[Low level laser therapy : A narrative literature review on the efficacy in the treatment of rheumatic orthopaedic conditions]. / Low-Level-Lasertherapie : Eine narrative Literaturübersicht zur Wirksamkeit bei der Behandlung rheumatologisch-orthopädischer Krankheitsbilder.

BACKGROUND: In low level laser therapy (LLLT) low wattage lasers are used to irradiate the affected skin areas, joints, nerves, muscles and tendons without any sensation or thermal damage. Although the exact mechanism of its effect is still unknown, it seems beyond dispute that LLLT induces a variety of stimulating processes at the cellular level affecting cell repair mechanisms, the vascular system and lymphatic system. LLLT has been popular among orthopaedic practitioners for many years, whereas university medicine has remained rather sceptical about it. OBJECTIVES: Overview of studies on the efficacy of LLLT in the treatment of rheumatic orthopaedic conditions, i. e. muscle, tendon lesions and arthropathies. MATERIALS AND METHODS: Narrative literature review (PubMed, Web of Science). RESULTS: While earlier studies often failed to demonstrate the efficacy of LLLT, several recent studies of increasing quality proved the efficacy of LLLT in the treatment of multiple musculoskeletal pain syndromes like neck or lower back pain, tendinopathies (especially of the Achilles tendon) and epicondylolpathies, chronic inflammatory joint disorders like rheumatoid arthritis or chronic degenerative osteoarthritis of the large and small joints. In addition, there is recent evidence that LLLT can have a preventive capacity and can enhance muscle strength and accelerate muscle regeneration. CONCLUSION: LLLT shows potential as an effective, noninvasive, safe and cost-efficient means to treat and prevent a variety of acute and chronic musculoskeletal conditions. Further randomized controlled studies, however, are required to confirm this positive assessment.

[MALDI mass spectrometry of the meniscus. Objectification of morphological findings]. / MALDI-Massenspektrometrie am Meniskus. Objektivierung morphologischer Befunde.

BACKGROUND: The classification of meniscal lesions requires correlation with clinical data. For the standardization of histopathology reports a discrimination between normal, low-grade lesions and high-grade lesions is feasible. This classification can be further specified using other methods. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded specimens of meniscal tissue from 68 patients were analyzed by matrix-assisted laser desorption ionization (MALDI) imaging. RESULTS: The classification of meniscal lesions and differentiation between low-grade and high-grade and acute versus non-acute degeneration is possible by determination of the differential expression of mass-to-charge ratios by statistical comparisons using the P-value from combined Wilcoxon and Kruskal-Wallis (PWKW) tests and a predefined average two-fold difference in intensity. CONCLUSION: The concept of a "meniscus report" is introduced for documentation of meniscus tissue specimens integrating histological, histochemical and proteomic data, thereby specifying the degree of degeneration and the assessment of acute or non-acute lesions. Mass spectrometry contributes to an objective histopathology report. An advisory opinion should always be based on close correlation of clinical and morphological evaluations.

Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is prevalent and difficult to treat. Autologous conditioned serum (ACS), marketed under the trade name Orthokine, is a novel, injectable antiarthritic derived from the patient's own blood. The present study is the first time ACS has undergone a controlled clinical trial. METHOD: We investigated 376 patients with knee OA in a prospective, randomized, patient- and observer-blinded, placebo-controlled trial using an intention-to-treat analysis (ITT). The clinical effects of ACS were compared to hyaluronan (HA) and saline (placebo) as assessed by patient-administered outcome instruments (Western Ontario and McMaster Universities osteoarthritis index, global patient assessment, visual analog scale, Short-Form 8) after 7, 13 and 26 weeks. After 104 weeks an observer-blinded follow-up was carried out. Frequency and severity of adverse events were used as safety parameters. RESULTS: In all treatment groups, intra-articular injections produced a reduction in symptoms as well as an improvement in quality of life. However, the effects of ACS were significantly superior to those of HA and saline for all outcome measures and time points, and improvements were clinically relevant; there were no differences between the effects of HA and saline. The frequency of adverse events was comparable in the ACS and saline groups, but higher in the HA group. CONCLUSION: The data demonstrate that ACS injection considerably improves clinical signs and symptoms of OA. It remains to be determined whether ACS is disease-modifying, chondroprotective, or chondroregenerative.

