Rumpel-Leede Phenomenon-An alarming rash with benign etiology in 4 healthy infants.

The Rumpel-Leede phenomenon (RLP) is a rare clinical presentation and in some cases shown to be related to serious systemic conditions. In children, it has been described in association with idiopathic thrombocytopenic purpura and Henoch-Schönlein purpura. We present a series of pediatric cases of RLP with mechanical etiologies that had a benign course. We propose minimal investigations for pediatric RLP cases who are systemically well and have a clear suggestive history of a mechanical cause.

Seizure-induced microvascular injury is associated with impaired neurovascular coupling and blood-brain barrier dysfunction.

OBJECTIVE: Blood-brain barrier (BBB) impairment, redistribution of pericytes, and disturbances in cerebral blood flow may contribute to the increased seizure propensity and neurological comorbidities associated with epilepsy. However, despite the growing evidence of postictal disturbances in microcirculation, it is not known how recurrent seizures influence pericytic membrane currents and subsequent vasodilation. METHODS: Here, we investigated successive changes in capillary neurovascular coupling and BBB integrity during recurrent seizures induced by 4-aminopyridine or low-Mg2+ conditions. To avoid the influence of arteriolar dilation and cerebral blood flow changes on the capillary response, we measured seizure-associated pericytic membrane currents, capillary motility, and permeability changes in a brain slice preparation. Arteriolar responses to 4-aminopyridine-induced seizures were further studied in anesthetized Sprague Dawley rats by using electrocorticography and tissue oxygen recordings simultaneously with intravital imaging of arteriolar diameter, BBB permeability, and cellular damage. RESULTS: Within the preserved vascular network in hippocampal slice cultures, pericytes regulated capillary diameter in response to vasoactive agents and neuronal activity. Seizures induced distinct patterns of membrane currents that contributed to the regulation of pericytic length. During the course of recurrent seizures, individual vasodilation responses eroded and BBB permeability increased, despite unaltered neurometabolic coupling. Reduced vascular responsiveness was associated with mitochondrial depolarization in pericytes. Subsequent capillary constriction preceded BBB opening, suggesting that pericyte injury mediates the breach in capillary integrity. In vivo findings were consistent with slice experiments, showing seizure-related neurovascular decoupling and BBB dysfunction in small cortical arterioles, accompanied by perivascular cellular injury despite normoxic conditions. SIGNIFICANCE: Our study presents a direct observation of gradually developing neurovascular decoupling during recurrent seizures and suggests pericytic injury as an inducer of vascular dysfunction in epilepsy.

Dermal capillary rarefaction as a marker of microvascular damage in patients with rheumatoid arthritis: Association with inflammation and disorders of the macrocirculation.

OBJECTIVE: Capillary rarefaction is observed in various cardiovascular diseases, yet it remains understudied in RA, a chronic inflammatory disease accompanied by excess cardiovascular risk. We quantified capillary density in RA patients and explored potential associations with macrocirculatory disorders, inflammation, and cardiovascular risk. METHODS: Dermal capillary density was assessed with nailfold capillaroscopy in RA and non-RA individuals, using specifically designed semiautomated software. Macrocirculation assessments included large artery stiffening, evaluated with PWV, and myocardial blood flow, calculated as cardiac index from impedance cardiography. Cardiovascular risk score was estimated from the Framingham Heart Study. RESULTS: The number of capillaries per visual field was lower in patients (n = 99) compared to controls (n = 35) (132.6 ± 30.3 vs 152.9 ± 25.2, P = .001). In the RA group, capillary density negatively correlated with CRP and PWV, and positively with HDL and cardiac index. In the multivariate analysis, CRP independently predicted capillary rarefaction (P = .044). Capillary density significantly correlated with cardiovascular risk, even after adjustment for inflammation (P = .030). CONCLUSION: Capillary rarefaction appears pronounced in RA and correlates with lower cardiac output, increased arterial stiffness, and cardiovascular risk. However, the associations with macrocirculatory disorders may be obscured by inflammation, which appears as the major contributor to capillary rarefaction in RA.

Glomerular basement membrane injuries in IgA nephropathy evaluated by double immunostaining for α5(IV) and α2(IV) chains of type IV collagen and low-vacuum scanning electron microscopy.

