Repair Attempts Research Articles

Analysis of articular cartilage as a composite using nonlinear membrane elements for collagen fibrils

To develop a composite fibre-reinforced model of the cartilage, membrane shell elements were introduced to represent collagen fibrils reinforcing the isotropic porous solid matrix filled with fluid. Nonlinear stress–strain curve of pure collagen fibres and collagen volume fraction were explicitly presented in the formulation of these membrane elements. In this composite model, in accordance with tissue structure, the matrix and fibril membrane network experienced dissimilar stresses despite identical strains in the fibre directions. Different unconfined compression and indentation case studies were performed to determine the distinct role of membrane collagen fibrils in nonlinear poroelastic mechanics of articular cartilage. The importance of nonlinear fibril membrane elements in the tissue relaxation response as well as in temporal and spatial variations of pore pressure and solid matrix stresses was demonstrated. By individual adjustments of the collagen volume fraction and collagen mechanical properties, the model allows for the simulation of alterations in the fibril network structure of the tissue towards modelling damage processes or repair attempts. The current model, which is based on a physiological description of the tissue structure, is promising in improvement of our understanding of the cartilage pathomechanics.

Radial Forearm Free Tissue Transfer in the Management of Persistent Cerebrospinal Fluid Leaks

Cerebrospinal fluid (CSF) leaks can occur after head trauma or skull base surgery. Persistent or spontaneous leaks should be repaired, since they put patients at risk for serious intracranial complications. Although numerous repair methods have been successful, the occasional patient develops a persistent leak. We describe our experience with free tissue transfer for repair of recalcitrant CSF leaks. Retrospective chart review of patients undergoing free tissue transfer for repair of a CSF leak between November 1995 and October 2004. Setting was an academic, tertiary care referral center. Twelve patients with persistent CSF leak were studied. Eleven of 12 patients had undergone a previous repair attempt ranging from endoscopic repair with fat graft to craniotomy and primary repair of the dural defect. All patients underwent radial forearm free tissue transfer. There were six female and six male patients. Average age was 52.7 years (range, 22-80 y). The most common presenting complaints were intracranial abscess, recurrent meningitis, or pneumocephalus (n=9) and CSF otorrhea or rhinorrhea (n=8). Cause was head trauma (n=6), prior surgery (n=4), cholesteatoma (n=1), or meningoencephalocele (n=1). Eleven of 12 patients failed prior procedures (range, 0-6 procedures; mean, 1.9). Ten flaps were placed in the anterior skull base and two were in the middle or posterior skull base. Radial forearm free tissue transfer resulted in sustained resolution of CSF leakage in all 12 patients. Free tissue transfer is an efficacious option in the repair of recalcitrant CSF leaks.

Management of complications after hypospadias repair

Objectives To review our experience with hypospadias complications (seen after 10%–15% of repairs) and to identify factors influencing outcome. Methods We reviewed the available medical records of 113 patients who underwent repeat operation for hypospadias complications. Of the 113 patients, 40% had undergone the initial repair at our institution (internal referral); 60% had undergone the initial repair elsewhere before referral (external referral). The variables potentially affecting outcome were reviewed, including the severity of the defect, concomitant disease, age at the initial operation and revisions, type of complications and treatment, and the number of revisions. Outcomes were compared on the basis of specialty and experience. Results Isolated hypospadias was present in 81% and other genitourinary abnormalities in 10%. External referral patients were older at the first revision (7.3 versus 4.2 years, P = 0.027). Complications included fistula (73%), stricture (12%), breakdown of repair (10%), and diverticulum formation (11%). Successful revision was independent of the initial defect. The first, second, and third revision was successful in 77%, 64%, and 67% of patients, respectively. The cumulative success rate was 77%, 92%, and 97% after each respective repair attempt. The success of the repair was independent of the patient’s age at the initial operation/revision and of the interval from the initial repair to reoperation. Internal referral and external referral patients had similar results. Specific experience with the repair of hypospadias complications correlated with a successful outcome ( P <0.001). Conclusions Complications after hypospadias repairs are common, with fistula accounting for approximately 75%. The outcome in our series was independent of hypospadias severity, patient age at repair, number of revisions, stent use, and referral status. Repairs performed by an experienced pediatric urologist were associated with improved outcomes ( P <0.001).

Glioblastoma-Induced Attraction of Endogenous Neural Precursor Cells Is Associated with Improved Survival

Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging.

Endovascular Stent-Grafting for Recurrent Aneurysm in Behcet's Disease

Arterial aneurysms represent a severe complication of Behcet's disease. A 42-year-old woman with Behcet's disease had a recurrence of an aneurysm after two surgical repair attempts using grafts. A covered stent-graft was implanted in her iliac external artery to occlude the neck of the aneurysm at the anastomosis of the bypass graft to her external iliac artery. The procedure reduced the size of the aneurysm by allowing the formation of a thrombus within its cavity. The implantation of an endovascular stent-graft may be a sound alternative to surgical repair for aneurysms associated with Behcet's disease.

The use of non-verbal repair strategies by children with autism

This study examined possible links between the occurrence of prosodic changes to vocalizations and gestures and the use of problem behaviors by children with autism when attempting to repair communication breakdowns. The repair strategies of six children with autism aged 2–5 years and with fewer than 10 words or signs were analyzed. Mother–child dyads were videotaped at home interacting in naturally occurring contexts. Videotapes were analyzed and coded for communication breakdowns and repair attempts made by the child. Repairs were further analyzed according to the type of repair strategy used, changes in prosidy, and whether the repair mode involved problematic or non-problematic behavior. In most situations, this group of children attempted to repair breakdowns in communication that occurred while interacting with their mothers. Most children used both non-problematic and problematic behaviors and were less likely to use augmentations as a repair strategy than repetitions and substitutions. Some repetitions and some augmentations involved the use of gestures or vocalizations with increased emphasis or prosidy. Possible links between repair strategies involving increased prosidy and the use of problem behaviors are discussed together with the implications and significance of these finding in relation to early intervention for children with significant communication impairments.

Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases.

The cellular mechanisms of degeneration and repair preceding rupture of the saccular cerebral artery aneurysm wall need to be elucidated for rational design of growth factor or drug-releasing endovascular devices. Patient records, preoperative vascular imaging studies, and the snap-frozen fundi resected after microsurgical clipping from 66 aneurysms were studied. Immunostainings for markers of smooth muscle cell (SMC) phenotype, proliferation, and inflammatory cell subtypes and TUNEL reaction were performed. Unruptured (24) and ruptured (42) aneurysms had similar dimensions (median diameter in unruptured 6 mm; median in ruptured 7 mm; P=0.308). We identified 4 basic types of aneurysm wall that associated with rupture: (1) endothelialized wall with linearly organized SMCs (17/66; 42% ruptured), (2) thickened wall with disorganized SMCs (20/66; 55% ruptured), (3) hypocellular wall with either myointimal hyperplasia or organizing luminal thrombosis (14/66; 64% ruptured), and (4) an extremely thin thrombosis-lined hypocellular wall (15/66; 100% ruptured). Apoptosis, de-endothelialization, luminal thrombosis, SMC proliferation, and T-cell and macrophage infiltration associated with rupture. Furthermore, macrophage infiltration associated with SMC proliferation, and both were increased in ruptured aneurysms resected <12 hours from rupture, suggesting that these were not just reactive changes. Before rupture, the wall of saccular cerebral artery aneurysm undergoes morphological changes associated with remodeling of the aneurysm wall. Some of these changes, like SMC proliferation and macrophage infiltration, likely reflect ongoing repair attempts that could be enhanced with pharmacological therapy.

Novel strategies for enhancing tissue integration in cartilage repair

Introduction Articular cartilage is unable to initiate a spontaneous repair response when injured due to its avascular and aneural properties. Within adult cartilage, chondrocytes are entrapped within an extensive extracellular matrix and are unable to migrate to sights of injury to regulate tissue repair. Injury to this tissue therefore inevitably leads to degeneration of the cartilage and the development of degenerative diseases such as osteoarthritis.The surgical technique of autologous chondrocyte transplantation (ACT) was developed for the treatment of full‐thickness cartilage defects (Brittberg et al. 1994). Implantation of chondrocytes into the defect site repairs the injury site with a mixture of fibrocartilaginous and hyaline‐like tissue that poorly integrates with the existing cartilage and frequently degenerates with time. In this current study, we have developed an in vitro model to investigate methods for enhancing this integration and the development of a more biomechanically stable repair tissue.Materials and methods Bovine articular cartilage explants from the metacarpalphalangeal joint were experimentally injured using a stainless steel trephine and cultured for a period of 28 days. Autologous chondrocytes in an agarose suspension were injected into the interface region at the injury site. Media was collected and analysed for proteoglycan and collagen content using the DMMB and hydroxyproline assays, respectively. Matrix metalloproteinase (MMP) expression was also analysed using zymography and an adapted collagen fibril assay.Results Morphological analyses indicate attempts at repair and integration within both control and experimental treatment groups, although the presence of autologous chondrocytes appeared to amplify this repair response. Although not statistically significant, considerable differences in proteoglycan release between injured explants and the intact control group were seen. Collagen release into the media was only seen at day 28 within experimental cultures. An up‐regulation of MMP‐2 and MMP‐9 was seen within the experimental cultures compared to the controls. Preliminary data also suggest up‐regulation of collagenases in the experimental group when compared to controls.Discussion As seen with clinical ACT treatment, the presence of autologous chondrocytes appears to enhance repair and integration attempts; however, morphologically, this repair tissue appears to be fibrocartilaginous. Further analysis will establish whether the repair tissue is true hyaline cartilage and monitor the synthesis and turnover of macromolecules within the established culture system.

