Publications by authors named "Stephan Sehmisch"

43 Publications

Cage or Pelvic Graft-Study on Bony Fusion of the Ventral Thoracic and Lumbar Spine in Traumatic Vertebral Fractures.

Medicina (Kaunas) 2021 Jul 31;57(8). Epub 2021 Jul 31.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany.

Stabilization of the spine by cage implantation or autologous pelvic bone graft are surgical methods for the treatment of traumatic spine fractures. These methods serve to stably re-adjust the spine and to prevent late detrimental effects such as pain or increasing kyphosis. They both involve ventral interventions using interbody fusion to replace the intervertebral disc space between the vertebral bodies either by cages or autologous pelvic bone grafts. We examined which of these methods serves the patients better in terms of bone fusion and the long-term clinical outcome. Forty-six patients with traumatic fractures (12 cages; mean age: 54.08/34 pelvic bone grafts; mean age: 42.18) who received an anterior fusion in the thoracic or lumbar spine were included in the study. Postoperative X-ray images were evaluated, and fusion of the stabilized segment was inspected by two experienced spine surgeons. The time to discharge from hospital and gender differences were evaluated. There was a significant difference of the bone fusion rate of patients with autologous pelvic bone grafts in favor of cage implantation ( = 0.0216). Also, the stationary phase of patients who received cage implantations was clearly shorter (17.50 days vs. 23.85 days; = 0.0089). In addition, we observed a significant gender difference with respect to the bony fusion rate in favor of females treated with cage implantations ( < 0.0001). Cage implantations after spinal fractures result in better bony fusion rates as compared to autologous pelvic bone grafts and a shorter stay of the patients in the hospital. Thus, we conclude that cage implantations rather than autologous pelvic bone grafts should be the preferred surgical treatment for stabilizing the spine after fracture.
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http://dx.doi.org/10.3390/medicina57080786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398686PMC
July 2021

Inhibition of Lipoxygenases Showed No Benefit for the Musculoskeletal System in Estrogen Deficient Rats.

Front Endocrinol (Lausanne) 2021 20;12:706504. Epub 2021 Jul 20.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany.

Background: In previous studies, we reported the beneficial impact of two lipoxygenase-inhibitors, Baicalein and Zileuton, on osteoporotic bone in a postmenopausal rat model. Whereas subcutaneous Baicalein predominantly improved cortical bone, Zileuton enhanced vertebral and femoral trabecular bone. In this study, we aimed to reveal whether the oral administration of Baicalein caused similar effects on bone and whether a combined administration of Baicalein and Zileuton could act synergistically to ameliorate the formerly reported effects in the musculoskeletal system.

Methods: We treated ovariectomized (OVX) female Sprague-Dawley rats either with Baicalein (10mg/kg BW), Zileuton (10mg/kg BW) or a combination of both (each 10mg/kg BW) for 13 weeks and compared with untreated OVX and NON-OVX groups (n=12-16 rats per group). Lumbar vertebral bodies and femora were analyzed. Tibiae were osteotomized, plate-stabilized (at week 8 after OVX) and likewise analyzed by biomechanical, histological, micro-computed tomographical and ashing tests. The skeletal muscle structure was analyzed.

Results: Oral administration of Baicalein did not confirm the reported favorable cortical effects in neither vertebra nor femur. Zileuton showed a beneficial effect on trabecular vertebra, while the femur was negatively affected. Callus formation was enhanced by all treatments; however, its density and biomechanical properties were unaltered. Lipoxygenase inhibition did not show a beneficial effect on skeletal muscle. The combination therapy did not ameliorate OVX-induced osteoporosis but induced even more bone loss.

Conclusions: The preventive anti-osteoporotic treatments with two lipoxygenase inhibitors applied either alone or in combination showed no benefit for the musculoskeletal system in estrogen deficient rats.
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http://dx.doi.org/10.3389/fendo.2021.706504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329538PMC
July 2021

Gene Expression-Based Diagnosis of Infections in Critically Ill Patients-Prospective Validation of the SepsisMetaScore in a Longitudinal Severe Trauma Cohort.

Crit Care Med 2021 08;49(8):e751-e760

Department of Anesthesiology, University Medical Centre, Georg August University, Goettingen, Germany.

Objectives: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression-based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools to bedside. This study aimed to validate the SepsisMetaScore, an 11-gene signature previously reported by our study group, in a representative longitudinal cohort of trauma patients.

Design: Prospective observational cohort study.

Setting: Surgical ICUs of the University Medical Center Goettingen, Germany.

Patients: Critically ill patients with severe traumatic injuries.

Interventions: None.

Measurements And Main Results: Paired box gene (PAXgene) RNA blood tubes were drawn at predefined time points over the course of disease. The performance of the SepsisMetaScore was tested using targeted polymerase chain reaction and compared with Procalcitonin using area under the receiver operating characteristics analyses. The SepsisMetaScore showed significant differences between infected and noninfected patients (n = 52). It was able to accurately discriminate infectious from noninfectious acute inflammation with an area under the receiver operating characteristics of 0.92 (95% CI, 0.85-0.99) and significantly outperformed Procalcitonin (area under the receiver operating characteristics curve = 0.53; 95% CI, 0.42-0.64) early in the course of infection (p = 0.014).

Conclusions: We demonstrated the clinical utility for diagnosis of infections with higher accuracy using the SepsisMetaScore compared with Procalcitonin in a prospective cohort of severe trauma patients. Future studies should assess whether the SepsisMetaScore may substantially improve clinical practice by accurate differentiation of infections from sterile inflammation and identification of patients at risk for sepsis. Our results support further investigation of the SepsisMetaScore for the development of tailored precision treatment of critically ill patients.
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http://dx.doi.org/10.1097/CCM.0000000000005027DOI Listing
August 2021

Ostarine and Ligandrol Improve Muscle Tissue in an Ovariectomized Rat Model.

Front Endocrinol (Lausanne) 2020 17;11:556581. Epub 2020 Sep 17.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University of Göttingen, Göttingen, Germany.

In postmenopausal women, hormonal decline changes muscle function and structure. The non-steroidal selective androgen receptor modulators (SARMs) Ostarine (OS) and Ligandrol (LG) have been shown to increase muscle mass and physical function while showing a relative low risk profile. Information about their effects on muscle structure and metabolism is lacking. To analyze this, two experiments were performed using ovariectomized rats as a standard model for postmenopausal conditions. In each experiment, 3-month old Sprague-Dawley rats were divided into five groups ( = 12 to 15). One group remained intact (Non-OVX), the other four groups were ovariectomized (OVX) and remained untreated for eight (OS Experiment) or nine (LG Experiment) weeks. Thereafter, rats of three of the four OVX groups were treated with OS or LG (with doses of 0.04, 0.4, or 4 mg/kg body weight/day) for 5 weeks. Then, uterus, gastrocnemius, and soleus muscles were weighed, fiber size, capillary density, and enzyme activity (lactate dehydrogenase [LDH], citrate synthase [CS], and complex I) were analyzed. In the LG experiment, intramuscular fat content was determined in the quadriceps femoris muscle. All OS treatments resulted in a higher capillary density in the gastrocnemius and longissimus muscles compared with the Non-OVX and the OVX rats, whereas all LG treatments showed a higher capillary density compared with the Non-OVX group. Muscle fiber size and distribution patterns were not changed under either SARM. The CS activity was higher in the longissimus muscle under OS treatment. LG resulted in a higher activity of CS in the gastrocnemius and of LDH in the longissimus muscle. Both SARMs showed an uterotrophic effect, OS at 4 and 0,4 mg dosages, LG at 4 mg dosage. In sum, beneficial effect on muscle vascularization was observed for both SARMs with a stronger impact for OS. LG showed more effect on muscle metabolism. However, a higher muscle weight and intramuscular fat content observed after LG treatment (4 mg) as well as an uterotrophic effect of both SARMs at higher dosages could be considered as an unfavorable side effects and might be a limitation for their application at these dosages.
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http://dx.doi.org/10.3389/fendo.2020.556581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528560PMC
May 2021

