bluuebunny/crossref_metadata_2025 huggingface dataset:
High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL
Authors: Goldstein Alisa M. , Chan May , Harland Mark , Gillanders Elizabeth M. , Hayward Nicholas K. , Avril Marie-Francoise , Azizi Esther , Bianchi-Scarra Giovanna , Bishop D. Timothy , Bressac-de Paillerets Brigitte , Bruno William , Calista Donato , Cannon Albright Lisa A. , Demenais Florence , Elder David E. , Ghiorzo Paola , Gruis Nelleke A. , Hansson Johan , Hogg David , Holland Elizabeth A. , Kanetsky Peter A. , Kefford Richard F. , Landi Maria Teresa , Lang Julie , Leachman Sancy A. , MacKie Rona M. , Magnusson Veronica , Mann Graham J. , Niendorf Kristin , Newton Bishop Julia , Palmer Jane M. , Puig Susana , Puig-Butille Joan A. , de Snoo Femke A. , Stark Mitchell , Tsao Hensin , Tucker Margaret A. , Whitaker Linda , Yakobson Emanuel ,   The Lund Melanoma Study Group,   the Melanoma Genetics Consortium (GenoMEL)
Published: October 2006

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)
Attenuation of CD8+ T-Cell Function by CD4+CD25+ Regulatory T Cells in B-Cell Non-Hodgkin's Lymphoma
Authors: Yang Zhi-Zhang , Novak Anne J. , Ziesmer Steven C. , Witzig Thomas E. , Ansell Stephen M.
Published: October 2006

The underlying mechanisms by which tumor cells are resistant to CTL-mediated apoptosis are not clear. Using a human model of B-cell non-Hodgkin's lymphoma (B-cell NHL), we show that intratumoral Treg cells inhibit the proliferation and granule production of activated autologous infiltrating CD8+ T cells. Our results also show that degranulation and subsequent cytotoxic activity of infiltrating CD8+ T cells exposed to lymphoma B cells is completely attenuated by the presence of intratumoral Treg cells. Furthermore, we show that increased numbers of intratumoral Treg cells correlates with the number of CD8+ T cells in biopsy specimens from patients with B-cell NHL, supporting the in vitro findings that intratumoral Treg cells inhibit proliferation of infiltrating CD8+ T cells. Taken together, these data indicate that human lymphoma B cells are sensitive to autologous CTL-mediated cell death but are protected by the inhibitory function of intratumoral Treg cells. (Cancer Res 2006; 66(20): 10145-52)
A Prospective Nested Case-Control Study of Vitamin D Status and Pancreatic Cancer Risk in Male Smokers
Authors: Stolzenberg-Solomon Rachael Z. , Vieth Reinhold , Azad Azar , Pietinen Pirjo , Taylor Philip R. , Virtamo Jarmo , Albanes Demetrius
Published: October 2006

Sun exposure is associated with lower death rates for pancreatic cancer in some ecological studies. Skin exposure to UVB light induces cutaneous production of precursors to 25-hydroxyvitamin D [25(OH)D]. Pancreatic islet and duct cells express 25(OH)D3-1α-hydroxylase that generates the biologically active 1,25(OH)2 vitamin D form. Thus, 25(OH)D concentrations could affect pancreatic function and possibly pancreatic cancer etiology. We conducted a prospective nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort of male Finnish smokers, ages 50 to 69 years at baseline, to test whether more adequate vitamin D status, as determined by prediagnostic serum 25(OH)D concentrations, was associated with lower pancreatic cancer risk. Two hundred incident exocrine pancreatic cancer cases that occurred between 1985 and 2001 (up to 16.7 years of follow-up) were matched by age and date of blood draw to 400 controls who were alive and free of cancer at the time the case was diagnosed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Higher vitamin D concentrations were associated with a 3-fold increased risk for pancreatic cancer (highest versus lowest quintile, >65.5 versus <32.0 nmol/L: OR, 2.92; 95% CI, 1.56-5.48, Ptrend = 0.001) that remained after excluding cases diagnosed early during follow-up. Contrary to expectations, subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status. Our findings need to be replicated in other populations and caution is warranted in their interpretation and implication. Our results are intriguing and may provide clues that further the understanding of the etiology of this highly fatal cancer. (Cancer Res 2006; 66(20): 10213-9)
Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells
Authors: Braeuer Susanne J. , Büneker Chirlei , Mohr Andrea , Zwacka Ralf Michael
Published: October 2006

The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-κB (NF-κB) has been implicated, but its exact role is controversial. We studied different cell lines displaying varying responses to TRAIL and found that TRAIL can activate NF-κB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-κB via adenoviral expression of the IκB-α super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-κB, pointing to a possible role of preactivated NF-κB in protection from TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-κB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-κB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-κB and/or XIAP only in tumor cells with constitutively activated NF-κB. (Mol Cancer Res 2006;4(10):715–28)
The Functions of Mammalian Amyloid Precursor Protein and Related Amyloid Precursor-Like Proteins
Authors: Anliker Brigitte , Müller Ulrike
Published: October 2006

