bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring allosteric coupling in the α-subunit of Heterotrimeric G proteins using evolutionary and ensemble-based approaches
Authors: Sayar Kemal , Uğur Özlem , Liu Tong , Hilser Vincent J , Onaran Ongun
Published: June 2008

Background

Allosteric coupling, which can be defined as propagation of a perturbation at one region of the protein molecule (such as ligand binding) to distant sites in the same molecule, constitutes the most general mechanism of regulation of protein function. However, unlike molecular details of ligand binding, structural elements involved in allosteric effects are difficult to diagnose. Here, we identified allosteric linkages in the α-subunits of heterotrimeric G proteins, which were evolved to transmit membrane receptor signals by allosteric mechanisms, by using two different approaches that utilize fundamentally different and independent information.

Results

We analyzed: 1) correlated mutations in the family of G protein α-subunits, and 2) cooperativity of the native state ensemble of the Gαi1 or transducin. The combination of these approaches not only recovered already-known details such as the switch regions that change conformation upon nucleotide exchange, and those regions that are involved in receptor, effector or Gβγ interactions (indicating that the predictions of the analyses can be viewed with a measure of confidence), but also predicted new sites that are potentially involved in allosteric communication in the Gα protein. A summary of the new sites found in the present analysis, which were not apparent in crystallographic data, is given along with known functional and structural information. Implications of the results are discussed.

Conclusion

A set of residues and/or structural elements that are potentially involved in allosteric communication in Gα is presented. This information can be used as a guide to structural, spectroscopic, mutational, and theoretical studies on the allosteric network in Gα proteins, which will provide a better understanding of G protein-mediated signal transduction.
Involvement of GTA protein NC2β in Neuroblastoma pathogenesis suggests that it physiologically participates in the regulation of cell proliferation
Authors: Di Pietro Cinzia , Ragusa Marco , Barbagallo Davide , Duro Laura R , Guglielmino Maria R , Majorana Alessandra , Giunta Veronica , Rapisarda Antonella , Tricarichi Elisa , Miceli Marco , Angelica Rosario , Grillo Agata , Banelli Barbara , Defferari Isabella , Forte Stefano , Laganà Alessandro , Bosco Camillo , Giugno Rosalba , Pulvirenti Alfredo , Ferro Alfredo , Grzeschik Karl H , Di Cataldo Andrea , Tonini Gian P , Romani Massimo , Purrello Michele
Published: June 2008

Background

The General Transcription Apparatus (GTA) comprises more than one hundred proteins, including RNA Polymerases, GTFs, TAFs, Mediator, and cofactors such as heterodimeric NC2. This complexity contrasts with the simple mechanical role that these proteins are believed to perform and suggests a still uncharacterized participation to important biological functions, such as the control of cell proliferation.

Results

To verify our hypothesis, we analyzed the involvement in Neuroblastoma (NB) pathogenesis of GTA genes localized at 1p, one of NB critical regions: through RT-PCR of fifty eight NB biopsies, we demonstrated the statistically significant reduction of the mRNA for NC2β (localized at 1p22.1) in 74% of samples (p = 0.0039). Transcripts from TAF13 and TAF12 (mapping at 1p13.3 and 1p35.3, respectively) were also reduced, whereas we didn't detect any quantitative alteration of the mRNAs from GTF2B and NC2α (localized at 1p22-p21 and 11q13.3, respectively). We confirmed these data by comparing tumour and constitutional DNA: most NB samples with diminished levels of NC2β mRNA had also genomic deletions at the corresponding locus.

Conclusion

Our data show that NC2β is specifically involved in NB pathogenesis and may be considered a new NB biomarker: accordingly, we suggest that NC2β, and possibly other GTA members, are physiologically involved in the control of cell proliferation. Finally, our studies unearth complex selective mechanisms within NB cells.
A novel adenovirus vector for easy cloning in the E3 region downstream of the CMV promoter
Authors: Mailly Laurent , Boulade-Ladame Charlotte , Orfanoudakis Georges , Deryckere François
Published: June 2008

The construction of expression vectors derived from the human adenovirus type 5 (Ad5), usually based on homologous recombination, is time consuming as a shuttle plasmid has to be selected before recombination with the viral genome. Here, we describe a method allowing direct cloning of a transgene in the E3 region of the Ad5 genome already containing the immediate early CMV promoter upstream of three unique restriction sites. This allowed the construction of recombinant adenoviral genomes in just one step, reducing considerably the time of selection and, of course, production of the corresponding vectors. Using this vector, we produced recombinant adenoviruses, each giving high-level expression of the transgene in the transduced cells.
Study protocol for a three-armed randomized controlled trial to assess whether house screening can reduce exposure to malaria vectors and reduce malaria transmission in The Gambia
Authors: Kirby Matthew J , Milligan Paul J , Conway David J , Lindsay Steve W
Published: June 2008

Background

Mosquito-proofing homes was one of the principal methods of environmental management in the early 1900s. House screening provides protection against malaria by reducing exposure to malaria parasites and has the added benefit of protecting everyone sleeping in the house, avoiding issues of inequity within the household. The aim of this study is to determine whether house screening protects people against malaria in Africa. It is hoped that this study will mark the beginning of a series of trials assessing a range of environmental interventions for malaria control in Africa.

