bluuebunny/crossref_metadata_2025 huggingface dataset:
Fisiopatología de la fibrosis quística
Authors: Donaldson Scott H. , Boucher Richard C.
Published: February 2007

El conocimiento del desarrollo de la neumopatía en la fibrosis quística (FQ) ha sido la meta perseguida durante varias décadas. Con la clonación del gen regulador de conductancia transmembránica de la FQ (RTFQ) y otros avances en el estudio de la biología de los tejidos epiteliales de las vías respiratorias, se dispone de un cuadro mucho más nítido de la fisiopatología de la enfermedad. Nuestras mejores pruebas señalan la desregulación del transporte de iones como trastorno subyacente, causante de la depleción del volumen de líquido de la superficie de las vías respiratorias, es decir, la deshidratación, y un deterioro asociado de la depuración de moco. A su vez, la mucostasis predispone al pulmón de la FQ a la infección bacteriana, que rápidamente adquiere cronicidad debido a la propia naturaleza de las secreciones de la FQ. La respuesta inflamatoria neutrofílica, no resolutiva, a esta infección crónica causa a su vez una lesión progresiva y permanente de las vías respiratorias, de tal modo que la bronquiectasia y la insuficiencia respiratoria son los procesos corrientes de la neumopatía de la FQ en su fase terminal. El desarrollo de nuevos tratamientos que aborden el trastorno subyacente de la deshidratación de las vías respiratorias constituye la esperanza de prevención de esta cascada de acontecimientos.
Procedimientos diagnósticos, características clínicas y asesoramiento en la fibrosis quística
Authors: De Boeck Kris
Published: February 2007

La mayoría de los pacientes con diagnóstico final de fibrosis quística (FQ) presenta síntomas clásicos, como íleo meconial, incapacidad de medrar y tos recurrente o persistente, en los primeros meses de vida. Las manifestaciones patológicas son evidentes, progresivas y afectan a diferentes sistemas de órganos. En estos pacientes, la prueba diagnóstica estándar es la prueba del sudor. Una concentración de cloruros en el sudor >60 mmol/l confirma el diagnóstico de sospecha clínica. Desde el descubrimiento del gen RTFQ (regulador de la conductancia transmembránica de la FQ), ha llegado a ser evidente que el espectro clínico es amplio. Se ha demostrado que diversas categorías de pacientes son portadores de dos mutaciones de RTFQ: pacientes con FQ clásica; pacientes con síntomas más leves e inicio de la enfermedad durante la adolescencia o incluso la edad adulta; pacientes con una única característica clínica, como por ejemplo, pancreatitis recurrente, colangitis esclerosante, bronquiectasia ‘idiopática’ o infertilidad masculina. Las dos últimas categorías se describen como FQ atípica o no clásica. Es muy importante que estos pacientes sepan que, si bien no sufren de FQ clásica, tienen un factor de riesgo para desarrollar una enfermedad similar a la FQ que justifica el seguimiento intermitente por parte de médicos familiarizados con el muy amplio espectro de la enfermedad. En pacientes con FQ clásica, la infección sinopulmonar bacteriana progresiva y la inflamación con exacerbaciones intermitentes son las manifestaciones patológicas más típicas. El 90% de los pacientes presentan insuficiencia pancreática. Los hombres postpuberales son estériles. Durante toda su vida, los pacientes afectados de FQ pueden presentar manifestaciones y complicaciones patológicas en los senos, los pulmones, el páncreas, el hígado, el intestino, el esófago, los huesos, las articulaciones, etc. La mezcla compleja de posibles manifestaciones patológicas confiere un carácter único a cada paciente. A medida que el paciente se hace mayor, el número de complicaciones tiende a incrementarse y su estado físico, a empeorar. Numerosos pacientes con FQ adultos jóvenes presentan un menoscabo de la tolerancia al esfuerzo debido a la neumopatía avanzada; el 20% presenta diabetes mellitus relacionada con FQ. La FQ clásica es un trastorno potencialmente mortal e, incluso con el tratamiento y el seguimiento más intensivos, la mediana de supervivencia actual gira en torno a 34 años. Este hecho genera un enorme estrés psicológico a los pacientes y sus familias. El asesoramiento para prevenir la recurrencia de la enfermedad en hermanos y en la familia ampliada es importante y complejo.
Island Vertical Trapezius Myocutaneous Flap Procedure under the Tumescent Technique
Authors: Papadopoulos O. , Konofaos P. , Medvedev V. , Chrisostomidis C.
Published: February 2007

We describe the application of local anesthesia with intravenous sedation for covering a large defect of the upper back with the use of the island vertical trapezius myocutaneous flap to an 85-year-old male. According to the anesthesiologist, the patient was graded as ASA IV. A 200-ml solution which consisted of 0.75 mg xylocaine, 2 mg adrenaline (1/2,000,000) and 10 mmol/l sodium bicarbonate in a physiologic saline solution was used. The total operating time was about 90 min. During the first postoperative 24 h, the flap pedicle was checked every hour by Doppler. The postoperative course of the patient was uneventful. We believe that in selected cases, when microsurgery is not indicated due to the general medical condition of the patient, the combination of the tumescent technique with sedation and the vertical trapezius myocutaneous flap can be considered a reliable and low-risk procedure.
The C19007T Polymorphism of ERCC1 and Its Correlation with the Risk of Epithelial Ovarian and Endometrial Cancer in Korean Women
Authors: Jo Hoenil , Kang Sokbom , Kim Sung Il , Kim Jae Weon , Park Noh Hyun , Song Yong Sang , Park Sang-Yoon , Kang Soon Beom , Lee Hyo Pyo
Published: February 2007