It is well established that proteolytic processing of the β-amyloid precursor protein (APP) generates β-amyloid which plays a central role in the pathogenesis of Alzheimer’s disease. In contrast, the physiological role of APP and the question of whether a loss of these functions contributes to Alzheimer’s disease are still unclear. For a long time, the characterization of APP functions was markedly hampered by the high redundancy between APP and the related APP family members amyloid precursor-like proteins 1 and 2. The generation and analyses of combined gene deficiencies for APP and amyloid precursor-like proteins in mice finally marked the beginning of uncovering the in vivo roles of these proteins in mammals. In the current review, we summarize recent insights into the functions of the APP gene family from mice lacking one, two or all three family members.
Control of Amyloid-β-Peptide Generation by Subcellular Trafficking of the β-Amyloid Precursor Protein and β-Secretase
Authors: Walter Jochen
Published: October 2006

Amyloid-β (Aβ) peptides are major components of Alzheimer’s disease (AD)-associated senile plaques and generated by sequential cleavage of the β-amyloid precursor protein (βAPP) by β-secretase and γ-secretase. While β-secretase activity is exerted by the aspartic protease BACE1, γ-secretase consists of a protein complex of at least four essential proteins with the presenilins as the catalytically active components. The understanding of the subcellular trafficking of βAPP and proteases involved in its proteolytic processing has increased rapidly in the last years. βAPP as well as the secretases are membrane proteins, and recent work demonstrated that alterations in the lipid composition of cellular membranes could affect the proteolytic processing of βAPP and Aβ generation. We identified glycosphingolipids as membrane components that modulate the subcellular transport of βAPP and the generation of Aβ. By cell biological and biochemical methods we also characterized the role of BACE1 and its homologue BACE2 in the proteolytic processing of βAPP. Here, I summarize and discuss these findings in the context of other studies focused on the function of BACE1 and BACE2 and the role of subcellular trafficking in the proteolytic processing of βAPP.
α-Secretase Activation – An Approach to Alzheimer’s Disease Therapy
Authors: Fahrenholz Falk , Postina Rolf
Published: October 2006

The nonamyloidogenic pathway of processing the amyloid precursor protein (APP) involves the cleavage within the amyloid-β peptide sequence, and thus precludes amyloid-β formation. The identification of a member of the disintegrin and metalloproteinase family, ADAM10, as an α-secretase that prevents plaque formation and hippocampal deficits in vivo gave us the possibility to examine the α-secretase as a potential target for the therapy of Alzheimer’s disease. Within the priority program Cellular Mechanisms of Alzheimer’s Disease, we investigated several approaches to stimulate the α-secretase pathway. Two protein convertases were found to be responsible for the removal of the prodomain, and for the formation of the mature enzyme with α-secretase activity. The cloning and characterization of the human ADAM10 promoter provided the basis to examine ADAM10 gene expression. We found a common upregulation of ADAM10, APP, and APP-like protein 2 during differentiation of neuronal cells by retinoic acid, and increased α-secretase cleavage of the two substrates. Other approaches for enhancing α-secretase activity are the reduction of cellular cholesterol and the stimulation of G protein-coupled neuropeptide receptors. Our results suggest medications and dietary regiments which enhance the nonamyloidogenic pathway of APP processing to be a valuable approach to Alzheimer’s disease therapy.
The Cost of Medical Care for the Acromegalic Patient
Authors: Knutzen Robert , Ezzat Shereen
Published: October 2006

Despite ample proof to the contrary, the overwhelming number of health care practitioners still believe that acromegaly is a disease that they will rarely encounter, let alone have to treat. However, the reality is quite a bit different for both doctors and patients. Many of the obvious symptoms and signs of this disease manifest slowly and insidiously. As such, the majority of patients are often treated for seemingly unrelated conditions for years before the actual diagnosis of acromegaly is established. Thus, the overall cost of medical care for the acromegalic patient is considerably higher than appreciated at first glance. The financial cost of managing this disease must include the cost of care of comorbid conditions before and following the diagnosis of acromegaly. It is only through a higher degree of awareness that this disease will be identified earlier in its course and the true number of acromegalic patients is realized. We anticipate that such measures will serve to limit the psychological, emotional and economic burden of this potentially debilitating disease.
The Role of Insulin-Like Growth Factor Binding Proteins
Authors: Holly Jeff , Perks Claire
Published: October 2006

Insulin-like growth factors (IGFs) are fundamental cell regulators with an evolutionary conserved role synchronising tissue growth, development and function according to metabolic conditions. Although structurally very similar to insulin, the IGFs act in a very different way as cell regulators. Whereas insulin is stored in a specific gland and released when needed, the IGFs are stored outside of cells with soluble binding proteins. A very complex system of six IGF binding proteins, each of which exists in various modified states and interacts with other proteins, provides a sophisticated system for conferring specificity to provide a finely tuned system for local regulation at the tissue level.
Quality of Life in Acromegaly
Authors: Webb Susan M.
Published: October 2006

