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PubMedDate not supplied

Cost and efficiency of HIV voluntary counselling and testing centres in Andhra Pradesh, India.

BACKGROUND: [corrected] As part of the effort to control HIV/AIDS, the number of HlV voluntarycounselling and testingcentres (VCTCs) is increasing rapidly in the public health system of the Indian state of Andhra Pradesh, which is estimated to have one of the highest rates of HIV infection in India. However, systematic data on the cost and efficiency of providing VCT services in India are not available to help guide efficient use of resources for these services. METHODS: We used standardized methods to obtain detailed cost and output data for the 2002-03 fiscal year from written records and interviews in 17 VCTCs in the public health system in Andhra Pradesh. We calculated the economic cost per client receiving VCT services, and analysed the variation and determinants of total and unit costs across VCTCs. We used multivariate regression techniques to estimate incremental unit costs. We assessed hurdles towards serving an optimal number of clients by VCTCs. RESULTS: In the 2002-03 fiscal year, 32 413 clients received the complete sequence of services at the 17 VCTCs, including post-HIV test counselling. The number of clients served by each VCTC ranged from 334 to 7802 (median 979). The overall HIV-positive rate in post-test counselled clients was 20.5% (range 5.4%-52.6%). The cost per client for the complete VCT sequence varied 6-fold between VCTCs (range Rs 141.5-829.6 [US 2.92-17.14 dollars], median Rs 363.5 [US 7.51 dollars]). The cost per client was significantly lower at VCTCs with more clients (p < 0.001, R2 = 0.83; power function) due to substantial fixed costs. Personnel made up the largest component of cost (53.7%). The cost per client had a significant direct relation with percent personnel cost for VCTCs (p < 0.001, R2 = 0.58; exponential function). A multiple regression model revealed that the incremental cost of providing complete VCT services to each HIV-positive and -negative client was Rs 123.5 (US 2.54 dollars) and Rs 59.2 (US 1.22 dollars), respectively. Fourteen VCTCs (82.4%) reported that they could serve more clients with the available personnel and infrastructure, and that inadequate demand for their services was the main hurdle towards achieving this. CONCLUSION: These data suggest that the efforts of the National AIDS Control Organisation of India and the Andhra Pradesh State AIDS Control Society in increasing VCTCs could yield even higher benefit if the demand for these services was enhanced, as this would increase the number of clients served and reduce the cost per client. Ongoing systematic cost-efficiency analysis is necessary to help guide efficient use of HIV-control resources in India.

AIDS Serodiagnosis↗
PubMed2007

Dynamics of hospital-based plastic surgery.

BACKGROUND: Legislative regulations, decreasing reimbursements for office procedures, and malpractice premiums have transformed plastic surgery from an office-based specialty into a hospital-based one. Simultaneously, hospital economics has altered, wherein the "business model" has all but subsumed the old "medical care" model. Integration between plastic surgeons and the new hospital structure has been difficult for both. Limited understanding of the financial dynamics of hospital-based practices, unfamiliarity with the administrative processes, and resistance to accept and assimilate changes by both sides pose hurdles, in some situations even forcing plastic surgeons out of hospital settings. METHODS: Using well-defined financial terminology, changing national development in health care policy, and hospital-based administrative strategies as a backdrop, this study finds common ground for the plastic surgery specialty to coapt with the hospital. RESULTS: Key missing elements in the interaction between plastic surgeons and hospital administrations and ways of integrating these components are identified. To do so effectively, plastic surgeons must first understand the basic tenets of management that drive hospital administrators, participate at every level they can in guiding these processes, and assume leadership roles that will ultimately dictate the way they work and conduct their professional lives. CONCLUSIONS: It is critical that plastic surgeons engage in important processes that govern the economics of hospital-based health care delivery. This commitment will also ensure that all three groups (the patients, physicians, and hospital administrators) achieve a degree of satisfaction. The message to plastic surgeons is clear: be proactive and lead a campaign of change.

