Spongecake and eggroll: two hereditary diseases in Drosophila resemble patterns of human brain degeneration

Various neuronal degenerative diseases are characterized by late onset, relentless progression, and finally death. Many have a direct genetic basis; others are of still unknown etiological mechanisms [1,2]. The study of human neurodegenerative diseases is complicated by the difficulty of obtaining tissue samples at various stages of progression, especially early in the course of the disease. Since neurodegeneration occurs in many organisms [3-5], model organisms amenable to genetic and molecular techniques, such as the mouse, offer important advantages. Much less laborious and expensive are worms or flies, which have short generation times and can be rapidly screened for mutations. To investigate the use of the fly as a model system for identifying genes related to such diseases, we screened for mutants having reduced lifespan, then examined them for brain degeneration. We describe here two such mutants, each with a different pattern of degeneration as characterized by light and transmission electron microscopy. The brain of the aging spongecake mutant exhibits regionally specific, membrane-bound vacuoles similar to those seen in spongiform degenerations such as Creutzfeldt-Jakob disease [6,7]. The mutant eggroll develops dense, multilamellated structures in the brain, resembling ones found in lipid storage diseases such as Tay-Sachs [8].     

Do minocycline and other tetracyclines have a place in rheumatology?

Tetracyclines are a family of antimicrobials with activity against a broad range of organisms including those that develop intracellularly. Links have been reported between some infections and some inflammatory joint diseases, with the most notable example involving mycoplasmas and rheumatoid arthritis. Reactive arthritides are known to be triggered by organisms found in the gastrointestinal or genitourinary tract, and antigenic material from these organisms has recently been demonstrated in synovial tissue from patients with reactive arthritis. These facts led to the hypothesis that tetracyclines may be useful in rheumatoid arthritis and reactive arthritis. Two controlled studies found that minocycline benefited rheumatoid arthritis patients when it was given either as an adjunct to another second-line treatment or as the only slow-acting drug. Lymecycline has been found to expedite recovery from reactive arthritis due to Chlamydia trachomatis, and tetracycline to decrease the incidence of reactive arthritis due to sexually-transmitted diseases. The safety profiles of these treatments were acceptable in all available studies but require further investigation during long-term administration. The benefits may be related to the immunomodulating effects of tetracyclines and/or to their ability to inhibit metalloproteases such as collagenases. Whether tetracycline therapy influences the course of radiologic lesions in rheumatoid arthritis remains unknown. However, minocycline therapy has given sufficient proof of its efficacy to make it an attractive alternative in rheumatoid arthritis.     

Acinetobacter species as a cause of catheter-related infections

In recent years, Acinetobacter species have emerged as clinically important pathogens. Though these organisms are widely prevalent in nature, most human infections are hospital-acquired. Acinetobacter baumannii is the predominant species. Nosocomial Acinetobacter baumannii infections such as respiratory tract infections, urinary tract infections, meningitis following neurosurgical procedures, and bacteremia mainly affect patients with severe underlying disease in the ICU and often, in the setting of nosocomial outbreak. The occurrence of multiresistant strains often limits therapeutic options. A substantial part of Acinetobacter baumannii bacteremia cases represent catheter-related infections that usually carry a favorable prognosis. Acinetobacter species other than Acinetobacter baumannii are less frequently reported as a cause of infection in humans. Bacteremia due to these organisms is mostly sporadic and almost exclusively related to intravascular devices. The underlying diseases are often less severe than those of patients affected by Acinetobacter baumannii infections. The clinical course is usually benign and the infection responds readily to catheter removal irrespective of the appropriateness of antimicrobial therapy.     

The nature of diseases: evolutionary, thermodynamic and historical aspects

Physico-chemical sciences are dominated by the deterministic interpretation. Scientific medicine has generally been assigned to the area of functional biology and thence to the physico-chemical sciences. In as much as diseases are alterations of physiological processes, they share the ontological status of the latter. However, many diseases cannot be accommodated within a deterministic interpretation. First, many diseases are initiated by errors in transmission of information and followed by natural selection. These diseases, such as tumoural transformations and autoimmune processes, behave as evolutionary processes. Second, physiological processes do not cause irreversible changes while diseases may do so when not followed by restitutio ad integrum. The tendency of living organisms to maintain stationary states of great stability and minimum energy dissipation is largely due to intermolecular forces-stabilized structures, the information for which is selected during phylogenesis and decodified during ontogenesis. Diseases cause alterations of the biological structures, thereby shifting living organisms toward stationary states of lower stability and increased dissipation. The shift, reversible or irreversible, to less stable and efficient stationary states is a common thermodynamic feature of diseases. In spite of the uniqueness of their genotype, living organisms, during ontogenetic development, form spatio-temporal unrestricted classes of infinite membership. Neither stationarity nor environment-induced perturbations and consequent adaptations are sources of historicity because of the genomic programme constraint. Historicity is conferred, however, to each organism by the permanent record of such unique events as: a) the variation-selection processes occurring in the brain-mind and immunological systems; and b) irreversible alterations induced by diseases. The disease-induced changes have ontological and epistemological consequences. Since biological structures and functions are transformed into individual, historical entities, the laws of scientific medicine must be applied in clinical practice to higher levels of organization, namely to the ensembles or groups of individuals affected by the diseases.     

