bluuebunny/crossref_metadata_2025 huggingface dataset:
T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells
Authors: Vera Juan , Savoldo Barbara , Vigouroux Stephane , Biagi Ettore , Pule Martin , Rossig Claudia , Wu Jessie , Heslop Helen E. , Rooney Cliona M. , Brenner Malcolm K. , Dotti Gianpietro
Published: August 2006

There has been interest in generating T cells expressing chimeric artificial receptors (CARs) targeting CD19/CD20 antigens to treat B-cell lymphomas. If successful, however, this approach would likely impair humoral immunity because T cells may persist long-term. Most low-grade lymphoma and chronic lymphocytic leukemia (B-CLL) cells express monoclonal immunoglobulins carrying either κ or λ light chains. We, therefore, explored whether T lymphocytes could be genetically modified to target the tumor-associated light chain, sparing B lymphocytes expressing the reciprocal light chain, and consequently reduce impairment of humoral immunity. We found that T lymphocytes expressing the anti-κ light chain CAR showed cytotoxic activity against Igκ+ tumor cell lines and B-CLL cells both in vitro and in vivo. We also found that the incorporation of the CD28 endodomain within the CAR enhanced the in vitro and in vivo expansion of transgenic T cells after tumor-associated antigen stimulation. Free Igκ+ did not compromise the ability of redirected T lymphocytes to eliminate Igκ+ tumors because these free immunoglobulins served to sustain proliferation of CAR-CD28 transgenic T cells. Thus, adoptive transfer of T lymphocytes targeting the appropriate light chain could be a useful immunotherapy approach to treat B-lymphocyte malignancies that clonally express immunoglobulin without entirely compromising humoral immunity.
Umbilical cord blood transplantation and cytomegalovirus: posttransplantation infection and donor screening
Authors: Albano Maria S. , Taylor Patricia , Pass Robert F. , Scaradavou Andromachi , Ciubotariu Rodica , Carrier Carmelita , Dobrila Ludy , Rubinstein Pablo , Stevens Cladd E.
Published: August 2006

This study assessed the incidence of cytomegalovirus (CMV) infection after transplantation of cord blood (CB) from unrelated donors and evaluated strategies for screening CB donors. Posttransplantation CMV infection, reported in 23% of 1221 CB recipients, was associated with patient pretransplantation CMV serology (P < .001), but not with CMV serology in CB donors or their mothers. A total of 26 988 infant CB donors were evaluated by viral culture of saliva. Subgroups were evaluated by polymerase chain reaction in CB (CB-PCR) in 2 case-control studies. In the first study, 33 of 47 saliva culture–positive CB donors were confirmed by CB-PCR. All mothers of the 33 infants with confirmed CMV infection were CMV–total antibody positive, but only 1 of 3 had CMV-IgM antibody. The second study evaluated infants born to mothers with CMV-IgM antibody. Of these, 5 of 170 saliva culture–negative infants were positive by CB-PCR. The incidence of congenital CMV infection in CB donors was low (0.12%). Maternal serology had poor predictive value for CMV infection in their infant CB donors and bore no detected relationship to CMV infection in CB recipients. Saliva culture for CMV had both false-positive and -negative results. CB-PCR was a useful alternative for detecting CMV in CB donors.
Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice
Authors: Bobé Pierre , Bonardelle Danielle , Benihoud Karim , Opolon Paule , Chelbi-Alix Mounira K.
Published: August 2006

MRL/lpr mice develop a human lupuslike syndrome and, as in autoimmune lymphoproliferative syndrome (ALPS), massive lymphoproliferation due to inactivation of Fas-mediated apoptosis. Presently, no effective therapy exists for ALPS, and long term, therapies for lupus are hazardous. We show herein that arsenic trioxide (As2O3) is able to achieve quasi-total regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 activated caspases and eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions, leading to significantly prolonged survival rates. This treatment also markedly reduced anti-DNA autoantibody, rheumatoid factor, IL-18, IFN-γ, nitric oxide metabolite, TNF-α, Fas ligand, and IL-10 levels and immune-complex deposits in glomeruli. As2O3 restored cellular reduced glutathione levels, thereby limiting the toxic effect of nitric oxide, which is overproduced in MRL/lpr mice. Furthermore, As2O3 protected young animals against developing the syndrome and induced almost total disease disappearance in older affected mice, thereby demonstrating that it is a novel promising therapeutic agent for autoimmune diseases.
Proteomic approaches to dissect platelet function: half the story
Authors: Gnatenko Dmitri V. , Perrotta Peter L. , Bahou Wadie F.
Published: August 2006

