Tetrodotoxin block of A-fibre afferents from skin and muscle - a tool to study pure C-fibre effects in the spinal cord

The properties of tetrodotoxin (TTX)-resistant C-fibre afferents of the dorsal roots were tested in Sprague-Dawley rats. Dorsal roots (L4-L6) were blocked with TTX (0.5-1 micro M) and the amplitude of the first response of the dorsal horn superficial interneurones (cord dorsum potential, CDP) to electrical stimulation of peripheral C-fibres in combination with natural noxious stimulation was taken as measure for intact conductivity of different kinds of noxious input by means of the C-fibre refractory period. After blockade of dorsal roots with TTX, formerly masked CDPs from muscle C-fibre afferents were uncovered. Noxious pressure to the gastrocnemius soleus muscle belly and noxious pinch to the calcanean tendon proved to be TTX resistant and therefore was propagated centrally. For cutaneous heat nociceptors it could also be shown that conductivity was intact after blockade of the dorsal roots with TTX. However, we could not exclude the TTX resistance of non-nociceptive receptors of muscle or skin. Nevertheless, blockade of afferents with TTX together with suitable stimulation techniques proves to be a reliable method to investigate central effects from C-fibre afferents without contaminating effects from A-fibres in the rat.     

Muscular Performance and Fatigue in Primary Hyperparathyroidism

The purpose of this study was to evaluate changes in muscular strength and endurance, work capacity, and subjective fatigue following surgical treatment of primary hyperparathyroidism (pHPT), and to assess whether changes in muscular function were due to changes in activation of the muscles. A prospective consecutive study design was used, and patients surgically treated for nontoxic goiter served as controls. Nineteen female patients with mild to moderate pHPT and 20 controls were included. Maximal isometric handgrip and quadriceps strength, quadriceps endurance (intermittent stimulation), and quadriceps activation (superimposed twitch technique) were used for evaluation of muscular function. All patients were operated on successfully. Knee extension strength increased by 17 ± 17% (mean ± SD; p= 0.0004) in the patients, whereas no change was observed in the controls. The relative strength increase correlated positively to patient age at operation (r= 0.52, p= 0.02). Handgrip strength, quadriceps endurance, and general work capacity did not change in any group after operation. Subjective fatigue was preoperatively higher in patients than in controls (p= 0.01), and decreased postoperatively to the level of controls. In conclusion, women with pHPT increase knee extension force after parathyroidectomy as a result of increased force generation capacity of the muscle. If change in physical performance is a determinant for change in subjective fatigue in pHPT after operation, then change in strength of the quadriceps muscle seems to be of primary importance, whereas handgrip strength, muscular endurance, and work capacity do not seem to be important. The cause of the increasing strength benefit with increasing age at operation as found in this study needs further investigation.     

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.     

Fibrosarcoma in Children: A Rare Tumour with Long-Term Survival even with Advanced Disease A Report of 3 Cases

Fibrosarcoma is a rare tumour in children. The potential of malignancy has been questioned. We present three cases of fibrosarcoma in children. The follow-up periods range from 10 to 37 years. The first patient had pulmonary metastases at the time of diagnosis in 1958. The primary tumour in fossa ischio-rectalis was resected in 1960. Lung metastases were resected in 1960 and 1989. Radiotherapy was given in 1992. He is still alive with metastases 37 years after the first manifestation of disease. The second patient had a primary tumour and several local recurrences in the mandible. He is alive without evidence of disease 4 years after resection of pulmonary metastases and 21 years after resection of the primary tumour. The third patient has no signs of recurrence or metastasic spread 10 years after a wide excision of subcutanous tumours of the left upper arm. The cases demonstrate a special tumour-entity of low-grade malignancy, which show a good prognosis and a wide spectrum of biological behaviour.     

Die Kölner Nephro-Krabbelgruppe

Monatsschrift Kinderheilkunde - Eine angeborene chronische Nierenerkrankung geht nicht nur für das betroffene Kind mit immensen Einschränkungen einher. Auch auf die Eltern, die in vielen...     

Long‐term Radiological and Clinical Outcome after Lumbar Spinal Fusion Surgery in Patients with Degenerative Spondylolisthesis: A Prospective 6‐Year Follow‐up Study

ObjectiveTo assess which radiological alignment parameters are associated with a satisfactory long‐term clinical outcome after performing lumbar spinal fusion for treating degenerative spondylolisthesis.MethodsThis single‐center prospective study assessed the relation between radiological alignment parameters measured on standing lateral lumbar spine radiographs and the patient‐reported outcome using four different questionnaires (COMI, EQ‐5D, ODI and VAS) as primary outcome measures (level of evidence: II). The following spinopelvic alignment parameters were used: gliding angle, sacral inclination, anterior displacement, sagittal rotation, lumbar lordosis, sacral slope, pelvic tilt and pelvic incidence. Furthermore, the length of stay and perioperative complications were documented. Only cases from 2013 to 2015 of low‐grade degenerative lumbar spondylolisthesis (Meyerding grades I and II) were considered. The patients underwent open posterior lumbar fusion surgery by pedicle screw instrumentation and cage insertion. The operative technique was either a posterior lumbar interbody fusion (PLIF) or a transforaminal lumbar interbody fusion (TLIF) performed by three different senior orthopedic surgeons. Exclusion criteria were spine fractures, minimally invasive techniques, underlying malignant diseases or acute infections, previous or multisegmental spine surgery as well as preoperative neurologic impairment. Of 89 initially contacted patients, 17 patients were included for data analysis (11 males, six females).ResultsThe data of 17 patients after mono‐ or bisegmental lumbar fusion surgery to treat low‐grade lumbar spondylolisthesis and with a follow‐up time of least 72 months were analyzed. The mean age was 66.7 ± 11.3 years. In terms of complications two dural tears and one intraoperative bleeding occurred. The average body mass index (BMI) was 27.6 ± 4.4 kg/m² and the average inpatient length of stay was 12.9 ± 3.8 days (range: 8–21). The long‐term clinical outcome correlated significantly with the change of the pelvic tilt (r _s = −0.515, P < 0.05) and the sagittal rotation (r _s = −0.545, P < 0.05). The sacral slope was significantly associated with the sacral inclination (r _s = 0.637, P < 0.01) and the pelvic incidence (r _s = 0.500, P < 0.05). In addition, the pelvic incidence showed a significant correlation with the pelvic tilt (r _s = 0.709, P < 0.01). The change of the different clinical scores over time also correlated significantly between the different questionnaires.ConclusionsThe surgical modification of the pelvic tilt and the sagittal rotation are the two radiological alignment parameters that can most accurately predict the long‐term clinical outcome after lumbar interbody fusion surgery.     

