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PubMed2005

Gene therapy progress and prospects: gene therapy for diabetes mellitus.

Diabetes mellitus has long been targeted, as yet unsuccessfully, as being curable with gene therapy. The main hurdles have not only been vector-related toxicity but also the lack of physiological regulation of the expressed insulin. Recent advances in understanding the developmental biology of beta-cells and the transcriptional cascade that drives it have enabled both in vivo and ex vivo gene therapy combined with cell therapy to be used in animal models of diabetes with success. The associated developments in the stem cell biology and immunology have opened up further opportunities for gene therapy to be applied to target autoimmune diabetes.

Animals↗
PubMed2003

Psychiatric rehabilitation: an empowerment-based approach to mental health services.

Psychiatric rehabilitation is a framework for providing services to people with mental illness that encourages adaptive community functioning in all life domains. Despite its well-established inclusion in community mental health treatment programs, psychiatric rehabilitation has received little attention in the discipline-specific social work literature. The philosophical base of psychiatric rehabilitation is built around the principles of empowerment, competence, and recovery. Its goal of promoting adaptive community functioning is consistent with social work values and contemporary social work practice models. This article provides an overview of the history, philosophy, and services components of psychiatric rehabilitation and analyzes its compatibility with social work. Further integration of psychiatric rehabilitation and social work services is suggested.

Community Health Planning↗
PubMed2004

Duration of end-stage renal disease and kidney transplant outcome.

BACKGROUND: Patients nearing end-stage renal disease (ESRD) increasingly choose pre-emptive renal transplant (PRT) to avoid pre-transplant dialysis and to minimize ESRD. Compared with long-term dialysis, PRT has been shown to increase allograft survival. However, the merit of short-term dialysis is not well characterized, and it may be the better medical choice in some patients. The goal of the study was to characterize the relationship between the duration of dialysis vs allograft and patient survival. METHODS: We performed a retrospective nationwide cohort study of all kidney transplants (Tx) between January 1, 1990 and December 31, 1999, with a follow-up period through December 31, 2000. Participants were identified using the United States Renal Data System (USRDS), which tracks all ESRD cases in the nation including patients on dialysis and with kidney Tx. Patients with the history of more than one kidney Tx were excluded. Allograft survival and recipient survival were the primary outcomes of this study. Duration of ESRD as a continuous variable as well as divided into categories (14 days, 15-60 days, 61-180 days, 181-365 days, 1-2 years, 2-3 years, 3-5 years and >5 years) was the primary risk factor of interest. Models were adjusted for multiple donor and recipient factors, including demographics and co-morbidities, as well as for Tx procedure characteristics. RESULTS: A total of 81,130 patient records were used for analysis (age 44.1+/-14.3 years, 61% males, 24% black, 29% diabetic, pre-transplant ESRD duration 27.1+/-26.4 months, 26% living donors). ESRD duration, as a continuous variable, is associated with a modest increase in the risk of graft failure over time [hazard ratio (HR) 1.02 per year of ESRD duration, P<0.001]. When ESRD is studied as a categorical variable (duration of 0-14 days vs longer durations), the increased risk of allograft failure reached statistical significance only when the time on dialysis was > or =181 days. The duration of ESRD was a significant risk for recipient death (HR 1.04 per year, P<0.001); however, mortality risk reached statistical significance only when the patient had been on dialysis for > or =1 year. CONCLUSIONS: This study of USRDS records suggests that a short (<6 months) dialysis course has no detrimental effect on graft and patient survival, and should not be deferred if medically indicated.

Adult↗
PubMed2006

Interfering antiviral immunity: application, subversion, hope?

RNA interference (RNAi), initially recognized as a natural antiviral mechanism in plants, has rapidly emerged as an invaluable tool to suppress gene expression in a sequence-specific manner in all organisms, including mammals. Its potential to inhibit the replication of a variety of viruses has been demonstrated in vitro and in vivo in mouse and monkey models. These results have generated profound interest in the use of this technology as a potential treatment strategy for viral infections for which vaccines and drugs are unavailable or inadequate. In this review, we discuss the progress made within the past 2-3 years towards harnessing the potential of RNAi for clinical application in viral infections and the hurdles that have yet to be overcome.

Animals↗
PubMed2004

Prospects for new TB vaccines: Stop TB Working Group on TB Vaccine Development.

