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At least 523 records · Page 29Linked to original sources
PubMed1997

Enzyme therapy in Gaucher disease type 1: effect of neutralizing antibodies to acid beta-glucosidase.

Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid beta-glucosidase locus. Periodic infusions of macrophage-targeted acid beta-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid beta-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid beta-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid beta-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid beta-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.

Adolescent↗
PubMed2005

Amyloid imaging: from benchtop to bedside.

Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

Alzheimer Disease↗
PubMed2003

Signal detection behavior in humans and rats: a comparison with matched tasks.

Animal models of human cognitive processes are essential for studying the neurobiological mechanisms of these processes and for developing therapies for intoxication and neurodegenerative diseases. A discrete-trial signal detection task was developed for assessing sustained attention in rats; a previous study showed that rats perform as predicted from the human sustained attention literature. In this study, we measured the behavior of humans in a task formally homologous to the task for rats, varying two of the three parameters previously shown to affect performance in rats. Signal quality was manipulated by varying the increment in the intensity of a lamp. Trial rate was varied among values of 4, 7, and 10 trials/min. Accuracy of signal detection was quantified by the proportion of correct detections of the signal (P(hit)) and the proportion of false alarms (P(fa), i.e. incorrect responses on non-signal trials). As with rats, P(hit) in humans increased with increasing signal intensity whereas P(fa) did not. Like rats, humans were sensitive to the trial rate, though the change in behavior depended on the sex of the subject. These data show that visual signal detection behavior in rats and humans is controlled similarly by two important parameters, and suggest that this task assesses similar processes of sustained attention in the two species.

Journal Article↗
PubMed2001

Successful autologous peripheral blood stem cell transplantation for relapsed intravascular lymphomatosis.

We describe a case of relapsed intravascular lymphomatosis (IVL) successfully treated with autologous PBSCT. A 59-year-old Japanese female patient with IVL who had achieved CR after six courses of biweekly CHOP therapy developed lymphoma. She achieved a second CR after six courses of modified biweekly CHOP therapy, followed by autologous PBSCH and high-dose chemotherapy (CBDCA, VP-16, MCNU, CY) with PBSCT. There has not been any evidence of recurrence 48 months after PBSCT. Our case suggests that PBSC is acceptable as a source for stem cell rescue in IVL.

Antigens, CD34↗
PubMed2001

Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma.

Unresectable hepatocellular carcinoma (HCC) lacks effective therapy and entails very poor prognosis. In this study, we have explored a gene-therapeutic approach to stimulate antitumor immunity by adenoviral-mediated transfer of CD40 ligand to treat HCC in rats. In vitro infection of a rat HCC cell line (McA-RH7777) with adenoviral vector expressing CD40 ligand (AdCMVmCD40L) induced CD40L expression in a dose-dependent manner. Expression of CD40L in McA-RH7777 cells did not alter their growth rate in vitro, but it abrogated their tumorigenicity when CD40L-expressing cells were implanted into the liver of syngenic Buffalo rats. In vivo gene therapy of established orthotopic HCC nodules (6.5 mm in diameter) in Buffalo rats by intratumor injection of AdCMVmCD40L vector led to complete tumor eradication and long-term survival in 69.5% of treated animals. Therapy with AdCMVmCD40L induced strong lymphocytic infiltration of the tumoral tissue and increased apoptosis of malignant cells. The observed antitumoral effect was mediated by CD8(+) T cells and was associated with increased interleukin (IL)-12 serum levels and enhanced natural killer (NK) activity. Animals that eliminated the tumor after in vivo gene therapy developed protective antitumor immunity being resistant to rechallenge with neoplastic cells. Toxicity of the therapy with AdCMVmCD40L was slight, with only a transient increase in the level of serum transaminases and minor lymphocyte infiltration of normal liver tissue. These data demonstrate that intratumoral administration of AdCMVmCD40L may provide an efficient and safe treatment for HCC.