The role of bone in the treatment of osteoarthritis

Bone, and especially the subchondral bone plate, is involved in the pathogenesis of osteoarthritis (OA). OA bone tissue is sclerotic yet undermineralized indicating abnormal bone cell metabolism. Studies in both human and animal models of OA support the concept that bone sclerosis could precede cartilage degradation and loss. Clinical studies show that the indices of bone resorption and formation are increased in OA patients. A working hypothesis of the sequence of changes leading to OA holds that enhanced bone remodeling is the initiating event triggering cartilage damage. The attempt to repair the damaged cartilage then leads to a number of biochemical adaptations in bone and cartilage. In bone, this repair attempt modifies insulin-like growth factor 1 (IGF-1), IGF binding proteins (IGFBPs), and transforming growth factor-β (TGF-β), and alters the urokinase plasminogen activator (uPA)/plasmin system. In the cartilage, it also modifies IGF-1/IGFBP levels and the uPA/plasmin system. However, bone changes may overwhelm the attempts to repair cartilage, and lead to further sclerosis and damage. Some of these specific pathways have been investigated, and indeed are modified in OA subchondral osteoblasts. Thus, subchondral bone sclerosis in OA may be due to abnormal osteoblasts characterized by increased metabolic activities that result in an increase in osteoid matrix that is undermineralized. The exact role played by cytokines and prostaglandins remains controversial. However, restraining collagen deposition and mineral removal, and/or improving mineral deposition, could provide a better, more mineralized, bone matrix in OA patients.

Recent developments and future research in the bone and joint decade 2000-2010.

Musculoskeletal disorders encompass a broad spectrum of conditions of multifactorial origin and very different clinical appearance. Connective tissues are primarily affected in osteoporosis and joint diseases such as osteoarthritis and rheumatoid arthritis, which cause severe long-term pain and physical disability and give rise to heavy costs to society. Many of the major connective tissue diseases involve inflammatory mechanisms. Rheumatoid arthritis, psoriasis, and systemic lupus erythematosus are among the last-remaining widespread diseases for which the scientific community has insufficient knowledge of pathogenesis or treatments that can prevent or reverse the disease course. Mechanisms and pathways leading to destructive inflammation may to a large extent be shared among these diseases and may also operate in other conditions such as osteoarthritis, vasculitis, arteriosclerosis, and osteoporosis. This is clearly demonstrated in genetic studies of animal models in which many genes have been shown to be associated with a wide spectrum of inflammatory diseases, and many diseases include components of spreading the inflammation to various other organs. One prominent example is rheumatoid arthritis, in which vasculitis and increased arteriosclerosis morbidity occur. It is also important to take into account that the mere occurrence of widespread inflammatory diseases in humans is likely to be caused not only by rapidly changing environmental factors but also by natural selection for protection against infectious diseases. In addition, there is often a connection between infections, especially chronic infections, and inflammatory diseases. Most inflammatory diseases affect connective tissues, either by inducing catabolic events or by triggering repair attempts; both will lead to altered function and may develop further to fibrosis. Key features of connective tissues are to take up and distribute load and to provide a barrier and protective function, as well as to retain shape. The component of tissue destruction may be initiated by factors such as mechanical overload that brings the normally very dynamic turnover out of balance. This turnover is aimed at replacing fatigued tissue, for example, with new and mechanically more stable tissue. Many factors govern the basis for this remodelling in connective tissues. Exaggerated load will lead to damage and a higher risk for initiation of a pathological process. In addition, inflammation is a condition that will affect the metabolism in connective tissue cells and usually hamper their ability to repair. This is likely to increase the sensitivity to mechanical load and may perhaps drive the process into a pathological condition. Interestingly, components released from connective tissues as a result of a pathological process appear to have the capability to modulate the inflammatory response and in some cases also to trigger autoimmune reactions. It is thus becoming apparent that the reactions in connective tissues leading to tissue damage are extensively influenced by environmental factors, including vascular and nerve ingrowth and local inflammation. The gap between biology and clinical research The wide gap between clinical approaches and more basic approaches to understanding the disease mechanisms has been difficult to overcome. The clinically oriented approach had its golden age decades ago, when empirical observations could lead to major breakthroughs and built the basis of today's clinical practice. It has, however, shown clear limitations in solving the pathways of disease: some of the treatments given today still have no rational explanation or produce side-effects because of unspecific targeting. The molecular approach has recently been successful in providing tools such as the genome sequence, specific molecular structure and tissue composition but has not yet been significantly explored in understanding disease processes. …