Financial Management, Hospital↗
PubMed2003

Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance.

The transplantation of donor hematopoietic stem cells has been used successfully in numerous experimental settings to induce donor-specific tolerance. After appropriate host conditioning, hematopoietic stem-cell transplantation leads to a lasting state of donor macrochimerism that is associated with a robust form of tolerance. One of the key factors in the success of this approach is its reliance on intrathymic clonal deletion to ensure lifelong tolerization of newly developing T cells. Evidence for ongoing central deletion comes from studies following superantigen-reactive T cells and from experiments using mice transgenic for an alloreactive T-cell receptor. In protocols inducing tolerance through macrochimerism, the preexisting mature T-cell repertoire is controlled by either globally destroying all T cells before the hematopoietic cell transplantation or, in more recent models, by tolerizing it through co-stimulation blockade. The peripheral mechanisms induced by hematopoietic stem-cell transplantation and co-stimulation blockade include both extrathymic clonal deletion and the nondeletional mechanisms anergy, suppression, or both. In addition to these immunologic hurdles, a physiologic engraftment barrier has to be surmounted for the successful induction of mixed chimerism. This can be achieved by cytoreductive host treatment or by the infusion of high numbers of donor hematopoietic cells. A detailed delineation of the mechanisms responsible for tolerance induction after hematopoietic stem-cell transplantation is expected to help in the translation of these experimental protocols to clinical organ transplantation.

Animals↗
PubMed1996

Carboxymethylcellulose-sodium based transdermal drug delivery system for propranolol.

Propranolol, a beta-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (< 10%) following administration with conventional oral formulations. To circumvent this significant therapeutic hurdle, we formulated a carboxymethylcellulose-sodium (CMC-Na) based transdermal system for propranolol and evaluated the patch for its in-vitro and in-vivo performance. In-vitro permeation studies using the excised hair-free rat skin model resulted in 66.54% permeation at the end of 24 h in a modified Franz diffusion cell. This zero-order permeation profile was characterized by a drug permeation rate of 52.87 +/- 11.63 micrograms cm-2 h-1. Skin irritation studies in rats (n = 5), evaluated for flare-and-wheal with respect to a formalin control, indicated that the drug-containing patch evoked only a mild response over a 7-day period. Preliminary in-vivo studies in male albino rabbits (n = 3), indicated that plasma drug levels averaged 11.75 +/- 3.40 ng mL-1 in a 24-h study period before patch removal.

Administration, Cutaneous↗
PubMed2004

Femoral neck structure in adult female athletes subjected to different loading modalities.

UNLABELLED: Loading modality is a strong external determinant of structure and concomitant strength of the femoral neck. Particularly effective seem to be loadings, which arise from high impacts or impacts from atypical loading directions. INTRODUCTION: Physical loading plays an important role, not only in the process of bone modeling and remodeling, but also in shaping a mechanically appropriate bone structure. This study aimed at testing the hypothesis that the type of loading partly determines the femoral neck structure. MATERIALS AND METHODS: A total of 255 premenopausal female athletes representing volleyball, hurdling, squash-playing, soccer, speed skating, step aerobics, weight-lifting, orienteering, cross-country skiing, cycling, and swimming and their 30 nonathletic counterparts were measured with DXA. Besides the conventional areal BMD (aBMD) of the femoral neck, the hip structure analysis (HSA) was used to estimate the cross-sectional area (CSA), subperiosteal width (W), and section modulus (Z, an index of bone strength) at the narrowest section of the femoral neck. Also, training history, muscle strength, and calcium intake were assessed. The above-mentioned sports were classified according to the type of loading they apparently produce at the hip region; that is, high-impact loading (volleyball, hurdling), odd-impact loading (squash-playing, soccer, speed-skating, step aerobics), high-magnitude loading (weightlifting), low-impact loading (orienteering, cross-country skiing), and nonimpact loading (swimming, cycling). RESULTS: High-impact and odd-impact loading sports were associated with the highest age-, weight-, and height-adjusted aBMD (23% and 29% higher values compared to nonathletic referents), CSA (22% and 27%), and Z (22% and 26%). In contrast, repetitive, nonimpact loading sports were not associated with any clear benefit in any bone value compared with the referents. The W at the narrowest femoral neck section was similar in all groups. Body height and weight accounted virtually for one-half of the variation in Z, whereas the type of loading predicted 13% of the total variation of this variable-clearly more than the 2% attributable to isometric leg extension strength. Both high-impact and odd-impact loading modalities were associated with a large benefit in Z, corresponding to >1 SD in the reference group, whereas repetitive, low-impact loading showed a benefit that was only one-half of that. Surprisingly, high-magnitude loading (weightlifting) was not associated with a statistically significant increase in Z. CONCLUSION: We conclude that mechanical loading and its modality are strong external determinants of structure and concomitant strength of the femoral neck. Particularly effective seem to be loadings, which arise from high impacts or impacts from atypical loading directions.

