The role of complement in Ascaris suum induced histopathology

The role of complement in the histopathology of primary and challenge re-infection by Ascaris suum was assessed. Guinea-pigs deficient in C4 or depleted of the terminal components C3 to C9 by cobra venom factor (CVF) were employed. Pathological changes in the livers of complement-deficient guinea-pigs differed slightly from controls. The most striking findings were in the lungs of CVF-treated infected animals, where marked eosinophilic abscesses were observed following either a primary or repeat infection with Ascaris suum. Additionally, greater numbers of larvae were harvested from the lungs of both CVF-treated and C4-deficient infected guinea-pigs as compared with controls. Serum C4 levels varied over the first 7 days after primary infection, declining in several of the normal and CVF-treated animals, but remaining stable in others. The C4 levels remained unchanged in re-infected animals. The C3 to C9 levels remained within the normal range in both primary and re-infected guinea-pigs. The data suggests that complement is involved in the host responses to infection with Ascaris suum. In the absence of complement (C3 to C9), enhanced pulmonary eosinophilic infiltration and eosinophilic granuloma formation occur in both primary and re-infected animals.     

Eradication of established tumors by CD8+ T cell adoptive immunotherapy

We generated the DUC18 T cell receptor transgenic mouse expressing an H-2Kd -restricted transgenic T cell receptor specific for the syngeneic CMS5 fibrosarcoma rejection antigen mutated ERK2(136-144). DUC18 mice were capable of specifically eliminating lethal CMS5 tumor challenges, and transfer of DUC18 splenocytes to naive nontransgenic recipients conferred protection from subsequent and established CMS5 tumor burdens. Eradication of established tumor burdens by adoptive transfer of DUC18 splenocytes was dose and time dependent. Transferred tumor-specific T cells remained functional in vivo and capable of rejecting small tumors even in the presence of large, established tumor burdens. These findings highlight the kinetic battle between tumor growth and the production of a tumor-specific response and have critical implications for effective adoptive immunotherapy.     

Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) defines a group of otherwise healthy elderly subjects with a markedly elevated risk of developing Alzheimer's disease (AD). In the search for biomarkers of MCI, we assessed whether MCI shares neurochemical abnormalities with AD in areas affected early in the course of the disease. As a secondary study aim, we tested to what extent neurochemical findings reflect neuropsychological deficits. Proton spectroscopy was performed in 19 MCI patients, 18 AD patients and 22 age and gender matched controls (CON) within the parietal gray and white matter (PWM and PGM) and the hippocampus (HIP). The cognitive test battery used included measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The N-acetyl-aspartate to creatine ratio (NAA/Cr) was significantly reduced in the HIP of MCI and AD compared with CON (p < 0.05). Only AD patients showed parietal abnormalities, namely significantly elevated myoinositol (mI/Cr and mI/NAA) in PGM, reduced NAA/Cr and elevated mI/NAA in PWM. MCI subjects were significantly impaired in categorical verbal fluency (VF) (p < 0.001) and delayed verbal recall (DVR) (p < 0.001). VF was positively correlated with hippocampal NAA/Cr (p < 0.05) and parietal mI/NAA (p < 0.05). In summary, this study demonstrates shared neurobiological hippocampal abnormalities in MCI and AD, whereas parietal lobe neurochemical profiles and functions were normal in MCI. Thus, biological evidence is provided that MCI represents a precursor stage of AD. Moreover, multivoxel 1H MRS may enable an objective staging of the neurodegenerative process underlying the age-dependent cognitive deficits eventually leading to dementia.     

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.     

KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Hämostase und Hämatokrit

Zusammenfassung In einer prospektiven Studie wurden bei 500 Patienten mit angeborenen Herzfehlern, davon 55% mit azyanotischen und 45% mit zyanotischen Vitien, die Thrombozytenzahl, einige Globaltests der plasmatischen Gerinnung (Quick-Wert, partielle Thromboplastinzeit, Thrombinzeit) und des Vollblutes (Thrombelastogramm) sowie der Proaktivator-Plasminogen-Komplex als Parameter der Fibrinolyse-Aktivität im Vollblut untersucht. Die Ergebnisse wurden nach Herzfehlertyp (azyanotisch/zyanotisch), Lebensalter (Neugeborene/Säuglinge/Kinder) und Hämatokrit-Bereichen (bis 40%/41–50%/51–60%/über 60%) gruppiert. Die Signifikanz zwischen den einzelnen Gruppen wurde mit Hilfe der Varianz-Analyse, die Korrelation der Parameter zum Hämatokrit-Wert mit Hilfe der linearen Regression berechnet.Bei azyanotischen Herzfehlern lagen die untersuchten Hämostase-Parameter im Normbereich, während bei zyanotischen Herzfehlern die Mittelwerte der Thrombozytenzahl, der plasmatischen und der Vollblut-Gerinnung sowie des Proaktivator-Plasminogen-Komplexes mit zunehmendem Lebensalter zum pathologischen Bereich tendierten; die niedrigsten Werte fanden sich im Neugeborenenalter, und zwar ohne Abhängigkeit vom Herzfehlertyp, wobei ursächlich die altersphysiologische Unreife des Gerinnungssystems anzuschuldigen ist. Bei Patienten mit zyanotischen Herzfehlern nahm die Gerinnbarkeit des Vollblutes mit zunehmender Polyglobulie kontinuierlich ab, während die Parameter der plasmatischen Gerinnung bis zu Hämatokrit-Werten von 60% durchaus im Normbereich blieben; eine ausreichende Korrelation der Hämostase-Parameter zum Schweregrad der Polyglobulie war nur für Patienten mit Hämatokrit-Werten über 60% nachzuweisen. Auch die Fibrinolyse-Aktivität im Vollblut war bei zyanotischen Patienten generell und ohne gesetzmäßige Abhängigkeit vom Lebensalter vermindert und nahm entgegen dem Anstieg des Hämatokrit-Wertes deutlich ab; dieses Verhalten spricht genen die in der Literatur vielfach diskutierte Steigerung der Fibrinolyse-Aktivität bei zyanotischen Patienten, welche allerdings von anderen Autoren nur im Plasma und nicht im Vollblut bestimmt wurde.Es empfiehlt sich daher, bei höhergradiger Polyglobulie Gerinnung und Fibrinolyse vorzugsweise im Vollblut zu untersuchen und nach den hier gefundenen, hämatokrit-bezogenen Richtwerten zu beurteilen, insbesondere vor diagnostischen und chirurgischen Eingriffen. Eine Behandlung mit gerinnungsaktiven Medikamenten ist streng zu indizieren; bei extremer Polyglobulie mit Hämatokrit-Werten über 70% können therapeutische Erythropheresen im Rahmen der präoperativen Vorbereitung Rheologie und Hämostase-Parameter kurzfristig verbessern.Mit Unterstützung der Deutschen Forschungsgemeinschaft, Bad Godesberg. Für die Durchführung der Laborarbeiten und die Dokumentation der Ergebnisse danken wir Frau Gudrun Godec herzlich. Die Studie wurde auszugsweise auf der Jahrestagung der Deutschen Gesellschaft für Pädiatrische Kardiologie am 25.9.79 in Berlin vorgetragen     

Complex indications in surgery of the lumbar spinal canal

Opinions on the treatment of disc herniation are very controversial and the results reported vary, very much indeed. Most often, one decided--and still decides--to excise the disc herniation in conjunction with hemilaminotomy or flavectomy; this method having been carried out from 1974 to 1983 on 598 patients, at the department of Orthopaedic Surgery, Balgrist, of the University of Zurich. A follow-up of over 400 patients has proved to be very informative: whereas very good or good clinical results can be reported in 73.6% of such cases with disc herniation, alone, these not having undergone operation before, similar results were only found in 27.2% of those who had also been suffering from additional causes of lumbalgia like a relatively narrow spinal canal, spondylolisthesis, spondylolysis or nearthrosis for instance. This finding is of paramount importance when attempting to improve the overall results. It is very necessary to separate the complex cases from the "simple" disc herniation ones. At the same time, those patients suffering from lumbalgia due not only to a herniated disc but also to other additional causes arising from alterations to the lumbar spinal canal must be judged and treated differentially. The present follow-up permits conclusions and considerations correspondingly.     

A critical look at survival of diabetics with end-stage renal disease. Transplantation versus dialysis therapy

The survival of 100 consecutive patients with diabetic nephropathy after treatment with hemodialysis, peritoneal dialysis, or renal transplantation was reviewed at our institution from 1976 to 1982. Standard actuarial survival analysis revealed an overall survival of 83% and 61% at one and two years, respectively. Coronary angiography was used as a screening procedure for renal transplantation. In the dialysis group, 27 patients were considered acceptable transplant candidates on the basis of the coronary angiography but were not transplanted for other reasons. When the survival analysis was limited to those "transplant candidates" the survival rates were 78%, 51%, and 8% at 1, 2, and 5 years, respectively. In comparison, survival after transplantation was 81%, 67%, and 45%, at 1, 2, and 5 years, respectively. In order to eliminate bias, survival comparisons were subsequently made using the Cox Proportional Hazard Model to take into account the time the transplant patients spent on dialysis prior to renal transplantation. When this analysis was performed, there was no significant difference in survival between transplantation and dialysis for the first two years, but overall survival after five years was significantly better after renal transplantation even when the comparison was limited to acceptable transplant candidates who remained on dialysis (P = .04). Survival for patients with significant coronary disease (greater than 70% stenosis of a coronary vessel or moderate to severe left ventricular dysfunction) was analyzed according to therapeutic modality. Although overall prognosis was poor in this group as a whole (1, 2, and 5 year survivals were 76%, 45%, and 19%, respectively), the cardiac patients had a trend to better survival after renal transplantation than when maintained on dialysis (P = .22). In addition to other factors such as quality of life, rehabilitation, and progression of other diabetic complications, the benefit of renal transplantation on patient survival must be considered when deciding between renal transplantation and maintenance dialysis therapy for diabetic patients with renal failure.