Bacteriophages: antibacterials with a future?

The hypothesis as to whether a benign species of bacteria could kill a virulent kind has to this point been untested. Recently it was shown that in the macrophage, bacteriophages, when properly introduced through a nonvirulent microbe, had a killing rate for virulent AIDS Mycobacterium tuberculosis and Mycobacterium avium far in excess of modern day antibiotics. The study in effect brought a natural phenomena, lysogeny, whereby one bacterial colony kills another thru phage weaponry, to bear in the conquest of hard-to-kill, antibiotic resistant pathogens. This killing occurred intracellularly, within the white blood cell using Mycobacterium smegmatis, a benign bacterial species found generally in smegma secretions from human genitalia as well as soil, dust and water, and first identified in 1884. The subsequent treatment of M. avium-infected, as well as M. tuberculosis-infected RAW 264.7 macrophages, with M. smegmatis transiently infected with TM4 resulted in a unexpectedly large time- and titer-dependent reduction in the number of viable intracellular bacilli. In addition, the M. smegmatis vacuole harboring TM4 fused with the M. avium vacuole in macrophages. These results suggested a potentially novel concept to kill intracellular pathogenic bacteria and warrant future development.     

Does Cognitive Neuropsychology have a future?

Reflections stimulated by Rapp, B. (Ed.) (2001). 'The handbook of cognitive neuropsychology: What deficits reveal about the human mind'. Philadelphia: Psychology Press.     

The unfolded protein response and cancer: a brighter future unfolding?

Mammalian cells are bathed in an interstitial fluid that has a tightly regulated composition in healthy states. Interstitial fluid provides cells with all the necessary metabolic substrates (oxygen, glucose, amino acids, etc.), and waste molecules are removed by diffusion gradients that are controlled by local vascular perfusion. The health and normal function of all cells within a body is dependent on the maintenance of this microenvironment. However, many disease states cause fluctuations in this, and in some instances, these might be of sufficient severity to stress and/or be toxic to the cell. Cells have developed a number of responses to enable their survival in a hostile environment. This article discusses one such pathway--the unfolded protein response and its relationship to cancer. The molecular signalling cascade, the mechanism of its activation in cancer and the consequences of its activation for a tumour are discussed, as are clinical studies and potential translational approaches for utilising this pathway for tumour targeting.     

Is there a future for spermatid injections?

Microinjection of spermatids into oocytes has proven to be a successful assisted reproduction procedure in the animal model. In the human, low fertilization and cleavage to the 4-cell stage were reported after intracytoplasmic sperm injection (ICSI) with round spermatids. In comparison with a conventional ICSI-testicular sperm extraction (TESE) programme, the implantation rate after round spermatid injection is dramatically low. Different problems have been encountered during the development of the spermatid injection technique and they could be partially responsible for the lower outcome when using round spermatids. Compared with the round spermatid cells, spermatids in the elongation phase are easy to isolate and identify from other round cells present in a wet preparation. The morphological identification does not reveal anything about the viability or the genetic normality of the round spermatids. Severe testicular dysfunction may have consequences on the quality of the few spermatogenic cells present. Others factors, such as the pathology of the patient, play an important role in the successful treatment. Even if the results are extremely low, spermatid injection seems more favourable for men who have already proven their capacity to produce some spermatozoa. A spermatogenic block at the round spermatid level has led to early abortions, increasing the suspicion of the role of a genetic factor. In order for this technique to be safe for use in clinics, more intensive work is needed to improve the selection and handling of cells and to ascertain the genomic imprinting and gene expression necessary for embryonic development. Hence, when using immature cells for conception, the screening of the patient and the follow-up of the pregnancies and babies should be mandatory.     

What future for zirconia as a biomaterial?