All-ceramic single-tooth restorations: choosing the material to match the preparation--preparing the tooth to match the material.

The shape of a crown preparation is the prime determinant for the choice of material for an all-ceramic restoration. One essential factor is the available space for the restoration, which requires a certain occlusal thickness. The dentist's preparation design determines the available vertical clearance, and the dental technician has the responsibility of advising the dentist with regard to either choosing the right material to match the preparation or to preparing the tooth to match the material. Assuming a minimum static fracture strength of > 2000 N, the following materials can be used for all-ceramic crowns: Laboratory surveys have shown that in most situations, the available occlusal clearance in clinical reality is only 0.8 to 0.9 mm (after cementing). This shows that the available space will often be insufficient for providing monoblock crowns and still on the tight side for veneered oxide ceramics (In Ceram, zirconia, etc.). However, crowns made of veneered oxide ceramics are much more complex to fabricate and much more expensive. By simply providing a minimal occlusal thickness of 1.5 mm, the treatment provider could therefore easily facilitate the use of the much more economical monoblock crowns without compromising either esthetics or strength. Actually, crowns with veneered oxide ceramic copings do not offer any higher fracture resistance compared to Mark II crowns as long as the minimum thickness requirements are met. The flexural strength of CAD/CAM-fabricated lithium disilicate rods is about twice that of CAD/CAM-fabricated Mark II rods. When used for crowns with a wall thickness of 1.5 mm, however, both materials exhibit the same fracture strength of between 2000 and 2500 N. This is related to the different reinforcing action of the adhesive luting agent, which is essentially required for both these materials. When choosing a material, preparation shapes, technical complexity and cost should be thoroughly compared and scrutinized and should figure prominently in the discussions between dentists and dental technician. Unfavorable preparation shapes for single crowns will necessitate compromises in terms of the choice of materials that result in high cost but do not offer anything in the way of higher fracture resistance. What constitutes an appropriate all-ceramic restoration for a single tooth? Do all-ceramic single crowns require the same material bulk as multi-unit bridges? Everything would indicate that a suitable preparation geometry allows feldspathic ceramic monoblock crowns to be milled that do not require any extensive finishing efforts such as thermal annealing or in-laboratory veneering while at the same time demanding no compromises in terms of esthetics and load-bearing capacity.

VITA CAD-Temp for inLab and Cerec 3D.

VITA CAD-Temp is a composite block which enables high-quality provisional restorations to be created using the Sirona milling units. The new Cerec MC XL and inLab MC XL units are the preferred choice on account of their significantly higher milling speeds. The technical requirements are described and an illustrated practical example presented. CAD-Temp constitutes a good example of rapid and efficient collaboration between dentists and dental technicians. This is illustrated on the basis of an example relating to the field of implant prosthetics.

Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep.

Osteoporosis, a major public health burden, is associated with increased fracture risk. Fracture healing in osteoporosis is delayed, with reduced callus formation and impaired biomechanical properties of newly formed bone leading to high risk of fixation failure. Adenoviral gene transfer of bone morphogenetic protein-2 (BMP-2) has been shown to enhance fracture healing. This study evaluated the ability of gene transfer to enhance bone healing in osteoporosis. An established sheep model of osteoporosis with well-characterized alterations in fracture healing was used. Osteotomies were created surgically in the tibias of adult female sheep and monitored for 8 weeks, using radiographic, biomechanical, and histological methods. For pilot experiments, primary ovine osteoblasts and mesenchymal stem cells were transduced with a recombinant adenovirus carrying BMP-2 cDNA (Ad.BMP-2). Large increases in alkaline phosphatase production and mineralization confirmed the ability of human BMP-2 to stimulate osteoblastic differentiation in sheep. In vivo bending stiffness measurements during fracture healing as well as ex vivo torsional stiffness measurements demonstrated stiffer callus tissue after treatment with Ad.BMP-2. The differences were found mainly in the early fracture-healing period. Computed tomography demonstrated that animals receiving the BMP-2 cDNA had larger cross-sectional callus area and higher callus density. Histological examination of the tibias confirmed enhanced callus formation. Direct, local adenoviral delivery of an osteogenic gene thus led to enhanced healing of fractures in an ovine model of osteoporosis. These promising data encourage the further development of genetic approaches to enhance bone healing in patients suffering osteoporosis-associated fractures.