Platelets play critical roles in diverse hemostatic and pathologic disorders and are broadly implicated in various biological processes that include inflammation, wound healing, and thrombosis. Recent progress in high-throughput mRNA and protein profiling techniques has advanced our understanding of the biological functions of platelets. Platelet proteomics has been adopted to decode the complex processes that underlie platelet function by identifying novel platelet-expressed proteins, dissecting mechanisms of signal or metabolic pathways, and analyzing functional changes of the platelet proteome in normal and pathologic states. The integration of transcriptomics and proteomics, coupled with progress in bioinformatics, provides novel tools for dissecting platelet biology. In this review, we focus on current advances in platelet proteomic studies, with emphasis on the importance of parallel transcriptomic studies to optimally dissect platelet function. Applications of these global profiling approaches to investigate platelet genetic diseases and platelet-related disorders are also addressed.
Successful treatment of AL amyloidosis with high-dose melphalan and autologous stem cell transplantation in patients over age 65
Authors: Seldin David C. , Anderson Jennifer J. , Skinner Martha , Malek Karim , Wright Daniel G. , Quillen Karen , Finn Kathleen , Oran Betul , Sanchorawala Vaishali
Published: August 2006

Recently, protocols using high-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) have been developed for the treatment of patients with immunoglobulin light chain (AL) amyloidosis. Although peritransplantation mortality is greater than for other hematologic diseases, treatment leads to durable hematologic complete responses, improvements in organ function and quality of life, and extended survival in a substantial proportion of patients. To determine whether this treatment can be applied to older patients, we have analyzed HDM/SCT treatment outcomes for 65 patients (aged 65 years or older) with AL amyloidosis compared with outcomes for 280 younger patients. For patients over age 65 years who meet the same eligibility criteria as younger patients, toxicity, hematologic remission rate, and survival were not significantly different from those observed in younger patients, indicating that older patients should not be excluded a priori from consideration for HDM/SCT treatment.
Female genital schistosomiasis as an evidence of a neglected cause for reproductive ill-health: a retrospective histopathological study from Tanzania
Authors: Swai Britta , Poggensee Gabriele , Mtweve Sabina , Krantz Ingela
Published: August 2006

Background

Schistosomiasis affects the reproductive health of women. Described sequelae are ectopic pregnancy, infertility, abortion, and cervical lesions and symptoms mimicking cervical cancer and STIs. There are indications that cervical schistosomiasis lesions could become co-factors for viral infection such as HIV and HPV.

Methods

In a retrospective descriptive histopathological study clinical specimens sent between 1999 and 2005 to the pathology department of a consultant hospital in Tanzania were reviewed to analyse the occurrence and features of schistosomiasis in female genital organs.

Results

During the study period, schistosomiasis was histopathologically diagnosed in 423 specimens from different organs (0.7% of all specimens examined in the study period), out of those 40% were specimens from female and male organs. The specimens were sent from 24 hospitals in 13 regions of mainland Tanzania. Female genital schistosomiasis was diagnosed in 125 specimens from 111 patients. The main symptoms reported were bleeding disorders (48%), ulcer (17%), tumor (20%), lower abdominal pain (11%) and infertility (7%). The majority of cases with genital schistosomiasis were diagnosed in cervical tissue (71 cases). The confirmation of cervical cancer was specifically requested for 53 women, but the diagnosis could only be verified for 13 patients (25%), in 40 cases only severe cervical schistosomiasis was diagnosed. Vulval/labial schistosomiasis was seen in specimens from young women. Infertility was reported in four patients with schistosomiasis of the Fallopian tubes.

Conclusion

Genital schistosomiasis adds to the disease burden of women in all age groups. Pathological consequences due to the involvement of different genital organs can be damaging for the affected women. Clinical unawareness of genital schistosomiasis can lead to misdiagnosis and therefore false and ineffective therapy. In endemic areas cervical schistosomiasis should be considered as differential diagnosis of cancer.
Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line
Authors: Fiebig Aline A , Zhu Weijia , Hollerbach Catherine , Leber Brian , Andrews David W
Published: August 2006

Background

Bcl-2 and Bcl-XL are anti-apoptotic paralogues that inhibit apoptosis elicited by a wide variety of stimuli, and play critical roles in cancer development and resistance to treatment. Many clinical studies have indicated that expression of these anti-apoptotic proteins in tumours is associated with poor prognosis. It has therefore been assumed that in cells the essential difference between Bcl-2 and Bcl-XL involves regulation of expression and that they are otherwise functionally similar. To examine this issue, we have compared the function of the proteins and of mutants of Bcl-2 and Bcl-XL specifically targeted to different subcellular sites.

Methods

We generated clones of the human breast cancer line MCF-7 stably expressing known amounts of Bcl-2, or Bcl-XL as determined by quantitative immunoblotting. Clones expressing equivalent amounts of wild-type and mutants of Bcl-2 and Bcl-XL with subcellular localization restricted to the cytoplasm, endoplasmic reticulum or outer mitochondrial membrane were studied in both MCF-7 and Rat-1 fibroblasts. In MCF-7 cells we measured the functional activities of these proteins in preventing apoptosis induced by four different agents (doxorubicin, ceramide, thapsigargin, TNF-α). Etoposide and low serum were used to compare the effect of Bcl-2, Bcl-XL and mutants located at the endoplasmic reticulum on induction of apoptosis in fibroblasts.

