Spina bifida as an independent risk factor for sensitization to latex.

PURPOSE: Patients with spina bifida are at a high risk for having an immediate type allergy to latex products. The number of surgical interventions, atopy and catheterization are well known responsible factors, whereas the condition of spina bifida per se has not been established as an independent risk factor. MATERIALS AND METHODS: A total of 131 patients with a shunted hydrocephalus (48 with spina bifida and 83 of other origin) were investigated for sensitization to latex by skin prick tests and determination of specific IgE. We hypothesized that the diagnosis of spina bifida will increase the risk for latex sensitization while considering potential confounding factors. Thus, we performed a multiple logistic regression analysis to determine independent risk factors. RESULTS: Whereas 56.3% (27/48) of children with spina bifida proved sensitized against latex, this result was the case in only 16.9% (14/83) with another cause of hydrocephalus (p <0.001). The mean number of surgical interventions was 6.2 for patients with no latex sensitization and 9.3 for those with sensitization (p = 0.02). Of patient sensitized to latex 43.9% had a history of atopy compared to 15.5% of those not sensitized (p = 0.02). Sensitized and nonsensitized patients were comparable regarding gender and catheterization. In a multiple logistic regression analysis the cause of the hydrocephalus (odds ratio 6.76 for spina bifida), atopy (odds ratio 3.37) and the number of surgical interventions (odds ratio 1.14 per operation) were identified as independent risk factors. CONCLUSIONS: The increased risk of latex sensitization in patients with spina bifida seems to be disease associated. Possible explanations for this finding may be genetic, antigen mediated, early latex exposure and immunological reasons.

Increased tacrolimus levels during diarrhea.

While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

Central liver hematomas caused by mountain-bike crashes.

BACKGROUND: Mountain biking, one of the most popular sports in recent years with more than 10 million riders, is implicated more and more in severe bike accidents with complicated injuries. In addition to head injuries, which are common and account for most of the fatalities, we have observed an increase in liver trauma over the years. METHOD: Approximately 19000 bike associated accidents were reported in 1998 in Austria. A total of 52 patients were admitted to our trauma ward between 1995 and 1997 with mountain-bike associated injuries. Of the 52, eight presented with subcapsular hematoma of the liver sustained by falling while riding. In all patients, nonoperative management was successful. These injuries were associated with a special form of bar-ends used on the mountain-bikes. After a broad response from the industry, facilitated by many articles in newspapers, life-style magazines, radio and television stations, this type of bar end has nearly vanished from the market. RESULTS: As a result, in 1998, only one case of liver injury was observed, and from 1999 to August 2000, no such injuries have been reported thus far.

Network of vascular-associated dendritic cells in intima of healthy young individuals.

In earlier studies, our group has established a new "immunological" hypothesis for atherogenesis supported by experimental and clinical studies showing that inflammatory immunological reactions against heat shock protein 60 initiate the development of atherosclerosis. In the present study, we describe the discovery of a so-far-unknown network of dendritic cells in the innermost layer of arteries, the intima, but not veins of healthy humans and rabbits. The number of these dendritic cells is comparable to that of Langerhans cells in the skin, and dendritic cells show a similar phenotype (CD1a(+) S-100(+) lag(+) CD31(-) CD83(-) CD86(-) and no staining for von Willebrand factor or smooth muscle cell myosin). These vascular-associated dendritic cells accumulate most densely in those arterial regions that are subjected to major hemodynamic stress by turbulent flow conditions and are known to be predisposed for the later development of atherosclerosis. These results open new perspectives for the activation of the immune system within the arterial wall.

Renal allograft rupture is associated with rejection or acute tubular necrosis, but not with renal vein thrombosis.

BACKGROUND: Whereas rejection was reported to be the most common cause of renal allograft rupture (RAR) in the pre-cyclosporin era, renal vein thrombosis (RVT) is purported to be the main cause of RAR in patients taking cyclosporin. The extremely low incidence of RVT in our series (0.11%) prompted us to analyse our collective with regard to RAR. METHOD: Between 1974 and 1999, 1811 renal transplants were performed. Patients with RAR, defined as a tear of the renal capsule and parenchyma, were identified and possible underlying factors studied. RESULTS: RAR was diagnosed in nine male and five female recipients (0.8%) with a median age of 36 years. Immunosuppression consisted of azathioprine and prednisolone in seven patients and of cyclosporin-based therapy in the seven others. At exploration five grafts were removed immediately: three because of irreversible rejection, one because of deep wound infection, and one with a twisted renal vein. Six of the nine salvaged kidneys have been functioning after a mean observation time of 45 months. In the pre-cyclosporin era RAR was associated with acute rejection in five out of seven cases as compared with only three of the seven on cyclosporin treatment. Core biopsies might have been the cause in three cases. CONCLUSION: RAR is a rare complication after renal transplantation. Acute rejection still represents the most frequent cause of RAR in the cyclosporin era.