Effect of Selective Androgen Receptor Modulator Enobosarm on Bone Healing in a Rat Model for Aged Male Osteoporosis.

Calcif Tissue Int 2020 12 2;107(6):593-602. Epub 2020 Sep 2.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Robert-Koch Str. 40, 37075, Goettingen, Germany.

Enobosarm (ostarine, MK-2866, or GTx-024) is a non-steroidal selective androgen receptor modulator. This study evaluated the effect of various regimens of enobosarm (EN) on bone healing in an orchiectomized rat model for aged male osteoporosis and compared it to testosterone (T) treatment. Ninety eight-month-old male Sprague Dawley rats were either orchiectomized (Orx) or left intact (Non-Orx) and divided into groups (n = 15/group): (1) Non-Orx; (2) Orx; (3) Orx+T-th; (4) Orx+EN-th; (5) Orx+T-pr; and (6) Orx+EN-pr. Prophylaxis (Pr) treatments were applied immediately after Orx for up to 18 weeks. Therapy (Th) treatments were applied 12 weeks after Orx for up to 6 weeks. Bilateral tibia osteotomy with plate osteosynthesis was performed 12 weeks after Orx in all groups. EN and T were mixed with the diet; the daily dosage was 0.35 ± 0.06 and 41 ± 8 mg/kg BW, respectively. Both T treatments improved bone healing by increasing callus volume and area, bone volume and density, and cortical width; they had no effect on prostate or levator ani weight. EN-pr increased the callus area and callus density and decreased cortical density, but increased prostate weight. The effect of T-pr and T-th on bone was stronger than EN-pr. EN-th affected bone healing negatively by reducing callus density and area and delaying osteotomy bridging. Levator ani weight was increased in both EN groups. EN treatment after fracture is not advisable in aged males. EN-pr treatment as a therapy for bone healing in men could be further investigated; endocrinological side effects must be closely monitored.
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http://dx.doi.org/10.1007/s00223-020-00751-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593387PMC
December 2020

Chronic hyponatremia in patients with proximal femoral fractures after low energy trauma: A retrospective study in a level-1 trauma center.

Bone Rep 2020 Jun 6;12:100234. Epub 2019 Dec 6.

Department of Trauma-, Orthopaedic- and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany.

Introduction: We evaluated the prevalence and influence of chronic hyponatremia in patients with low energy trauma. We also investigated the influence of medication and diseases on hyponatremia.

Material And Methods: This retrospective study included 314 cases of proximal femoral fracture due to low energy trauma. Patients were treated in the University Medical Center Goettingen within 3 years. Hyponatremia was defined as serum sodium <135 mmol/L at admission.

Results: Overall, 15.6% of patients in the low energy trauma group had hyponatremia. Among patients older than 80 years, women showed distinctly higher rates of hyponatremia (female: 16.4%; male: 5.9%). In contrast only 4.7% of patients who underwent elective hip arthroplasty showed hyponatremia. Patients on sartanes and aldosterone antagonists showed significantly higher rates of hyponatremia. Alcoholism was significantly associated with hyponatremia.

Conclusions: We confirmed a high prevalence of chronic hyponatremia in patients with fractures due to low energy trauma. Our data underscore chronic hyponatremia as a contributing factor to hip fractures. Women older than 80 have a higher risk of developing hyponatremia. Sartanes, aldosterone antagonists, and alcohol disease are associated with hyponatremia. Treating hyponatremia may decrease the risk of fracture after low energy trauma. Therefore, physicians of different specialties should focus on treatment of chronic hyponatremia to reduce the fracture rate associated with low energy trauma.
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http://dx.doi.org/10.1016/j.bonr.2019.100234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940722PMC
June 2020

Hip Fractures: Therapy, Timing, and Complication Spectrum.

Orthop Surg 2019 Dec 30;11(6):994-1002. Epub 2019 Sep 30.

Department of Trauma Surgery, Orthopaedics, and Plastic Surgery, University Medical Center Göttingen, Göttingen, Germany.

Objective: Investigation of the treatment of femur fractures and the type of femur fracture-associated complications regarding timing of surgery and length of hospital stay.

Methods: In this retrospective cohort study, a total of 358 hip fractures were evaluated retrospectively from 1 January 2008 until 31 December 2010 at a level I trauma center in Germany. Inclusion criteria was age >18 years and a proximal femur fracture. Both sexes were evaluated. Mean age was 75.5 years, most patients were female (63.7%). Intervention was the operative treatment of proximal femur fracture. Outcome parameters were time until surgery, complications, reoperations, mortality, and length of hospital stay.

Results: Among the proximal femur fractures (n = 358), 46.6% were pertrochanteric, 11.2% subtrochanteric, and 42.2% femoral neck fractures. Operation upon hip fractures was managed regularly within 24 hours of injury (73%; mean for femoral neck: 28.3 hrs.; mean for pertrochanteric fractures: 21.4 hrs.; mean for subtrochanteric fractures: 19.5 hrs.). Delayed treatment, as well as implantation of hip total endoprosthesis (TEP), increased the overall length of hospital stay (15.4 vs 17.6 days; 18.1 vs 15.8 days). Accordingly, surgical procedures performed within 24 hours of injury resulted in a shorter hospital residence. Longest delay of operation was measured for hip fractures (28.3 hrs.). In 351 patients, secondary injuries were detected in 94 individuals (26%), with fractures being the most common secondary injury (n = 40). We recorded postoperative complications of nonsurgical and surgical origin, and 33.6% of our patient cohort displayed complications. Complications were distributed among 118 patients. There was no significant difference in complications regarding the time of operation, with most nonsurgical and surgical complications appearing within 24 hours after operation (n = 110 vs n = 31). Nonsurgical complications, such as anemia (n = 49) and electrolyte imbalances (n = 30), were observed more frequently than surgical complications (n = 107 vs n = 34); however, these complications were reduced by delay in surgery (82.0% in 6-24 hrs. vs 74.2% in ≥24 hrs.). Anticoagulant therapy and age did not affect postoperative complications. The hospital mortality of patients was 6.2%. Follow-up was restrained to ambulatory visits in the clinic.