Acromegaly is a disease with an important impact on health-related quality of life (HRQoL). Cross-sectional evaluation of HRQoL in patients with acromegaly using generic questionnaires and the specific questionnaire AcroQoL has confirmed severe impairment; active disease, female gender, ageing, disease duration, joint symptoms and prior radiotherapy are associated with worse HRQoL. The most affected dimension is appearance and the least affected, personal relations; comparable results have been observed in Spanish, Dutch, German, English and Turkish speaking patients. Patients with active acromegaly show a worse score (mean range 43–56) than those in remission (mean range 65–71). In longitudinal studies, in patients with stable acromegaly, no change was observed on retesting at 1 month, demonstrating a good test-retest reliability. In patients with active acromegaly, after 6 months of treatment, an improvement in the AcroQoL score was observed (56 ± 20 to 66 ± 18; p < 0.01). The internal consistency of AcroQoL was good (Cronbach’s α >0.7). No correlation between AcroQoL and insulin-like growth factor-I/growth hormone levels was observed, even though a trend was found for the most affected dimension (appearance) and insulin-like growth factor-I (p = 0.051). In summary, HRQoL is severely affected in acromegaly, even in patients with controlled disease. Thus, to optimise management, not only biochemical and radiological parameters but also dimensions that reflect HRQoL should be evaluated in acromegaly.
Considering the Rationality of Ritual Behavior
Authors: MortSlone JoelD. Jason
Published: October 2006

Engagement in religious ritual acts is, from a scientific point of view, a surprising feature of human behavior given the inherent commitment to counterintuitive worlds, including, generally invisible entities such as superhuman agents. Why people engage in such behaviors has preoccupied many scholars in the history of the study of religion (including scholars from within anthropology, psychology, sociology, and numerous other disciplines). These scholars have engaged in the Rationality Debate; the goal of which is to determine standards that could be used to make judgments about the rationality of human behavior. While ritual behavior might be ineffective for the achievement of purported goals and fail to conform to principles of reasoning based on rules of logic, the simple fact that this behavior is widespread, transmitted in a stable fashion, and the result (at least indirectly) of evolutionary processes suggest that considering its rationality or lack thereof is largely irrelevant. The question should not be “if” ritual behavior is rational but rather “why” this behavior is consistently exhibited. We argue that in order to answer this question anthropologists ultimately depend on heuristics recast as postulated entities. These are conceived as causal variable(s) governing patterned human behavior and consequently circle back and affirm a fallacious Durkheimian description of ritual behavior. This is a major and fundamental flaw in the current anthropological research tradition; the correction of which requires fundamental shifts in the philosophical commitments held—knowingly or unknowingly—by anthropologists.
Dosing of Gentamicin in Patients With End‐Stage Renal Disease Receiving Hemodialysis
Authors: Teigen Mette Maja B. , Duffull Stephen , Dang Lily , Johnson David W.
Published: October 2006

The aim of this study was to evaluate dosing schedules of gentamicin in patients with end‐stage renal disease and receiving hemodialysis. Forty‐six patients were recruited who received gentamicin while on hemodialysis. Each patient provided approximately 4 blood samples at various times before and after dialysis for analysis of plasma gentamicin concentrations. A population pharmacokinetic model was constructed using NONMEM (version 5). The clearance of gentamicin during dialysis was 4.69 L/h and between dialysis was 0.453L/h. The clearance between dialysis was best described by residual creatinine clearance (as calculated using the Cockcroft and Gault equation), which probably reflects both lean mass and residual clearance mechanisms. Simulation from the final population model showed that predialysis dosing has a higher probability of achieving target maximum concentration (Cmax) concentrations (>8 mg/L) within acceptable exposure limits (area under the concentration‐time curve [AUC] values >70 and <120 mg·h/L per 24 hours) than postdialysis dosing.
Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection
Authors: Wang Xiaolei , Rasmussen Terri , Pahar Bapi , Poonia Bhawna , Alvarez Xavier , Lackner Andrew A. , Veazey Ronald S.
Published: October 2006

Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)–infected adult macaques and human immunodeficiency virus (HIV)–infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that “activated” central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques.
Comparison of protein interaction networks reveals species conservation and divergence
Authors: Liang Zhi , Xu Meng , Teng Maikun , Niu Liwen
Published: October 2006

Background

Recent progresses in high-throughput proteomics have provided us with a first chance to characterize protein interaction networks (PINs), but also raised new challenges in interpreting the accumulating data.