Good short- to medium-term results after osteochondral autograft transplantation (OAT) in middle-aged patients with focal, non-traumatic osteochondral lesions of the knee.

BACKGROUND: Osteochondral autograft transplantation (OAT) offers the opportunity to repair cartilaginous defects by restoring hyaline cartilage anatomy. Encouraging results have been reported in patients suffering from acute knee trauma or osteochondritis dissecans. Patients with focal chronic, non-traumatic osteochondral (FCNO) lesions of the knee, however, have rarely been the subject of investigation. Some authors even consider higher age as contraindications to OAT. OBJECTIVES: To assess the short- to medium-term outcomes of OAT in middle-aged patients with FCNO lesions of the knee and to identify predictors of clinical outcome. HYPOTHESIS: Filling FCNO defects with autologous osteochondral grafts should restore the congruency of the middle-aged knee joint and thereby reduce pain and loss of function on the one hand, and increase quality of life on the other hand. METHODS: One hundred and twelve patients (48.01±1.12yrs) with FCNO of the knee were assessed before OAT and 26.2±0.24 months after surgery. Clinical outcome was measured by WOMAC Index and the Visual Analogue Scale (VAS) for pain. RESULTS: Pain (pre-OAT VAS vs. post-OAT VAS: 7.14±0.19 vs. 3.74±0.26, P<0.001) was reduced and quality of life (pre-OAT WOMAC vs. post-OAT WOMAC: 134.88±5.84 vs. 65.92±5.34, P<0.001) improved. Retropatellar defects were associated with poor outcome, while overall surface and number of cylinders were not. DISCUSSION: Middle-aged patients with FCNO of the knee also profit from OAT at a short follow-up. LEVEL OF EVIDENCE: IV. Mono-centric, prospective clinical series.

Physiological apoptosis in hormone-dependent tissues: involvement of caspases.

Physiological apoptosis in mammals is a type of programmed cell death, an important element in the developmental repertoire ensuring tissue homeostasis and proper disposal of cells that are no longer needed, such as milk-producing epithelial cells in the mammary gland after lactation, luteal cells in the post partum Corpus luteum or secretory cells in the prostate after castration. Although incompletely described, apoptosis in hormone-dependent tissues is apparently initiated and executed using common biochemical strategies. These include survival pathways governed by local and systemic factors and hormones, diverse regulatory pathways and caspase-dependent execution pathways. Using an antibody that recognizes processed effector caspases or a fluorogenic caspase substrate, we present for the first time evidence that caspases are activated in the mammary gland, in the prostate and in the ovary at the time when apoptosis occurs. Most likely phagocytosis of apoptotic cells by neighboring cells may represent an important step, since only a modest involvement of professional phagocytes is apparent. Here, we will summarize and discuss recent data and will attempt to draw a generalized picture of how physiological apoptosis may occur in these organs.

Mouse mammary gland involution is associated with cytochrome c release and caspase activation.

At weaning, milk producing mammary epithelial cells undergo apoptosis and are removed by phagocytosis. Here, we show that mouse mammary gland involution is associated with mitochondrial cytochrome c release and processing of numerous caspases, including caspase-1, -3, -7, -8 and -9. Induction of caspase-3-like activity paralleled cleavage of poly-(ADP--ribose) polymerase. Dexamethasone inhibited processing of caspase-3, -7 and -8 and apoptosis, but had no effect on caspase-1 accumulation and cytochrome c release. In Bcl-2 transgenic animals, cytochrome c release, caspase activation and apoptosis were impaired. Thus, the pro-apoptotic signaling pathway in mammary epithelial cells during involution involves the release of cytochrome c and activation of caspases. It is inhibited by Bcl-2 at the mitochondrial level and by dexamethasone at a post-mitochondrial level.

Shading of ceramic crowns using digital tooth shade matching devices.

