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At least 559 records · Page 31Linked to original sources
PubMed2007

Plasmid-based gene therapy of diabetes mellitus.

Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-beta). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

Animals↗
PubMed2003

Otomastoiditis-related facial nerve palsy.

A 9-year-old girl with persistent otitis media, despite antibiotic therapy developed a facial nerve palsy. Computed tomography (CT) scan revealed ipsilateral mastoiditis, prompting admission for intravenous antibiotic and steroid therapies. Acute mastoiditis, uncommon in the post-antibiotic era, is usually diagnosed on physical examination findings, but two variants, masked mastoiditis or silent mastoiditis, may be difficult to appreciate clinically. Patients who present with facial nerve palsy in the setting of persistent otitis media should undergo CT scan for evaluation of intracerebral or extracerebral pathology, including mastoiditis. Failure to identify associated concomitant pathology may result in treatment failure or persistent neurological deficit.

Anti-Bacterial Agents↗
PubMed2003

Long-term functional consequences of transient occlusion of the middle cerebral artery in rats: a 1-year follow-up of the development of epileptogenesis and memory impairment in relation to sensorimotor deficits.

Post-stroke seizures occur in 5-20% of patients. Modeling of stroke-induced seizures in animals provides a useful tool for investigating the molecular basis of epileptogenesis and for developing therapies for stroke patients at increased risk for epileptogenesis. The questions addressed in the study were: (1) Do rats develop spontaneous seizures after transient occlusion of the middle cerebral artery (MCAO)? (2) Is epileptogenesis associated with impaired hippocampus-dependent spatial learning and memory? (3) Are the functional abnormalities linked to axonal plasticity in the dentate gyrus? (4) Does the sensorimotor impairment induced by MCAO predict the risk of epileptogenesis? Adult male Sprague-Dawley rats were subjected to MCAO for 120 min. Development of spontaneous seizures was monitored by 1 week of continuous video-electroencephalographic (EEG) recordings at 3, 7, and 12 months after MCAO. Spontaneous seizures were not detected during 1-year follow-up in ischemic rats. Animals were, however, impaired in the spatial memory task (P<0.001), which was not associated with altered hippocampal LTP or abnormal mossy fiber sprouting (Timm staining). Animals also had a long-lasting sensorimotor deficit (P<0.05). The present study indicates that MCAO causes long-lasting sensorimotor and spatial memory impairment, but does not induce epileptogenesis or spontaneous seizures.

Animals↗
PubMed2005

Development and validation of a fluorescence polarization-based competitive peptide-binding assay for HLA-A*0201--a new tool for epitope discovery.

Various approaches are currently proposed to successfully develop therapies for the prevention and treatment of infectious diseases and cancer. One of the most promising approaches is the development of vaccines that elicit cytotoxic T lymphocyte (CTL) responses. Consequently, identification and exact definition of molecular parameters involved in peptide-MHC class-I interactions of putative CTL epitopes are of prime importance for the development of immunomodulating compounds. To better facilitate epitope discovery, we developed and validated a novel state-of-the-art biochemical HLA-A0201 assay, which is comprised of technologically advanced cutting edge reagents. The technique is based on competition and uses a FITC-labeled reference peptide and highly purified soluble HLA-A0201 molecules to quantitatively measure the binding capacity of nonlabeled peptide candidates. Detection by fluorescence polarization allows real-time measurement of binding ratios without separation steps. During standardization, the problem of assay parameter variation is discussed, showing the dramatic influence of HLA and reference peptide concentrations as well as the choice of the reference peptide itself on IC(50) determinations. For validation, a panel of 15 well-defined HLA-A0201 ligands from various sources covering a broad range of binding affinities was tested. Binding data were used to compare against pre-existing quantitative assay systems. The results obtained demonstrated significant correlation among assay procedures, suggesting that the application of fluorescence polarization in combination with recombinant sHLA molecules is highly advantageous for the accurate assessment of peptide binding. Furthermore, the assay also features high-throughput screening capacity, providing uniquely efficient means of identifying and evaluating immune target molecules.

Binding Sites↗
PubMed2006

Acquired Fanconi's syndrome associated with tenofovir therapy.