Background: Excision repair cross-complementing group 1 (ERCC1) is a major DNA repair protein. Recent studies have addressed the association between ERCC1 polymorphism and carcinogenesis. Methods: We investigated a polymorphism of ERCC1 at nucleotide 19007 (C→T, Asn118Asn) in 94 epithelial ovarian cancer patients, 102 endometrial cancer patients, and in 329 control subjects. Results: We observed no evidence of associations between the C19007T ERCC1 polymorphism and risk of epithelial ovarian or endometrial cancer, which had the same adjusted odds ratios of 0.91 (p = 0.711, 0.691 respectively). Conclusion: Our findings suggest that the C19007T ERCC1 polymorphism is unlikely to play an important role in epithelial ovarian or endometrial cancer in Korean women.
Amphotericin B Dose Optimization in Children with Malignant Diseases
Authors: Nath Christa E. , McLachlan Andrew J. , Shaw Peter J. , Coakley John C. , Earl John W.
Published: February 2007

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (Css,trough) and plasma creatinine concentrations (Ccreat) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB Css,trough were identified by determining the probability of large (>24%, 75th percentile) increases in Ccreat after 6 days of AmB for a series of Css,trough ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76–1.05 mg/l Css,trough range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces Css,trough within this range for children weighing 25–45 kg. Lighter children (10–25 kg) require higher AmB doses (1.25–1.5 mg/kg/day) to achieve target Css,trough, while heavier children (45–55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.
Genotype and Plasma Concentration of Cystatin C in Patients with Late-Onset Alzheimer Disease
Authors: Chuo Liang-Jen , Sheu Wayne H.H. , Pai Ming-Chyi , Kuo Yu-Min
Published: February 2007

Background: A polymorphism locating at position 73 of cystatin C (CST3) exon 1 was suggested to be associated with Alzheimer disease (AD), but with contradictory results. The relationship between the CST3 genotype and the cystatin C plasma level in AD remains unknown. Objective: We aim to determine the association between CST3 polymorphism and the plasma levels of cystatin C in AD and nondemented control individuals. Method: The polymorphisms of the CST3 genotype were determined using PCR followed by restriction fragment length polymorphism analysis, and the plasma cystatin C concentrations were quantified by sandwich ELISA in 175 AD and 461 control subjects. Results: Although the CST3A allele frequencies were similar between the two groups, the CST3A/A homozygote was significantly associated with late-onset AD. As expected, the established AD genetic risk factor APOE Ε4 allele was overrepresented in the AD cohort. The plasma cystatin C levels were lower in the AD patients than in the control group. Furthermore, plasma cystatin C levels were associated positively with age and negatively with CST3A allele in the control group. Conclusion: The homozygous CST3A/A genotype confers a risk for AD in Taiwan Chinese. Such an association may be due to the reduced level of cystatin C in the peripheral circulation.
Progression of Coronary Artery Calcification in Predialysis Patients
Authors: Russo Domenico , Corrao Salvatore , Miranda Ida , Ruocco Carolina , Manzi Simona , Elefante Rosanna , Brancaccio Diego , Cozzolino Mario , Biondi Maria L. , Andreucci Vittorio E.
Published: February 2007

Background: In patients on dialysis coronary artery calcification (CAC) rapidly proceeds due to impaired mineral metabolism and/or exogenous calcium load. Progression has not been assessed in patients with chronic kidney disease not yet requiring dialysis (CKD patients). In this study, rate and determinants of CAC progression have been evaluated in CKD patients who are exposed to minor derangement of mineral metabolism and calcium load. Methods: Consecutive patients were enrolled. Exclusion criteria were: symptomatic coronary disease, arrhythmia, myocardial infarction, and diabetes. Serum calcium, phosphorus, parathyroid hormone, homocysteine, C-reactive protein, triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol were serially measured. Fetuin-A was assessed at entry into the study. CAC progression was detected by measuring total calcium score (TCS) with computed tomography. Initial and final scans were obtained. Predictive factors of progression were investigated. Results: Fifty-three patients had CKD (stage 3–5 CKD; K-DOQI classification) not yet requiring dialysis, and 60 patients had normal renal function (NRF patients). Follow-up lasted 24 ± 4.2 months (mean ± SE). Patients with CAC were older with lower serum fetuin-A. TCS increased from 73 ± 17 to 80 ± 20 (mean ± SE; p = NS) in NRF patients, and from 384 ± 116 to 602 ± 140 (mean ± SE; p < 0.01) in CKD patients. Serum phosphorus [OR = 1.97 (1.14–3.41, 95% CI); p = 0.015] was the only variable that was associated with CAC progression. Cardiovascular events occurred in CKD patients with CAC. Conclusion: CAC progression was prominent in CKD patients and correlated with serum phosphorus. Fatal and nonfatal cardiovascular events were more frequent in CKD patients. Studies are required to ascertain whether the attainment of serum phosphorus concentration lower than that suggested by current guidelines may reduce CAC progression and ultimately mortality.
Simplified Method to Implant Chronic Stimulating Electrode in the Gasserian Ganglion
Authors: Spaziante Renato , Ferone Aldo , Cappabianca Paolo
Published: February 2007