Research towards the development of improved TB vaccines has reached an important turning point. A large number of vaccine candidates such as modified BCG, attenuated Mycobacterium tuberculosis and protein or DNA subunit vaccines, resulting from over a decade of work in experimental laboratory models, are now getting ready for clinical testing. The transition from laboratory to clinical trials has a wide range of strategic and technical implications. Facilities and funding need to be identified for the production of clinical vaccine lots, an issue that is difficult to tackle due to the live organisms in some of the new vaccine candidates; regulatory hurdles need to be overcome; protocols and trial sites need to be developed, for phase III clinical efficacy trials in particular. The Stop TB Working Group on TB Vaccine Development provides a global forum that brings laboratory and clinical researchers together with experts in tuberculosis control and representatives from commercial and non-profit funding agencies to address these issues and to facilitate progress towards the common goal of improved vaccination strategies for tuberculosis.

Animals↗
PubMed2004

Tackling the plant proteome: practical approaches, hurdles and experimental tools.

The study of complex biological questions through comparative proteomics is becoming increasingly attractive to plant biologists as the rapidly expanding plant genomic and expressed sequence tag databases provide improved opportunities for protein identification. This review focuses on practical issues associated with comparative proteomic analysis, including the challenges of effective protein extraction and separation from plant tissues, the pros and cons of two-dimensional gel-based analysis and the problems of identifying proteins from species that are not recognized models for functional genomic studies. Specific points are illustrated using data from an ongoing study of the tomato and pepper fruit proteomes.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2007

From the test tube to the cell: exploring the folding and aggregation of a beta-clam protein.

A crucial challenge in present biomedical research is the elucidation of how fundamental processes like protein folding and aggregation occur in the complex environment of the cell. Many new physico-chemical factors like crowding and confinement must be considered, and immense technical hurdles must be overcome in order to explore these processes in vivo. Understanding protein misfolding and aggregation diseases and developing therapeutic strategies to these diseases demand that we gain mechanistic insight into behaviors and misbehaviors of proteins as they fold in vivo. We have developed a fluorescence approach using FlAsH labeling to study the thermodynamics of folding of a model beta-rich protein, cellular retinoic acid binding protein (CRABP) in Escherichia coli cells. The labeling approach has also enabled us to follow aggregation of a modified version of CRABP and chimeras between CRABP and huntingtin exon 1 with its glutamine repeat tract. In this article, we review our recent results using FlAsH labeling to study in-vivo folding and present new observations that hint at fundamental differences between the thermodynamics and kinetics of protein folding in vivo and in vitro.

Animals↗
PubMed2004

Issues for countries considering introducing the "fourth hurdle": the case of Hungary.

OBJECTIVES: This study outlines the needs and current development of the "fourth hurdle" (i.e., requirement of effectiveness and cost-effectiveness data for drug coverage policy decisions) in Hungary, describes the legal background and seeks to address some of the most important questions in this field. METHODS: The study draws on international experiences and discusses five issues that a given jurisdiction needs to consider before introducing the "fourth hurdle" for pharmaceuticals. RESULTS: The "fourth hurdle" is very relevant in Hungary because many existing drugs are unevaluated and many new, expensive drugs are becoming available. On the other hand, the existing resources for health technology assessment, including economic evaluation, are quite limited. All the five issues are relevant in the Hungarian setting and were helpful in determining exactly how the "fourth hurdle" should be applied. CONCLUSIONS: The most important issue seems to be that the implementation of the "fourth hurdle" needs to be achieved in a way consistent with the limited resources for HTA in Hungary. Specifically this means that, in setting priorities for drugs to evaluate, additional criteria need to be applied. In particular, priority should be given to assessing drugs that have been evaluated in other countries, because this affords the opportunity to adapt existing studies or models to the Hungarian situation.

Cost-Benefit Analysis↗
PubMed2026

Post-Translational Modifications in Traumatic Brain Injury: Decoding the Proteomic Landscape and Molecular Mechanisms of Secondary Injury.

