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1.  Effect of public deliberation on attitudes toward surrogate consent for dementia research 
Neurology  2011;77(24):2097-2104.
Objective:
To assess the informed, deliberative views of the older general public toward a policy of allowing surrogate consent for Alzheimer disease (AD) research.
Methods:
A total of 503 persons aged 50+ recruited by random digit dialing were randomly assigned to 1 of 3 groups: deliberation, education, or control. The deliberation group attended an all-day education/peer deliberation session; the education group received written information only. Participants were surveyed at baseline, after deliberation session (or equivalent time), and 1 month after the session, regarding their attitudes toward a policy of allowing surrogate consent for research studies of varying risks and potential benefits (a lumbar puncture study, a drug randomized controlled trial, a vaccine randomized controlled trial, and an early phase gene transfer trial).
Results:
At baseline, a policy of surrogate consent for AD research was supported by 55%–91%, depending on the scenario. The education group had a transient increase in support for one research scenario after receiving the information materials. In the deliberation group, support for surrogate consent was higher after deliberation for all scenarios (67% to 97%), with much of the increase sustained 1 month after the deliberation session. No changes occurred in the control group. The study's limitations include self-selection of participants due to the demanding nature of attendance at the deliberation sessions.
Conclusions:
This sample of the older general public generally supported a policy of surrogate consent for AD research at baseline. Their support increased with democratic deliberation involving informed, in-depth exploration of the relevant scientific and ethical issues.
doi:10.1212/WNL.0b013e31823648cb
PMCID: PMC3235352  PMID: 21975207
2.  Surrogate consent for dementia research 
Neurology  2009;72(2):149-155.
Background
Research in novel therapies for Alzheimer disease (AD) relies on persons with AD as research subjects. Because AD impairs decisional capacity, informed consent often must come from surrogates, usually close family members. But policies for surrogate consent for research remain unsettled after decades of debate.
Methods
We designed a survey module for a random subsample (n = 1,515) of the 2006 wave of the Health and Retirement Study, a biennial survey of a nationally representative sample of Americans aged 51 and older. The participants answered questions regarding one of four randomly assigned surrogate-based research (SBR) scenarios: lumbar puncture study, drug randomized control study, vaccine study, and gene transfer study. Each participant answered three questions: whether our society should allow family surrogate consent, whether one would want to participate in the research, and whether one would allow one’s surrogate some or complete leeway to override stated personal preferences.
Results
Most respondents stated that our society should allow family surrogate consent for SBR (67.5% to 82.5%, depending on the scenario) and would themselves want to participate in SBR (57.4% to 79.7%). Most would also grant some or complete leeway to their surrogates (54.8% to 66.8%), but this was true mainly of those willing to participate. There was a trend toward lower willingness to participate in SBR among those from ethnic or racial minority groups.
Conclusions
Family surrogate consent–based dementia research is broadly supported by older Americans. Willingness to allow leeway to future surrogates needs to be studied further for its ethical significance for surrogate-based research policy.
doi:10.1212/01.wnl.0000339039.18931.a2
PMCID: PMC2663398  PMID: 19139366
3.  Surrogate consent for dementia research 
Neurology  2009;72(2):149-155.
Background:
Research in novel therapies for Alzheimer disease (AD) relies on persons with AD as research subjects. Because AD impairs decisional capacity, informed consent often must come from surrogates, usually close family members. But policies for surrogate consent for research remain unsettled after decades of debate.
Methods:
We designed a survey module for a random subsample (n = 1,515) of the 2006 wave of the Health and Retirement Study, a biennial survey of a nationally representative sample of Americans aged 51 and older. The participants answered questions regarding one of four randomly assigned surrogate-based research (SBR) scenarios: lumbar puncture study, drug randomized control study, vaccine study, and gene transfer study. Each participant answered three questions: whether our society should allow family surrogate consent, whether one would want to participate in the research, and whether one would allow one’s surrogate some or complete leeway to override stated personal preferences.
Results:
Most respondents stated that our society should allow family surrogate consent for SBR (67.5% to 82.5%, depending on the scenario) and would themselves want to participate in SBR (57.4% to 79.7%). Most would also grant some or complete leeway to their surrogates (54.8% to 66.8%), but this was true mainly of those willing to participate. There was a trend toward lower willingness to participate in SBR among those from ethnic or racial minority groups.
Conclusions:
Family surrogate consent–based dementia research is broadly supported by older Americans. Willingness to allow leeway to future surrogates needs to be studied further for its ethical significance for surrogate-based research policy.