Adult↗
PubMed1995

[Prospects for antisense therapy].

Inability to distinguish between normal and diseased cells by chemotherapeutic agents causes systemic toxic effects. This problem may be solved by the direct genetic approach using antisense oligodeoxynucleotide (AS ODN) based on the specificity of Watson-Crick base pair formation, if an appropriate disease-specific target can be identified. Since the pioneering works by Zamecnik and Stephenson to inhibit gene expression using AS ODN, recent progress in cloning of pathogenic genes and technical advance in the synthesis of ODN analogues have spurred a research effort dedicated to the development of AS therapy for cancer and viral disease. Chemically-modified ODNs such as phosphorothioate analogues, which are nuclease resistant and considered to be suitable for clinical use, can effectively inhibit the expression of activated oncogenes or the viral replication and lead to the growth suppression of cancer cells and viral genomes in vitro and in experiments using animal models as well. Phase I clinical trials, designed to evaluate the toxicity of these compounds in leukemia or AIDS patients, have already commenced. In these trials, which are now in its infancy, a considerable number of problems will be encountered. However, these hurdles may not be insurmountable.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Risk assessment of the use of sub-optimal levels of weak-acid preservatives in the control of mould growth on bakery products.

The hurdle technology approach was used to prevent fungal growth of common contaminants of bakery products including isolates belonging to the genera Eurotium, Aspergillus and Penicillium. Several levels (0.003%, 0.03% and 0.3%) of calcium propionate, potassium sorbate and sodium benzoate were assayed on a model agar system in a full-factorial experimental design in which the other factors assayed were pH (4.5, 6 and 7.5) and a(w) (0.80, 085, 0.90 and 0.95). Potassium sorbate was found to be the more suitable preservative to be used in combination with the common levels of pH and a(w) in Spanish bakery products. Sub-optimal concentrations (0.003% and sometimes 0.03%) led to an enhancement of fungal growth. None of the preservatives had a significant inhibitory effect at neutral pH.

Antifungal Agents↗
PubMed2000

A structural basis for drug-induced long QT syndrome.

Mutations in the HERG K(+) channel gene cause inherited long QT syndrome (LQT), a disorder of cardiac repolarization that predisposes affected individuals to lethal arrhythmias [Curran, M. E. , Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D. & Keating, M. T. (1995) Cell 80, 795-804]. Acquired LQT is far more common and is most often caused by block of cardiac HERG K(+) channels by commonly used medications [Roden, D. M., Lazzara, R., Rosen, M., Schwartz, P. J., Towbin, J. & Vincent, G. M. (1996) Circulation 94, 1996-2012]. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. Here we use alanine-scanning mutagenesis to determine the structural basis for high-affinity drug block of HERG channels by MK-499, a methanesulfonanilide antiarrhythmic drug. The binding site, corroborated with homology modeling, is comprised of amino acids located on the S6 transmembrane domain (G648, Y652, and F656) and pore helix (T623 and V625) of the HERG channel subunit that face the cavity of the channel. Other compounds that are structurally unrelated to MK-499, but cause LQT, also were studied. The antihistamine terfenadine and a gastrointestinal prokinetic drug, cisapride, interact with Y652 and F656, but not with V625. The aromatic residues of the S6 domain that interact with these drugs (Y652 and F656) are unique to eag/erg K(+) channels. Other voltage-gated K(+) (Kv) channels have Ile and Val (Ile) in the equivalent positions. These findings suggest a possible structural explanation for how so many commonly used medications block HERG but not other Kv channels and should facilitate the rational design of drugs devoid of HERG channel binding activity.

