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PubMed2007

Design and optimization of molecular nanovalves based on redox-switchable bistable rotaxanes.

Redox-controllable molecular nanovalves based on mesoporous silica nanoparticles have been fabricated, using two bistable [2]rotaxanes with different spacer lengths between their recognition sites as the gatekeepers. Three different linkers with varying chain lengths have been employed to attach the bistable [2]rotaxane molecules covalently to the silica substrate. These nanovalves can be classified as having IN or OUT locations, based on the positions of the tethered bistable [2]rotaxanes with respect to the entrances to the nanopores. The nanovalves are more efficient when the bistable [2]rotaxane-based gatekeepers are anchored deep within (IN) the pores than when they are attached closer to (OUT) the pores' orifices. The silica nanopores can be closed and opened by moving the mechanically interlocked ring component of the bistable [2]rotaxane closer to and away from the pores' orifices, respectively, a process which allows luminescent probe molecules, such as coumarins, tris(2-phenylpyridine)iridium, and rhodamine B, to be loaded into or released from the mesoporous silica substrate on demand. The lengths of the linkers between the surface and the rotaxane molecules also play a critical role in determining the effectiveness of the nanovalves. The shorter the linkers, the less leaky are the nanovalves. However, the distance between the recognition units on the rod section of the rotaxane molecules does not have any significant influence on the nanovalves' leakiness. The controlled release of the probe molecules was investigated by measuring their luminescence intensities in response to ascorbic acid, which induces the ring's movement away from the pores' orifices, and consequently opens the nanovalves.

Journal Article↗
PubMed2003

Dentate granule cell GABA(A) receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology.

The dentate gyrus (DG) normally functions as a filter, preventing propagation of synchronized activity into the seizure-prone hippocampus. This filter or 'gatekeeper' attribute of the DG is compromised in various pathological states, including temporal lobe epilepsy (TLE). This study examines the role that altered inhibition may play in the deterioration of this crucial DG function. Using the pilocarpine animal model of TLE, we demonstrate that inhibitory synaptic function is altered in principal cells of the DG. Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in dentate granule cells (DGCs) from epileptic animals were larger, more sensitive to blockade by zinc and less sensitive to augmentation by the benzodiazepine type site 1 modulator zolpidem. Furthermore, mIPSCs examined during a quiescent period following injury but preceding onset of epilepsy were significantly smaller than those present either in control or in TLE DGCs, and had already acquired sensitivity to blockade by zinc prior to the onset of spontaneous seizures. Rapid agonist application experiments demonstrated that prolonged (>35 ms) exposure to zinc is required to block GABAA receptors (GABAARs) in patches pulled from epileptic DGCs. Therefore, zinc must be tonically present to block DGC GABAARs and alter DG function. This would occur only during repetitive activation of mossy fibres. Thus, in the pilocarpine animal model of TLE, an early, de novo, expression of zinc-sensitive GABAARs is coupled with delayed, epilepsy-induced development of a zinc delivery system provided by aberrant sprouting of zinc-containing mossy fibre recurrent collaterals. The temporal and spatial juxtaposition of these pathophysiological alterations may compromise normal 'gatekeeper' function of the DG through dynamic zinc-induced failure of inhibition, predisposing the hippocampal circuit to generate seizures.

Animals↗
PubMed1996

Neuropsychiatry at the Courtroom Gates: Selective Entry or Anything Goes?

