Summary: Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.

Dengue Virus Pathogenesis: an Integrated View

In 1925, Thomas Cooley and Pearl Lee described a form of severe anemia, occurring in children of Italian origin and associated with splenomegaly and characteristic bone changes.1 Over the next deca...

https://www.nejm.org/doi/pdf/10.1056/NEJM199907083410207?articleTools=true

The β-Thalassemias

Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

Human skin Langerhans cells are targets of dengue virus infection.

The authors discuss the molecular pathogenesis of opisthorchiasis and associated cholangiocarcinogenesis, particularly nitrative and oxidative DNA damage and the clinical manifestations of cholangiocarcinoma.

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Liver fluke induces cholangiocarcinoma.

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.

Histopathological alterations of white seabass, Lates calcarifer, in acute and subchronic cadmium exposure.

Opisthorchiasis is an endemic parasitic disease in northeastern Thailand. The concomitant occurrence of the parasite and cholangiocarcinoma as well as the incidence of such tumors are higher in that part of the country than in other areas. Nitrosating agents, nitrosatable substances, and nitrosamine compounds are commonly present in several kinds of stable foods in that region. To study the interactions between the parasite and the nitroso compounds, we divided Syrian golden hamsters into four groups: Group 1, untreated; Group 2, dimethylnitrosamine (DMN, 0.0025% or 25 ppm)-treated; Group 3, 100 metacercariae-treated; and Group 4, DMN (0.0025% or 25 ppm) plus 100 metacercariae-treated groups. The animals that received both DMN and parasites (Group 4) developed cholangiocarcinoma (100%) and cholangiofibrosis (100%). The tumor was not observed in the group that received either DMN (Group 2) or parasites alone (Group 3), although cholangiofibrosis was found in some animals in the DMN group (Group 2). It is postulated that cholangiocarcinomas in these animals arose because the DMN exerted a carcinogenic effect on the altered proliferating epithelial cells of bile ducts that had been stimulated by the parasite. These findings suggest that the combination of DMN ingestion and liver fluke infestation may play an important role in the carcinogenesis of the intrahepatic duct neoplasms in human beings.

https://cancerres.aacrjournals.org/content/canres/38/12/4634.full.pdf

Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters.

In Oreochromis niloticus that had been exposed for 3 months to sublethal concentrations (5 and 15 ppm) of the commercial glyphosate herbicide (C(3)H(8)NO(5)P) Roundup, the organs exhibited varying degrees of histopathological change. In the gills filament cell proliferation, lamellar cell hyperplasia, lamellar fusion, epithelial lifting, and aneurysm were observed. In the liver there were vacuolation of hepatocytes and nuclear pyknosis. Kidney lesions consisted of dilation of Bowman's space and accumulation of hyaline droplets in the tubular epithelial cells. The structural damages could be correlated to the significant increase (p </= 0.05) in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities in the second and third months of exposure. The results indicated that long-term exposure to glyphosate at sublethal concentrations had adverse effects on the histopathological and biochemical alterations of the fish.

Biochemical and histopathological effects of glyphosate herbicide on Nile tilapia (Oreochromis niloticus)

The acute toxicity of Roundup, a glyphosate herbicide, to Nile tilapia, Oreochromis niloticus, was investigated with emphasis on histopathological effects. The values of 24-h, 48-h, 72-h and 96-h LC50 for young tilapia were 17.5, 17.1, 16.9 and 16.8 ppm, respectively, and those for adult tilapia were 46.9, 44.4, 40.0 and 36.8 ppm, respectively. They indicated that adult fish were more tolerant to Roundup than the much smaller young fish. Roundup concentration corresponding to the 96-h LC50 value for adult tilapia was used to study the effects of Roundup exposure in inducing histopathological changes of gills, liver and kidneys. In the gills, filament cell proliferation, lamellar cell hyperplasia, lamellar fusion, epithelial lifting and aneurysm were observed. In the liver, there was vacuolation of hepatocytes and nuclear pyknosis. Kidney lesions consisted of dilation of Bowman's space and accumulation of hyaline droplets in the tubular epithelial cells. These changes occurred predominantly in the 96-h exposure.

/pdf/histopathological-effects-of-roundup-a-glyphosate-herbicide-2oqtsm675x.pdf

Histopathological Effects of Roundup, a Glyphosate Herbicide, on Nile tilapia (Oreochromis niloticus)

Electron microscopic studies were performed from skin biopsies taken from patients aged between 1-14 years suffering from dengue hemorrhagic fever. Several capillaries showed marked distortion, but severely damaged vessels were not observed in this study. In many cases, however, swelling of a single endothelial cell was noted. This was characterized by a rarefaction of the cytoplasm and formation of the plasma membrane which extruded into lumen and narrowed it. In many vessels examined, these blebs became detached from the endothelium and were found free within the capillary lumen. Myelin figures were often observed in such vessels. Mitochondria in the swollen endothelial cells often showed contraction of the inner compartments. Although, most of the endothelial junctional complexes were intact, several gap formations, in vascular wall were observed. Vacuolation of the cytoplasm and increase in the pinocytotic vesicles in endothelial cells which represented transport of plasma fluids from the capillary to the pericapillary space were quite evident. In no case did there seem to be marked alternation of the basement membrane of the capillary. The morphological alterations observed in this study only suggest the non-specific response of the dermal capillaries. These findings were similar to the findings observed in capillaries after being subjected to heat or ischemia.

Somphong Sahaphong

Papers

Histopathological alterations of white seabass, Lates calcarifer, in acute and subchronic cadmium exposure.

Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters.

Biochemical and histopathological effects of glyphosate herbicide on Nile tilapia (Oreochromis niloticus)

Histopathological Effects of Roundup, a Glyphosate Herbicide, on Nile tilapia (Oreochromis niloticus)

Electron microscopic study of the vascular endothelial cell in dengue hemorrhagic fever.