Design

A 3-armed randomised-controlled trial will be conducted in and around Farafenni town in The Gambia, West Africa, to assess whether screening windows, doors and closing eaves or installing netting ceilings in local houses can substantially reduce malaria transmission and anaemia compared to homes with no screening. Eligible houses will be sorted and stratified by location and the number of children in each house, then randomly allocated to the interventions in blocks of 5 houses (2 with full screening, 2 with screened ceilings and 1 control house without screening). Risk of malaria transmission will be assessed in each house by routine collections of mosquitoes using light traps and an anaemia prevalence study in children at the end of the main transmission period.

Discussion

Practical issues concerning intervention implementation, as well as the potential benefits and risks of the study, are discussed.

Trial Registration

ISRCTN51184253 – Screening-homes to prevent malaria
Prostate Cancer Stem Cells: A New Target for Therapy
Authors: Maitland Norman J. , Collins Anne T.
Published: June 2008

The existence of prostate cancer stem cells offers a theoretical explanation for many of the enduring uncertainties surrounding the etiology and treatment of the most commonly diagnosed tumor in US males. The study of cancer stem cells in prostate, as in other complex tissues, is critically dependent on the availability of pure cell populations, a situation complicated by the heterogeneity of prostate tumors. However, selection of cells with a CD133+/α2β1 integrin/ CD44+ phenotype enriches for a tumor-initiating population from human prostate cancers. Among the most pressing needs is for enduring therapy in patients who have experienced failure of hormonal treatments. Because the putative cancer stem cell does not express androgen receptor, it is likely to be immune from most androgen-based therapies, and an inherent genetic instability would enable the tumor to develop the new variants present in hormone-refractory disease. Prostate cancer stem cells have a unique gene expression signature that can also be related to Gleason grade and patient outcome. The scarcity of cancer stem cells in a prostate tumor will probably limit their usefulness in cancer diagnosis and prognosis. However, the emergence of new stem-cell therapeutic targets not only will require new assays for efficacy (because of their relatively quiescent nature), but also holds real promise of more lasting treatments to augment those currently directed against the remaining tumor cells, which comprise 99.9% of tumor mass, but paradoxically have a poor tumor-initiating capacity.
Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis
Authors: Eyler Christine E. , Rich Jeremy N.
Published: June 2008

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.
Implications of the Cancer Stem-Cell Hypothesis for Breast Cancer Prevention and Therapy
Authors: Kakarala Madhuri , Wicha Max S.
Published: June 2008

Recent research in breast biology has provided support for the cancer stem-cell hypothesis. Two important components of this hypothesis are that tumors originate in mammary stem or progenitor cells as a result of dysregulation of the normally tightly regulated process of self-renewal. As a result, tumors contain and are driven by a cellular subcomponent that retains key stem-cell properties including self-renewal, which drives tumorigenesis and differentiation that contributes to cellular heterogeneity. Advances in stem-cell technology have led to the identification of stem cells in normal and malignant breast tissue. The study of these stem cells has helped to elucidate the origin of the molecular complexity of human breast cancer. The cancer stem-cell hypothesis has important implications for early detection, prevention, and treatment of breast cancer. Both hereditary and sporadic breast cancers may develop through dysregulation of stem-cell self-renewal pathways. These aberrant stem cells may provide targets for the development of cancer prevention strategies. Furthermore, because breast cancer stem cells may be highly resistant to radiation and chemotherapy, the development of more effective therapies for this disease may require the effective targeting of this cell population.
Pancreatic Cancer Stem Cells
Authors: Lee Cheong J. , Dosch Joseph , Simeone Diane M.
Published: June 2008

Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). Recent data has been provided to support the existence of CSCs in human blood cell–derived cancers and solid organ tumors of the breast, brain, prostate, colon, and skin. Study of human pancreatic cancers has also revealed a specific subpopulation of cancer cells that possess the characteristics of CSCs. These pancreatic cancer stem cells express the cell surface markers CD44, CD24, and epithelial-specific antigen, and represent 0.5% to 1.0% of all pancreatic cancer cells. Along with the properties of self-renewal and multilineage differentiation, pancreatic CSCs display upregulation of important developmental genes that maintain self-renewal in normal stem cells, including Sonic hedgehog (SHH) and BMI-1. Signaling cascades that are integral in tumor metastasis are also upregulated in the pancreatic CSC. Understanding the biologic behavior and the molecular pathways that regulate growth, survival, and metastasis of pancreatic CSCs will help to identify novel therapeutic approaches to treat this dismal disease.
Brain Tumor Stem Cells: Bringing Order to the Chaos of Brain Cancer
Authors: Dirks Peter B.
Published: June 2008

Brain tumors are generally incurable cancers. Work from a number of laboratories strongly suggests that they are organized as a hierarchy based on a subset of cancer cells that have stem-cell properties. These cells have now been shown to be resistant to conventional therapy and responsive to differentiation therapy. New in vitro and in vivo models for interrogating brain tumor cells in stem-cell conditions have been developed that provide important new opportunities for elucidating the key pathways responsible for driving the proliferation of these cells. Continued application of the principles of stem-cell biology to the study of brain cancers is likely to continue to bring further important insight into these aggressive cancers, bringing new treatments and understanding of the origins.
Human Colon Cancer Stem Cells: A New Paradigm in Gastrointestinal Oncology
Authors: Boman Bruce M. , Huang Emina
Published: June 2008

For the past half century, oncologists have had systemic drugs available, agents that are able to induce tumor responses in patients with colorectal cancer. However, in cases of advanced colorectal cancer, these regimens are almost never curative. The recently introduced concept that cancer stem cells (SCs) drive tumor growth suggests a reason for these therapeutic failures— current chemotherapeutics target rapidly dividing cells but cancer SCs divide only slowly, and, they are relatively resistant to cytotoxic systemic therapies. It also suggests a solution—development of therapeutics that target cancer SCs. However, there is a paucity of information about the mechanisms by which SC populations are maintained and about the mechanisms by which tumor SCs are involved in colon cancer development. In this article, we discuss these mechanisms and recent developments in the identification and isolation of colon cancer SCs using new SC markers. We then discuss the role of SCs in homeostasis of normal colonic epithelium, and mechanisms by which dysregulation of crypt mechanisms can lead to initiation and progression of colon cancer. Our hypothesis, which has received recent experimental support, is that the mechanism that links abnormalities at the gene level (eg, APC mutations) and abnormalities at the tissue level (eg, proliferative shift, dysplasia, carcinoma) from cancer initiation to metastasis is SC overpopulation. Finally, we discuss the concept that symmetric cancer SC division is an essential mechanism that drives tumor growth, and that development of a new generation of therapeutics that target colon cancer SCs by inhibiting symmetric SC division holds promise for truly curative approaches for patients with advanced colorectal cancers.
Effect of Heat Stress on Expression of Junction-Associated Molecules and Upstream Factors Androgen Receptor and Wilms’ Tumor 1 in Monkey Sertoli Cells
Authors: Chen Min , Cai Huan , Yang Jun-Ling , Lu Cui-Ling , Liu Tao , Yang Wei , Guo Jian , Hu Xiao-Qian , Fan Cui-Hong , Hu Zhao-Yuan , Gao Fei , Liu Yi-Xun
Published: June 2008

Sertoli cells are important in determining the fate of spermatogenic cells by providing nutrition and structural support via cell junctions. In this study, we sought to examine the effect of 43 C warming on cell junctions in seminiferous epithelium and the expression of junction-associated molecules in Sertoli cells. Electron microscopy showed the appearance of large vacuoles between Sertoli and germ cells and adjacent Sertoli cells, leading to disruption of corresponding cell junctions 24 h after terminating the heat treatment. Using primary Sertoli cells isolated from pubertal monkey testes, we demonstrated that expression of adherens junction-associated molecules, such as N-cadherin and β-catenin, and tight junction-associated molecule zonula occludens protein 1 was significantly reduced in 24–48 h after heat treatment. In contrast, intermediate filament vimentin expression was up-regulated in 6–48 h. Androgen receptor (AR) and Wilms’ tumor gene 1 expression dramatically decreased after heat treatment. Both proteins completely disappeared immediately after terminating heat treatment and began to recover after 6 h. Treatment of the monkey Sertoli cells with an AR antagonist, flutamide, could mimic the heat-induced changes in the expression of junction-associated molecules in Sertoli cells. Furthermore, overexpression of AR in the Sertoli cells up-regulated the expression of N-cadherin, β-catenin, and zonula occludens protein 1 and down-regulated vimentin expression. Their expression after heat treatment could be rescued by the AR overexpression. These results indicate that the decreased AR expression after heat treatment is involved in heat-induced cell junction disruption.
Estrogen Receptor-α Signaling in Growth of the Ventral Prostate: Comparison of Neonatal Growth and Postcastration Regrowth
Authors: Omoto Yoko
Published: June 2008

