[Recommendations for the healthcare of patients with FOP]. / Empfehlungen zur Versorgung von Patient:innen mit FOP.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible. AIM OF THE RECOMMENDATIONS: This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.

Transient hyperthyroidism after surgery for secondary hyperparathyroidism: a common problem.

BACKGROUND: Postoperative hyperthyroidism occurs in approximately one third of patients following parathyroidectomy due to primary hyperparathyroidism (PHP), but has only rarely been described in secondary hyperparathyroidism (SHP). The frequency, course, and laboratory markers of postoperative hyperthyroidism in SHP remain unknown. Our purpose was to evaluate the frequency and the clinical course of postoperative hyperthyroidism following surgery of SHP and to determine the diagnostic value of thyroglobulin in this setting. MATERIAL AND METHODS: A total of 40 patients undergoing parathyroidectomy because of SHP were included in this study. Thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and thyroglobulin (Tg) were determined one day before and on day 1, 3, 5, 10, and 40 after surgery. At each of these visits patients were clinically evaluated for signs or symptoms of hyperthyroidism. RESULTS: Biochemical evidence of hyperthyroidism was evident in 77% of patients postoperatively despite of preoperatively normal serum levels. TSH dropped from 1.18 ± 0.06mU/L to 0.15 ± 0.07mU/L (p = 0.0015). Free triiodothyronine (fT3) and fT4 levels increased from 2.86 ± 0.02ng/L and 10.32 ± 0.13ng/L, respectively, to their maximum of 4.83 ± 0.17ng/L and 19.35 ± 0.58ng/L, respectively. Thyroglobulin levels rose from 3.8 ± 0.8ng/mL to 111.8 ± 45.3ng/mL (p<0.001). At day 40 all thyroid related laboratory values were within normal range. Correlation analysis of postoperative values revealed significant correlations for lowest TSH (r = -0.32; p = 0.038), and highest fT3 (r = 0.55; p<0.001) and fT4 levels (r = 0.67; p<0.001) with Tg. CONCLUSION: Transient hyperthyroidism is frequent after parathyroidectomy for SHP with Tg being a suitable marker. Awareness of this self-limiting disorder is important to avoid inappropriate and potentially harmful treatment.

Prediction of immediate and long-term benefit after kyphoplasty of painful osteoporotic vertebral fractures by preoperative MRI.

BACKGROUND: It is unclear if an MR-detectable bone marrow edema is a prerequisite for pain reduction and morphological correction by kyphoplasty. This comparative trial evaluates clinical and radiomorphological outcomes after kyphoplasty of painful osteoporotic vertebral fractures with and without preoperative MR-detectable bone marrow edema for 1 year of follow-up. METHODS: Preoperative MR-images of 45 patients who received kyphoplasty for treatment of painful osteoporotic vertebral fractures were evaluated with regard to presence (n = 27) or absence (n = 18) of vertebral bone marrow edema. Pain scores (VAS 0-100) and radiomorphological measures (midline vertebral height, kyphosis angle) were analysed at baseline, postoperatively and after 12 months. RESULTS: In the "bone edema" group, pain scores improved from 72.7 to 46.8 (postoperative) and 48.0 (12 months, P < 0.001, both). In the group without preoperative bone edema, pain score improved from 70.7 to 60.3 (postoperative, P = 0.013) and to 50.1 (12 months, P = 0.001). Pain scores of both groups were significantly different directly postoperative (P = 0.026), but not after 12 months (P = 0.714). Vertebral height restoration was slightly greater in the "bone edema" group (10.2% vs. 7.8%, P = 0.289). Correction of the kyphosis angle was greater in the "bone edema" group (P = 0.014) compared to the "no bone edema" group (P = 0.838). CONCLUSION: A preoperative MR-detectable vertebral bone marrow edema predicts a better short-term outcome after kyphoplasty, but is not a prerequisite for long-term pain reduction in patients with old, chronically painful osteoporotic vertebral fractures.

Vertebroplasty and kyphoplasty - inefficient treatments for degenerative spine disease.