In the 1990s, there was great optimism due to the development of devices for measuring tooth shade. The frequently not so simple, visual determination of the shade of a tooth was to be done with the aid of a device which recognizes the shade and describes it accurately by reference to a color chart. However, the skepticism towards such devices was also great. It is known that the color effect frequently differs strongly when comparing a tooth from the shade guide with a metal ceramic crown, despite identical shade designation. Anyone who considers visual shade determination to be inadequate and places his hopes in digital shade matching devices will be disappointed. It is the shade-generating structures of the metal ceramic and frequently of the veneer layers that turn out to be too thin which, despite correct shade selection, cause a different color perception. Such problems have been reduced decisively with the development of fracture-proof hard porcelain caps (Vita In-Ceram) with optical characteristics similar to teeth. In addition, the Vita System 3D-Master tooth shade system developed in 1998 by Vita in cooperation with Dr. Hall from Australia, leads the practitioner to a better understanding of the primary tooth shade characteristics of "brightness (value)", "color intensity (chroma)" and "color (wave length of the visible light, hue)". These two innovations allow a more accurate estimate of the basic shade of a natural tooth (reference tooth) and the imitation in the laboratory of its natural, shade-generating structures. If digital shade measurement supplements the visual shade estimate, then a further improvement can be expected--especially in the recognition of the basic shade. Qualitative descriptions of subjective shade measurement of a natural tooth and of its imitation in the dental laboratory by ceramics can be found frequently in professional journals and publications. With digital tooth shade matching devices, which apart from the color code of the color chart also reproduce exact, colorimetric values, such work processes can be recorded quantitatively and objectively. Reports about this type of controlled shade determination and generation are found rarely in the literature, which is surprising in view of the large number of tooth shade matching devices and dental ceramic systems available. In the present paper, the influence of the individual ceramic layers on color perception is measured and described under standardized conditions. The creation of the basic shade as it results from the composition of the various ceramic layers is traced with a spectrophotometer. The Vita In-Ceram Alumina infiltration ceramic and the VitaVM7 veneer ceramic were selected as the ceramic system. MHT-SpectroShade and Vita Easyshade were used as shade matching devices.

Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells.

Caspases are aspartate-specific proteases that are specifically activated by numerous death stimuli. Caspase activation is thought to play a major role for the execution of apoptosis. Inactive caspase-9 zymogen is known to be localized within the mitochondrial intermembrane space where it is involved in monitoring mitochondrial damage-associated cytochrome c release and subsequent activation of procaspase-3. Here we show that in mammary epithelial cell lines a significant fraction of caspase-9 proform is associated with discrete structures in the nucleus. Stimulation of cells with chemotherapeutic agents leads to the processing of nuclear procaspase-9 and to the accumulation of nuclear and cytoplasmic caspase activity. Using cell-free extracts from caspase-3-deficient MCF-7 cells we show that caspase-8-mediated processing of nuclear procaspase-9 requires caspase-3. In caspase-3-expressing breast cancer cells, cytochrome c-induced processing of nuclear procaspase-9 is blocked by the caspase inhibitors z-VAD and DEVD but not by YVAD. Purified active caspase-3 is sufficient to cleave nuclear caspase-9 zymogen. These results suggest that, in addition to the mitochondrial localization, caspase-9 proform is found within the nucleus and its processing can be regulated by caspase-3.

Caspases: decoders of apoptotic signals during mammary involution. Caspase activation during involution.

At weaning most of the alveolar epithelial cells in the mammary gland die by apoptosis and are removed by phagocytosis. Caspases are a family of aspartate specific cysteine proteases. Activation of caspases is generally thought to represent a major and irreversible event in the apoptotic process. We analyzed caspase expression and activation during mammary gland involution. A quantitative RT-PCR based approach revealed that levels of mRNA expression of several caspases are induced during involution. Using an antibody that specifically recognizes activated caspases we measured a transient induction of caspase activity in situ and found a maximal activation at days two and three of involution. These data were corroborated by monitoring caspase-3 like activity in mammary extracts with a synthetic DEVD-afc peptide as caspase-3 substrate. Using Fas-deficient mice we present evidence that the Fas signaling pathway is not essential for caspase activation and apoptosis during mammary gland involution. In summary, signaling pathways during involution seem to involve activation of caspases as intraepithelial triggers of mammary epithelial cell apoptosis.

[Increasing expression of growth factors by adenovirus gene transfer. A new method of fracture treatment?]. / Verstärkung der Expression von Wachstumsfaktoren durch adenoviralen Gentransfer. Eine neue Methode zur Frakturbehandlung?