The failure events of Prozyr femoral heads in 2001-2002 have opened a strong, controversial issue on the future of zirconia as a biomaterial. The aim of this paper is to review and analyze the current knowledge on ageing process and on its effect on the long term performance of implants in order to distinguish between scientific facts and speculation. Current state of the art shows the strong variability of zirconia to in vivo degradation, as a consequence of the strong influence of processing on ageing process. As different zirconia from different vendors have different process related microstructure, there is a need to assess their ageing sensitivity with advanced and accurate techniques, and ISO standards should be modified, especially to gain confidence from clinicians. There is a trend today to develop alumina-zirconia composites as an alternative to monolithic alumina and zirconia: the issue of ageing is also discussed for these composites.     

Is hippocampal atrophy a future drug target?

Hippocampus is the brain structure, vital for episodic and declarative memory. Atrophy of the human hippocampus is seen in a variety of psychiatric and neurological disorders e.g. recurrent depression, schizophrenia, bipolar disorder, post-traumatic stress disorder, epilepsy, head injury, and Alzheimer's disease (AD). Importantly, aging hippocampus also undergoes atrophy. In many instances, for example, AD, the atrophy precedes the development of symptoms while in others, there is a temporal relationship between atrophy and symptomatology. The presence of atrophied hippocampus is one of the most consistent features of many common psychiatric disorders. Several factors contribute to this atrophy. Stress is one of the most profound factors implicated and the mechanisms involve glucocorticoids, serotonin, excitatory amino acids etc. Hippocampal formation as a whole can undergo atrophy or its individual structural components e.g. apical dendrities can exhibit atrophy. Several drugs of unrelated classes have been shown to prevent atrophy indicating heterogenous manner in which hippocampal atrophy is produced. These include, tianeptine (affects structural plasticity in hippocampus and is an effective antidepressant); phenytoin (antiseizure and neuroprotective); fluoxetine (downregulates neurodegenerative enzyme and increases neuroprotective hippocampal S100 beta); lithium (neuroprotective and antiapoptotic); tricyclic antidepressants (increase hippocampal neurogenesis); antipsychotics (reduce hippocampal neuronal suppression); sodium valproate (increases neurogenesis) and mifepristone (antioxidant, neuroprotective and anti-glucocorticoid). Now the most important question is: to what extent does the hippocampal atrophy play a role in the genesis of symptoms of diseases or their progression? And if it does, can we achieve the same degree of prevention or reversal seen in experimental animals, in humans also. An even more important question is: whether the prevention of atrophy would be clinically useful in affecting disease, viz slowing its progression, reducing morbidity, complications or positively affecting the outcome of one or more of its clinically important aspects. If the answer to this is yes, we would have to know at what stage of the disease we use the drugs, dose, duration, follow-up and efficacy. The use of these drugs in the above mentioned conditions can not only test the potential of atrophy as a future drug target, but could also help in learning more about the hippocampus in both health and diseases.     

Pathogen-derived immunomodulatory molecules: future immunotherapeutics?

The identification of molecules from various pathogens that modulate innate and/or adaptive immunity is a dynamic and rapidly developing area of research. These immunomodulatory molecules (IM) have been optimized during pathogen-host co-evolution, and have a potential application as novel immunotherapeutics. In this review, we illustrate the use of pathogen IM that have been produced as recombinant proteins, with different modes of modulatory activity, and discuss their potential to modulate undesirable immune responses in human diseases.     

Is there a future for TNF promoter polymorphisms?

The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied -308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.     

DNA vaccines: are they still just a powerful tool for the future?

Vaccination is historically one of the most successful strategies for the prevention of infectious diseases. For safety reasons, modern vaccinology tends toward the usage of inactivated or attenuated microorganisms and uses predominantly subunit vaccines. The antigens need to be clearly defined, pure, stable, appropriately composed, and properly presented to the immune system of the host. Differing ratios of various proportions between specific CD4⁺ and CD8⁺ T cell responses are essential for conferring the required protection in the case of individual vaccines. To stimulate both CD4⁺ and CD8⁺ T cells, the antigens must be processed and presented to both antigen-presentation pathways, MHC I and MHC II. Protein antigens delivered by vaccination are processed as extracellular antigens. However, extracellularly delivered antigen can be directed towards intracellular presentation pathways in conjugation with molecules involved in antigen cross-presentation, e.g. heat shock proteins, or by genomic-DNA vaccination. In this overview, current knowledge of the host immune response to DNA vaccines is summarized in the introduction. The subsequent sections discuss techniques for enhancing DNA vaccine efficacy, such as DNA delivery to specific tissues, delivery of DNA to the cell cytoplasm or nucleus, and enhancement of the immune response using molecular adjuvants. Finally, the prospects of DNA vaccination and ongoing clinical trials with various DNA vaccines are discussed.     