Results

We noted both qualitative and quantitative differences in the functional activity of these two anti-apoptotic proteins in cells: Bcl-2 localized to the endoplasmic reticulum inhibits apoptosis induced by ceramide and thapsigargin but not by doxorubicin or TNFα, while Bcl-XL at the endoplasmic reticulum is active against all four drugs. In fibroblasts Bcl-2 localized to the ER did not prevent cell death due to etoposide whereas Bcl-XL in the same location did. Finally in MCF-7 cells, Bcl-XL is approximately ten times more active than Bcl-2 in repressing apoptosis induced by doxorubicin. This difference can be manifest as a large difference in clonal survival.

Conclusion

When examined in the same cellular context, Bcl-2 and Bcl-XL differ substantially in the potency with which they inhibit apoptosis, mediated in part by differences in the inhibition of specific subcellular pathways.
Patients in long-term maintenance therapy for drug use in Italy: analysis of some parameters of social integration and serological status for infectious diseases in a cohort of 1091 patients
Authors: Quaglio Gianluca , Lugoboni Fabio , Pattaro Cristian , GICS  , Montanari Linda , Lechi Alessandro , Mezzelani Paolo , Des Jarlais Don C
Published: August 2006

Background

Heroin addiction often severely disrupts normal social functioning. The aims of this multi-centre study of heroin users in long-term replacement treatment were: i) to provide information on aspects of social condition such as employment, educational background, living status, partner status and any history of drug addiction for partners, comparing these data with that of the general population; ii) to assess the prevalence of hepatitis, syphilis and HIV, because serological status could be a reflection of the social conditions of patients undergoing replacement treatment for drug addiction; iii) to analyse possible relationships between social conditions and serological status.

Methods

A cross-sectional study was carried out in sixteen National Health Service Drug Addiction Units in northern Italy. The data were collected from February 1, 2002 to August 31, 2002. Recruitment eligibility was: maintenance treatment with methadone or buprenorphine, treatment for the previous six months, and at least 18 years of age. In the centres involved in the study no specific criteria or regulations were established concerning the duration of replacement therapy. Participants underwent a face-to-face interview.

Results

The conditions of 1091 drug treatment patients were evaluated. The mean duration of drug use was 14.5 years. Duration was shorter in females, in subjects with a higher educational background, and in stable relationships. Most (68%) had completed middle school (11–14 years of age). Seventy-nine percent were employed and 16% were unemployed. Fifty percent lived with their parents, 34% with a partner and 14% alone. Males lived more frequently with their parents (55%), and females more frequently with a partner (60%). Sixty-seven percent of male patients with a stable relationship had a partner who had never used heroin. HCV prevalence was 72%, HBV antibodies were detected in 42% of patients, while 30% had been vaccinated; 12.5% of subjects were HIV positive and 1.5% were positive for TPHA.

Conclusion

A significant percentage of heroin users in treatment for opiate addiction in the cohort study have characteristics which indicate reasonable integration within broader society. We posit that the combination of effective treatment and a setting of economic prosperity may enhance the social integration of patients with a history of heroin use.
Cross-diagnostic validity in a generic instrument: an example from the Functional Independence Measure in Scandinavia
Authors: Lundgren-Nilsson Å , Tennant A , Grimby G , Sunnerhagen KS
Published: August 2006

Background

To analyse the cross-diagnostic validity of the Functional Independence Measure (FIM™) motor items in patients with spinal cord injury, stroke and traumatic brain injury and the comparability of summed scores between these diagnoses.

Methods

Data from 471 patients on FIM™ motor items at admission (stroke 157, spinal cord injury 157 and traumatic brain injury 157), age range 11–90 years and 70 % male in nine rehabilitation facilities in Scandinavia, were fitted to the Rasch model. A detailed analysis of scoring functions of the seven categories of the FIM™ motor items was made prior to testing fit to the model. Categories were re-scored where necessary. Fit to the model was assessed initially within diagnosis and then in the pooled data. Analysis of Differential Item Functioning (DIF) was undertaken in the pooled data for the FIM™ motor scale. Comparability of sum scores between diagnoses was tested by Test Equating.

Results

The present seven category scoring system for the FIM™ motor items was found to be invalid, necessitating extensive rescoring. Despite rescoring, the item-trait interaction fit statistic was significant and two individual items showed misfit to the model, Eating and Bladder management. DIF was also found for Spinal Cord Injury, compared with the other two diagnoses. After adjustment, it was possible to make appropriate comparisons of sum scores between the three diagnoses.