Results

Motivated by the need of analyzing and interpreting the fast-growing data in the field of proteomics, we propose a comparative strategy to carry out global analysis of PINs. We compare two PINs by combining interaction topology and sequence similarity to identify conserved network substructures (CoNSs). Using this approach we perform twenty-one pairwise comparisons among the seven recently available PINs of E.coli, H.pylori, S.cerevisiae, C.elegans, D.melanogaster, M.musculus and H.sapiens. In spite of the incompleteness of data, PIN comparison discloses species conservation at the network level and the identified CoNSs are also functionally conserved and involve in basic cellular functions. We investigate the yeast CoNSs and find that many of them correspond to known complexes. We also find that different species harbor many conserved interaction regions that are topologically identical and these regions can constitute larger interaction regions that are topologically different but similar in framework. Based on the species-to-species difference in CoNSs, we infer potential species divergence. It seems that different species organize orthologs in similar but not necessarily the same topology to achieve similar or the same function. This attributes much to duplication and divergence of genes and their associated interactions. Finally, as the application of CoNSs, we predict 101 protein-protein interactions (PPIs), annotate 339 new protein functions and deduce 170 pairs of orthologs.

Conclusion

Our result demonstrates that the cross-species comparison strategy we adopt is powerful for the exploration of biological problems from the perspective of networks.
Use of CFSE staining of borreliae in studies on the interaction between borreliae and human neutrophils
Authors: Tuominen-Gustafsson Helena , Penttinen Markus , Hytönen Jukka , Viljanen Matti K
Published: October 2006

Background

Species of the tick-transmitted spirochete groupBorrelia burgdorferisensu lato (B. burgdorferi) cause Lyme borreliosis. Acute borrelial infection of the skin has unusual characteristics with only a mild local inflammatory response suggesting that the interaction between borreliae and the cells of the first-line defence might differ from that of other bacteria. It has been reported that human neutrophils phagocytose motile borreliae through an unconventional mechanism (tube phagocytosis) which is not observed with non-motile borreliae. Therefore, it would be of great interest to visualise the bacteria by a method not affecting motility and viability of borreliae to be able to study their interaction with the cells of the innate immunity. Carboxyfluorescein diacetate, succinimidyl ester (CFSE) labelling has been previously used for studying the adhesion of labelled bacteria to host cells and the uptake of labelled substrates by various cells using flow cytometry.

Results

In this study, CFSE was shown to efficiently stain different genospecies ofB. burgdorferiwithout affecting bacterial viability or motility. Use of CFSE staining allowed subsequent quantification of borreliae associated with human neutrophils with flow cytometry and confocal microscopy. As a result, no difference in association between different borrelial genospecies (Borrelia burgdorferisensu stricto,Borrelia afzelii,Borrelia garinii), or between borreliae and the pyogenic bacteriumStreptococcus pyogenes, with neutrophils could be detected. Borrelial virulence, on the other hand, affected association with neutrophils, with significantly higher association of a non-virulent mutantB. burgdorferisensu stricto strain compared to the parental virulent wild type strain.

Conclusion

These results suggest that the flow cytometric assay using CFSE labelled borreliae is a valuable tool in the analysis of the interaction between borreliae and human neutrophils. The results also indicate a clear difference in the association with neutrophils between virulent and non-virulent borrelial strains.
Evaluation of a 'virtual' approach to commissioning health research
Authors: McCourt Christine A , Morgan Philip A , Youll Penny
Published: October 2006

Background

The objective of this study was to evaluate the implementation of a 'virtual' (computer-mediated) approach to health research commissioning. This had been introduced experimentally in a DOH programme – the 'Health of Londoners Programme' – in order to assess whether is could enhance the accessibility, transparency and effectiveness of commissioning health research. The study described here was commissioned to evaluate this novel approach, addressing these key questions.

Methods

A naturalistic-experimental approach was combined with principles of action research. The different commissioning groups within the programme were randomly allocated to either the traditional face-to-face mode or the novel 'virtual' mode. Mainly qualitative data were gathered including observation of all (virtual and face-to-face) commissioning meetings; semi-structured interviews with a purposive sample of participants (n = 32/66); structured questionnaires and interviews with lead researchers of early commissioned projects. All members of the commissioning groups were invited to participate in collaborative enquiry groups which participated actively in the analysis process.

Results

The virtual process functioned as intended, reaching timely and relatively transparent decisions that participants had confidence in. Despite the potential for greater access using a virtual approach, few differences were found in practice. Key advantages included physical access, a more flexible and extended time period for discussion, reflection and information gathering and a more transparent decision-making process. Key challenges were the reduction of social cues available in a computer-mediated medium that require novel ways of ensuring appropriate dialogue, feedback and interaction. However, in both modes, the process was influenced by a range of factors and was not technology driven.