Is immunosuppression a future therapeutic strategy for multiple sclerosis?

Although in previous studies no clear demonstration was found of the efficacy of azathioprine, cyclophosphamide and methotrexate as immunoprophylactic agents in cases of multiple sclerosis (MS), over the past five years a number of well-designed clinical trials utilizing immunosuppressive and immunomodulatory agents have shown partial efficacy regarding the drugs involved, but they have not been able to determine in what way these drugs can modify the natural course of this disease. Among the immunosuppressors, mitoxantrone is of particular interest as during the past two years three controlled trials have taken place in Europe and have demonstrated its efficacy both as regards clinical (frequency of symptoms, progression of the disease) and magnetic resonance imaging (MRI) criteria. Due to its potentially severe cardiotoxicity related to total cumulative dose, mitoxantrone is only prescribed for a limited period, and its use is limited to selected patients with a high relapse rate and incomplete remission, or to those who do not respond to beta-interferon treatment. The immunomodulatory agents have less immediate efficacy, but because they are well tolerated they can be used early in the course of the disease and over a prolonged period of time. The beta-interferons (1a or 1b) have been given market approval for use in the treatment of MS: three large, randomized, double-blind studies have demonstrated their capacity to reduce by 30% the frequency of symptoms and the appearance of disabilities associated with relapse and with the progression of the disease. Glatirameracetate or copolymer 1, which is available in France (ATU), has been found to reduce the frequency of relapse by 30%. It constitutes an alternative immunomodulatory treatment for relapsing-remitting patients without major functional disabilities and who suffer from severe side effects with beta-interferon treatment. In the future, the early use of immunomodulatory agents and therapeutic drug combinations may be introduced. Therapeutic trials are currently in progress to determine the viability of this approach.     

Cancer vaccines: is the future now?

Cancer immunotherapy is an area with a tremendous amount of promise. The field has matured in that the approaches and antigens appear very specific and highly reasonable. Furthermore, the pre-clinical models support their evaluation. In fact, the human immune responses against many of the vaccines are approaching thresholds that should start to impact disease. While the creativity and progress in technology was clearly evident, there is much work left to pursue. Clear evidence for this situation is reflected the low number of products and approaches that are in late-stage trials. This again reflects that many apparently promising technologies have trouble making the transition from mouse to human. However, the success in the antibody field strongly supports that once understood, the correct immunization strategies and antigens will have dramatic impact on disease. One improvement would be some optimization of approaches at least for immunogenicity in nonhuman primates. Another important issue for standardization, is to focus on the use of quantitative immune measurement systems rather than a reliance on bulk assay systems for decision-making. Such a minor change would allow more standardization of data interpretation across the field and allow for more rapid and intuitive vector evaluation, even if trials were not head to head. In this regard, the development of class II tetramer technology to the evaluation of tumor antigens where available would be a welcome advance. Furthermore, in general, flow-based assays for immune evaluation are similarly gaining acceptance. It is important to remember that the success of recent antibody products for lymphoma and breast cancer did not happen overnight. Rather, those successes were 20 years in the making. In this regard, for cancer immunotherapy, which is T-cell based, this similar anniversary is not yet upon us but it is getting close. The next few years are critical to this emerging field and likely to be full of promise, surprises and even success.     

Is there a future for vaccination as a treatment for Alzheimer's disease?

Vaccination of APP transgenic mice with Abeta has been shown to prevent amyloid deposits. A clinical trial of Abeta vaccination in Alzheimer's disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with Abeta should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human Abeta so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen-antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically.