Ridder Dirk , Nilius Bernd
Published: August 2011

This review gives an overview of morphological and functional characteristics in the human prostate. It will focus on the current knowledge about transient receptor potential (TRP) channels expressed in the human prostate, and their putative role in normal physiology and prostate carcinogenesis. Controversial data regarding the expression pattern and the potential impact of TRP channels in prostate function, and their involvement in prostate cancer and other prostate diseases, will be discussed.
Functions of Fasciculation and Elongation Protein Zeta-1 (FEZ1) in the Brain
Authors: Maturana Andrés D. , Fujita Toshitsugu , Kuroda Shun'ichi
Published: August 2011

Fasciculation and elongation protein zeta-1 (FEZ1) is a mammalian ortholog of theCaenorhabditis elegansUNC-76 protein that possesses four coiled-coil domains and a nuclear localization signal. It is mainly expressed in the brain. Suppression of FEZ1 expression in cultured embryonic neurons causes deficiency of neuronal differentiation. Recently, proteomic techniques revealed that FEZ1 interacts with various intracellular partners, such as signaling, motor, and structural proteins. FEZ1 was shown to act as an antiviral factor. The findings reported so far indicate that FEZ1 is associated with neuronal development, neuropathologies, and viral infection. Based on these accumulating evidences, we herein review the biological functions of FEZ1.
Heat Shock Proteins: Cell Protection through Protein Triage
Authors: Lanneau David , Wettstein Guillaume , Bonniaud Philippe , Garrido Carmen
Published: August 2011

Heat shock proteins (HSPs) are chaperones that catalyze the proper folding of nascent proteins and the refolding of denatured proteins. The ubiquitin-proteasome system is an error-checking system that directs improperly folded proteins for destruction. A coordinated interaction between the HSPs (renaturation) and the proteasome (degradation) must exist to assure protein quality control mechanisms. Although it still remains unknown how the decision of folding vs. degradation is taken, many pieces of evidence demonstrate that HSPs interact directly or indirectly with the proteasome, assuring quite selectively the proteasomal degradation of certain proteins under stress conditions. In this review, we will describe the different data that demonstrate a role for HSP90, HSP70, HSP27, and alpha-B-crystallin in the partitioning of proteins to either one of these pathways, referred as protein triage.
Penile Microvascular Arterial Bypass Surgery: Indications, Outcomes, and Complications
Authors: Munarriz Ricardo
Published: August 2011

Penile microarterial bypass surgery (MABS) may be the only treatment capable of restoring normal erectile function without the necessity for the chronic use of vasoactive medications or placement of a penile prosthesis. Lack of standardization in patient selection, hemodynamic evaluation, surgical technique, and limited long-term outcome data using validated instruments has resulted in this surgery being considered experimental. The members of the Erectile Dysfunction Guideline Update Panel reviewed the available MABS publications and only four of 31 manuscripts met the criteria for the Arterial Occlusive Disease Index patient. The total studied population of these four publications was 50, which was considered too small to determine if MABS is effective or not. Reported successful outcomes were 36-80 and 91% for inferior epigastric artery (IEA) to dorsal vein and IEA to dorsal artery MABS, respectively. We recently published the largest long-term outcome MABS study using validated questionnaires (71 men aged 30.5 ± 9.2 years; mean follow-up 34.5 ± 18 months). The mean pre- and postoperative total International Index of Erectile Function, erectile function domain, questions 3 and 4 scores were 35.5 ± 14.8, 13.7 ± 6.7, 2.2 ± 1.4, 2.1 ± 1.3, and 56.2 ± 16.6, 23.8 ± 6.6, 4.1 ± 1.4, and 3.9 ± 1.5, respectively. In addition, 55 and 73% of patients reported erectile function domain scores ≥26 and 21, respectively, and almost 90% of patients would recommend or undergo MABS again. In addition, changes in pre- and postoperative sexual distress scale scores and the Center for Epidemiologic Studies Depression Scale were statistically significant. More importantly, treatment satisfaction (EDITS) was very high, and 87% of patients would recommend the surgery to someone else and 88.7% reported a significant improvement in their erectile function. In patients with no vascular risk factors and pure cavernosal arterial insufficiency, MABS provides long-term improvements in erectile function, depression, and overall satisfaction.
Dysfunction of G Protein-Coupled Receptor Kinases in Alzheimer's Disease
Authors: Suo William Z. , Li Longxuan
Published: August 2011

