Posttransplantation encapsulating peritoneal sclerosis contributes significantly to mortality after kidney transplantation.

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD) and may present after kidney transplantation, a condition known as posttransplantation EPS. The prevalence and impact of posttransplantation EPS on survival after kidney transplantation is unknown. From January 1, 1996 until July 1, 2007, 1241 PD patients were transplanted. Thirty-eight cases of posttransplantation EPS (3%) were identified from the Dutch multicenter EPS study. In EPS patients the mean pretransplant dialysis duration was longer than in the controls (71.4 ± 37.5 months vs. 34.7 ± 25.5, p < 0.0001). The majority of EPS cases were observed within the first 2 years after transplantation, but some cases appeared many years after transplantation. Two hundred and one (16.2%) patients died after transplantation, of which 17 were EPS patients. After infection (23.9%), cardiovascular disease (21.9%) and malignancy (10.9%), EPS (8.5%) was the fourth known cause of death after transplantation. Kaplan-Meier analysis showed a significant decreased survival for transplanted patients with posttransplantation EPS compared to transplanted patients without EPS. In conclusion, posttransplantation EPS is rare but carries a high mortality. A prolonged clinical vigilance and a high index of suspicion for the diagnosis are warranted, specifically in PD patients with a relatively long cumulative pretransplant duration of PD.

Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons.

Tropomyosin-related kinase (Trk) receptors modulate neuronal structure and function both during development and in the mature nervous system. Interestingly, TrkB and TrkC are expressed as full-length and as truncated splice variants. The cellular function of the kinase-lacking isoforms remains so far unclear. We investigated the role of the truncated receptor TrkB.T1 in the hippocampus of transgenic mice overexpressing this splice variant by analyzing both neuronal structure and function. We observed an impairment in activity-dependent synaptic plasticity as indicated by deficits in long-term potentiation and long-term depression in acute hippocampal slices of transgenic TrkB.T1 mice. In addition, dendritic complexity and spine density were significantly altered in TrkB.T1-overexpressing CA1 neurons. We found that the effect of TrkB.T1 overexpression differs between subgroups of CA1 neurons. Remarkably, overexpression of p75(NTR) and its activation by chemical induction of long-term depression in slice cultures rescued the TrkB.T1-dependent morphological alterations specifically in one of the two subgroups observed. These findings suggest that the TrkB.T1 and p75(NTR) receptor signaling systems might be cross-linked. Our findings demonstrate that TrkB.T1 regulates the function and the structure of mature pyramidal neurons. In addition, we showed that the ratio of expression levels of p75(NTR) and TrkB.T1 plays an important role in modulating dendritic architecture and synaptic plasticity in the adult rodent hippocampus, and, indeed, that the endogenous expression patterns of both receptors change reciprocally over time. We therefore propose a new function of TrkB.T1 as being dominant-negative to p75(NTR).

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Rituximab for the treatment of glomerulonephritis in hepatitis C associated cryoglobulinaemia.

Mixed-type cryoglobulins are strongly associated with hepatitis C virus (HCV) infection and may lead to vasculitis with renal involvement. The treatment of this condition is antiviral therapy for HCV, but this may be ineffective or not tolerated because of side effects. Alternative strategies such as immunosuppressive drugs and plasmapheresis are of limited use, especially in patients after liver transplantation (LTx). We describe an LTx patient with cryoglobulinaemia-associated glomerulonephritis, who was treated successfully with the B cell depleting monoclonal antibody rituximab.

111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity.

AIM: Trastuzumab can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial human epidermal growth factor receptor 2 (HER2) expression may be transiently upregulated by a compensatory mechanism following cardiac stress. 111In-DTPA-trastuzumab, scintigraphy can detect HER2 positive tumour lesions, however previously, we found myocardial uptake in only 1 of the 15 anthracycline-pre-treated patients with a median of 11 months after the last anthracycline administration. To evaluate whether myocardial HER2 expression is upregulated by anthracycline-induced cardiac stress or in case of heart failure by chronic pressure or volume overload, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracyclines and with non-anthracycline-related heart failure. METHODS: Patients within 3 weeks after undergoing 4-6 cycles first-line anthracycline-based chemotherapy and patients with heart failure due to cardiac disease underwent gammacamera imaging 48 and 96 h after 111In-DTPA-trastuzumab intravenously. RESULTS: Myocardial 111In-DTPA-trastuzumab uptake was observed in 5 out of 10 anthracycline-treated patients, who all were without symptomatic cardiac dysfunction. None of the 10 heart failure patients showed myocardial uptake. CONCLUSION: Shortly after completion of anthracycline treatment, myocardial HER2 over-expression was detectable in 50% of the patients. 111In-DTPA-trastuzumab scintigraphy after anthracyclines prior to adjuvant trastuzumab potentially identifies patients susceptible for trastuzumab-related cardiotoxicity and thus may facilitate the optimal timing of trastuzumab therapy.