Microglia as a source and target of cytokines.

Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling.

Modeling repair events under intermittent failures and failures subject to unsuccessful repair

AbstractIntermittent failures are sometimes observed for a repairable system, such as an automobile. Such failures often lead to a series of unsuccessful repair attempts before the source of the failure has been identified and removed. Unsuccessful repair is also observed in cases where the failures are not intermittent. In order to model data involving repeated repair attempts related to the same failure, repair times cannot usually be assumed negligible and the model must be designed or modified to account for these. In this paper, we propose a modified version of the branching Poisson process model introduced by Lewis (1964). We discuss statistical inference procedures for this model and demonstrate these procedures using the service history of a new automobile. Copyright © 2002 John Wiley &amp; Sons, Ltd.

A Composite Element Binding the Vitamin D Receptor and the Retinoic X Receptor α Mediates the Transforming Growth Factor-β Inhibition of Decorin Gene Expression in Articular Chondrocytes

Decorin, a small leucine-rich proteoglycan may play an important role in the attempt of cartilage repair initiated by chondrocytes in early stages of osteoarthritis, through its ability to bind collagen fibrils and growth factors such as transforming growth factor-beta (TGF-beta). We previously demonstrated that TGF-beta decreased decorin mRNA steady state levels in articular chondrocytes (Demoor, M., Rédini, F., Boittin, M., and Pujol, J.-P. (1998) Biochim. Biophys. Acta 1398, 179-191). Here, we investigated the effect of TGF-beta on decorin gene expression in both primary cultures of articular chondrocytes and chondrocytes dedifferentiated by serial passages. Transient transfection of cells with plasmid constructs of the decorin promoter linked to the luciferase reporter gene revealed transcriptional repression by TGF-beta, in fully differentiated as well as dedifferentiated chondrocytes. Experiments with 5'-deleted constructs allowed characterization of a TGF-beta-responsive element in the shortest construct (base pairs (bp) -155/+269). DNase I footprinting analysis delineated a negative TGF-beta-responsive region between -140 and -111 bp in the decorin proximal promoter. Gel retardation assays demonstrated that TGF-beta modulates decorin gene expression through transcription factors, the nature and mode of action of which depend on the differentiation state of the chondrocytes; two DNA-protein complexes were formed in the region -144/-127 bp with nuclear extracts from primary chondrocytes, whereas a higher mobility complex was observed in the -127/-111 bp region for dedifferentiated cells. Antibodies against vitamin D and retinoic acid receptors used in supershift experiments showed that these nuclear receptors are involved in the regulation of decorin gene expression in articular chondrocytes.

Combined omental pedicle grafts and thoracodorsal axial pattern flaps for the reconstruction of chronic, nonhealing axillary wounds in cats.

To assess the results of an omental pedicle graft in combination with a thoracodorsal axial pattern flap for the reconstruction of chronic nonhealing axillary wounds in 10 cats caused by forelimb entrapment within a collar. A prospective, clinical trial. ANIMALS USED: Ten client-owned domestic shorthair cats. Routine biochemical and hematologic evaluation was performed on each cat, and all were tested for feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV). Microbial culture was performed on samples from the wounds. After surgical debridement, omentalization using a vascular pedicle of greater omentum, and closure of the chronic axillary wounds, using a thoracodorsal axial pattern flap, was performed. All excised tissue was examined histologically. The sex distribution was 7 males and 3 females, with a mean age of 3.5 years. The cats had undergone a median number of 3 previous repair attempts over a 1.5- to 25-month period before referral (mean, 10.2 months). No hematologic or biochemical abnormalities were noted apart from moderately elevated creatine kinase and aspartate transaminase concentrations in some cats. All cats were negative for FIV and FeLV. Histologic examination of resected tissue revealed hair (foreign body) in 2 cats and an unidentified foreign-body reaction in 3 other cats. Complete healing occurred in all cats (mean follow-up period of 21.7 months), with 2 cats requiring further surgery: 1 for flap dehiscence at 4 days after surgery, and 1 for donor-site dehiscence at 4 days after surgery. One other cat developed a large seroma in the axilla that resolved by 10 days following surgery. The use of an omental pedicle graft in combination with a thoracodorsal axial pattern flap is the first consistently successful 1-step technique for the management of chronic nonhealing axillary wounds in cats.