Although mutations and variations of several genes have been identified to be involved in Alzheimer's disease (AD), the efforts towards understanding the pathogenic mechanisms of the disease still have a long journey to go. One such effort is to identify the signal transduction deficits, for which previous studies have suggested that the central problems appear to be at the interface between G proteins and their coupled receptors. G protein-coupled receptor kinases (GRKs) are a small family of serine/threonine protein kinases primarily acting at the “receptor-G protein interface”. Recent studies have indicated the possible involvement of GRK, primarily GRK2 and GRK5, dysfunction in the pathogenesis of AD. It seems that mild, soluble, β-amyloid accumulation can lead to a reduced membrane (functional) and an elevated cytosolic GRK2/5. The increased cytosolic GRK2 appears to be colocalized with damaged mitochondria and neurofibrillary tangles. Moreover, the total levels of GRK2, not only in the brain, but also in peripheral blood samples, are increased in a manner inversely correlated with the patient's cognitive levels. The deficiency of GRK5, on the other hand, impairs presynaptic M2 autoreceptor desensitization, which leads to a reduced acetylcholine release, axonal/synaptic degenerative changes, and associated amnestic, mild cognitive impairment. It also promotes an evil cycle to further increase Beta-amyloid accumulation and exaggerates brain inflammation, possibly even the basal forebrain cholinergic degeneration. Therefore, continuous efforts in this direction are necessary before translating the knowledge to any therapeutic strategies.
Phosphorus Leaching in an Acid Tropical Soil “Recapitalized” with Phosphate Rock and Triple Superphosphate
Authors: Gikonyo E. , Zaharah A.R. , Hanafi M.M. , Anuar R.
Published: August 2011

With high rates of phosphorus applied to increase “capital P” as a stock for plant uptake over several years, the question of P leaching is inevitable. We conducted an intact soil column experiment in the field to evaluate P leached from soils treated with triple superphosphate (TSP) and Gafsa phosphate rock (GPR) at 300, 600, and 900 kg P ha-1with and without integration of cattle manure. The lysimeters, made from PVC tubes of 30-cm length, were inserted into the soil up to the 25-cm depth. The tubes were fitted with a resin bag containing a mixture of cation and anion exchange resin (50:50) at the lower end of the tube inserted into the soil. The tubes, arranged in a completely randomized design, were sampled randomly at 10-week intervals for 12 months. Phosphorus extractable from the top- and subsoil at the end of experiment and leached P were determined. More P was leached out from TSP (threefold) compared to GPR, and the amount of P leached increased with increasing rates of P fertilizer applied. Application of manure intensified the amounts of P leached from TSP, particularly at the 6-month sampling time. There was hardly any substantial P leached from the soil treated with GPR. Thus, for effective and efficient long-term P fertilizer management strategies, choosing the right P fertilizer source and monitoring P losses through leaching has to be done for enhanced fertilizer use efficiency and thus reducing P pollution of ground waters.
β-Carboline Alkaloids and Essential Tremor: Exploring the Environmental Determinants of One of the Most Prevalent Neurological Diseases
Authors: Louis Elan D. , Zheng Wei
Published: August 2011

Essential tremor (ET) is among the most prevalent neurological diseases, yet its etiology is not well understood. Susceptibility genotypes undoubtedly underlie many ET cases, although no genes have been identified thus far. Environmental factors are also likely to contribute to the etiology of ET. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent, tremor-producing β-carboline alkaloid, and emerging literature has provided initial links between this neurotoxin and ET. In this report, we review this literature. Two studies, both in New York, have demonstrated higher blood harmane levels in ET cases than controls and, in one study, especially high levels in familial ET cases. Replication studies of populations outside of New York and studies of brain harmane levels in ET have yet to be undertaken. A small number of studies have explored several of the biological correlates of exposure to harmane in ET patients. Studies of the mechanisms of this putative elevation of harmane in ET have explored the role of increased dietary consumption, finding weak evidence of increased exogenous intake in male ET cases, and other studies have found initial evidence that the elevated harmane in ET might be due to a hereditarily reduced capacity to metabolize harmane to harmine (7-methoxy-1-methyl-9H-pyrido[3,4-β]-indole). Studies of harmane and its possible association with ET have been intriguing. Additional studies are needed to establish more definitively whether these toxic exposures are associated with ET and are of etiological importance.
Evaluation of a Positive Youth Development Program for Adolescents with Greater Psychosocial Needs: Integrated Views of Program Implementers
Authors: Shek Daniel T. L. , Ma Cecilia M. S. , Sun Rachel C. F.
Published: August 2011

