Analysis Tools
mortality/aging
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• untreated nontransgenic mice show no effects beyond reduced activity and ruffled fur after 28 days of 100 mg/kg/day ganciclovir (GCV) treatment
• when treated with GCV up to 7 days, mice survive for at least 35 days; when treated for 14 days then stopped, mice become terminally ill and death occurs between 13 and 19 days (100% mortality) with or without a brain injury
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homeostasis/metabolism
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• many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice
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• transgenic mice receiving GCV for 14 days have mildly (30%) elevated serum urea levels
• moribund treated transgenics have 3-fold elevated serum urea levels compared to untreated controls
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• in some affected mice, interstitial edema separating the epithelium from the lamina propria is observed
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• in GCV-treated transgenic mice, a substantial increase in myeloperoxidase (MPO) activity, a quantitative measure of inflammatory response, in ileum not duodenum or colon compared to nontransgenic mice
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• untreated nontransgenic mice show no effects beyond reduced activity and ruffled fur after 28 days of 100 mg/kg/day ganciclovir (GCV) treatment
• when treated with GCV up to 7 days, mice survive for at least 35 days; when treated for 14 days then stopped, mice become terminally ill and death occurs between 13 and 19 days (100% mortality) with or without a brain injury
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• GCV-treated transgenic mice show reactive astrocyte death and impaired glial scar formation after stab injury to the brain
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digestive/alimentary system
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• the fecal contents of transgenic mice given GCV for >11 days are black, melanic and test positive for occult blood
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• surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris
• villus atrophy is minor, but villi exhibit patchy lesions ranging from mild epithelial changes and nonspecific granulocytic infiltrate to marked hemorrhagic necrosis
• villus tips show flattening, vacuolization and loss of polarity of surface epithelium; loss of brush border and pronounced dilation of capillaries with erythrostasis with chronic GCV treatment
• villi in severely affected regions can show disintegration of the tips resulting in a hemorrhagic and inflammatory exudates into the lumen of intestine
• lamina propria becomes inflamed in affected mice; fibrosis of, and hemorrhage into lamina propria can be seen in severe cases
• surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris in trangenics after chronic GCV treatment
• progressive changes include increased sloughing of epithelial cells
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• some treated animals with severe pathology show loss of goblet cells
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• a significant 50% increase in crypt depth is seen with chronic GCV treatment
• progressive changes include crypt hyperplasia
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• ileum and jejunum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibit moderate distention
• small intestine shows patchy skip lesions ranging from small inflammatory foci to large apthoid and linear ulcers exhibiting gangrenous necrosis in extreme cases
• inflammation and hemorrhagic necrosis of the submucosa and muscularis externa can be seen in severely affected regions
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• ileum of affected mice is generally more severely affected than jejunum; lesions occur with equal frequency within the proximal, central or distal portions
• some areas of severely affected ileal mucosa is associated with necrosis of the underlying smooth muscle and transmural perforation
• the smooth muscle wall of the ileum shows an obvious 100% thickening
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• ileum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibits moderate distention
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• jejunum of GCV-treated mice displays similar pathology to the ileum, but usually with less severity
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• jejunum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibits moderate distention
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• transgenic mice receiving 100 mg/kg/day GCV for 14 show growth of gram-negative organisms (>300 colonies per spleen or ml of blood or peritoneal fluid) while controls have none
• GCV-treated mice have a 10- to 100-fold increase in numbers of aerobic and anaerobic bacterial colonies per gram tissue in ileum compared to untreated or GVC-treated nontransgenic mice
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• ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage
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• ileum and jejunum of transgenics treated with GCV for >11 days show severe inflammation
• progression changes in inflammation lead to increased transmigration of polymorphonuclear leukocytes leading to granulocytic inflammatory infiltrate of lamina propria
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nervous system
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• uninjured transgenic mice receiving 100 mg/kg/day GCV for 14-17 days show no evidence of neuronal damage or astrocyte loss throughout the CNS
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• in treated control mice and untreated transgenic mice, blood-brain barrier (BBB) is repaired and resealed by 14 days after injury where stab injury damage occurred; GCV-treated transgenics still show BBB disruption by IgG entry into CNS parenchyma at 35 days after injury
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• many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice
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• in transgenic mice treated daily with low-dose ganciclovir (GCV), number of dividing cells decreases substantially in subependymal zone (SEZ) to 18.6% of controls and in subgranular zone (SGZ) to 29.6% of control
• transgenic mice treated chronically (14 days) with low-dose GCV have almost no newly generated neurons in SEZ, SGZ, or rostral migratory stream (RMS); in olfactory bulb 0% of neurons are NeuN-positive and in dentate gyrus only 1.8% are positive compared to controls (>98% reduction in neurogenesis)
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• in GCV-treated mutants, at 7 days after stab injury, there is marked interstitial edema within 400 microns of wound with numerous phagocytic and inflammatory cells and substantial neuronal degeneration
• blood vessels are dilated, a 25-fold greater density of leukocytes are present and persist for 14 days, and extravasated leukocytes (monocytes, macrophages, neutrophils, and lymphocytes) are common up to 2 mm from wound
• many microglia are seen adjacent to wound at 7 or 14 days and at 35 days, numerous leukocytes are still observed, while non-transgenic GCV-treated and transgenic untreated show little edema, a low density of leukocytes scattered around wound, and extravasated monocytes are rarely found in parenchyma at >1 mm from wound margin
