Dengue, a major public health problem throughout subtropical and tropical regions, is an acute infectious disease characterized by biphasic fever, headache, pain in various parts of the body, prostration, rash, lymphadenopathy, and leukopenia. In more severe or complicated dengue, patients present with a severe febrile illness characterized by abnormalities of hemostasis and increased vascular permeability, which in some instances results in a hypovolemic shock. Four distinct serotypes of the dengue virus (dengue-1, dengue-2, dengue-3, and dengue-4) exist, with numerous virus strains found worldwide. Molecular cloning methods have led to a greater understanding of the structure of the RNA genome and definition of virus-specific structural and nonstructural proteins. Progress towards producing safe, effective dengue virus vaccines, a goal for over 45 years, has been made. Images

The dengue viruses.

Russell's viper, Vipera russelli (Shaw), is distributed erratically in 10 south Asian countries and is a leading cause of fatal snake bite in Pakistan, India, Bangladesh, Sri Lanka, Burma and Thailand. In Burma it has been the 5th most important cause of death. Its venom is of great interest to laboratory scientists and clinicians. The precoagulant activity of the venom was used by Macfarlane and others to elucidate the human clotting cascade. Up to 70% of the protein content is phospholipase A2, present in the form of at least 7 isoenzymes. Possible clinical effects of the enzyme include haemolysis, rhabdomyolysis, pre-synaptic neurotoxicity, vasodilatation and shock, release of endogenous autacoids and interaction with monoamine receptors. Russell's viper bite is an occupational hazard of rice farmers throughout its geographical range. Defibrination, spontaneous haemorrhage, shock and renal failure develop with frightening rapidity. In several countries, Russell's viper bite is the commonest cause of acute renal failure. There is a fascinating geographical variation in the clinical manifestations, doubtless reflecting differences in venom composition. Conjunctival oedema is unique to Burma, acute pituitary infarction to Burma and south India, and rhabdomyolysis and neurotoxicity to Sri Lanka and south India. Treatment with potent specific antivenom rapidly controls bleeding and clotting disorders, but may not reverse nephrotoxicity and shock. Causes of death include shock, pituitary and intracranial haemorrhage, massive gastrointestinal haemorrhage and acute tubular necrosis or bilateral renal cortical necrosis. The paddy farmer and the Russell's viper coexist in fragile symbiosis. The snake controls rodent pests but inevitably interacts with man, often with mutually disastrous results.

Snake venoms in science and clinical medicine 1. Russell's viper: biology, venom and treatment of bites

Handbook for Clinical Management of Dengue

Among arthropod-borne and related viruses, the Flaviviridae are medically the most important group and biologically one of the most intriguing. Elucidation of perplexingly complex virus- and host-specified factors that underlie virulence and pathogenesis has lagged behind other areas of virology, and the available information is largely descriptive. Ultimately, flavivirus biology and pathogenesis will be understood in terms of viral gene expression, virus receptor—host cell membrane interactions, biochemical alterations in host cells, physiological responses, and immune and nonimmune mechanisms that control virus replication and virus spread, subjects to which other chapters in this book are devoted. There will remain, however, a need to understand and synthesize this information with observations relating to infection at the level of the intact organism (virus, vector, and host) and of populations of organisms in nature. It is at these levels that the phenomena that require explanation first present themselves.

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Pathobiology of the Flaviviruses

While dengue virus is thought to replicate in mononuclear phagocytic cells in vivo, attempts to detect it in peripheral blood mononuclear cells (PBMC) by virus isolation or antigen detection have had variable and generally low rates. In this study, we developed a reverse transcription (RT)-real-time PCR assay to quantify positive- and negative-sense RNA of dengue virus type 2 within the cells. The assay includes an RT step using either sense or antisense primer followed by a real-time PCR step using the designed primers and probe, which target a capsid region highly conserved in dengue virus type 2 strains. It can be used to monitor the dynamic change of intracellular dengue virus RNA species during the course of infection. When this assay is employed in quantification of dengue virus RNA species in PBMC from 10 patients infected with dengue virus type 2, both positive- and negative-sense dengue RNA can be detected, indicating that dengue virus is actively replicating in PBMC in vivo. Moreover, the amounts of negative-sense dengue virus RNA in PBMC correlate very well with the viral load of dengue virus in plasma, suggesting that quantification of negative-sense dengue virus RNA in PBMC may provide another indicator of dengue virus replication in vivo. Use of this convenient, sensitive, and accurate method of quantification in clinical samples from patients with different disease severity would further our understanding of the pathogenesis of dengue.

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Detection of Dengue Virus Replication in Peripheral Blood Mononuclear Cells from Dengue Virus Type 2-Infected Patients by a Reverse Transcription-Real-Time PCR Assay

The effects of Russell's viper venom (RVV) on blood coagulation, platelts and fibrinolysis were studied in vivo and in vitro in rabbits and dogs as experimental subjects. RVV was shown to be a strong coagulant, and at the time of manifestation of bleeding due to consumption coagulopathy, the most striking hemostatic abnormalities were fall of fibrinogen level, reduction in platelet count, delayed ADP aggregation of platelets, increased fibrinolytic activity and presence of fibrin degradation products. These findings showed that RVV interfered with blood coagulation, caused abnormalities of platelet function and also activated the fibrinolytic enzyme system.

Effects of Russell′s Viper Venom on Blood Coagulation,Platelets and the Fibrinolytic Enzyme System

A total of 100 post-mortems were done on patients clinically diagnosed as dengue haemorrhagic fever from Rangoon Children's Hospital. Histopathological changes in bone marrow, thymus, spleen, lymph nodes and other associated tissues of the immune system were analysed and correlated with the clinical picture and serology results. The major changes in cases with a positive serology result for secondary dengue infection consist of hypoplasia of the bone marrow, acute atrophy and wasting of the thymus, atrophy and depletion of cells in the periarterial lymphatic sheaths of the spleen and the paracortical areas of the lymph nodes. The tissues affected are the thymus-dependent areas of the spleen and lymph nodes, and the thymus itself. Thymus-independent areas of the secondary lymphatic tissues are also affected but to a lesser extent. The pathological observations suggest that immunodepression may be an integral part of the pathophysiology of dengue haemorrhagic fever.

M. Aung-Khin

Papers

Effects of Russell′s Viper Venom on Blood Coagulation,Platelets and the Fibrinolytic Enzyme System

Changes in the tissues of the immune system in dengue haemorrhagic fever.