Adenoviridae↗
PubMed2004

Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy.

BACKGROUND: Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. METHODS: Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. RESULTS: With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. CONCLUSIONS: TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed1995

2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.

PURPOSE: 2-chlorodeoxyadenosine (2-CdA; cladribine) is a purine analog with activity in patients with chronic lymphocytic leukemia (CLL) who fail to respond to alkylator therapy. We conducted a phase II trial of 2-CdA in previously untreated CLL patients. PATIENTS AND METHODS: 2-CdA was administered to 20 patients with previously untreated CLL as a 0.1-mg/kg/d 7-day continuous intravenous infusion every 28 to 35 days until maximum response or prohibitive toxicity. RESULTS: A median of four courses (range, one to nine) was administered to each patient. Five patients (25%) achieved a complete response and 12 (60%) achieved a partial response, for an overall response rate of 85%. The median response follow-up duration was 8+ months (range, 3 to 27). Myelosuppression was the principal toxicity. Four of 20 patients (20%) experienced grade III or IV thrombocytopenia. Three patients, all of whom received corticosteroid therapy, developed opportunistic infections at a median of 19 months following discontinuation of 2-CdA therapy. CONCLUSION: 2-CdA has major activity in patients with previously untreated CLL, and the lower response rates seen in previously treated patients may be due in part to poor marrow reserve from prior therapy. Determination of the relative effectiveness of 2-CdA, fludarabine, and chlorambucil in the treatment of CLL patients will require a randomized trial.

Adult↗
PubMed2003

Newborn screening for cystic fibrosis.

CF newborn screening benefits growth and prevents malnutrition in children with CF. Increasing evidence suggests long-term pulmonary benefits, but these data are still accumulating. With a standardized approach to clinical care for these pre-symptomatic patients, we should be able to ask questions about the optimal treatment strategy for therapies that are currently available, perhaps through randomized clinical trials in this group. For developing therapies, Massachusetts will have identified its CF patients before they have sustained significant malnutrition and lung injury, and it may be these patients who will benefit most from therapies still on the horizon.

Costs and Cost Analysis↗
PubMed2005

The inhalation of drugs: advantages and problems.

Inhalation is a very old method of drug delivery, and in the 20th century it became a mainstay of respiratory care, known as aerosol therapy. Use of inhaled epinephrine for relief of asthma was reported as early as 1929, in England. An early version of a dry powder inhaler (DPI) was the Aerohalor, used to administer penicillin dust to treat respiratory infections. In the 1950s, the Wright nebulizer was the precursor of the modern hand-held jet-venturi nebulizer. In 1956, the first metered-dose inhaler (MDI) was approved for clinical use, followed by the SpinHaler DPI for cromolyn sodium in 1971. The scientific basis for aerosol therapy developed relatively late, following the 1974 Sugarloaf Conference on the scientific basis of respiratory therapy. Early data on the drug-delivery efficiency of the common aerosol delivery devices (MDI, DPI, and nebulizer) showed lung deposition of approximately 10-15% of the total, nominal dose. Despite problems with low lung deposition with all of the early devices, evidence accumulated that supported the advantages of the inhalation route over other drug-administration routes. Inhaled drugs are localized to the target organ, which generally allows for a lower dose than is necessary with systemic delivery (oral or injection), and thus fewer and less severe adverse effects. The 3 types of aerosol device (MDI, DPI, and nebulizer) can be clinically equivalent. It may be necessary to increase the number of MDI puffs to achieve results equivalent to the larger nominal dose from a nebulizer. Design and lung-deposition improvement of MDIs, DPIs, and nebulizers are exemplified by the new hydrofluoroalkane-propelled MDI formulation of beclomethasone, the metered-dose liquid-spray Respimat, and the DPI system of the Spiros. Differences among aerosol delivery devices create challenges to patient use and caregiver instruction. Potential improvements in aerosol delivery include better standardization of function and patient use, greater reliability, and reduction of drug loss.