Conclusion

The seven-category response function is a problem for the FIM™ instrument, and a reduction of responses might increase the validity of the instrument. Likewise, the removal of items that do not fit the underlying trait would improve the validity of the scale in these groups. Cross-diagnostic DIF is also a problem but for clinical use sum scores on group data in a generic instrument such as the FIM™ can be compared with appropriate adjustments. Thus, when planning interventions (group or individual), developing rehabilitation programs or comparing patient achievements in individual items, cross-diagnostic DIF must be taken into account.
Differences in perception of the WHO International Code of Marketing of Breast Milk Substitutes between pediatricians and obstetricians in Japan
Authors: Mizuno Katsumi , Miura Fumihiro , Itabashi Kazuo , Macnab Iona , Mizuno Noriko
Published: August 2006

Background

The World Health Organization International Code of Marketing of Breast-Milk Substitutes (WHO Code) aims to protect and promote breastfeeding. Japan ratified the WHO Code in 1994, but most hospitals in Japan continue to receive free supplies of infant formula and distribute discharge packs to new mothers provided by infant formula companies. The aim of this study was to explore the knowledge and attitudes of pediatricians and obstetricians in Japan to the WHO Code.

Methods

A self-completion questionnaire was sent to 132 pediatricians in the 131 NICUs which belonged to the Neonatal Network of Japan, and to 96 chief obstetricians in the general hospitals in the Kanto area of Japan, in 2004.

Results

Responses were received from 68% of pediatricians and 64% of obstetricians. Sixty-six percent of pediatricians agreed that "Breastmilk is the best", compared to only 13% of obstetricians. Likewise, pediatricians were more likely to be familiar with the WHO Code (51%) than obstetricians (18%).

Conclusion

In Japan, pediatricians and obstetricians, in general, have low levels of support for breastfeeding and low levels of familiarity with the WHO Code. To increase the breastfeeding rates in Japan, both pediatricians and obstetricians need increased knowledge about current infant feeding practices and increased awareness of international policies to promote breastfeeding.
Design Displacements for Base Isolators considering Bidirectional Seismic Effects
Authors: Tena-Colunga Arturo , Pérez-Osornio Miguel Ángel
Published: August 2006

Currently, there is not available in the literature a specific recommendation to combine peak displacements in orthogonal directions for the design of base isolators. The 100%+30% combination rule prescribed by many seismic codes worldwide to account for orthogonal effects in the design of conventional structures is sometimes used for base-isolated structures. This combination rule was formerly proposed to account for lateral forces, but it should be studied whether or not this rule still applies for the design displacements of isolated systems. This paper presents a parametric study where it is found that the statistical responses to combine peak displacements in orthogonal directions are not independent from the effective period for both linear and bilinear isolators, so a constant combination rule is somewhat incorrect.
Liquefaction Hazard Mapping with LPI in the Greater Oakland, California, Area
Authors: Holzer Thomas L. , Bennett Michael J. , Noce Thomas E. , Padovani Amy C. , Tinsley John C.
Published: August 2006

Cumulative frequency distributions of the liquefaction potential index (LPI) of surficial geologic units were used to define the liquefaction hazard in a 140- km2 area along the eastern shore of San Francisco Bay near Oakland, California. LPI values were computed for 202 cone penetration tests conducted in surficial geologic units in the study area. The hazard of each unit was defined by the cumulative frequency at LPI=5. The distributions predict that 73% and 3%, respectively, of the area underlain by artificial fill and Holocene alluvial fan deposits will show surface manifestations of liquefaction during a M7.1 earthquake on the nearby Hayward Fault. The predictions are consistent with recent earthquakes in other areas where similar types of deposits experienced near-field ground motion.
Exploring the Causal Relationship between Exposure to the 1994 Northridge Earthquake and Pre- and Post-Earthquake Preparedness Activities
Authors: Nguyen Loc H. , Shen Haikang , Ershoff Daniel , Afifi Abdelmonem A. , Bourque Linda B.
Published: August 2006

Whether, when, and why individuals prepare for disasters are major concerns of disaster preparedness researchers. Using population-based survey data collected after the 1994 Northridge earthquake, multinomial logistic models are imposed to examine if preparedness activities were adopted after the quake because of quake-related financial loss, physical and emotional injury, and proximity to the earthquake epicenter and shaking. The extent to which people invest in sustained preparedness was also examined by comparing the preparedness activities occurring both before and after the earthquake. The results indicated that exposure to physical, financial, and emotional injuries, and to shaking increased post-quake preparedness. Engaging in certain types of pre-quake preparedness increased the likelihood of post-quake preparedness. Post-quake preparedness is not affected by socioeconomic status or demographic factors, except that married persons are more likely to prepare in all situations and immigrants are more likely to adopt post-quake preparedness activities.
Identification, Model Updating, and Response Prediction of an Instrumented 15-Story Steel-Frame Building
Authors: Skolnik Derek , Lei Ying , Yu Eunjong , Wallace John W.
Published: August 2006

Identification of the modal properties of the UCLA Factor Building, a 15-story steel moment-resisting frame, is performed using low-amplitude earthquake and ambient vibration data. The numerical algorithm for subspace state-space system identification is employed to identify the structural frequencies, damping ratios, and mode shapes corresponding to the first nine modes. The frequencies and mode shapes identified based on the data recorded during the 2004 Parkfield earthquake ( Mw=6.0) are used to update a three-dimensional finite element model of the building to improve correlation between analytical and identified modal properties and responses. A linear dynamic analysis of the updated model excited by the 1994 Northridge earthquake is performed to assess the likelihood of structural damage.
Shaking Table Tests of a Four-Story Miniature Steel Building— Model Validation
Authors: Rodríguez Mario E. , Restrepo José I. , Blandón John J.
Published: August 2006

