Drug desensitization to lumacaftor/ivacaftor: A fast lane to drug tolerance.

We present the case of a girl (now 11 years and 9 months old) with cystic fibrosis (F508del homozygote), who developed pruritic rash and urticaria six days after the first dose of the CFTR modulators lumacaftor/ivacaftor. The treatment was paused and had to be interrupted due to an immediate recurrence of the urticarial rash after rechallenge. We developed a drug desensitization protocol, aligned to protocols used for desensitization against oral antibiotics. In contrast to other published protocols, it was performed by rapidly increasing the dose of lumacaftor/ivacaftor granulate at 15 min intervals. The medication was continued without interruption, the rash did not reappear during follow-up of two years. This drug desensitization protocol provides a potential new therapeutic option for patients with drug hypersensitivity reactions to CFTR modulators, especially when there are no alternative treatments. Lumacaftor/ivacaftor is available as granulate, doses can be titrated during desensitization and used for long-term treatment.

Vasomotion of mice mesenteric arteries during low oxygen levels.

BACKGROUND: Ischemia of intestinal organs is a main cause of complications in surgical intensive care patients. Changes in the tonus of arteries contributing to vascular resistance play an important role in the determination of blood flow and thus oxygen supply of various abdominal organs. It is generally acknowledged that hypoxia itself is able to alter arterial tonus and thus blood flow. METHODS: The present study compared the effects of various degrees of hypoxia on second-order mesenteric arteries from male C57BL/6J mice. After vessel isolation and preparation, we assessed vessel diameter using an arteriograph perfusion chamber. Investigating mechanisms promoting hypoxia-induced vasodilatation, we performed experiments in Ca2+-containing and Ca2+-free solutions, and furthermore, Ca2+-influx was inhibited by NiCl2, eNOS-/--, and TASK1-/--mice were investigated too. RESULTS: Mild hypoxia 14.4% O2 induced, in 50% of mesenteric artery segments from wild-type (wt) mice, a vasodilatation; severe hypoxia recruited further segments responding with vasodilatation reaching 80% under anoxia. However, the extension of dilatation of luminal arterial diameter reduced from 1.96% ± 0.55 at 14.4% O2 to 0.68% ± 0.13 under anoxia. Arteries exposed to hypoxia in Ca2+-free solution responded to lower oxygen levels with increasing degree of vasodilatation (0.85% ± 0.19 at 14.4% O2 vs. 1.53% ± 0.42 at 2.7% O2). Inhibition of voltage-gated Ca2+-influx using NiCl2 completely diminished hypoxia-induced vasodilatation. Instead, all arterial segments investigated constricted. Furthermore, we did not observe altered hypoxia-induced vasomotion in eNOS-/-- or TASK1-/- mice compared to wt animals. CONCLUSIONS: The present study demonstrated that hypoxic vasodilatation in mice mesenteric arteries is mediated by a NO-independent mechanism. In this experimental setting, we found evidence for Ca2+-mediated activation of ion channels causing hypoxic vasodilatation.

[Time intervals during and after emergency room treatment. An analysis using the trauma register of the German Society for Trauma Surgery]. / Zeitintervalle während und nach Schockraumversorgung. Eine Analyse anhand des Traumaregisters der Deutschen Gesellschaft für Unfallchirurgie (DGU).

BACKGROUND: The prognosis of severely injured patients depends on a rapid diagnosis and early initiation of therapeutic procedures. MATERIAL AND METHODS: To that end a total of 6,927 prospectively documented severely injured patients with an Injury Severity Score (ISS) > or =16 from the Trauma Registry of the German Trauma Society (DGU, 2002-2007) were analyzed with respect to time intervals during emergency trauma treatment. RESULTS: In cases of indicated emergency surgery the average +/-time in the emergency department was 42+/-34 min, in cases of early surgery 75+/-41 min and in cases of transfer to the intensive care unit (ICU) 83+/-43 min, respectively. The time from the last diagnostic procedure until the end of emergency treatment was 12 min (emergency surgery), 26 min (early surgery) and 32 min (ICU), respectively. Level I (78 min) and level II (72 min) trauma centres showed similar mean times in the emergency department while level III trauma centres had a mean time of 86 min. According to this analysis no general correlation between shorter duration of emergency trauma care and reduced mortality could be observed. CONCLUSION: The duration of time intervals depends on injury severity, treatment after completion of emergency trauma care and the level of the trauma centre. Time management in emergency trauma care can potentially be optimized after completion of the last diagnostic procedure in the emergency room.