Conclusion

There is potential for using computer-mediated communication within the research commissioning process. This may enhance access, effectiveness and transparency of decision-making but further development is needed for this to be fully realised, including attention to process as well as the computer-mediated medium.
Analysis of bronchoalveolar lavage fluid proteome from systemic sclerosis patients with or without functional, clinical and radiological signs of lung fibrosis
Authors: Fietta AM , Bardoni AM , Salvini R , Passadore I , Morosini M , Cavagna L , Codullo V , Pozzi E , Meloni F , Montecucco C
Published: October 2006

Lung fibrosis is a major cause of mortality and morbidity in systemic sclerosis (SSc). However, its pathogenesis still needs to be elucidated. We examined whether the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) might have a protective or a causative role in the lung fibrogenesis process. For this purpose we compared the BALF protein profile obtained from nine SSc patients with lung fibrosis (SScFib+) with that obtained from six SSc patients without pulmonary fibrosis (SScFib-) by two-dimensional gel electrophoresis (2-DE). Only spots and spot-trains that were consistently expressed in a different way in the two study groups were taken into consideration. In total, 47 spots and spot-trains, corresponding to 30 previously identified proteins in human BALF, showed no significant variation between SScFib+ patients and SScFib- patients, whereas 24 spots showed a reproducible significant variation in the two study groups. These latter spots corresponded to 11 proteins or protein fragments, including serum albumin fragments (13 spots), 5 previously recognized proteins (7 spots), and 4 proteins (3 spots) that had not been previously described in human BALF maps, namely calumenin, cytohesin-2, cystatin SN, and mitochondrial DNA topoisomerase 1 (mtDNA TOP1). Mass analysis did not determine one protein-spot. The two study groups revealed a significant difference in BALF protein composition. Whereas levels of glutathione S-transferase P (GSTP), Cu–Zn superoxide dismutase (SOD) and cystatin SN were downregulated in SScFib+ patients compared with SScFib- patients, we observed a significant upregulation of α1-acid glycoprotein, haptoglobin-α chain, calgranulin (Cal) B, cytohesin-2, calumenin, and mtDNA TOP1 in SScFib+ patients. Some of these proteins (GSTP, Cu–Zn SOD, and cystatin SN) seem to be involved in mechanisms that protect lungs against injury or inflammation, whereas others (Cal B, cytohesin-2, and calumenin) seem to be involved in mechanisms that drive lung fibrogenesis. Even if the 2-DE analysis of BALF did not provide an exhaustive identification of all BALF proteins, especially those of low molecular mass, it allows the identification of proteins that might have a role in lung fibrogenesis. Further longitudinal studies on larger cohorts of patients will be necessary to assess their usefulness as predictive markers of disease.
NF-κB is required for STAT-4 expression during dendritic cell maturation
Authors: Remoli Maria Elena , Ragimbeau Josiane , Giacomini Elena , Gafa Valerie , Severa Martina , Lande Roberto , Pellegrini Sandra , Coccia Eliana M
Published: October 2006

The transcription factor STAT-4 plays a pivotal role in the IL-12-mediated development of naive CD4+ T cells into the Th1 phenotype. Initially thought to be restricted to the lymphoid lineage, STAT-4 was subsequently shown to be expressed in the myeloid compartment, mainly in activated monocytes, macrophages, and dendritic cells (DC). Here, we have studied STAT-4 in human monocyte-derived DC, and we demonstrated that its expression can be induced by multiple stimuli, such as the ligands for TLR-4, TLR-2, and TLR-3, different pathogens, CD40 ligand, and the proinflammatory cytokines TNF-α and IL-1β. It is interesting that we found that STAT-4 is tyrosine-phosphorylated in response to type I IFN but not IL-12 in human mature DC. Cloning and functional analysis of the STAT-4 promoter showed that a NF-κB binding site, localized at –969/–959 bp upstream of the transcriptional start site, is involved in the regulation of this gene in primary human DC. EMSAs using a probe containing this NF-κB binding sequence and chromatin immunoprecipitation indicated that p65/p50 and p50/p50 dimers were the main NF-κB/Rel proteins involved in STAT-4 gene expression in maturing DC. The mutation of this κB site or the overexpression of the repressor IκBα exerted an inhibitory effect on a STAT-4 promoter-driven reporter as well as on STAT-4 expression. Altogether, these results indicate that STAT-4 can be finely tuned along with DC maturation through NF-κB activation and that its induction may be involved in preparing the DC to be receptive to the cytokine environment present in lymphoid organs.
Impact and Perceptions of Mandatory Tumor Biopsies for Correlative Studies in Clinical Trials of Novel Anticancer Agents
Authors: Agulnik Mark , Oza Amit M. , Pond Gregory R. , Siu Lillian L.
Published: October 2006

Purpose

To assess the impact and perceptions of patients, physicians, and institutional review board members (IRBs) on the issue of mandatory serial tumor biopsies to acquire tissues for correlative studies.

Patients and Methods

Complementary, self-administered questionnaires were circulated to trial patients who had previously undergone serial research-related biopsies (TPs), clinic patients who had prior diagnostic but not research-related biopsies (CPs), academic medical oncologists in Canada (MOs), and IRBs at the affiliated academic centers.