This paper discusses an analytical model developed to study the linear and nonlinear dynamic response of a four-story steel miniature building subjected to low-level and high-level shake table tests inducing nominally elastic and inelastic response, respectively. The analytical model was calibrated and validated against the results of the experimental program. A comparison of measured and calculated responses is made in the paper. Of particular interest, absolute floor accelerations were found more sensitive to high-frequency content than other response parameters such as base shear force and overturning base moment. The seismic performance of gravity-dominated beams is also examined in this paper. It was found that the cumulative nature of rotation demands in this type of beams should be considered in seismic design. The model is also used to observe differences in dynamic response of buildings when subjected to shake table tests with low fidelity in the reproduction of earthquake records.
A State-of-Knowledge Review of the Influence of Strong-Motion Duration on Structural Damage
Authors: Hancock Jonathan , Bommer Julian J.
Published: August 2006

The important role played by the duration of ground shaking in the response of saturated soil deposits is universally acknowledged, but no such consensus exists regarding the degree of influence that duration exerts on structural damage. There are several hundred papers in the literature that link structural damage to parameters related either directly or indirectly to the duration of strong ground motion. The conclusions of these studies differ widely with regard to the influence of strong-motion duration on structural demand. This paper provides a summary and critical review of the literature on this subject. It is found that studies employing damage measures related to cumulative energy usually find a positive correlation between strong-motion duration and structural damage, while studies employing damage measures using maximum response generally do not find strong correlations between duration and damage.
Simplified Expression for Seismic Fragility Estimation of Sliding-Dominated Equipment and Contents
Authors: Hutchinson Tara C. , Chaudhuri Samit Ray
Published: August 2006

Damage to small equipment and contents during seismic events has gained considerable attention following recent earthquakes, largely due to the potential for operational downtime, which results in significant economic losses. The estimation of losses from this interior building damage is a daunting task, due to the complexity of types of equipment and the randomness of their location within the structure. Nonetheless, a precursor to calculating such losses is a reasonable association between structural and nonstructural (equipment or contents) demands. Cast in a probabilistic framework, such an association is best represented through the use of seismic fragility curves, where the probabilities of exceeding a given damage state is correlated with an input parameter. In this paper, analytically developed seismic fragility curves for various unattached equipment and contents are calculated and presented. The emphasis of the study is on rigid scientific equipment and contents, which are often placed on the surface of ceramic laboratory benches in science laboratories or other buildings. Only uniaxial seismic excitation is considered to provide insight into the form of the fragility function. Generalized fragility curves are then developed and a simple expression is presented, which is envisioned to be very useful from a design perspective. The usefulness of the proposed expression is illustrated via a simple numerical example coupled with a design code-specified horizontal acceleration distribution profile for an example building structure.
Post-Earthquake Restoration Planning for Los Angeles Electric Power
Authors: Çağnan Zehra , Davidson Rachel A. , Guikema Seth D.
Published: August 2006

This paper describes the application of a new discrete-event-simulation model of the post-earthquake electric power restoration process in Los Angeles. The findings are that (1) Los Angeles residents may experience power outages lasting up to 10 days; (2) what we call the power rapidity risk (the joint probability distribution of restoration of a specified number of customers in a specified amount of time) varies throughout the area; (3) there is a relatively high likelihood that more repair materials than are currently available will be required if a large earthquake occurs; and (4) there are ways to reduce the expected duration of earthquake-initiated power outages and they should be subjected to cost-benefit analysis. These results should be useful to utilities and emergency planners in Los Angeles. The new simulation modeling approach could be used in other seismically active cities to gain insights into the restoration process that other modeling approaches cannot provide.
Allometric Scaling Law Questions the Traditional Mechanical Model for Axillary Lymph Node Involvement in Breast Cancer
Authors: Demicheli Romano , Biganzoli Elia , Boracchi Patrizia , Greco Marco , Hrushesky William J.M. , Retsky Michael W.
Published: August 2006

Purpose

To find a quantitative relationship between tumor size and frequency of axillary lymph node involvement.

Patients and Methods

The frequency of axillary node involvement versus primary tumor volume was analyzed in 10 selected series of patients incorporating a total of 57,244 women with resectable breast cancer. The average number of events per unit volume resulting in tumor spread to axillary lymph nodes before tumor surgical removal Θ(V)/V, was estimated under simple probabilistic assumptions.

Results

The allometric scaling law Θ(V)/V = 0.0586V−0.7457 was estimated on the data, fitting the proportion of lymph node involvement on tumor volume V (in microliters). The estimate 0.7457 (95% CI, 0.7200 to 0.7713) suggests that the true scaling exponent, under the assumed model, may be the fractional value, which characterizes scaling relationships for a wide variety of biologic variables at both the whole organism level and organ level.