A role for estrogen receptor (ER)-α in branching morphogenesis in the ventral prostate (VP) has previously been demonstrated; in the VP of ERα−/− mice, there are fewer side branches than in wild-type littermates. In the present study, we show that in the postnatal VP, fibroblast growth factor 10 (FGF10) is expressed in wild-type mice but not in ERα−/− mice, and because branching involves proliferation pathways also used in malignant growth, we investigated whether branching during regrowth of the VP after castration involves ERα and FGF10. ERα was not detectable in the prostates of sham-operated or castrated mice but was expressed in the prostatic epithelium between d 3 and 5 after testosterone replacement. Blocking either ERα or ERβ with ICI 182,780 had no detectable effects on epithelial cell proliferation during regrowth by testosterone. The ERα agonist, propylpyrazoletriol, did not induce regrowth by itself, but exposure to propylpyrazoletriol on d 3–5 of testosterone replacement resulted in cyclin D1-positive cells in the ductal epithelium, invasion of FGF10-positive immune cells in the regrowing prostate, and budding 14 d later. Testosterone replacement alone did not induce cyclin D1, FGF10, or bud formation. These results indicate that stimulation of ERα is essential for ductal branching during postnatal prostate growth. During regrowth after castration, there is a window in time when selective stimulation of ERα can also induce ductal branching. The FGF10 for this growth comes from the immune system, not from the prostatic mesenchyme.
Involvement of Tetrodotoxin-Resistant Na+ Current and Protein Kinase C in the Action of Growth Hormone (GH)-Releasing Hormone on Primary Cultured Somatotropes from GH-Green Fluorescent Protein Transgenic Mice
Authors: Yang Seung-Kwon , Wang Kun , Parkington Helena , Chen Chen
Published: June 2008

GHRH depolarizes the membrane of somatotropes, leading to an increase in intracellular free Ca2+ concentration and GH secretion. Na+ channels mediate the rapid depolarization during the initial phase of the action potential, and this regulates Ca2+ influx and GH secretion. GHRH increases a tetrodotoxin-sensitive somatotrope Na+ current that is mediated by cAMP. TTX-resistant (TTX-R) Na+ channels are abundant in sensory neurons and cardiac myocytes, but their occurrence and/or function in somatotropes has not been investigated. Here we demonstrate expression of TTX-R Na+ channels and a TTX-R Na+ current, using patch-clamp method, in green fluorescent protein-GH transgenic mouse somatotropes. GHRH (100nm) increased the TTX-R Na+ current in a reversible manner. The GHRH-induced increase in TTX-R Na+ current was not affected by the cAMP antagonist Rp-cAMP or protein kinase A inhibitors KT5720 or H89. The TTX-R current was increased by 8-bromoadenosine-cAMP (cAMP analog), forskolin (adenylyl-cyclase activator), and 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor), but the additional, GHRH-induced increase in TTX-R Na+ currents was not affected. U-73122 (phospholipase C inhibitor) and protein kinase C (PKC) inhibitors, Gö-6983 and chelerythrine, blocked the effect of GHRH. PKC activators, phorbol dibutyrate and phorbol myristate acetate, increased the TTX-R Na+ current, but GHRH had no further effect on the current. Na+-free extracellular medium significantly reduced GHRH-stimulated GH secretion. We conclude that GHRH-induced increase in the TTX-R Na+ current in mouse somatotropes is mediated by the PKC system. An increase in the TTX-R Na+ current may contribute to the GHRH-induced exocytosis of GH granules from mouse somatotropes.
JAWS coordinates chondrogenesis and synovial joint positioning
Authors: Sohaskey Michael L. , Yu Jane , Diaz Michael A. , Plaas Anna H. , Harland Richard M.
Published: June 2008

Properly positioned synovial joints are crucial to coordinated skeletal movement. Despite their importance for skeletal development and function, the molecular mechanisms that underlie joint positioning are not well understood. We show that mice carrying an insertional mutation in a previously uncharacterized gene, which we have named Jaws (joints abnormal with splitting), die perinatally with striking skeletal defects, including ectopic interphalangeal joints. These ectopic joints develop along the longitudinal axis and persist at birth, suggesting that JAWS is uniquely required for the orientation and consequent positioning of interphalangeal joints within the endochondral skeleton. Jaws mutant mice also exhibit severe chondrodysplasia characterized by delayed and disorganized maturation of growth plate chondrocytes, together with impaired chondroitin sulfation and abnormal metabolism of the chondroitin sulfate proteoglycan aggrecan. Our findings identify JAWS as a key regulator of chondrogenesis and synovial joint positioning required for the restriction of joint formation to discrete stereotyped locations in the embryonic skeleton.
Research Note—A Model of Conflict, Leadership, and Performance in Virtual Teams
Authors: Wakefield Robin L. , Leidner Dorothy E. , Garrison Gary
Published: June 2008