That the influx of technology into our lives will include its entry into law and legal proceedings is a foregone conclusion. "Progress" of this kind can be slowed or regulated, perhaps, but it cannot be stopped. The proposed use of positron emission tomography (PET) scan-derived data on brain functioning in a criminal insanity case is merely one of the latest efforts to put biotechnology to forensic use. How the court reacts to this particular admissibility proposition-in or out?-may serve as a useful example of how the larger battle is fought. Trial judges are the gatekeepers in our legal system. They make the initial decision as to whether a piece of controversial evidence, scientific or otherwise, may go to the jury. Trial judges are under pressure to admit innovative factual evidence or theory from several sources, among which trial attorneys, the purveyors and practitioners of the new techniques, and the law itself (as personified by the "progressive" rulings of appellate judges or legislators) are the more obvious. The 1975 Federal Rules of Evidence exemplify the success of this sort of pressure. Pertaining to the admissibility of evidence generally and of scientific evidence in particular, the Federal Rules are clearly more liberal in intent and effect than was the doctrine that preceeded them: the 1923 Frye rule, which required "general acceptance" of the proffered new technology or theory. In the recent case of Daubert v. Merrell Dow Pharmaceuticals, however, the U.S. Supreme Court has let it be known that standards of reliability continue to be in force for scientific evidence submitted under the Federal Rules and that gatekeeping remains an important function of the trial judge. Nonetheless, a "sleeper" rule permitting experts to support the opinions they offer in court with reasonable clarifying information opens the evidentiary door a bit wider than the restrictions of Daubert might suggest. In the case at hand, this rule led to a preliminary decision that PET scan data concerning the defendant could come in, despite the lack of a scientifically established connection between such data and the criminal behavior at issue. This particular result is probably a bad one. Does that mean PET scan evidence in the courts is an example of general forensic misuse of neurotechnology? Are the new admissibility rules hopelessly out of whack? There is no need for such broadsides. The better conclusion is that neuropsychiatrists should continue to work together with lawyers and lawmakers to ensure, as much as possible, the appropriate application of this technology to legal proceedings.

Journal Article↗
PubMed2000

[Social change in the physician's role and medical practice caused by managed care in Switzerland].

Switzerland is the first European country where health maintenance organizations (HMOs) characterised by capitation (per capita lumpsum) and gatekeeping were implemented according to the HMO staff model known in the USA. The development of managed health care in Switzerland relies on the belief that adequate economic incentives and competition result in cost reduction and high quality health care. Whether this is true or not--in any case the deregulation of legally accepted forms of health insurance and managed care result in profound changes in the Swiss health care system. Observations are made by using expert interviews and analysis of documents. The implementation of managed care induces socio-cultural changes of the medical profession which are as profound as the induced economic changes. We discuss conflicts of interests among physicians using four main dimensions of conflict: (1) control, (2) monopolization, (3) valuation, and (4) specialization. In the HMOs we observe pronounced conflicts of the physicians' role. The changes of the physicians' role in HMOs is on the one hand the result of new duties. On the other hand it expresses strategies of coping with the role conflict between the main clinical duties and the new obligation to control cost and to monitor treatment via gatekeeping. In HMOs the teamwork of doctors and the quality control of care promotes the satisfaction of physicians with their work, however, it can also have dysfunctional effects.

Cost Control↗
PubMed2006

Suppression of gross chromosomal rearrangements by yKu70-yKu80 heterodimer through DNA damage checkpoints.

The inactivation of either subunit of the Ku70-Ku80 heterodimer, which functions in nonhomologous end-joining and telomere maintenance, generates severe defects such as sensitivity to DNA damage, telomere shortening, and increased gross chromosomal rearrangements (GCRs) that are frequently observed in many cancers. To understand the mechanism of Ku as a genome gatekeeper, we overexpressed the yKu70-yKu80 heterodimer and monitored the formation of GCRs. Ku overexpression suppressed the formation of either spontaneously generated GCRs or those induced by treatments with different DNA damaging agents. Interestingly, this suppression depended on Ku's interaction with DNA damage checkpoints and not through nonhomologous end-joining. We also demonstrate that the inactivation of telomerase inhibitor, Pif1 along with Ku overexpression or the overexpression of Pif1 in either yku70 or yku80 strains arrested the cell cycle at S phase in a DNA damage checkpoint-dependent fashion. Lastly, Ku overexpression causes cell growth delay, which depends on intact Rad27. In summary, the results presented here suggest that Ku functions as a genomic gatekeeper through its crosstalk with DNA damage checkpoints.

Antigens, Nuclear↗
PubMed2002

GAAP-1: a transcriptional activator of p53 and IRF-1 possesses pro-apoptotic activity.

The mechanisms that regulate the transcription of the tumour suppressor genes p53 and IRF-1 are poorly understood. We have characterized a 68-kDa transcription factor, GAAP-1 (gatekeeper of apoptosis activating proteins), encoded by an alternative splice product of the PRDII-BF1 gene, that recognizes a novel regulatory element within the p53 and IRF-1 promoters. Transfection of U937 cells with GAAP-1 activates p53 and IRF-1 expression and leads to apoptosis, whereas over-expression of GAAP-1 in K562 cells that lack p53 and IRF-1 induces cell differentiation. Alterations in the 6p24 locus containing the GAAP-1 gene are frequent in acute myelogenous leukemia (AML), and AML-derived cell lines display reduced GAAP-1 mRNA levels. Together, these results suggest that GAAP-1 acts as a gatekeeper at a critical point in the tumour suppressor gene pathway.

