CORTICOTROPIN (ACTH) AND CORTISONE—Newer Concepts of Their Use in Clinical Practice

On the basis of three years'' experience with corticotropin and cortisone, it seems probable that the place of these hormones in clinical medicine will be one of increasing importance. At present they may be used to attain certain specific objectives:1. To return a large number of chronic invalids to a place of full activity in the community. This applies particularly to patients with rheumatoid arthritis and bronchial asthma. Many years of continuous therapy will be required in the majority of such patients.2. As life-saving agents in patients with certain diseases of unknown etiologic delineation that almost always cause death. In some patients treated for some of those diseases, therapy may eventually be discontinued.3. As life-saving agents (in conjunction with intensive antibiotic therapy) in patients with severe infections inadequately responsive to chemotherapy alone.Many of the untoward effects of hormonal therapy may be minimized or prevented by appropriate adjuvant measures.     

Antifungal activity of nontraditional antifungal agents

Invasive fungal infections are becoming increasingly important in the management of critically ill and immunocompromised patients. As organ and stem cell transplantation becomes more prominent and immune therapies are employed for diseases such as rheumatoid arthritis and plaque psoriasis, the population of patients at risk continues to grow. Many invasive fungal infections are associated with extremely high mortality rates. Antifungal options are limited and novel therapies are intriguing as we attempt to improve patient outcomes and preserve the antifungal armamentarium. Many other classes of pharmaceuticals typically seen as non-antifungal do in fact have significant antifungal activity. Prominent among these are calcineurin inhibitors, antiarrhythmics, antidepressants, antibacterials, and others. Some have activity alone and some augment the activity of conventional antifungals. Unfortunately, clinical data are lacking for most of these agents and their role in therapy remains undefined. This review focuses on several representative non-antifungal agents with antifungal activity.     

Aérosolthérapie à la kanamycine dans 200 cas de suppurations bronchopulmonaires

This paper describes the results obtained in 200 patients with bronchopulmonary suppurative diseases who received kanamycin aerosol therapy under intermittent positive pressure and in whom bacterial sensitivity study (antibiogram) was favourable.This method of treatment was well tolerated and was practically free of side effects. In most cases the improvement was rapid, was maintained and was often life-saving.The first series contained nine patients with pulmonary tuberculosis and a constant finding of sputum positive for Koch bacillus; four of these became negative after eight weeks of treatment. This suggested that kanamycin aerosol therapy had some effect on the Koch bacillus and that the study should be continued with a much larger group of patients with tuberculous suppurative pulmonary diseases to determine the efficacy of this antibiotic.     

Association of Soluble HLA-G with Acute Rejection Episodes and Early Development of Bronchiolitis Obliterans in Lung Transplantation

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS. We conducted a retrospective, single-center, pilot review of 38 lung transplant recipients who underwent collection of serum and bronchoalveolar lavage fluid 3, 6 and 12 months after transplantation, and compared soluble HLA-G concentrations in each to the presence of type A rejection and lymphocytic bronchiolitis in the first 12 months and to the presence of BOS at 24 months after transplantation. Lung soluble HLA-G concentrations were directly related to the presence of type A rejection but not to lymphocytic bronchiolitis. Our data demonstrate that soluble HLA-G concentrations in bronchoalveolar lavage but not in serum correlates with the number of acute rejection episodes in the first 12 months after lung transplantation, and thus may be a reactive marker of rejection.     

The role of DNA repeats and associated secondary structures in genomic instability and neoplasia

Tumour-associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent of such rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage-induced rearrangement, and discuss the possible role of interstitial, inverted telomere-like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours.     

Medical Assistance to the Aged

Aerosol therapy has three principal objectives: Mobilization of bronchial secretions, relief of bronchospasm and topical chemotherapy. It has become an important tool in the treatment of bronchopulmonary diseases. The equipment for inhalation therapy, however, should be adequate. Both large-capacity and small-capacity nebulizers must be available, and they must be the kind that will produce a mist with most of its particles only 0.5 to 2.5 micra in diameter. These nebulizers may be used alone or in conjunction with a variety of appliances that will deliver the aerosols to the respiratory tract. The use of humidifying agents as aerosols is extremely helpful in patients with retained bronchopulmonary secretions. In some patients who have particularly thick or gelatinous secretions and in patients with mucoviscidosis, ordinary water or saline solution is often not enough. Hypertonic saline may be of value in these cases, and it is suggested that half-molar (2.9 per cent) saline be administered in 10 per cent propylene glycol. In these cases, preparations containing detergents (tyloxypal) or other preparations containing enzymes (desoxyribonuclease or trypsin) may be given by the aerosol technique, with care not to cause irritation.The bronchodilator aerosol agents are of proved benefit in the treatment of bronchospastic disorders and are indicated in most cases of asthma and in those cases of emphysema in which there is definite evidence of associated bronchospasm.The value of the aerosol method of administering chemotherapeutic and antibiotic drugs has probably been overrated, and it is suspected that much of the benefit previously attributed to the therapeutic agent was actually a result of humidification and liquefaction.     