Conclusions: Surgical management of hip fractures performed within 24 hours of injury minimizes hospital stay. We did not detect significant differences in the spectrum or number of complications regarding delay of surgery. Surgical complications mainly occur with rapid primary care, and medical complications can be reduced by more intensive preparation of patient and operation procedures.
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http://dx.doi.org/10.1111/os.12524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904609PMC
December 2019

The Selective Androgen Receptor Modulator Ostarine Improves Bone Healing in Ovariectomized Rats.

Calcif Tissue Int 2020 02 17;106(2):147-157. Epub 2019 Sep 17.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, Robert-Koch Str. 40, 37075, Goettingen, Germany.

Non-steroidal selective androgen receptor modulators, including ostarine, have been developed as an alternative to steroidal hormones. Ostarine has shown a beneficial effect on bone in experimental studies, but no data regarding the effect of ostarine on bone healing have yet been reported. We investigated effects of ostarine on bone healing in ovariectomized rats. Sprague-Dawley rats (3 months old) were ovariectomized (Ovx, n = 46) or left intact (Non-Ovx, n = 10). After 8 weeks, an osteotomy of the tibia metaphysis was created in all rats, and the Ovx rats were divided into four groups: untreated Ovx (n = 10) and three Ovx groups (each of 12 rats) treated with ostarine at doses of 0.04, 0.4, or 4 mg/kg BW (OS-0.04, OS-0.4, and OS-4 groups). Five weeks later, bone healing was analyzed. The OS-4 dose enhanced callus formation, increased callus density, accelerated bridging time of the osteotomy, and elevated alkaline phosphatase gene expression in callus and its protein expression in serum. In the Ovx group, most of the callus parameters were diminished. All OS treatments increased the weight of the gastrocnemius muscle, but only partly enhanced uterus weight in OS-0.4 and OS-4. Serum cholesterol level was reduced, and serum phosphorus was elevated in OS-0.04 and OS-4. Ostarine appeared to have a positive effect on early bone healing in ovariectomized rats. Considering its favorable effect on non-osteotomized bone and muscle, this treatment could be further explored as a therapy for osteoporosis. However, possible metabolic side effects should first be evaluated.
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http://dx.doi.org/10.1007/s00223-019-00613-1DOI Listing
February 2020

It is time for a change in the management of elderly severely injured patients! An analysis of 126,015 patients from the TraumaRegister DGU.

Eur J Trauma Emerg Surg 2020 Jun 13;46(3):487-497. Epub 2019 Sep 13.

Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University of Göttingen Medical Center, Göttingen, Germany.

Background: The number of elderly patients among the severely injured has been increasing continuously. It has been suggested that an increased life expectancy and a higher level of activity and mobility in older ages could explain this observation. Elderly trauma patients have relevant higher mortality rates and poorer functional outcomes. The reasons remain unclear. The aim of this study was to look for differences in the management of severely injured elderly patients compared to younger age groups and to evaluate their potential impact on outcome.

Methods: The TraumaRegister DGU is a multicenter database that documents de-identified data of severely injured patients since 1993. Trauma cases documented between 2009 and 2016 with an ISS ≥ 9 were divided in four age groups. The groups were compared with respect to mechanism of injury, pattern of injury, severity of injury, management and outcome.

Results: The analysis of 126,015 severely injured patients showed that 37.5% of the population were elderly patients (≥ 60 years). Their rate actually increased every year by 1.7%. The elderly trauma patients experience different mechanisms of injury (more low energy trauma) and different pattern of injuries (more brain trauma, less abdominal and extremity injuries). Evaluating the management of patients showed that elderly patients have lower intubation rates and less volume replacement in the prehospital setting. Diagnostic interventions like CT scans in the emergency room were performed more restrictively. Elderly trauma patients also received fewer surgical interventions for brain injuries, pelvic fractures and femur fractures. Their hospital mortality rates were higher.

Conclusions: Severely injured elderly patients are treated with a more "wait and see approach" resulting in higher mortality rates. We suggest that this population needs a more "aggressive management" to improve their outcome, if the wish to perform complete treatment including surgical procedures and intensive care medicine has not been excluded by the patients or their legal guardian.
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http://dx.doi.org/10.1007/s00068-019-01229-8DOI Listing
June 2020

Of Cestodes and Men: Surgical Treatment of a Spinal Hydatid Cyst.

J Neurol Surg A Cent Eur Neurosurg 2020 Jan 4;81(1):86-90. Epub 2019 Sep 4.

Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August-University of Göttingen, Göttingen, Germany.

Background:  The cestode causes hydatid disease. In addition to manifestations in the liver and lung, it can lead to cystic lesions in the spine.

Case Description:  We report a 42-year-old male patient with primary hydatid disease in the eighth thoracic vertebra. The only clinical symptom was chronic back pain. Although laboratory findings were normal, imaging displayed lytic destruction that raised the suspicion of a metastatic disease. Diagnostics of the thoraces and abdomen did not reveal other pathologic abnormalities. Follow-up magnetic resonance imaging (MRI) depicted a progressive compression of the spinal cord and inhomogeneous structure in the fat-suppressed sequences. Because the Jamshidi biopsy was inconclusive, the tumor board recommended surgery. Dorsal decompression, spondylodesis of T6-T10, and vertebral column resection of T8 with complete cyst removal were performed. The resected vertebrae showed a mucous-like lesion with white granular tissue interfusing the whole vertebral body. A pathologic examination and enzyme-linked immunosorbent assay confirmed . Thus chemotherapy with albendazole was initiated. A follow-up MRI of the whole spine confirmed complete remission and found no additional resettlements. The patient's back pain was resolved without neurologic deficits.

Conclusions:  For lytic manifestations of the vertebral column, hydatid cysts should be considered a differential diagnosis in addition to malignant metastasis, tuberculosis, and osteomyelitis. Thorough surgical resection and strict follow-up are necessary.
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http://dx.doi.org/10.1055/s-0039-1693707DOI Listing
January 2020

Changes in Musculoskeletal System and Metabolism in Osteoporotic Rats Treated With Urocortin.

Front Endocrinol (Lausanne) 2019 24;10:400. Epub 2019 Jun 24.

Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August-University of Göttingen, Göttingen, Germany.