Tenofovir (Viread) is a nucleotide reverse transcriptase inhibitor introduced into the United States in 2001. It is frequently prescribed not only for its efficacy but also for its decreased side effect profile compared with other nucleoside analogs. It is now increasingly recognized as a cause of acquired Fanconi's syndrome (FS) in human immunodeficient individuals. We describe a case of a patient with AIDS, who, after starting tenofovir therapy, developed myalgias, renal failure, and profound electrolyte abnormalities compatible with the classic features of FS. On discontinuation of tenofovir and replacement of electrolytes, the individual improved clinically with normalization of his renal failure and electrolyte abnormalities. With the success of tenofovir in the anti-HIV drug market, practitioners should remain alert to the possibility of the development of FS. Frequent urine, renal, and electrolyte parameters should be measured at regular intervals following initiation of tenofovir therapy.

Adenine↗
PubMed2005

Management of chronic low back pain.

Chronic low back pain is common. It presents a clinical challenge with widespread implications for resource utilization on a national scale. The causes of chronic low back pain may be mechanical or nonmechanical, nociceptive or neuropathic. Diagnosis is problematic because available tools lack both specificity and sensitivity. In rare instances, the cause of chronic low back pain can be attributed to an identified cause. Comprehensive pain management relies on the use of pharmacotherapy, physical therapy, and a multidisciplinary approach to treatment. Recent studies have shown a benefit for traditional adjunctive therapies and interdisciplinary treatment. Antidepressants and opioids have been and remain key elements for medical management, and some recently developed therapies have shown promising results in clinical trials. The following article presents an overview of evidence-based management for chronic low back pain, with an emphasis on pharmaceutical therapies.

Catheter Ablation↗
PubMed1995

The management of relapsed Wilms tumor.

Relapsed Wilms tumor is often very responsive to re-treatment, and cures are possible in many cases. Recurrent Wilms tumor forms a heterogeneous group because initial therapies vary widely. Given the complexity of the problem, there is a great need for an organized clinical investigative approach. Ideally, the treatment of initial relapse should be specified by the primary treatment protocol in order to better evaluate overall survival as an end-point for new primary therapy strategies. This is especially appropriate for Wilms tumor, because the investigations of this tumor over the last 20 years have attempted to determine the minimal therapy necessary for cure. Thus, survival rather than relapse-free survival is the most appropriate criterion for the success of a primary retreatment regimen. This investigative approach would also allow evaluation of treatment strategies tailored to a specific patient population. Important questions remain for those who treat recurrent Wilms tumor. Defining the role of high-dose therapy, defining the role of total body irradiation in high-dose therapy regimens, and defining the benefit and toxicity of cyclophosphamide compared with ifosfamide are three current questions under investigation. Developing new agents and regimens effective against Wilms tumor, especially against anaplastic tumors, RTK, and CCSK, is extremely important if progress is to be made in treating these tumors after relapse. Finally, there is a strong need to develop biologic information about tumors that recur, so not only will we better understand why patients relapse but also we can develop therapy tailored specifically to the biology of the recurrent tumor.

Antineoplastic Agents↗
PubMed2006

Approach to the complications of treatment for acute leukemia in the elderly.

Acute leukemia is common in the elderly and, due to the aging population and poorer prognosis, represents a major challenge. Elderly acute leukemia patients have been arbitrarily defined as >or=55 to 65 years of age and are underrepresented in clinical trials. There are physiologic differences between elderly and non-elderly patients. A comprehensive understanding of these differences allows the development of a systematic approach to assessing the risks for treatment-related complications. Use of a comprehensive geriatric assessment (CGA), initially developed and validated in the general geriatric population, may allow more accurate assessment of the likelihood of chemotherapy-induced complications and allow for proactive risk minimization. Once complications to therapy develop, aggressive treatment is essential. Treatment related to common complications that arise from therapy will be reviewed. Further research directed at this population is required.

Acute Disease↗
PubMed1988

The reception of family therapy: a view from the psychiatric journals.

An analysis of the reviews of books on family studies and therapy in psychiatric journals was done to determine how mental health professionals perceived the family therapy movement and how they responded to its basic theoretical and clinical tenets. The reviews published in leading psychiatric journals from 1955 to 1970 illustrate the rich debate that accompanied the family therapy movement in the first fifteen years of its history in the U.S. Concern over efficacy, theory, limits and affiliation dominated the reviews. The reviewers' responses evolved in a fluctuating pattern from an early acceptance of family therapy to a middle phase of resistance and contestation when family treatment seemed to challenge the domination of the individual approach in the field of psychiatry and, finally, a renewed support of the family approach as an addition to the expanding psychotherapeutic armamentarium. This paper challenges the prevailing view among family therapists and others that family therapy developed in a hostile psychiatric environment.