'Axogenic' and 'somagenic' neurodegenerative diseases: definitions and therapeutic implications.

Neurodegenerative diseases are characterized by a relentless loss of specific groups of neuronal subtypes. Many of these diseases share similar molecular mechanisms and extracellular mediators of neuronal loss. We now suggest that neurodegeneration originating in the neuronal cell bodies (e.g. in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) should be distinguished from that originating in the axons (e.g. in glaucoma, certain peripheral neuropathies and spinal stenosis). We propose that the former group of diseases be defined as 'somagenic' and the latter as 'axogenic'. Although axogenic disorders may share common symptoms and mediators of toxicity with somagenic disorders, they have distinct temporal, subcellular and signal-transduction features. We further suggest that, by adopting this classification of disorders based on pathophysiological processes, we will come to recognize additional diseases (in particular, those defined as axogenic) as being neurodegenerative and therefore possibly amenable to neuroprotective therapy.     

The status of corticosteroid therapy in dermatology

Therapy with systemic corticosteroids, despite attendant serious risks, is mandatory in diseases such as pemphigus, acute disseminated lupus erythematosus and some cases of exfoliative dermatitis that are ordinarily fatal, for in such cases life may be prolonged and the patients made comfortable. If no contraindications exist, therapy with corticosteroids is desirable, for diseases of short duration-contact dermatitis, serum sickness reactions and drug eruptions of all kinds-provided the causative factors have been removed and the reactions are causing severe distress.On the basis of encouraging reports in the literature corticosteroid therapy may be instituted with justification for a group of unrelated, intractable and discomforting diseases such as maddening pruritus ani, sclerema neonatorum, dermatomyositis, certain cases of sarcoidosis, berylliosis, Behcet's syndrome, universal calcinosis, Reiter's disease and ulcers of sickle-cell anemia. One must always bear in mind the well-defined contraindications to corticosteroid therapy and the hazards of its use, particularly if therapy is to be prolonged. Results from topical hydrocortisone therapy are particularly pleasing in chronic eczematous otitis externa and especially when it is combined with an antibiotic drug. Results are excellent also in nuchal eczema, dermatitis of the eyelids and in pruritus ani. More often than not, hydrocortisone ointment and lotions benefit more than do other standard remedies such diseases as atopic eczema, contact dermatitis, lichen simplex-chronicus and eczematized phases of conditions such as psoriasis and superficial mycotic infections. Preparations containing a combination of hydrocortisone and an antibiotic are more useful than hydrocortisone alone. When used with discrimination, with full attention to the selection of cases and proper concentration in the correct vehicle, hydrocortisone preparations in combination with antibiotics are excellent antieczematous agents.     

Cell-based therapies for the preterm infant

The severely preterm infant receives a multitude of life-saving interventions, many of which carry risks of serious side effects. Cell therapy is an important and promising arm of regenerative medicine that may address a number of these problems. Most forms of cellular therapy use stem/progenitor cells or stem-like cells, which have the capacity to migrate, engraft and exert anti-inflammatory effects. Although some of these cell-based therapies have made their way to clinical trials in adults, little headway has been made in the neonatal patient group. This review discusses the efficacy of cell therapy in preclinical studies to date and their potential applications to diseases that afflict many prematurely born infants. Specifically, we identify the major hurdles that must be overcome before cell therapies can be safely used in the neonatal intensive care unit.     