Chronic radiofrequency stimulation of the gasserian ganglion by a percutaneous electrode is a new method for treating facial pain. The authors report their simplified technique to bring the distal end of the electrode from the cheek to the neck.
Stimulation of the Spinal Cord in the Treatment of Traumatic Injuries of Cervical Spine
Authors: Kiwerski Jerzy
Published: February 2007

Since 1974, clinical experiments have been conducted at the Rehabilitation Clinic in Konstancin (Poland) on the effects of electrostimulation on the damaged spinal cord. 30 patients with stimulation after injury to the cervical spinal cord are reported. Patients with complete and incomplete cervical cord injury were compared. The patients were treated by surgical decompression with simultaneous implantation of stimulating electrodes in contact with the spinal cord. The control group of patients were operated upon in the same period for similar injuries, but had no stimulators implanted. Neurological improvement was better in the stimulated compared to the nonstimulated patients, both as regards number of neurological improvements as well as quality of neurological function. The comparison also confirmed a favorable effect of spinal cord stimulation on the development of bladder automatism.
Effects of Thalamic Sensory Relay Nucleus Stimulation on the Jaw-Opening Reflex in Response to Tooth-Pulp Stimulation in the Cat
Authors: Tsubokawa Takashi , Katayama Yoichi , Hirayama Teruyasu , Yamamoto Takamitsu , Nishimoto Hiroshi
Published: February 2007

The effects of stimulation of the thalamic sensory relay nucleus (TSRN, nucleus ventralis posteromedialis) on the jaw-opening reflex (JOR) in response to tooth pulp stimulation were compared with the effects of stimulation of the periaqueductal gray (PAG) and nucleus raphe magnus (NRM) in the cat. After stimulation of the TSRN, PAG and NRM, the JOR was inhibited. However, while the inhibitory effects of PAG and NRM stimulation lasted for more than 500 ms and were antagonized by the opiate antagonist, naloxone, the inhibitory effects of TSRN stimulation lasted for approximately 100 ms and were resistant to naloxone. These findings suggest that although TSRN stimulation exerts descending inhibitory effects on segmental nociceptive activity, similarly to PAG or NRM stimulation, the descending inhibitory pathways mediating the effect of TSRN stimulation may be largely distinct physiologically as well as pharmacologically from those mediating the effect of PAG and NRM stimulation.
Social Practices and Normativity
Authors: Rouse Joseph
Published: February 2007

Turner’s The Social Theory of Practices effectively criticized conceptions of social practices as rule-governed or regularity-exhibiting performances. Turner’s criticisms nevertheless overlook an alternative, “normative” conception of practices as constituted by the mutual accountability of their performances. Such a conception of practices also allows a more adequate understanding of normativity in terms of accountability to what is at issue and at stake in a practice. We can thereby understand linguistic practice and normative authority without having to posit stable meanings, rules, norms, or presuppositions underlying the manifest diversity of social life.
Estimating ωh for Structures Containing Two Group Factors: Perils and Prospects
Authors: Zinbarg Richard E. , Revelle William , Yovel Iftah
Published: February 2007

One of the most serious difficulties in the estimation of omegahierarchical (ωh) has not been previously studied. Although it is true that one can impose a set of identifying constraints on one’s solution to derive an estimate of ωh in the two-group factor case, there is the potential for introducing bias into the process of estimating ωh, depending on the extent to which one’s set of identifying constraints corresponds to the structure that actually underlies the scale. The authors demonstrate that this potential bias is only considerable when the ratio of the covariance between items loading on different group factors to the covariance between items loading on the same group factor is low. Four methods for estimating ωh are compared to each other, and the results suggest that Cronbach’s alpha and a method based on the first unrotated principal factor should be rejected as estimates of ωh.
Effect of Percolation on the Mechanical Properties of Sand-filled Polyethylene Composites
Authors: Verbeek C. J. R.
Published: February 2007

In this study, percolation theory is applied to explain the transitions in mechanical properties in sand-filled polyethylene composites. It is well known that the mechanical properties of polymers are highly dependent on the presence of fillers. When the particle content in a polymer matrix is increased, particles will eventually touch and form a continuous path of connected particles, called the percolation point. A lesser studied phenomenon is the rigidity percolation point in particulate composites. At this volume fraction filler, there is just enough resin present in the composite to yield a rigid structure. At a volume fraction polymer less than the rigidity percolation point, the particles may very well form a continuous network, but this network has no rigidity and hence no mechanical strength. In this study, it is found that the rigidity percolation point occurs at approximately 20-25 vol% polymer, depending on which mechanical property is tested. The particle percolation point or the second transition at higher volume fraction polymer occurs over a wider range of resin volume fraction and falls between 65 and 85 vol% polymer, depending on which mechanical property is used for its measurement. It is found that the mechanical properties change dramatically at both these points, although not in the order of magnitude as has been reported for changes in electrical conductivity near the percolation point for polymers filled with conductive fillers.
Effect of Inorganic Fillers on the Flammability Behavior of Polypropylene Composites
Authors: Razak J. Abd. , Akil H. Md. , Ong Huilin
Published: February 2007

