Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma.

The fast proliferation of tumor cells develops faster than the vasculature, resulting, in most malignant tumors, in generation of hypoxic regions. Hypoxia renders solid tumors resistant to radiation and chemotherapeutics while providing opportunities for tumor-selective therapies targeting tumor hypoxia. Here we exploit two properties of tumors: propagation of tumor cells and ongoing generation of hypoxic regions to construct a system that preferentially leads to the death of tumor cells and thus hinders tumor growth. We constructed murine leukemia virus replication-competent (RCR) viruses that infect only propagating cells. These viruses express small hairpin RNAs (shRNAs) targeting cyclic AMP-response-element binding protein (CREB), hypoxia-inducible factors 1 (HIF)-1 or HIF-2 individually or all three together (X3). These viruses efficiently infected in vitro human hepatocellular carcinoma (HepG2 and FLC4) cells and established persistence of the virus and knocked down the expression of the regulators of the hypoxia-responding genes. Knockdown of either HIF-1 or CREB or both in hypoxia reduced the expression of hypoxia-response elements- and CRE-mediated gene expression, diminished cell proliferation and increased caspase-3 activity. We did not detect any significant effect of the efficiently knocked down HIF-2 on any of the functions tested in vitro. Moreover, severe combined immunodeficiency mice implanted subcutaneously with HepG2 stably infected with recombinant RCRs showed reduction of tumor growth and vascular endothelial growth factor expression, and no hypoxia-guided neovascularization. Combined treatment (RCRs+doxorubicin) improved efficacy in the context of in vitro hypoxia and in vivo (with either vACE-CREB or vACE-X3). This synergistic effect may lead to an improved efficacy and safety profile of the treatment that may result in fewer side effects.

[METACERCERIAE OF BRACHYPHALLUS CRENARUS RUDOLPHI, 1802 (TREMATODA: HENIURIDAE) IN PLANKTON CRUSTACEANS FROM THE PROSTOR GULF (ITURUP ISLAND, RUSSIA)].

Samples of Zooplankton collected in waters of the Prostor Gulf (Iturup Island) were examined. Metacercariae of Brachyphallus crenatus were found in copepods Pseudocalanus newmani and Acartia longiremis. This is the first record of the second intermediate hosts of this species in the North Pacific.

Consensual medicine and the therapeutic partnership: reducing the costs of defensive medicine and litigation.

Marking the start of our 25th Anniversary Year, Marcel Frenkel, MD, MBA, Founder and Editor Emeritus of this Journal, returns with a prescription that has interest for all players in the healthcare system. Though he focuses on the costs of defensive medicine and malpractice litigation, he proposes a significant change in medicine's cultural approach that can bring universal rewards: empower the patient.

Ruthenium-106 plaque brachytherapy for thick posterior uveal melanomas.

AIMS: Ruthenium-106 brachytherapy is an effective method for treating small to medium uveal melanomas. The purpose of this study was to examine its effectiveness and safety in the management of thick posterior uveal melanoma (apical height >/=8.0 mm) and to compare it with enucleation. METHODS: 126 consecutive patients with thick uveal melanoma were included. 63 patients treated with Ruthenium-106 brachytherapy were compared with 63 patients treated with enucleation. The main outcome measures were visual acuity, eye retention, local recurrence, metastases, all-cause mortality and melanoma-related mortality. RESULTS: Patients treated with brachytherapy were significantly younger and had significantly smaller tumours, compared with patients treated with enucleation. Tumour thickness in the brachytherapy group was 9.3 (SD 0.9) mm compared with 12.2 (1.9) mm in the enucleation group. The 5- and 10-year melanoma-related mortality was 20.5% and 46.2% for brachytherapy patients and 28.1% and 44.0% for enucleation patients (p = 0.6 and p = 0.9). When comparing 15 brachytherapy with 15 matched enucleation patients, the 5-year melanoma-related mortalities were similar, 28.6% and 33.3% respectively (p = 0.7). Complications associated with brachytherapy included tumour regrowth (n = 15), scleral melt (n = 3), neovascular glaucoma (n = 5) and vitreous haemorrhage (n = 3). In the brachytherapy group, no significant difference in survival was noted between patients who did and did not develop local recurrence (p = 0.9). Of the eyes that were initially treated with brachytherapy, 71.4% were saved from enucleation. Of these, 70.8% had a final visual acuity of 20/200 or better. CONCLUSIONS: Ruthenium-106 brachytherapy is an alternative to enucleation in some thick posterior uveal melanomas.