Amino Acid Sequence↗
PubMed2004

New perspectives in the studies on endocannabinoid and cannabis: a role for the endocannabinoid-arachidonic acid pathway in drug reward and long-lasting relapse to drug taking.

Growing evidence on the involvement of cannabinoids in the rewarding effects of various kinds of drugs of abuse has suggested that not only the classical dopaminergic and opioidergic, but also the most recently established endocannabinoid system is implicated in the brain reward system. Furthermore, the interplay between the three systems has been shown to be an essential neural substrate underlying many aspects of drug addiction including craving and relapse. Relapse, the resumption of drug taking following a period of drug abstinence, is considered the main hurdle in treating drug addiction. Yet, little is known about its underlying mechanisms. The link between the endocannabinoid system and the arachidonic cascade is currently being clarified. While several findings have, indeed, shown the essential role of the endocannabinoid system in the reinstatement model, the endocannabinoid-arachidonic acid pathway may also be an important part in the neural machinery underlying relapse. This evidence may provide an alternative approach that will open a novel strategy in combating drug addiction.

Amphetamine-Related Disorders↗
PubMed2005

Effect of donors' intravenous drug use, cigarette smoking, and alcohol dependence on kidney transplant outcome.

BACKGROUND: The shortage of organ donors for kidney transplants has made the expansion of the kidney donor pool a clinically significant issue. Previous studies suggest that kidneys from donors with a history of intravenous (IV) drug, cigarette, and/or alcohol use are considered to be a risky choice. However, these kidneys could potentially be used and expand the kidney supply pool if no evidence shows their association with adverse transplant outcomes. METHODS: This study analyzed the United Network for Organ Sharing dataset from 1994 to 1999 using Kaplan-Meier survival analysis and Cox modeling. The effects on transplant outcome (graft and recipient survival) were examined with respect to the donors' IV drug use, cigarette smoking, and alcohol dependency. Covariates including the recipient variables, the donor variables, and the transplant procedure variables were included in the Cox models. RESULTS: The results show that the donors' history of cigarette smoking is a statistically significant risk factor for both graft survival (hazard ratio=1.05, P<0.05) and recipient survival (1.06, P<0.05), whereas neither IV drug use nor alcohol dependency had significant adverse impact on graft or recipient survival. CONCLUSIONS: Assuming that adequate testing for potential infections is performed, there is no evidence to support avoiding the kidneys from donors with IV drug use or alcohol dependency in transplantation. Utilizing these kidneys would clearly expand the potential pool of donor organs.

Alcoholism↗
PubMed1991

Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys.

Infection of macaques with simian immunodeficiency virus (SIV) and human immunodeficiency virus type 2 (HIV-2) are useful models for studies of immunotherapy and vaccination against HIV as well as for testing of antiviral drugs. Vaccine research showing protective immunity in immunized monkeys has indicated that it will be possible to develop a vaccine for prevention of human HIV infection, although many hurdles remain. The design of an HIV vaccine would be helped if the basis of the protective immunity could be elucidated. Passive immune prophylaxis offers a means to determine the relative role of antibodies in protection against infection. We have studied whether a transfer of antibodies can prevent HIV-2 and SIVsm (SIV of sooty mangabey origin) infection in cynomolgus monkeys. Sera with high antibody titres were collected, heat-treated and injected into naive animals 6 h before challenge with 10-100 monkey-infectious doses of live homologous virus. All control animals treated with normal monkey serum (n = 6) or no serum (n = 39) became infected by the challenge virus, whereas five out of seven animals pretreated with antibody-containing serum at a dose of 9 ml kg-1 resisted infection. Thus passively transferred antibodies can protect against a low-dose lentivirus challenge in a nonhuman primate.

