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PubMed2004

The impact of cyclosporine on the development of immunosuppressive therapy: perspective from a transplant nephrologist involved with the development of C2.

The availability of Neoral in place of Sandimmun offered better pharmacokinetics and improved results but emphasized the poor accuracy of trough levels as a tool for monitoring drug exposure and dosage adjustment. Subsequent studies confirmed that Neoral exposure correlated with clinical events and it was found that C2 was the single point that correlated best with exposure as determined by AUC(0-4h). Single and multicenter studies have now shown that C2 monitoring is practically feasible and that its use resulted in very low rates of acute rejection with excellent renal function. One retrospective comparison suggested that rates of acute rejection were lower with C2 than with C0 monitoring. This tool has now been shown to be effective in managing African-American renal transplants and those with delayed graft function. A very recent international randomized trial has shown equivalent rates of acute rejection in liver transplant recipients treated with both Neoral and Prograf. Studies now in progress will permit further refinement of target levels with the potential to improve long-term results.

Area Under Curve↗
PubMed2003

Tension pneumocephalus following transsphenoid surgery for pituitary adenoma - report of two cases.

Occurrence of symptomatic pneumocephalus following transsphenoid surgery is a rare event. Two cases of symptomatic pneumocephalus were observed in our series of 480 transsphenoidal surgeries. The first case reported presented with a head injury 4 years earlier and had a left frontotemporal haematoma evacuation. He underwent surgery for sellar mass extending into suprasellar region. He developed postoperative CSF rhinorrhea and in spite of conservative therapy, developed progressive visual deterioration necessitating a re-exploration and repair leading to resolution of the neurological deficits. The second case presented with delayed CSF rhinorrhea leading to rapid alteration in sensorium, requiring external ventricular drainage. The leak subsided without any further surgical intervention.

Accidents, Traffic↗
PubMed1988

Rates and dates of divergence between AIDS virus nucleotide sequences.

The acquired immune deficiency syndrome (AIDS), caused by a retrovirus called human immunodeficiency virus (HIV), has become a pandemic. A knowledge of the rate of nucleotide substitution in HIV and of the history and pattern of spread of the virus is important for understanding the epidemiology and pathogenesis of AIDS and for developing therapies and vaccine strategies. A new model has been developed and used to estimate the substitution rates in various regions in the HIV genome. The rate of nonsynonymous (amino acid-changing) substitution is lowest in the regions coding for the capsid proteins and the reverse transcriptase, being approximately 1.7 X 10(-3) nucleotide substitutions/site/year. The nonsynonymous rate is extremely high (14 X 10(-3] in the hypervariable regions of the envelope gene, suggesting extremely rapid change in viral antigenicity. The nonsynonymous rates in the other coding regions are between 3 X 10(-3) and 7 X 10(-3). The average synonymous rate for the HIV genome is 10 X 10(-3). These rates are 10(6) times greater than the rates in DNA genomes and at least as high as the rates in other RNA viruses. Evidence is provided for a case of recombination between different HIV strains. Our analysis suggests that the AIDS virus had existed in central Africa before 1960 and spread to North America before the mid 1970s. The evolutionary relationships among HIV isolates are inferred from nucleotide sequence data, and the result is consistent with the view that AIDS spread from Haiti to the United States.

Base Sequence↗
PubMed2005

Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer.

Individuals harboring germ-line mutations in the BRCA1 or BRCA2 genes are at highly elevated risk of a variety of cancers. Ten years of research has revealed roles for BRCA1 and BRCA2 in a wide variety of cellular processes. However, it seems likely that the function of these proteins in DNA repair is critically important in maintaining genome stability. Despite this increasing knowledge of the defects present in BRCA-deficient cells, BRCA mutation carriers developing cancer are still treated similarly to sporadic cases. Here we describe our efforts, based on understanding the DNA repair defects in BRCAdeficient cells, to define the optimal existing treatment for cancers arising in BRCA mutation carriers and, additionally, the development of novel therapeutic approaches. Finally, we discuss how therapies developed to treat BRCA mutant tumors might be applied to some sporadic cancers sharing similar specific defects in DNA repair.

Animals↗
PubMed2000

Vulvar vestibulitis syndrome and vaginismus. A case report.