Osteoporotic vertebral fractures and pathological vertebral lesions are frequent clinical situations causing severe back pain. The pharmacological treatment of the underlying disease and the analgetic treatment of the associated back pain usually do not rid the patient's back pain completely and are insufficient to prevent the fracture-weakened vertebral body from further fracturing with long term consequences for the biomechanical competence of the entire spine. In the last 10 years the minimal invasive treatment options vertebroplasty (VP) and balloon kyphoplasty (BK) have spread quickly because these procedures appeared to be promising treatments to stop the fracture and vertebral lesion associated back pain and to internally stabilize a fractured vertebral body. Numerous published reports on VP and BK appeared to support the notion of an immediate and lasting pain reduction after VP and BK in additon to a prevention of further fracturing of the treated vertebrae. The first three randomized controlled and partly blinded trials have been published this year. Two of these trials demonstrate that VP does not result in a better pain control than a sham operation whereas BK was shown to reduce back pain due to verterbal fractures for at least 12 months. Considering that more than 1.5 million people world-wide have been treated with VP and BK until now this work discusses the recent trials and suggests clinical and academic consequences on the basis of the most recent evidence.

The -174G>C IL-6 gene promoter polymorphism and diabetic microvascular complications.

This study examined a possible association of the G>C polymorphism at nucleotide -174 in the promoter region of the interleukin-6 (IL-6) gene (rs1800795) with the prevalence of diabetic complications in 235 patients with type 1 and 498 patients with type 2 diabetes. Genotyping was performed using polymerase chain reaction (PCR) and subsequent cleavage by Nla III restriction endonuclease. Analyzing all diabetic patients together demonstrated that 301 patients (41.1%) carried the GG genotype, 114 (15.6%) the CC genotype, and 318 (43.3%) were heterozygous for the GC genotype. However, there was no correlation of any of the genotypes with the prevalence of diabetic nephropathy or diabetic neuropathy, but subjects with the CC genotype had a significantly higher prevalence of diabetic retinopathy compared to patients with the GC and GG genotype (p=0.016). This association was mainly lost when a logistic regression model was adjusted for diabetes duration (p=0.07). Consistently, a weak but not significant association of the polymorphism with diabetic retinopathy was observed when type 1 and type 2 diabetic patients were analyzed separately (patients with type 1 diabetes: p=0.12; patients with type 2 diabetes: p=0.09). Analogically, no association of the polymorphism was found for diabetic nephropathy or diabetic neuropathy in these groups. In conclusion these data suggest no major influence of the -174G>C variant in the promoter region of the IL-6 gene on the development of microvascular complications in patients with diabetes.

[Indications and results of kypho- and vertebroplasty]. / Indikationen und Ergebnisse der Kypho- und Vertebroplastie.

The best currently available evidence based treatment reduces vertebral fracture risk but does not totally prevent osteoporotic and malignant follow-up fractures. Kyphoplasty and vertebroplasty are options of a causal treatment to reduce pain by internal stabilization of fractured vertebrae. The indication for these minimal invasive procedures requires an interdisciplinary discussion of the individual case to guarantee technical feasibility, to increase the likelihood that these procedures will indeed reduce pain and to embed these procedures into the long term therapeutic concept of every single patient. In addition to internal stabilization of a painfully fractured vertebra kyphoplasty also seeks to restore lost vertebral height which appears promising in acute vertebral fractures. Due to the procedure there are more cement leakages after vertebroplasty. Available controlled prospective studies demonstrate only for kyphoplasty a long-term benefit for the patient in terms of pain reduction, increased mobility and improved quality of life.

Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.

Thiazolidinediones such as pioglitazone have been shown to exert anti-inflammatory effects independent of their insulin sensitizing effects by reducing activation of the proinflammatory transcription factor NF-kappaB in animal models of experimental diabetes. Furthermore, short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries of patients with type 2 diabetes. Since inflammation is supposed to impair flow-mediated vasodilatation, we studied the effects of an 8-week pioglitazone intervention on endothelial function and mononuclear NF-kappaB activation in patients with type 2 diabetes. Twenty patients were included in a randomized, double-blind, placebo-controlled study receiving 30 mg pioglitazone or placebo, respectively. Flow-mediated endothelium dependent vasodilatation (FMD) of the brachial artery, NF-kappaB binding activity in peripheral blood mononuclear cells [pBMC, determined by electrophoretic mobility shift assay (EMSA)] and interleukin-6 (IL-6)-transcription rates (determined by real-time PCR) were measured at study entry and after eight weeks of intervention. Pioglitazone treatment resulted in a significant improvement of FMD (4.3%+/-3.3; p=0.003), while no effect was seen under placebo medication (2.0%+/-2.7; p=0.71). The correction of FMD was neither paralleled by a pioglitazone-dependent reduction in mononuclear NF-kappaB binding activity (DeltaNF-kappaB activity: pioglitazone: 9.2%+/-6.7, p=0.24; placebo: 5.7%+/-19.6; p=0.82) nor in NF-kappaB dependent gene transcription as determined for IL-6 (DeltaIL-6 pioglitazone: +1.8%+/-12.0, p=0.93; placebo: -0.2%+/-9.7; p=0.92). These data demonstrate for the first time that pioglitazone treatment improves endothelial dysfunction in patients with type 2 diabetes without affecting NF-kappaB binding activity and NF-kappaB dependent proinflammatory gene expression in pBMC.