In aging population, postmenopausal osteoporosis and decline of musculoskeletal function, referred to as "frailty syndrome" lead to loss of bone and muscle, causing falls, and fall-related injuries. To limit the impact of this portentous duo, simultaneous treatment of both is needed. Urocortin (UCN) has been reported to improve osteoporotic bone properties while its effect on muscle has not been addressed yet. We aimed to investigate the effect of urocortin on skeletal muscle structure in osteopenic rats. Sixty Sprague-Dawley rats were divided into five groups: four were ovariectomized (OVX) and one underwent sham operation (SHAM). One ovariectomized group was left untreated (OVX), while one was treated with urocortin s.c. in 3 μg/kg body weight (bw) (OVX+UCN low), one with 30 μg/kg (OVX+UCN high), while one group was treated with estradiol orally (OVX+E: 0.2 mg/kg bw), each for 35 days. , and were isolated and capillary density as well as diameters of type I and II fibers were measured. In addition, we examined the effect of UCN on tibia using biomechanical, micro-CT and ashing analysis and investigated the blood serum. We demonstrated a positive effect of UCN on , in which fiber diameter was positively influenced. The biomechanical and structural parameters of bone were not changed in UCN treated rats. The higher cholesterol, glucose and triglyceride levels in the "UCN high" group raise concern about this treatment. Our results portray urocortin as a substance that can be assessed for future therapeutic treatments of estrogen deficiency. Urocortin has a positive effect on (diameter). Urocortin raises serum cholesterol and triglyceride levels. Bone tissue was not affected by UCN.
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http://dx.doi.org/10.3389/fendo.2019.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601316PMC
June 2019

[Dorsal stabilization of C1/C2 modified according to Goel-Harms with C1 pedicle screws].

Oper Orthop Traumatol 2019 Aug 25;31(4):275-283. Epub 2019 Jun 25.

Klinik für Unfallchirurgie, Orthopädie und Plastische Chirurgie, Universitätsmedizin Göttingen (Direktor: Prof. W. Lehmann), Robert-Koch-Straße 40, 37075, Göttingen, Deutschland.

Objective: Stabilization of the atlantoaxial transition by an alternative screw position in C1.

Indications: Instabilities C1/C2 due to inflammation, tumor or trauma.

Contraindications: Presence of a very small pedicle of C1. Variations in the course of the vertebral arteries.

Surgical Technique: The midline approach to the upper cervical spine is used for the modified instrumentation of C1 with pedicle screws instead of Harms screws and for the unaltered instrumentation of C2. Depending on the indication, dorsal spondylodesis is performed by opening the laminae and attaching ceramic bone substitute material.

Postoperative Management: In mobile patients, additional immobilisation with a soft collar is recommended for 6 weeks. Full recovery is given 3-4 months after surgery.

Results: From January 2017 to September 2018, 21 stabilizations of the atlantoaxial transition were performed. The mean age was 72.52 ± 15.45 years. A total of 42 screws were placed in C1. In all, 21 (50%) C1 pedicle screwscould be placed, and in other 21 cases Harms screws were used. Complications were seen in 3 patients. Overall, considering the contraindications, the instrumentation of C1 with pedicle screws appears as a safe alternative to instrumentation with Harms screws.
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http://dx.doi.org/10.1007/s00064-019-0615-7DOI Listing
August 2019

[Intraoperative revision of initially loosened pedicle screws].

Oper Orthop Traumatol 2019 Aug 3;31(4):293-300. Epub 2019 Jun 3.

Klinik für Unfallchirurgie, Orthopädie und Plastische Chirurgie, Universitätsmedizin Göttingen, Robert-Koch-Straße 40, 37099, Göttingen, Deutschland.

Objective: Intraoperative revision of initially loosened pedicle screws.

Indications: Intraoperatively loosened/stripped pedicle screws.

Contraindications: None.

Surgical Technique: Removal of the loosened/stripped pedicle screw. Checking the screw channel and re-implantation using a different trajectory, a larger screw diameter or a cement-augmented pedicle screw.

Postoperative Management: Early functional mobilization and initiation of osteoporosis therapy if indicated.

Results: A biomechanical study with human vertebral bodies was performed. Augmented and not augmented pedicle screws were tested until loosening using a fatigue testing setup. After loosening occurred a subsequent augmentation of the loosened, not augmented screw was performed, and it was tested using a fatigue test again. Both the initial (p = 0.009) and the augmentation after loosening (p = 0.001) showed a significant increase in failure load compared to the non-augmented pedicle screws. In our own patient collective from April 2016 to August 2018, 11 of 524 patients treated with pedicle screws showed intraoperative screw loosening. This was revised in 6 cases with a subsequent augmentation and in 5 cases with a larger screw diameter. In the postoperative control at 6 weeks, none of these screws showed loosening again.
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http://dx.doi.org/10.1007/s00064-019-0611-yDOI Listing
August 2019

[Techniques to increase pedicle screw stability in osteoporotic vertebrae].

Oper Orthop Traumatol 2019 Aug 3;31(4):284-292. Epub 2019 Jun 3.

Klinik für Unfallchirurgie, Orthopädie und Plastische Chirurgie, Universitätsmedizin Göttingen, Robert-Koch-Straße 40, 37099, Göttingen, Deutschland.

Objective: Operative stabilisation of osteoporotic vertebral fractures.

Indications: Fractures of the thoracic and lumbar spine.

Contraindications: None.

Surgical Technique: Preoperative determination of expected bone mineral density. Implantation of pedicle screws in special trajectories, cement augmentation of the screws and use of alternative implants.

Postoperative Management: Early functional mobilisation and initiation of osteoporosis therapy if indicated.

Results: A biomechanical cadaver study with human vertebral bodies was performed. There was a highly significant correlation between bone mineral density and the fatigue load (r = 0.839, p < 0.001). Specimens with bone mineral density below 80 mg/cm only reached 60% of the fatigue load compared to the specimens with adequate bone quality (>120 mg/cm) and therefore stability mightbe insufficient and an additional stabilisation should be considered. In osteoporotic vertebrae, the fatigue strength of cement augmented screws was increased by 52% compared to the non-augmented screws (fatigue load non-augmented: 173 N, augmented: 263 N; p = 0.001). Studies conducted by other research groups have demonstrated the effect of various screw trajectories and alternative implants to improve stability in the treatment of osteoporotic vertebral body fractures.
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http://dx.doi.org/10.1007/s00064-019-0608-6DOI Listing
August 2019

Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats.

Nutr Metab (Lond) 2019 11;16. Epub 2019 Jan 11.

1Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany.

Background: Osteoporosis is one of the world's major medical burdens in the twenty-first century. Pharmaceutical intervention currently focusses on decelerating bone loss, but phytochemicals such as baicalein, which is a lipoxygenase inhibitor, may rescue bone loss. Studies evaluating the effect of baicalein in vivo are rare.

Methods: We administered baicalein to sixty-one three-month-old female Sprague-Dawley rats. They were divided into five groups, four of which were ovariectomized (OVX) and one non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, bilateral tibial osteotomy with plate osteosynthesis was performed and bone formation quantified. Baicalein was administered subcutaneously using three doses (C1: 1 mg/kg BW; C2: 10 mg/kg BW; and C3: 100 mg/kg BW) eight weeks after ovariectomy for four weeks. Finally, femora and tibiae were collected. Biomechanical tests, micro-CT, ashing, histological and gene expression analyses were performed.

Results: Biomechanical properties were unchanged in tibiae and reduced in femora. In tibiae, C1 treatment enhanced callus density and cortical width and decreased callus area. In the C3 group, callus formation was reduced during the first 3 weeks after osteotomy, correlating to a higher mRNA expression of , and . In femora, baicalein treatments did not alter bone parameters.