Challenges to therapy in the future

Quadruple therapy (with a proton pump inhibitor (PPI), metronidazole, tetracycline and bismuth) is generally reserved for second-line treatment; however, studies using this regimen for 7 days have found it to be effective even in metronidazole-resistant strains. Resistance is an ongoing problem with antimicrobial therapy but considerable progress has now been made into understanding the underlying genetic mechanisms of this process. Metronidazole resistance in Europe is usually in the range of 20-30% of strains but may be as high as 70% in some countries. One genetic mechanism involved is thought to be a mutation of the rdxA gene. Macrolide resistance appears to be on the increase in Europe, varying from 1% in some countries to 13% in others. The genetic mechanism involved has been shown to be a point mutation of a ribosomal RNA. Amoxicillin resistance is an emerging problem that has an adverse effect on eradication rates in clinical practice. Resistance has been shown to be caused by the absence of one of the four binding proteins in the cell wall. Few novel antibiotics have been developed for use in eradication therapy, although rifabutin, secnidazole and furazolidone have shown some success as part of combination therapy. Alternative therapies that have been tested include mucosal protective agents which have been used in place of a PPI in some eradication regimens with some success, and the somatostatin analog, octreotide, that has been used as part of quadruple therapy in place of a PPI and produced eradication rates of approximately 88%. The ultimate challenge is still to develop a safe and effective vaccine against Helicobacter pylori. Current and future research will also focus on identifying genetic targets for therapy, adhesion molecule analogs to prevent binding of the bacterium, and urease inhibitors. The current triple therapy treatment options available for the eradication of Helicobacter pylori infection are over 90% effective in susceptible organisms and there are very few medical conditions to which we can offer such efficacious treatment. Unfortunately, the recommendations made at consensus conferences are not always put into practice and physicians in primary care may be unaware of the true efficacy of eradication therapy. Treatment is very simple: three drugs, twice a day for 1 week. The main focus for both primary care physicians and gastroenterologists should be to reinforce the need for patient compliance, otherwise we will see an increase in antibiotic resistance. Patients should be prewarned that they may experience some mild side effects and should be encouraged to complete the course of treatment. The real challenge for the future will be the management of patients who do not respond to first-line treatment. This paper will focus on potential problems with therapy, such as antibiotic resistance, and possible future solutions, such as novel antibiotics and vaccines.     

Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

A range of physical and chemical agents induce the mitochondrial 'petite' mutation in the yeast Saccharomyces cerevisiae. DNA intercalating agents as well as chemicals which can interfere with DNA synthesis induce this mutation, but only in growing cells. Many chemical or physical agents that produce a DNA lesion which is not simply reversed can induce various levels of the petite mutation, and may be more effective in non-growing cells. A limited number of chemicals act like ethidium bromide, inducing a high frequency of petites which is partially reversible with increasing concentration or time. The ability of a specific compound to be transported into mitochondria or its affinity for AT base pairs in DNA may determine whether it acts primarily as a nuclear or mitochondrial mutagen. In mammalian cells, some neoplastic changes occur at the mitochondrial level. Analogies between yeast and mammalian mitochondria suggest that agents which increase petite mutagenesis in yeast may have some carcinogenic potential. Although some types of petite inducer may have potential as antitumour drugs, those which are very effective antimitochondrial agents appear to be too toxic for therapeutic use. A process comparable to early stages in petite mutagensis occurs in human degenerative diseases and it seems possible that a consequence of exposure to petite mutagens could be an increase in the rate of degenerative diseases or of the aging process.     

The future of new oral antibiotics including the quinolones.

It is estimated that more than 110 million dollars'' worth of oral antibiotics will have been sold in Canada in 1987. In the next few years several new oral antimicrobial agents will reach the market, including beta-lactamase inhibitors, cephalosporins, monobactams, erythromycins and quinolones. Most of these new agents have a broader spectrum of antibacterial activity than the presently available oral antibiotics. A few have a longer half-life and can be administered once a day. The new oral drugs, especially the quinolones and possibly beta-lactams, will now be used to treat infections that in the past could be treated only parenterally. Exacerbations of pulmonary infections due to Pseudomonas aeruginosa in cystic fibrosis can now be successfully treated at home with the new quinolones. Osteomyelitis, arthritis, pneumonia and pyelonephritis will most likely be treated at home in the future. In severe infections patients will be admitted to hospital for short courses of parenteral therapy, followed by oral treatment. If used appropriately the new oral agents may lead to new approaches to the treatment of infectious diseases.     

