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PubMed2000

[The probability of assessing the pathogenesis of ischemic stroke. Study of 81 patients].

81 patients with ischemic stroke were studied in order to assess the pathogenesis, the accuracy of the pathogenetic diagnosis and the relationship between pathogenesis and infarct site. The pathogenetic mechanisms were grouped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system. TOAST system settles five pathogenetic diagnosis: 1) Large artery atherosclerosis (LM); 2) Cardioembolism (CE); 3) Small artery occlusion (SAO); 4) Other etiologies (SOE); 5) Undetermined pathogenesis. As regards the site, the patients were divided into the following groups: Posterior Circulation Infarcts (POCI) 8.6%, Total Anterior Circulation Infarcts (TACI) 19.8%, Partial Anterior Circulation Infarcts (PACI) 29.6%, Lacunar Anterior Circulation Infarcts (LACI) 30.9%, Multiple Site Infarcts 11.1%. A probable or certain diagnosis was issued only in 33.3%. The diagnosis was not complete in 22.2%. That was due either to the severe clinical status or the patient and his relatives' refusal. Most of the incomplete diagnosis occurred in TACI patients. The undetermined pathogenesis due to absent clues occurred in 18.5%. CE often brought about TACI, whereas LM was likely to provoke PACI. SOE, like systemic hypotension, brought about Multiple Site Infarcts. Unfortunately assessing the pathogenetic diagnosis is still a controversial issue and TOAST method itself is not satisfactory as an overall classification system.

Adult↗
PubMed2000

Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The pathogenesis regarding heterogeneity of vascular malformations in patients with HHT has been obscure, although it has become possible to partially explain the pathogenesis from the identification of two distinct genes, endoglin and ALK-1. Endoglin and ALK-1 are type III and type I TGF-beta receptors, respectively, and are exclusively expressed on vascular endothelial cells. Binding of TGF-beta to the type II TGF-beta receptor on endothelial cells, which is accelerated in the presence of endoglin, phosphorylates type I TGF-beta receptors, ALK-5 and ALK-1, and phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively. These activated Smad proteins dissociate from the type I TGF-beta receptor, bind to Smad4, and enter the nucleus to transmit TGF-beta signaling by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between these two signaling pathways via ALK-5 and ALK-1 plays an important role in determining the properties of endothelial cells during angiogenesis. Mutations of endoglin and ALK-1 genes are genetic pathogenesis of HHT type 1 and HHT type 2, respectively. To date, at least 29 and 17 different kinds of mutations in endoglin and ALK-1, respectively, have been found, including missense, nonsense, frameshift, and deletion mutations. The precise mechanisms of vascular abnormalities elicited by these mutations observed in HHT patients are still uncertain, although elucidation of the mechanism of intracellular signal transduction and the change in targeted gene expressions using mutant recombinant endoglin or ALK-1 proteins and knockout mice will enable us to understand the genetic and molecular pathogenesis of HHT and to effectively treat patients with HHT.

Activin Receptors↗
PubMed1989

Alcohol-induced pancreatic injury (Part I). Unexplained features and ductular theories of pathogenesis.

The pathogenesis of alcoholic pancreatitis continues to be a puzzle. Classical theories of pathogenesis tend to overlook the dual nature of the disease, i.e., symptomatic acute attacks and chronic progressive parenchymal destruction. Furthermore, it is unknown why only a small minority of alcoholics develop clinical pancreatic injury. In addition, there is a lack of basic data concerning the natural history of the condition after cessation of alcohol consumption. The most widely accepted theory of pathogenesis postulates the deposition of protein plugs in peripheral pancreatic ducts as the initial lesion. However, it has not been established that these plugs are the cause rather than a result of pancreatic injury. The so-called "Big Duct" theories of pathogenesis (biliary-pancreatic reflux, duodeno-pancreatic reflux, and obstruction-hypersecretion) are confounded by a lack of agreement concerning the effect of alcohol on the sphincter of Oddi. Nutritional factors and heredity may be responsible for the selectivity of alcohol in this condition; in this regard, a number of dietary and HLA studies have been performed, but these have generally been inadequately controlled. Subcellular pancreatic injury (fat droplets, autophagic vacuoles, and mitochondrial lesions) has been observed in alcoholics without pancreatitis and in animals fed alcohol. In addition, ethanol feeding in animals has been shown to affect pancreatic cholesterol, phospholipid, and fatty acid metabolism as well as pancreatic content of digestive enzymes. Research is hampered by the lack of a suitable animal model of the disease.