BACKGROUND: Recent reports have argued for a revision of the criteria used for the establishment of a diagnosis of vulvar vestibulitis syndrome (VVS). On theoretical grounds it might be hypothesized that women with VVS also suffer from vaginismus. CASE: A young woman presented with a history, symptoms and objective findings typical of vaginismus, yet she suffered from continuous, burning pain and itching in the vestibule. Earlier in the course of the problem she had received a diagnosis VVS. The patient was treated with behavioral therapy developed for vaginismus. Notations made during the course of therapy supported the assumption that the pain and itching were conditioned responses to penetration in the same way that a vaginal muscular reflex is. CONCLUSION: Differential diagnostic difficulties exist in the field of VVS and vaginismus. Psychophysiologic theories are needed as the basis for research to clarify the connections between different diagnostic entities associated with coital burning pain and itching in the vestibule.

Adolescent↗
PubMed2000

Immunogenetic therapy for B-cell malignancies.

Neoplastic B cells are stealthlike in their ability to evade immune detection, even by allogeneic T cells of normal healthy donors. This stealthlike phenotype can be reversed by activating neoplastic B cells through ligation of CD40, a cell surface molecule that can interact with a ligand expressed on activated T cells. The gene encoding this ligand, CD154, can be transferred into neoplastic B cells ex vivo through infection with a modified adenovirus vector called Ad-CD154. This results in a dramatic change in the phenotype and function of the neoplastic B cells. Infected malignant B cells can stimulate T cells reactive with potential tumor antigens and induce autologous cytotoxic T cells capable of destroying the neoplastic B cells in vitro. This formed the basis for an immune gene therapy protocol in which patients were infused with Ad-CD154-transduced leukemic B cells. Treatment was well tolerated, without apparent long-term toxicity, and without a maximum tolerated dose. Biologic and clinical responses were observed, including significant reductions in leukemia cell counts and lymph node sizes after a single one-time infusion. Furthermore, preliminary data suggest that this approach can enhance antibody-dependent cellular cytotoxicity and thereby augment the activity of antitumor monoclonal antibody therapy. Development of such strategies may allow for effective immunogenetic therapy for B-cell malignancies.

Antibodies, Monoclonal↗
PubMed1986

[Antibiotic-resistant Corynebacteria--a new problem of infection in immunosuppressed patients].

Corynebacterium species can normally be found on the skin and mucous membranes but rarely cause infections. They are sensitive to most antibiotics. Two patients with severe aplastic anemia undergoing antilymphocyte globulin therapy developed septicemia with a highly antibiotic-resistant corynebacterium (JK-group) only sensitive to vancomycin. Both patients had prolonged severe neutropenia, defects of the mucocutaneous barrier and intensive antibiotic treatment for gram negative infections. In both cases surveillance cultures already revealed the causative microorganism before fever started. One patient was even colonized with corynebacterium for several months before. If this strain is detected in the blood when new fever develops during prolonged neutropenia and broad-spectrum antibiotic therapy, it indicates serious infection in these highly compromised patients. Both cases illustrate that regular microbial surveillance can help to reveal colonization of high risk patients with multiple antibiotic-resistant corynebacterium strains and thus allow early initiation of treatment with vancomycin, which is the only effective antibiotic.

Anti-Bacterial Agents↗
PubMed1995

Tiludronate: development as an osteoporosis therapy.

The clinical development of tiludronate (tiludronic acid, disodium salt) for the treatment of Paget's disease of bone is now being complemented by another clinical trials program to investigate its use in osteoporosis. It is expected that osteoporosis will become a major indication for tiludronate, and this paper describes the trial design and treatment goals that will be employed in these new studies. In studies to assess the incidence of fracture, the primary efficacy end point is the occurrence of vertebral fractures after 3 years of therapy. Secondary end-points include changes in lumbar bone mineral density, spinal deformity index, and height. Changes in biochemical markers and quality of life will also be assessed. Safety evaluations include clinical laboratory parameters, adverse events and, in selected patients, histomorphometry of the iliac crest bone. For the nonfracture studies, the primary efficacy end-point is the effect on bone mineral density after 2 years of therapy. Secondary end-points include vertebral fracture rate, spinal deformity index, and height. Biochemical markers, quality of life, and safety (including bone biopsies in selected patients) will be evaluated as in the fracture studies. The studies are expected to be completed in early 1997, followed by worldwide regulatory applications in late 1997.

Animals↗
PubMed1985

Short-term and long-term effect of prophylactic treatment of superficial bladder cancer with intravesical adriamycin.

