[Serious complications of urinary tract infection in diabetes: emphysematous pyelonephritis and endogenous endophthalmitis]. / Ernstige complicaties van urineweginfectie bij diabetes.

BACKGROUND: Patients with poorly regulated diabetes mellitus may develop severe infectious complications. In this article we describe a diabetic patient with urosepsis, complicated by emphysematous pyelonephritis and endogenous endophthalmitis. CASE DESCRIPTION: A 42-year-old diabetic woman presented with drowsiness and flank pain at the right side. She turned out to have diabetic ketoacidosis and urosepsis caused by Escherichia coli. Ultrasonography and CT scan of the abdomen showed subcapsulary gas configurations in the right kidney, which fit with the diagnosis of emphysematous pyelonephritis. Two days later, the patient complained of severe pain of the left eye with photophobia and blurred vision. The diagnosis of endogenous endophthalmitis was made. Treatment consisted of vitrectomy of the left eye, silicone oil injection and intravitreal and systemic antibiotics. The pyelonephritis was treated with antibiotics and percutaneous drainage. CONCLUSION: Both endogenous endophthalmitis and emphysematous pyelonephritis are rare complications of infection, which can result in severe damage to the eye and kidney. Treatment comprises both local and systemic therapy. With the increasing number of diabetics, we can expect more rare complications.

Transient retinal venous and arterial occlusive events in a case of sneddon syndrome.

PURPOSE: We report a case with venous and arterial occlusive events in Sneddon syndrome and describe the accompanying fluorescein angiographic findings. METHODS: Observational case report. RESULTS: This 27-year-old white woman developed acute visual loss and a central scotoma in her right eye in consequence of a central retinal vein occlusion and, 2 years later, a paracentral scotoma in her left eye in consequence of an incomplete branch retinal artery occlusion. Fluorescein angiography revealed an unusual laminar hyperfluorescence downstream to the arterial obstruction. Patient became seropositive for anticardiolipin antibodies in the course of the 2 years. Eventually, the ocular together with neurologic and cardiac manifestations led to the diagnosis of Sneddon syndrome. CONCLUSION: Sneddon syndrome should be considered in any ocular vascular occlusive event under the age of 50 years. In addition, this case reports for the first time unusual fluorescein angiographic findings of incomplete branch retinal arterial occlusions, possibly associated with endothelial damage in Sneddon syndrome.

Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas.

Progressive tumor growth depends on angiogenesis to sustain metabolic needs of tumor cells, thus providing a potential target for cancer therapy. Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Gliomas are a suitable tumor type for probing angiogenesis inhibition as their proliferation is characterized by a prominent proliferative vascular component. In the present review, we discuss the current status and future directions of angiogenesis inhibition in gliomas. We focus on recently developed approaches inducing an antiangiogenic response such as targeted gene delivery, protein tyrosine kinase inhibitors and encapsulated producer cells. Although several of these modalities have shown promising results on their own, the true potential of these novel approaches lies in their combined use with radiotherapy or 'metronomically scheduled' chemotherapy. A combined approach potentially counteracts the selective pressure on hypoxia-resistant malignant tumor cells, circumvents endothelial resistance induced by local cytoprotective responses and enhances the delivery of cytotoxic agents by normalizing vascular physiology. Surrogate markers of angiogenesis currently under study may provide accurate assessment of response in individual patients. Future research on endothelial markers expressed on tumor-associated vasculature as well as endothelial responses to cytotoxic treatment will provide new avenues for molecularly targeted therapy in malignant gliomas.

In vivo angiogenic phenotype of endothelial cells and pericytes induced by vascular endothelial growth factor-A.

VEGF-A is a major angiogenesis and permeability factor. Its cellular effects, which can be used as targets in anti-angiogenesis therapy, have mainly been studied in vitro using endothelial cell cultures. The purpose of the present study was to further characterize these effects in vivo in vascular endothelial cells and pericytes, in an experimental monkey model of VEGF-A-induced iris neovascularization. Two cynomolgus monkeys (Macaca fascicularis) received four injections of 0.5 microg VEGF-A in the vitreous of one eye and PBS in the other eye. After sacrifice at day 9, eyes were enucleated and iris samples were snap-frozen for immunohistochemistry (IHC) and stained with a panel of antibodies recognizing endothelial and pericyte determinants related to angiogenesis and permeability. After VEGF-A treatment, the pre-existing iris vasculature showed increased permeability, hypertrophy, and activation, as demonstrated by increased staining of CD31, PAL-E, tPA, uPA, uPAR, Glut-1, and alphavbeta3 and alphavbeta5 integrins, VEGF receptors VEGFR-1, -2 and -3, and Tie-2 in endothelial cells, and of NG2 proteoglycan, uPA, uPAR, integrins and VEGFR-1 in pericytes. Vascular sprouts at the anterior surface of the iris were positive for the same antigens except for tPA, Glut-1, and Tie-2, which were notably absent. Moreover, in these sprouts VEGFR-2 and VEGFR-3 expression was very high in endothelial cells, whereas many pericytes were present that were positive for PDGFR-beta, VEGFR-1, and NG2 proteoglycan and negative for alpha-SMA. In conclusion, proteins that play a role in angiogenesis are upregulated in both pre-existing and newly formed iris vasculature after treatment with VEGF-A. VEGF-A induces hypertrophy and loss of barrier function in pre-existing vessels, and induces angiogenic sprouting, characterized by marked expression of VEGFR-3 and lack of expression of tPA and Tie-2 in endothelial cells, and lack of alpha-SMA in pericytes. Our in vivo study indicates a role for alpha-SMA-negative pericytes in early stages of angiogenesis. Therefore, our findings shed new light on the temporal and spatial role of several proteins in the angiogenic cascade in vivo.