Anticoagulant action of melagatran: a comparison between neonates and adults using calibrated automated thrombography (CAT)

In the present study, we comparatively evaluated the anticoagulant efficacy of the new direct thrombin inhibitor melagatran in cord vs. adult plasma. In contrast to heparin, melagatran does not require antithrombin as a cofactor. Thus, anticoagulant treatment with melagatran is of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We evaluated the anticoagulant action of increasing amounts of melagatran (0.1–2.0 μmol/l) in both cord and adult plasma by means of calibrated automated thrombography (CAT) with respect to the lag time until the onset of thrombin formation, time to thrombin peak maximum (TTP), endogenous thrombin potential (ETP), and thrombin peak height. Melagatran exhibited approximately the same ability to prolong lag times or TTPs in both cord and adult plasma. Similar concentrations (IC₅₀) of melagatran were required to double the lag times (0.44±0.04 μmol/l vs. 0.52±0.05 μmol/l) or to double the TTPs (0.91±0.08 μmol/l vs. 1.06±0.09 μmol/l) in cord vs. adult plasma. Melagatran exhibited a higher ability to suppress ETPs or thrombin peak heights in cord vs. adult plasma. Markedly lower concentrations (IC₅₀) of melagatran were required to suppress ETPs (0.27±0.03 μmol/l vs. 0.70±0.06 μmol/l) or thrombin peak heights by 50% (0.29±0.03 μmol/l vs. 0.53±0.04 μmol/l) in cord vs. adult plasma. We conclude that our results suggest a higher ability of melagatran to suppress thrombin formation in cord vs. adult plasma. Thus, lower amounts of melagatran might be required in neonates undergoing antithrombotic therapy.     

Bioactive isocoumarins isolated from the endophytic fungus Microdochium bolleyi

Three new isocoumarin derivatives ( 2- 4) were isolated together with monocerin ( 1) from Microdochium bolleyi, an endophytic fungus from Fagonia cretica, a herbaceous plant of the semiarid coastal regions of Gomera. Compounds 2 and 3 are both 12-oxo epimers of 1, and 4 is a ring-opened derivative of 1. The structures were elucidated by detailed spectroscopic analysis and comparison with reported data. The absolute configurations were determined by a modified Mosher's method. Compounds 1, 3, and 4 showed good antifungal, antibacterial, and antialgal activities against Microbotryum violaceum, Escherichia coli, Bacillus megaterium, and Chlorella fusca. Compound 2 was moderately antifungal and antialgal.     

Tierexperimentelle Beobachtungen über das intracerebrale Wachstum menschlicher Tumoren

Zusammenfassung Das Wachstumsverhalten zweier in das Gehirn von Goldhamstern implantierter menschlicher Tumoren (H. Ad. Nr. 1 und H. S. Nr. 1) wurde untersucht. Bei allen Tieren konnte ein Tumorwachstum histologisch nachgewiesen werden. Cortisonvorbehandlung der Wirtstiere begünstigte bei H. Ad. Nr. 1 die Tumorausbreitung und führte frühzeitiger zum Tode. Das intracerebrale Tumorwachstum führte jedoch auch unabhängig von der Wirtsvorbehandlung bei allen Tieren zum Tode innerhalb von 4 Wochen nach der Transplantation. Beide Geschwulst-typen wuchsen am besten in den liquorhaltigen Räumen, weniger in der Hirnsubstanz. Die Bevorzugung der Meningen durch beide Tumortypen entspricht der allgemeinen Erfahrung über die cerebrale Metastasierung entdifferenzierte Sarkome und Adenocarcinome.

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Summary The growth behavior of two human tumors (H. Ad. No. 1 and H. S. No. 1) transplanted to the hamster brain has been studied. Tumor growth could be histologically verified in all animals inoculated. Cortisone-conditioning of the host increased tumor expansion and resulted in an earlier and more rapid death rate in the H. Ad. No. 1 group. Regardless of tumor or host-conditioning employed, all animals succumbed to intracerebral tumor growth by the end of the fourth week post transplantation. Both tumor types grew better in the ventricles and subarachnoid space than in the brain tissue itself. The predilection of these two tumor types for the meninges confirms our clinical knowledge on the pattern of cerebral metastasis of dedifferentiated sarcomas and adenocarcinomas.

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