Attitude of Health Personnel↗
PubMedDate not supplied

Cytology of pleural effusion associated with disseminated infection caused by varicella-zoster virus in an immunocompromised patient. A case report.

BACKGROUND: Pleural effusion caused by varicella-zoster virus (VZV) is rare. We report a case of a woman with acute lymphocytic leukemia (ALL) who developed a pleural effusion caused by VZV infection. CASE: A 55-year-old woman with ALL treated with consolidation therapy developed skin vesicles and a pleural effusion. Pleural fluid smears contained numerous mesothelial cells, which had ground-glass nuclei or eosinophilic nuclear inclusions. Some multinucleated giant cells were also seen. Electron microscopic examination revealed intranuclear virus particles, about 150 nm in diameter, in some mesothelial cells. Tissue samples from the skin, lungs, pleura, liver, pancreas, kidneys and gastrointestinal tract, obtained at autopsy, contained many virus-infected cells. They were positive for VZV glyco-protein 1 by immunohistochemistry. CONCLUSION: VZV infection should be considered in the differential diagnosis of an unexplained exudative pleural effusion, especially in immunocompromised hosts.

Cytodiagnosis↗
PubMed2002

Pharmacotherapy for biochemical recurrences after therapy for localised prostate cancer.

Prostate-specific antigen (PSA) has revolutionised screening for and monitoring of prostate cancer (CaP). Currently, most men failing potentially curative CaP therapies develop biochemical evidence of recurrent disease (defined by detectable PSA levels) long before the onset of clinical symptoms. Androgen deprivation therapy (ADT) remains the gold standard for the treatment of metastatic CaP. Conventional ADT is orchiectomy or luteinising hormone-releasing hormone agonists. ADT is most commonly associated with side effects such as erectile dysfunction, decreased libido, gynecomastia and osteoporosis. Intermittent ADT or oral anti-androgens may limit the side effects associated with ADT while retaining efficacy. Although widely studied, the optimal timing to begin ADT remains an important and unanswered question. Future advances in gene therapy and immunotherapy hold the greatest promise to provide effective treatments against recurrent CaP while minimising morbidity.

Androgen Antagonists↗
PubMed1991

[Optimal correction of blood loss based on the adaptation reaction of the body in gastroduodenal hemorrhage].

The mathematical analysis of the cardiac rhythm was used for the evaluation of the body adaptation reserves in gastroduodenal hemorrhages that are considered as a stress factor. It has been established that the cardiac rhythm analysis enables one to evaluate the functioning level of the body regulation system, and to estimate the blood loss severity. The assessment of the adaptation reactions in 132 patients with gastroduodenal hemorrhages has shown that the mathematical analysis of the cardiac rhythm is an objective indicator, and its changes are closely related to all parameters of the hemostasis. The proposed objective indicator (adequacy of infusion-transfusion therapy) developed on the basis of studying individual reactions of the vegetative nervous system to hemorrhage, enables optimization of the transfusion therapy and its conduction on the principle of reasonable adequacy, and achievement of replacement efficiency in shorter terms and with lower volumes of transfusion media.

Adaptation, Physiological↗
PubMed2000

Development of a cytomegalovirus vector for somatic gene therapy.

The development of new and improved vector systems is central for realization of new concepts for gene therapy. The tropism of human cytomegalovirus (CMV) for hematopoietic progenitor cells and the large genome size (230 kbp) that offers a unique cloning capacity make this virus a promising vector candidate for gene transfer into hematopoietic cells and for therapy of congenital and acquired diseases of the hematopoietic system. Recently, we cloned the CMV genome as a bacterial artificial chromosome (BAC) in Escherichia coli and established efficient mutagenesis procedures for CMV - a prerequisite for vector construction. Here, we report on the construction of a recombinant GFP virus that will be used to re-evaluate the tropism of CMV and to monitor gene transfer into target cells. Further goals of CMV vector development are the evaluation of the cloning capacity and the construction of replication-deficient vectors.

Cytomegalovirus↗
PubMed2004

Development of gene therapy to target pancreatic cancer.