A role for BDNF in the late-phase of hippocampal long-term potentiation.

The neurotrophin family of growth factors has received enormous attention recently for its role in modulating synaptic strength in the developing and adult nervous system. Several recent studies have indicated a role for brain-derived neurotrophic factor (BDNF) in long-term potentiation (LTP), a form of long-lasting plasticity observed at synapses in the hippocampus and other brain areas. The late-phase (L-LTP; e.g. > 2 h) of LTP has been shown to require the synthesis of new proteins. We have examined whether BDNF or other TrkB ligands participate in L-LTP in two ways: by examining transgenic mice which lack BDNF or by acutely blocking TrkB function using function-blocking antibodies. Slices from BDNF knock-out animals or slices treated with TrkB antibodies failed to exhibit L-LTP, indicating that TrkB ligands participate in extending synaptic enhancement from a short-lasting to a long-lasting form.

Shc-binding site in the TrkB receptor is not required for hippocampal long-term potentiation.

Recent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation but also in modulating synaptic strength in the developing and adult nervous system. To understand how neurotrophins induce changes in synaptic strength, we have investigated signaling pathways downstream of the TrkB receptor, which binds brain-derived neurotrophic factor (BDNF) or NT-4/5. To test whether the Shc-site activated signaling pathway, which has been shown to be important for neuronal survival in vivo, also plays a role in processes like long-term potentiation (LTP), we have generated a mouse strain carrying a mutation in the Shc-binding site of the TrkB receptor. In hippocampal slices from these mice we investigated whether basal synaptic transmission, early-LTP (E-LTP) or late-LTP (L-LTP) were affected by this mutation. We found that homo- and heterozygous mutant mice show no difference in the induction-rate or magnitude of E-LTP and L-LTP induced by theta-burst or tetanus stimulation, suggesting that the Shc-binding site in the TrkB receptor and its downstream activated signaling cascade is not involved in hippocampal synaptic plasticity.

Rapid gene transfer into cultured hippocampal neurons and acute hippocampal slices using adenoviral vectors.

Primary cultures of hippocampal neurons were infected with an adenovirus coding for beta-galactosidase. Expression could be detected as early as 4 h after infection and steadily increased to high levels at 24 h without evidence for a functional impairment of the infected neurons. Similarly, adenovirus-mediated gene transfer into acute hippocampal slices was detectable 4 h after infection and could be localized to discrete areas of the CA1 region by microinjection of the virus stock solution. Infected slices were still suitable for electrophysiological experiments.

Effects of small doses of dioxins on the immune system of marmosets and rats.

There is no doubt that TCDD is capable of inducing effects on a variety of components and functions of the immune system in a variety of species. In fact, such changes seem to belong to the most sensitive variables affected by TCDD. Some of the biological effects, induced at rather high doses of TCDD exhibiting general toxicity (> 3 micrograms TCDD/kg body wt), may be considered unspecific or the result of the pronounced thymus involution. However, other effects (such as that on lymphocyte subtype patterns in marmosets or a reduced resistance of mice to influenza viruses) have been reported to occur at dose levels far from those leading to thymic involution or general toxicity. It should be remembered that the pathognomonic relevance for man of subtle modifications in the pattern of lymphocyte surface receptors is largely unknown. Until now, such deviations are considered rather as biological phenomena than indications or causes of specific diseases. Nevertheless, such changes represent clear-cut biological effects induced by TCDD. Since effects of TCDD on components and defined functions of the immune system have been revealed in several species, it would be surprising if humans were largely resistant to such effects, but reliable data in humans with high exposures to defined dioxins verified by an appropriate quantification of the exposure are scarce as of now. Data published so far have not revealed pronounced alterations of such variables. However, no studies of well-defined human populations with quantified body burdens have been performed with modern methods (such as flow cytometry) analyzing a wide variety of surface receptors. Performance of such studies is essential for a better and reliable risk assessment, and the technology is available. Some of the effects observed (such as the changes in the pattern of lymphocyte subpopulations) must certainly be considered as biological effects induced by TCDD, and the situation is similar to the induction of hepatic monooxygenases, which are also observable in this dose range. However, the relevance of such changes with respect to adverse health effects in humans is presently difficult to judge in the absence of clear-cut functional deficits demonstrated so far either in vivo or in vitro.