Results

Ten (72%) of 14 TPs, 265 (82%) of 325 CPs, 137 (66%) of 209 MOs, and 142 (49%) of 291 IRBs responded. A 5% to 10% risk of a major biopsy complication was acceptable to 22% of CPs but only to 1% of MOs or IRBs. Anxiety was reported by 30% of TPs and 45% of CPs before their biopsies. More than 82% of MOs or IRBs believed the average patient would have at least borderline anxiety before their biopsy. Among the patients, 84% would authorize their samples for additional unrelated research and 75% would agree to genetic testing. Nearly all MOs and 86% of IRBs considered it ethical to request for additional unrelated research testing. With respect to genetic testing, 82% of MOs and 72% of IRBs would request it.

Conclusion

Although nearly all MOs and IRBs see the value in the biopsy, their threshold for acceptable risk is lower and they anticipate more associated anxiety than patients. Most patients recalled a tendency to tolerate their biopsies well with an average associated anxiety, and would allow their specimens to be tested for research purposes.
Bone Sialoprotein Is Predictive of Bone Metastases in Resectable Non–Small-Cell Lung Cancer: A Retrospective Case-Control Study
Authors: Papotti Mauro , Kalebic Thea , Volante Marco , Chiusa Luigi , Bacillo Elisa , Cappia Susanna , Lausi Paolo , Novello Silvia , Borasio Piero , Scagliotti Giorgio V.
Published: October 2006

Purpose

Bone metastases (BM) in non–small-cell lung cancer (NSCLC) may be detected at diagnosis or during the course of the disease, and are associated with a worse prognosis. Currently, there are no predictive or diagnostic markers to identify high-risk patients for metastatic bone dissemination.

Patients and Methods

Thirty patients with resected NSCLC who subsequently developed BM were matched for clinicopathologic parameters to 30 control patients with resected NSCLC without any metastases and 26 patients with resected NSCLC and non-BM lesions. Primary tumors were investigated by immunohistochemistry for 10 markers involved in bone resorption or development of metastases. Differences among groups were estimated by χ2test, whereas the prognostic impact of clinicopathologic parameters and marker expression was evaluated by univariate (Wilcoxon and Mantel-Cox tests) and multivariate (Cox proportional hazards regression model) analyses.

Results

The presence of bone sialoprotein (BSP) was strongly associated with bone dissemination (P < .001) and, independently, with worse outcome (P = .02, Mantel-Cox test), as defined by overall survival. To evaluate BSP protein expression in nonselected NSCLC, a series of 120 consecutive resected lung carcinomas was added to the study, and BSP prevalence reached 40%. No other markers showed a statistically significant difference among the three groups or demonstrated a prognostic impact, in terms of both overall survival and time interval to metastases.

Conclusion

BSP protein expression in the primary resected NSCLC is strongly associated with BM progression and could be useful in identifying high-risk patients who could benefit from novel modalities of surveillance and preventive treatment.
An Anatomical Evaluation of the Mini-Supraorbital Approach and Comparison with Standard Craniotomies
Authors: Figueiredo Eberval G. , Deshmukh Vivek , Nakaji Peter , Deshmukh Pushpa , Crusius Marcelo U. , Crawford Neil , Spetzler Robert F. , Preul Mark C.
Published: October 2006

OBJECTIVE:

To compare anatomically the surgical exposure provided by pterional (PT), orbitozygomatic (OZ), and minisupraorbital (SO) craniotomies. @@METHODS:@@ Seven sides of six fixed cadaver heads injected with silicone were used. The mini-SO craniotomy followed by the PT and OZ approaches were performed sequentially. The bony flaps were attached with miniplates and screws, allowing easy conversion between the approaches. A frameless stereotactic device was used to calculate an area of surgical exposure and the angles of approach for six different anatomic targets. An image guidance system was used to demonstrate the limits of the surgical exposure for each technique.

RESULTS:

No significant differences were observed in the total area of surgical exposure when comparing the mini-SO (A = 1831.2 ± 415.3 mm2), PT (A = 1860.0 ± 617.2 mm2), and OZ approaches (A = 1843.3 ± 358.1 mm2; P > 0.05). Angular exposure was greater for the OZ and PT approaches than for the mini-SO approach, either in the vertical and horizontal axes, considering all of the six targets studied (P< 0.05). Except for the distal segment of the ipsilateral sylvian fissure, no practical differences in the limits of the exposure were detected.

CONCLUSION:

The mini-SO approach may offer a similar surgical working area compared with that provided by standard craniotomies and constitutes an excellent alternative to the OZ and PT craniotomies in selected patients. Selection should not be based primarily on the area to be exposed, but rather on the working angles that are anticipated to be required. The key point is to use the most adequate technique for a particular patient, rather than using a one-size-fits-all approach for all patients.
Endovascular Treatment of Spinal Cord Arteriovenous Malformations
Authors: Veznedaroglu Erol , Nelson Peter K. , Jabbour Pascal M. , Rosenwasser Robert H.
Published: October 2006

SPINAL CORD ARTERIOVENOUS malformations are rare lesions that represent one-tenth of the brain arteriovenous malformations. Depending on their location and relationship to the dura, these lesions are divided into four categories. Their clinical manifestations may vary from mild symptoms to severe motor deficits. Spinal angiography remains the “gold standard” for diagnosing spinal cord vascular lesions. Although the type of shunting remains difficult to determine by the magnetic resonance imaging, it is well analyzed by spinal angiography. The cure of the shunting is not by itself a therapeutic goal, but the objective is the creation of a new hemodynamic equilibrium between the lesion and the spinal cord to decrease the risk of hemorrhage and prevent the progression of the spinal cord ischemia. The endovascular tools seem to be a reasonable therapeutic option for the treatment of the majority of the spinal cord arteriovenous malformations.
Surgical Anatomy of Microneurosurgical Sulcal Key Points
Authors: Ribas Guilherme C. , Yasuda Alexandre , Ribas Eduardo C. , Nishikuni Koshiro , Rodrigues Aldo J.
Published: October 2006

OBJECTIVE:

The brain sulci constitute the main microanatomic delimiting landmarks and surgical corridors of modern microneurosurgery. Because of the frequent difficulty in intraoperatively localizing and visually identifying the brain sulci with assurance, the main purpose of this study was to establish cortical/sulcal key points of primary microneurosurgical importance to provide a sulcal anatomic framework for the placement of craniotomies and to facilitate the main sulci intraoperative identification.

METHODS:

The study was performed through the evaluation of 32 formalin-fixed cerebral hemispheres of 16 adult cadavers, which had been removed from the skulls after the introduction of plastic catheters through properly positioned burr holes necessary for the evaluation of cranial–cerebral relationships. Three-dimensional anatomic and surgical images are displayed to illustrate the use of sulcal key points.

RESULTS:

The points studied were the anterior sylvian point, the inferior rolandic point, the intersection of the inferior frontal sulcus with the precentral sulcus, the intersection of the superior frontal sulcus with the precentral sulcus, the superior rolandic point, the intersection of the intraparietal sulcus with the postcentral sulcus, the superior point of the parieto-occipital sulcus, the euryon (the craniometric point that corresponds to the center of the parietal tuberosity), the posterior point of the superior temporal sulcus, and the opisthocranion, which corresponds to the most prominent point of the occipital bossa. These points presented regular neural and cranial–cerebral relationships and can be considered consistent microsurgical cortical key points.

CONCLUSION:

These sulcal and gyral key points can be particularly useful for initial intraoperative sulci identification and dissection. Together, they compose a framework that can help in the understanding of hemispheric lesion localization, in the placement of supratentorial craniotomies, as landmarks for the transsulcal approaches to periven-tricular and intraventricular lesions, and in orienting the anatomic removal of gyral sectors that contain infiltrative tumors.
Dynactin targets Pavarotti-KLP to the central spindle during anaphase and facilitates cytokinesis inDrosophilaS2 cells
Authors: Delcros Jean-Guy , Prigent Claude , Giet Régis
Published: October 2006

The dynactin complex cooperates with the dynein complex in various systems for mitotic completion. Here we analysed the mitotic phenotype of Drosophila S2 cells following the knockdown of the dynactin subunit p150Glued. We found that p150Glued-depleted cells were delayed in metaphase and that the centrosomes were poorly connected to mitotic spindle poles. In addition, anaphase occurred with asynchronous chromosome segregation. Although cyclin B was degraded in these anaphase cells, Aurora B, MEI-S322 and BubR1 were not released from the non-segregating chromosomes. We also found that the density and organisation of the central spindle were compromised, with Aurora B and polo kinases absent from the diminished number of microtubules. Pavarotti-KLP, a component of the centralspindlin complex required for the formation of stable microtubule bundles, was not immediately targeted to the plus ends of the microtubules following anaphase onset as happened in controls. Instead, it accumulated transiently at the cell cortex during early anaphase and its targeting to the central spindle was delayed. These data suggest that the dynactin complex contributes to cytokinesis by promoting stable targeting of the centralspindlin complex to microtubule plus ends at anaphase onset. The contribution of the dynein-dynactin complex to synchronous chromosome segregation and cytokinesis is discussed.
Influence of ultraviolet radiation on selected physiological responses of earthworms
Authors: Chuang Shu-Chun , Lai Wei-Shan , Chen Jiun-Hong
Published: October 2006