Organizations in many different industries employ virtual teams in a variety of contexts, including research and development, customer support, software development, and product design. Many virtual teams are geographically and culturally dispersed in order to facilitate around-the-clock work and to allow the most qualified individuals to be assigned to a project team. As such dispersion increases, virtual teams tend to experience greater and more diverse conflict compared to co-located teams. Since the dynamics of virtual team leadership are not yet well understood, research that examines how team leaders alleviate threats to team cohesion and provide strategies for conflict resolution makes significant contributions to the literature. Our study uses a survey-based methodology to examine the perceptions of 159 virtual team members employed by a large U.S. telecommunications corporation and five Korean firms involved in construction, finance, business consulting, sales, and distribution. The study integrates the dynamic model of conflict in distributed teams with the behavioral complexity in leadership theory to investigate the roles that virtual team leaders must effectively employ to reduce various forms of virtual team conflict. Our findings indicate that communication technologies are effective in reducing task conflict; however, the team leader may also mitigate task conflict by assuming the role of monitor. Likewise, process conflict may be abated in the virtual team as the leader performs coordinator activities. An effective virtual team leader exhibits specific roles to manage different types of conflict and the leader's response to conflict plays an important part in virtual team success.
Is there a role for lengthening flexor hallucis and flexor digitorum longus tendons in surgery for club foot?
Authors: Lahoti O. , Bajaj S.
Published: June 2008

Most cases of club foot (congenital talipes equinovarus) respond to non-operative treatment but resistant cases may need surgery. It is broadly accepted that lengthening of tendo Achillis, the tendon of tibialis posterior and capsulotomy of the ankle and subtalar joints are necessary during surgical release, but there is no consensus as to whether lengthening of the tendons of flexor hallucis longus and flexor digitorum longus is required.

We randomised 13 children with severe bilateral club foot deformities to undergo lengthening of the flexor hallucis longus and flexor digitorum longus tendons on one side and simple decompression on the other. We found no difference in the deformities of the toes between the lengthened and non-lengthened sides at a mean follow-up of four years (2 to 6).

We conclude that routine lengthening of the tendons of flexor hallucis longus and flexor digitorum longus during soft-tissue surgery for resistant club foot is not necessary.
Metal-on-metal hip resurfacing in developmental dysplasia
Authors: McBryde C. W. , Shears E. , O’Hara J. N. , Pynsent P. B.
Published: June 2008

Metal-on-metal hip resurfacing was performed for developmental dysplasia in 96 hips in 85 patients, 78 in women and 18 in men, with a mean age at the time of surgery of 43 years (14 to 65). These cases were matched for age, gender, operating surgeon and date of operation with a group of patients with primary osteoarthritis who had been treated by resurfacing, to provide a control group of 96 hips (93 patients). A clinical and radiological follow-up study was performed. The dysplasia group were followed for a mean of 4.4 years (2.0 to 8.5) and the osteoarthritis group for a mean of 4.5 years (2.2 to 9.4). Of the dysplasia cases, 17 (18%) were classified as Crowe grade III or IV.

There were five (5.2%) revisions in the dysplasia group and none in the osteoarthritic patients. Four of the failures were due to acetabular loosening and the other sustained a fracture of the neck of femur. There was a significant difference in survival between the two groups (p = 0.02). The five-year survival was 96.7% (95% confidence interval 90.0 to 100) for the dysplasia group and 100% (95% confidence interval 100 to 100) for the osteoarthritic group. There was no significant difference in the median Oxford hip score between the two groups at any time during the study.

The medium-term results of metal-on-metal hip resurfacing in all grades of developmental dysplasia are encouraging, although they are significantly worse than in a group of matched patients with osteoarthritis treated in the same manner.
Early infection after hip fracture surgery
Authors: Edwards C. , Counsell A. , Boulton C. , Moran C. G.
Published: June 2008

Prospective data on hip fracture from 3686 patients at a United Kingdom teaching hospital were analysed to investigate the risk factors, financial costs and outcomes associated with deep or superficial wound infections after hip fracture surgery.

In 1.2% (41) of patients a deep wound infection developed, and 1.1% (39) had a superficial wound infection. A total of 57 of 80 infections (71.3%) were due to Staphylococcus aureus and 39 (48.8%) were due to MRSA.