Conclusions: Baicalein enhanced callus density and cortical width but impaired early callus formation in tibiae. In femora, it diminished the biomechanical properties and calcium-to-phosphate ratio. Thus, it is not advisable to apply baicalein to treat early bone fractures. To determine the exact effects on bone healing, further studies in which baicalein treatments are started at different stages of healing are needed.
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http://dx.doi.org/10.1186/s12986-018-0327-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329162PMC
January 2019

Effects of RANKL Knockdown by Virus-like Particle-Mediated RNAi in a Rat Model of Osteoporosis.

Mol Ther Nucleic Acids 2018 Sep 11;12:443-452. Epub 2018 Jul 11.

Primate Genetics Laboratory, Junior Research Group "Medical RNA Biology," German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany.

Rebalancing of the RANKL/OPG system seems to be an effective treatment strategy in postmenopausal osteoporosis. Here, we evaluate the knockdown of RANKL by in-vivo-delivered siRNA in a rat model of osteoporosis. Virus-like-particles (VLPs) derived from polyoma JC virus were used for delivering RANKL siRNA in ovariectomized (OVX) rats. 48 rats were ovariectomized and treated with either 17β-estradiol (E2), VLPs containing RANKL siRNA (siRANKL), or VLPs containing non-cognate siRNA (siCtrl). All OVX groups were subdivided into the prophylaxis group (PG) and the therapy group (TG). The PG received treatment directly after being OVX for 10 weeks. The TG received treatment 5 weeks after being OVX for 5 weeks. Rats were sacrificed 10 weeks after being OVX. Bone and blood samples were analyzed. E2 and siRANKL showed a significant knockdown of RANKL mRNA. A protein knockdown was observed with E2 and siRANKL in the TG but not in the PG. No distinct improvements in biomechanical and morphological properties of the bones were observed after siRANKL treatment. In the PG, E2 protected the bone structure. We demonstrated successful mRNA and protein knockdown by VLP-mediated RNAi in vivo. Knockdown of membranous RANKL did not result in significant improvements of bone properties in this model of early-stage postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.omtn.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041464PMC
September 2018

Biomechanical and histological analyses of the fracture healing process after direct or prolonged reduction.

Eur J Med Res 2018 Sep 4;23(1):39. Epub 2018 Sep 4.

Hannover Medical School (MHH) -Trauma Department, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Reduction of femoral shaft fractures remains a challenging problem in orthopaedic surgery. Robot-assisted reduction might ease reduction and fracture treatment. However, the influence of different reduction pathways on patients' physiology is not fully known yet. Therefore, the aim of this study was to examine the biomechanics and histology of fracture healing after direct and prolonged robot-assisted reduction in an in vivo rat model.

Methods: 144 male CD rats were randomly assigned to 12 groups. Each animal received an external fixator and an osteotomy on the left femoral shaft. On the fourth postoperative day, the 1× reduction groups received a single reduction maneuver, whereas the 10× reduction groups received the same reduction pathway with ten repetitions. The control groups did not undergo any reduction maneuvers. Animals were killed after 1, 2, 3 and 4 weeks, respectively, and the composition of the fracture gap was analyzed by µCT and non-decalcified histology. Biomechanical properties were investigated by a three-point bending test, and the bone turnover markers PINP, bCTx, OPG, sRANKL, TRACP-5b, BALP, and OT/BGP were measured.

Results: One week after the reduction maneuver, µCT analysis showed a higher cortical bone volume in the 1× reduction group compared to the 10× reduction group. Biomechanically, the control group showed higher maximum force values measured by three-point bending test compared to both reduction groups. Furthermore, less collagen I formation was examined in the 10× reduction group compared to the control group after 1 week of fracture healing. PINP concentration was decreased in 10× reduction group after 1 week compared to control group. The same trend was seen after 3 weeks.

Conclusion: A single reduction maneuver has a beneficial effect in the early phase of the fracture healing process compared to repeated reduction maneuvers. In the later phase of fracture healing, no differences were found between the groups.
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http://dx.doi.org/10.1186/s40001-018-0337-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122772PMC
September 2018

German validation of Quality of Life after Brain Injury (QOLIBRI) assessment and associated factors.

PLoS One 2017 24;12(5):e0176668. Epub 2017 May 24.

Institute of Medical Psychology and Medical Sociology, University Medical Center Goettingen, Goettingen, Germany.

The consequences of traumatic brain injury (TBI) for health-related quality of life (HRQoL) are still poorly understood, and no TBI-specific instrument has hitherto been available. This paper describes in detail the psychometrics and validity of the German version of an internationally developed, self-rated HRQoL tool after TBI-the QOLIBRI (Quality of Life after Brain Injury). Factors associated with HRQoL, such as the impact of cognitive status and awareness, are specifically reported. One-hundred seventy-two participants after TBI were recruited from the records of acute clinics, most of whom having a Glasgow Coma Scale (GCS) 24-hour worst score and a Glasgow Outcome Scale (GOSE) score. Participants had severe (24%), moderate (11%) and mild (56%) injuries as assessed on the GCS, 3 months to 15 years post-injury. The QOLIBRI uses 37 items to measure "satisfaction" in the areas of "Cognition", "Self", "Daily Life and Autonomy", and "Social Relationships", and "feeling bothered" by "Emotions"and "Physical Problems". The scales meet standard psychometric criteria (α = .84 to .96; intra-class correlation-ICC = .72 to .91). ICCs (0.68 to 0.90) and αs (.83 to .96) were also good in a subgroup of participants with lower cognitive performance. The six-subscale structure of the international sample was reproduced for the German version using confirmatory factor analyses and Rasch analysis. Scale validity was supported by systematic relationships observed between the QOLIBRI and the GOSE, Patient Competency Rating Scale for Neurorehabilitation (PCRS-NR), Hospital Anxiety and Depression Scale (HADS), Profile of Mood States (POMS), Short Form 36 (SF-36), and Satisfaction with Life Scale (SWLS). The German QOLIBRI contains novel information not provided by other currently available measures and has good psychometric criteria. It is potentially useful for clinicians and researchers, in post-acute and rehabilitation studies, on a group and individual level.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443488PMC
September 2017

In Vivo siRNA Delivery Using JC Virus-like Particles Decreases the Expression of RANKL in Rats.

Mol Ther Nucleic Acids 2016 Mar 22;5:e298. Epub 2016 Mar 22.

Primate Genetics Laboratory, Junior Research Group "Medical RNA Biology," German Primate Center, Göttingen, Germany.