Gastrointestinal disease in the immunocompromised patient

Gastrointestinal (GI) disease is frequent in all types of immunocompromised patients but occurs with greatest frequency in patients with acquired immunodeficiency syndrome (AIDS). Thus, much of this review deals with human immunodeficiency virus (HIV)-related GI diseases. Gastrointestinal diseases in other immunocompromised patients are compared with those in patients with AIDS. Conditions unique to transplant recipients, such as graft-versus-host disease (GVHD) and posttransplant lymphoproliferative disorders (PTLDs), are discussed separately. We have divided these GI diseases into four main categories: (1) HIV-related inflammatory conditions other than opportunistic infections (HIV-related enteropathy, proctocolitis, and CD8 lymphocytosis); (2) inflammatory conditions unrelated to HIV or opportunistic infections (neutropenic enterocolitis, regional enteritislike enteropathy, and GVHD); (3) opportunistic infections (illnesses caused by herpesvirus, cytomegalovirus, and miscellaneous other viruses; Mycobacterium, Candida, Histoplasma, Cryptococcus, Cryptosporidium, Microsporida, Isospora, Leishmania, Toxoplasma and Strongyloides organisms as well as Pneumocystitis carinii; and (4) neoplasias (Kaposi's sarcoma [KS], AIDS-related non-Hodgkin's lymphoma [NHL], HIV-related Hodgkin's disease [HD], PTLDs, and miscellaneous neoplasms). The prevalence, pathogenesis, clinical manifestations, gross pathological findings, and microscopic features of each disease entity are discussed.     

Bacterial adherence and its importance in the pathogenesis of infections

Bacteria usually attack the susceptible animal or human organisms at mucosal surfaces of the respiratory, gastrointestinal or genitourinary tract. To colonize these surfaces they must penetrate a number of nonspecific defense barriers including cleansing mechanisms such as sneezing, coughing, peristalsis and fluid flow. Successful microorganisms escape recognition by soluble immune or nonimmune molecules, and bind to the mucosal surfaces via specialised molecules exposed on their surface (adhesions) which recognize and interact with complementary molecules (receptors) on the surface of specific host cells. This key step in the pathogenesis of infectious diseases is currently the subject of intensive investigation. In this review the mechanism and the role of adherence in different bacterial infections are considered.     

Proteases of Porphyromonas gingivalis: what don't they do?

The gram-negative anaerobic bacterium Porphyromonas gingivalis has been strongly associated with the causation of human periodontal diseases. One distinguishing property of these organisms that has been implicated in periodontal destruction is the expression of potent protease activity. Recent biochemical and genetic approaches have clearly demonstrated that at least five distinct proteases are elaborated by these organisms. The utilization of monospecific mutants defective in individual proteases has demonstrated that protease activity is important in virulence but also has suggested the complexity of the functions of the enzymes in the physiology of these microorganisms. This review summarizes current progress in assessing the role of these enzymes in periodontal inflammation and discusses some unresolved issues relevant to the significance of P. gingivalis proteases in virulence.     

Fungal infections of the larynx

Some generalizations regarding fungal infections of the larynx can be made. The reader is cautioned to refer to discussions of the individual infections for exceptions to these generalizations. For the most part, the mycoses are organisms of low pathogenicity emerging as opportunistic organisms thriving in a compromised host. The isolated fungal infections of the larynx reported are exceptions to the rule. Involvement of the larynx and other body sites outside the lung generally indicates a widely disseminated form of the disease. Fungal infections most commonly occur in the immunocompromised patient, including those afflicted with AIDS, cancer, leukemia, and other lymphoreticular neoplasms, patients on long-term corticosteroid therapy, patients with chronic systemic diseases, including diabetes mellitus and severe pulmonary disease, and patients who have undergone successful organ transplantation, which depends on immunologic suppression. Although specific fungi are characteristically found in designated endemic areas, the diseases may surface in remote areas in persons who have recently traveled through the endemic sites. The pathologic picture can be confusing, and pseudoepitheliomatous changes at times resemble malignancy. When atypical features occur in a patient with a suspicious history, special stains and cultures as well as skin tests and serologic studies may be helpful in establishing the diagnosis. For the most part, amphotericin B has been the mainstay of therapy, although the introduction of the newer azole drugs (ketoconazole, itraconazole and fluconazole) may present a breakthrough in the future therapy of these lesions. Ketoconazole has been proven efficacious in certain fungal infections. Itraconazole has recently been released for clinical use. Because of its lower incidence of toxic side effects, it may replace ketoconazole in the therapy of these diseases. Finally, fluconazole, taken orally, effectively crosses the blood-brain barrier; appropriate clinical trials may prove it to be an acceptable agent for those fungi commonly affecting the central nervous system.     