No statistically significant pre-operative risk factors were detected. Length of stay, cost of treatment and pre-discharge mortality all significantly increased with deep wound infection. The one-year mortality was 30%, and this increased to 50% in those who developed an infection (p < 0.001). A deep infection resulted in doubled operative costs, tripled investigation costs and quadrupled ward costs.

MRSA infection increased costs, length of stay, and pre-discharge mortality compared with non-MRSA infection.
Total shoulder replacement in young and middle-aged patients with glenohumeral osteoarthritis
Authors: Raiss P. , Aldinger P. R. , Kasten P. , Rickert M. , Loew M.
Published: June 2008

Our aim in this prospective study was to evaluate the outcome of total shoulder replacement in the treatment of young and middle-aged active patients with primary glenohumeral osteoarthritis. We reviewed 21 patients (21 shoulders) with a mean age of 55 years (37 to 60). The mean follow-up was seven years (5 to 9). The same anatomical, third-generation, cemented implant had been used in all patients. All the patients were evaluated radiologically and clinically using the Constant and Murley score.

No patients required revision. In one a tear of the supraspinatus tendon occurred. Overall, 20 patients (95%) were either very satisfied (n = 18) or satisfied (n = 2) with the outcome. Significant differences (p < 0.0001) were found for all categories of the Constant and Murley score pre- and post-operatively. The mean Constant and Murley score increased from 24.1 points (10 to 45) to 64.5 points (39 to 93), and the relative score from 30.4% (11% to 50%) to 83% (54% to 116%). No clinical or radiological signs of loosening of the implant were seen.

For young and middle-aged patients with osteoarthritis, third-generation total shoulder replacement is a viable method of treatment with a low rate of complications and excellent results in the mid-term.
Callus distraction for humeral nonunion with bone loss and limb shortening caused by chronic osteomyelitis
Authors: Liu T. , Zhang X. , Li Z. , Zeng W. , Peng D. , Sun C.
Published: June 2008

Nonunion of the humerus with bone loss and shortening due to osteomyelitis is rare but difficult to treat. We describe our experience with a callus distraction technique using a monolateral external fixator for the treatment of this condition.

Between October 1994 and January 2004, 11 patients were treated. There were seven males and four females, with a mean age of 14 years (10 to 17). The mean bone loss was 1.9 cm (1 to 2.7) and the mean length discrepancy in the upper limb was 5.6 cm (3.5 to 8.0).

The mean follow-up was for 106 months (54 to 166). The mean external fixation index was 34.8 days/cm (29.8 to 40.5). The mean lengthening was 9.5 cm (5.5 to 13.4). There were seven excellent results, three good and one poor. There were nine excellent functional results and two good.

The treatment of humeral nonunion with bone loss and shortening due to osteomyelitis by callus distraction is a safe and effective means of improving function and cosmesis.
Peri-articular steroid injection improves the outcome after unicondylar knee replacement
Authors: Pang H.-N. , Lo N.-N. , Yang K.-Y. , Chong H.-C. , Yeo S.-J.
Published: June 2008

We have performed a prospective double-blind, randomised controlled trial over two years to evaluate the efficacy and safety of an intra-operative peri-articular injection of triamcinolone acetonide in patients undergoing medial unicondylar knee replacement. We randomised 90 patients into two equal groups. The study group received an injection of triamcinolone acetonide, bupivacaine, and epinephrine into the peri-articular tissues at the end of the operation. The control group received the same injection mixture but without the addition of triamcinolone. The peri-operative analgesic regimen was standardised.

The study group reported a significant reduction in pain (p = 0.014 at 12 hours, p = 0.031 at 18 hours and p = 0.031 at 24 hours) and had a better range of movement (p = 0.023 at three months). There was no significant difference in the rate of infection and no incidence of tendon rupture in either group.

The addition of corticosteroid to the peri-articular injection after unicondylar knee replacement had both immediate and short-term benefits in terms of relief from pain, and rehabilitation with no increased risk of infection.
Statistical Methods for Monitoring the Relationship between the IFCC Reference Measurement Procedure for Hemoglobin A1c and the Designated Comparison Methods in the United States, Japan, and Sweden
Authors: Geistanger Andrea , Arends Sabine , Berding Christoph , Hoshino Tadao , Jeppsson Jan-Olof , Little Randie , Siebelder Carla , Weykamp Cas ,   the IFCC Working Group on Standardization of Hemoglobin A1c
Published: June 2008

Background: The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD)/International Diabetes Federation (IDF)/IFCC Consensus Statement on the worldwide standardization of HbA1c states that “… [HbA1c] results are to be reported world-wide in IFCC units … and derived NGSP units … , using the IFCC-NGSP master equation.”

