Die Bedeutung des Natriums für den renal-tubulären Calcium-Transport bei Rana ridibunda

Zusammenfassung In Anlehnung an frühere Experimente zur Na⁺-Abhängigkeit der renal-tubulären Transporte von Glucose, PAH und Urea wurden Versuche über die Bedeutung des Na⁺ für die Ca⁺⁺-Reabsorption an der isolierten künstlich perfundierten Niere von Rana ridibunda durchgeführt.Erniedrigung des Na⁺-Angebotes von 76,5 auf 20,0 mMol/l vermindert sowohl die Menge reabsorbierten Natriums als auch die des reabsorbierten Calciums, letztere allerdings weniger als erstere. Der Quotient reabsorbiertes Na⁺/reabsorbiertes Ca⁺⁺ verschiebt sich zugunsten des Ca⁺⁺.Fehlendes Na⁺-Angebot auf der Lumen- oder der Blutseite der Tubulusepithelien hat keinen sicheren Einfluß auf die Menge reabsorbierten Calciums, dagegen sinkt die Reabsorptionsrate von Ca⁺⁺ auf weniger als 10% des filtrierten, wenn Na⁺ weder auf der Lumen- noch auf der Blutseite angeboten wird.Die Ca⁺⁺-Reabsorptionsrate ist gesteigert bei Angebot von Ca⁺⁺ ausschließlich auf der Lumenseite, vermutlich wegen des unter physiologischen Bedingungen nicht existenten Konzentrationsgradienten, der blutwärts gerichtet ist. Bei Angebot von Ca⁺⁺ nur von der Blutseite erscheint kein Ca⁺⁺ im Harn: die Tubulusepithelien sind für Ca⁺⁺ im Richtungssinne der Sekretion undurchlässig.Durch die Hemmstoffe der Na⁺-Reabsorption Convallatoxin und Furosemid wird auch die Reabsorption von Ca⁺⁺ — sogar relativ stärker als die von Na⁺ — gehemmt. Da in den Versuchen mit Hemmstoffen das Na⁺-Angebot (extracelluläre Konzentration) konstant bleibt, wird geschlossen, daß die Ca⁺⁺-Reabsorption mit dem Na⁺ über dessen Transport gekoppelt ist.Im Prinzip folgt die Verknüpfung der Ca⁺⁺-Reabsorption mit dem Na⁺ den gleichen Gesetzmäßigkeiten wie die Verknüpfung des Na⁺ mit den Transporten von Glucose, PAH und Harnstoff. Damit ist ein weiteres Indiz für die Vermutung gewonnen, daß die Na⁺-Abhängigkeit ein zellphysiologisches Prinzip von weiter Gültigkeit ist.

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Summary With regard to earlier experiments about the influence of Na⁺ on the tubular transport of glucose, PAH and urea, the effect of Na⁺ on the reabsorption of Ca⁺⁺ in the isolated artificially perfused kidney of Rana ridibunda was studied.Lowering of the Na⁺-concentration from 76.5–20.0 mMol/l results in a decrease of the reabsorbed amounts of both Na⁺ and Ca⁺⁺, the decrease being less marked in the latter. The quotient Na⁺ reabsorbed/Ca⁺⁺ reabsorbed changes in favour of the calcium.Lack of Na⁺ on the luminal or the contraluminal side of the tubular wall does not significantly influence the amount of Ca⁺⁺ being reabsorbed. If, however, Na⁺ is missing on both sides the rate of reabsorption of Ca⁺⁺ falls below 10% of the filtered amount.The rate of Ca⁺⁺-reabsorption increases if Ca⁺⁺ is offered on the luminal side only. Presumably this increase is due to a concentration gradient for Ca⁺⁺ which does not exist under physiological conditions. If Ca⁺⁺ is offered on the contraluminal side only, no Ca⁺⁺ appears in the urine. Apparently the tubular epithelium is impermeable for Ca⁺⁺ from the blood to the tubular lumen.The decrease of the reabsorption of Ca⁺⁺ brought about by substances inhibiting the reabsorption of Na⁺ such as Convallatoxin and Furosemid is relatively more marked than the concomitant inhibition of the reabsorption of Na⁺.Since in the experiments with the above mentioned inhibitors the extracellular Na⁺-concentration remains constant, it is concluded that the Ca⁺⁺-reabsorption is coupled with the transport of Na⁺.In principle the Na⁺-dependence of the Ca⁺⁺-reabsorption follows the same pattern as the Na⁺-dependence of the transports of glucose, PAH and urea, thus supporting our contention that the Na⁺-dependence of active transports is a physiological mechanism of general importance.

     

Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival

Bam32 is an adaptor protein recruited to the plasma membrane upon B cell receptor (BCR) crosslinking in a phosphoinositol 3-kinase (PI3K)-dependent manner; however, its physiologic function is unclear. To determine its physiologic function, we produced Bam32-deficient mice. Bam32(-/-) B cells develop normally but have impaired T-independent antibody responses in vivo and diminished responses to BCR crosslinking in vitro. Biochemical analysis revealed that Bam32 acts in a novel pathway leading from the BCR to MAPK/ERK Kinases (MEK1/2), MAPK/ERK Kinase Kinase-1 (MEKK1), extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (p38). This pathway appears to be initiated by hematopoietic progenitor kinase-1 (HPK1), which interacts directly with Bam32, and differs from all previously characterized BCR signaling pathways in that it is required for normal BCR-mediated proliferation but not for B cell survival.     