Conclusion

Results suggest that the phenomenon should be related to some internal structural trait of the tumor. The vascular network seems to be the best candidate. This result does not support a mere mechanical model of lymphatic tumor spread. A more complex biology-based model of lymphohematogenous spread is suggested, in which the axillary nodes draining the lymph from the primary tumor may become activated by factors produced by both tumor cells and tumor stroma, thus favoring cell-selective homing of otherwise circulating tumor cells. The success of fractal features related to the internal architecture brings additional support to the consideration of primary breast cancer as an organ-like structure.
Association of Specific Symptoms and Metabolic Risks with Serum Testosterone in Older Men
Authors: Zitzmann Michael , Faber Stephanie , Nieschlag Eberhard
Published: August 2006

Context: Although attention and concern about health disorders in aging men have been growing, the structure of psychological and somatic complaints of actual patients, not population-based cohorts, has not been elucidated in relation to sex hormone patterns and metabolism.

Objective: The objective of the study was investigation of factors influencing complaint structures in aging male patients.

Design: This was a cross-sectional cohort study.

Setting: The study was conducted in an andrological outpatient department.

Patients: Subjects included 434 consecutive male patients aged 50–86 yr.

Main Outcome Measures: The following hypotheses were measured: 1) psychosomatic complaints and metabolic factors in aging male patients are related to sex hormone levels in a symptom-specific manner, and 2) patients form subcohorts.

Results: A clear-cut threshold for late-onset hypogonadism was not found; rather, prevalence of psychosomatic symptoms and metabolic risk factors accumulated with decreasing androgen levels. For example, androgen-induced prevalence of loss of libido or vigor increased below testosterone concentrations of 15 nmol/liter (P < 0.001), whereas depression and diabetes mellitus type 2 (also in nonobese men) were significantly more present in men with testosterone concentrations below 10 nmol/liter (P < 0.001). Erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depressivity, whereas only testosterone concentrations below 8 nmol/liter contributed to that symptom (P = 0.003). Cluster analysis revealed aging men to present within three independent groups characterized by psychosomatic complaints, metabolic disorders, and sexual health problems. These subgroups of patients exhibit distinct features in terms of androgen levels, age, and body mass index.

Conclusions: There is no evidence that a uniform structure of testosterone concentrations and complaints exists within the cohort of elderly male patients. Rather, in aging male patients, psychosomatic complaints and metabolic risk relate to testosterone in a symptom-specific manner.
Serum Insulin-Like Factor 3 Levels during Puberty in Healthy Boys and Boys with Klinefelter Syndrome
Authors: Wikström Anne M. , Bay Katrine , Hero Matti , Andersson Anna-Maria , Dunkel Leo
Published: August 2006

Context: Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development.

Objective: The objective of the study was to characterize changes in INSL3 levels during spontaneous puberty in healthy boys, boys with aromatase inhibitor-induced hypergonadotropic hyperandrogenism, and boys with Leydig cell dysfunction.

Design: This was a prospective clinical study.

Setting: The study was conducted at a university hospital pediatric endocrinology outpatient clinic.

Patients: Patients included 30 healthy boys with idiopathic short stature (ISS) aged 9.0–14.5 yr and 14 boys with Klinefelter syndrome (KS) aged 10–13.9 yr.

Intervention: In ISS boys, intervention included aromatase inhibitor letrozole or placebo for 24 months.

Main Outcome Measures: Serum INSL3 levels in relation to bone age, Tanner pubertal stages, and LH and testosterone levels were measured.

Results: Onset of puberty was associated with a significant increase in INSL3 levels from 0.06 ± 0.01 ng/ml at Tanner G1 to 0.32 ± 0.16 ng/ml at G2 (P < 0.0001). Adult INSL3 levels (≥0.55 ng/ml) were attained at bone age 13–14 yr. ISS boys with letrozole-induced hypergonadotropic hyperandrogenism had, after 12 months of therapy, higher INSL3 levels than did placebo treated (0.85 ± 0.54 vs. 0.26 ± 0.17 ng/ml, P < 0.01). In KS boys during spontaneous puberty, after an initial increase similar to that in healthy boys, INSL3 concentrations leveled off despite hyperstimulation by LH. Positive correlations occurred between serum INSL3 and LH and between INSL3 and testosterone levels in all three groups (P < 0.0001).

Conclusions: In boys, the Leydig cell-specific hormone INSL3 may serve as a new marker for onset and progression of puberty. Pubertal increase in INSL3 levels seems to depend on LH. In KS subjects, INSL3 concentrations indicate Leydig cell dysfunction from midpuberty onward.
SHBG Gene Promoter Polymorphisms in Men Are Associated with Serum Sex Hormone-Binding Globulin, Androgen and Androgen Metabolite Levels, and Hip Bone Mineral Density
Authors: Eriksson A. L. , Lorentzon M. , Mellström D. , Vandenput L. , Swanson C. , Andersson N. , Hammond G. L. , Jakobsson J. , Rane A. , Orwoll E. S. , Ljunggren Ö. , Johnell O. , Labrie F. , Windahl S. H. , Ohlsson C.
Published: August 2006

Context: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity.