To help adolescents with greater psychosocial needs, the Tier 2 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) was designed and implemented by school social workers and teachers. Based on subjective outcome evaluation data collected from the program participants (n = 2,542) in 49 schools, program implementers were invited to write down five conclusions based on an integration of the evaluation findings. With reference to 245 conclusions included in the 49 evaluation reports, secondary data analyses showed that most of the conclusions concerning perceptions of the Tier 2 Program, instructors, and program effectiveness were positive. In addition, difficulties encountered and recommendations for program improvement were highlighted. In conjunction with previous evaluation findings, the present study suggests that the Tier 2 Program was well received and was perceived to be beneficial to the development of adolescents with greater psychosocial needs.
Ureteral Obstruction by the Vas Deferens after Urostomy
Authors: Vaidyanathan Subramanian , Hughes Peter L. , Soni Bakul M. , Singh Gurpreet
Published: August 2011

A male patient with spina bifida and paraplegia, born in 1968, underwent urostomy in 1973. In 1999, he developed urine infections. Intravenous urography showed bilateral hydronephrosis and hydroureter. This patient continued to get recurrent urine infections. In 2009, computed tomography of the abdomen revealed dilatation of the ureters, but the ureters reverted to normal calibre as they passed forward through the anterior abdominal wall. The vas deferens on either side was crossing and kinking the ureter. Magnetic resonance imaging of the abdomen confirmed that the level of obstruction in both ureters was at the site where the vas deferens crossed the ureter and kinked it. While performing urostomy, the ureters below the crossover by the vas deferens were detached from the bladder and attached to the skin for urinary diversion, thus causing the vas deferens to hook the lower end of the ureters. As the patient gained height and weight, thereby increasing abdominal girth, kinking of the ureters by the vas deferens was accentuated. In hindsight, bilateral midline cutaneous urostomy using the ureters below the crossover by the vas deferens represents a poor surgical technique for urinary diversion.
Reinduction of Hormone Sensitivity to Goserelin following Chemotherapy with Vinorelbine in Castration-Resistant Prostate Cancer
Authors: Grenader Tal , Goldberg Anthony
Published: August 2011

Primary androgen ablation leads to symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels in patients with advanced prostate cancer, but all patients eventually become refractory to hormone therapy with progression of the disease and a life expectancy of about a year. We describe a patient who developed castration resistance, was treated with vinorelbine, and continues to be progression free on therapy with luteinizing hormone releasing hormone agonists alone, more than 2.5 years following cessation of treatment with vinorelbine.
Role of Adenosine A2AReceptors in Modulating Synaptic Functions and Brain Levels of BDNF: a Possible Key Mechanism in the Pathophysiology of Huntington's Disease
Authors: Tebano Maria Teresa , Martire Alberto , Chiodi Valentina , Ferrante Antonella , Popoli Patrizia
Published: August 2011

In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A2Areceptors (A2ARs) and brain-derived neurotrophic factor (BDNF). Not only are A2ARs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A2ARs, is involved in such effects. Furthermore, a basal tonus of A2ARs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A2ARs KO mice. The crucial role of adenosine A2ARs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A2ARs seems to play a pathogenetic role.
DJ-1 as a Modulator of Autophagy: An Hypothesis
Authors: González-Polo Rosa A. , Niso-Santano Mireia , Gómez-Sánchez Ruben , Bravo-San Pedro Jose M. , Fuentes José M.
Published: August 2011

The etiology of Parkinson's disease (PD) is not completely defined, although environmental factors (for example, exposure to the herbicide paraquat [PQ]) and genetic susceptibility (such as DJ-1 mutations that have been associated with an autosomal-recessive form of early-onset PD) have been demonstrated to contribute. Alterations in macroautophagy have been described in the pathogenesis of this neurodegenerative disease. We have established a model system to study the involvement of the DJ-1 protein in PQ-induced autophagy. When we transfected cells exposed to PQ with DJ-1–specific siRNA, we observed an inhibition of the autophagic events induced by the herbicide, as well as sensitization additive with PQ-induced apoptotic cell death and exacerbation of this cell death in the presence of the autophagy inhibitor 3-methyladenine. These results suggest, for the first time, an active role for DJ-1 in the autophagic response produced by PQ, opening the door to new strategies for PD therapy.
Examination of Chinese Gambling Problems through a Socio-Historical-Cultural Perspective
Authors: Tse Samson , Yu Alex C.H. , Rossen Fiona , Wang Chong-Wen
Published: August 2011