[Quality of prehospital and early clinical care of pediatric trauma patients of school age compared to an adult cohort. A matched-pair analysis of 624 patients from the DGU trauma registry]. / Prä- und frühklinische Versorgungsqualität pädiatrischer Traumapatienten im Schulalter im Vergleich mit dem Erwachsenenkollektiv. Matched-Pair-Analyse an 624 Patienten aus dem Traumaregister der DGU.

Conflicting reports exist regarding the quality of prehospital treatment of pediatric trauma patients. The purpose of this investigation was to determine whether prehospital treatment and emergency management in pediatric trauma patients were similar to that in adult patients. All patients who had been prospectively documented in the registry of the German Trauma Society (DGU) between 2002 and 2005 were selected for this study. A total of 312 matched pairs of adult and pediatric patients suffering from identical injuries were defined and compared with respect to cause of trauma, diagnostic and therapeutic interventions, and outcome. Within the study group, 63% were male, and the average age was 10.5+/-2.7 (SD) years in the pediatric group and 33.9+/-9.3 years in the adult group. There was no significant difference regarding prehospital intubation, reanimation, fluid management, chest drainage, ground and air transport to the hospital, time to arrival or interval in the emergency room. In contrast, significant differences (p<0.05) were observed in terms of the cause of trauma and pre-existing diseases. Pediatric trauma patients were not triaged or treated differently from adult trauma patients in respect to key issues of prehospital and early clinical trauma management.

[Interventional emergency embolization for severe pelvic ring fractures with arterial bleeding. Integration into the early clinical treatment algorithm]. / Interventionelle Notfallembolisation bei schweren Beckenfrakturen mit arterieller Blutung. Integration in den frühklinischen Behandlungsalgorithmus.

OBJECTIVE: Presentation of our own experiences and results of an early clinical algorithm for treatment integrating emergency embolization (TAE) in cases of unstable pelvic ring fractures with arterial bleeding. METHOD: Consecutive patient series from April 2002 to December 2006 at a level 1 trauma center. The data of the online shock room documentation (Traumawatch) of patients with a pelvic fracture and arterial bleeding detected on multislice computed tomography (MSCT) were examined for the following parameters: demographic data, injury mechanism, fracture classification according to Tile/AO and severity of the pelvic injury assessed with the Abbreviated Injury Score (AIS), accompanying injuries with elevation of the cumulative injury severity according to the Injury Severity Score (ISS), physiological admission parameters (circulatory parameters and initial Hb value) as well as transfusion requirement during treatment in the shock room, time until embolization, duration of embolization, and source of bleeding. RESULTS: Of a total of 162 patients, arterial bleeding was detected in 21 patients by contrast medium extravasation on MSCT, 12 of whom were men and 9 women with an average age of 45 (14-80) years. The mechanism of injury was high energy trauma in all cases. In 33% it involved type B pelvic fractures and in 67% type C fractures with an average AIS pelvis of 4.4 points (3-5) and a total severity of injury with the ISS of 37 points (21-66). Upon admission 47.6% presented hemodynamic instability with an average Hb value of 7.8 g/dl (3.2-12.4) and an average transfusion requirement of 6 red blood cell units (4-13). The time until the TAE was started was on average 62 min (25-115) with a duration period of the TAE of 25 min (15-67). Branches of the internal iliac artery were identified as the sole source of bleeding. The success rate of TAE amounted to over 90%. CONCLUSION: Interventional TAE represents an effective as well as a fast procedure for hemostasis of arterial bleeding detected on MSCT in patients with pelvic fractures. If an experienced radiologist on 24-h stand-by is assured and the infrastructure is efficient, this can be performed shortly after hospital admission and therefore should be integrated into the early clinical treatment protocol.