[Balloon kyphoplasty in the therapy of vertebral fractures]. / Ballonkyphoplastie in der Therapie von Wirbelkörperfrakturen.

Approximately 500,000 vertebral fractures occur as a result of osteoporosis every year in Europe. One third of the patients thus affected complain of severe back pain and seek treatment. In the past, the treatment of such fractures was limited to conservative methods, such as the use of braces and analgesics and long-term immobilisation followed by physiotherapy. Since 1998 balloon kyphoplasty, a minimally invasive procedure, has also been available for their treatment. During balloon kyphoplasty a balloon system is introduced into a fractured vertebral body to achieve bitranspedicular augmentation, after which low-viscosity bone cement is injected into the vertebral body, where it sets very quickly. In general the patient can be fully mobilized 24-48 h after the procedure and in most cases the symptoms are then considerably attenuated; many patients are actually free of pain. Published studies and our own experience indicate that balloon kyphoplasty is a safe method of treating painful vertebral compression fractures sustained in various ways and that complications are rare with this procedure.

[Balloon kyphoplasty in the treatment of back pain]. / Die Ballonkyphoplastie in der Behandlung des Rückenschmerzes.

BACKGROUND: Experience of just under 5 years has shown that balloon kyphoplasty can be just as successfully employed as the longer-stablished vertebroplasty for the treatment of back pain due to recent or prior osteoporotic fractures as well as new traumatic fractures. MATERIAL AND METHOD: Among 345 patients with a total of 690 treated vertebral bodies, the change in pain symptomatology was analyzed for a follow-up period of 12 months in 40 study patients who underwent kyphoplasty and a control group of 20 patients. In addition, the pain experienced by a further 29 patients with new traumatic vertebral body fractures was monitored over a 12-month period. These fractures were partly managed by fixateur interne alone and by a combination of fixateur interne and kyphoplasty. RESULTS: The 40 patients treated by kyphoplasty had a baseline VAS score of 26.2+/-2.00, which increased to 44.4+/-3.11 after 12 months, while the respective scores for the control group were 33.6+/-4.21 and 34.3+/-4.35. In the 29 patients with new traumatic vertebral body fractures, the initial VAS score was 62 and after 12 months a distinct reduction of pain was noted with a score of 20 (100 = maximum pain, 0 = no pain). The number of times that the 40 patients managed by kyphoplasty had to consult their general practitioner was significantly reduced by the pain therapy. CONCLUSION: Balloon kyphoplasty verifiably improved the pain symptomatology after vertebral fracture over a period of 12 months. Comparison with the control group, which received the same osteoporosis drug therapy, confirmed the effect of this minimally invasive treatment form.

Osseous integration of calcium phosphate in osteoporotic vertebral fractures after kyphoplasty: initial results from a clinical and experimental pilot study.

INTRODUCTION: This study evaluated the radiological changes at the bone-cement interface of calcium phosphate cement (CPC) and polymethylmethacrylate (PMMA) 12 months after kyphoplasty. In a pilot experiment, we additionally performed a histomorphometric analysis in osteopenic foxhounds to analyze the process of osseous integration of CPC and PMMA. METHODS: Twenty postmenopausal female patients with 46 vertebral compression fractures (VCF) were treated by kyphoplasty, utilizing CPC (N=28) or PMMA (N=18) for intravertebral stabilization. After a 12-month follow-up, we measured the density changes of border voxels at the bone-cement interface by computed tomography (CT) using dedicated software algorithms. We defined the border-voxel density (BVD) as a parameter of cement resorption at the interface. We also investigated the bone-implant interface in three osteopenic foxhounds by histomorphometry 3, 6, and 12 months after cement implantation. RESULTS: Twelve months after kyphoplasty, only CPC showed a significant decrease of the BVD compared to PMMA (p<0.01), indicating a slow progress of resorption at the interface. Histomorphometry of the dog vertebrae showed near total bone coverage of CPC implants, whereas the PMMA surface exhibited only 30% direct bone contact (p<0.01). We also observed a time-dependent increase in the number of discernable osteons close to the interface of CPC, but no bone tissue within PMMA (p<0.01). CONCLUSIONS: The decrease of the BVD 12 months after kyphoplasty may indicate osseous integration of CPC by: (1) the ingrowth of bone tissue and (2) osteonal penetration close to the interface.