Administration, Inhalation↗
PubMed1990

A profile of faculty development in physical therapy education programs.

The purpose of this study was to report on the status of faculty development in physical therapy education programs. A survey questionnaire was sent to the directors of 110 physical therapy programs nationwide. Analysis of responses from respondents (n = 79; 72%) demonstrated 1) criteria used to evaluate faculty members were similar among different institutions, 2) fewer than half of the institutions have a faculty development plan (FDP), 3) the majority of those institutions that have an FDP supported similar areas and activities to facilitate faculty development, and 4) respondents used creative ways to support faculty development. The results appear to indicate that most physical therapy programs do not have a formalized program to assist faculty members in their development of skills in research, teaching, and service. [Rothman J. Rinehart ME: A profile of faculty development in therapy education programs.

Education, Continuing↗
PubMed2006

Functional analysis of encapsulated hepatic progenitor cells.

A major challenge in developing therapies based on progenitor or stem cell populations (from sources other than bone marrow) involves developing a mode to deliver these cells in a manner that optimizes their viability, engraftment, proliferation, and differentiation. We have previously isolated a hepatic progenitor cell (HPC) population from adult liver tissue that differentiates into hepatic and biliary cell subtypes. We postulated that, using electrostatic encapsulation, we could reproducibly generate an ex vivo environment for the HPCs. We also theorized that this approach would foster cellular viability and function of the progenitor cell population. Using this encapsulation process, we consistently produced beads with uniform diameters between 200 and 700 microm. In vitro analysis of the encapsulated beads demonstrated extended periods of viability and function based on albumin production, urea metabolism, and glycogen storage. In conclusion, HPC encapsulation fosters the subsequent differentiation of HPCs into functional cells while maintaining their viability in long-term culture. These results demonstrate the efficacy of this method using somatic-derived progenitor cell populations and pave the way for clinical therapies.

Albumins↗
PubMed2002

Androgen replacement therapy and prostate safety.

Progress in the understanding of the action of exogenous testosterone has diminished many of the concerns that existed regarding its safety. The major interest is now focused on the effects of androgen supplementation on the prostate gland. Many such concerns have been addressed but others remain to be fully elucidated. It is well established that hypogonadal men receiving adequate androgen therapy develop a prostate with a volume similar to what would be expected from their eugonadal counterparts. Androgen therapy results in modest elevations in the PSA and minor changes in flow parameters. Prostate cancer, on the other hand, remains the most prominent of the safety concerns. Although there is no evidence that normal levels of testosterone promote the development of cancer of the prostate, it is clear that the administration of testosterone enhances a pre-existing prostatic malignancy. Androgen supplementation studies have been, in most cases, of short duration and lacked a control cohort. The current evidence does not support the view that appropriate treatment of hypogonadal elderly men with androgens has a causal relationship with prostate cancer. Larger experience, however, is needed. The same criteria applies to the use of other hormones such as dehydrotestosterone, dehydroepiandrosterone follicle stimulating and growth hormone. A set of recommendations regarding androgen replacement therapy and prostate safety is proposed.

Age Factors↗
PubMed1976

Polyuria associated with an antibody to vasopressin.

1. A patient with polyuria in whom diabetes insipidus had been diagnosed was treated with Pitressin. Resistance to this therapy developed after 18 months and a circulating antibody to vasopressin was then demonstrated. Withdrawal of therapy led to a fall in titre of the antibody and an increase in maximal urinary concentration. 2. The antibody to vasopressin was associated with the IgA fraction of the serum immunoglobulins and its characteristics are described.

Adult↗
PubMed1998

Oral tolerance as therapy for experimental autoimmune encephalomyelitis and multiple sclerosis: demonstration of T cell anergy.