Objective: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)n microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men.

Design and Study Subjects: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n ≅ 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr).

Main Outcome Measures: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5α-androstane-3α,17β-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry.

Results: In both cohorts, (TAAAA)n and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5α-androstane-3α,17β-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass.

Conclusions: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
Influence of Body Fat Content and Distribution on Variation in Metabolic Risk
Authors: Vega Gloria Lena , Adams-Huet Beverley , Peshock Ron , Willett DuWayne , Shah Brijen , Grundy Scott M.
Published: August 2006

Objectives: Several reports indicate that the body fat compartments, especially ip fat, predict metabolic risk better than total body fat. The objective of the study was to determine whether this can be confirmed and generalized throughout the population.

Participants: A representative sample of 1934 Black and White women and men of the Dallas Heart Study participated in the study.

Design: We measured the fat in total body, trunk, and lower body with dual-energy x-ray absorptiometry and in abdominal compartments (sc, ip, and retroperitoneal) with magnetic resonance imaging. Other measurements included body mass index (BMI), waist circumference, blood pressure, plasma lipids, glucose, insulin (including homeostasis model), and C-reactive protein.

Results: In all groups, total body fat correlated positively with key metabolic risk factors, i.e. homeostasis model, triglyceride/high-density lipoprotein-cholesterol ratios, C-reactive protein, and blood pressure; however, it explained less than one third of the variability of all the risk factors. After adjustment for total body fat, truncal fat conferred additional positive correlation with risk factors. Furthermore, with multivariable regression analysis, ip fat conferred independent correlation with plasma lipids beyond a combination of other compartments including truncal fat. Still, except for insulin levels, all combinations including ip fat still explained less than one third of the variability in risk-factor levels. Conversely, lower body fat correlated negatively with risk factors; i.e. lower body fat appeared to offer some protection against risk factors.

Conclusions: Body fat distribution has some influence on risk factors beyond total body fat content. Both waist circumference and BMI significantly predicted risk factors after adjustment for total body fat, and for clinical purposes, most of the predictive power for men was contained in waist circumference, whereas for women, BMI and waist circumference were similarly predictive. Finally, even though the correlations between combined body fat parameters and risk factors explained only a portion of the variation in the latter, the average number of categorical metabolic risk factors increased progressively with increasing obesity. Hence, obesity seemingly has more clinical impact than revealed in these correlative studies.
Endocrine Dysfunction in Patients with Fabry Disease
Authors: Faggiano A. , Pisani A. , Milone F. , Gaccione M. , Filippella M. , Santoro A. , Vallone G. , Tortora F. , Sabbatini M. , Spinelli L. , Lombardi G. , Cianciaruso B. , Colao A.
Published: August 2006

Background: Fabry disease (FD) is a genetic disorder caused by lysosomal α-galactosidase-A deficiency and is characterized by the systemic accumulation of globotriaosylceramide. All endocrine glands are susceptible to globotriaosylceramide accumulation because of their high vascularization and low cellular proliferation rate. Nevertheless, this endocrine system has never been investigated in detail.

Objective: We aimed to investigate the function and morphology of the endocrine glands in FD.

Patients: The thyroid, gonadal, adrenal, and GH/IGF-I axes were evaluated in 18 FD patients (nine females and nine males, aged 21–64 yr) and 18 sex- and age-matched healthy subjects.

Study design: We conducted an observational, analytical, open, prospective study.

Interventions: Ten of the 18 patients received enzyme replacement therapy (ERT) with recombinant human α-galactosidase-A (agalsidase β) at a dose of 1 mg/kg body weight every 2 wk.

Results: FD patients had higher baseline TSH levels than controls (P < 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menses abnormalities, miscarriage, or assisted delivery was found in 89% of FD women. Asthenozoospermia, oligozoospermia, or both were found in all FD men through seminal fluid analysis. FD patients had significantly higher circulating ACTH and lower cortisol levels than controls (P < 0.05). In patients under ERT, a suboptimal cortisol response to the 250-μg ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P < 0.05).