[Balloon kyphoplasty in the treatment of vertebral fractures]. / Ballonkyphoplastie in der Therapie von Wirbelkörperfrakturen.

Approximately 500,000 vertebral fractures occur as a result of osteoporosis every year in Europe. One third of the patients thus affected complain of severe back pain and seek treatment. In the past, the treatment of such fractures was limited to conservative methods, such as the use of braces and analgesics and long-term immobilisation followed by physiotherapy. Since 1998 balloon kyphoplasty, a minimally invasive procedure, has also been available for their treatment. During balloon kyphoplasty a balloon system is introduced into the fractured vertebral body to achieve bitranspedicular augmentation, after which low-viscosity bone cement is injected into the vertebral body, where it sets very quickly. In general the patient can be fully mobilized 24-48 h after the procedure and in most cases the symptoms are then considerably attenuated; many patients are actually free of pain. Published studies and our own experience indicate that balloon kyphoplasty is a safe method of treating painful vertebral compression fractures sustained in various ways and that complications are rare with this procedure.

Endothelin-1 levels in patients with Paget's disease of bone.

A locally accelerated bone turnover is the pathophysiological basis of Paget's disease of bone (PD) and may result in severe bone deformations and pain. Affected bone sites are hypervascularized. Secreted endothelial products such as endothelin-1 (ET-1), influence bone metabolism. We investigated a possible correlation between ET-1 plasma concentrations and bone metabolism in patients with PD and whether ET-1 plasma levels are regulated by i. v. bisphosphonate treatment. Plasma ET-1 levels were determined in 22 patients with PD and found to be significantly (p = 0.006) elevated (0.75 +/- 0.48 fmol/ml) compared to 19 healthy controls (0.20 +/- 0.24 fmol/ml). In a group of five patients with PD, plasma ET-1 levels were determined before and after treatment with i. v. pamidronate. On the average, ET-1 levels decreased by 21 % after pamidronate infusions (p = 0.045). The results suggest that bone metabolism in pagetic bone affects endothelial cell metabolism and may also be modulated by endothelial cell products. ET-1 plasma levels may indicate PD activity.

No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications.

AIM: This study examined a possible association of the T/G polymorphism at nucleotide 94 in the adiponectin gene with the prevalence of diabetic complications. METHODS: The study was performed in 696 patients with type 1 diabetes and type 2 diabetes. Genotyping was performed by means of polymerase chain reaction and subsequent cleavage by using SmaI restriction endonuclease. RESULTS: The 94G/G genotype was significantly more prevalent in patients with type 2 diabetes (2.2%) than in type 1 diabetics (0.0%) (p = 0.02), whereas no differences were found for frequencies of the 94T/T and the 94G/T genotypes, respectively. In patients with type 1 diabetes, 45 of 239 patients were heterozygous for the 94T/G polymorphism (carrier rate (CR): 18.8%; allele frequency (AF): 0.094). In type 2 diabetics, 71 of 457 patients were heterozygous and 10 patients were homozygous for the 94G/G genotype (CR: 17.7%; AF: 0.10). No association with diabetic nephropathy, diabetic neuropathy or diabetic retinopathy was found for either genotype in patients with type 1 and type 2 diabetes. CONCLUSIONS: The 94T/G polymorphism in the adiponectin gene is not associated with diabetic complications. The significance of a higher prevalence of the G allele in type 2, compared to type 1 diabetes remains to be clarified.

CT volumetry of intravertebral cement after kyphoplasty. Comparison of polymethylmethacrylate and calcium phosphate in a 12-month follow-up.