Judaism, genetic screening and genetic therapy

Genetic screening, gene therapy and other applications of genetic engineering are permissible in Judaism when used for the treatment, cure, or prevention of disease. Such genetic manipulation is not considered to be a violation of God's natural law, but a legitimate implementation of the biblical mandate to heal. If Tay-Sachs disease, diabetes, hemophilia, cystic fibrosis, Huntington's disease or other genetic diseases can be cured or prevented by "gene surgery," then it is certainly permitted in Jewish law. Genetic premarital screening is encouraged in Judaism for the purpose of discouraging at-risk marriages for a fatal illness such as Tay-Sachs disease. Neonatal screening for treatable conditions such as phenylketonuria is certainly desirable and perhaps required in Jewish law. Preimplantation screening and the implantation of only "healthy" zygotes into the mother's womb to prevent the birth of an affected child are probably sanctioned in Jewish law. Whether or not these assisted reproduction techniques may be used to choose the sex of one's offspring, to prevent the birth of a child with a sex-linked disease such as hemophilia, has not yet been ruled on by modern rabbinic decisions. Prenatal screening with the specific intent of aborting an affected fetus is not allowed according to most rabbinic authorities, although a minority view permits it "for great need." Not to have children if both parents are carriers of genetic diseases such as Tay-Sachs is not a Jewish option. Preimplantation screening is preferable. All screening test results must remain confidential. Judaism does not permit the alteration or manipulation of physical traits and characteristics such as height, eye and hair color, facial features and the like, when such change provides no useful benefit to mankind. On the other hand, it is permissible to clone organisms and microorganisms to facilitate the production of insulin, growth hormone, and other agents intended to benefit mankind and to cure and treat diseases.     

Toxin-mediated streptococcal and staphylococcal disease

After several decades of seemingly decreasing virulence, streptococcal and staphylococcal infections have reemerged as a major source of morbidity and mortality. Within the past 2 decades, not only have well-established diseases such as rheumatic fever begun to reappear. but also many new entities, such as toxic shock syndrome, streptococcal toxic shock syndrome, recurrent toxin-mediated perineal erythema, and recalcitrant erythematous desquamating disorder have been described. Central to the renewed importance of these bacteria has been the production of circulating toxins, which often function as superantigens in causing the clinical manifestations, morbidity and mortality associated with these diseases.     

Clinical importance and antibiotic resistance of Acinetobacter spp. Proceedings of a symposium held on 4-5 November 1996 at Eilat, Israel

Members of the genus Acinetobacter, particularly multiresistant strains of A. baumannii, are implicated in a wide spectrum of nosocomial infections, including bacteraemia, secondary meningitis and urinary tract infection, but have now assumed a particularly important role as agents of nosocomial pneumonia in intensive care units (ICUs). Rapid genotyping methods for the identification and typing of these organisms have allowed a better appreciation of the epidemiology and survival of these organisms in the hospital environment. Their emergence as significant pathogens seems to be related partly to their survival ability and partly to their ability to develop resistance rapidly to the major groups of antibiotics, resulting in a considerable selective advantage in environments (such as ICUs) with widespread and heavy uses of antibiotics. Molecular and biochemical mechanisms of resistance to the major beta-lactam, aminoglycoside and quinolone groups of antibiotics have now been elucidated in some detail for these organisms, and experimental models, including a mouse model of A. baumannii pneumonia, have been developed to examine the efficacy of different therapeutic regimens for difficult-to-treat-infections caused by these bacteria. 'Non-classic' antibiotic combinations--such as ticarcillin with clavulanic acid and sulbactam--seem to show promise for treating systemic infections caused by otherwise multiresistant strains, but revised screening procedures in the pharmaceutical industry may be required in the near future to select novel compounds with activity against multiresistant Acinetobacter spp. and other emerging gram-negative, non-fermentative bacilli in general.     

Genetic dissection of obesity in polygenic animal models

In contrast to diseases caused by single-gene defects, many of the most common human maladies such as obesity, atherosclerosis, diabetes, and hypertension exhibit continuous phenotypic variation and a predominantly multifactorial and polygenic basis. Genes with roles in energy balance, nutrient partitioning, lipid and insulin metabolism, and a variety of behavioral traits are likely interacting with environmental stimuli to regulate obesity phenotypes. With the current proliferation of highly polymorphic genetic markers and the refinement of experimental approaches, it is now possible to screen thoroughly the genomes of model organisms for the individual genes or quantitative trait loci (QTL) that control measurable polygenic traits such as obesity. With the growing wealth of comparative mapping, it will be possible to predict the location of a homologous locus in the human after first mapping it in the mouse. Many experiments have been conducted in mice, rats, and pigs to estimate the number, location, and effect of QTL controlling obesity and related traits. This review describes the design and strategies of such studies and summarizes the results and their implications toward understanding the complex nature of obesity in humans.     

