Atrial natriuretic peptide and verapamil can prevent gentamicin induced acute renal failure in the rat

Summary: Calcium channel blockers are able to improve renal function in acute renal failure (ARF) and natriuretic peptides can also exert beneficial effects. At present it is unknown whether administration of atrial natriuretic peptide (ANP) and a calcium channel blocker given before a toxic lesion can prevent gentamicin induced ARF. the mechanisms of action of natriuretic peptides and calcium channel blockers are different and, as yet, it has not been clarified if combined administration can augment the effects on renal function. After a basal period we investigated the effects of verapamil (VER, 0.66 mg/kg), ANP, (30 μg/kg) and a combination of both (identical doses as described individually). the drugs were given intravenously for a period of 40 min (infusion period) before gentamicin (15 mg/kg, i.v.) was administered for induction of ARF. Basal values for glomerular filtration rate (GFR, mL/min) were around 1.8 with no differences between the groups. At the end of the infusion period (before application of gentamicin) GFR was significantly elevated with VER + ANP (3.13 ± 0.51), ANP (2.70 ± 0.59) and VER (2.34 ± 0.47) compared to controls (saline, 1.7 ± 0.48). After application of gentamicin GFR significantly dropped in the control group (0.77 ± 0.21, 0.75 ± 0.19, respectively), indicating development of ARF. In contrast with VER + ANP, ANP and VER GFR could be maintained for 30 min (2.47 ± 0.39, 2.28 ± 0.33, 2.22 ± 0.43, respectively) and 130 min (2.11 ± 0.32, 1.86 ± 0.29, 2.11 ± 0.28, respectively) after gentamicin. Moreover ANP and VER revealed natriuretic activity and, due to their vasorelaxing potency, also influenced arterial blood pressure. We conclude that both VER and ANP are able to prevent early gentamicin induced ARF when given before the toxic lesion. Both drugs induce hyperfiltration while infused, in particular when administered in combination.     

Intensity dependence of auditory evoked potentials (AEPs) as biological marker for cerebral serotonin levels: effects of tryptophan depletion in healthy subjects

Rationale: The intensity dependence of the auditory evoked potentials (AEP) has been suggested to be a specific biological marker of central serotonergic activity. Objective: While previous studies used circumstantial evidence to support this hypothesis, we manipulated (decreased) cerebral levels of serotonin directly by using tryptophan depletion. Methods: Twelve healthy young subjects were investigated using placebo and two different amino acid mixtures in a double blind cross over design on three different occasions. AEPs recorded during tryptophan depletion were analyzed by dipole analysis and regional sources using methods published in the literature. Results: For none of the mixtures a significant effect of tryptophan depletion was found. There was a trend towards reduced intensity dependency after tryptophan depletion, especially in the right hemisphere. This reduction correlated with the amount of reduced tryptophan in plasma. Conclusions: The results indicate, in contrast to earlier indirect studies, that the intensity dependence of AEPs is not a specific marker of central serotonergic activity. Received: 8 March 1999 / Final version: 25 May 1999     

In‐Depth Analysis of Hyaline Fibromatosis Syndrome Frameshift Mutations at the Same Site Reveal the Necessity of Personalized Therapy

Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a two base insertion leads to the synthesis of a protein that is rapidly targeted to the ER‐associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the nonsense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying one base insertion but not in those carrying two base insertions. This study highlights the importance of in‐depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.     

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19/IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.     

Prognose der postoperativen Endophthalmitis

BACKGROUND: The outcome of 20 patients is summarized in a retrospective study to identify clinical findings that influence the long-term prognosis of postoperative endophthalmitis. PATIENTS: Between 1991 and 1997 a total of 20 patients with postoperative endophthalmitis were admitted. Median age was 80 years (range: 9-95), 11 patients were male, 9 female. Sixteen pars-plana vitrectomies, 2 anterior vitrectomies and 2 rinsings of the anterior chamber without vitrectomy were performed. Furthermore, all patients received intraocular and systemic antibiotic treatment. For microbiological investigation, specimens from vitreous, anterior chamber and conjunctiva were sent in. Long-term outcome was controlled for an average of 14 months after treatment of the endophthalmitis (range: 4-36 months). RESULTS: At the end of treatment, 40% of patients had a visual acuity of 0.4 or better, 80% had 1/20 or better. Patients with a preoperative visual acuity of at least hand movement had a better postoperative visual outcome than patients with only light perception. Visual acuity was better in patients with chronic endophthalmitis than in patients with acute or subacute endophthalmitis. In patients with chronic or subacute endophthalmitis, improvement of visual acuity was found some months after the operation more often than in patients with acute endophthalmitis. However, in 40% of cases with an acute onset, no improvement or even worsening of the visual acuity was documented. Best postoperative results were found after infection with Staphylococcus epidermidis and Propionibacterium acnes. CONCLUSION: Important prognostic factors of postoperative endophthalmitis are visual acuity, the onset of the endophthalmitis (acute, subacute or chronic) and the microbiological findings. At the time of surgery and antibiotic treatment, visual acuity should be at least hand motion to expect an improvement in the visual outcome.     

Stellenwert der Radiokephalometrie in der Diagnostik bei OSAS im Erwachsenenalter

Zusammenfassung Untersuchungen zum Zusammenhang zwischen kephalometrischen und polysomnographischen Befunden wurden bisher von mehreren Autoren überwiegend mit linearen statistischen Methoden durchgeführt. Die eigene Arbeitsgruppe interessierte, ob durch den Einsatz mehrdimensionaler statistischer Verfahren der Informationsgehalt der Radiokephalometrie stärker ausgeschöpft werden kann. 77 Patienten mit OSAS (Alter 25 69 Jahre, RDI 3,6 ­ 90,1/h) wurden polysomnographisch und kephalometrisch untersucht. Die Vermessung der knöchernen Parameter erfolgte mit dem Computerprogramm WinCeph und die der Pharynxweichteile in Anlehnung an Hochban et al. (Dtsch Zahnärztl Z 49: 777 782, 1994). Mittels logistischer Regressionen wurde geprüft, ob polysomnographische RDI-Werte > 20 aus dem Röntgenbild vorhergesagt werden können. Die Kopplung der 10 knöchernen Parameter ergab bezüglich der Erkennung erhöhter RDI-Werte eine Sensitivität von 93 % bei einer Spezifität von 44 %. Vier Parameter fielen durch besonders hohe relative Risiken auf. Die alleinige Verwendung der Weichteilparameter zeigte eine Sensitivität von 98 % bei einer Spezifität von 13 %. Die gleichzeitige Betrachtung von Weichteil- und knöchernen Parametern erbrachte eine Sensitivität von 96 % bei einer Spezifität von 40 % in der Erkennung erhöhter RDI-Werte. Die Radiokephalometrie gehört nicht zur Basisdiagnostik des OSAS, sie kann aber bei kieferchirurgischen Operationsentscheidungen einen Beitrag leisten.