Conclusion: A variety of latent endocrine dysfunctions, including life-threatening conditions, occur in patients with FD. Endocrine dysfunctions are also present in patients already receiving ERT and are in part related to their persistent poor quality of life. An endocrine work-up should be recommended in all FD patients. Adequate monitoring and hormonal therapy, when required, have to be performed in cases of subclinical endocrine dysfunction to avoid life-threatening events.
Golgi structural stability and biogenesis depend on associated PKA activity
Authors: Bejarano Eloy , Cabrera Margarita , Vega Lucia , Hidalgo Josefina , Velasco Angel
Published: August 2006

The mammalian Golgi complex consists of stacks of cisternae linked laterally into a continuous perinuclear ribbon structure. Protein kinase A is stably associated with the Golgi complex during interphase. To analyze its role in Golgi structural maintenance cells were depleted of protein kinase A regulatory subunits using small interfering RNAs. Under these conditions, the catalytic subunits redistributed to the cytosol and the entire Golgi complex underwent disassembly into multiple juxtanuclear fragments. A similar effect took place following pharmacological inhibition or redistribution of the complete holoenzyme to the cytosol. Golgi fragments maintained their polarization and competence for anterograde protein trafficking. By electron microscopy, they were identified as whorl-like structures composed of concentrically arrayed cisternae. To test a possible role of protein kinase A in Golgi biogenesis we analyzed its involvement during Golgi reassembly from the endoplasmic reticulum. In cells incubated with protein kinase A inhibitors, Golgi reconstruction was arrested at a late step of the reassembly process. This is consistent with the stage of enzyme recruitment from cytosol to emerging Golgi membranes during the reassembly process. We conclude that protein kinase A activity plays a relevant role in the assembly and maintenance of a continuous Golgi ribbon from separated membrane stacks.
Arl1p is involved in transport of the GPI-anchored protein Gas1p from the late Golgi to the plasma membrane
Authors: Liu Ya-Wen , Lee Szu-Wei , Lee Fang-Jen S.
Published: August 2006

The molecular mechanisms involved in the transport of GPI-anchored proteins from the trans-Golgi network (TGN) to the cell periphery have not been established. Arl1p is a member of the Arf-like protein (Arl) subfamily of small GTPases and is localized in the late Golgi. Although Arl1p is implicated in regulation of Golgi structure and function, no endogenous cargo protein that is regulated by Arl1p has been identified in yeast. In this study, we demonstrate that Arl1p is involved in the anterograde transport from the Golgi to the cell surface of the glycosylphosphatidylinositol (GPI)-anchored plasma-membrane-resident protein Gas1p, but not the cell-wall-localized GPI-anchored proteins Crh1p, Crh2p and Cwp1p, or non-GPI-anchored plasma membrane-protein Gap1p. We also show that regulators of Arl1p (Sys1p, Arl3p and Gcs1p) and an effector (Imh1p) all participate in the transport of Gas1p. Thus, we infer that the signaling cascade Sys1p-Arl3p-Arl1p-Imh1p specifically participates in the transport of a GPI-anchored protein from the late Golgi to the plasma membrane.
Dissection of amoeboid movement into two mechanically distinct modes
Authors: Yoshida Kunito , Soldati Thierry
Published: August 2006

The current dominant model of cell locomotion proposes that actin polymerization pushes against the membrane at the leading edge producing filopodia and lamellipodia that move the cell forward. Despite its success, this model does not fully explain the complex process of amoeboid motility, such as that occurring during embryogenesis and metastasis. Here, we show that Dictyostelium cells moving in a physiological milieu continuously produce `blebs' at their leading edges, and demonstrate that focal blebbing contributes greatly to their locomotion. Blebs are well-characterized spherical hyaline protrusions that occur when a patch of cell membrane detaches from its supporting cortex. Their formation requires the activity of myosin II, and their physiological contribution to cell motility has not been fully appreciated. We find that pseudopodia extension, cell body retraction and overall cell displacement are reduced under conditions that prevent blebbing, including high osmolarity and blebbistatin, and in myosin-II-null cells. We conclude that amoeboid motility comprises two mechanically different processes characterized by the production of two distinct cell-surface protrusions, blebs and filopodia-lamellipodia.
Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle
Authors: Ohtake Yohei , Tojo Hideaki , Seiki Motoharu
Published: August 2006

Sequential activation of muscle-specific transcription factors is the critical basis for myogenic differentiation. However, the complexity of this process does not exclude the possibility that other molecules and systems are regulatory as well. We observed that myogenic differentiation proceeded through three distinct stages of proliferation, elongation and fusion, which are distinguishable by their cellular morphologies and gene expression patterns of proliferation- and differentiation-specific markers. Treatment of the differentiating myoblasts with inhibitors of matrix metalloproteinases (MMPs) revealed that MMP activity at the elongation stage is a critical prerequisite to complete the successive myoblast cell fusion. The MMP regulated the myogenic differentiation independently from the genetic program that governs expression of the myogenic genes. Membrane-type 1 matrix metalloproteinase (MT1-MMP) was identified as a major contributor to this checkpoint for morphological differentiation and degraded fibronectin, a possible inhibitory factor for myogenic cell fusion. A MT1-MMP deficiency caused similar myogenic impediments forming smaller myofibers in situ. Additionally, the mutant mice demonstrated some central nucleation of the myofibers typically found in muscular dystrophy and MT1-MMP was found to cleave laminin-2/4 in the basement membrane. Thus, MT1-MMP is a new multilateral regulator for muscle differentiation and maintenance through processing of stage-specific distinct ECM substrates.