Long-term survival of uveal melanoma patients after surgery for liver metastases.

AIMS: To evaluate the posthepatectomy survival of uveal melanoma patients with liver metastases. METHODS: Data were collected from the files in the Departments of Ophthalmology, General Surgery and Oncology, for uveal melanoma patients who were seen in the Ocular Oncology Clinic at the Hadassah Medical Center from 1988 to 2007. The main outcome was posthepatectomy survival. Statistical analysis was performed using JMP statistical software. RESULTS: Of the 558 patients, 74 (13%) developed metastases after a median of 35.0 months from the initial diagnosis. Thirty-five patients underwent hepatectomy. These patients had similar clinical characteristics as those who did not undergo hepatectomy. The median survival time from the detection of metastasis was 3.7-fold higher in the operated patients in comparison with the non-operated patients. Posthepatectomy survival of patients who were found in surgery to have 1-5 metastatic nodules was 3.1 times longer than those with six or more lesions. The hepatectomies of 13 patients resulted in complete resection of the hepatic metastases with clean histological margins (R0). These patients survived 1.9 times longer than those with residual disease (R1/R2). CONCLUSION: It is possible to extend significantly the life expectancy of uveal melanoma patients who develop isolated hepatic metastases by complete resection of the lesions.

Verbal, visual, and spatio-sequential short-term memory: assessment of the storage capacities of children and teenagers with Down's syndrome.

BACKGROUND: It is recognized that individuals with Down's syndrome have a specific deficit in verbal short-term memory. On the other hand, non-verbal short-term memory seems to be preserved or even be a strong point for these persons. Nevertheless, the extent and specificity of the deficit must be determined. To do so, we carried out a research programme that allowed us to simultaneously assess various short-term memory systems in a developmental perspective, and to compare our participants' performance to that obtained by typically developing individuals of the same mental age. METHOD: Three span tasks are used (auditory word span/visual patterns test/Corsi blocks task) with 54 children and teenagers with Down's syndrome and 54 typically developing children as control group. Participants were matched according to their cognitive level. RESULTS: For the auditory word span task, participants with Down's syndrome obtained performances significantly lower than those of the typically developing participants. On the other hand, compared with typically developing children, children and teenagers with Down's syndrome have a spatio-sequential span significantly higher for the lowest developmental ages. No significant differences were found for visual span. CONCLUSIONS: Individuals with Down's syndrome exhibited a distinctive pattern of memory performance, in addition to their developmental specificities.

Prevalence of clinical asymptomatic retinal detachment in myopic population.

AIM: To evaluate the prevalence of clinical asymptomatic retinal detachment (ARD) in myopic population. METHODS: A retrospective study including all myopic individuals who underwent ophthalmic evaluation prior to excimer laser procedures at the Hadassah Center for Refractive Surgery between March 2002 and March 2006. Medical records were reviewed to extract demographics and refraction, and to identify patients who were diagnosed as having asymptomatic retinal detachment. RESULTS: Data were collected on 6547 myopic individuals (12 815 eyes); of these, 2907 (44.4%) were males, and 3640 (55.6%) were females. The mean age was 31.5 (SD 10) years (range 18-64 years). The mean preoperative spheric equivalence was -4.42 (2.07) (range -0.75 to -16.00). The mean best spectacle-corrected visual acuity was 20/20 (range 20/32 to 20/12.5). Five eyes (0.039% or one of approximately 2563 eyes) of four patients had clinical ARD which was diagnosed during the routine preoperative examination. Three eyes underwent successful scleral buckling procedure while two patients were lost to follow-up. CONCLUSIONS: Clinical asymptomatic retinal detachment is uncommon, accounting for a minority of retinal detachments in myopes, and may be diagnosed during routine ophthalmoscopy prior to a refractive procedure.

Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience.