The purpose of this study was to investigate the adverse effects of ultraviolet (UV) radiation on earthworms. Earthworms that crawl out of the soil may die within a few hours after sunrise. This study shows that UV exposure can be lethal. In general, UV-B had a stronger damaging effect than UV-A. Different species of earthworms had different tolerances to UV exposure. In this study, Pontoscolex corethrurus showed the highest tolerance of the three tested species to UV radiation, while Amynthas graciliswas the most sensitive. UV radiation induced both acute and chronic responses. The acute response, which occurred immediately on or after UV exposure, was characterized by the appearance of abnormally strong muscle contractions,including S-shaped movements and jumping behavior, possibly caused by bad coordination between the circular and longitudinal muscles. The chronic response included damage to the skin and muscle cells, which resulted in a high mortality rate. Oxygen consumption by A. gracilis was significantly decreased after exposure to UV-A or UV-B. Since the circulation in earthworms is mediated by muscle contraction and the skin is the main organ of respiration, it is reasonable to expect that abnormal muscle contraction and a damaged epithelium could cause suffocation. Because of their sensitive responses, we propose that some earthworms, such as A. gracilis,could serve as a new model for studying UV-induced photodamage.
Voice rehabilitation following blunt trauma to the larynx
Authors: Ogura Joseph H.
Published: October 2006

Two case reports illustrate different ways for restoration of quality of the voice. In both instances the vocal cords were displaced by trauma and restored by surgical correction.
Electrophysiological responses from the cochlea and inferior colliculus in guinea pigs after head injury
Authors: Makishima Kazumi , Snow James B.
Published: October 2006

Electrical responses from the inferior colliculus (ER) and round window (CP) to acoustical stimuli were compared in control and experimental guinea pigs which had received a single blow to the freely movable head. After the blow to the head, all of the animals showed signs of commotio cerebri, and some of them died. The experimental animals were divided into two groups so that the physiologic responses to sound could be evaluated one day (early group) and seven days (intermediate group) following the head blow. The animals of the early group had elevated ER thresholds over the entire frequency range tested with an average threshold of 37.8 db. The animals of the intermediate group also had elevated ER thresholds which averaged 23.9 db. Input‐output intensity function of ER for the experimental animals showed a recruitment‐like phenomenon. The CP thresholds in the injured animals did not differ significantly from those in the control group. Damage to the VIIIth nerve and higher central pathways is very likely a more frequent cause of the otoneurologic manifestations following head injury than end organ damage.
Preoperative laminagraphic evaluation of the sphenoid sinus for transsphenoidal surgery
Authors: Rothman S. L. G. , Kier E. L. , Kirchner J. A. , Allen W. E.
Published: October 2006

In recent years the transethmoidal and transnasal approaches to the pituitary gland have become increasingly popular. In each case, detailed preoperative analysis of the anatomy of the sphenoid sinus and its boundaries is crucial in facilitating entry to the pituitary fossa and in reducing intraoperative complications.

Certain operative difficulties and complications are the result of the marked variability in the anatomy of the sphenoid bone and its sinus. These include: loss of orientation within a capacious sinus; perforation of the carotid artery or cavernous sinus; injury to the optic nerve or ophthalmic artery; and violation of the subarachnoid space with resultant pneumocephalus or cerebrospinal fluid rhinorrhea.

Pneumatization develops originally within the presphenoid, beginning anteriorly and proceeding posteriorly. Around the time of puberty the pneumatization usually penetrates up to the spheno‐occipital synchondrosis. Dense bony septa remain within the sinus along the plane of fusion of the various sphenoidal segments.

Preoperative laminagraphy of these ridges and septa is extremely helpful in planning the safest and most direct route to the sella. Laminagraphy is preferable to routine skull films because the septal detail is unobscured by the overlying facial structures. Pleuridirectional laminagraphic motion (circular or hypocycloidal) is preferred to linear motion because of the clarity and detail that they provide.
Meningoencephalocele of the paranasal sinuses
Authors: Kane Arden M. , Loré John
Published: October 2006

Meningoencephaloceles are not commonly seen by the otolaryngologist. They occur most frequently in the lumbosacral area where they are five times as common as in the occipital area. The anterior cranial presentation is quite rare.

Most patients with meningoencephaloceles present early with large lesions and are treated by the neurosurgeon. Two patients are presented who had small meningoencephaloceles which were located in the paranasal sinuses and successfully treated by an extracranial approach. This approach is recommended for those lesions of the paranasal sinus where the resulting bony defect from the removal of the lesion is small and the sinus is not infected.
The negative acoustic reflex in retrocochlear disorders
Authors: Mangham Charles A. , Lindeman Roger C.
Published: October 2006

The most frequent impedance abnormality of an acoustic tumor is an absent reflex. However, this finding also occurs with middle ear disorders and is therefore nonspecific.

This study recorded the contralateral acoustic reflex of human subjects suspected of having an acoustic tumor. Many tumor subjects, by visual inspection of the impedance bridge balance meter, appeared to have an absent reflex. Most of these subjects, in fact, had small amplitude negative reflexes by offline analysis on an averaging computer. Recognition of these negative reflexes increases the specificity and sensitivity of the reflex test for acoustic tumors. We recommend reflex testing with averaging computer monitoring to ensure their recognition.