Alcohol Drinking↗
PubMed1989

Genetics and molecular pathogenesis of Legionella pneumophila, an intracellular parasite of macrophages.

In addition to providing a powerful approach for identifying bacterial factors required for full infectivity and disease production, genetic analysis of Legionella pathogenesis should also lend critical insight into the biology of the macrophage and into the pathogenesis of other intracellular parasites. The interaction between L. pneumophila and the macrophage exhibits many features found in a wide variety of prokaryotic and eukaryotic intracellular human pathogens. For example, binding to complement receptors has been shown to occur for Mycobacterium tuberculosis, M. leprae, Leishmania donovani, Leishmania major and Histoplasma capsulatum. Coiling phagocytosis has been observed during entry of L. donovani. Phagosomes that contain Toxoplasma gondii or M. tuberculosis fail to fuse with lysosomes and, in the case of T. gondii, have been shown to remain close to neutral pH. Although the molecular bases for these phenomena are unknown, their functional similarities to the L. pneumophila-macrophage interaction provide optimism that generally applicable principles are involved. The genetic techniques reviewed here will provide the molecular tools with which such questions of a general biologic nature can be framed and eventually answered. Together with more traditional methods in biochemistry, microbiology and cell biology, molecular genetics offers a robust means toward identifying and understanding the bacterial factors involved in the pathogenesis of Legionnaires' disease. Molecular studies of L. pneumophila can also help address questions concerning the epidemiology, diagnosis and prevention of disease. For example, the distribution of virulence factors might help explain and predict the attack rates of different L. pneumophila strains or Legionella species. Moreover, bacterial genes/factors that are shown to be conserved in Legionella strains could be used to develop such diagnostic tools as DNA probes. Novel types of vaccines consisting of genetically constructed, avirulent L. pneumophila strains or subunit vaccines based on the molecular characterization of virulence factors might be developed and tested as protective immunogens. In this way, the capacity to analyze and to manipulate L. pneumophila genetically may facilitate the use of Legionnaires' disease as a model infection for studying protective cell-mediated immunity. Apart from its clinical significance as the etiologic agent of Legionnaires' disease, L. pneumophila may be a key to broader understandings in microbial pathogenesis and human cell biology and immunology. Although the extremely complex processes of bacterial infection and virulence are best understood when a variety of experimental approaches are employed, we believe that the evolving molecular genetic techniques reviewed here will be critical elements in many important breakthroughs in the future.

Animals↗
PubMed1987

[Cytotoxicity of bile acids and lysolecithin--a factor in the pathogenesis of stomach ulcer?].

The role of bile acids and lysolecithin in the pathogenesis of peptic ulcer is as yet not unequivocally defined. Based on the physiochemical properties of bile acids and animal experiments they have damaging potential on the mucosal cell. However, the majority of results reported in patients do not favour a significant role of bile acids in the pathogenesis of peptic ulcer. With regard to lysolecithin a sufficient data base is missing. Based on the damaging potential in animal experiments and the few reported patient studies a role in pathogenesis is more probable than for bile acids. Studies on concentrations and effects of both, bile acids and lysolecithin over prolonged periods of time in patients with ulcer disease are necessary to further clarify their role in pathogenesis of ulcer disease.

Animals↗
PubMed1983

Hypersensitivity pneumonitis--pathology and pathogenesis.