AIM: To describe our experience in treating vitreoretinal involvement of primary central nervous system lymphoma, by intravitreal injections of methotrexate (MTX). METHODS: Patients with suspected intraocular lymphoma underwent a diagnostic vitrectomy. Samples were sent for cytology, genetic evaluation and for interleukin level measurements. Treatment protocol included injection of 400 microg/0.1 ml MTX intravitreally twice weekly for 4 weeks, once weekly for 8 weeks, and then once monthly for 9 months, for a total of 25 injections. Data were collected from the patients' records and included, inter alia, response to intravitreal MTX measured by time to disappearance of vitreal cells and retinal infiltrates, changes in visual acuity, and clinical recurrence rate. RESULTS: In the past 10 years we have treated 44 eyes of 26 patients; seven patients had monocular involvement, and 19 binocular. Six patients were initially diagnosed as having a non-responsive uveitis, and 16 with either CNS or systemic lymphoma with later involvement of the eye. Four patients had systemic lymphoma; one of them was found to have CNS lymphoma after the ocular involvement. Three patients had T cell lymphoma, and the rest had B cell lymphoma. Clinical remission was reached after 6.4 (3.4) (2-16) injections of MTX (mean (SD) (range)), with 95% of the eyes needing 13 injections or less to be cleared of malignant cells. None of the patients had an intraocular recurrence. Among the side effects, the most common was corneal epitheliopathy, which usually appeared after the third injection and began to subside when the intervals between injections increased. CONCLUSIONS: Vitreoretinal involvement of lymphoma can be controlled effectively and without serious adverse reactions by intravitreal MTX injections. The treatment protocol described herein has resulted in no intraocular recurrence so far and has had bearable side effects. The accumulating clinical results bring us to propose the consideration of this protocol as a good first-line treatment option for intraocular lymphoma.

Maculopathy in patients with primary CNS lymphoma treated with chemotherapy in conjunction with blood-brain barrier disruption.

AIM: To determine the incidence and characteristics of maculopathy associated with blood-brain barrier disruption (BBBD) which is used in treating primary central nervous system lymphoma (PCNSL). METHODS: Files of all 56 patients with PCNSL, with or without intraocular lymphoma (IOL), treated at Hadassah University Hospital during the years 1997-2007 were reviewed. Data on 46 patients for whom we had documentation of ocular examination were studied. Those who were alive at the time of the data collection were invited for further evaluation of the presence or absence of maculopathy. The patients were divided into four groups according to treatment protocol. Group 1: systemic intravenous chemotherapy; Group 2: systemic intravenous chemotherapy and intravitreal methotrexate (MTX); Group 3: systemic intra-arterial (IA) chemotherapy and BBBD; Group 4: systemic IA chemotherapy, BBBD, and intravitreal MTX. RESULTS: Of the 23 patients of Groups 1 and 2 who were not treated by BBBD, none developed maculopathy. Of those 23 patients who were treated by BBBD, 12 of 17 (70.5%) in Group 3 and three of six (50%) in Group 4, for a total of 15 of 23 (65.2%) developed maculopathy. The maculopathy did not significantly affect visual acuity in any of them. CONCLUSIONS: BBBD may cause maculopathy in almost two-thirds of patients treated for PCNSL, without affecting significantly the visual acuity. Intravitreal injection of MTX, according to the protocol which we apply, is not associated with maculopathy.

Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography.

PURPOSE: Vasculogenic mimicry patterns, formed by highly invasive melanoma cells, connect to endothelial cell-lined blood vessels and contain fluid in vitroand in vivo. This study was designed to determine if fluid leaks into vasculogenic mimicry patterns without circulation, or if fluid circulates in and clears from these patterns. METHODS: Indocyanine green (ICG) laser scanning confocal angiography (Heidelberg Retinal Angiograph (HRA); Heidelberg Engineering, Heidelberg, Germany) was performed on nine patients with posterior choroidal melanoma in an institutional setting. Blood was drawn before the ICG injection and from the contralateral arm of the ICG injection site and 1 min after the injection. Outcome measures include time to first filling of retinal vessels and vasculogenic mimicry patterns and the time at which no fluorescence could be detected by the HRA instrument. After fluorescence was no longer detected in vessels or patterns, the tubes containing the patient's blood was imaged by the Heidelberg HRA. RESULTS: Looping vasculogenic mimicry patterns were detected focally in five patients within 30 s after injection and were detectable up to 12 min post-injection. Blood drawn before ICG injection did not autofluoresce but ICG-containing blood pooled in the tube continued to fluoresce at 1-month post-injection. CONCLUSIONS: Vasculogenic mimicry patterns are not part of the endothelial cell-lined vascular system and fluid enters these patterns through leakage. The rapid infusion of ICG into these patterns after injection and the disappearance of fluorescence detectable by the Heidelberg HRA suggest that fluid circulates in these patterns and does not accumulate as a stagnant pool.