Apoptosis↗
PubMed2001

Referral of patients with a family history of breast/ovarian cancer--GPs' knowledge and expectations.

BACKGROUND: Primary care is expected to play a significant role in the management of patients with genetic problems. Currently, this particularly involves patients with a family history of cancer. If GPs are to exercise their gatekeeper role efficiently in this area, they must be able to evaluate genetic risk and make appropriate referral decisions. OBJECTIVES: The aim of this study was to examine GPs' ability to assess risk and to make appropriate referral decisions for women with a family history of breast/ovarian cancer, and to determine their expectations of a referral to secondary care. METHOD: A questionnaire survey was carried out of the 282 GP principals working within Bedfordshire Health Authority. GPs were asked to make decisions for six simulated cases of women presenting with a family history of breast or ovarian cancer. RESULTS: A total of 164 (58%) GPs returned completed questionnaires. Across the six family histories, the percentage of GPs making an appropriate risk assessment ranged from 21% [95% confidence interval (CI) 14-27%] to 63% (95% CI 56-71%), and an appropriate referral decision ranged from 40% (95% CI 32-48%) to 80% (95% CI 73-86%). Regardless of their accuracy of risk assessment, most GPs were consistent in deciding not to refer low risk women and to refer moderate and high risk women (range 71-85% of GPs for the six family histories). Only 43 (26%, 95% CI 20-33%) of GPs knew the three most important criteria for risk assessment. CONCLUSIONS: GPs require more help and education to enable them to perform their gatekeeper role satisfactorily when assessing patients with a family history of breast/ovarian cancer.

Adult↗
PubMed1982

Paths and gates: the sources of recidivism and length of stay on a psychiatric ward.

Four "pathway" (age, sex, social class, and number of dependents) and three "gatekeeper" (previous admission, previous ward terms, and severity of patient disorder) variables are used to predict recidivism rates and lengths of stay for patients admitted to a psychiatric ward in a general hospital during a 1-year period. There were three major findings. First, the gatekeeper variables were, by themselves, useful for predicting length of stay; additional information, in the form of the pathway variables, was needed to adequately explain differences in recidivism. Second, while most of the effects on recidivism were direct, most of the effects on length of stay were indirect or mediated through the variable of the severity of patient problems. Third, it was discovered that recidivism and length of stay are inversely related: patients with high recidivism rates, for example, tend to have relatively short average lengths of stay. Based on four patterns of recidivism and length of stay, a typology was developed to facilitate a better understanding of patient behavior.

Adult↗
PubMedDate not supplied

Characteristics of African American women caregivers of children with asthma.

PURPOSE: To describe the attributes and characteristics of African American women who were the primary caregivers of children with asthma. METHODS: Descriptive qualitative ethnography. Data collection consisted of formal interviews, participant observation, and fieldnotes. Each study participant was formally and informally interviewed (audiotaped) during a 1-year period. The researchers also observed and participated in family activities in various naturalistic settings. RESULTS: Six themes emerged that depict the characteristics of these women: (1) Knowledge about the child's asthma; (2) Gatekeepers to the child's care; (3) Being religious; (4) Support; (5) Roles as teacher, counselor, and advisor to the child; and (6) Self-sufficiency and industriousness. CLINICAL IMPLICATIONS: Nurses should use the information in this study to examine the ways in which they interact with caregivers of asthmatic children. The caregivers personal beliefs, need for information, and previous experiences with asthma and family illness should be assessed. These mothers and grandmothers should be respected as the gatekeeper to the family's healthcare. Nurses should be nonjudgmental and supportive of caregivers when they express their religious beliefs and practices. Nurses who understand how mothers cope can reinforce these coping skills and provide better nursing care.

Adaptation, Psychological↗
PubMed2006

Recruiting and retaining Arab Muslim mothers and children for research.