37 patients with recurrent Ta/T1 bladder cancer were treated with intravesical adriamycin (80 mg monthly) after complete TUR (1977-1979). Within a minimum follow-up of 5 years, 11 of them developed evidence of progression - muscle invasion or distant metastases. 8 of them have died of bladder cancer. Ten patients showed a complete response to adriamycin therapy, developing no new tumors during the period of treatment (1 year). One of them developed distant metastases. The remaining 27 patients continued to develop recurrences, despite adriamycin therapy, though the recurrence rate was reduced by at least 50% in 5 of them. The risk of progression and death remains high if the patient continues to have recurrences, even in cases in which the recurrence rate is apparently reduced. Recurrent superficial bladder cancer remains a dangerous disease. The prognosis is good if recurrences cease altogether during prophylactic intravesical adriamycin treatment.

Aged↗
PubMed2006

Epigenetic therapy--a new development in pharmacology.

Epigenetics, heritable changes in gene expression that do not involve changes in DNA sequence, is known to be involved in disease. Two important epigenetic changes that are known to contribute to disease are abnormal methylation patterns of DNA and modifications of histones in chromatin. This review describes a new development in pharmacology, epigenetic therapy, which attempts to correct these changes. At present two groups of drugs are being developed. One inhibits DNA methyltransferases (DNMTs) resulting in the inhibition of DNA methylation. This group of drugs may prove to be useful in the treatment of cancer where hypermethylation of tumour suppressor genes is known to lead to silencing of these genes. The other group of drugs inhibits histone deacetylases (HDACs) resulting in the accumulation of acetylated histones which are thought to mediate the anticancer effects of these drugs. Both these drug groups have shown promising results in drug trials for the treatment of cancer. Since epigenetic changes are thought to underlie a wide range of diseases, the scope of epigenetic therapy is likely to expand.

Clinical Trials as Topic↗
PubMed2003

Research and development of radiation therapy in clinical routines.

In an investigation conducted by the Swedish Cancer Society, the present status, critical issues and future aspects and potentials were described by an expert group for each of nine major areas of radiation therapy research. In this report, research and development in radiation therapy clinical routines is described. The terms research, development, quality assurance, quality control and clinical routines in radiation therapy are also defined.

Clinical Competence↗
PubMed1987

Neuroplasticity and the developing brain: implications for therapy.

Normal brain development consists of a series of interdependent and temporally overlapping processes. These include cell division, migration and aggregation, dendritic elaboration, axonal elongation and arborization, and synaptogenesis. There is a general pattern in all of these of predictable early development with evidence of specificity, followed by a period of remodeling. Lesions of the central nervous system occurring during development will affect these developmental processes at different points in the sequence and therefore have disparate effects on different portions of the brain at any given time of occurrence, as well as different effects depending on the time when the insult occurs. Unlike lesions occurring in the more steady-state condition of the adult nervous system, lesions during development have additional effects in redirecting subsequent development. It is arguable that this implies enhanced opportunities to mitigate the deleterious effects of such lesions. Potential therapeutic interventions can be divided by whether they are applied acutely, subacutely or late after injury. There are reasons for optimism regarding development of powerful new treatments in each of these categories. Further delineation of plasticity and the application of the resulting insights promise exciting and therapeutically important advances.

Animals↗
PubMed2006

Psychological and behavioral treatment of insomnia:update of the recent evidence (1998-2004).