This report summarizes the effect of various inorganic fillers such as alumina (α-Al2O3), calcium carbonate (CaCO3), silica (SiO2), and feldspar (KAlSi3O8) on the flammability behavior of polypropylene (PP) composites. The effect of various filler loadings (by weight percent), typically at 40 and 60% has also been investigated for each of the fillers used. Initially, the compounding of composites (filler and polypropylene) was carried out using a two-roll mill; later, the test specimens were prepared using the compression molding technique. For each composite system, the linear rate of burning at two filler loadings was calculated, analyzed, and compared. Consequently, the characteristics of the flame, typically smoke suppression and char formation, were also analyzed as recommended by ASTM and UL 94 methods. From the results, it is clear that adding alumina fillers to polypropylene, at both percentages, results in decreasing the linear rate of burning, and hence improves flammability resistance. It is also interesting to note that alumina-filled PP shows greater flame-retardant behavior at both the 40 and 60% filler loadings.
Social Pacts as Coalitions of the Weak and Moderate: Ireland, Italy and South Korea in Comparative Perspective
Authors: Baccaro Lucio , Lim Sang-Hoon
Published: February 2007

This article examines the emergence and institutionalization of social pacts in Ireland, Italy and South Korea. It argues that pacts emerge as deals between a weak government faced with a political–economic crisis and the more moderate sections of the trade union movement, and are institutionalized when (and if) organized employers come to support them fully. The unions become strategically committed to a social pact if the moderate factions prevail over the radical. Decision-making rules bringing the preferences of the rank-and-file to bear on the process of organizational decision-making seem to help the moderate union factions. The robustness of the analysis is tested by examining briefly a number of counterfactual cases.
Hgh prevalence of antibodies to platelet factor 4 heparin in patients with antiphospholipid antibodies in absence of heparin-induced thrombocytopenia
Authors: Martin-Toutain I , Piette JC , Diemert MC , Faucher C , Jobic L , Ankri A
Published: February 2007

Seventy-two patients with antiphospholipid antibodies (aPL), with or without antiphospholipid syndrome (APS), were studied for detection of heparin-PF4-induced antibodies (HPIA) using a commercial kit (Asserachrom® HPIA) PF4-dependant enzyme-linked immunoassay (ELISA) test. None of the patients had a medical history of heparin induced thrombocytopenia (HIT). Eleven percent of patients were positive for HPIA. Plasma from 40 of the 72 patients (seven positive and 33 negative), was also tested with the other available HPIA ELISA (GTI®) kit. Five patients were positive with both ELISA kits, two were highly positive only with Asserachrom® HPIA and four only with GTI®. None of the positive patients had severe thrombocytopenia. Two patients have never received heparin treatment. No relationship was found between HPIA presence and patients' age, sex, aPL levels or presence of lupus anticoagulant. No significant difference in HPIA presence was observed in patients with primary APS, secondary APS or aPL without APS. We found a poor correlation between the two commercial ELISA showing that, on the same blood sample, a patient could be highly positive with one technique and negative with the other. The PF4-dependant enzyme-linked immunoassay, which is often the first test used for the diagnosis of HIT, should be interpreted cautiously in patients with aPL since there is a danger of overdiagnosis and overtreatment.
Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus
Authors: Sun LY , Zhang HY , Feng XB , Hou YY , Lu LW , Fan LM
Published: February 2007

Bone marrow-derived mesenchymal stem cells (MSCs) are key components of the hematopoietic microenvironment and provide support to hematopoiesis and modulate immune system. Several studies suggest that SLE may be seen as stem cell disorders. However, it is unclear that whether MSCs from SLE patients are defective. So in this research, we studied the biological character of bone marrow derived MSCs in patients with SLE, focused on their phenotype (morphology and immunophenotype), karyotype, cytokines expression and hematopoietic support of MSCs. Our results showed that MSCs from SLE patients and normal controls can be successfully culture-expanded, but the MSCs from SLE grew more slowly than those of normal controls ( P < 0.05). Cells from both groups were positive for CD29, CD44 and CD105, and negative for CD14, CD34, CD45 and HLADR. MSCs from SLE have a normal karyotype. Both groups express IL-6, IL7, IL-11, macrophage colony stimulating factor (M-CSF) and stem cell factor (SCF) at mRNA level. While IL-6 and IL-7 were down-regulated in MSCs from SLE patient ( P < 0.05) at mRNA level. The MSCs from SLE patients and normal controls were infused into ICR (Tac: Icr: Ha strain) mice after high-dose chemotherapy, with no adverse events in either group. Recovery of white blood cells, hemoglobin and platelet was more rapid ( P < 0.05) compared with the group without MSCs infusion. We conclude that MSCs in patient with SLE have abnormalities compared with those in normal control. MSCs in patient with SLE may play an important role in the SLE pathogenesis.
Management as a Regulated Profession
Authors: Spender JC
Published: February 2007