[Entrapped motorists and air rescue services: analysis of tactical rescue approach, rescue techniques, and emergency medical services illustrated by a helicopter emergency medical service]. / Eingeklemmte Fahrzeuginsassen in der Luftrettung: Einsatztaktik, rettungstechnische und notfallmedizinische Analyse am Beispiel einer Rettungshubschrauberstation.

BACKGROUND: Analysis of the results and presentation of a treatment concept of a helicopter emergency medical service (HEMS) in prehospital acute care of entrapped motorists. METHODS: Consecutive patient data collection from primary rescue missions of a helicopter emergency medical service (HEMS) from the years 2000-2004. Evaluation based on data collected regarding emergency medical care, rescue techniques, and tactical rescue approach. RESULTS: A total of 359 cases of entrapped motorists were documented: 237 patients were male, 122 were female, and the average age was 37 (range: 2-82 years). The motor vehicle accidents (MVA) occurred in 21% of the cases on the highway, in 29% on a main road, in 43% on a rural road, and in 7% in city/urban areas. Concerning the vehicle types, 86% were automobiles, 5% vans, and 9% trucks. Drivers accounted for 86% of the patients, front seat passengers for 10.1%, and back seat passengers for 3.9%. The average length of motorist entrapment amounted to 17 min with an average on-scene time of 27 min for the HEMS. The total rescue time averaged 56 min. A Glasgow Coma Scale (GCS) score between 3 and 8 was recorded in 33.7% of the patients; in 24% of the cases the shock index was <1; a respiratory rate of <10/min or >20/min was documented in 25.2% of the patients. An NACA score between I and III was recorded in 34.2% of the cases, NACA IV in 18.9%, and NACA >/=V in 46.8%; 11.9% of the patients died before hospital admission. CONCLUSION: For both the emergency control center personnel and the emergency medical technicians (EMT), a case of motorist entrapment must be considered as a trigger mechanism of injury, activating a sophisticated and time-sensitive prehospital acute care and transportation service. In the German emergency medical service this involves primarily the HEMS. Even in cases of potentially critically injured entrapped motorists, the prehospital adherence to"the golden hour of shock" is made possible, despite the resulting higher personnel and equipment expenses.

[Motor vehicle accidents with entrapment. A medical and technical investigation of crash mechanism, injury pattern and severity of entrapment of motor vehicle occupants between 1983 and 2003]. / "Einklemmungstrauma" im Strassenverkehr. Unfallanalyse, Verletzungsschwere und -verteilung eingeklemmter PKW- und LKW-Insassen der Jahre 1983-2003.

AIM: Crash mechanisms, injury patterns, and severity of injury of entrapped motor vehicle occupants were analysed by the Accident Research Unit's scientific teams between 1983 and 2003. RESULTS: Of the 1281 vehicle passenger entrapments in our study, 18.3% happened on highways, 25.6% on federal roads, 35.9% on country roads, and 18.3% on city roads. Of those involved, 69.9% were drivers, 19.4% were front passengers, and 8.5% were rear passengers. Coinvolved objects in car collisions were: other cars 30.9%, trucks 50.2%, objects 18.6%, and motorbikes 0.3%. Coinvolved objects in truck collisions were: other trucks 61.8% and objects 38.2%. The mean Delta-V was 42 km/h (cars 46.2, trucks 32.2). Maximum AIS levels were 31% I, 25.2% II, 19.4% III, 7.8% IV, 7.8% V, and 8.6% VI. Of injuries, 68.7% were to the head, 23.5% to the neck, 50.8% to the chest, 43.6% to upper extremities, 15.4% to the abdomen, 16.4% to the pelvis, and 52.9% to lower extremities. The incidence of multiple injuries (ISS>16) was 23.7%, and mortality was 15.9%. CONCLUSION: Car drivers are more at risk of accidents with entrapment on rural streets, and truck drivers are more at risk on highways. In most cases car occupants crash with trucks or other cars, and truck drivers collide more frequently with other trucks or objects. Besides a high degree of severe single injuries, there is also a high incidence of multiple injury victims and high mortality. Of the fatalities, 74.5% occur during the preclinical course and 24.5% during the clinical course.