Traumatic brain injury (TBI) initiates a complex secondary injury cascade that significantly contributes to long-term neurological deficits, with post-translational modifications (PTMs) emerging as pivotal molecular regulators of this process. Unlike primary mechanical damage, secondary injury evolves over hours to years and involves intricate proteomic alterations that changes in gene expression alone cannot fully explain. PTMs-including phosphorylation, ubiquitination, acetylation, SUMOylation, glycosylation, and emerging modifications such as succinylation, lactylation, and nitrosylation-serve as dynamic molecular switches that fine-tune protein function, stability, localization, and interactions in response to TBI-induced stressors. These modifications play dual roles: they can either promote neuroprotection and recovery or drive pathological processes such as neuronal cell death (via apoptosis, necroptosis, and ferroptosis), neuroinflammation through glial activation and inflammasome signaling, blood-brain barrier disruption, mitochondrial dysfunction, and impaired synaptic plasticity. Critically, extensive crosstalk exists among different PTM pathways-such as the interplay between phosphorylation and ubiquitination in protein degradation or the competitive balance between acetylation and SUMOylation-that collectively shape cellular fate after injury. This nuanced regulatory network presents both challenges and opportunities for therapeutic intervention. Targeting PTM-related enzymes, including kinases, phosphatases, E3 ligases, and histone deacetylases, has shown promise in preclinical models, while novel strategies like Proteolysis-Targeting Chimeras (PROTACs) and repurposed drugs (e.g., metformin, resveratrol) offer innovative avenues for modulating the PTM landscape. Advances in high-throughput proteomics and mass spectrometry are enabling the mapping of TBI-specific PTM signatures across spatiotemporal phases, facilitating the identification of pro-survival versus pro-death modification thresholds. Despite hurdles in clinical translation-such as blood-brain barrier penetration and off-target effects-the growing understanding of PTM dynamics underscores their potential as both biomarkers and therapeutic targets. Future TBI management may thus rely on precision medicine approaches that integrate multi-PTM profiling to guide combination therapies aimed at tipping the balance toward neural repair and functional recovery.

Brain Injuries, Traumatic↗
PubMedDate not supplied

Avoiding tolerance against prostatic antigens with subdominant peptide epitopes.

A potential novel therapy for prostate cancer is the induction of immune responses to normal prostate-associated antigens (PAA). One approach is to use synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hurdle when using normal PAA for this type of therapy is the tolerance that the immune system may already have for PAA. To evaluate mechanisms for overcoming tolerance, the authors assessed the level of tolerance to SV40T antigen in a transgenic mouse. The SV40T antigen is selectively expressed in the prostates of mice from the transgenic adenocarcinoma mouse prostate (TRAMP) model. The authors have shown that TRAMP mice are tolerant to a dominant cytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with nontransgenic littermates. The tolerance was exhibited as early as 4 weeks and as late as 24 weeks. The use of multiple injections of an oligonucleotide that contains an unmethylated CpG induced high levels of hematopoiesis but did not overcome the tolerance. Injection of an antibody to activate CD40 increased the CTL response in normal mice but also did not overcome tolerance. However, tolerance in the TRAMP mice was avoided when an epitope that had previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to induce prostatitis and antitumor responses. The results of this work should facilitate the development of immune-based therapies for prostate cancer.

Amino Acid Sequence↗
PubMed2003

Direct text entry in electronic progress notes. An evaluation of input errors.

OBJECTIVES: It is not uncommon that the introduction of a new technology fixes old problems while introducing new ones. The Veterans Administration recently implemented a comprehensive electronic medical record system (CPRS) to support provider order entry. Progress notes are entered directly by clinicians, primarily through keyboard input. Due to concerns that there may be significant, invisible disruptions to information flow, this study was conducted to formally examine the incidence and characteristics of input errors in the electronic patient record. METHODS: Sixty patient charts were randomly selected from all 2,301 inpatient admissions during a 5-month period. A panel of clinicians with informatics backgrounds developed the review criteria. After establishing inter-rater reliability, two raters independently reviewed 1,891 notes for copying, copying errors, inconsistent text, inappropriate object insertion and signature issues. RESULTS: Overall, 60% of patients reviewed had one or more input-related errors averaging 7.8 errors per patient. About 20% of notes showed evidence of copying, with an average of 1.01 error per copied note. Copying another clinician's note and making changes had the highest risk of error. Templating resulted in large amounts of blank spaces. Overall, MDs make more errors than other clinicians even after controlling for the number of notes. CONCLUSIONS: Moving towards a more progressive model for the electronic medical record, where actions are recorded only once, history and physical information is encoded for use later, and note generation is organized around problems, would greatly minimize the potential for error.