PURPOSE: To describe successful and not-so-successful strategies for recruiting and retaining Arab Muslim immigrant women and their adolescent children for research. DESIGN AND METHODS: A longitudinal study of mother-child adjustment of Arab immigrants to the US is used for illustration. A panel of experts was assembled and provided culturally specific advice about gatekeepers, advertising, data collectors, data collection, and how to track and encourage participation at subsequent time points in the study. FINDINGS: Most of the strategies recommended by the panel were overwhelmingly positive, including advice about data collectors, how to collect data, financial incentives, avoiding offending families, and personal contacts. Hiring data collectors who were able to establish personal and culturally appropriate relationships with study participants was the single most successful recruitment and retention strategy. Advice from cultural experts about which gatekeepers to engage and how to advertise for study participants was not productive. CONCLUSIONS: Researchers should not only assemble a panel of cultural experts to provide advice about group specific strategies to build trust and maintain cultural sensitivity, but also to budget generously for time for data collectors to build and maintain rapport with study populations who, like Arab immigrant women, highly value personal relationships.

Adaptation, Psychological↗
PubMed2001

Structure-based mutational analysis of the hepatitis C virus NS3 helicase.

The carboxyl terminus of the hepatitis C virus (HCV) nonstructural protein 3 (NS3) possesses ATP-dependent RNA helicase activity. Based on the conserved sequence motifs and the crystal structures of the helicase domain, 17 mutants of the HCV NS3 helicase were generated. The ATP hydrolysis, RNA binding, and RNA unwinding activities of the mutant proteins were examined in vitro to determine the functional role of the mutated residues. The data revealed that Lys-210 in the Walker A motif and Asp-290, Glu-291, and His-293 in the Walker B motif were crucial to ATPase activity and that Thr-322 and Thr-324 in motif III and Arg-461 in motif VI significantly influenced ATPase activity. When the pairing between His-293 and Gln-460, referred to as gatekeepers, was replaced with the Asp-293/His-460 pair, which makes the NS3 helicase more like the DEAD helicase subgroup, ATPase activity was not restored. It thus indicated that the whole microenvironment surrounding the gatekeepers, rather than the residues per se, was important to the enzymatic activities. Arg-461 and Trp-501 are important residues for RNA binding, while Val-432 may only play a coadjutant role. The data demonstrated that RNA helicase activity was possibly abolished by the loss of ATPase activity or by reduced RNA binding activity. Nevertheless, a low threshold level of ATPase activity was found sufficient for helicase activity. Results in this study provide a valuable reference for efforts under way to develop anti-HCV therapeutic drugs targeting NS3.

Adenosine Triphosphatases↗
PubMed2000

Role of chromosome 3p12-p21 tumour suppressor genes in clear cell renal cell carcinoma: analysis of VHL dependent and VHL independent pathways of tumorigenesis.

AIMS: Chromosome 3p deletions and loss of heterozygosity (LOH) for 3p markers are features of clear cell renal cell carcinoma but are rare in non-clear cell renal cell carcinoma. The VHL tumour suppressor gene, which maps to 3p25, is a major gatekeeper gene for clear cell renal cell carcinoma and is inactivated in most sporadic cases of this disease. However, it has been suggested that inactivation of other 3p tumour suppressor genes might be crucial for clear cell renal cell carcinoma tumorigenesis, with inactivation (VHL negative) and without inactivation (VHL positive) of the VHL tumour suppressor gene. This study set out to investigate the role of non-VHL tumour suppressor genes in VHL negative and VHL positive clear cell renal cell carcinoma. METHODS: Eighty two clear cell renal cell carcinomas of known VHL inactivation status were analysed for LOH at polymorphic loci within the candidate crucial regions for chromosome 3p tumour suppressor genes (3p25, LCTSGR1 at 3p21.3, LCTSGR2 at 3p12 and at 3p14.2). RESULTS: Chromosome 3p12-p21 LOH was frequent both in VHL negative and VHL positive clear cell renal cell carcinoma. However, although the frequency of 3p25 LOH in VHL negative clear cell renal cell carcinoma was similar to that at 3p12-p21, VHL positive tumours demonstrated significantly less LOH at 3p25 than at 3p12-p21. Although there was evidence of LOH for clear cell renal cell carcinoma tumour suppressor genes at 3p21, 3p14.2, and 3p12, both in VHL negative and VHL positive tumours, the major clear cell renal cell carcinoma LOH region mapped to 3p21.3, close to the lung cancer tumour suppressor gene region 1 (LCTSGR1). There was no association between tumour VHL status and tumour grade and stage. CONCLUSIONS: These findings further indicate that VHL inactivation is not sufficient to initiate clear cell renal cell carcinoma and that loss of a gatekeeper 3p21 tumour suppressor gene is a crucial event for renal cell carcinoma development in both VHL negative and VHL positive clear cell renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed2006

Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680.

