A technique for respiratory-gated radiotherapy treatment verification with an EPID in cine mode

Respiratory gating based on external surrogates is performed in many clinics. We have developed a new technique for treatment verification using an electronic portal imaging device (EPID) in cine mode for gated 3D conformal therapy. Implanted radiopaque fiducial markers inside or near the target are required for this technique. The markers are contoured on the planning CT set, enabling us to create digitally reconstructed radiographs (DRRs) for each treatment beam. During the treatment, a sequence of EPID images can be acquired without disrupting the treatment. Implanted markers are visualized in the images and their positions in the beam's eye view are calculated off-line and compared to the reference position by matching the field apertures in corresponding EPID and DRR images. The precision of the patient set-up, the placement of the beam-gating window, as well as the residual tumour motion can be assessed for each treatment fraction. This technique has been demonstrated with a case study patient, who had three markers implanted in his liver. For this patient, the intra-fractional variation of all marker positions in the gating window had a 95% range of 4.8 mm in the SI direction (the primary axis of motion). This was about the same (5 mm) as the residual motion considered in the planning process. The inter-fractional variation of the daily mean positions of the markers, which indicates the uncertainty in the set-up procedure, was within +8.3 mm/-4.5 mm (95% range) in the SI direction for this case.     

In vivo monitoring of age-related changes in rat brain using quantitative diffusion magnetic resonance imaging and magnetic resonance relaxometry

Ghrelin is a novel peptide that stimulates the release of growth hormone from the pituitary and is involved in hypothalamic feeding regulation. A pre-embedding immunostaining technique was used to study the ultrastructure and synaptic relationships of ghrelin-containing neurons in the rat arcuate nucleus (ARC). Ghrelin-like immunoreactive (ghrelin-LI) neurons were found in the ARC, and were especially abundant in its ventral part. At the electron microscopic level, ghrelin-LI neurons received afferent synapses from many unknown axon terminals. Ghrelin-LI products in the immunoreactive cell bodies, processes, and axon terminals were detected mainly in dense granular vesicles about 110 nm in diameter. Ghrelin-LI presynaptic axon terminals often made synapses with unknown immunonegative neurons. These results suggest that ghrelin acts to regulate food intake through synaptic connections in hypothalamic neuronal networks.     

Functional defects in the fanconi anemia pathway in pancreatic cancer cells

Biallelic BRCA2-mutations can cause Fanconi anemia and are found in approximately 7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconi-defective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G(2)/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.     

Only minor spinal motor reflex effects from feline group IV muscle nociceptors

The contribution of group III and IV muscle nociceptors activated by injection of KCl or bradykinin into the muscle artery (i.a.) of the gastrocnemius-soleus muscle to spinal motor reflex pathways was investigated in high spinal cats. Group I-III fibres were completely blocked by TTX, leaving group IV-fibre conduction intact. Thus, effects from i.a. KCl or bradykinin injection persisting after TTX were attributed to TTX resistant group IV fibres while the contribution of group III fibres was approximately defined by the difference between those effects and the control effects before TTX. Confirming former findings the chemical activation of group III and IV muscle afferents induced distinct reflex facilitation of the flexor posterior biceps semitendinosus and inhibition of the extensor quadriceps. After the block of all myelinated fibres by TTX the same stimuli induced only minor reflex effects mediated by the persistently conducting TTX resistant group IV afferents. It is concluded that the main functional meaning of group IV muscle afferents, which respond preferentially with a higher threshold to mechanical stimuli, is probably less related to reflex motor control than that of group III afferents.     

Effekte einer Captopriltherapie auf die Natrium- und Wasserausscheidung bei Patienten mit Leberzirrhose und Aszites

Summary Ascites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium,-potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 × 6.25 mg/d captopril for 5 days and 4 × 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril.PRA increased significantly after 2 days of captopril treatment. 2 × 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 × 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again. Conclusion: In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.

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Abkürzungen ACE Angiotensin-Converting-Enzym - A-II Angiotensin II - C_{H 2 O} Frei-Wasser-Clearance - C_Krea Kreatinin-Clearance - C_Osmo Osmolale Clearance - g Gramm - h Stunde - kg Kilogramm - l/d Liter pro Tag - MAP Mittlerer arterieller Blutdruck - mg Milligramm - mg/d Milligramm pro Tag - ml/min Milliliter pro Minute - mmHg Millimeter Quecksilbersäule (Torr) - mmol/d Millimol pro Tag - NaCl Natriumchlorid - ng/ml/h Nanogramm pro Milliliter und Stunde - PA Plasma-Aldosteron - pg/ml Picogramm pro Milliliter - PRA Plasma-Renin-Aktivität - RAAS Renin-Angiotensin-Aldosteron-System - SEM Standardfehler des Mittelwertes - S_Krea Kreatininkonzentration im Serum - S_Osm Serum-Osmolalität - U_Krea Kreatininkonzentration im Urin - U_Osm Urin-Osmolalität - V Urinminutenvolumen - vgl. vergleiche - µmol/l Micromol pro Liter     

Low-dose prednisolone/chlorambucil therapy in patients with severe membranous glomerulonephritis

Because of the high rate of spontaneous remission, treatment of membranous nephropathy with prednisolone and chlorambucil is still controversial. The aim of this study was to give this therapy only to those patients at risk of developing renal insufficiency and to test the efficacy of a low-dose therapeutic regimen. Seventeen patients with more than 10 g protein excretion per day (mean 16.9) and/or a deterioration in renal function (mean serum creatinine, 162 mol/l) were included. Serum total protein, serum lipids, proteinuria, serum creatinine, and blood pressure were measured, along with the diuretic and antihypertensive medication. The observation time before the start of treatment was 27 ± 27 months. Steroids were given during months 1, 3, and 5 (methylprednisolone 3 × 500 mg intravenously) prednisolone 0.5 mg/kgBW daily per os for 1 week, then tapered by 0.1 mg/kg BW/week for 1 month. Chlorambucil was given during months 2, 4, and 6 at a dose of 0.12 mg/kgBW daily. At the end of treatment proteinuria had significantly decreased (mean of all patients, 7.8 ± 1.4 g/d) in all patients. Six months after the end of treatment proteinuria was significantly lower than at baseline in 14 of 17 patients. Hypoproteinemia and hyperlipidemia had improved; diuretic and antihypertensive medication were reduced. Elevated serum creatinine decreased in 7 of 9 patients (pretreatment, 227 ± 39 mol/1; 6 months, 176 ± 28 mol/l). Nonresponders with respect to serum creatinine responded with respect to proteinuria. Regarding adverse effects, two patients complained of dyspepsia while taking steroids; during chlorambucil treatment two patients experienced nausea and lack of appetite, and one developed leukopenia (1600/l). Chlorambucil was stopped and cell counts normalized 2 weeks later. We conclude that low-dose prednisolone/chlorambucil is both safe and efficient in the majority of patients with severe membranous nephropathy.Abbreviations MGN membranous glomerulonephritis Correspondence to: R. Brunkhorst     

In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.

PURPOSE: BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor. EXPERIMENTAL DESIGN: Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents. RESULTS: A distinct dichotomy of drug responses was observed. Fanconi anemia-defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11(FANCC) did not. CONCLUSIONS: MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.