Pancreatic cancer remains one of the most difficult cancers to treat. Its high propensity to infiltrate and metastasize early from a small primary focus necessitates development of a new therapy which can track down the disseminated cancer cells in vivo. Gene therapy may offer new opportunities for a variety of targeting strategies, and we review here some of our work related to the development of targeted gene therapy: 1) Targeting by specific molecular abnormality: Many pancreatic cancer cells show "addiction" to K-ras mutation, while normal cells appear resistant to suppression of K-ras-mediated signaling by antisense K-ras RNA expression adenoviral vector. 2) Targeting by in vivo tumor characteristics: In a peritoneal dissemination model, intraperitoneal lipofection/polyfection can deliver and express transgenes highly preferentially in tumor nodules. 3) Targeting by vector: An efficient protocol for construction of an adenovirus expression vector library has been developed, which will enable a direct functional selection of fiber knob-modified targeting vector species for given cells. 4) Targeting by tumor immunity: Several cytokines not only induce direct cytotoxicity, but are also expected to activate specific immunity to achieve targeted suppression of cancer cells in vivo. Unlike parenteral administration of short-lived recombinant interferon protein, local interferon gene transfer can provide a target tissue-restricted distribution and sustained expression, which may improve the efficacy/safety balance of cytokine therapy. Cancer gene therapy development is, in general, at the stage of proof of principles and safety. However, it is an art of integrated science. The recent rapid progress of related sciences and technologies will expand the potential and consolidate the clinical reality of gene therapy.

Adenocarcinoma↗
PubMed1991

Early combination of selegiline and low-dose levodopa as initial symptomatic therapy in Parkinson's disease. Experience in 26 patients receiving combined therapy for 26 months.

Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age, 57.3 years; mean Parkinson's disease duration, 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage, 2; mean motor scores, 11.4) were given selegiline (Deprenyl), 10 mg daily, and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet, 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy, seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa, with significant decreases in their rated motor scores, such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%, compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose, 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild, transient, abnormal involuntary movements, and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Therapy, Combination↗
PubMed2004

Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy.

The development of new therapies for treatment of chronic wounds has not matched the availability of treatment modalities forecast by the pharmaceutical industry. This is attributable in large part to difficulties encountered in clinical trials as well as in isolating study design variables. Our hypothesis attempts to address this shortcoming. We are proposing that chronic wound pathogenesis is based on 3 fundamental factors: the cellular and systemic changes of aging, repeated ischemia-reperfusion injury, and bacterial colonization with resulting inflammatory host response. The derivation of this hypothesis is founded on the observation that the 3 primary categories of chronic wounds--pressure ulcers, diabetic ulcers, and venous ulcers, which are the overwhelming majority of chronic wounds--have these common causative factors. Our hypothesis incorporates major implications for treatment modalities based on these factors. Addressing the first issue, the cellular and systemic changes of aging, Regranex (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a platelet-derived growth factor drug, has shown great promise. Additional treatment modalities that address the second and third problems, repeated ischemia-reperfusion injury and bacterial colonization, include vacuum-assisted closure, warming of local tissue, and water irrigation using pulsed lavage. Additionally, treatment comprising a combination of these approaches has demonstrated success.

Aging↗
PubMed2001

Non-steroidal and steroidal sulfamates: new drugs for cancer therapy.

The development of inhibitors to block the formation of estrone and 5-androstenediol from sulfated precursors is an important new strategy for the treatment of breast cancer. In this study a series of tricyclic coumarin sulfamates (665-668 COUMATE) and a tricyclic oxepin sulfamate have been synthesised and tested for their ability to inhibit estrone sulfatase activity (E1-STS). In addition the effect of the steroid-based E1-STS inhibitor, 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) on the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts was also examined. The tricyclic coumarin sulfamates and oxepin sulfamate were potent inhibitors of E1-STS activity with IC(50)s ranging from 8 to 250 nM. Of this series 667 COUMATE was the most potent inhibitor (IC(50)=8 nM) and was three-times more potent than estrone-3-O-sulfamate (EMATE, IC(50)=25 nM). 667 COUMATE did not stimulate the growth of MCF-7 breast cancer cells and is therefore devoid of estrogenicity. In vivo, 667 COUMATE inhibited E1-STS activity in rat liver tissue to a similar extent to that of EMATE. 2-MeOEMATE had a marked effect on the morphology of MDA-MB-231 cells and breast tumour-derived fibroblasts causing a significant increase in the number of rounded cells. 667 COUMATE and 2-MeOEMATE therefore offer considerable potential for development for cancer therapy.

Animals↗