Thrombospondin 1 acts as a strong promoter of transforming growth factor beta effects via two distinct mechanisms in hepatic stellate cells.

BACKGROUND AND AIMS: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor beta (TGF-beta) but little is known of the expression patterns and functions of TSP-1 in liver cells. We therefore analysed if and how TSP-1 acts on TGF-beta during fibrogenesis. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction, we demonstrated that hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a lesser extent, by tumour necrosis factor alpha in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-beta mRNA expression and a TSP-1 dependent increase in TGF-beta/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-beta or antibodies against TSP-1 not only abrogated activation of latent TGF-beta but also reduced the effects of the active dimer itself. CONCLUSIONS: Our data suggest that TSP-1 expression is important for TGF-beta effects and that it is regulated by the profibrogenic mediator PDGF-BB in HSC. Furthermore, the presence of TSP-1 seems to be a prerequisite for effective signal transduction by active TGF-beta not only in rat HSC but also in other cell types such as human dermal fibroblasts.

[Thoracic injuries associated with acute traumatic paraplegia of the upper and middle thoracic spine]. / Die Akutbehandlung der traumatischen Brustmarklähmung Wird das Thoraxtrauma übersehen oder unterschätzt?

AIM: The aim of this study was to analyse the number of thoracic injuries associated with acute traumatic paraplegia of the upper and middle thoracic spine and review the early management in respect to treatment standards. METHODS: Using a prospective study protocol, data were sampled and analyzed from 12 December 2000 to 31 March 2002 at a level 1 trauma center. RESULTS: Twenty-two consecutive patients were included in the study. Sixteen suffered severe chest traumata. Lung contusion was diagnosed in 81%, followed by haemopneumothorax (75%) and fracture of the bony chest (75%). Intubation was performed 12 times in all. Chest drainage was performed in 14 patients. The mean duration of artificial ventilation was 20 days (range 2-93) and of intensive care treatment 25 days (range 2-93). Five patients died. CONCLUSIONS: Acute traumatic paraplegia of the upper and middle thoracic spine caused by high energy trauma is highly associated with severe chest trauma. Therefore, respiratory impairment must be kept in mind during the early treatment. If respiratory failure becomes more evident, emergency procedures such as intubation and chest drainage have to be performed. Secondary transfer should be avoided.

[Open pelvic fracture. Treatment strategy and results for 12 patients]. / Die offene Beckenfraktur. Behandlungsstrategie und Resultate anhand von 12 Patienten.

This article presents treatment priorities for open pelvic fracture and the results of 12 patients. In a retrospective study we analyzed 12 patients treated at a level 1 trauma center between 1994 and 1998 of whom eight were male and four female with an average age of 29.6 years. Six type C (6 x III degrees open) and six type B (4 x II degrees and 2 x III degrees open) were identified. On average, 15 EKs were necessary within the first 12 h of treatment (type C=17, type B=13). All type C fractures underwent emergency stabilization with the pelvic C-clamp. Early laparotomy was performed in 60%. Perineal laceration was identified in 58%, followed by nerve and plexus lesions in 42%, injuries of the genitourinary tract in 33%, and lesions of the fecal stream in 25%. Altogether, there were more peripelvic injuries associated with type C fracture than with type B (12 vs 8). On average, there were 27 second-look operations necessary with 3-.2 operations per patient. The average stay in the ICU was 82 days (80-360); 25% died. Control of hemorrhage is fundamental; therefore, emergency stabilization of the pelvis is essential followed by surgical procedures. Early surgical definitive stabilization of the fracture decreases septic complications. Such complex injuries should be treated at specialized trauma centers.

Trauma care in Germany.

Trauma Care in Germany fulfils all requirements to deal with injured young and mobile individuals as well as with an increasing number of injured elderly patient. Furthermore, it is prepared to cope with mass casualties of injured. As a public task the Trauma System in Germany is well organized and follows clear cut demands. To perform technical and medical therapy at highest available level as soon as possible, a ground system of physician staffed ambulances is supported by a network of physician-staffed HEMS all over Germany. Therefore, enormous efforts in financing, basic research and quality management have been undertaken during recent years to create such a sophisticated rescue system.