Gene therapy in orthopedic surgery is a new technic based on the idea of biological tissue healing. External gene segments are transferred to cells that overexpress growth factors locally to achieve this effect. The influence of growth factors on fracture healing is very well documented in the literature. Experimental data demonstrate that defect healing in bone can be accelerated by the application of different cytokines in vivo. Gene transfer is a promising, new technic of in situ tissue engineering that will enter clinics within the next decade.

Lumbar microdiscectomy. Technique and complications.

Lumbar Microdiscectomy requires special instruments and provides a good view with a narrow approach. The microscope is the best surgical aid. Alternatives are a retractorintigrated light or headlamp. A specific complication of lumbar microdiscectomy - the wrong level - can be minimized by an exact preoperative planning. Other complications like dural lesions and exessive bleeding are less frequent with the microscope because of the better view. The most severe complications that can occur with any lumbar disc operation, major vessel or visceral injury, can be avoided by lusing the new rongeur with a depth guard.

Arthroscopic repair of radial-sided lesions of the triangular fibrocartilage complex.

Disruptions of the triangular fibrocartilage from its attachment to the radius are common. The authors present their methods for reattachment. The question that lingers is whether the blood supply at the radial attachment is sufficient for healing. This clinical series suggests that it is.

[Injuries specific to ice skating--documentation of the injuries of competitive athletes during a pre-season training camp]. / Eiskunstlaufspezifische Verletzungen--Verletzungsdokumentation von Hochleistungsathleten während eines saisonvorbereitenden Trainingscamps.

A Prospective Study. Competitive figure skaters absolve a comprehensive training schedule. The musculoskeletal system of pair and single skaters have to tolerate enormous impacts, especially throughout landings after repetitive jumps. Intense training leads therefore to specific sports injuries and chromic overuse injuries of the ice skaters. Twenty-five skaters were studied. We concentrated on the different types and localisations of injuries and on the individual loss of training sessions resulting from these injuries. The results are based on questionnaires and a clinical examination of the athletes. Typical acute and chronic injuries in figure skating mainly manifest at the lower extremity. It is striking that the first symptoms often occur during the preseason and persist the complete season or even for several years. The significance of sport specific and not ice skating related influences with regard to injury susceptibility is explained. Methodical "off-ice-training" seems to be useful to prevent injuries resulting from physical dysbalances. Improvements of the skating boots might protect from typical high impact during the landings after repetitive jumps.

[Sonographic standard values for the patellar tendon in competitive athletes]. / Sonografische Dimensionen der Patellasehne von Hochleistungssportlern.

BACKGROUND: The sonographic validity of a thickened tendon as a morphological correlate of patellar tendinopathy is beyond dispute, regarding the proximal insertion at the very least. There is, however, a lack of mandatory standard values for competitive athletes and normal individuals. In addition, research findings concerning the clinical relevance of qualitative changes such as hypoechogenic regions are still inconclusive. PARTICIPANTS: 202 national squad athletes from the German track and field federation and 199 age-matched normal individuals were examined sonographically. METHOD: 404 patellar tendons of athletes were compared as to tendon diameter at the (i) proximal insertion, (ii) waist, and (iii) distal insertion with 398 patellar tendons of normal individuals using the portable ultrasound scanner "Just Vision". Furthermore, qualitative pathologies and clinical symptoms were assessed. RESULTS: Athletes reported more clinical symptoms and their tendons were thicker than normal tendons at all three positions (all p's < 0.01). In athletes, proximal diameters above 6.0 mm were very likely to go along with clinical symptoms. There was an association between tendon diameter and symptoms at all three positions among the athletes, whereas in controls, this was only true for the proximal insertion. Only few consistent qualitative differences were found between athletes and normal individuals. CONCLUSION: The pattern of results confirms the clinical relevance of the proximal tendon diameter for patellar tendinopathy and provides standard values which should be evaluated in future research with regard to their prognostic utility in competitive sports. The importance of qualitative pathologies such as hypoechogenic regions could not be firmly asserted.

[Training adaptation of the Achilles tendon in competitive athletes--sonographic standard values for the Achilles tendon]. / Trainingsadaptation der Achillessehne beim Hochleistungssportler--sonografische Grenzwerte für Achillessehnen.