The aim of this review is to highlight emerging trends about Chinese people and gambling addiction over the last 15 years, and to provide a discourse on the potential link between gambling and Chinese culture and history. The authors reported on the phenomenon of gambling among Chinese people using relevant research studies and reports and traditional Chinese literature. Chinese people have elevated levels of gambling addiction compared to their Western counterparts. These elevated rates are coupled with the rapid expansion of gambling venues within the Pan-Pacific region. While there is an accumulated body of research on Chinese and gambling, a systematic cultural analysis of Chinese gambling is still under development. We undertook a brief comparison between two ancient civilizations, China and Rome, in order to gain better understanding about gambling among Chinese people. To effectively deal with gambling addictions among Chinese people, it is imperative to develop culturally responsive interventions.
Role of Neutrophil Apoptosis in the Resolution of Inflammation
Authors: El Kebir Driss , Filep János G.
Published: August 2011

Neutrophil granulocytes play a central role in host defense to infection and tissue injury. Their timely removal is essential for resolution of inflammation. Increasing evidence identified neutrophil apoptosis as an important control point in the development and resolution of inflammation. Delayed apoptosis and/or impaired clearance of neutrophils aggravate and prolong tissue injury. This review will focus on outside-in signals that provide survival cues for neutrophils, the hierarchy of pro- and antiapoptotic signals, and molecular targets in the antiapoptotic signaling network that can be exploited by endogenously produced bioactive lipids, such as lipoxins or pharmacological inhibitors, including cyclin-dependent kinase inhibitors, to redirect neutrophils to apoptosis in vivo, thus promoting resolution of inflammation.
Potential Damage to Modern Building Materials from 21st Century Air Pollution
Authors: Brimblecombe Peter , Grossi Carlota M.
Published: August 2011

The evolution of damage to building materials has been estimated for the 21stcentury, with a particular focus on aluminum, zinc, copper, plastic, paint, and rubber in urban areas. We set idealized air pollution and climates to represent London and Prague across the period 1950–2100. Environmental parameters were used to estimate future recession, corrosion, and loss of properties through published damage or dose-response functions. The 21stcentury seems to provide a less aggressive environment for stone and metals than recent times. Improvements in air quality are the most relevant drivers for this amelioration. Changes in climate predicted for the 21stcentury do not alter this picture. On the other hand, polymeric materials, plastic, paint, and rubber might show slightly increased rates of degradation, to some extent the result of enhanced oxidant concentrations, but also the possibility of contributions from more solar radiation.
Secondary Data Analyses of Subjective Outcome Evaluation Findings of the Project P.A.T.H.S. in Hong Kong
Authors: Shek Daniel T. L. , Sun Rachel C.F.
Published: August 2011

The Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) is a positive youth development program in Hong Kong. After completion of the program, program implementers were required to draw five conclusions based on the subjective outcome evaluation findings collected from the program participants and implementers as reported in the evaluation report. Secondary analyses of the data collected from 48 schools that had joined the Secondary 3 program showed that most of the conclusions concerning perceptions of the program, instructors, and effectiveness of the program were positive in nature. There were also conclusions indicating strengths and possible improvement of the program. The present findings are consistent with the previous findings that suggest that the Project P.A.T.H.S. is well received by the stakeholders and the program is beneficial to the development of Chinese adolescents in Hong Kong.
Radiotherapeutic Strategies in the Management of Low-Risk Prostate Cancer
Authors: Choe Kevin S. , Liauw Stanley L.
Published: August 2011