Experimental autoimmune encephalomyelitis (EAE) is an important model for developing therapies for multiple sclerosis (MS). The oral administration of the central nervous system antigen, myelin basic protein (MBP), to Lewis rats and susceptible mouse strains prior to MBP immunization prevents the induction of EAE. Clinical trials administering myelin orally to MS patients have met with only partial success, and thus require that oral tolerance be further studied to improve this treatment strategy. Clonal anergy, clonal deletion, immune deviation from Th1 to Th2 T cell subsets, and active suppression by TGF-beta-secreting T cells have all been implicated as possible mechanisms in oral tolerance. Which mechanism predominates depends on antigen dosage, frequency of feeding, and timing of antigen administration. In this study, we have characterized T cells derived from MBP-fed rats and determined the level of their unresponsiveness. Myelin basic protein-specific T cells are indeed present although in reduced numbers in lymphoid tissue of orally tolerized animals. Following several cell divisions in the presence of IL-2, these MBP-specific T cells undergo a dramatic reversal of unresponsiveness, proliferate in response to MBP and are capable of transferring EAE. These results support clonal anergy as an important mechanism for oral tolerance. Recent developments in clinical trials of oral tolerance are described.

Administration, Oral↗
PubMed2005

Treatment-related neurotoxicity.

Two challenges need to be addressed to improve the outcome of patients with primary central nervous system lymphoma. The first challenge is to develop therapies that result in less toxicity and improved long-term outcome. The second challenge is to develop interventions to help those patients who develop treatment-related neurotoxicity; ongoing collaborative efforts are required to improve communication and understanding of this complication. Long-term follow up of prospective therapeutic studies should report on both disease control and the development of neurotoxicity. New protocols should include prospective longitudinal measures of neurocognitive function.

Antineoplastic Agents↗
PubMed2004

[Molecule based diagnosis].

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Antineoplastic Agents↗
PubMed2001

Multiple basal cell carcinomas developed after radiation therapy for tinea capitis: a case report.

Development of skin neoplasms is the most important complication of radiation therapy. There are contradictive reports about the type of these neoplasms. Squamous cell carcinomas are considered the most frequent tumors arising on chronic radiodermatitis areas, but recent studies have demonstrated that the type of neoplasm occurring in response to ionizing radiation exposure depends on several factors. Herein we report a patient who had received low-dose radiation for the treatment of tinea capitis and developed multiple basal cell carcinomas in the radiated areas after a long latent period of 53 years.

Basal Cell Carcinoma↗
PubMed2005

Treatment response and drug resistance in patients infected with HIV type 1 group O viruses.

Information about the efficacy of antiretroviral drugs in HIV-1 group O strains as well on the virus evolution in terms of resistance development in vivo is very limited. We assessed the clinical, immunological, and virological response to antiretroviral therapy as well as the selection of drug resistance in six HIV-1 group O-infected patients. All but one initiated antiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one protease inhibitor (PI). At baseline, median plasma HIV-1 group O RNA and CD4 counts were 32,256 (15,770-74,132) copies/ml and 88 cells/microl (13-170), respectively. Four patients reached undetectable plasma viremia 12 weeks after beginning treatment. However, viremia rebounded in one of them due to poor compliance. Another two patients had an initial reduction in plasma HIV-RNA greater than 1 log, but rebounded soon thereafter. At baseline, all patients' viruses revealed changes associated with NNRTI resistance (98G and 181C). Two out of three patients failing therapy developed resistance mutations. One selected changes M41L, E44D, D67N, V75M, M184V, and T215Y at the RT, and G48M, F53L, I54V, V82A, and L90M at the protease. Another selected mutations K70N, V75A, and M184V at the RT, and D30D/N and I84V at the protease while failing on indinavir. Interestingly, both patients showed a shift at codon 181 from C to Y, which might restore NNRTI susceptibility. Sustained viral suppression in HIV-1 group O-infected patients can be successfully achieved using antiretroviral regimens based on two NRTI and a boosted PI. Drug resistance mutations in HIV-1 group O seem to be selected at similar positions to those in HIV-1 group M viruses.

Adolescent↗