Animals↗
PubMed2006

[One year of the German Health System Modernization Act and its impact on quality in medicine from the Joint Federal Committee's point of view].

The objective of the German Health System Modernisation Act (GMG) has been to release probable profitability reserves within the current healthcare system by increasing the regulative competition between health insurances and healthcare providers and simultaneously improve the quality of healthcare. But the legislator has deliberately excluded the Statutory Health Insurances' services catalogue and the selection of its contents from this competition and conferred the guidance competence for shaping the contents of the statutory services catalogue and specifying quality requirements on healthcare delivery to the Joint Federal Committee. The legislator's objectives are targeted to cross-sectoral regulations, whereas the modelling of the organisational structure of the Joint Federal Committee and its statutory tasks still remain to be strongly sector-related, thus compromising the legal security of the Joint Federal Committee's normative decisions. The Joint Federal Committee has successfully taken the first hurdles of regulatory orders concerning the limitation of certain service areas and the formation of new fixed price groups. More emphasis of its future work will be placed on the further development and the cross-sectoral coordination of quality assurance measures.

Delivery of Health Care↗
PubMed1992

Transgenic farm animals - A critical analysis.

The notion of directly introducing new genes or otherwise manipulating the genotype of an animal is conceptually straightforward and appealing from the standpoints of both speed and precision with which phenotypic changes can be made. Thus, it is little wonder that the imagination of many animal scientists has been captivated by the success others have achieved in introducing foreign genes into mice. Transgenic mice not only exhibit unique phenotypes, but they also pass those traits on to their progeny. However, before transgenic farm animals become a common component of the livestock industry, a number of formidable obstacles must be overcome. In this review we attempt to identify the critical issues that should be considered by both those currently working in the field and those scientists considering the feasibility of initiating a transgenic livestock project. The inefficiency of producing transgenic animals has been well documented. This does not constrain investigators using laboratory animal models, but it has a major impact on applying transgenic technology to farm animals. The molecular mechanisms of transgene integration have not been elucidated, and as a consequence it is difficult to design strategies to improve the efficiency of the process. In addition to the problems associated with integration of new genes, there are inefficiencies associated with collecting and culturing fertilized eggs as well as embryo transfer in farm animals. Transgenic farm animal studies are major logistical undertakings. Even in the face of these practical hindrances, some may be pressured by administrators to embrace this new technology. As powerful as the transgenic animal model system is, currently there are limits to the kinds of agricultural questions that can be addressed. Some uses are so appealing, however, that several commercial organizations have explored this technology. Within the next decade or two, it is likely that many of the technical hurdles will be overcome. Combining new techniques with a better understanding of the genetic control of physiological systems will make it possible to improve the characteristics of farm animals in highly imaginative ways.

Journal Article↗
PubMed2004

Assessing the likelihood of recurrence during RNA evolution in vitro.