BACKGROUND: The glomerulus contains well-developed capillaries, which are at risk of injury due to high hydrostatic pressure, hyperfiltration, hypertension and inflammation. However, the pathological alterations of the injured glomerular basement membrane (GBM), the main component of the glomerular filtration barrier, are still uncertain in cases of glomerulonephritis. METHODS: We examined the alterations of the GBM in 50 renal biopsy cases with IgA nephropathy (31.8 ± 17.6 years old) using double immunostaining for the α2(IV) and α5(IV) chains of type IV collagen, and examining the ultrastructural alterations by transmission electron microscopy (TEM) and low-vacuum scanning electron microscopy (LV-SEM). RESULTS: The GBM of IgA nephropathy cases showed various morphological and qualitative alterations. In the TEM findings, thinning, gaps, rupture, thickening with a lamellar and reticular structure and double contours were detected in the GBM. Double immunostaining for α5(IV) and α2(IV) showed thickening of the GBM with reduced α5(IV) and increased α2(IV), or mosaic images of α5(IV) and α2(IV), and holes, fractures, spiny projections and rupture of α5(IV) in the GBM. In addition, LV-SEM showed an etched image and multiple holes in a widening and wavy GBM. These findings might be associated with the development of a brittle GBM in IgA nephropathy. CONCLUSION: Glomerular basement membrane alterations were frequently noted in IgA nephropathy, and were easily evaluated by double immunostaining for α2(IV) and α5(IV) of type IV collagen and LV-SEM. The application of these analyses to human renal biopsy specimens may enhance our understanding of the alterations of the GBM that occur in human glomerular diseases.

Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice.

AKI predicts the future development of CKD, and one proposed mechanism for this epidemiologic link is loss of peritubular capillaries triggering chronic hypoxia. A precise definition of changes in peritubular perfusion would help test this hypothesis by more accurately correlating these changes with future loss of kidney function. Here, we have adapted and validated a fluorescence microangiography approach for use with mice to visualize, analyze, and quantitate peritubular capillary dynamics after AKI. A novel software-based approach enabled rapid and automated quantitation of capillary number, individual area, and perimeter. After validating perfusion in mice with genetically labeled endothelia, we compared peritubular capillary number and size after moderate AKI, characterized by complete renal recovery, and after severe AKI, characterized by development of interstitial fibrosis and CKD. Eight weeks after severe AKI, we measured a 40%±7.4% reduction in peritubular capillary number (P<0.05) and a 36%±4% decrease in individual capillary cross-sectional area (P<0.001) for a 62%±2.2% reduction in total peritubular perfusion (P<0.01). Whereas total peritubular perfusion and number of capillaries did not change, we detected a significant change of single capillary size following moderate AKI. The loss of peritubular capillary density and caliber at week 8 closely correlated with severity of kidney injury at day 1, suggesting irreparable microvascular damage. These findings emphasize a direct link between severity of acute injury and future loss of peritubular perfusion, demonstrate that reduced capillary caliber is an unappreciated long-term consequence of AKI, and offer a new quantitative imaging tool for understanding how AKI leads to future CKD in mouse models.

The Biomechanics of Cranial Forces During Figure Skating Spinning Elements.

Several facets of figure skating, such as the forces associated with jumping and landing, have been evaluated, but a comprehensive biomechanical understanding of the cranial forces associated with spinning has yet to be explored. The purpose of this case study was to quantify the cranial rotational acceleration forces generated during spinning elements. This case report was an observational, biomechanical analysis of a healthy, senior-level, female figure skating athlete who is part of an on-going study. A triaxial accelerometer recorded the gravitational forces (G) during seven different spinning elements. Our results found that the layback spin generated significant cranial force and these forces were greater than any of the other spin elements recorded. These forces led to physical findings of ruptured capillaries, dizziness, and headaches in our participant.

Lung capillary injury and repair in left heart disease: a new target for therapy?

The lungs are the primary organs affected in LHD (left heart disease). Increased left atrial pressure leads to pulmonary alveolar-capillary stress failure, resulting in cycles of alveolar wall injury and repair. The reparative process causes the proliferation of MYFs (myofibroblasts) with fibrosis and extracellular matrix deposition, resulting in thickening of the alveolar wall. Although the resultant reduction in vascular permeability is initially protective against pulmonary oedema, the process becomes maladaptive causing a restrictive lung syndrome with impaired gas exchange. This pathological process may also contribute to PH (pulmonary hypertension) due to LHD. Few clinical trials have specifically evaluated lung structural remodelling and the effect of related therapies in LHD. Currently approved treatment for chronic HF (heart failure) may have direct beneficial effects on lung structural remodelling. In the future, novel therapies specifically targeting the remodelling processes may potentially be utilized. In the present review, we summarize data supporting the clinical importance and pathophysiological mechanisms of lung structural remodelling in LHD and propose that this pathophysiological process should be explored further in pre-clinical studies and future therapeutic trials.