Test-retest variability in visual field testing using frequency doubling technology.

PURPOSE: To quantify the magnitude of test-retest variability (TRV) for normal subjects in serial visual fields (VF) using the frequency doubling technology (FDT) instrument. METHODS: Twenty-one healthy adults, aged 23 to 60 years, underwent four serial FDT VF tests, using the full-threshold C-20 program of the Zeiss-Humphrey FDT analyzer, on one randomly chosen eye. The VF tests were spaced 2 to 4 days apart. All subjects performed two preliminary FDT tests in order to minimize any learning effect. Test-retest variability was calculated as the standard deviation of each location's sensitivity value across the four VF tests. RESULTS: Mean TRV (+/-SD) for the entire field was 2.44+/-1.32 dB. Mean TRV (+/-SD) for the superior, inferior, nasal, and temporal hemifields were 2.48+/-1.3, 2.40+/-1.4, 2.40+/-1.3, and 2.48+/-1.3 dB, respectively. Mean TRV (+/-SD) for the foveal location, the 4 central, and the 12 peripheral locations were 2.49+/-1.4, 2.16+/-1.2, and 2.54+/-1.4 dB, respectively. CONCLUSIONS: TRV was found to be rather uniform across the visual field of the commercially available FDT device, with only a mild, clinically insignificant, effect of both eccentricity and age on TRV. Variability in the FDT VF, for normal subjects, was found to be more uniform than that of both standard and short wavelength automated perimetry. In addition, a strong inverse correlation was found, in normal subjects, between the mean sensitivity and TRV.

Regeneration of articular cartilage--evaluation of osteochondral defect repair in the rabbit using multiphasic implants.

OBJECTIVE: To investigate whether two different multiphasic implants could initiate and sustain repair of osteochondral defects in rabbits. The implants address the malleable properties of cartilage while also addressing the rigid characteristics of subchondral bone. DESIGN: The bone region of both devices consisted of D, D-L, L-polylactic acid invested with hyaluronan (HY). The cartilage region of the first device was a polyelectrolytic complex (PEC) hydrogel of HY and chitosan. In the second device the cartilage region consisted of type I collagen scaffold. Eighteen rabbits were implanted bilaterally with a device, or underwent defect creation with no implant. At 24 weeks, regenerated tissues were evaluated grossly, histologically and via immunostaining for type II collagen. RESULTS: PEC devices induced a significantly better repair than untreated shams. Collagen devices resulted in a quality of repair close to that of the PEC group, although its mean repair score (19.0+/-4.2) did not differ significantly from that of the PEC group (20.4+/-3.7) or the shams (16.5+/-6.3). The percentage of hyaline-appearing cartilage in the repair was highest with collagen implants, while the degree of bonding of repair to the host, structural integrity of the neocartilage, and reconstitution of the subchondral bone was greatest with PEC devices. Cartilage in both device-treated sites stained positive for type II collagen and GAG. CONCLUSIONS: Both implants are capable of maintaining hyaline-appearing tissue at 24 weeks. The physicochemical region between the cartilage and bone compartments makes these devices well suited for delivery of different growth factors or drugs in each compartment, or different doses of the same factor. It also renders these devices excellent vehicles for chondrocyte or stem cell transplantation.

Histological measurement of retinal nerve fibre layer thickness.