The history of management education shows the rigor and relevance gap has been around for centuries, well before its appearance in the United States. Nor is it peculiar to management. It is neither germane to our discipline's present difficulties nor an appropriate focus for our critics. Rather, history suggests we finally parted company with managers after the 1959 Ford and Carnegie reports, as we presumed rationality alone was the sufficient basis for understanding them and their doings. These reports helped us turn management education into a profession even as management itself has yet to become one. To return closer to managers, the author suggests rationality captures one dimension of their practice, whereas the notion of business as an art form might capture its complement. Reformed art education, covering art's history, aesthetics, criticism, and production, provides a framework for studying the managerial art, and leads us to a rich, dynamic theory of the firm.
Psychopathy in Adolescence and Criminal Recidivism in Young Adulthood
Authors: Edens John F. , Cahill Melissa A.
Published: February 2007

Very few studies to date have examined the long-term predictive validity of psychopathy among juveniles. The current study reports general and violent recidivism data for an ethnically heterogeneous sample of male offenders (n = 75) who had been administered the Psychopathy Checklist: Youth Version (PCL: YV) in 1996 when they were on average 16 years of age. Neither total scores nor factor scores of the PCL: YV predicted general or violent reconvictions throughout this time frame. These modest effects underscore recent concerns raised about the utility of psychopathy as a risk factor for future criminality, particularly among multiethnic offender samples.
Embracing the Catastrophe
Authors: Berry Keith
Published: February 2007

This article examines the constitution of gay male identity through embodied performances in Steamworks, a gay male bathhouse in Chicago. Motivated by Kabat-Zinn's (1990) Buddhist conceptualizations of catastrophe and mindfulness, I reflectively track the ways in which desirability influences disconnection and identity negotiation as it occurs within a pervasive, generalized, and highly influential conceptualization of the idealized gay male body. Personal narratives scan experiences at Steamworks in which my body—less than the “ideal”—matters to me and to others culturally. I use Butler's (1990) notion of performativity to propose stylized and normative ways in which subjectivity comes to be through uses of the body.
“Awakening to” an Aspect in the Other
Authors: Witz Klaus G.
Published: February 2007

This article discusses “awakening to” deeper aspects in a person and “articulating” them and contrasts this way of developing concepts and new understandings in qualitative research with “fashioning concepts at a level of words and phrases in an arena of public discourse.” “Awakening to and articulating” may be epistemologically based on C. H. Cooley's (1909/1956) “sympathetic introspection,” to the effect that after prolonged contact with a participant or immersion in a social context, where one “absorbed” nuances of feeling, emotion, consciousness, this contact “awakens in oneself a life similar to that in the participant” or social context. The article discusses some of the characteristics of “awakening and articulating,” such as the way it involves the consciousness of the investigator, and how it represents a grounded theory approach, and argues that there is a great need to bring concepts developed by “awakening and articulating” into public discourse.
CD28-mediated regulation of multiple myeloma cell proliferation and survival
Authors: Bahlis Nizar J. , King Anne M. , Kolonias Despina , Carlson Louise M. , Liu Hong Yu , Hussein Mohamad A. , Terebelo Howard R. , Byrne Gerald E. , Levine Bruce L. , Boise Lawrence H. , Lee Kelvin P.
Published: February 2007

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFκB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)–induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.
The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy
Authors: Caffieri Sergio , Di Lisa Fabio , Bolesani Federico , Facco Monica , Semenzato Gianpietro , Dall'Acqua Francesco , Canton Marcella
Published: February 2007

The generation of photoproducts of psoralen (POPs) might be relevant in cell death induced by psoralen plus UVA, namely PUVA, which is a recognized effective treatment for cutaneous T-cell lymphoma, chronic graft-versus-host disease, and psoriasis. We investigated the occurrence of POP-induced cell death and the underlying mechanisms. POPs were produced by irradiating a psoralen solution with UVA. Jurkat cells treated in the dark with these mixtures died mainly through an apoptotic mechanism. POPs were separated by high-performance liquid chromatography (HPLC), and cells were added with each of these fractions. A total of 2 dimers of psoralen and 6-formyl-7-hydroxycoumarin (FHC) were identified in the apoptogenic fractions. Apoptosis was preceded by mitochondrial dysfunction caused by the opening of the mitochondrial permeability transition pore (PTP). In fact, both mitochondrial depolarization and cell death were prevented by the PTP inhibitor cyclosporin A (CsA). PTP opening was also documented in isolated mitochondria added with POP, suggesting that apoptosis is caused by a direct effect of POP on mitochondria. In fact, FHC alone induced PTP opening and CsA-inhibitable cell death of Jurkat cells, whereas nontransformed T lymphocytes were resistant. Along with identifying novel apoptogenic molecules, the present results indicate that POP generation directs transformed cells to apoptosis.
Perforin gene mutations in patients with acquired aplastic anemia
Authors: Solomou Elena E. , Gibellini Federica , Stewart Brian , Malide Daniela , Berg Maria , Visconte Valeria , Green Spencer , Childs Richard , Chanock Stephen J. , Young Neal S.
Published: February 2007

Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural killer cells. Inherited perforin mutations account for 20% to 40% of familial hemophagocytic lymphohistiocytosis, a fatal disease of early childhood characterized by the absence of functional perforin. Aplastic anemia, the paradigm of immune-mediated bone marrow failure syndromes, is characterized by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. We examined whether mutations in the perforin gene occurred in acquired aplastic anemia. Three nonsynonymous PRF1 mutations among 5 unrelated patients were observed. Four of 5 patients with the mutations showed some hemophagocytosis in the bone marrow at diagnosis. Perforin protein levels in these patients were very low or absent, and perforin granules were completely absent. Natural killer (NK) cell cytotoxicity from these patients was significantly decreased. Our data suggest that PRF1 genetic alterations help explain the aberrant proliferation and activation of cytotoxic T cells and may represent genetic risk factors for bone marrow failure.
A new ELISA kit which uses a combination of Plasmodium falciparum extract and recombinant Plasmodium vivax antigens as an alternative to IFAT for detection of malaria antibodies
Authors: Doderer Cecile , Heschung Aurelie , Guntz Phillippe , Cazenave Jean-Pierre , Hansmann Yves , Senegas Alexandre , Pfaff Alexander W , Abdelrahman Tamer , Candolfi Ermanno
Published: February 2007

Background

The methods most commonly used to measure malarial antibody titres are the Indirect Fluorescence Antibody Test (IFAT), regarded as the gold standard, and the Enzyme-Linked ImmunoSorbent Assay (ELISA). The objective here was to assess the diagnostic performance, i.e. the sensitivity and specificity, of a new malaria antibody ELISA kit in comparison to IFAT. This new ELISA kit, the ELISA malaria antibody test (DiaMed), uses a combination of crude soluble Plasmodium falciparum extract and recombinant Plasmodium vivax antigens.

Methods

Two groups were used: 95 samples from malaria patients to assess the clinical sensitivity and 2,152 samples from blood donors, who had not been exposed to malaria, to assess the clinical specificity.

Results

The DiaMed ELISA test kit had a clinical sensitivity of 84.2% and a clinical specificity of 99.6% as compared with 70.5% and 99.6% respectively, using the IFAT method. The ELISA method was more sensitive than the IFAT method for P. vivax infections (75% vs. 25%). However, in 923 malaria risk donors the analytical sensitivity of the ELISA test was 40% and its specificity 98.3%, performances impaired by large numbers of equivocal results non-concordant between ELISA and IFAT. When the overall analytical performances of ELISA was compared to IFAT, the ELISA efficiency J index was 0.84 versus 0.71 for IFAT. Overall analytical sensitivity was 93.1% and the analytical specificity 96.7%. Overall agreement between the two methods reached 0.97 with a reliability k index of 0.64.

Conclusion

The DiaMed ELISA test kit shows a good correlation with IFAT for analytical and clinical parameters. It may be an interesting method to replace the IFAT especially in blood banks, but further extensive investigations are needed to examine the analytical performance of the assay, especially in a blood bank setting.
A cost-effectiveness analysis of artemether lumefantrine for treatment of uncomplicated malaria in Zambia
Authors: Chanda Pascalina , Masiye Felix , Chitah Bona M , Sipilanyambe Naawa , Hawela Moonga , Banda Patrick , Okorosobo Tuoyo
Published: February 2007

Background

Malaria remains a leading cause of morbidity, mortality and non-fatal disability in Zambia, especially among children, pregnant women and the poor. Data gathered by the National Malaria Control Centre has shown that recently observed widespread treatment failure of SP and chloroquine precipitated a surge in malaria-related morbidity and mortality. As a result, the Government has recently replaced chloroquine and SP with combination therapy as first-line treatment for malaria. Despite the acclaimed therapeutic advantages of ACTs over monotherapies with SP and CQ, the cost of ACTs is much greater, raising concerns about affordability in many poor countries such as Zambia. This study evaluates the cost-effectiveness analysis of artemether-lumefantrine, a version of ACTs adopted in Zambia in mid 2004.

Methods

Using data gathered from patients presenting at public health facilities with suspected malaria, the costs and effects of using ACTs versus SP as first-line treatment for malaria were estimated. The study was conducted in six district sites. Treatment success and reduction in demand for second line treatment constituted the main effectiveness outcomes. The study gathered data on the efficacy of, and compliance to, AL and SP treatment from a random sample of patients. Costs are based on estimated drug, labour, operational and capital inputs. Drug costs were based on dosages and unit prices provided by the Ministry of Health and the manufacturer (Norvatis).

Findings

The results suggest that AL produces successful treatment at less cost than SP, implying that AL is more cost-effective. While it is acknowledged that implementing national ACT program will require considerable resources, the study demonstrates that the health gains (treatment success) from every dollar spent are significantly greater if AL is used rather than SP. The incremental cost-effectiveness ratio is estimated to be US$4.10. When the costs of second line treatment are considered the ICER of AL becomes negative, indicating that there are greater resource savings associated with AL in terms of reduction of costs of complicated malaria treatment.