The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments.

Brain-derived neurotrophic factor (BDNF) is a member of the NGF gene family, which has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes like long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF-gene. We then used hippocampal slices from these mice to investigate whether LTP is affected by this mutation. Mutant mice showed significantly weaker LTP in the CA1 region. The magnitude of the potentiation as well as the percentage of cases in which LTP could be induced successfully was clearly reduced whereas important pharmacological and morphological control parameters in the hippocampus of these animals were unaffected. Adenoviral vectors were used to re-express BDNF in acute slices of BDNF-knock-out mice. In most cases LTP could be rescued with this approach. These results suggest that BDNF has an important functional role in the expression of LTP in the hippocampus.

Absence of antisperm antibodies in anejaculatory men.

Antisperm antibodies were assessed in the serum samples of 73 men unable to ejaculate naturally and on the sperm cells of 13 of these men. None of the serum samples were found to be positive by sperm agglutination or sperm immobilization methods and antibodies were detected by an immunobead assay on the sperm cells of one of the 13 men examined.

[Familial hyperactivity of angiotensin-converting enzyme (ACE)]. / Familiaire hyperactiviteit van angiotensineconverterend enzym (ACE).

An extremely high level of serum angiotensin-converting enzyme (ACE) activity was found in eight individuals, women aged 31, 60, 42 and 67 years, and men aged 50, 47, 23 and 50 years. They had consulted a specialist due to a wide range of non-specific complaints or abnormalities (fatigue, dyspnoea, arthralgia, kidney stones with high urinary calcium, neurological symptoms and an elevated blood alkaline phosphatase activity level). As each of these complaints could be a symptom of sarcoidosis, the ACE activity was measured. However, sarcoidosis was not diagnosed in any of these patients. A subsequent analysis revealed that all eight individuals had family members with a similar elevation of ACE. Therefore, the increase in ACE activity was familial. Patients with this disorder have serum ACE levels of between 3 and 7 times the upper limit of normal, whereas in the case of sarcoidosis, serum ACE levels rarely exceed three times this limit. Familial ACE hyperactivity is not accompanied by clinical symptoms. It is caused by a point mutation in the ACE gene, which results in the cell-bound ACE being more readily loosened from the cell surface into the circulatory system.

Maintaining stable memory engrams: new roles for Nogo-A in the CNS.

Nogo-A interaction with its different receptors (Nogo receptor 1 (NgR1), S1P receptor 2 (S1PR2), paired immunoglobulin-like receptor B (PirB)) restricts plasticity and growth-dependent processes leading, via the activation of different signaling pathway to the stabilization of the neuronal networks (either developmentally or during processes of memory consolation in the mature nervous system). Taking away these molecular brakes might allow for the induction of extensive structural and functional rearrangements and might promote compensatory growth processes after an injury of the CNS, in cortical structures as well as in the spinal cord. However, it is important to keep in mind that this could as well be a dangerous endeavor, since it might facilitate unwanted and unnecessary (and probably even maladaptive) neuronal connections.

Management of encapsulating peritoneal sclerosis: a guideline on optimal and uniform treatment.

Encapsulating peritoneal sclerosis (EPS) represents a rare complication of long-term peritoneal dialysis (PD). It is characterised by diffuse peritoneal membrane fibrosis, progressive intestinal encapsulation and the clinical spectrum of intestinal obstruction. The pathogenesis is as yet not well understood but includes inflammation, angiogenesis and fibrosis. The current diagnosis of EPS lacks specificity and relies on clinical, radiographic or macroscopic evaluation. There is no general agreement on managing EPS although accumulating clinical data suggest drug treatment (steroids, tamoxifen), surgery (enterolysis) or a combination of both. Here, we provide a short overview on the current knowledge of EPS, with a focus on treatment. Moreover, we present a diagnostic and a therapeutic algorithm for EPS based on the best available published data and our combined experience.