Hospital Information Systems↗
PubMed2005

The application of the Haddon matrix to public health readiness and response planning.

State and local health departments continue to face unprecedented challenges in preparing for, recognizing, and responding to threats to the public's health. The attacks of 11 September 2001 and the ensuing anthrax mailings of 2001 highlighted the public health readiness and response hurdles posed by intentionally caused injury and illness. At the same time, recent natural disasters have highlighted the need for comparable public health readiness and response capabilities. Public health readiness and response activities can be conceptualized similarly for intentional attacks, natural disasters, and human-caused accidents. Consistent with this view, the federal government has adopted the all-hazards response model as its fundamental paradigm. Adoption of this paradigm provides powerful improvements in efficiency and efficacy, because it reduces the need to create a complex family of situation-specific preparedness and response activities. However, in practice, public health preparedness requires additional models and tools to provide a framework to better understand and prioritize emergency readiness and response needs, as well as to facilitate solutions; this is particularly true at the local health department level. Here, we propose to extend the use of the Haddon matrix--a conceptual model used for more than two decades in injury prevention and response strategies--for this purpose.

Disaster Planning↗
PubMed2004

Portfolio evaluation of health programs: a reply to Sendi et al.

Sendi et al. (Soc. Sci. Med. 57 (2003) 2207) extend previous research on cost-effectiveness analysis to the evaluation of a portfolio of interventions with risky outcomes using a "second best" approach that can identify improvements in efficiency in the allocation of resources. This method, however, cannot be used to directly identify the optimal solution to the resource allocation problem. Theoretically, a stricter adherence to the foundations of portfolio theory would permit direct optimization in portfolio selection, however, when we include uncertainty in our analysis in addition to the traditional concept of risk (which is often mislabelled uncertainty) complexities are introduced that create significant hurdles in the development of practical applications of portfolio theory for health care policy decision making.

Cost-Benefit Analysis↗
PubMed2001

Clinical efforts to modulate angiogenesis in the adult: gene therapy versus conventional approaches.

A gene therapy approach towards the modulation of neovascularization provides important advantages that could be crucial for the success of therapies that target blood vessels. These advantages include sustained local expression and the ability to supply multiple pro- or anti-angiogenic factors. There is potential near-term success in the application of this approach for the treatment of ischemic vascular diseases. Although there is convincing proof of concept in animal models that an anti-angiogenesis gene therapy approach can be used to treat cancer, this is a highly competitive field with small molecules, recombinant proteins and monoclonal antibodies already in clinical trials. The scientific rationale for the use of gene therapy is sound, but realization of its full potential for the treatment of a broad array of diseases will require several challenging technical hurdles to be overcome and safety concerns to be alleviated.

Journal Article↗
PubMed2002

Development and validation of capillary electrophoresis method for tobramycin with precapillary derivatization and UV detection.

One of the major drawbacks in the analysis of aminoglycoside antibiotics is their lack of UV chromophore and/or fluorophore. Tobramycin, a representative member of this group, was examined in this study. To overcome the detection hurdle, a precapillary derivatization followed by capillary electrophoresis analysis with direct UV detection was investigated. A central composite design was applied to optimize the method and three parameters were selected in this study: buffer pH, temperature and % acetonitrile (ACN). Selectivity between tobramycin main component and its adjacent peaks as well as the peak efficiency and symmetry factors were established as responses. For each response, a model was obtained by a second-order mathematical expression. Successful results were obtained with a simple background electrolyte (BGE) containing 30 mM sodium tetraborate, pH 10.2, and ACN (75:25 v/v). Under these conditions, baseline separation of tobramycin from its adjacent kanamycin B and an unknown peak was achieved. A temperature of 20 degrees C and applied voltage of 28.0 kV were used. The method showed good validation data in terms of precision, limits of quantitation and detection, specificity and linearity and was found to be suitable for analysis of tobramycin bulk pharmaceutical samples.

Acetonitriles↗
PubMed2006

Completely self-contained cell culture system: from storage to use.