Conclusion

This study suggests the decision to adopt AL is justifiable on both economic and public health grounds.
Parallel evolution of conserved non-coding elements that target a common set of developmental regulatory genes from worms to humans
Authors: Vavouri Tanya , Walter Klaudia , Gilks Walter R , Lehner Ben , Elgar Greg
Published: February 2007

Background

The human genome contains thousands of non-coding sequences that are often more conserved between vertebrate species than protein-coding exons. These highly conserved non-coding elements (CNEs) are associated with genes that coordinate development, and have been proposed to act as transcriptional enhancers. Despite their extreme sequence conservation in vertebrates, sequences homologous to CNEs have not been identified in invertebrates.

Results

Here we report that nematode genomes contain an alternative set of CNEs that share sequence characteristics, but not identity, with their vertebrate counterparts. CNEs thus represent a very unusual class of sequences that are extremely conserved within specific animal lineages yet are highly divergent between lineages. Nematode CNEs are also associated with developmental regulatory genes, and include well-characterized enhancers and transcription factor binding sites, supporting the proposed function of CNEs as cis-regulatory elements. Most remarkably, 40 of 156 human CNE-associated genes with invertebrate orthologs are also associated with CNEs in both worms and flies.

Conclusion

A core set of genes that regulate development is associated with CNEs across three animal groups (worms, flies and vertebrates). We propose that these CNEs reflect the parallel evolution of alternative enhancers for a common set of developmental regulatory genes in different animal groups. This 're-wiring' of gene regulatory networks containing key developmental coordinators was probably a driving force during the evolution of animal body plans. CNEs may, therefore, represent the genomic traces of these 'hard-wired' core gene regulatory networks that specify the development of each alternative animal body plan.
Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines
Authors: Hatzfeld-Charbonnier Anne Sophie , Lasek Audrey , Castera Laurent , Gosset Philippe , Velu Thierry , Formstecher Pierre , Mortier Laurent , Marchetti Philippe
Published: February 2007

Mild heat stress can modulate the activities of immune cells, including dendritic cells (DC) and theoretically, would constitute an innovative approach capable of enhancing the antitumor functions of DC. Therefore, we tested the effects of mild heat stress on the physiology and viability of human monocyte-derived DC, the major type of DC used in tumor immunotherapy trials. We first designed a heat-stress protocol consisting of repetitive, sublethal heat shocks throughout the generation of DC. Using this protocol, we observed that heat stress did not perturb the morphology and the phenotype of immature or mature DC or the capacities of immature DC to uptake antigens efficiently. It is noteworthy that in response to heat stress, mature DC produced higher levels of IL-12p70 and TNF-α, which are two cytokines involved in the stimulation of inflammatory reaction, whereas IL-10 production remained low. After heat-stress exposure, mature DC have the full ability to stimulate naive T cells with Th1 response polarization (high IFN-γ and low IL-4 production) in an allogeneic MLR. It is interesting that heat stress enhanced the migratory capacities of DC in response to MIP-3β/CCL19. Finally, heat stress partly protected DC from apoptosis induced by cytokine withdrawal. Overall, these findings validate the feasibility of improving immune response by heating human monocyte-derived DC and provide a strong rationale for using mild heat stress in combination with DC vaccination to increase antitumor response.
Older Breast Cancer Survivors: Factors Associated With Change in Emotional Well-Being
Authors: Clough-Gorr Kerri M. , Ganz Patricia A. , Silliman Rebecca A.
Published: February 2007

Purpose

During the 5 years after primary breast cancer diagnosis for women ≥ 65 years old, we examined factors associated with change in emotional well-being.

Patients and Methods

We identified women diagnosed with primary breast cancer and selected women with stage I to IIIa disease, age ≥ 65 years, and for whom we had permission from the attending physician to contact. Data were collected during 5 years of follow-up from consenting patients' medical records and telephone interviews with patients. Outcomes included a five-question Mental Health Inventory general measure of emotional health (MHI5) and two cancer-specific measures: breast cancer–specific emotional health (BCSEH) and Cancer Rehabilitation Evaluation System–Short Form (CARES-SF) Psychosocial Summary Scale.

Results

During 5 years of follow-up of older breast cancer survivors, 57% had less than a ± 10-point change in MHI5, 38% had less than a ± 10-point change in BCSEH, and 52% had less than a ± 10-point change in CARES-SF Psychosocial Summary Scale. Women with less than 12 years of education were at greatest risk for having negative changes in both general and breast cancer–specific emotional health. Moreover, we also found that women who perceived themselves as never being cured had greater negative changes in all outcomes. Conversely, those who had better physical function, emotional social support, and positive ratings regarding the quality of medical interactions at baseline were less likely to have poor emotional health during follow-up.