PURPOSE: Accurate assessment of the retinal nerve fibre layer (RNFL) is central to the diagnosis and follow-up of glaucoma. The in vivo measurement of RNFL thickness by a variety of digital imaging technologies is becoming an important measure for early detection, as well as for follow-up, of glaucomatous damage. However, when drawing clinical inference concerning the state of the RNFL, it is important to have valid reference data on RNFL thickness in both healthy and diseased eyes. In this review, we summarize the knowledge currently available about RNFL thickness in human and primate eyes. METHODS: A review of the literature on histological analysis of RNFL thickness in the context of glaucomatous damage. CONCLUSIONS: Six studies have so far analysed RNFL thickness. Despite the diverse study methodology taken, a consistent feature of all the data is that the superior and inferior quadrants of the peripapillary retina are thicker than the nasal and temporal quadrants; that the RNFL thickness rapidly diminishes with increasing distance from the disc margin; and that apparently at different locations the ratio of axons to supportive tissue varies significantly. We conclude that limited data are available to describe the normal variation in RNFL thickness in the normal human eye. Further studies may help better characterize the RNFL thickness in health and disease and to facilitate the correlation with clinical methods for nerve fibre layer assessment.

Inter-device reproducibility of the scanning laser polarimeter with variable cornea compensation.

OBJECTIVE: To evaluate the interdevice reproducibility of retinal nerve fibre layer (RNFL) thickness measurements obtained with the commercially available GDx-VCC, a scanning laser polarimeter with variable (individualized) corneal compensation. METHODS: A prospective instrument validation study in which 13 GDx-VCC devices were tested. One eye each, from three normal subjects were used to test each of the devices, on the same day, by an experienced operator. Variability and reproducibility for each of five GDx parameters were calculated. RESULTS: For each of five tested GDx parameters, the coefficient of variation and 95% confidence interval range (microm), for the 13 devices, respectively, were: TSNIT avg: 5.1%, 3.84 microm; Superior avg: 5.3%, 4.82 microm; Inferior avg: 6.1%, 5.50 microm; TSNIT standard deviation: 8.6%, 2.92 microm; and nerve fibre indicator (NFI): N/A, 5.69. Item reliability (Cronbach's alpha) for the five GDx parameters are: TSNIT-Avg: 0.97, Sup-Avg: 1.00, Inf-Avg: 0.84, TSNIT-SD: 0.99, NFI: 0.99. CONCLUSIONS: With the commercially available GDx-VCC, our results indicate that RNFL measurements appear reproducible across devices.

The effect of alendronate (Fosamax) and implant surface on bone integration and remodeling in a canine model.

Patients at high risk for osteoporosis and its associated morbidity, including postmenopausal women, are being pharmacologically managed to stabilize and improve bone mass. Alendronate sodium (Fosamax) is a commonly used antiresorptive agent effective in osteopenic women for reducing bone resorption, increasing bone density, and decreasing fracture incidence. With the increased incidence of alendronate-treated women who are undergoing hip replacement or fracture repair by prosthesis placement, data are needed to predict how alendronate affects host bone integration with uncemented surfaces. The aim of this study was to determine the effect of alendronate on new bone formation and attachment to implant surfaces in a normal and simulated estrogen-deficient, calcium-deficient canine model, using an implantable bone growth chamber. Alendronate did not affect host bone integration to surfaces commonly used in uncemented total joint arthroplasty, but there were significant differences dependent solely on the type of surface.

Transforming growth factor beta superfamily members: role in cartilage modeling.

Normal and abnormal extracellular matrix turnover is thought to result, in part, from the balance in the expression of metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). The clinical manifestations of an imbalance in these relationships are evident in a variety of pathologic states, including osteoarthritis, deficient long-bone growth, rheumatoid arthritis, tumor invasion, and inadequate cartilage repair. Articular cartilage defects commonly heal as fibrocartilage, which is structurally inferior to the normal hyaline architecture of articular cartilage. Transforming growth factor-beta 1 (TGF-beta1), a cytokine central to growth, repair, and inflammation, has been shown to upregulate TIMP-1 expression in human and bovine articular cartilage. Additionally, members of the TGF-beta superfamily are thought to play key roles in chondrocyte growth and differentiation. Bone morphogenetic protein-2 (BMP-2), a member of this superfamily, has been shown to regulate chondrocyte differentiation states and extracellular matrix composition. It was proposed that, by optimizing extracellular matrix composition, BMP-2 would enhance articular cartilage healing. After determining the release kinetics of BMP-2 from a collagen type I implant (Long-Evans male rats; two implants/rat, n = 14), it was found that, in a tissue engineering application, BMP-2 induced a hyaline-like repair of New Zealand White rabbit knee articular cartilage defects (3-mm full-thickness defects in the femoral trochlea; 2 defects/rabbit, n = 36). The quality of cartilage repair with BMP-2 (with or without chondrocytes) was significantly better than defects treated with BMP-2, as assessed by a quantitative scoring scale. Immunohistochemical staining revealed TIMP-1 production in the cartilage defects treated with BMP-2. When studied in vitro, it was found that BMP-2 markedly increased TIMP-1 mRNA by both bovine articular and human rib chondrocytes. Additionally, increased TIMP-1 mRNA was translated into increased TIMP-1 protein production by bovine chondrocytes. Taken together, these data suggest that BMP-2 may be a useful cytokine to improve healing of cartilaginous defects. Furthermore, these data suggest that the beneficial effects of BMP-2 may be, in part, related to alterations in extracellular matrix turnover.