GLOSSARY
= Alzheimer disease;
= confidence interval;
= Health and Retirement Study;
= legally authorized representatives;
= lumbar puncture;
= odds ratio;
= randomized controlled trial;
= surrogate-based research.
doi:10.1212/01.wnl.0000339039.18931.a2
PMCID: PMC2663398  PMID: 19139366
4.  Histamine and TNF-α release by rat peritoneal mast cells stimulated with Trichomonas vaginalis  
Mast cells have been reported to be predominant in the vaginal smears of patients infected with T. vaginalis. In this study, we investigated whether T. vaginalis could induce mast cells to migrate and to produce TNF-α and histamine. Rat peritoneal mast cells (RPMC), a primary mast cell, were used for the study. T. vaginalis induced an increase in chemotactic migration of the mast cells toward excretory and secretory product (ESP) of T. vaginalis, and the mast cells activated with T. vaginalis showed an increased release of histamine and TNF-α. Therefore, mast cells may be involved in the inflammatory response caused by T. vaginalis.
doi:10.1051/parasite/2011181049
PMCID: PMC3671398  PMID: 21395205
Trichomonas vaginalis; rat; mast cell; migration; histamine; TNF-α; Trichomonas vaginalis; rat; mastocyte; migration; histamine; TNF-α
6.  Adiponectin Haploinsufficiency Promotes Mammary Tumor Development in MMTV-PyVT Mice by Modulation of Phosphatase and Tensin Homolog Activities 
PLoS ONE  2009;4(3):e4968.
Background
Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.
Methodology/Principal Findings
In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K)/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN) activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1) and thioredoxin reductase (TrxR1) were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.
Conclusion
Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/Akt signalling pathway through a mechanism involving Trx1/TrxR1 redox regulations.
doi:10.1371/journal.pone.0004968
PMCID: PMC2656613  PMID: 19319191
7.  Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers 
Neurology  2012;78(1):55-61.
Objective:
The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.
Methods:
CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.
Results:
Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.
Conclusions:
The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.
doi:10.1212/WNL.0b013e31823ed101
PMCID: PMC3466497  PMID: 22170881
8.  The mechanism of biomineralization of bone-like apatite on synthetic hydroxyapatite: an in vitro assessment. 
The mechanism of biomineralization of bone-like apatite on synthetic hydroxyapatite (HA) has been investigated in vitro, in which the HA surface was surveyed as a function of soaking time in simulated body fluid (SBF). In terms of surface structure by transmission electron microscopy with energy-dispersive X-ray spectrometry, the HA whose Ca/P atomic ratio was 1.67 revealed three different characteristic soaking periods in SBF, i.e. the first soaking period, in which the HA surface increased the Ca/P ratio up to 1.83 to form an amorphous phase of Ca-rich calcium phosphate; the second soaking period, in which the HA surface decreased the Ca/P ratio up to 1.47 to form an amorphous phase of Ca-poor calcium phosphate; and the third soaking period, in which the HA surface gradually increased the Ca/P ratio up to 1.65 to eventually produce the bone-like nano-cerystallites of apatite, which grew forming complex crystal assemblies with a further increase in immersion time. Analysis using electrophoresis spectroscopy indicated that, immediately after immersion in SBF, the HA revealed a highly negative surface potential, which increased to reach a maximum positive value in the first soaking period. The surface potential then decreased to again reach a negative value in the second soaking period and thereafter converge to a constant negative value in the third soaking period. This implies that the HA induces biomineralization of apatite by smartly varying its surface potential to trigger an electrostatic interaction, first with positive calcium ions and second with negative phosphate ions in the SBF.
doi:10.1098/rsif.2004.0003
PMCID: PMC1618931  PMID: 16849149
9.  Role of Hck in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice 
Journal of Virology  2001;75(4):1949-1957.
Soluble mediators such as interleukin-1β, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic β cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of β cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lyn in macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hck showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgr and p56/p53Lyn did not. The p59/p56Hck activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56Hck activity and almost complete inhibition of the production of TNF-α and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-α and nitric oxide, leading to the destruction of pancreatic β cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.
doi:10.1128/JVI.75.4.1949-1957.2001
PMCID: PMC115141  PMID: 11160694
10.  A comparative study of the surgical procedures to treat advanced Kienböck's disease. 
Journal of Korean Medical Science  1996;11(2):171-178.
We have treated a total of 16 cases of advanced Kienböck's disease, stage III and IV by Lichtman's classification, with triscaphe fusion, tendon ball replacement arthroplasty after excision of lunate, proximal row carpectomy as a salvage procedure and limited wrist fusion, since 1985. All cases were followed for minimal 16 months after each operation. Tendon ball replacement arthroplasty after excision of lunate could not prevent further carpal collapse with persistent chronic wrist pain. The triscaphe fusion or radio-lunate fusion induced a marked limited wrist motion later, and the triscaphe fusion alone was not fit for the treatment of advanced one because of progressive proximal migration of capitate and continuous wrist pain due to ligamentous carpal instability in follow-up. So we tried to simultaneously combine tendon ball replacement arthroplasty after excision of lunate with triscaphe fusion in far advanced Kienböck's disease, and their end results was favorable. Proximal row carpectomy could be done in far advanced Kienböck's disease with reasonably painless wrist motions. The overall end results of proximal row carpectomy are much better than any form of carpal arthrodesis. Conclusively the proper way to treat advanced Kienböck's disease seems to depend on the patient's age, their job and sex, and the stage of disease. And the cause of wrist pain in advanced Kienböck's disease seems due to ligamentous carpal instability rather than osteoarthritis on radio-lunate joint.
PMCID: PMC3053935  PMID: 8835766

Results 1-10 (10)