BACKGROUND: Recognition that psychological and behavioral factors play an important role in insomnia has led to increased interest in therapies targeting these factors. A review paper published in 1999 summarized the evidence regarding the efficacy of psychological and behavioral treatments for persistent insomnia. The present review provides an update of the evidence published since the original paper. As with the original paper, this review was conducted by a task force commissioned by the American Academy of Sleep Medicine in order to update its practice parameters on psychological and behavioral therapies for insomnia. METHODS: A systematic review was conducted on 37 treatment studies (N = 2246 subjects/patients) published between 1998 and 2004 inclusively and identified through Psyclnfo and Medline searches. Each study was systematically reviewed with a standard coding sheet and the following information was extracted: Study design, sample (number of participants, age, gender), diagnosis, type of treatments and controls, primary and secondary outcome measures, and main findings. Criteria for inclusion of a study were as follows: (a) the main sleep diagnosis was insomnia (primary or comorbid), (b) at least 1 treatment condition was psychological or behavioral in content, (c) the study design was a randomized controlled trial, a nonrandomized group design, a clinical case series or a single subject experimental design with a minimum of 10 subjects, and (d) the study included at least 1 of the following as dependent variables: sleep onset latency, number and/or duration of awakenings, total sleep time, sleep efficiency, or sleep quality. RESULTS: Psychological and behavioral therapies produced reliable changes in several sleep parameters of individuals with either primary insomnia or insomnia associated with medical and psychiatric disorders. Nine studies documented the benefits of insomnia treatment in older adults or for facilitating discontinuation of medication among chronic hypnotic users. Sleep improvements achieved with treatment were well sustained over time; however, with the exception of reduced psychological symptoms/ distress, there was limited evidence that improved sleep led to clinically meaningful changes in other indices of morbidity (e.g., daytime fatigue). Five treatments met criteria for empirically-supported psychological treatments for insomnia: Stimulus control therapy, relaxation, paradoxical intention, sleep restriction, and cognitive-behavior therapy. DISCUSSION: These updated findings provide additional evidence in support of the original review's conclusions as to the efficacy and generalizability of psychological and behavioral therapies for persistent insomnia. Nonetheless, further research is needed to develop therapies that would optimize outcomes and reduce morbidity, as would studies of treatment mechanisms, mediators, and moderators of outcomes. Effectiveness studies are also needed to validate those therapies when implemented in clinical settings (primary care), by non-sleep specialists. There is also a need to disseminate more effectively the available evidence in support of psychological and behavioral interventions to health-care practitioners working on the front line.

Adult↗
PubMed1995

Prevention of graft-versus-host disease and the induction of transplant tolerance by low-dose UV-B irradiation of BM cells combined with cyclosporine immunosuppression.

GVHD is prevented and stable chimerism is induced in the rat BMT model by 700 J/m2 but not 100-500 J/m2 UV-B irradiation of allogeneic BM cells. Paradoxically, CsA which prevents GVHD in clinical BMT causes an aggressive autoimmune disease termed syngeneic GVHD in irradiated syngeneic BMT recipients after its withdrawal. Recently, we have shown that while 500-700 J/m2 UV-B irradiation of syngeneic BM cells combined with a 30-day course of CsA recipient immunosuppression impairs hemopoiesis due to lack of hemopoietic factors, a low dose of 100-300 J/m2 UV-B is effective in preventing CsA-induced autoimmune disease without endangering BM engraftment. This study extends these findings to the P-to-F1 hybrid and fully allogeneic rat BMT models and examines the effectiveness of low-dose UV-B irradiation of BM cells combined with a short course of CsA treatment in the prevention of GVHD and induction of transplant tolerance. Lethally gamma-irradiated (10.5 Gy) LBNF1 recipients of naive or UV-B irradiated (100-700 J/m2) BMT were treated with CsA (12.5 mg/kg/day) for 30 consecutive days after BMT. All lethally irradiated LBNF1 that did not receive BMT died in < 16 days, while animals transplanted with UV-B (700 J/m2) BMT survived > 1 year without GVHD. In contrast, all recipients of naive BMT died of lethal GVHD in < 50 days. Similarly, all recipients of naive BMT that received a 30-day course of CsA therapy developed severe GVHD with 60% mortality after cessation of CsA therapy. CsA-treated recipients of BMT irradiated with 700 J/m2 died between 12 and 25 days from failure of hemopoiesis. In contrast, CsA-treated recipients of 100-200 J/m2 UV-B irradiated BMT showed full BM engraftment without GVHD after cessation of CsA and survived > 1 year. These results were reproducible in the fully allogeneic UV-B BMT model. To test for donor-specific tolerance, the animals challenged 100 days after BMT with cardiac allografts accepted permanently (> 100 days) Lewis but not BN (non-BMT parental donor) cardiac allografts. Our results confirm that 700 J/m2 UV-B irradiation of BM cells combined with CsA recipient immunosuppression impairs the recovery capacity of stem cells while the use of lower UV-B (100-200 J/m2) is effective in preventing CsA-induced autoimmune disease without endangering BM engraftment and leads to induction of transplant tolerance.