In vitro cell culture systems provide researchers the appropriate tools for effectively studying cell growth and differentiation, understanding cellular response to specific environmental stimuli, and elucidating the function of heterologous biological molecules produced from expression systems. All in vitro cell culture systems require a specific culture media formulated to the nutritional and metabolic requirements of the particular cell type to be cultured. However, the complexity of these systems varies depending on the model organism origin of the cells being cultured (e.g., bacteria, plants, yeast or animal). Unlike bacteria and yeast, mammalian cell cultures require sophisticated auxiliary technologies (e.g., controlled gas mixtures and pressure flow systems, specialized facilities and equipment) and careful handling by trained personnel. These complex requirements pose a limitation to transferring cells to and from remote field locations for investigations. Furthermore, this limitation is a technical hurdle in the development of technologies involving use of live cells (e.g., cytosensors). We identified a novel and unrealized feature in the conventional cell culture system that may be exploited to adapt simple existing technologies to form a portable apparatus for storing and growing cells. The approach we describe is a completely self-contained cell culture system that not only will bring down the cost of culturing cells but also will expand cell culture applications in medicine, research, environmental health, and safety.

Animals↗
PubMed2003

Referral gridlock: primary care physicians and mental health services.

BACKGROUND: Patients' barriers to mental health services are well documented and include social stigma, lack of adequate insurance coverage, and underdiagnosis by primary care physicians. Little is known, however, about challenges primary care physicians face arranging mental health referrals and hospitalizations. OBJECTIVE: To examine how practice setting and environment influence primary care physicians' ability to refer patients for medically necessary mental health services. DESIGN: Cross-sectional analysis using nationally representative survey data from the 1998 to 1999 Community Tracking Study physician survey. The overall survey response rate was 61%. PARTICIPANTS: A 1998 to 1999 telephone survey of 6586 primary care physicians. MEASUREMENTS: Primary care physicians' report of whether they could obtain medically necessary referrals to high-quality mental health specialists or psychiatric admissions. RESULTS: Overall, 54% of primary care physicians reported problems obtaining psychiatric hospital admissions, and 54% reported problems arranging outpatient mental health referrals. Primary care physicians practicing in staff and group model HMOs were much less apt to report difficulties than physicians in solo and small-group practices (P <.001). Reports of inadequate time with patients (P <.001) and smaller numbers of psychiatrists in a market area (P <.01) also were associated with problems obtaining mental health referrals. Pediatricians were more apt to report problems than general internists (P <.001). CONCLUSIONS: Primary care physicians face greater hurdles obtaining mental health services than other medical services. Primary care is an important entry point for mental health services, yet inadequate referral systems between medical and mental health services may be hampering access.

Cross-Sectional Studies↗
PubMed2026

Toward simple, rapid, and deep plant proteome analysis with an in-cell proteomics strategy.

While liquid chromatography-mass spectrometry (LCMS) has revolutionized plant proteomics over the past decade, plant sample preparation remains a major challenge due to rigid cell walls, abundant secondary metabolites, and wide dynamic range of protein abundance. These hurdles demand laborious tissue disruption, complex precipitation, and extensive cleanup prior to LCMS analysis, limiting the widespread adoption of proteomic technologies within the plant biology community. To overcome these barriers, we introduced an "in-cell proteomics" strategy that bypasses cell lysis and protein extraction by performing digestion directly inside methanol-fixed cells. We systematically benchmarked this strategy against conventional lysate-based workflows across 4 model plants (Arabidopsis thaliana, Nicotiana benthamiana, Zea mays, and Sorghum bicolor) and 3 tissue types (leaves, pollen, and seeds). Combined with minimal input material and single-shot LCMS, the in-cell approach consistently identified 9,000 to 12,000 proteins from leaves, 7,000 to 9,000 from pollen grains, and approximately 8,000 from seeds. Our comprehensive dataset demonstrates that this in-cell digestion approach substantially simplifies plant sample preparation while delivering proteomic performance equivalent to established workflows. Finally, to demonstrate the biological utility of this approach, we characterized the proteomes of N. benthamiana leaves infected with 2 fungal strains that exhibit different host specificities. Our in-depth proteomic data revealed distinct host response signatures differentiating the host-adapted Colletotrichum destructivum from the nonhost-adapted Colletotrichum sublineola strain. Overall, this study provides a simple, unbiased alternative for plant proteomic analysis that can be readily applied to tackle complex agricultural and physiological challenges in plant biology.

Proteomics↗