Conclusion

For the majority of older breast cancer survivors, cancer-specific well-being and general emotional health do not change substantially after a breast cancer diagnosis. Among those in whom change occurs, risk factors are similar and may be related to other age-related diseases.
Impaired Peroxisome Proliferator-Activated Receptor γ Function through Mutation of a Conserved Salt Bridge (R425C) in Familial Partial Lipodystrophy
Authors: Jeninga Ellen H. , van Beekum Olivier , van Dijk Aalt D. J. , Hamers Nicole , Hendriks-Stegeman Brenda I. , Bonvin Alexandre M. J. J. , Berger Ruud , Kalkhoven Eric
Published: February 2007

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at position 425 into a cysteine (R425C), has been reported in a patient with familial partial lipodystrophy subtype 3 (FPLD3). The strong conservation of arginine 425 among nuclear receptors that heterodimerize with retinoic acid X receptor prompted us to investigate the functional consequences of the R425C mutation on PPARγ function. Here we show that this mutant displayed strongly reduced transcriptional activity compared with wild-type PPARγ, irrespective of cell type, promoter context, or ligand, whereas transrepression of nuclear factor-κB activity remained largely intact. Our data indicate that the reduced transcriptional activity of PPARγ R425C is not caused by impaired corepressor release, but due to reduced dimerization with retinoic acid X receptor α in combination with reduced ligand binding and subsequent coactivator binding. As a consequence of these molecular defects, the R425C mutant was less effective in inducing adipocyte differentiation. PPARγ R425C did not inhibit its wild-type counterpart in a dominant-negative manner, suggesting a haploinsufficiency mechanism in at least some FPLD3 patients. Using molecular dynamics simulations, substitution of R425 with cysteine is predicted to cause the formation of an alternative salt bridge. This structural change provides a likely explanation of how mutation of a single conserved residue in a patient with FPLD3 can disrupt the function of the adipogenic transcription factor PPARγ on multiple levels.
Differential detergent resistance of the apical and basolateral NPPases: relationship with polarized targeting
Authors: Delaunay Jean-Louis , Breton Michelyne , Goding James W. , Trugnan Germain , Maurice Michèle
Published: February 2007

Targeting of glycosylphosphatidylinositol-anchored proteins to the apical surface of epithelial cells involves clustering in Triton X-100-resistant membrane microdomains or rafts. The role of these microdomains in sorting transmembrane proteins is more questionable because, unlike glycosylphosphatidylinositol-anchored proteins, apical transmembrane proteins are rather soluble in Triton X-100. They are, however, resistant to milder detergents such as Lubrol WX or Tween 20. It has been proposed that specific membrane microdomains, defined by resistance to these detergents, would carry transmembrane proteins to the apical surface. We have used MDCK cells stably transfected with the apical and basolateral pyrophosphatases/phosphodiesterases, NPP3 and NPP1, to examine the relationship between detergent resistance and apical targeting. The apically expressed wild-type NPP3 was insoluble in Lubrol WX whereas wild-type NPP1, which is expressed basolaterally, was essentially soluble. By using tail mutants and chimeric constructs that combine the cytoplasmic, transmembrane and extracellular domains of NPP1 and NPP3, we show that there is not a strict correlation between detergent resistance and apical targeting. Lubrol resistance is an intrinsic property of NPP3, which is acquired early during the biosynthetic process irrespective of its final destination, and depends on positively charged residues in its cytoplasmic tail.
Requirement of subunit co-assembly and ankyrin-G for M-channel localization at the axon initial segment
Authors: Rasmussen Hanne B. , Frøkjær-Jensen Christian , Jensen Camilla S. , Jensen Henrik S. , Jørgensen Nanna K. , Misonou Hiroaki , Trimmer James S. , Olesen Søren-Peter , Schmitt Nicole
Published: February 2007

The potassium channel subunits KCNQ2 and KCNQ3 are believed to underlie the M current of hippocampal neurons. The M-type potassium current plays a key role in the regulation of neuronal excitability; however, the subcellular location of the ion channels underlying this regulation has been controversial. We report here that KCNQ2 and KCNQ3 subunits are localized to the axon initial segment of pyramidal neurons of adult rat hippocampus and in cultured hippocampal neurons. We demonstrate that the localization of the KCNQ2/3 channel complex to the axon initial segment is favored by co-expression of the two channel subunits. Deletion of the ankyrin-G-binding motif in both the KCNQ2 and KCNQ3 C-terminals leads to the disappearance of the complex from the axon initial segment, albeit the channel complex remains functional and still reaches the plasma membrane. We further show that although heteromeric assembly of the channel complex favours localization to the axon initial segment, deletion of the ankyrin-G-binding motif in KCNQ2 alone does not alter the subcellular localization of KCNQ2/3 heteromers. By contrast, deletion of the ankyrin-G-binding motif in KCNQ3 significantly reduces AIS enrichment of the complex, implicating KCNQ3 as a major determinant of M channel localization to the AIS.
WRN at telomeres: implications for aging and cancer
Authors: Multani Asha S. , Chang Sandy
Published: February 2007

Werner Syndrome (WS) is a premature aging syndrome characterized by early onset of age-related pathologies and cancer. Since WS is due to a single gene defect, it has attracted much interest from researchers seeking to understand pathways that contribute to cancer and aging at cellular and molecular levels. The protein mutated in WS, WRN, appears to play a major role in genome stability, particularly during DNA replication and telomere metabolism. Much of the pathophysiology associated with WS, including the rapid onset of cellular senescence, early cancer onset and premature aging, can be attributed to a defect in telomere maintenance. Recent genetic evidence from the mTerc–/–Wrn–/– mouse demonstrates that mice with critically shortened telomeres display aging phenotypes reminiscent of human WS, further reinforcing the notion that telomere dysfunction is required for the manifestation of aging pathophysiologies in the setting of WRN deficiency.