Early reports of hypersensitivity pneumonitis postulated that the disease was infectious or resulted from the toxic properties of the inhaled organic dusts. The finding of precipitating antibodies to moldy hay in farmers afflicted with farmer's lung suggested a role for antibody in pathogenesis, and a type III (antigen-antibody complex-mediated or Arthus) hypersensitivity reaction based on the classification of allergic reactions by Gell and Coombs was postulated. Subsequent studies have indicated the importance of cell-mediated (delayed) hypersensitivity (type IV). It must be recognized that hypersensitivity mechanisms are quite complicated and that the classification of Gell and Coombs is an oversimplification; interreacting humoral and cellular responses are typical of most hypersensitivity reactions of whatever classic type as originally defined. The prime importance of T-cell- and macrophage-mediated inflammation in HP, however, is indicated by histopathology, animal models, and in vitro correlates in humans. Major difficulties in defining completely the exact effector mechanisms involved in the pathogenesis of HP include the absence of a reliable in vitro correlate of antigen-specific effector T cells (the so called TDH cell) and the overwhelming versatility of the macrophage. There is no direct evidence to support contributions by precipitins, complement, or genetic host factors in the pathogenesis of hypersensitivity pneumonitis, nor are there studies as yet of cellular cytotoxicity contributions. Cellular and antibody interactions may lead to immunosuppressive processes modulating inflammatory responses and preventing disease despite immunogenesis. Animal models are helpful in dissecting mechanisms and defining effector functions. The eventual goal in studies of pathogenesis is to provide better tools for definitive diagnosis and methods of disease prevention, modulation, and cure.

Alveolitis, Extrinsic Allergic↗
PubMed1982

[Morphology and pathogenesis of visceral manifestations of chronic alcoholism].

Chronic alcoholism is accompanied by systemic involvement of the internal organs. Clinico-morphological forms of chronic alcoholism are distinguished on the basis of the prevailing organ pathology, Morphological data are presented, and pathogenesis of the lesions of the liver, heart, pancreas, and kidneys in patients with chronic alcoholism is analysed. The hepatic form may present alcoholic dystrophy, hepatitis or cirrhosis which are stages of progressing hepatopathy. The toxic and metabolic effect of ethanol is important in the pathogenesis of liver lesion. The cardiac form is characterized by the development of alcoholic myocardiodystrophy. In addition to the toxic influence of ethanol, hormonal and electrolyte changes and microcirculatory disorders play a role in its pathogenesis. Chronic calcifying pancreatitis in chronic alcoholism is associated with the effect of ethanol on the mediatory system. The renal form any present necronephrosis, hepatorenal syndrome, glomerulonephritis or pyelonephritis. Their pathogenesis is determined by toxicity of ethanol, circulation of immune complexes in the blood, or immunosuppression.

Alcoholism↗
PubMed1981

Theories of pathogenesis.

Theories of pathogenesis can be influenced by shared unconscious fantasies. This may determine the speedy enthusiasm with which some theories are accepted. In keeping with primitive, pleasure-seeking trends, it is appealing to blame illness on others and to view pathogenesis in terms of the intrusion into the self of some alien, noxious agent. These ideas can be seen in certain current theories that ascribe pathogenesis to inadequate, unempathic mothering. Such theories influence psychoanalytic technique. Analysis becomes a form of replacement therapy, in which the analyst facilitates normal development by serving as an appropriate object. This approach may gratify unconscious needs in analyst and analysand alike. The attempt to isolate one specific pathogenic factor as crucial fails to do justice to the complexity of pathogenesis and may lead to the failure to recognize the role of unconscious conflict and to analyze resistances.

Fantasy↗
PubMed1988

Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials.

We reviewed the current status of pathogenesis and therapeutic trials in amyotrophic lateral sclerosis (ALS). Clinical studies have identified several rare but definable causes for apparent ALS. Certain clinical features previously considered unlikely to occur in ALS are found on careful examination. Epidemiologic surveillance and recent studies of neurotoxic plant seeds used in Guam have shed light on the pathogenesis of endemic ALS. Extensive analyses of biochemical, metabolic, immunologic, viral, and toxic factors have provided provocative results requiring further studies. Reflecting on some of these hypotheses, therapeutic trials have been performed more vigorously than ever. Amyotrophic lateral sclerosis is now investigated at the molecular genetic level. Human autopsy and experimental animal studies have expanded our understanding of basic mechanisms involving motoneuronal degeneration. In the future, we must continue a relentless search for the pathogenesis of ALS, prospective clinical studies to define the limits of ALS, and well-designed, controlled therapeutic trials.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis.