Recurrence is the possibility of resulting in the same endpoint multiple times when a living system is allowed to evolve repeatedly starting from a given initial point. This concept is of concern to both evolutionary theoreticians and molecular biologists who use nucleic acid selection techniques to mimic biotic and computorial processes in the test tube. Using the continuous in vitro evolution methodology, many replicate experimental evolutionary lineages with populations of catalytic RNA were performed to gain insight into the parameters that could affect recurrence. The likelihood that the same genotype will result in parallel trials of an evolution experiment in vitro depends on several factors, including the phenotype under selection, the size and composition of the initial diverse pool of nucleic acids used in the experiment, the degree of mutation possible during the experiment, the shape of the fitness landscape through which the population evolves, and the strategies used to invoke selection and to search the landscape, among others. By considering these factors, it can be predicted that recurrence is more likely when a small, wild-type-based starting pool is used with efficient selection and search strategies involving little online mutagenesis within a rugged adaptive landscape with a strong local optimum. The recurrence experiments performed here on the 150-nucleotide ligase ribozyme demonstrate that it repeatedly jumps from one peak in a fitness landscape to another, apparently hurdling a deep fitness valley. These predictions can and should be tested by additional multiple replicates of actual evolution experiments in the laboratory.

Base Sequence↗
PubMedDate not supplied

Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models.

BACKGROUND: Apolipoprotein (apo) A-I is the major component of HDL, and it displays antiatherogenic properties. METHODS AND RESULTS: The human apoA-I gene has been transferred into different mouse models by use of a recombinant adenovirus under the control of an RSV-LTR promoter (AV RSV apoA-I). Administration of AV RSV apoA-I to C57BL/6 mice resulted in moderate expression of human apoA-I for 3 weeks, leading to a transient elevation (40% at day 11 after injection) of HDL cholesterol concentration. In contrast, administration of AV RSV apoA-I to human apoA-I-transgenic mice induced a large increase of human apoA-I and HDL cholesterol concentrations (300% and 360%, respectively, at day 14 after injection) for 10 weeks, indicating that an immune response to the transgene was one major hurdle for long-term duration of expression. Recombinant adenovirus expressing human apolipoprotein A-I (AV RSV apoA-I) was also injected into human apoA-I-transgenic/apoE-deficient mice, which are prone to develop atherosclerosis. Over a 6-week period, overexpression of human apoA-I inhibited fatty streak lesion formation by 56% in comparison with control. CONCLUSIONS: Somatic gene transfer of human apoA-I prevents the development of atherosclerosis in the mouse model.

Adenoviridae↗
PubMed2000

Safety evaluation of sous vide-processed products with respect to nonproteolytic Clostridium botulinum by use of challenge studies and predictive microbiological models.

Sixteen different types of sous vide-processed products were evaluated for safety with respect to nonproteolytic group II Clostridium botulinum by using challenge tests with low (2. 0-log-CFU/kg) and high (5.3-log-CFU/kg) inocula and two currently available predictive microbiological models, Food MicroModel (FMM) and Pathogen Modeling Program (PMP). After thermal processing, the products were stored at 4 and 8 degrees C and examined for the presence of botulinal spores and neurotoxin on the sell-by date and 7 days after the sell-by date. Most of the thermal processes were found to be inadequate for eliminating spores, even in low-inoculum samples. Only 2 of the 16 products were found to be negative for botulinal spores and neurotoxin at both sampling times. Two products at the high inoculum level showed toxigenesis during storage at 8 degrees C, one of them at the sell-by date. The predictions generated by both the FMM thermal death model and the FMM and PMP growth models were found to be inconsistent with the observed results in a majority of the challenges. The inaccurate predictions were caused by the limited number and range of the controlling factors in the models. Based on this study, it was concluded that the safety of sous vide products needs to be carefully evaluated product by product. Time-temperature combinations used in thermal treatments should be reevaluated to increase the efficiency of processing, and the use of additional antibotulinal hurdles, such as biopreservatives, should be assessed.

Botulinum Toxins↗
PubMed1999

The prospects for antisense therapy.

The use of short spans of nucleic acid--DNA or RNA--to disrupt the expression of disease-related genetic code is an idea potentially applicable to a vast number of illnesses, including most neoplasms. On several fronts, including hematologic malignancies, the concept has reached clinical trials--where appreciation of the in vivo hurdles is leading to new approaches for delivery of this new magic bullet.

Antisense Elements (Genetics)↗