This study was intended to measure the volume of intravertebral cement after balloon kyphoplasty with high resolution computed tomography (CT) and dedicated software. Volume changes of biocompatible calcium phosphate cement (CPC) were detected during a follow-up of 12 months. Measurements were compared with a control group of patients treated with polymethylmethacrylate (PMMA). Twenty-three vertebrae (14 CPC, 9 PMMA) of 12 patients were examined with CT using an identical imaging protocol. Dedicated software was used to quantify intravertebral cement volume in subvoxel resolution by analyzing each cement implant with a density-weighted algorithm. The mean volume reduction of CPC was 0.08 ml after 12 months, which corresponds to an absorption rate of 2 vol%. However, the difference did not reach significance level (P>0.05). The mean error estimate was 0.005 ml, indicating excellent precision of the method. CT volumetry appears a precise tool for measurement of intravertebral cement volume. CT volumetry offers the possibility of in vivo measurement of CPC resorption.

[The evaluation of balloonkyphoplasty for osteoporotic vertebral fractures. An interdisciplinary concept]. / Die Wertigkeit der Ballonkyphoplastie bei der osteoporotischen Wirbelkörperfraktur. Ein interdisziplinäres Konzept.

BACKGROUND DATA: Patients with osteoporotic vertebral compression fractures frequently complain of pain and a loss of function and mobility. Such fractures are associated with an increased mortality. The common treatment with bed rest, bracing or osteosynthesis does not lead to satisfying results. With two new surgical techniques, vertebroplasty and kyphoplasty, an internal stabilisation of osteoporotic vertebral fractures is possible. METHODS: All patients were treated by kyphoplasty. With a minimal invasive dorsal approach, an inflatable bone tamp is placed in the fractured vertebral body. This tamp can restore the vertebral body height and create a cavity, which is filled with bone cement under low pressure. The advantage of kyphoplasty compared to vertebroplasty is the restoration of the vertebral height and a decreased cement leakage rate. We performed a prospective, interdisciplinary study with a follow-up of 12 months. We treated 192 vertebral fractures in 102 patients. Augmentation was performed with polymethylmethacrylate in 138 cases and with a new injectable calcium phosphate-cement in 54 vertebral bodies. Outcome data were obtained with two different spine-scores and by the radiomorphometric evaluation of x-rays before and after treatment. RESULTS: We noticed a significant improvement in pain and function in 89% of the patients. All patients showed a regain of vertebral height of on average 17%. In 7% of all treated vertebral bodies, we noticed cement leakage, which was, however, far below the rates published for vertebroplasty (20-70%). There were two complications, bleeding due to an unknown coagulopathy and a violation of the myelon by malpunction. CONCLUSION: Kyphoplasty is a reliable and minimally invasive method for stabilizing fractured osteoporotic vertebral bodies. Improvement of pain and function and a regain in height of the treated vertebral body can be accomplished.

[Kyphoplasty and vertebroplasty in fractures in the elderly: effort and effect]. / Kyphoplastie und Vertebroplastie bei Frakturen im hohen Lebensalter. Aufwand und Ergebnisse.

Kyphoplasty and vertebroplasty are two minimally invasive percutaneous techniques used for treatment of osteoporotic vertebral compression fractures in the thoracic and lumbar spine. The injection of polymethylmetacrylate (PMMA) is often a final attempt at therapeutic treatment of complications due to such fractures. Vertebroplasty involves injection of cement via one or both pedicles under high pressure, thus filling and stabilizing the vertebra without reduction of fracture. Extravertebral cement leakage is a common complication: an intact posterior wall normally prevents cement leakage into the epidural space. Kyphoplasty involves transpedicular inflation of balloon tamps, thus creating a cavity which is then filled with PMMA under low pressure. Restoration of vertebral height is possible and the potential for extravertebral cement leakage lessened.

[Results of ERA-hearing-tests during infancy (author's transl)]. / Auswertung des Kinder-ERA-Krankengutes an der HNO-Klinik der Med. Akademie Dresden.

The results of 50 children with partial or complex hearing loss, referred to the hospital for diagnosis, were evaluated according to different aspects. Haloperidol (0,1 mg/kg) administered orally causes potential changes similar to those known in the literature for natural sleep and chloral hydrate sleep (Freigang and Kevanishvili 1975). The components N2 and P3 are dominant in the potential picture instead of N1 and P2. Regarding sedation, the drug meets all requirements. The identification of the hearing level by means of the input/output functions could be performed in 24 per cent of all cases, whereas summation curves must be employed in 26 per cent and threshold determinations according to Biesalski in 30 per cent. Deafness is assumed in 20 per cent of the patients with nondetectable AEP. The average hearing loss evaluated according to age groups is between 55 and 70 dB.