Proximal nail fold intralesional steroid injection responsible for Hoigné syndrome.

BACKGROUND: Hoigné syndrome is the most common name given to a condition which has been called in different ways. OBJECTIVE: We want to show that an intralesional injection of prednisolone into the proximal nail fold may produce dorsal pain, dyspnoea and headaches within the 2 min following the injection and to explain the pathophysiology of his condition. METHODS: We studied the different drugs responsible for Hoigné syndrome by comparing the size of the crystals taking into account the diameter of pulmonary capillaries. The drug Company informed us that the size of the microcrystals were 2-4 µm vs. the 8 µm on average of the diameter of the pulmonary capillaries. CONCLUSION: All the symptoms of Hoigné syndrome can be explained, especially the neuropsychiatric and neuropulmonary ones. Therefore, dermatologists should be aware of this phenomenon when they inject steroids in psoriatic nail patients.

A multilevel hierarchical finite element model for capillary failure in soft tissue.

Bruising, the result of capillary failure due to trauma, is a common indication of abuse. However, the etiology of capillary failure has yet to be determined as the scale change from tissue to capillary represents several orders of magnitude. As a first step toward determining bruise etiology, we have developed a multilevel hierarchical finite element model (FEM) of a portion of the upper human arm using a commercial finite element tool and a series of three interconnected hierarchical submodels. The third and final submodel contains a portion of the muscle tissue in which a single capillary is embedded. Nonlinear, hyperelastic material properties were applied to skin, adipose, muscle, and capillary wall materials. A pseudostrain energy method was implemented to subtract rigid-body-like motion of the submodel volume experienced in the global model, and was critical for convergence and successful analyses in the submodels. The deformation and hoop stresses in the capillary wall were determined and compared with published capillary failure stress. For the dynamic load applied to the skin of the arm (physiologically simulating a punch), the model predicted that approximately 8% volume fraction of the capillary wall was above the reference capillary failure stress, indicating bruising would likely occur.

Alveolar oxygen tension and angio-architecture of the distal adult lung.

The present study demonstrates the fine structure of pulmonary capillaries first injured and then undergoing growth in response to a change in the ambient alveolar oxygen tension. Breathing a high fraction of inspired oxygen (FiO2 0.75) triggers restriction by endothelial cell injury and effacement leading to segment narrowing and shortening and segment loss as demonstrated by a fall in density. Subsequently, breathing a relatively low fraction (FiO2 0.21) triggers capillary assembly (angiogenesis), which reverses the changes. The data underscore the structural reprogramming (reduction and restoration) of pulmonary capillaries in response to significant shifts in oxygen tension.

Theoretical microbubble dynamics in a viscoelastic medium at capillary breaching thresholds.

In order to predict bioeffects in contrast-enhanced diagnostic and therapeutic ultrasound procedures, the dynamics of cavitation microbubbles in viscoelastic media must be determined. For this theoretical study, measured 1.5 to 7.5 MHz pulse pressure waveforms, which were used in experimental determinations of capillary breaching thresholds for contrast-enhanced diagnostic ultrasound in a rat kidney, were used to calculate cavitation nucleated from contrast agent microbubbles. A numerical model for cavitation in tissue was developed based on the Keller-Miksis equation (a compressible extension of the Rayleigh-Plesset equation for spherical bubble dynamics), with a Kelvin-Voigt constitutive relation. From this model, the bubble dynamics corresponding to the experimentally obtained capillary breaching thresholds were determined. Values of the maximum radius and temperature corresponding to previously determined bioeffect thresholds were computed for a range of ultrasound pulses and bubble sizes for comparison to inertial cavitation threshold criteria. The results were dependent on frequency, the gas contents, and the tissue elastic properties. The bioeffects thresholds were above previously determined inertial cavitation thresholds, even for the tissue models, suggesting the possibility of a more complex dosimetry for capillary injury in tissue.

Postinsertion pain in region of mandibular dental implants: a case report.

This report describes the role of severe pain in failure of dental implants. A 27-year-old woman presented to the clinic to replace the missing mandibular right first molar and second premolar. A panoramic radiograph was taken, and a clinical examination was done. A decision was made to extract the mandibular right second molar, which had failing endodontics, and two dental implants were placed. Two days later, the patient reported severe pain in that area. Microscopic examination of the surgical specimen revealed longitudinal section of peripheral nerve in the implant site.