Molecular events in cartilage formation and remodeling

Cartilage extracellular matrix contains a major component of highly anionic proteoglycan contributing fixed charges creating and osmotic environment and a swelling pressure important for resisting pressure load. Another key element is a network of fibers with collagen 2 as the major constituent providing tensile properties and an ability to take up load. In forming the cartilage matrix the cells produce the macromolecules that constitute the building blocks. These are assembled into the structures of the tissue outside of the cells in a number of specific interactions. An example is the fiber network where collagen molecules form fibrils by interactions where a variety of matrix molecules act as catalysts/chaperons or inhibitors. Examples of molecules interacting with collagen are particularly found among the leucine rich repeat proteins (LRRP). These include decorin, fibromodulin, lumican and biglycan all with known capacity to bind collagens and influence fibrillogenesis in vitro. This binding occurs via the LRR-domain. Furthermore, the molecules have an additional functional domain, that in the case of decorin carries dermatan sulfate chains capable of interacting with other constituents in the matrix including other collagen fibers thereby crossbridging and creating a fibrillar network covering large parts of the tissue. In the case of decorin, lumican and fibromodulin, mice with inactivated genes show alterations in collagen fibril assembly indicative of roles at different stages of the process. PRELP binds collagen via its repeat domain and heparan sulfate via a characteristic N-terminal extension. This includes binding heparan sulfate at the cell surface. Chondroadherin binds cells via their a2b1 integrin. The molecule can actually be isolated from cartilage bound to collagen 2 molecules after activation of endogenous proteinases. COMP represents a different class of molecules with five identical subunits held together in their N-terminal end. The C-terminal end of each chain has a structure allowing tight and specific interactions with triple helical collagen. There are four sites along the collagen molecule each with a KD of 10-9. COMP in vitro has a marked effect in catalyzing the correct assembly of collagen fibers, while not binding to the completed fiber. Thus, the molecule act as a chaperon. Interestingly COMP is upregulated in early phases of osteoarthritis, where a repair attempt of the damaged tissue is likely to be a component. The molecule or fragments thereof released to synovial fluid and blood, actually serves as an indicator of processes in the cartilage leading to its destruction. In processes in cartilage remodeling, many of the constituents in the matrix are degraded and lost to surrounding body fluids. This degradation is likely to be a response to remodeling following material fatigue, altered load or growth. It may also occur as part of a pathological process. It is likely that it is coupled to attempts at repair laying down new matrix constituents to produce an adequately functioning matrix. In disease it is apparent that the imbalance between breakdown and adequate repair leads to progressive changes in cartilage composition characteristic for the various stages of the disease.

Use of omental pedicle grafts in the management of non-healing axillary wounds in 10 cats.

A retrospective analysis of the clinical case histories of 10 domestic shorthaired cats that underwent omentalisation, using a vascular pedicle of greater omentum, of chronic non-healing axillary wounds was carried out. Wounds were debrided and closed in a primary fashion following omentalisation. The cats had undergone a modal number of three previous repair attempts over a three- to 18-month period (mean 11 months) before referral. Further dehiscence occurred in eight cases, requiring a modal number of one further attempt at closure of the wound. Other complications included incisional herniation (two cats), serous exudate from the axillary wound (two cats) and paracostal abscessation (one cat). Long-term cure was achieved in seven of the 10 cases, with wounds finally having healed at a mean of 24 days post-omentalisation. Chronic axillary wounds are particularly difficult to treat and there are no reports of consistently successful techniques for their repair. This report suggests that omentalisation of these wounds may be a step towards such a repair procedure.