Prostate cancer is the most common nonskin malignancy among men in the United States. Since the introduction of screening with prostate-specific antigen (PSA), most patients are being diagnosed at an early stage with low-risk disease. For men with low-risk prostate cancer, there exists an array of radiotherapeutic strategies that are effective and well tolerated, such as external-beam radiotherapy and brachytherapy. In recent years, there have been tremendous advances in the field of radiation oncology that have transformed the way radiation is used to treat prostate cancer, such as intensity-modulated radiotherapy, image-guided radiotherapy, and stereotactic radiotherapy. It is now feasible to deliver high doses of radiation to the target volume with improved precision and spare more of the neighboring tissues from potentially damaging radiation. Disease outcomes are generally excellent in low-risk prostate cancer. Improvements are expected with further integration of innovative technologies in radiation delivery, tumor imaging, and target localization.
Epithelial-to-Mesenchymal Transition in Pancreatic Adenocarcinoma
Authors: Cano Carla , Motoo Yoshiharu , Iovanna Juan L.
Published: August 2011

Epithelial to mesenchymal transition (EMT) is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/aggressiveness, and the drug resistance of pancreatic cancer cells.
Pancreatic Cancer: Molecular, Biochemical, Chemopreventive, and Therapeutic Aspects
Authors: Iovanna Juan , Neira José Luis
Published: August 2011

Pancreatic cancer (PC) is the fourth leading cause of cancer death, with a median survival of 6 months and a dismal 5-year survival rate of 35%, a figure which has remained relatively unchanged over the past 25 years. PC is one of the most difficult diseases to treat due to late initial diagnosis and to resistance to the usual treatments. The presence of occult or clinical metastases at the time of diagnosis, together with the lack of effective chemotherapies, contributes to the high mortality in patients with PC. Its lethal nature stems from its propensity to disseminate rapidly to the lymphatic system and distant organs. Yet, understanding and stopping metastasis may prove to be one of the great potential strategies of treating PC. There is a dire need for the design of new and targeted therapeutic strategies that can overcome the drug resistance and improve the clinical outcome for patients diagnosed with the illness. The knowledge of the molecular aspects of PC is very important, and it is likely to be helpful in the design of newer drugs and the molecular selection of existing agents for targeted therapy. The inhibition of signal pathways can be carried out not only by small molecules, able to bind to selected regions of the target protein, but also by using large molecules as antibodies. The pathway to successful new therapies has been inhibited because of the rapidity with which agents tend to move into randomized, controlled trials without the extensive early testing necessary to optimize treatment regimens. However, lessons have been learned and our collective research effort has generated a substantial platform of knowledge from which further work will spring. The bioavailability of compounds such as antisense oligonucleotides and siRNAs in humans remains a big hurdle, which will require further improvement of gene-delivery strategies. Finally, the long-term goal of the therapy individualization for patients is possible if factors that predict treatment response, such as biological markers, could be determined accurately. These approaches are likely to comprise a mixture of targeted agents in combination with conventional chemotherapy and radiotherapy. For a clinically significant effect to be achieved, treatment strategies should either be in the form of (1) a horizontal approach, in which several oncogenic pathways (as those described in this series of reviews) are inhibited; or (2) a vertical approach, whereby multiple levels of a major pathway are targeted. Combination therapies, together with improved diagnostic tools and predictive markers, are ultimately desired in order to improve the bleak outlook for patients diagnosed with PC.
Why is theNew York TimesWriting so Much about Alzheimer's Disease Therapies?
Authors: Bartfai Tamas
Published: August 2011

Can we go back to proving that drugs work in preventing, postponing, and ameliorating familial Alzheimer's disease (ad)? Ad is so devastating that there is a great public interest in the drug discovery process as evinced by the sheer number of articles in the serious popular press. The presently available, yet poorly performing, drugs have been approved despite their multiple peripheral side effects. The research on disease-modifying agents for the treatment of ad is largely focused on reducing amyloid plaques. However, it is now clear that companies and researchers alike are losing hope in finding an efficacious therapy rapidly that works in ad patients who are already cognitively impaired, and that people who staked their scientific and professional career on finding a cure for ad based on the amyloid hypothesis are shaken by the series of failed clinical trials within a short period of time. It is emerging that we may start to treat ad far too late to be able to make any significant slowing of the disease or postponing the onset of the symptoms of the disease. The history of drug development for other diseases should encourage us to focus on patients in whom we can identify the genetic markers associated with familial ad. Then when we have an efficacious and very safe drug, we will be able to establish its efficacy on, most importantly, cognition, but also at the level of plaques. This will provide the pharmacological evidence needed to show that it is worth fighting amyloidosis because it saves memory. We have a successful and lucrative history of preventive medicine on a large scale, all we need now is the foresight and will to switch strategy and no longer look for a magic bullet to fix ad, but to discover drugs that will delay and prevent the onset of ad, drugs that may be safely taken by symptom-free patients who are vulnerable and susceptible to ad. The initial population that might be preventatively treated against ad would indeed be those with genetic predisposition. While prevention trials are long and expensive as emphasized by the industry, the market for a safe and effective drug would be extended to the large number of patients susceptible to sporadic ad. Since the highest risk factor for sporadic ad is age, this would be an extraordinarily large market.
Stress Proteins and Pancreatic Cancer Metastasis
Authors: Cano Carla E. , Iovanna Juan L.
Published: August 2011