The involvement of spleen macrophages in the early stages of scrapie pathogenesis was studied by applying the 'macrophage-suicide technique' to scrapie-infected mice. This method comprises critically the intravenous administration to mice of dichloromethylene disphosphonate encapsulated into liposomes. Depletion of spleen macrophages before scrapie infection induced an increased amount of scrapie inoculum in the spleen, consequently leading to accelerated scrapie agent replication in the early phase of pathogenesis, as followed by PrPres accumulation, a specific hallmark of scrapie. The same effect was observed when spleen macrophages were depleted just before the beginning of scrapie agent replication. These findings suggest that macrophages may partly control scrapie infection in peripheral tissues by sequestration of the scrapie inoculum and may thus impair early scrapie agent replication in the spleen. In addition to macrophages, most follicular dendritic cells and B lymphocytes, which are thought to support scrapie agent replication, were also transiently depleted by dichloromethylene disphosphonate administration. This suggests that a compensatory mechanism is sufficient to ensure the persistence of infection in these early stages of pathogenesis.

Analgesics, Non-Narcotic↗
PubMed1998

Muscle contractility decrement and correlated morphology during the pathogenesis of streptozotocin-diabetic mice.

BACKGROUND: Peripheral neuropathy of both motor and sensory nerves has been well documented in diabetes mellitus, but the evidence for physiological and correlated morphological changes during the pathogenesis of myopathy is scarce. In the present report, we have chosen the dorsiflexor muscle of adult male mice as a model for studying in situ muscle contraction and neuromuscular ultrastructure during the pathogenesis of streptozotocin-induced diabetes. METHODS: Thirty mice (30 g bodyweight) were injected once i.p. with streptozotocin solution (200 mg/Kg) to induce experimental diabetes mellitus. Comparative analyses of in situ muscle isometric contractile characteristics were studied (at 1 Hz, 5 Hz and 30 Hz nerve stimulation) in urethane-anesthetized (2 mg/g, i.p.) control and diabetic mice at three time points, 2 weeks, 4 weeks, and 8 weeks postinjection. Synaptic delay was also recorded in diabetic and age-matched control mice. RESULTS: There was a significant increase in synaptic delay in both 4-week and 8-week diabetic mice compared with control mice (8.9 +/- 1.2 msec and 7.6 +/- 0.6 msec, respectively, compared with 6.1 +/- 0.5 msec). At all three stimulation frequencies, diabetes did not affect muscle contractile speed but significantly reduced the twitch tension after 8 weeks, with no changes at 2 weeks or 4 weeks. The recorded single-twitch tension values were 2.6 +/- 0.3 g, 2.1 +/- 0.6 g, 2.2 +/- 0.7 g, and 1.2 +/- 0.1 g for control, 2 weeks, 4 weeks, and 8 weeks, respectively. At 30 Hz, the recorded tension values were 4.6 +/- 1.6 g, 3.1 +/- 1.2 g, 3.1 +/- 1.1 g, and 2.1 +/- 1.0 g for control, 2 weeks, 4 weeks, and 8 weeks, respectively. Ultrastructural changes in neuromuscular junctions were similar to those that have been described in disuse and aging. These changes were observed after 8 weeks and included serve loss of synaptic vesicles, electron-dense bodies, and myelin-like figures as well as degeneration of mitochondria. CONCLUSIONS: The results reveal that streptozotocin-induced diabetes affects presynaptically the neuromuscular junction as well as muscle itself. Actions at both sites may contribute to the functional alterations seen in muscle contractile properties and may play a role in the pathogenesis of diabetic neuromyopathy.

Animals↗
PubMedDate not supplied

Paramyxovirus replication and pathogenesis. Reverse genetics transforms understanding.

A recent breakthrough in the field of nonsegmented negative strand RNA viruses (Mononegavirales), including paramyxoviruses, is the establishment of a system to recover an infectious virus entirely from complementary DNA and hence allow reverse genetics. Mutations can now be introduced into viral genomes at will and the resulting phenotypes studied as long as the introduced mutations are not lethal. This technology is being successfully applied to answer outstanding questions regarding the roles of viral components in replication and their contribution to pathogenicity, which are difficult to address using conventional virology. For instance, how the paramyxovirus accessory proteins V and C contribute to actual viral replication and pathogenesis has remained unanswered since their first description more than 20 years ago. Using Sendai virus, which causes fatal pneumonia in mice, it has been shown that the V protein is completely dispensable for viral replication in cell cultures but encodes a luxury function required for pathogenesis in vivo. The Sendai virus C proteins were also defined to be nonessential gene products which greatly contributed to replication both in vitro and in vivo. It is also now possible to design live vaccines by introducing predetermined or plausible attenuating mutations. In addition, the use of paramyxoviruses to express foreign genes has also become feasible. Paramyxovirus reverse genetics is thus renovating our understanding of viral replication and pathogenesis and will further mark an era in recombinant technology for disease prevention and gene therapy.