Germline alteration by gene therapy: assessing and reducing the risks

Developments in gene therapy are certain to lead to the treatment of an increasing variety of diseases, some of which will affect patients who might wish to have children following their gene therapy treatment. These circumstances raise the concern that germline integration of gene therapy vector DNA could occur. Although our current understanding of reproductive biology and of the biodistribution of gene therapy vectors administered to extragonadal sites indicate that this risk is low, animal experiments and clinical studies designed specifically to address this question are warranted; because of this risk, every gene therapy vector should be tested for its potential to integrate into germ cells and preimplantation embryos.     

β-Carotene Biosynthesis in Probiotic Bacteria

Susceptibility to deadly diarrheal diseases is partly due to widespread pediatric vitamin A deficiency. To increase vitamin A coverage in malnourished children, we propose to engineer a probiotic bacterium that will produce β-carotene in the intestine, which will be metabolized to vitamin A. Such a therapy has the potential to broadly stimulate mucosal immunity and simultaneously reduce the incidence and duration of diarrheal disease. To that end, a β-carotene-producing variant of the probiotic Escherichia coli strain Nissle 1917 (EcN-BETA) was generated. Notably, the strain produces β-carotene under anaerobic conditions, reflective of the gut environment. EcN-BETA also retains β-carotene production capability after lyophilization, suggesting that it may be amenable to dry formulation. Moreover, EcN-BETA activates murine dendritic cells in vitro, suggesting that the presence of β-carotene may not diminish the immunostimulatory capacity of EcN. Finally, we present a framework through which further improvements may enable approaches such as the one described in this report to yield innovative life-saving therapies for the developing world.     

Modelling insect diseases as functional predators

Abstract. Many larval diseases of insects allow no recovery once infected. Furthermore, infected individuals are not able to develop into adults and will not therefore reproduce. A simple modelling approach emphasizes the fact that, accordingly, the agents that cause these diseases are functionally predators. It is important to make this distinction and to be cautious in applying inference drawn from models of parasites to these diseases. Sublethal effects are well known in these insect larval diseases, and models show that they have important dynamical implications. Sublethal effects have received less attention in predator–prey interactions, but their functional relationship with insect diseases emphasizes that nonmortality effects of predators may have correspondingly important dynamical implications.     

Understanding emerging treatment paradigms in rheumatoid arthritis

Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed - and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice.     

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.     

生物被膜分散方式的研究进展

临床上生物被膜与感染的慢性迁延不愈密切相关,而生物被膜菌的分散又会造成感染的反复急性发作,给临床感染的有效控制带来很大困难。生物被膜菌的分散过程受到了遗传和环境等多因素的调控,主要是通过蜂式分散、块式分散和毯式分散3种形式来实现的。深入进行生物被膜基础研究对改变目前临床感染治疗的窘境有重大意义。     

Application of oncoproteomics to aberrant signalling networks in changing the treatment paradigm in acute lymphoblastic leukaemia

Oncoproteomics is an important innovation in the early diagnosis, management and development of personalized treatment of acute lymphoblastic leukaemia (ALL). As inherent factors are not completely known – e.g. age or family history, radiation exposure, benzene chemical exposure, certain viral exposures such as infection with the human T‐cell lymphoma/leukaemia virus‐1, as well as some inherited syndromes may raise the risk of ALL – each ALL patient may modify the susceptibility of therapy. Indeed, we consider these unknown inherent factors could be explained via coupling cytogenetics plus proteomics, especially when proteins are the ones which play function within cells. Innovative proteomics to ALL therapy may help to understand the mechanism of drug resistance and toxicities, which in turn will provide some leads to improve ALL management. Most important of these are shotgun proteomic strategies to unravel ALL aberrant signalling networks. Some shotgun proteomic innovations and bioinformatic tools for ALL therapies will be discussed. As network proteins are distinctive characteristics for ALL patients, unrevealed by cytogenetics, those network proteins are currently an important source of novel therapeutic targets that emerge from shotgun proteomics. Indeed, ALL evolution can be studied for each individual patient via oncoproteomics.     

A syndromic approach to common parasitic diseases

Standard textbooks discuss parasitic disease according to specific organisms. In contrast, patients with parasitic infections present to physicians with a variety of clinical manifestations that may involve any of several organ systems and that often mimic nonparasitic diseases. A syndromic approach to the clinical situation may help the physician in considering the most important parasitic agents. Many parasitic infections can be acquired in temperate climates. While often considered tropical or exotic, other parasitic diseases are now seen more frequently in developed countries because of immigration and increased world travel. In this review the clinical syndromes associated with common parasitic diseases in North America are discussed, with an emphasis on risk factors and diagnosis of specific infections.