Expression of vascular endothelial growth factor receptors 1, 2, and 3 in quiescent endothelia.

The vascular endothelial growth factor (VEGF) family is involved in angiogenesis, and therefore VEGFs are considered as targets for anti-angiogenic therapeutic strategies against cancer. However, the physiological functions of VEGFs in quiescent tissues are unclear and may interfere with such systemic therapies. In pathological conditions, increased levels of expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 accompany VEGF activity. In this study we investigated normal human and monkey tissues for expression patterns of these receptors. Immunohistochemical staining methods at the light and electron microscopic level were applied to normal human and monkey tissue samples, using monoclonal antibodies (MAbs) against the three VEGFRs and anti-endothelial MAbs PAL-E and anti-CD31 to identify blood and lymph vessels. In human and monkey, similar distribution patterns of the three VEGFRs were found. Co-expression of VEGFR-1, -2, and -3 was observed in microvessels adjacent to epithelia in the eye, gastrointestinal mucosa, liver, kidney, and hair follicles, which is in line with the reported preferential expression of VEGF-A in some of these epithelia. VEGFR-1, -2, and -3 expression was also observed in blood vessels and sinusoids of lymphoid tissues. Furthermore, VEGFR-1, but not VEGFR-2 and -3, was present in microvessels in brain and retina. Electron microscopy showed that VEGFR-1 expression was restricted to pericytes and VEGFR-2 to endothelial cells in normal vasculature of tonsils. These findings indicate that VEGFRs have specific distribution patterns in normal tissues, suggesting physiological functions of VEGFs that may be disturbed by systemic anti-VEGF therapy. One of these functions may be involvement of VEGF in paracrine relations between epithelia and adjacent capillaries.

Altered expression patterns of VEGF receptors in human diabetic retina and in experimental VEGF-induced retinopathy in monkey.

PURPOSE: The vascular endothelial growth factor (VEGF) family is involved in vascular leakage and angiogenesis in diabetic retinopathy (DR) in the eye, but may also have physiological functions. Based on the hypothesis that differential VEGF receptor (VEGFR) expression in the retina is an important determinant of effects of VEGF, this study was conducted to investigate VEGFR expression in the diabetic retina and in an experimental monkey model of VEGF-A-induced retinopathy. METHODS: In retinas of 27 eyes of diabetic donors, 18 eyes of nondiabetic control donors, and 4 monkey eyes injected with PBS or VEGF-A, expression patterns of VEGFR-1, -2, and -3 in relation to leaky microvessels, as identified by the marker pathologische anatomie Leiden-endothelium (PAL-E) were studied by immunohistochemistry. RESULTS. In control human retinas and retinas of PBS-injected monkey eyes, all three VEGFRs were expressed in nonvascular areas, but only VEGFR-1 was constitutively expressed in retinal microvessels. In diabetic eyes, increased microvascular VEGFR-2 expression was found in association with PAL-E expression, whereas microvascular VEGFR-3 was present in a subset of PAL-E-positive cases. In VEGF-A-injected monkey eyes, VEGFR-1, -2, and -3 and PAL-E were expressed in retinal microvessels. CONCLUSIONS: The VEGFR-1, -2, and -3 expression patterns in control retinas suggest physiological functions of VEGFs that do not involve the vasculature. Initial vascular VEGF signaling may act primarily through VEGFR-1. In diabetic eyes, expression of retinal VEGFR-2 and -3 is increased, mainly in leaky microvessels, and VEGF-A induces vascular expression of the VEGF-A receptor VEGFR-2 and the VEGF-C/D receptor VEGFR-3. These findings indicate a dual role of VEGFs in the physiology and pathophysiology of the retina and suggest that microvascular VEGFR-2 and -3 signaling by VEGFs occurs late in the pathogenesis of DR, possibly initiated by high levels of VEGF-A in established nonproliferative DR.