Fluid shear stress induces heat shock protein 60 expression in endothelial cells in vitro and in vivo.

Recent investigations indicate that the initial event in the pathogenesis of atherosclerosis involves an (auto)immunologic injury to the vessel wall. Heat shock proteins (hsps), which are expressed on the endothelial cell surface, constitute possible autoantigens. After being exposed to shear stress of 30 dyne/cm(2) in vitro by means of a rotational viscometer, human umbilical vein endothelial cells were immunohistochemically stained for hsp 60 by the monoclonal antibody ML-30; static control cells were negative. Maximal hsp 60 induction was observed after 12 hours of hemodynamic stress. In Northern blots, the level of hsp 60 mRNA was markedly increased after only 1 hour of shear stress in human umbilical vein endothelial cells compared with static control cells. In vivo investigations in Lewis rats confirmed these in vitro findings: the intima and media of frozen sections of the right common carotid artery exposed to increased wall shear stress (after ligation of the left common carotid artery) were stained for hsp 60. The vessel wall of the left low-shear-stress-exposed side was negative. These findings demonstrate that shear stress results in hsp 60 induction in endothelial cells in vivo and in vitro, providing the prerequisite for humoral and cellular reactions to endothelial hsp in the earliest stages of atherosclerosis.

Bilateral nephrectomy, peritoneal dialysis and subsequent cadaveric renal transplantation for treatment of renal failure due to polycystic kidney disease requiring continuous ventilation.

We report here on a newborn with end-stage renal failure due to autosomal recessive polycystic kidney disease, also causing ventilation-requiring respiratory distress. Peritoneal dialysis was able to keep the newborn alive but not wean it from the respirator. After removal of both huge kidneys, dialysis became more effective and allowed the neonate to be extubated only 5 days later. It was decided to register the baby for a pediatric cadaveric kidney transplant when it reached 6 kg/body wt or to perform a living related transplant if no such kidney became available and the baby grew to 7 kg/body wt. At the age of 9 months and a weight of 6 kg a cadaveric kidney from a 20-month-old donor became available and was transplanted extraperitoneally. Prophylactic immunosuppression included cyclosporin, mycophenolate mofetil and steroids. Pneumonia on post-operative day 10 required respiratory care for several days and acute rejection requiring peritoneal dialysis. Both complications were controlled with antibiotics and conversion from cyclosporin to tacrolimus and a temporary increase in steroids. Thirteen months later the child is alive and well with a serum creatinine of 0.6 mg%. From this experience we would recommend early removal of both polycystic kidneys causing end-stage renal failure and respiratory insufficiency, starting peritoneal dialysis and performing a renal transplant as soon as possible. This therapeutic strategy seems appropriate for this complex situation.

Expression of stress proteins, adhesion molecules, and interleukin-8 in endothelial cells after preservation and reoxygenation.

Endothelial activation is a central feature of preservation-induced allograft injury. The present study aims at a quantitative assessment of stress proteins, adhesion molecules, and interleukin-8 in a cell culture-based model of organ preservation. Human umbilical vein endothelial cells were exposed to cold, hypoxic storage in University of Wisconsin (UW), histidine-tryptophane-ketoglutarate (HTK), and EuroCollins solutions for 8 h with subsequent rewarming/reoxygenation (rew/reox) for 1 and 4 h. A cell-based ELISA was designed for detection of heat shock proteins (HSP) 60 and 70, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). Immunohistochemical staining was performed for comparison. Interleukin-8 was quantified by ELISA. HSP 70 was expressed after cold storage in HTK and EuroCollins solution and after rew/reox in all groups. A constitutive expression of HSP 60 was observed with further upregulation after rew/reox following cold storage in all experimental groups. ICAM-1 was clearly upregulated, but VCAM-1 showed only weak expression after cold storage and rew/reox. ELAM-1 was detectable in minimal amounts after cold storage but was considerably upregulated after 4 h of rew/reox. A significant increase of interleukin-8 release could be found after 4 h of rew/reox following storage in EuroCollins solution. Expression of stress proteins can be considered as a new parameter of preservation-associated endothelial activation. Apart from possible protective effects, allograft vasculopathy could be in part a consequence of the antigeneic potential of heat shock proteins connected with effects caused by adhesion molecules and inflammatory cytokines.