We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.

Aurora Kinases↗
PubMed2003

Accessing the community: gaining insider perspectives from the outside.

Accessing participants for research projects is often treated as unproblematic. However the experience outlined here of negotiating access to participants within a community setting illustrates the inherent difficulties of recruitment. The authors describe the techniques used and practical challenges faced when accessing participants within a socially deprived community for a qualitative research project on social capital. They used a number of different strategies to generate a diverse sample including advertising, snowballing, accessing gatekeepers, and street surveys. The value of a stakeholder analysis is described alongside issues surrounding the use of gatekeepers. Rather than acting as outsiders seeking participants at every available opportunity, a more fortuitous strategy involved the ethnographic approach of "being there" as active contributors to community life. Here, the cornerstones of credibility and trust were addressed in a process of continually negotiating access from a semi-insider position.

Adult↗
PubMed1990

A profile of alcohol and prescription drug abuse in a high-risk community-based elderly population.

Substance abuse among the elderly is relatively common but often remains undetected or ignored by health and social workers. Psychosocial and health factors related to the aging process are the major contributors to alcoholism and other drug abuse. It is estimated that between two and ten percent of individuals over the age of 60 suffer from alcoholism. This article profiles alcohol and prescription drug abuse among the geriatric clientele of Elderly Services of Spokane (ESS), a division of the Spokane (Washington) Community Mental Health Center. In addition to traditional channels, ESS uses a unique gatekeeper network to identify high-risk, community-based elderly. Elderly persons referred by gatekeepers are regarded as "hidden" elderly and at highest risk; notably, 37 percent of ESS clients are referred via this mechanism. Case management records of 1668 ESS clients were reviewed for a history of alcoholism, and a total of 161 persons (9.6 percent) were diagnosed with either primary or secondary alcohol abuse. Fifty subjects (about five percent of the average active ESS caseload) were referred for prescription drug abuse. Misused prescription drug classes were sedative-hypnotics, antianxiety agents, and analgesics. Diazepam, codeine, meprobamate, and flurazepam were the top four agents, and 92 percent of the subjects were found to have a duration of prescription drug abuse in excess of five years. A 60 percent correlation between prescription drug abuse and previous or active alcoholism was found. Additional characteristics of the geriatric study population are discussed in detail, including specific psychosocial factors, source of referral, age, gender, living situation, marital status, psychiatric history, and presence of polypharmacy.

Aged↗
PubMed2005

A qualitative study of the impact of the implementation of advanced access in primary healthcare on the working lives of general practice staff.

BACKGROUND: The North American model of 'advanced access' has been emulated by the National Primary Care Collaborative in the UK as a way of improving patients' access in primary care. The aim of this study was to explore the impact of the implementation of advanced access on the working lives of general practice staff. METHODS: A qualitative study design, using semi-structured interviews, was conducted with 18 general practice staff: 6 GPs, 6 practice managers and 6 receptionists. Two neighbouring boroughs in southeast England were used as the study sites. NUD*IST computer software assisted in data management to identify concepts, categories and themes of the data. A framework approach was used to analyse the data. RESULTS: Whilst practice managers and receptionists saw advanced access as having a positive effect on their working lives, the responses of general practitioners (GPs) were more ambivalent. Receptionists reported improvements in their working lives with a change in their role from gatekeepers for appointments to providing access to appointments, fewer confrontations with patients, and greater job satisfaction. Practice managers perceived reductions in work stress from fewer patient complaints, better use of time, and greater flexibility for contingency planning. GPs recognised benefits in terms of improved consultations, but had concerns about the impact on workload and continuity of care. CONCLUSION: AA has improved working conditions for receptionists, converting their perceived role from gatekeeper to access facilitator, and for practice managers as patients were more satisfied. GP responses were more ambivalent, as they experienced both positive and negative effects.

Administrative Personnel↗
PubMed2006

Dynamic wait-listed designs for randomized trials: new designs for prevention of youth suicide.