Genetics and the pathobiology of ageing

Genetics offers a powerful approach to the elucidation of mechanisms underlying specific components of the senescent phenotype of our species. Perhaps thousands of gene variations have escaped the force of natural selection and thus play roles in the genesis of different patterns of ageing in man. It is possible that a subset of these genes may be of particular importance in how most people age. While variations at the Werner helicase locus could be one such example, several lines of evidence suggest that mutation at that locus leads to a 'private' mechanism of ageing. It will be important, however, to investigate polymorphisms underlying the regulation of expression of this gene in the general population. Polymorphisms (normally occurring variants of a gene, or sequence of DNA), rather than mutations, may also prove to be more relevant to our understanding of the differing susceptibilities of people to common disorders such as late onset Alzheimer's disease. Polymorphic forms of the Apolipoprotein E gene is a good example. It remains to be seen if the pathogenetic framework (beta amyloidosis) derived from studies of the several rare mutations responsible for early onset familial forms of the disease proves relevant to the pathogenesis of the vastly more prevalent sporadic forms of the disorder. In contrast to the satisfying progress on the genetics of the diseases of ageing, research on the genetic basis for unusually robust retention of structure and function in old age has been neglected and requires a higher priority for the future. Such research should include studies of environmental agents and should address mechanisms of 'sageing', a stage in the life course characterized by an extensive utilization of behavioural and physiological adaptations to compensate for functional declines. For the genetics of longevity, we have to turn to genetically tractable organisms such as nematodes and fruit flies. Such studies have provided significant support for the oxidative stress theory of ageing. It will be important to learn more about the age-related pathologies and pathophysiologies of these organisms.     

Monoclonal antibodies to a 100-kd protein reveal abundant A beta-negative plaques throughout gray matter of Alzheimer''s disease brains

Methionine metabolism and transmethylation are central to the metabolism and differentiation of all known cells. In enkaryotic organisms, methionine metabolism and transmethylation are of paramount importance in modification and regulation of proteins, lipids, and nucleic acids. The differential methylation of genes regulates their expression in the myriad of cells in eukaryotic organisms. Disruption and abnormalities in methionine metabolism and transmethylation seems to be associated with the major diseases of mankind, including cancer, heart disease, aging, obesity, and Parkinson's disease. In this review, we describe how aberrant and abnormal methionine metabolism and transmethylation are related to these major diseases. Most importantly, we review and hypothesize how the developing therapeutic recombination methioninase (rMETase) can be utilized to cure or prevent all of these diseases.     

Immunising the population. Are we succeeding?

While diseases such as diphtheria and poliomyelitis have disappeared in this country, other vaccine preventable diseases such as measles, pertussis and rubella are quite common and result in epidemics from time to time. There are some groups in the community with particularly low coverage with specific vaccines and they need extra attention. Immunisation providers need to identify the barriers to achieving high coverage rates and adopt measures to overcome these barriers.     

MRI in acute transverse myelopathy

Cytokines have been widely tested in clinical trials during recent years and beneficial responses have been observed in a variety of malignant, infectious and autoimmune diseases. Interferon-alpha induces remissions in patients with certain hematological malignancies such as hairy cell leukemia and chronic myelogenous leukemia. A proportion of patients with chronic viral hepatitis is cured upon application of interferon-alpha. Treatment with interferon-gamma reduces the number of infections in patients with chronic granulomatous disease. In addition, several chronic infections with intracellular pathogens also respond to treatment with this cytokine. With the exception of some patients with renal cell carcinoma and malignant melanoma, solid tumors are largely resistant to administration of these cytokines. Cytokine treatment has changed the outlook for a small group of patients with selected chronic diseases. However, clinical experience with cytokines is still limited and only interferons have been tested for treatment of a variety of diseases. Thus, it seems reasonable to expect that more cytokine-responsive diseases might be identified by continued research efforts.     

Spotted fever group rickettsiae in southern Africa--a review and current concepts

Until recently our understanding of spotted fever group (SFG) rickettsioses in southern Africa was based on research carried out in the 1930s and 1940s. In the last decade there have been considerable advances in the techniques available to study rickettsias and the application of these in southern Africa has greatly increased our knowledge of the organisms in the region and the epidemiology of diseases they cause. In this review we describe the new advances used to study rickettsias and the current data available on SFG rickettsioses in the region.