Animals↗
PubMed1999

Editorial

Remarkable advances have occurred in wound healing during the past decade in both basic wound biology, as well as applied research into novel treatments of chronic wounds. Newly developed therapies have included the use of growth factors to enhance wound epithelialization, and the use of bioengineered dressings, including skin substitutes. These advances were recently highlighted in the December 1998 JCMS supplement on Wound Care. The lead article in this current issue of JCMS focuses on potential mechanisms to establish quantifiable end points during wound healing, and speculates on the potential relevance to the development of novel therapies. Palenske and Morhenn have found that measurement of skin capacitance is a useful tool in determining endpoints in wound healing. While our ultimate goal in wound healing is to completely re-epithelialize and heal a wound, sometimes interventions are less successful. In evaluating wound healing agents in preclinical or early clinical studies, surrogate markers may be necessary. Skin capacitance may serve as such a marker. In our Point Counterpoint Section, Drs Goldhar and Gratton address the controversial issue of whether dermatologists should promote treatment products. There are strong opinions on both sides of this question, and these two practitioners have concisely addressed the respective sides of this issue. The Grand Rounds Section features an article by Bergman and co-authors in which they describe a case of crusted scabies in association with HTLV-1. Dermatologists are frequently faced with individuals with generalized pruritic eruptions, where scabies is frequently in the differential diagnosis. Indeed, scabies is quite common worldwide. However, crusted scabies, or Norwegian scabies, is much less common, and one clearly has to consider immune deficiencies. This report highlights the association of crusted scabies with immune deficiency. In our CME sections of this issue, we have two important articles. The first, by Dr. Sherri Bale, is a continuation of our Genetic Studies in skin disease research, and the article reviews the area of mapping of hereditary skin disease by focusing on the gene for pseudoxanthoma elasticum. In our day-to- day clinical practice, we frequently discuss the clinical diseases we see in terms of prognosis that is often based on our own individual experience. Evidence based prognostic modelling may provide a very important technique to more accurately assess our patients' outcomes. Drs. Kantor and Margolis review the models and enhance our understanding of these techniques. In this issue of the Journal we introduce a new section of structured book reviews. Two books, Morphologic Diagnosis of Skin Disease and Handbook of Dermatology for Primary Care are reviewed. The structured review provides a concise analysis of these books to allow readers to determine application of these publications to their needs. I hope that each and every one of our readers had a very happy holiday season and I wish you the best for the new year.

Journal Article↗
PubMedDate not supplied

Developing a complementary therapy policy.

Increasingly, healthcare professionals from a variety of settings are looking to integrate complementary therapies into mainstream healthcare. Robust policy development is a prerequisite for effective integration and the building of sustainable services. Unfortunately many of those wanting to drive forward the complementary therapy agenda have little knowledge of policy development. For those individuals planning to integrate complementary therapies into care, this article will address some of the issues around developing a complementary therapy policy: the need for a robust policy, how to begin developing a policy and suggested inclusions for such a policy.

Advisory Committees↗
PubMed1999

Necrotizing fasciitis caused by Serratia marcescens in two patients receiving corticosteroid therapy.

Necrotizing fasciitis (NF), a devastating soft tissue infection, is rarely attributed to Serratia marcescens. We here report two patients with S. marcescens NF, both of whom had underlying renal disease and had been receiving corticosteroid therapy. The first patient, a 40-year-old man with systemic lupus erythematosus and uremia on prednisolone therapy, developed fulminant cellulitis and septic shock 1 month after a skin biopsy for cutaneous vasculitis of the left foot. The cellulitis evolved to NF, and blood and necrotic tissue cultures both grew S. marcescens. The patient completely recovered after debridement and ceftazidime therapy. The second patient, a 73-year-old man receiving prednisolone therapy for nephrotic syndrome, developed right leg cellulitis that evolved to NF. Blood and necrotic tissue cultures both grew S. marcescens. After aggressive debridement and ciprofloaxcin therapy, the NF improved. However, the patient died of aspiration pneumonia and massive gastrointestinal bleeding 1 month later. These findings illustrate that S. marcescens should be considered as a potential pathogen causing NF in susceptible hosts.

Adult↗
PubMed1998

[Current problems of antibacterial therapy].

The development of medicine has been accompanied by the increase of the proportion of immunocompromised patients and as a consequence of antibiotic use, bacterial resistance has reached an unexpected level. Along with these changes, we have been witnessing the rapid development of antimicrobial therapy that comprises several components besides the development of new molecules. The learning of pharmacodynamic effects of particular antibiotic classes can improve the efficacy of therapy and a better cure rate can be achieved in empiric therapy by the knowledge of risk factors and local resistance patterns. It has become clear that an antibiotic policy based exclusively on restriction would result in increased bacterial resistance rate after a temporary decrease of antibiotic cost and was unable to prevent the emerge and spread of multiresistant strains. The solution is the rational and adequate use of antimicrobials, based on the modern theory and practice of antibiotic policy and infection control, that cannot be carried out without the activities of experts in this field.

Anti-Bacterial Agents↗