[Fracture dislocation of the elbow involving the coronoid process]. / Luxationsfrakturen des Ellenbogens mit Beteiligung des Processus coronoideus.

INTRODUCTION: Elbow dislocations are associated with osseus lesions in 30-50%. Integrity of the coronoid process is essential for stability of the elbow joint. METHODS: A retrospective study of 39 patients out of 51 was conducted to evaluate a result of surgical treatment in fracture dislocation of the elbow involving the coronoid process. The patients were followed for an average of 45 months. RESULTS: Operative results were assessed using the Morrey-Score. 3 patients presented an excellent, 19 a good, 14 a moderate and 3 a non satisfactory result. CONCLUSION: Results of operative treatment of fracture dislocation of the elbow are essentially determined by the extent of associated osseus lesions of the radial head and the olecranon. To achieve acceptable functional results early reconstruction and fixation of the coronoid process as well as early mobilisation of the joint is necessary.

[The reality of preclinical treatment in thoracic trauma - a prospective study]. / Die Wirklichkeit der präklinischen Versorgung des Thoraxtraumas - Ergebnisse einer prospektiven Studie.

AIM OF THE STUDY: Because of the well proven fact of outcome improvement by early, preclinical intubation and ventilation of multiple injured and polytraumatized patients, the guidelines of different medical associations recommend this procedure especially in combination with blunt chest trauma. By the means of a prospective study protocol we analyzed whether these treatment standards were respected and whether the kind of preclinical treatment was influencing treatment outcome. PATIENTS AND METHODS: Using a prospective study protocol data were sampled and analyzed. From 1.12.2000 to 25.9.2001 48 consecutive patients were included into the protocol. 12 patients (25 %) had preclinical intubation (group A). 8 patients of group A were intubated by the helicopter emergency team. 36 patients had no tracheal tube (group B). In 34 cases mechanical ventilation has to be started during the emergency room procedures. Two patients were intubated after they were admitted to the intensive care unit (ICU). Insertion of a chest tube was done in 5 patients at the scene by the emergency team, in 15 cases after admission to the hospital and 21 at the ICU. Although the average age of years of patients was higher in group B (37,2 +/- 15,0 y vs. 46,9 +/- 21,1 y), p values calculated by ANOVA test revealed no significant difference. The two groups did not differ regarding to injury severity assessed by the "Injury severity score" (group A: 30,9 +/- 13,3; group B: 29,5 +/- 9,2). The mean duration of mechanical ventilation was 9,4 +/- 9,0d vs. 19,2 +/- 20,4 d in group A vs group B. Patients of group A required intensive care treatment for 12,6 +/- 8,7d vs 21,9 +/- 20,4 d of group B. One patient of group A died because of severe cranio cerebral trauma. 13 Patients of group B died (1 x pulmonal embolism, 12 x multiple organ failure). CONCLUSIONS: Assessment of injury severity by the emergency medical teams failed in a very high percentage. Especially the blunt trauma to the chest was not diagnosed and therefore not respected.

Quantitative relationships of normal cartilage volumes of the human knee joint--assessment by magnetic resonance imaging.

The objective of this study was to assess the normal range of cartilage volumes in the knee joints of healthy adults, the ratio between the patellar, femoral, and tibial cartilages, and the correlation of the volumes with age, body weight, height, body mass index (obesity), patellar bone size, and the diameter of the tibial head. We examined the knee joints of nine healthy volunteers and eleven normal post-mortem specimens with an age range of 24 to 82 years. The cartilage volumes of the patella, femur, medial tibia and the lateral tibia were quantified, using a fat-suppressed FLASH-3D sequence (resolution 2x0.31x0.31 mm3) and digital postprocessing, involving three-dimensional reconstruction. The mean total volume of the knee joint cartilage was 23,245 mm3, the relative standard deviation (CV%) 19%, and the range 16,341 to 33,988 mm3. In the patella, femur and tibia, the CV% amounted to between 22 and 25%. These joint surfaces occupied a relatively variable proportion of the total knee joint volume, the percentage of the patella being 11 to 22%, that of the femur 54 to 69%, that of the medial tibia 7 to 12%, and that of lateral tibia 11 to 16%. The volumes of the lateral tibia were systematically higher than those of the medial tibia (P<0.001). There was no significant correlation of the knee joint cartilage volume with age (r=+0.05), body weight (r=+0.38), height (r=+0.39) or body mass index (r=+0.29), but a relatively high correlation with the diameter of the tibial head (r=+0.78, P<0.001). After normalising the volumes to this diameter, the CV% of the total knee joint cartilage volume was reduced to 13%, its variation being 12 to 21% in the patella, femur and tibia. MRI is available for measuring cartilage volume during growth, functional adaptation, and tissue loss in degenerative joint disease. The study shows that a wide variation of cartilage volumes exists in the knee joints of normal adults. To reduce the variability between individuals, the cartilage volumes may be normalised to the head of the tibial diameter.