Tumor metastasis is challenged by its resistance to microenvironmental stress infringed during escape from the primary tumor and the colonization of a foreign secondary tissue. Because of its great metastatic potential and its strong resistance to anticancer drugs, pancreatic cancer is regarded as a paradigm of the adaptation of cancer cells to microenvironmental stress. Thus, to understand how pancreatic cancer cells adapt to the different endogenous and therapy-related stresses is crucial for understanding their etiology and for the development of new efficient anticancer strategies. This review summarizes the multiple functions accomplished by one major factor of pancreatic cancer cell stress response, the stress protein p8.
Childhood Vitamin A Capsule Supplementation Coverage in Nigeria: A Multilevel Analysis of Geographic and Socioeconomic Inequities
Authors: Aremu Olatunde , Lawoko Stephen , Dalal Koustuv
Published: August 2011

Vitamin A deficiency (VAD) is a huge public health burden among preschool-aged children in sub-Saharan Africa, and is associated with a high level of susceptibility to infectious diseases and pediatric blindness. We examined the Nigerian national vitamin A capsule (VAC) supplementation program, a short-term cost-effective intervention for prevention of VAD-associated morbidity for equity in terms of socioeconomic and geographic coverage. Using the most current, nationally representative data from the 2008 Nigerian Demographic and Health Survey, we applied multilevel regression analysis on 19,555 children nested within 888 communities across the six regions of Nigeria. The results indicate that there was variability in uptake of VAC supplement among the children, which could be attributed to several characteristics at individual, household, and community levels. Individual-level characteristics, such as maternal occupation, were shown to be associated with receipt of VAC supplement. The results also reveal that household wealth status is the only household-level characteristic that is significantly associated with receipt of VAC, while neighborhood socioeconomic disadvantage and geographic location were the community-level characteristics that determined receipt of VAC. The findings from this study have shown that both individual and contextual socioeconomic status, together with geographic location, is important for uptake of VAC. These findings underscore the need to accord the VAC supplementation program the much needed priority with focus on characteristics of neighborhoods (communities), in addition to individual-level characteristics.
Subjective Outcome Evaluation Findings: Factors Related to the Perceived Effectiveness of the Tier 2 Program of the Project P.A.T.H.S.
Authors: Shek Daniel T.L. , Ma Cecilia M.S.
Published: August 2011

After completion of the Tier 2 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes), 8,489 participants in 196 schools responded to the Subjective Outcome Evaluation Form (Form C) to assess their views of the program, program workers, and perceived effectiveness of the program. Four major program elements were identified, including programs based on the adventure-based counseling approach (n = 48), programs concentrated on volunteer training and services (n = 44), programs with both the adventure-based counseling approach and volunteer training activities (n = 63), and other programs with different foci (n = 41). Descriptive statistics showed that the respondents had positive perceptions of the program, workers, and benefits of the program. Perceived qualities of the program and the program workers were positively associated with perceived effectiveness of the program. Multiple regression analysis revealed that perceived qualities of the program, but not the program workers, predicted perceived effectiveness of the program. The theoretical and practical implications of the findings are discussed.
New Antibody Conjugates in Cancer Therapy
Authors: Govindan Serengulam V. , Goldenberg David M.
Published: August 2011

Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb,90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions.
Cell Secretion: Current Structural and Biochemical Insights
Authors: Trikha Saurabh , Lee Elizabeth C. , M. Jeremic Aleksandar
Published: August 2011

Essential physiological functions in eukaryotic cells, such as release of hormones and digestive enzymes, neurotransmission, and intercellular signaling, are all achieved by cell secretion. In regulated (calcium-dependent) secretion, membrane-bound secretory vesicles dock and transiently fuse with specialized, permanent, plasma membrane structures, called porosomes or fusion pores. Porosomes are supramolecular, cup-shaped lipoprotein structures at the cell plasma membrane that mediate and control the release of vesicle cargo to the outside of the cell. The sizes of porosomes range from 150nm in diameter in acinar cells of the exocrine pancreas to 12nm in neurons. In recent years, significant progress has been made in our understanding of the porosome and the cellular activities required for cell secretion, such as membrane fusion and swelling of secretory vesicles. The discovery of the porosome complex and the molecular mechanism of cell secretion are summarized in this article.
Testicular Polyarteritis Nodosa Mimicking Testicular Neoplasm
Authors: Atis Gokhan , Memis Omer Faruk , Güngör Hasan Samet , Arikan Ozgur , Saglican Yesim , Caskurlu Turhan
Published: August 2011

Polyarteritis nodosa (PAN) presents mostly as a systemic disease characterized by necrotizing vasculitis affecting small- and medium-sized arteries. Rarely, the inflammatory process is isolated and involves a single organ without systemic manifestations. We described the case of a 57-year-old patient with isolated testicular PAN who presented with a testicular mass mimicking a primary testicular tumor.
Design and Generation of MLPA Probe Sets for Combined Copy Number and Small-Mutation Analysis of Human Genes: EGFR as an Example
Authors: Marcinkowska Malgorzata , Wong Kwok-Kin , Kwiatkowski David J. , Kozlowski Piotr
Published: August 2011

Multiplex ligation-dependent probe amplification (MLPA) is a multiplex copy number analysis method that is routinely used to identify large mutations in many clinical and research labs. One of the most important drawbacks of the standard MLPA setup is a complicated, and therefore expensive, procedure of generating long MLPA probes. This drawback substantially limits the applicability of MLPA to those genomic regions for which ready-to-use commercial kits are available. Here we present a simple protocol for designing MLPA probe sets that are composed entirely of short oligonucleotide half-probes generated through chemical synthesis. As an example, we present the design and generation of an MLPA assay for parallel copy number and small-mutation analysis of theEGFRgene.
Accumulation of Soil Carbon and Phosphorus Contents of a Rehabilitated Forest
Authors: Ahmed Osumanu Haruna , Hasbullah Nur Aainaa , Ab Majid Nik Muhamad
Published: August 2011

The world's tropical rainforests are decreasing at an alarming rate as they are converted to agricultural land, pasture, and plantations. Decreasing tropical forests affect global warming. As a result, afforestation progams have been suggested to mitigate this problem. The objective of this study was to determine the carbon and phosphorus accumulation of a rehabilitated forest of different ages. The size of the study area was 47.5 ha. Soil samples were collected from the 0-, 6-, 12-, and 17-year-old rehabilitated forest. Twenty samples were taken randomly with a soil auger at depths of 0–20 and 20–40 cm. The procedures outlined in the Materials and Methods section were used to analyze the soil samples for pH, total C, organic matter, total P, C/P ratio, yield of humic acid (HA), and cation exchange capacity (CEC). The soil pH decreased significantly with increasing age of forest rehabilitation regardless of depth. Age did not affect CEC of the rehabilitated forest. Soil organic matter (SOM), total C, and total P contents increased with age. However, C/P ratio decreased with time at 0–20 cm. Accumulation of HA with time and soil depth was not consistent. The rehabilitated forest has shown signs of being a C and P sink.
Subjective Outcome Evaluation of a Positive Youth Development Program in Hong Kong: Profiles and Correlates
Authors: Ma Hing Keung , Shek Daniel T.L.
Published: August 2011

Secondary school students (n = 33,867 from 213 secondary schools) responded to a subjective outcome evaluation form to assess their views of the program, workers (teachers and/or social workers), and perceived effectiveness of the program. Results showed that high proportions of the respondents had positive perceptions of the program and the instructors, and more than four-fifths of the respondents regarded the program as helpful to them. While schools admitting students with different academic abilities and hours did not differ in the subjective outcome evaluation ratings, subjective evaluation ratings for workers were highest, followed by ratings for the program and perceived effectiveness. The present study replicates the previously reported findings and provides additional support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in Hong Kong.
A Lesson in Survival, by Giardia lamblia
Authors: Rópolo Andrea A. S. , Touz Maria C.
Published: August 2011

In the relationships between host and parasites, there is a cross-talk that involves diverse mechanisms developed by two different genetic systems during years of evolution. On the one hand, immunocompetent hosts have developed effective innate and acquired immune responses that are used to restrict or avoid parasitism. On the other hand, parasites evade the immune response, expressing different antigens on their surface or by using other specific mechanisms, such as nutrient depletion. In this review, we analyze the survival mechanisms used by the protozoan parasiteGiardia lambliaduring infection. In particular, we examine the multiple roles played by the enzyme arginine deiminase during colonization of the gut, also involving the parasite's mechanism of antigenic variation. Potential drug targets for the treatment of giardiasis are also discussed.
Cigarette Smoke Extract Promotes Human Vascular Smooth Muscle Cell Proliferation and Survival through ERK1/2- and NF-κB–Dependent Pathways
Authors: Chen Qing-wen , Edvinsson Lars , Xu Cang-Bao
Published: August 2011

Tobacco use is one of the major risk factors of cardiovascular disease. The underlying molecular mechanisms that link cigarette smoke to cardiovascular disease remain unclear. The present study was designed to examine the effects of dimethyl sulfoxide (DMSO)–soluble smoke particles (DSPs) on human aortic smooth muscle cell (HASMC) cultures, and to explore the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) signal mechanisms involved. Serum-starved HASMCs were treated with DSPs for up to 48 h. DSPs promoted cell proliferation in a concentration-dependent manner from 0.05 to 0.2 ?l/ml. Activation of ERK1/2 and NF-κB was seen after exposure to DSPs. This occurred in parallel with the increase in cell population, bromodeoxyuridine incorporation, and cyclinD1/cyclin-dependent kinase 4 expression. Blocking phosphorylation of ERK1/2 by MAPK inhibitors U0126 and PD98059, and inhibiting activation of NF-κB by IκB (IκB) kinase inhibitors wedelolactone or IMD-0354, abolished the DSP effects. However, either a p38 inhibitor (SB203580) or an inhibitor of lipopolysaccharide (polymyxin B), or nicotinic receptor blockers (mecamylamine and α-bungarotoxin), did not inhibit a DSP-induced increase in the cell population. DSPs increased the expression of intercellular adhesion molecule 1 and the release of interleukin-6 in HASMCs, both of which were inhibited by ERK1/2 or NF-κB pathway inhibitors. Furthermore, cell apoptosis and necrosis were found in serum-starved HASMCs. DSPs decreased cell death and increased B-cell leukemia/lymphoma 2 expression. Blocking phosphorylation of ERK1/2 or NF-κB attenuated DSP-induced cell death inhibition. Cigarette smoke particles stimulate HASMC proliferation and inhibit cell death. The intracellular signal mechanisms behind this involve activation of ERK1/2 and NF-κB pathways.
CD73-Dependent Regulation of Interferon AlphaA and Interleukin-10 in the Inflamed Mucosa
Authors: Sotnikov Ilya , Louis Nancy A.
Published: August 2011

The ecto-5'-nucleotidase, CD73, catalyzes the rate-limiting step in the phosphohydrolysis of ATP to adenosine, and is a critical regulator of the balance between adenosine and its nucleotide precursors. Each of these classes of mediators signal through their independent receptor families to regulate downstream inflammatory signaling. CD73 activity is primarily regulated at the level of transcription in response to the oxygen-sensing transcription factor HIF1, and its tissue-specific expression correlates negatively with oxygen tension. HIF1-dependent induction of CD73 contributes to the protective effects of hypoxia in the inflamed intestinal mucosa. These beneficial effects of CD73 have largely been attributed to downstream adenosine signaling through its tissue-specific receptors. In addition, adenosine signaling has been directly implicated in the protective effects of hypoxic preconditioning against acute hypoxic or ischemic insults. However, recent work has demonstrated that CD73-/- animals lack the ability to produce interferon (IFN) αA, either at baseline or in response to inflammation. Furthermore, this IFN-αA deficiency is associated with the inability to elaborate interleukin (IL)-10–dependent anti-inflammatory signaling. It remains unclear whether interruption of IFN-αA and IL-10 signaling in the absence of CD73 activity results from a deficiency of its product adenosine or an accumulation of its substrate nucleotides. Current evidence for adenosine- and nucleotide-mediated mechanisms of tissue inflammation is reviewed below (Fig. 1).