Bone remodeling requires a precise balance between formation and resorption. This complex process involves numerous factors that orchestrate a multitude of biochemical events. Among these factors are hormones, growth factors, vitamins, cytokines, and, most notably, osteoprotegerin (OPG) and the receptor activator for nuclear factor-kappaB ligand (RANKL). Inflammatory cytokines play a major role in shifting the RANKL/OPG balance toward excessive RANKL, resulting in osteoclastogenesis, which in turn initiates bone resorption, which is frequently associated with osteoporosis. Rebalancing RANKL/OPG levels may be achieved through either upregulation of OPG or through transient silencing of RANKL by means of RNA interference. Here, we describe the utilization of a viral capsid-based delivery system for in vivo and in vitro RNAi using synthetic small interfering RNA (siRNA) molecules in rat osteoblasts. Polyoma JC virus-derived virus-like particles are capable of delivering siRNAs to target RANKL in osteoblast cells both in vitro and in a rat in vivo system. Expression levels were monitored using quantitative real-time polymerase reaction and enzyme-linked immunosorbent assay after single and repeated injections over a 14-day period. Our data indicate that this is an efficient and safe route for in vivo delivery of gene modulatory tools to study important molecular factors in a rat osteoporosis model.
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http://dx.doi.org/10.1038/mtna.2016.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014456PMC
March 2016

Effects of 8-Prenylnaringenin and Whole-Body Vibration Therapy on a Rat Model of Osteopenia.

J Nutr Metab 2016 19;2016:6893137. Epub 2016 Jan 19.

Department of Trauma and Reconstructive Surgery, University of Goettingen, 37075 Goettingen, Germany.

Background. 8-Prenylnaringenin (8-PN) is the phytoestrogen with the highest affinity for estrogen receptor-α (ER-α), which is required to maintain BMD. The osteoprotective properties of 8-PN have been demonstrated previously in tibiae. We used a rat osteopenia model to perform the first investigation of 8-PN with whole-body vertical vibration (WBVV). Study Design. Ovariectomy was performed on 52 of 64 Sprague-Dawley rats. Five weeks after ovariectomy, one group received daily injections (sc) of 8-PN (1.77 mg/kg) for 10 weeks; a second group was treated with both 8-PN and WBVV (twice a day, 15 min, 35 Hz, amplitude 0.47 mm). Other groups received either only WBVV or no treatment. Methods. The rats were sacrificed 15 weeks after ovariectomy. Lumbar vertebrae and femora were removed for biomechanical and morphological assessment. Results. 8-PN at a cancer-safe dose did not cause fundamental improvements in osteoporotic bones. Treatment with 8-PN caused a slight increase in uterine wet weight. Combined therapy using WBVV and 8-PN showed no significant improvements in bone structure and biomechanical properties. Conclusion. We cannot confirm the osteoprotective effects of 8-PN at a cancer-safe dose in primary affected osteoporotic bones. Higher concentrations of 8-PN are not advisable for safety reasons. Adjunctive therapy with WBVV demonstrates no convincing effects on bones.
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http://dx.doi.org/10.1155/2016/6893137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745283PMC
February 2016

The Impact of Strontium Ranelate on Metaphyseal Bone Healing in Ovariectomized Rats.

Calcif Tissue Int 2015 Oct 18;97(4):391-401. Epub 2015 Jun 18.

Department of Trauma Surgery and Reconstructive Surgery, University Medical Center Göttingen, Robert-Koch St. 40, 37075, Göttingen, Germany.

The following questions were addressed: whether therapy with strontium ranelate (SR) should be continued or interrupted if the fractures occur during SR treatment and whether SR could be applied directly after fracture to improve bone healing. Sprague-Dawley rats (3 month old) were ovariectomized (Ovx, n = 48) or left intact (n = 12). After 8 weeks, a bilateral transverse osteotomy of the tibia metaphysis was created in all rats. Ovx rats were divided into four groups: Ovx; SR applied directly after Ovx until osteotomy (prophylaxis, SR pr, 8 weeks); SR applied after osteotomy (therapy, SR th, 5 weeks); SR applied during the whole experiment (pr + th, 13 weeks). SR dosage was 625 mg/kg body weight/day, administered in the feed. Five weeks later, tibiae were analyzed by biomechanical, histological, micro-CT, and gene expression analyses. The SR pr + th treatment increased total bone mineral density (BMD), bone volume fraction, cortical BMD and volume, callus area and density, serum alkaline phosphatase, tartrate-resistant acid phosphatase mRNA, accelerated osteotomy bridging, and callus formation at weeks 2 and 3 of healing and decreased the osteoprotegerin/receptor activator of nuclear factor kB ligand mRNA ratio. SR th enlarged callus area and improved callus formation during the 5th week of healing. SR pr improved cortical BMD preserving bone after SR discontinuation (5-week rest); the bone healing was not affected. SR content in the tibia metaphysis was the highest in SR pr + th group and was not different between SR pr and SR th. SR has a positive effect on osteoporotic bone healing in rat and SR treatment can be continued after the fracture occurs or applied directly after the fracture.
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http://dx.doi.org/10.1007/s00223-015-0019-0DOI Listing
October 2015

Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats.

Bone 2014 Jul 13;64:187-94. Epub 2014 Apr 13.

Department of Trauma Surgery and Reconstructive Surgery, University of Goettingen, Robert-Koch 40, 37075 Goettingen, Germany.

Current osteoporosis therapies aim to delay bone destruction and have additional anabolic effects. While they have demonstrated some positive effects on bone healing, more progress is needed in this area. This study used the well-known osteoporotic agents estrogen (E) and raloxifene (R) in conjunction with biomechanical whole body vibration (WBV) at a frequency of 70 Hz twice daily for six weeks to stimulate bone healing. Eighty-four 3-month old female Sprague-Dawley rats (12 per group) were bilaterally ovariectomized to develop osteopenia within eight weeks. Osteotomy of the metaphyseal tibiae was performed and fracture healing was then studied using mechanical tests, histomorphometry, computed tomography (μCT), and gene analysis. We found that E and R improved the structure of osteopenic bones as did WBV alone, although significant levels for WBV were seldom reached. Combination treatments significantly enhanced stiffness (R+WBV; p<0.05), endosteal bone (R+WBV; p<0.01), and trabecular density (E+WBV; p<0.05, R+WBV; p<0.05). In addition, the expression of osteoclast-specific Trap was significantly reduced after treatment with E, R, or their combination with WBV (p<0.01). The effects were additive and not inhibitory, leading us to conclude that the combined applications of WBV with E or R may improve the healing of osteopenic bones. The therapies studied are all currently approved for human use, suggesting ready applicability to clinical practice. To better understand the effects of WBV on osteopenic bones, the ideal vibration regime will require further study.
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http://dx.doi.org/10.1016/j.bone.2014.04.008DOI Listing
July 2014

Effect of Urocortin on strength and microarchitecture of osteopenic rat femur.

J Bone Miner Metab 2015 Mar 16;33(2):154-60. Epub 2014 Mar 16.