Animals↗
PubMed1993

Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis.

BACKGROUND: The etiology of Hodgkin disease remains uncertain. Patterns of presentation of Hodgkin disease are analyzed by histologic subtype with implications for etiology and pathogenesis. METHODS: The authors performed a detailed analysis of anatomic sites of involvement, histopathologic findings, and clinical features in 719 patients with Hodgkin disease who underwent staging laparotomy with splenectomy between April 1969 and December 1986. The presence of disease in each of 17 sites of potential nodal involvement was determined for each patient from a combination of clinical and surgical staging. Association among nodal sites was assessed in 2 x 2 tables by estimating the odds ratio and testing the significance with the chi-square test. A strict significance level (P = 0.01) was used. Log-linear models were used for assessing association in 2 x 2 tables while adjusting for other factors. RESULTS: The mediastinum, left side of neck, and right side of neck were the most common sites involved for patients with nodular sclerosing (NS) or mixed cellularity (MC) histologic subtypes. Each of these sites was involved 60% of the time. These sites were four or more times as common as other nodal sites above or below the diaphragm. In contrast, the mediastinum was involved in only 8% of patients with lymphocyte predominance (LP) histologic subtype. Significant associations were found between mediastinal disease and low cervical/supraclavicular lymph node disease, mediastinal disease and NS histologic subtypes, peripheral nodal disease and LP histologic subtypes, and between splenic disease and mixed cellularity/lymphocyte depletion (MC/LD) Hodgkin disease. The age at onset and sex of patients with Hodgkin disease and the patterns of nodal distribution were somewhat different for NS and MC/LD histologic subtypes. Even greater differences were seen between LP and other histologic subtypes. CONCLUSIONS: This study supports the conclusion that NS and MC Hodgkin disease spread by continguity, most often originating in the neck or mediastinum, and is consistent with evidence suggesting an infectious agent in the pathogenesis of these subtypes of Hodgkin disease. In contrast, LP Hodgkin disease is characterized by different sites of presentation and patterns of spread. This suggests that two or perhaps three clinicopathologic subtypes of Hodgkin disease exist. Implications for etiology and pathogenesis are discussed.

Adult↗
PubMed2000

Novel pathways in the pathogenesis of respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory infections in infants and children. Extensive research in past decades has expanded our knowledge regarding the specific mechanisms involved in the pathogenesis of RSV bronchiolitis and subsequent chronic obstructive airway disease. Studies of RSV infection are performed in humans, cell culture models, and animal models, each with their own specific limitations. A recently developed murine model in which pulmonary dysfunction can be monitored and quantified appears to add a powerful tool for the study of specific pathogenic mechanisms of experimental RSV infections. Both immunologic and nonimmunologic factors have been implicated in the pathogenesis of RSV-induced diseases. Recently, a hypothesis that RSV bronchiolitis may be the result of production of Th2-type cytokines has become popular. There are, however, studies in human infants with RSV as well as in RSV-infected mice that suggest this theory is incorrect, or at least an oversimplification. There is compelling evidence that cells producing interferon gamma may contribute to RSV-induced wheezing, possibly through induction of leukotriene release. Among the nonimmunologic factors, pulmonary surfactant has recently attracted attention, especially because of the therapeutic implications for infants with severe bronchiolitis. A better understanding of the pathogenesis of RSV-induced diseases will be of considerable help in developing specific therapeutic strategies and in vaccine development.

Animals↗
PubMed1988

Pathogenesis of experimental scrapie.

Most of our understanding of the pathogenesis of the unconventional slow infections comes from studies of experimental scrapie in mice and hamsters. After injection by non-neural peripheral routes, pathogenesis necessarily involves the lymphoreticular system (LRS) before the central nervous system (CNS). Available evidence indicates haematogenous spread from the site of injection to the scrapie replication sites in the LRS; later, infection spreads along visceral autonomic nerves from the LRS to the thoracic spinal cord, and thence to brain. The cells in the LRS which are important to scrapie pathogenesis are long lived. Neuroinvasion and spread of infection within the CNS probably involve neuronal pathways. We suggest that disease develops after infection has reached certain clinical target areas in the CNS but only when scrapie replication there has caused sufficient functional damage. Restriction of the replication process in both LRS and CNS is indicated by the occurrence of plateau concentrations of infectivity, especially in some long incubation scrapie models. A remarkable feature of these is that both neuroinvasion and clinical disease occur long after infectivity plateaux have been reached in the LRS and CNS, respectively. We propose that the slowness of scrapie is related to (1) limitations of cell-to-cell spread of infection from LRS to CNS, and (2) limitations on spread between neurons, coupled with restrictions on replication in brain.