In vivo reproducibility of three-dimensional cartilage volume and thickness measurements with MR imaging.

OBJECTIVE: Previous studies suggest that MR imaging is capable of providing accurate data on knee joint cartilage volume and thickness in vitro, but the reproducibility of these data in living subjects has not been analyzed rigorously. Our aim was therefore to determine the in vivo reproducibility of volume and thickness measurements from replicated data sets, applying three-dimensional (3D) postprocessing methods. SUBJECTS AND METHODS: Eight healthy volunteers were imaged six times at a resolution of 2 x 0.31 x 0.31 mm with a fat-suppressed fast low-angle shot 3D sequence, the knee being repositioned in between replicated examinations. Three-dimensional reconstructions of the articular cartilage surfaces were obtained from sagittal data sets, and the cartilage volumes were calculated. The thickness distribution was analyzed throughout the joint surfaces independent of the section orientation, using a previously validated 3D minimal-distance algorithm. RESULTS: In the volunteers, the coefficient of variation for replicated volume measurements ranged from 1.3% (patella) to 3.4% (lateral tibia), and the standard deviation of the individual cartilage volumes ranged from +/- 16% (lateral tibia) to +/- 22% (femur). The intraclass correlation coefficient ranged from .959 (lateral tibia) to .995 (patella). The interobserver evaluation was similar to the interscan reproducibility. The mean interscan deviation of the maximal cartilage thickness interval ranged from 0.1 to 0.3 cartilage thickness intervals (of 0.5 mm); only in rare cases did we record deviations greater than one thickness interval. CONCLUSION: MR imaging can be used to determine cartilage volume and thickness in the knee joints of living subjects with high precision, provided that a fat-suppressed gradient-echo sequence with adequate resolution and 3D digital image processing are used.

[Three-dimensional thickness and volume measurements of the knee joint cartilage by MR tomography: reproducibility in volunteers]. / Dreidimensionale Dicken- und Volumenbestimmung des Kniegelenkknorpels mit der MRT: Reproduzierbarkeit am Probanden.

OBJECTIVE: To determine the reproducibility of three-dimensional volume and thickness measurements of the knee joint cartilage with MRI in volunteers. METHODS: The knees of 7 healthy individuals (ages 23 to 58 yrs.) were sagittally imaged with a resolution of 2 x 0.31 x 0.31 mm3, using a fat-suppressed FLASH-3 D sequence. The knee was repositioned in between replicate acquisitions, 6 data sets being obtained in each case. After semiautomatic segmentation and three-dimensional reconstruction of the cartilage, the thickness was determined independent of the original section orientation. The coefficient of variation for repeated volume measurements and the deviations of the maximal cartilage thickness values were calculated subsequently. RESULTS: The mean variation of the cartilage volumes of the replicate measurements was 1.4% (+/- 0.8%) in the patella, 1.7% (+/- 1.5%) in the femur, 3.0% (+/- 1.2%) in the medial tibial plateau and 3.5% (+/- 2.0%) in the lateral tibial plateau. The comparison of the distribution patterns of cartilage thickness yielded a high degree of agreement. Only in rare cases deviations of more than 0.5 mm were observed. CONCLUSIONS: The results show that the presented method for determining the quantitative distribution of articular cartilage yields a high degree of precision. It offers new possibilities in screening risk groups, monitoring the course of degenerative joint disease and the investigation of functional adaptation of the cartilage to mechanical loading.