Methods: We describe statistical methods to evaluate and monitor the relationships as expressed in master equations (MEs) between the IFCC Reference Measurement procedure (IFCC-RM) and designated comparison methods (DCMs) [US National Glycohemoglobin Standardization Program (NGSP), Japanese Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC), and Mono-S in Sweden]. We applied these statistics, including uncertainty calculations, to 12 studies in which networks of reference laboratories participated, operating the IFCC-RM and DCMs.

Results: For NGSP and Mono-S, slope, intercept, and derived percentage HbA1c at the therapeutic target show compliance with the respective MEs in all 12 studies. For JDS/JSCC, a slight deviation is seen in slope and derived percentage HbA1c in 2 of the 12 studies. Using the MEs, the uncertainty in an assigned value increases from 0.42 mmol/mol HbA1c (IFCC-RM) to 0.47 (NGSP), 0.49 (JDS/JSCC), and 0.51 (Mono-S).

Conclusions: We describe sound statistical methods for the investigation of relations between networks of reference laboratories. Application of these statistical methods to the relationship between the IFCC-RM and DCMs in the US, Japan, and Sweden shows that they are suitable for the purpose, and the results support the applicability of the ADA/EASD/IDF/IFCC Consensus Statement on HbA1c measurement.
Isolation and Transcriptional Profiling of Purified Hepatic Cells Derived from Human Embryonic Stem Cells
Authors: Chiao Eric , Elazar Menashe , Xing Yi , Xiong Anming , Kmet Muriel , Millan Maria T. , Glenn Jeffrey S. , Wong Wing H. , Baker Julie
Published: June 2008

The differentiation of human embryonic stem cells (hESCs) into functional hepatocytes provides a powerful in vitro model system for studying the molecular mechanisms governing liver development. Furthermore, a well-characterized renewable supply of hepatocytes differentiated from hESCs could be used for in vitro assays of drug metabolism and toxicology, screening of potential antiviral agents, and cell-based therapies to treat liver disease. In this study, we describe a protocol for the differentiation of hESCs toward hepatic cells with complex cellular morphologies. Putative hepatic cells were identified and isolated using a lentiviral vector, containing the α-fetoprotein promoter driving enhanced green fluorescent protein expression (AFP:eGFP). Whole-genome transcriptional profiling was performed on triplicate samples of AFP:eGFP+ and AFP:eGFP− cell populations using the recently released Affymetrix Exon Array ST 1.0 (Santa Clara, CA, http://www.affymetrix.com). Statistical analysis of the transcriptional profiles demonstrated that the AFP:eGFP+ population is highly enriched for genes characteristic of hepatic cells. These data provide a unique insight into the complex process of hepatocyte differentiation, point to signaling pathways that may be manipulated to more efficiently direct the differentiation of hESCs toward mature hepatocytes, and identify molecular markers that may be used for further dissection of hepatic cell differentiation from hESCs.

Disclosure of potential conflicts of interest is found at the end of this article.
A Comprehensive Study of Reservoirs Exhibiting Dual-Storage Effects During Well Testing
Authors: Azari Mehdi , Wooden W. O. , Petak K. R. , Soliman M. Y.
Published: June 2008

This paper presents a thorough investigation, the first of its kind, of well tests in which the early-time portion of the log-log plot of pressure and derivative data form parallel straight lines with slopes ranging from 0.5 to 1.0. Several well tests have exhibited this unusual pressure behavior that prevails over several log cycles and in a few cases over the entire test period.

Detailed modeling of various reservoir types exhibiting such early-time linear log-log profiles clearly indicated this type of behavior to be tied to secondary storage effects. The slope of this region was shown to depend on the magnitude of wellbore storage and its interaction with a secondary storage effect. Analysis techniques for this dual-storage pressure behavior are not documented in the literature and are presented herein for selected reservoir types.

The following represents reservoir configurations which have exhibited dual-storage behavior: a massive hydraulic fracture with significant fracture storagepressure falloff tests in water injection wells where liquid levels remain at the surface throughout the falloffnatural fractures intersected by a hydraulic fracture permeability variation away from the wellbore a horizontal wellbore intersected by natural fractures.

Reservoir characteristics that exhibit dual-storage behavior, an analysis technique, and several field examples are presented in this paper.
Democracy and Terrorism: What Roles for Universities?
Authors: Lindsay Beverly , Hickey Suzanne , Khoury Issam
Published: June 2008

In the aftermath of September 11, 2001, the study of terrorism has become prominent as a function of the social sciences. The purpose of this article is to examine how terrorism studies relate to university engagement in an effort to reduce violence and terrorist acts across the globe. Illustrations will be explicated from the University of St Andrews in Scotland, Tel Aviv University in Israel, and Al-Quds University in Jerusalem. The article concludes with correlating how these universities have not merely studied terrorism, but how these studies engage their students, faculty, and their communities in combating a phenomenon that is continually evident.
Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content
Authors: Ravikumar Balasubramanian , Gerrard Jean , Dalla Man Chiara , Firbank Michael J. , Lane Annette , English Philip T. , Cobelli Claudio , Taylor Roy
Published: June 2008

OBJECTIVE—Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes.