[Results of surgical treatment of combined trauma of extremities vessels and bones].

Results of diagnosis and treatment of 127 patients with combined trauma of extremities vessels and bones are analyzed. Amputations were performed at 11 (8,7%) patients, 3 (2,4%) patients died. Long-term results were evaluated at 82 patients followed-up from 12 months to 5 years after surgery. The poor results were revealed at 7 (8,5%), satisfactory -- at 53 (64,7%), good -- at 22 (26,8%) patients. The tactics of surgical treatment is described in details.

Wound healing: a model for the study of diabetic angiopathy.

Wound healing as a model for diabetic angiopathy has been studied by light and electron microscopy. Biochemical studies of the rate of incorporation of 3H-proline and 3H-thymidine into collagen and DNA, respectively, have confirmed the morphologic observations. In both the normal and the diabetic, there was a marked decrease in the rate of collagen and DNA synthesis, suggesting that most of the cells in the biopsies were stunned by the injury and ceased DNA replication during the initial phase. In control mice this decrease was followed by a modest but significant burst of DNA replication, which peaked at two hours and by the fourth hour had returned to the one-hour level. In the diabetic this burst of DNA replication was absent and no capillary morphogenesis was seen at two, four, and eight hours. At 16 hours, there were only a few abnormal nascent vessels observed in the diabetic and antiserum-treated mice. The peak in the rate of collagen synthesis at four hours correlated well with the condensation of collagen at the wound margin and the fibroblast rough-endoplasmic-reticulum (RER) proliferation. In the diabetic mice, there was a significantly attenuated rate of collagen synthesis for the entire 16-hour period. The lack of DNA replication, capillary morphogenesis, fibroblast RER proliferation, and decreased collagen synthesis in the diabetic mouse can be considered interrelated and significant factors in the diabetic's impaired response to cellular injury. In view of the increased frequency and severity of injury to the circulation of the diabetic and the impaired response to repair such injury, it is likely that wound healing is a promising model for diabetic angiopathy.

Loss of peritubular capillaries in the development of chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. In this study, we examined the role of peritubular capillary (PTC) injury in the development of CAN. METHODS: We studied renal biopsies (n = 79) obtained from grafts with CAN. PTC injury was examined morphologically by immunohistochemistry for CD34. These findings were correlated with interstitial fibrosis and graft dysfunction. Humoral immunity involved in CAN was studied by C4d staining. RESULTS: The CAN cases in the present study included chronic rejection (CR) (n = 14, 17.8%) and C4d-positive chronic humoral rejection (CHR; n = 6, 42.9% in CR cases). Irrespective of CR, CHR, or other CAN, the development of CAN was characterized by injury to and loss of identifiable PTCs, accompanied with the development of interstitial fibrosis. In CR and CHR cases, the loss of PTCs was prominent and seemed to progress within a relatively short period after transplantation. A decrease in the number of PTCs significantly correlated with the development of interstitial fibrosis (r = -0.75, P < .001) and impairment of graft function (r = -0.69, P < .001). CONCLUSIONS: Irrespective of whether CR, CHR, or other factors contribute to CAN, the processes involved in its development appear similar and are characterized by progressive injury and loss of PTCs, with the development of renal scarring. Immunohistochemistry for CD34 in human renal biopsies is a useful method for the detection of microvascular injury.

Reducing damage to the periosteal capillary network caused by internal fixation plating: An experimental study.

BACKGROUND: The importance of the periosteum in fracture healing is well-known. Preserving periosteal vascularisation is essential during internal plate fixation of fractures. METHODS: This was an experimental randomised, controlled animal study on nine sheep. Standard dynamic compression plate (DCP) and four different newly designed reefed plates, with different plate-bone contact surface areas and different reef directions, were fixated on to the tibia or radius. After two weeks the plates were removed and the underlying periosteum was analysed. Blood vessels were marked by immunohistochemical staining (CD31 and CD34), microphotographs were taken and blood vessels counted to calculate blood vessel density. RESULTS: Median blood vessel density beneath the standard plate was significantly lower than in the intact periosteum (18.0 vs 27.7mm(3)/cm(3)). Blood vessel density in the periosteum beneath plates with reefs was significantly increased compared with the intact periosteum, and was highest beneath the plate with the lowest bone-plate contact area and crosswise reefs (51.5mm(3)/cm(3)), followed by plates with transverse, oblique and longitudinal reefs, respectively. The direction of the reefs did not have much influence on the periosteal capillary network. Lower contact surface area seems to be the main factor that increases blood vessel density beneath the plates. CONCLUSIONS: The results show that plates with lower contact surface area stimulate angiogenesis in the underlying periosteum, which results in much higher blood vessel density compared with standard DCP. A randomised clinical trial is needed to prove the clinical relevance of these findings.