Department of Trauma and Reconstructive Surgery, Georg-August-University of Goettingen, Goettingen, Germany,

As yet there is no evidence of the potential antiosteoporotic effect of Urocortin-1 (UCN), a corticotropin releasing factor related peptide, in vivo. In this study, and for the first time, we investigated the effect of UCN in a rat osteopenia model. Sixty female Sprague-Dawley rats were divided into 5 groups: (1) sham-operated, (2) untreated ovariectomized (OVX) rats, (3) and (4) OVX animals treated for 5 weeks with daily subcutaneous low-dose UCN (3 μg/kg of BW) or high-dose UCN (30 μg/kg of BW) 8 weeks after ovariectomy, and (5) OVX rats treated with daily estrogen (0.2 mg/kg of BW p.o) 8 weeks after ovariectomy for 5 weeks (E). After sacrifice, the femurs were reserved for biomechanical, histomorphometric and ash testing. In the biomechanical test, the high-dose UCN rats showed significantly improved mechanical stiffness (341.6 N/mm) compared with the untreated OVX animals (275.9 N/mm). In the histomorphometric evaluation, the high-dose UCN rats demonstrated an improved trabecular microarchitecture especially and significantly at the distal femur (distal femur Tb.Ar = 41.4% and N.Nd/mm(2) = 26.8, proximal femur Tb.Ar = 71.8% and N.Nd/mm(2) = 28.7) compared with untreated OVX rats (distal femur Tb.Ar = 23.3% and N.Nd/mm(2) = 11.7, proximal femur Tb.Ar = 60.2% and N.Nd/mm(2) = 25.2). Our results show that short-term treatment with UCN seems to have a positive effect on the metaphyseal bone structure and strength of the femur in ovariectomized rats.
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http://dx.doi.org/10.1007/s00774-014-0578-6DOI Listing
March 2015

Coping strategies in individuals after traumatic brain injury: associations with health-related quality of life.

Disabil Rehabil 2014 3;36(25):2152-60. Epub 2014 Mar 3.

Institute of Medical Psychology and Medical Sociology, University Medical Centre Göttingen , Germany .

Purpose: This study investigates coping strategies after traumatic brain injury (TBI) and their associations with health-related quality of life (HRQoL).

Methods: Participants were 141 adults followed up 3 months to 15 years after TBI of all severity degrees. Coping was assessed by the Freiburg Questionnaire of Coping with Illness (FQCI) and HRQoL by the Quality of Life after Brain Injury (QOLIBRI) scale and the Short Form-36 Health Survey (SF-36). Coping dimensions were extracted by principal component analysis. Multiple linear regression analysis was used to identify predictors of coping strategies.

Results: Two factors for coping after TBI were extracted: Action/Distraction and Trivialisation/Resignation. The Trivialisation/Resignation strategy was negatively correlated with all aspects of HRQoL, while relationships with the Action/Distraction strategy were positive and significant for two domains. These two factors also showed significant associations with anxiety, depression, recovery, cognitive status, mood states and trauma severity. Multiple regression analysis identified recovery status as a predictor for the maladaptive Trivialisation/Resignation strategy.

Conclusion: Two coping factors were identified, which were differentially associated with HRQoL. Maladaptive coping strategies play a particularly important role, and less reliance on such strategies is associated with better HRQoL; use of adaptive strategies should correspondingly be fostered.

Implications For Rehabilitation: This study highlights the relationship of coping strategies and HRQoL after TBI. For the assessment of HRQoL a novel disease-specific instrument was applied, that provides in detail TBI-relevant aspects of well-being and HRQoL. Individuals after TBI use two main sets of coping strategies that are differentially associated with HRQoL (and clinical variables). One is adaptive and the other maladaptive for HRQoL after TBI. Maladaptive and adaptive coping strategies used by the individual should be identified and considered in rehabilitation efforts to improve HRQoL after TBI.
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http://dx.doi.org/10.3109/09638288.2014.893029DOI Listing
July 2015

Identification of a vibration regime favorable for bone healing and muscle in estrogen-deficient rats.

Calcif Tissue Int 2013 Jun 17;92(6):509-20. Epub 2013 Feb 17.

Department of Trauma Surgery and Reconstructive Surgery, University Medical Center Goettingen, Robert-Koch 40, 37075, Goettingen, Germany.

Numerous whole-body vibration (WBV) devices of various forces are available on the market, although their influence on the musculoskeletal system is not yet understood. The effect of different WBVs on bone healing and muscle function was evaluated in rats ovariectomized at 3 months of age. 2 months after ovariectomy, bilateral metaphyseal tibia osteotomy and T-plate osteosynthesis were performed. Rats were divided into groups: intact, OVX, and OVX exposed to vertical WBVs of 35, 50, 70, or 90 Hz (experiment 1) or horizontal WBVs of 30, 50, 70, or 90 Hz (experiment 2) 5 days after osteotomy (0.5 mm, 15 min/day for 30 days). The tibia and gastrocnemius and soleus muscles were collected. Vertical vibrations (>35 Hz) improved cortical and callus densities, enlarged callus area and width, suppressed the tartrate-resistant acid phosphatase gene, enhanced citrate synthase activity, accelerated osteotomy bridging (35 and 50 Hz), upregulated the osteocalcin (Oc) gene (70 Hz), and increased relative muscle weight (50 Hz). Horizontal vibrations reduced cortical width (<90 Hz) and callus density (30 Hz), enhanced alkaline phosphatase (Alp) gene expression (50 Hz), decreased the size of oxidative fibers (35 and 70 Hz), and increased capillary density (70, 90 Hz). Biomechanical data; serum Oc, Alp, and creatine kinase activities; body weight; and food intake did not change after WBVs. Vertical WBVs of 35 and 50 Hz produced more favorable results than the higher frequencies. Horizontal WBV showed no positive or negative effects. Further studies are needed to elucidate the effects of WBV on different physiological systems, and precautions must be taken when implementing WBV in the treatment of patients.
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http://dx.doi.org/10.1007/s00223-013-9706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654182PMC
June 2013

Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: quantitative assessment of inflammation and β-amyloid in the muscle.

Arthritis Rheum 2012 Dec;64(12):4094-103

University Medical Centre, Göttingen, Germany.

Objective: In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid-associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies.

Methods: Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model.

Results: In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged.

Conclusion: IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.
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http://dx.doi.org/10.1002/art.37692DOI Listing
December 2012

Navigated cementless total knee arthroplasty - medium-term clinical and radiological results.

Open Orthop J 2012 16;6:160-3. Epub 2012 Apr 16.

Department of Trauma Surgery, Plastic and Reconstructive Surgery, University Medicine Göttingen, D-37099 Göttingen, Germany.

Purpose: The objective of this prospective study was to evaluate the medium-term clinical and radiological results after navigated cementless implantation, without patella resurfacing, of a total knee endoprosthesis with tibial and femoral press-fit components, with a focus on survival rate and clinical outcome. The innovation is the non-cemented fixation together with the use of a navigation system.

Scope And Methods: Sixty patients with gonarthrosis were included consecutively in this study. In all cases, the cementless Columbus total knee endoprosthesis with a coating out of pure titanium was implanted, using a navigation system. The Knee Society Score showed a statistically significant increase from 75 (± 21.26) before surgery to 180 (± 16.15) after a mean follow-up of 5.6 (± 0.25) years. The last radiological examination revealed no osteolysis. No radiolucent lines were seen at any time in the area of the femoral prosthetic components. In the tibial area, radiolucent lines were seen in 24.4 % of the cases, mostly in the distal uncoated part of the stem. During follow-up, no prosthesis had to be replaced because of aseptic loosening while in 2 cases revision surgery was necessary due to septic loosening and in 1 case due to unexplainable pain.