Suppression of microphthalmia transcriptional activity by its association with protein kinase C-interacting protein 1 in mast cells.

Microphthalmia (mi) is a transcription factor that plays a major role in the regulation of growth and function in mast cells and melanocytes. Association of mi with other proteins is a critical step in the regulation of mi-mediated transcriptional activation. We found protein kinase C-interacting protein 1 (PKCI) specifically associated with mi in yeast two-hybrid screening. Immunoprecipitation of mi from quiescent rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of PKCI. This association was significantly reduced on engagement of the surface FcepsilonRI of mast cells or engagement of the Kit receptor on melanocytes. Hence, cell activation caused disengagement of mi from PKCI. Microphthalmia was previously shown to activate the mouse mast cell protease 6 (mMCP-6) promoter. Cotransfection of mi with PKCI in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated an up to 94% inhibition of mi-mediated transcriptional activation. PKCI by itself, although localized in the cytosol and nucleus of the cells, has no known physiological function and did not demonstrate transcriptional activity. Its ability to suppres mi transcriptional activity in the transient transfected fibroblast system suggests that it can function in vivo as a negative regulator of mi-induced transcriptional activation.

Degradation and repair of articular cartilage.

Approximately 95,000 total knee replacements and 41,000 other surgical procedures to repair cartilaginous defects of the knee are performed annually in the United States (1). The response of normal articular cartilage to injury or arthritic degeneration is often a sub-optimal repair; the biochemical and mechanical properties of the new tissue differ from the native cartilage, resulting in inadequate or altered function. It is believed that the chondrocytes from the surrounding areas, although perhaps capable of some limited migration at the damaged site, are not able to proliferate and produce the macromolecules necessary to create an organized matrix characteristic of normal articular cartilage (2,3). Current therapeutic options for articular cartilage injuries and degeneration have resulted in repair tissue which may be hyaline-like, but does not approximate the durability and function of the normal articular surface. Numerous studies have been performed to increase our understanding of the normal repair process of articular cartilage and its limitations, and to devise methods and materials to regenerate the joint surface.

Repair of articular cartilage defects: part II. Treatment options.

Articular cartilage injuries result in numerous clinical symptoms, such as pain and decreased functional levels. Current therapeutic options being used include articular surface debridement, such as chondral shaving, abrasion chondroplasty, and subchondral perforation; soft-tissue arthroplasties, such as perichondrial and periosteal grafts; and osteochondral transplantation. None of these therapies, however, has resulted in the successful regeneration of a hyaline-like tissue that withstands normal joint loading and activity over prolonged periods. As a result, research is also being conducted on alternative therapeutic procedures to enhance the repair process and to stimulate the regeneration of a repair tissue with hyaline-like structural and biologic properties. Part I of this paper, which was published in January, discussed the basic science of cartilage healing. Part II presents the treatment options.

Repair of articular cartilage defects: part I. Basic Science of cartilage healing.

Articular cartilage injuries result in numerous clinical symptoms, such as pain and decreased functional levels. The limited reparative capabilities of hyaline cartilage results in the generation of repair tissue that lacks the structure and biomechanical properties of normal cartilage. Chondrocytes are unable to adequately proliferate, migrate, and synthesize high-quality repair tissue in response to blunt, superficial, or deep penetrating trauma. Extensive research has been conducted to understand the healing process and devise techniques that would enhance this response. Part I of this paper will discuss the basic science of cartilage repair. Part II, which will be published in the February issue, will present the treatment options.