Thrombin generation measured ex vivo following microvascular injury is increased in SLE patients with antiphospholipid-protein antibodies.

Antiphospholipid-protein antibodies (APA) include lupus-type anticoagulant (LA) and antibodies recognizing complexes of anionic phospholipids (e.g. cardiolipin) and proteins (e.g. prothrombin and beta2-glycoprotein I). The presence of APA is associated with an increased risk of both arterial and venous thrombosis. However, the pathogenic mechanism leading to thrombosis in patients with APA remains unclear. We studied 32 patients with systemic lupus erythematosus (SLE) who were divided into two groups depending on the presence (n = 19) or absence (n = 13) of APA. Healthy volunteers (n = 12) matched by age and sex served as controls. In all subjects LA and IgG class anticardiolipin antibodies (ACA) were determined. Thrombin generation was monitored ex vivo measuring fibrinopeptide A (FPA) and prothrombin fragment F1 + 2 (F1 + 2) in blood emerging from a skin microvasculature injury, collected at 30 second intervals. In subjects with antiphospholipid antibodies mean FPA and F1 + 2 concentrations were significantly higher at most blood sampling times than in controls. In some SLE patients with APA the process of thrombin generation was clearly disturbed and very high concentrations of fibrinopeptide A were detected already in the first samples collected. Two minutes after skin incision SLE patients without APA produced slightly more FPA, but not F1 + 2, as compared to healthy subjects. Mathematical model applied to analyze the thrombin generation kinetics revealed that APA patients generated significantly greater amounts of thrombin than healthy controls (p = 0.02 for either marker). In contrast, in the same patients generation of thrombin in recalcified plasma in vitro was delayed pointing to the role of endothelium in the phenomenon studied. In summary, these data show for the first time that in SLE patients with antiphospholipid-protein antibodies thrombin generation after small blood vessel injury is markedly increased. Enhanced thrombin generation might explain thrombotic tendency observed in these patients.

Effect of external lymph drainage and of coumarin treatment on thermal injury in the rat hind leg.

1. External lymph drainage brings about a significant protective effect in thermal oedema of the rat hind leg. It is suggested that external lymph drainage prevents vasoactive substances drained from the site of injury from passing into the blood stream, which would further increase permeability of the injured blood capillaries.2. Coumarin (5,6-benzo-alpha-pyron) brings about a significant protective effect against the same injury in sham-operated rats.3. The strongest protective effect may be attained by combining external lymph drainage with the administration of coumarin.4. The additional therapeutic effect brought about by coumarin treatment in rats with external lymph drainage is not mediated by an increased flow. The possible mechanisms are discussed.

Noncytolytic human lymphocytes injure dermal microvessels in the huPBL-SCID skin graft model.

Recent transplantation experiments using perforin-deficient mice as allograft recipients have challenged the concept that allograft rejection is mediated exclusively by CTL. We sought to determine if human noncytolytic lymphocytes could mediate rejection of allogeneic human skin grafts in the huPBL-SCID mouse model of rejection. We generated short term lines of human lymphocytes from peripheral blood mononuclear cells using PHA as a mitogen. The first group was stimulated with PHA alone, the second with PHA plus IL-4 and neutralizing antibody to IL-12, and in the third group PBL were depleted of B cells and monocytes before stimulation as in group 2. After two passages, lines were tested for cytolytic ability and IFN-gamma production. Each line was injected i.p. to mice bearing allogeneic skin grafts. The grafts were harvested between day 16 and 21 after PBL injection, then the histology was scored by a blinded observer for degree of infiltration, microvessel injury, induction of epidermal MHC class II, and perforin expression. In vitro we found that PBL in groups 2 and 3 were unable to lyse cultured endothelial cells in a lectin-directed 111In release assay. In vivo 80% of the IL-4/anti-IL-12 groups maintained the IFN-gamma-low phenotype, and no perforin was detected in these grafts. Nevertheless, human microvessel injury was similar between the two groups. This was not antibody-dependent since the B-cell-depleted group showed similar injury. Moreover adjacent murine vessels were intact. We interpret these observations to show (1) these human PBL lines maintained their phenotype following in vivo restimulation, and (2) noncytolytic graft-infiltrating lymphocytes specifically promote injury of allogeneic human microvessels.