Results And Conclusions: Navigated cementless implantation of the Columbus total knee endoprosthesis yielded good clinical and radiological results in the medium term. The excellent radiological osteointegration of the prosthetic components, coated with a microporous pure titanium layer and implanted with a press-fit technique, should be emphasized.
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http://dx.doi.org/10.2174/1874325001206010160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339558PMC
August 2012

Nitric oxide stress in sporadic inclusion body myositis muscle fibres: inhibition of inducible nitric oxide synthase prevents interleukin-1β-induced accumulation of β-amyloid and cell death.

Brain 2012 Apr 21;135(Pt 4):1102-14. Epub 2012 Mar 21.

Department of Neurology, University Medical Centre Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

Sporadic inclusion body myositis is a severely disabling myopathy. The design of effective treatment strategies is hampered by insufficient understanding of the complex disease pathology. Particularly, the nature of interrelationships between inflammatory and degenerative pathomechanisms in sporadic inclusion body myositis has remained elusive. In Alzheimer's dementia, accumulation of β-amyloid has been shown to be associated with upregulation of nitric oxide. Using quantitative polymerase chain reaction, an overexpression of inducible nitric oxide synthase was observed in five out of ten patients with sporadic inclusion body myositis, two of eleven with dermatomyositis, three of eight with polymyositis, two of nine with muscular dystrophy and two of ten non-myopathic controls. Immunohistochemistry confirmed protein expression of inducible nitric oxide synthase and demonstrated intracellular nitration of tyrosine, an indicator for intra-fibre production of nitric oxide, in sporadic inclusion body myositis muscle samples, but much less in dermatomyositis or polymyositis, hardly in dystrophic muscle and not in non-myopathic controls. Using fluorescent double-labelling immunohistochemistry, a significant co-localization was observed in sporadic inclusion body myositis muscle between β-amyloid, thioflavine-S and nitrotyrosine. In primary cultures of human myotubes and in myoblasts, exposure to interleukin-1β in combination with interferon-γ induced a robust upregulation of inducible nitric oxide synthase messenger RNA. Using fluorescent detectors of reactive oxygen species and nitric oxide, dichlorofluorescein and diaminofluorescein, respectively, flow cytometry revealed that interleukin-1β combined with interferon-γ induced intracellular production of nitric oxide, which was associated with necrotic cell death in muscle cells. Intracellular nitration of tyrosine was noted, which partly co-localized with amyloid precursor protein, but not with desmin. Pharmacological inhibition of inducible nitric oxide synthase by 1400W reduced intracellular production of nitric oxide and prevented accumulation of β-amyloid, nitration of tyrosine as well as cell death inflicted by interleukin-1β combined with interferon-γ. Collectively, these data suggest that, in skeletal muscle, inducible nitric oxide synthase is a central component of interactions between interleukin-1β and β-amyloid, two of the most relevant molecules in sporadic inclusion body myositis. The data further our understanding of the pathology of sporadic inclusion body myositis and may point to novel treatment strategies.
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http://dx.doi.org/10.1093/brain/aws046DOI Listing
April 2012

Impact of 4-methylbenzylidene camphor, daidzein, and estrogen on intact and osteotomized bone in osteopenic rats.

J Endocrinol 2011 Nov 29;211(2):157-68. Epub 2011 Jul 29.

Department of Trauma Surgery and Reconstructive Surgery, University of Goettingen, Germany.

The study investigated the influence of 4-methylbenzylidene camphor (4-MBC), daidzein, and estradiol-17β-benzoate (E(2)) on either intact or osteotomized cancellous bone in ovariectomized (Ovx) rats. Three-month old Ovx rats were fed with soy-free (SF) diet over 8 weeks; thereafter, bilateral transverse metaphyseal osteotomy of tibia was performed and rats were divided into groups: rats fed with SF diet and SF diet supplemented with 4-MBC (200 mg), daidzein (50 mg), or E(2) (0.4 mg) per kilogram body weight. After 5 or 10 weeks, computed tomographical, biomechanical, histological, and ashing analyses were performed in lumbar spine and tibia of 12 rats from each group. 4-MBC and E(2) improved bone parameters in lumbar spine and tibia, were not favorable for osteotomy healing, and decreased serum osteocalcin level. However, daidzein improved bone parameters to a lesser extent and facilitated osteotomy healing. For lumbar spine, the bone mineral density was 338±9, 346±5, 361±6, and 360±5 mg/cm(3) in SF, daidzein, 4-MBC, and E(2), respectively, after 10 weeks. For tibia, the yield load was 98±5, 114±3, 90±2, and 52±4 N in SF, daidzein, 4-MBC, and E(2), respectively, after 10 weeks. Serum daidzein was 54±6 ng/ml in daidzein group and equol was not detected. Alp and Igf1 genes were down-regulated in callus after daidzein and E(2) compared with 4-MBC (week 5). The response of bone tissue and serum markers of bone metabolism could be ordered: daidzein<4-MBC
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http://dx.doi.org/10.1530/JOE-11-0096DOI Listing
November 2011

Influence of intermittent administration of parathyroid hormone on muscle tissue and bone healing in orchiectomized rats or controls.

J Endocrinol 2011 Apr 13;209(1):9-19. Epub 2011 Jan 13.

Department of Trauma Surgery and Reconstructive Surgery, University of Goettingen, Robert-Koch 40, 37075 Goettingen, Germany.

Influence of human parathyroid hormone (hPTH 1-34) on muscle and bone healing was studied in either orchiectomized (Orx at 8 months of age) or sham-operated male rats. Eleven-month-old Sprague-Dawley rats underwent bilateral transverse metaphyseal osteotomy of tibia and were divided into four groups (n=12): 1) sham-vehicle, 2) sham group-PTH everyday, 3) Orx-vehicle, 4) Orx-PTH everyday, and 5) Orx-PTH every other day. PTH dosage was 40  μg/kg body weight. After 5 weeks, fiber cross-sectional area, capillary density, and enzyme activity (lactate dehydrogenase, citrate synthase, and complex I) were measured in soleus (MS), gastrocnemius (MG), and longissimus (ML) muscles; tibiae were analyzed by computed tomographical, histological, and gene expression analyses. The effect of PTH in all rats was increased serum osteocalcin, cortical and callus densities and callus area. In sham rats capillary density was increased in limb muscles (MS: 1.3-1.7, MG: 1.2-1.4 capillaries/fiber), and rate of osseous bridging of osteotomy was enhanced (67-100%). In Orx rats serum creatine kinase was decreased (6670-2847 U/l), and bone genes (Igf-1, osteoprotegerin, and receptor activator of nuclear factor kB ligand) were up-regulated. Cross-sectional area, enzyme activity, food intake, weight of body, visceral organs, adipose tissue, MG, and MS were not affected by PTH. PTH had a favorable effect on muscle capillary density and improved bone healing being more effective in sham rats and having no adverse systemic effect. The effect was less if PTH was applied every other day. The findings may show up trends for therapeutic treatment of male patients.
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http://dx.doi.org/10.1530/JOE-10-0353DOI Listing
April 2011
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