BACKGROUND: The traditional wait-listed design, where half are randomly assigned to receive the intervention early and half are randomly assigned to receive it later, is often acceptable to communities who would not be comfortable with a no-treatment group. As such this traditional wait-listed design provides an excellent opportunity to evaluate short-term impact of an intervention. We introduce a new class of wait-listed designs for conducting randomized experiments where all subjects receive the intervention, and the timing of the intervention is randomly assigned. We use the term "dynamic wait-listed designs" to describe this new class. PURPOSE: This paper examines a new class of statistical designs where random assignment to intervention condition occurs at multiple times in a trial. As an extension of a traditional wait-listed design, this dynamic design allows all subjects to receive the intervention at a random time. Motivated by our search for increased statistical power in an ongoing school-based trial that is testing a program of gatekeeper training to identify suicidal youth and refer them to treatment, this new design class is especially useful when the primary outcome is a count or rate of occurrence, such as suicidal behavior, whose rate can fluctuate over time due to uncontrolled factors. METHODS: Statistical power is computed for various dynamic wait-listed designs under conditions where the underlying rate of occurrence is allowed to vary nonsystematically. We also present as an example a large ongoing trial to evaluate a gatekeeper training suicide prevention program in 32 schools which we initially began as a classic randomized wait-listed design. The primary outcome of interest in this study is the count of the number of children who are identified by the school system as having suicidal thoughts or behaviors who are then validated as being suicidal by mental health professionals in the community. RESULTS: A general result shows that dynamic wait-listed designs always have higher statistical power over a traditional wait-listed design. This power increase can be substantial. Efficiency gains of 33% are easy to obtain for situations where the intervention has a small effect and the variation in rate across time is quite high. When the rate variation for an outcome is very low or the intervention effect is large, efficiency gains approach 100%. A small increase in the number of times where random assignment occurs from 2 - for the standard wait-listed design, to say 4 can provide a large reduction in variance. Efficiency gains can also be high when converting standard wait-listed design to a dynamic one half-way into the study. LIMITATIONS: As with all wait-listed designs, dynamic wait-listed designs can only be used to evaluate short-term impact. Since all subjects eventually receive the intervention, no comparison can be made after the end of the random assignment period. The statistical power benefits are primarily limited to outcomes that can be treated as count or time to event data. CONCLUSIONS: A dynamic design randomly assigns units - either individuals or groups - to start the intervention at varying times during the course of the study. This design is useful in testing interventions that screen for new or existing cases, as well as testing the scalability of interventions as they are disseminated or expanded system wide. They can improve on the traditional wait-listed design both in terms of statistical power and robustness in the presence of exogenous factors. This paper demonstrates that such designs yield smaller standard errors and can achieve higher statistical power than that of a standard wait-listed design. Just as important, dynamic designs can also help reduce the logistical challenges of implementing an intervention on a wide scale. When the intervention requires that significant training resources be allocated throughout the study, the dynamic wait-listed design is likely to increase the rate of training and lead to a higher level of program implementation.

Adolescent↗
PubMed2004

Functional efficiency of the senescent cells: replace or restore?

It is generally accepted that aging is a phenomenon of irreversibility, inevitability, and universality with parenchymal loss and functional decline. Consequently, the major goals of aging research are focused on the development of a replace strategy of the aged organs or cells, based on immortalizing tools, stem cells, or artificial substitutes. Recently, however, a new concept of functional recovery has been introduced on the basis of the functional restoration of the responsiveness of the senescent cells toward a variety of agonists, including growth factors. The aging phenotypes of hyporesponsiveness and morphological alteration are shown to be readily adjusted by modulation of the several membrane-associated molecules, named gatekeeper molecules, among which caveolin is one of the major determinants. Caveolin is the essential component of the caveolae, responsible for regulation of signal transduction, endocytosis and trancytosis, and cytoskeletal arrangement via its scaffolding domain. The caveolin status is associated strictly with cellular transformation, if depleted, and with senescent phenotype, if overexpressed. Therefore, simple reduction of caveolin status in senescent cells leads to restoration of the functional responsiveness to mitogenic stimuli and even of the cellular shape. These data strongly suggest that the gatekeeper molecules, represented by caveolin, may play the prime role in determination of the senescent phenotypes. From these results, it can be summarized that the replace principle would not necessarily be the essential one, but the restore principle can be somehow substituted for the betterment of the aged cells and organisms.

Aging↗