BACKGROUND: Current theories and empirical results regarding the sonographic dimensions of the Achilles tendon as well as an alleged training adaptation of the tendon in competitive athletes are tested for the first time in a large in vivo sample. The pathological validity of a thickened tendon in competitive athletes is under scrutiny. MATERIAL AND METHOD: In addition to 202 national squad athletes from the German track and field federation, 199 age-matched normal individuals were examined sonographically. The portable ultrasound scanner Just Vision was used to compare 404 Achilles tendons of athletes with 398 Achilles tendons of normal individuals as to tendon diameter. Furthermore, pathologies were assessed. RESULTS: Achilles tendon diameter at the calcanear insertion was 4.2 ± 0.72 mm on average. Athletes' tendons were thicker than normal tendons (p < 0.001) - athletes, however, also reported more clinical symptoms (p < 0.001). In athletes, increasing diameters were associated with more clinical problems as opposed to normal individuals. At the tendon waist, diameters above 6.0 mm were very likely to go along with pathologies. CONCLUSIONS: For the first time, valid data of Achilles tendon diameters in competitive athletes and normal individuals have been presented. The emerging pattern of results clearly contradicts the notion of a physiological training adaptation of the Achilles tendon.

Effect of BMP-2 gene transfer on bone healing in sheep.

Critical size defects of bone and delayed fracture healing due to metabolic disorders are still problems in orthopaedic surgery. Adenoviral vectors encoding bone morphogenetic protein-2 (Ad.BMP-2) have been used to stimulate bone formation in small animals. The present study evaluated the use of direct adenoviral gene transfer for inducing bone formation in a large animal. Standardized iliac crest defects were created surgically on both sides of the pelvic bone of white mountain sheep. The efficiency of gene transfer was evaluated using recombinant adenoviruses carrying the cDNA for luciferase. High levels of transgene expression, restricted to the site of injection, were found for the 1st week. Transgene expression then fell considerably, but could still be detected for up to 5 weeks. To investigate the effect on bone healing, Ad.BMP-2 (10(11) particles in 200 mul saline) was unilaterally injected into iliac crest defects and into tibial osteotomies. The contralateral defects remained untreated to evaluate possible systemic effects. The controls were treated with saline solution. Bone formation within the defect, assessed by micro-computed tomography (CT) measurement at 8 weeks, and callus formation after osteotomy were significantly reduced following direct application of Ad.BMP-2. The retardation compared to untreated control animals was additionally found at the contralateral iliac crest indicating a systemic inhibitory effect. Histological analysis confirmed the CT measurement and showed an increased number of inflammatory cells within both defects. Antibodies against the adenovirus and the transgene product were detected in all treated animals. These data show a systemic retardation of bone formation following a single local injection of Ad.BMP-2 in sheep. This finding stands in contrast to the data obtained from small animal models. Further studies are needed to determine the contribution of the immune response to these results, and whether a lower dose of Ad.BMP-2 would be advantageous.

The potential of gene therapy for fracture healing in osteoporosis.

Osteoporosis-associated fractures impair a patient's function and quality of life and represent one of the major public health burdens. Demographic changes predict a dramatic increase in osteoporotic fractures. Experimental data have shown that osteoporosis impairs fracture healing. Clinical observations demonstrate high failure rates of implant fixation in osteoporosis. The reduced healing capacity, including impaired bone formation, in osteoporotic humans might be due to defects in mesenchymal stem cells that lead to reduced proliferation and osteoblastic differentiation. Growth factors show remarkable promise as agents that can improve the healing of bone or increase the proliferation and differentiation capacities of mesenchymal stem cells. Their clinical utility is limited by delivery problems. The attraction of gene-transfer approaches is the unique ability to deliver authentically processed gene products to precise anatomical locations at therapeutic levels for sustained periods of time. Unlike the treatment of chronic diseases, it is neither necessary nor desirable for transgene expression to persist beyond the few weeks or months needed to achieve healing. This review presents different approaches of gene therapy to enhance fracture healing and summarizes the promising results of preclinical studies. It focuses on applications of this new technique to fracture healing in osteoporosis. In our opinion, these applications represent some of the few examples in which gene therapy has a good chance of early clinical success.