MITRAL VALVE REPAIR vs REPLACEMENT: Current Recommendations and Long-Term Results

Techniques now exist to correct abnormalities of all components of the mitral valvular apparatus except extensive loss of pliable leaflet area. Thus, paradoxically, myxomatous valves with redundant leaflets represent the ideal candidates for mitral valve repair. Repair for mitral insufficiency can be performed for some rheumatic valves, but patient selection is critical. Loss of leaflet area, leaflet thickening, and extensive calcification of the leaflets or commissures are contraindications to repair. The abnormalities of the subvalvular apparatus are less important because a complete set of new chordae can be reconstructed using PTFE suture material. Some cases of endocarditis are ideal for repair using localized débridement and pericardial patch repair with or without PTFE chordal replacement. True ischemic mitral regurgitation of the Carpentier type I category is still something of a surgical enigma. Because it is a restrictive leaflet motion problem, annuloplasty alone is not always effective, and the outcome of any given repair attempt is less predictable. Repairs in patients with small annuli and multiple leaflet defects requiring complex series of maneuvers have a low probability of success. Furthermore, such patients with small left ventricular cavities are more prone to experience SAM. Several factors contributing to which therapy is chosen for mitral valve disease are summarized in Table 1. Patient selection, accurate evaluation of the cause or causes of mitral regurgitation, and well-executed application of the appropriate techniques for repair are all critical factors in the early and late success of mitral valve repair.

Early repair of injury to the ureter or bladder after hysterectomy.

In the present study we investigated the effectiveness of early diagnosis, repair of injuries to the ureter and urinary bladder sustained during hysterectomy, as compared to the results of delayed intervention. There were 46 ureteral injuries and 20 vesicovaginal fistulas in 55 patients. In 14 cases of ureteral injury an endoscopic approach management was employed. There was complete healing in 18 vesicovaginal fistulas while there was a single case of a ureteral injury that required nephrectomy because of stenosis. This study shows that early repair of urological injuries after hysterectomy has considerable advantages and the results are equally comparable with those of delayed intervention. In most cases of ureteral injury an attempt of an endoscopic repair is warranted before proceeding to open surgery.

Proliferation and phenotype regulation in the subventricular zone during experimental allergic encephalomyelitis: in vivo evidence of a role for nerve growth factor.

Proliferating cells in the subventricular zone (SVZ) of adult rat brain could provide a source of cells for repair attempts during degenerative diseases. However, very few reports dealt with the spontaneous regulation of this cell population during experimental conditions. In this paper, we describe an increase in the proliferation activity in the SVZ during experimental allergic encephalomyelitis, a demyelinating disease widely used as an experimental model for human multiple sclerosis. Moreover, p75(LNGFR)-immunoreactive elements in the SVZ were larger in experimental allergic encephalomyelitis compared with control groups, and they also showed multiple and branched elongations. Finally, a selective uptake of 125I-nerve growth factor was observed in the SVZ in neonatal rats, and positive elements migrated in the corpus callosum within a few days. These data indicate that cell populations in the SVZ are regulated during inflammatory conditions and degenerative diseases involving oligodendrocytes and neurotrophins, including nerve growth factor, could participate in these phenomena.

Aberrancies in signal transduction and cell cycle related events in Alzheimer's disease.

Neurodegeneration in Alzheimer's disease (AD) is associated with the appearance of dystrophic neuronal growth profiles that most likely reflects an aberrant attempt of neuronal repair. This process of neuronal reorganisation, which eventually goes awry and becomes a disease itself, might be initiated physiologically as a response to neuronal injuries. Minor neuronal damage due to a variety of life events or genetic pertubations that are usually compensated in the normal adult brain by adaptation and repair might thus be amplified and accumulated, thereby resulting in a progressive neurodegeneration. The present paper summarizes recent evidence supporting the hypothesis that a primary impairment of intracellular signal transduction that is mediated by a hierarchy of phosphorylation signals and associated with a aborted attempt of neurons to re-enter the cell-cycle is a key element in the pathomechanism of AD. These changes might result in malfunction of neuronal adaptation and repair and eventually lead to neuronal death. During the process of aging as well as in chronic neurodegenerative disorders such as Alzheimer's disease (AD), the continuous but rather slow action of pathogenetic factors might give room for the activation of compensatory mechanisms, serving to regain a neuronal population much of its synaptic connectivity in the presence of cell loss. An upregulation in the capacity to synthesize and store neurotransmitters (Lapchak et al., 1991), an increased expression of trophic factors (Hellweg et al., 1990; Arendt et al., 1995a,b), as well as regenerative sprouting (Fritschy and Grzanna, 1992), synaptic enlargement (Scheff et al., 1990; Lippa et al., 1992), and neosynaptogenesis (Ramirez and Ulfhake, 1992) have been described among other processes.