Decline of shear stress-induced activation of extracellular signal-regulated kinases, but not stress-activated protein kinases, in in vitro propagated endothelial cells.

We investigated the involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways in human endothelial cells in response to shear stress and alterations of these kinases in in vitro-propagated endothelial cells (ECs). Potent activation (10-fold) of extracellular signal-regulated kinase (ERK2), a member of the MAPK family, occurred within 10 min of shear stress (5 dynes/cm2), whereupon rapid inactivation ensued. Shear stress also induced activation of stress-activated protein kinase (SAPK) or c-Jun NH2-terminal protein kinase (JNK) in ECs. Suramin pretreatment completely inhibited shear stress stimulation of ERK2, but not SAPK/JNK, highlighting a role for growth factor receptors in ERK activation. Translocation of ERK2 from the cytoplasm to the nucleus was observed in shear-stressed endothelial cells. In addition, we compared activities of MAPKs in shear-stressed cells derived from passages 4 and 10 (older). The magnitude of ERK2 activation was significantly lower in aged ECs compared to those of passage 4, while SAPK/JNK was not altered in the in vitro aged ECs. A similar level of ERK2 activation was found in both young and older cells stimulated with phorbol-12-myristate-13-acetate (PMA), indicating an age-related alteration of the plasma membrane. Taken together, these findings suggest that MAP kinase activation may be crucial for the expression of many genes in ECs stimulated by shear stress, and that an alteration in MAPK activities could contribute to the age-related decline in proliferative capacity.

Activation of mitogen-activated protein kinases (ERK/JNK) and AP-1 transcription factor in rat carotid arteries after balloon injury.

Smooth muscle cell proliferation is a key event in neointimal formation after balloon angioplasty. The molecular signals that mediate this process have yet to be identified. Mitogen-activated protein (MAP) kinases are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate whether the signal transduction pathways of MAP kinases were involved in the development of restenosis in the injured arteries. Rat carotid arteries were isolated at various time points after balloon injury, and activities of MAP kinases, including extracellular signal-regulated kinases (ERK), and stress activated protein kinases (SAPK)/c-Jun N-terminal protein kinases (JNK), were determined in protein extracts of the vasculature using protein kinase assay and Western blot analysis. After balloon angioplasty, ERK2 and JNK1 activities in the vessel wall increased rapidly, reached a high level in 5 minutes and maintained for 1 hour. A sustained increase in ERK2 kinase activity was observed over the next 7 days in the arterial wall and 14 days in neointima after injury. In contrast, opposite and uninjured arteries did not show significant changes in these kinase activities. Concomitantly, Western blot analysis confirmed that the ERK2 kinase in the injured vessels was indeed activated or phosphorylated, showing a slowly migrating species of a 42-kDa protein containing phosphorylated tyrosine. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced activator protein 1 (AP-1) DNA-binding activity. Thus, balloon injury rapidly activates the MAP kinases in rat carotid arteries. These kinase activations may be crucial in mediating smooth muscle cell proliferation in response to vascular angioplasty.

Interrelationship between growth factor-induced activation of the Na+/H(+)-antiporter and mobilization of intracellular Ca2+ in NIH3T3-fibroblasts.

Addition of serum growth factors or bombesin to quiescent NIH3T3-fibroblasts leads to a simultaneous mobilization of intracellular Ca2+ and an increase in cytosolic pH which is inhibitable by dimethylamiloride. The mobilization of intracellular Ca2+ is a pH-dependent process with an optimum at pH 7.1. In quiescent cells with a pHi greater than or equal to 6.8, inhibition of the Na+/H(+)-antiporter by dimethylamiloride or reduction of extracellular Na+ attenuates the growth factor induced Ca2(+)-response. It is concluded that the growth factor induced activation of the Na+/H(+)-antiporter facilitates the mobilization of Ca2+ by shifting the internal pH towards the optimum for the Ca2(+)-release.