The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system

The Cbl family of proteins are evolutionarily conserved negative regulators of activated tyrosine kinase-coupled receptors. Antigen receptors are prominent targets of negative regulation by the Cbl family members, Cbl and Cbl-b, which proteins function as ubiquitin ligases. Cbl and Cbl-b contain substrate recognition domains that interact specifically with activated protein tyrosine kinases of the Src and Syk/ZAP-70 families. Cbl-mediated ubiquitination of these kinases leads to their degradation, resulting in attenuation of receptor signals. Cbl may also control activation-induced monoubiquitination of antigen receptors, thus facilitating their delivery to lysosomes for subsequent degradation. Finally, the interactions of Cbl proteins with downstream targets of tyrosine kinases, such as PI-3-kinase and Vav, could provide an additional mechanism to attenuate receptor signaling. By targeting multiple components of antigen receptor signaling for degradation, the Cbl protein family provides a critical mechanism to ensure an appropriate immune response. The hyperresponsiveness of Cbl(-/-) and Cbl-b(-/-) lymphocytes and the autoimmune phenotype of Cbl-b(-/-) mice lend strong support for this proposal. The ability to control early receptor signals through regulated protein degradation provides a novel paradigm of immunoregulation.     

Adoptive immunotherapy for posttransplantation viral infections.

Viral diseases are a major cause of morbidity and mortality after hemopoietic stem cell transplantation. Because viral complications in these patients are clearly associated with the lack of recovery of virus-specific cellular immune responses, reconstitution of the host with in vitro expanded cytotoxic T lymphocytes is a potential approach to prevent and treat these diseases. Initial clinical studies of cytomegalovirus and Epstein-Barr virus in human stem cell transplant patients have shown that adoptively transferred donor-derived virus-specific T cells may restore protective immunity and control established infections. Preclinical studies are evaluating this approach for other viruses while strategies for generating T cells specific for multiple viruses to provide broader protection are being evaluated in clinical trials. The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy.     

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.     

Comparative efficacy,speed, and adverse effects of three PTSD treatments: exposure therapy,EMDR, and relaxation training

The authors examined the efficacy, speed, and incidence of symptom worsening for 3 treatments of posttraumatic stress disorder (PTSD): prolonged exposure, relaxation training, or eye movement desensitization and reprocessing (EMDR; N = 60). Treaments did not differ in attrition, in the incidence of symptom worsening, or in their effects on numbing and hyperarousal symptoms. Compared with EMDR and relaxation training, exposure therapy (a) produced significantly larger reductions in avoidance and reexperiencing symptoms, (b) tended to be faster at reducing avoidance, and (c) tended to yield a greater proportion of participants who no longer met criteria for PTSD after treatment. EMDR and relaxation did not differ from one another in speed or efficacy.     

A new method to bind allergens for the measurement of specific IgE antibodies

BACKGROUND: Detection of allergen-specific IgE antibodies in patients' sera plays a key role for the diagnosis of IgE-mediated allergy. If no validated test system is available, diagnostic tools must be developed, usually by coupling or binding the allergens to a solid phase. Streptavidin ImmunoCAP is a new solid phase for binding of allergens which can be used in the Pharmacia CAP system. OBJECTIVE: It was the aim of this study to assess the diagnostic validity of Streptavidin ImmunoCAP. METHODS: Biotinylation and allergen concentration for binding to Streptavidin ImmunoCAP were optimized and IgE obtained with natural rubber latex, obeche wood, wheat and rye flour Streptavidin ImmunoCAP were compared with the results of ImmunoCAP and Enzyme Allergo-Sorbent Test (EAST) using sera from patients complaining of workplace-related respiratory symptoms. RESULTS: While the relation of biotin-label and protein was critical (best results were obtained with a 5- fold molar excess), labelled protein for coupling to streptavidin ImmunoCAP was applicable in a wide concentration range. On average, IgE values with streptavidin ImmunoCAP were as high as with ImmunoCAP but considerably higher than values obtained by EAST. CONCLUSION: Streptavidin ImmunoCAP is a valuable tool for sensitive and specific measurement of IgE binding to new allergens superior to cellulose disk-based methods.     

Indolent systemic mastocytosis with elevated serum tryptase, absence of skin lesions, and recurrent severe anaphylactoid episodes

BACKGROUND: In contrast to aggressive mastocytosis, patients with indolent systemic mastocytosis (ISM) usually present with urticaria pigmentosa-like skin lesions. In those who lack skin lesions, mastocytosis is often overlooked or confused with endocrinologic, allergic, or other internal disorders. CASE REPORT AND RESULTS: We report on a 33-year-old male patient in whom severe hypotensive episodes occurred after contact with ants or yellow jackets. Since no specific IgE was detected, the serum tryptase concentration was measured and found to be clearly elevated (70 ng/ml). Consecutive staging and examination of the bone marrow revealed ISM. The patient was advised to circumvent insect contact, to take antihistamines on demand, and to carry an epinephrine self-injector for emergency events. In a retrospective analysis of 40 patients seen between 1988 and 2003, only 2 had a life-threatening mediator-related episode before ISM was diagnosed. CONCLUSIONS: Our report confirms the diagnostic value of tryptase in patients with suspected mastocytosis. In addition, the report suggests that the lack of typical skin lesions does not exclude an indolent form of mastocytosis even if the serum tryptase is clearly elevated. Finally, our case further shows that mastocytosis can be an important differential diagnosis to be considered in patients with unexplained anaphylactoid or other mediator-related symptoms.