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• after 14 days of GCV treatment, transgenic mice show pronounced loss of glial (GFAP +ve) cells from myenteric plexus in jejunum and ileum; widespread loss from submucosal regions and lamina propria of villi throughout jejunum and ileum is seen
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• the dense network of glial cell processes that envelop the myenteric neurons in controls is markedly depleted in transgenic mice receiving GCV for 14 days
• in areas where many glial cells are absent, neuronal atrophy and loss can be observed
• in transgenics after GCV treatment there are 31% fewer myenteric neurons and remaining neurons have a 27% smaller mean cross-sectional area
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• GCV-treated mice by 21 or 35 days after stab injury show few surviving pyramidal neurons within 1500 microns of wound and extensive tissue collapse; in control mice, region with no neurons extends <100 microns from the wound
• loss of neurons is seen in all brain tissue around the stab injury in GCV-treated transgenics
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• remaining enteric glia after 14 days of GCV treatment are abnormal
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• after a stabbing injury to the forebrain, transgenic mice treated with ganciclovir (GCV) subcutaneously for 7 or 14 days show a reduction in astrocytes immediately adjacent to wound and for several hundred microns away, most strikingly the thalamus
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astrocytosis
(
J:113202
)
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• death of astrocytes immediately next to the wound triggers extensive astrocytosis in outwardly adjacent cells compared to controls
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• GCV-treated mutants show a dense network of many finely branched, randomly-oriented fibers with a sprouting appearance comfined to the wound margin and not extending into unaffected regions while control mice show very few fibers in scar-forming region
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• loss of enteric glia results in a patchy, moderate degeneration of neurons intrinsic to the ileal myenteric plexus
(J:104241)
• marked degeneration in the wound region is observed 7 days after injury in GCV-treated transgenics
(J:113202)
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• transgenic astrocytes are sensitive to prolonged exposure to subcutaneous GCV, resulting in cell death
• after a stab injury to brain and continuous GCV delivery in vivo for 7 or 14 days, transgenic mice show few astrocytes adjacent to wound margin and astrocytes in adjacent tissue look fragmented and abnormal (early stages of cell death)
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hematopoietic system
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• transgenic mice receiving 100 mg/kg/day GCV for 14 days have red blood cell counts reduced by 60%
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• transgenic mice receiving GCV for 14 days show a 10-fold increase in nucleated red blood cells
• moribund treated transgenics have high levels of nucleated red blood cells
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• transgenic mice receiving 100 mg/kg/day GCV for 14 days show 20-fold increase in neutrophils
• moribund treated transgenics have a high level of neutrophils relative to the number of red blood cells
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immune system
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• transgenic mice receiving 100 mg/kg/day GCV for 14 days show 20-fold increase in neutrophils
• moribund treated transgenics have a high level of neutrophils relative to the number of red blood cells
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• transgenic mice given 100 mg/kg/day GCV for 7 days show small patches of focal inflammation in the GI tract
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• ileum and jejunum of transgenics treated with GCV for >11 days show severe inflammation
• progression changes in inflammation lead to increased transmigration of polymorphonuclear leukocytes leading to granulocytic inflammatory infiltrate of lamina propria
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• in GCV-treated mutants, at 7 days after stab injury, there is marked interstitial edema within 400 microns of wound with numerous phagocytic and inflammatory cells and substantial neuronal degeneration
• blood vessels are dilated, a 25-fold greater density of leukocytes are present and persist for 14 days, and extravasated leukocytes (monocytes, macrophages, neutrophils, and lymphocytes) are common up to 2 mm from wound
• many microglia are seen adjacent to wound at 7 or 14 days and at 35 days, numerous leukocytes are still observed, while non-transgenic GCV-treated and transgenic untreated show little edema, a low density of leukocytes scattered around wound, and extravasated monocytes are rarely found in parenchyma at >1 mm from wound margin
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endocrine/exocrine glands
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• a significant 50% increase in crypt depth is seen with chronic GCV treatment
• progressive changes include crypt hyperplasia
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cellular
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• some treated animals with severe pathology show loss of goblet cells
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• in enriched subconfluent astrocyte cultures from neonatal mice, exposure to GCV for 7 days or more caused a 75% loss of astrocytes (GFAP +ve cells) with an increase in GFAP -ve cells compared to nontransgenic cultures
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• many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice
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• in transgenic mice treated daily with low-dose ganciclovir (GCV), number of dividing cells decreases substantially in subependymal zone (SEZ) to 18.6% of controls and in subgranular zone (SGZ) to 29.6% of control
• transgenic mice treated chronically (14 days) with low-dose GCV have almost no newly generated neurons in SEZ, SGZ, or rostral migratory stream (RMS); in olfactory bulb 0% of neurons are NeuN-positive and in dentate gyrus only 1.8% are positive compared to controls (>98% reduction in neurogenesis)
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• non-transgenic animals with or without GCV treatment show many proliferating astrocytes in narrow zone adjacent to stab wound associated with compact glial scar formation, but in GCV-treated mutants, essentially all proliferating astrocytes are ablated
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cardiovascular system
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• ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage
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• in treated control mice and untreated transgenic mice, blood-brain barrier (BBB) is repaired and resealed by 14 days after injury where stab injury damage occurred; GCV-treated transgenics still show BBB disruption by IgG entry into CNS parenchyma at 35 days after injury
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reproductive system
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• male transgenic mice are sterile
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