RESEARCH DESIGN AND METHODS—Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by 1H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging.

RESULTS—Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 ± 1.0 vs. 12.2 ± 0.7 μmol · kg−1 · min−1, P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 ± 0.25 vs. 1.26 ± 0.30 μmol · kg−1 · min−1, P < 0.001). Hepatic triglyceride content decreased by ∼50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by ∼55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = −0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP.

CONCLUSIONS—Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.
Relationship Between Risk Factors and Mortality in Type 1 Diabetic Patients in Europe
Authors: Soedamah-Muthu Sabita S. , Chaturvedi Nish , Witte Daniel R. , Stevens Lynda K. , Porta Massimo , Fuller John H. ,   for the EURODIAB Prospective Complications Study Group
Published: June 2008

OBJECTIVE—The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up.

RESULTS—There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15–61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44–2.20]), A1C (1.18 [0.95–1.46]), waist-to-hip ratio (WHR) (1.32 [1.14–1.52]), pulse pressure (1.33 [1.13–1.58]), and non-HDL cholesterol (1.33 [1.12–1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19–4.78]) and peripheral (1.88 [1.06–3.35]) and autonomic neuropathy (2.40 [1.32–4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality.

CONCLUSIONS—Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors.
Disruption of Glucocorticoid and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals
Authors: Odermatt Alex , Gumy Christel
Published: June 2008

Glucocorticoids and mineralocorticoids are key endocrine hormones modulating essential physiological processes such as energy metabolism, cell growth and differentiation, maintenance of blood pressure and immune responses. Despite their importance and the fact that their impaired function
has been associated with various diseases, there are only few studies on the potential disruption of glucocorticoid and mineralocorticoid action by xenobiotics. To facilitate the identification and characterization of such chemicals, we established cell-based assays to determine the impact
of xenobiotics on different steps of corticosteroid hormone action. Screening of a small library of chemicals led to the identification of several compounds inhibiting the 11?-hydroxysteroid dehydrogenase (11?-HSD) prereceptor enzymes 11?-HSD1 and/or 11?-HSD2 and of chemicals
blocking the function of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). These findings build a basis to extend the search for chemicals acting on additional targets of the corticosteroid hormone pathway and to apply in silico prediction tools in combination with
biological testing to screen large numbers of chemicals. The identification of chemicals interfering with corticosteroid action and the elucidation of the underlying molecular mechanisms are relevant with respect to the potential contribution to common diseases such as metabolic syndrome,
immune diseases, brain disorders and cancer.
First Evaluation of Human Sperm Quality in Various Geographic Regions of Switzerland
Authors: Crausaz Michel , Vargas Josefina , Parapanov Roumen , Chollet Yves , Wisard Marc , Stettler Eric , Senn Alfred , Germonda Marc
Published: June 2008

A decline in human sperm quality and quantity has been reported in numerous Western countries. This observation was also accompanied by an increase in urogenital malformations. The need for epidemiological studies dealing with unbiased populations in order to understand the causes of
these observations is obvious. In Switzerland, the large majority of young men are asked to attend a military camp to be drafted into the army. A few weeks before this camp, conscripts were contacted and invited to participate in a large national study on semen quality. The participation was
totally voluntary and anonymous. From September 2005 to June 2007, 770 volunteers filled out a questionnaire, underwent a clinical examination and provided sperm, blood and urine samples. Using self-rated health assessments, the observed cohort could be considered as healthy and no testicular
cancer was found. Moreover, the testicular volumes, measured using Prader's orchidometry and ultrasonography, were comparable to those already published for young male populations. The median sperm concentration was 47 × 106/ml, which is close to the concentration reported
in Denmark, known to have the highest incidence of testicular cancer in Europe. Statistically significant differences were observed between regions with a lower sperm concentration for men residing in the Alps (43 × 106/ml) and in the Zürich area (36 × 106/ml)
compared to men from West Plateau (54 × 106/ml) and from the Jura (54 × 106/ml). Such a regional discrepancy could be related to environmental factors, including endocrine disruptors. In order to confirm such regional differences more volunteers from the already
studied regions should be studied and other parts of the country should be investigated. The rather low sperm concentration of Swiss young volunteers should be considered as a national health issue and investigated further.