Animals↗
PubMed1986

Effect of bacterial flora and mouse genotype (euthymic or athymic) on scrapie pathogenesis.

Euthymic and athymic female BALB/c mice, reared under either germfree or defined flora conditions, were used to investigate the pathogenesis of scrapie after intracerebral or intraperitoneal inoculation. Time in days to onset of clinical signs (Stage I), to endstage (Stage II), and the time interval between Stage I and Stage II were compared among groups. In addition, scrapie agent titers in spleen were determined at 28 and 90 days after infection, as were agent titers in spleen and brain at Stage II. Three-way analysis of variance indicated that the bacterial flora, the presence or absence of a thymus, and the route of agent inoculation interact to produce significant differences in the pathogenesis of disease. The three factors in the experimental design also influenced the spleen titers of scrapie infectivity. The variation in scrapie pathogenesis among the groups of mice is likely to be mediated by differences in their reticuloendothelial systems. These differences may alter the agent's adsorption in spleen and/or route of transport from spleen to brain.

Animals↗
PubMed1995

Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis.

Apolipoprotein E (ApoE) genotype is a significant risk factor for the development of Alzheimer disease (AD) and the ApoE protein is associated with senile plaques (SP) and neurofibrillary tangles (NFT), the pathological lesions of AD. Despite this data, the relevance of ApoE to the disease pathogenesis is unknown. In this study we sought to understand the role that ApoE protein could play in the pathogenesis of AD. Using an in situ binding technique, we showed that ApoE bound avidly to SP and NFT in diseased brain. Molecular characterization of ApoE binding suggested that binding to NFT was mediated by tau, the main protein component of NFT, and that ApoE binding to SP was mediated by amyloid-beta, the main protein component of SP. There was no significant difference in binding or binding characteristics between the different ApoE isoforms, ApoE3 and ApoE4. These findings suggest that the interaction of ApoE with tau and amyloid-beta proteins in AD could play a important role in the formation of NFT and SP, respectively, contributing to the pathogenesis of AD.

Alzheimer Disease↗
PubMed1997

Re-assessing the virological approach to HIV pathogenesis: can it explain AIDS as an immunological disease?

Over 10 years after the discovery of HIV, its molecular virology still fails to explain the clinical immunology of AIDS. The prevailing paradigm of AIDS pathogenesis, called here the "virological hypothesis", argues that viral attributes such as cytopathicity, replicability, syncytiality, cell tropism, emergent virulence, and viral load explain why infection develops to a life-threatening immunodeficiency. However, these attributes-singly and in combination-are shown here to be inadequate to explain the latency, immunological damage, and clinical dynamics of the disease of AIDS. The virological paradigm cannot explain the disease-free period (clinical latency); the mechanism and dynamics of CD4 T cell loss; the reason for the onset of disease at a given time-point; the relationship of CD4 T cell loss to AIDS-type disease; nor the idiosyncratic constellation of immunological and clinical phenomena that comprise AIDS as a unique syndrome. HIV as it is currently understood does not have the virological characteristics necessary to create a disease such as AIDS through direct classical (i.e. cytopathic) mechanisms. It is clear that the pathogenesis of AIDS remains unknown. Therefore, treatment based solely on inhibiting viral mechanisms-as with antivirals-is very likely to be insufficient. In addition, the molecular epidemiology of pathogenesis has been very poor; there is an enormous amount that is not known about the clinical immunology of AIDS, and the central question remains of how CD4 cell loss relates to clinical immunodeficiency. The conclusion drawn is that the virology of HIV has been pursed at the cost of understanding AIDS itself; that an emphasis on AIDS as an immunological disease is long overdue; and that appropriate treatment of AIDS will not be possible until the clinical immunology of AIDS is understood.

Acquired Immunodeficiency Syndrome↗