Biomedical subjects

J Antoniou

Publications and source records attributed to J Antoniou.

At least 19 recordsLinked to original sources

PubMed2002

A biological approach to treating disc degeneration: not for today, but maybe for tomorrow.

The intervertebral disc unites the vertebrae in the spine, providing the flexibility required for bending and twisting and resisting the compression inflicted by gravity when in an upright posture. The discs have a complex structure, with the outer annulus fibrosus having lamellae of organized collagen fibrils and the inner nucleus pulposus having a more random collagen organization and an abundance of aggregating proteoglycans. This composite nature endows the disc with both the tension-resisting properties of a ligament and the compression-resisting properties of articular cartilage. Unfortunately, disc structure and function does not remain optimal throughout life, but undergoes progressive degeneration, commencing in the young adult, and is particularly evident in the nucleus pulposus. With time, disc degeneration may result in clinical symptoms, such as low back pain, and require medical intervention. Such treatment may involve removal of the offending disc by surgery rather than its repair, which would be the preferred course of action. In the near future, current bioengineering techniques may offer the possibility of repairing the damaged disc, if an engineered tissue with the appropriate functional properties can be generated to augment the ailing disc. In this report, we summarized our recent results, in which disc cells were implanted into a scaffold of collagen and hyaluronan, or entrapped into a chitosan gel, and growth factors were used to modulate matrix synthesis in an attempt to produce a tissue with a similar molecular composition to native nucleus pulposus tissue.

Cell Transplantation↗

PubMed2002

The role of proteoglycans in aging, degeneration and repair of the intervertebral disc.

The ability of the nucleus pulposus of the intervertebral disc to resist compressive loads is due to its high content of the proteoglycan aggrecan. Degeneration of the intervertebral disc is preceded and accompanied by a loss of aggrecan due to proteolysis. Biological repair of intervertebral disc degeneration should strive to restore aggrecan content to its optimal functional level. One approach to such repair is to supplement the degenerate nucleus with cells that are capable of aggrecan synthesis. Such cells can be supported in a biomolecular scaffold, but it is essential that the scaffold is compatible with high aggrecan retention if a functional tissue is to be attained.

Aggrecans↗

PubMed2001

Elevated synthetic activity in the convex side of scoliotic intervertebral discs and endplates compared with normal tissues.

STUDY DESIGN: We measured concentrations of specific molecules reflecting matrix synthesis and degradation in normal and scoliotic intervertebral discs and endplates. OBJECTIVES: The aim of this work was to quantitate markers of matrix turnover in normal versus adolescent idiopathic scoliotic intervertebral discs and cartilaginous endplates. SUMMARY OF BACKGROUND DATA: Changes in the intervertebral disc and endplate composition have been implicated as possible etiologic factors in the pathogenesis of adolescent idiopathic scoliosis. To better understand this process, it is important to compare the turnover of matrix components in scoliotic and normal intervertebral disc and endplate tissues. This comparison may help to improve our understanding of the role that disc and endplate tissues may play in the induction and/or progression of idiopathic scoliosis. METHODS: Fifteen scoliotic and 17 normal intervertebral discs and endplates were analyzed for their water, collagen, proteoglycan, and protein content. In addition, newly synthesized aggrecan and collagen Types I and II were measured. Percent total denatured collagen was also determined. RESULTS: The total collagen content was significantly lower in the scoliotic anulus and endplate regions, whereas glycosaminoglycan (GAG) content was significantly lower in the scoliotic endplates and nucleus regions. Conversely, total protein content was significantly higher in scoliotic endplates and elevated in scoliotic nucleus regions. Water content was significantly lower in the scoliotic anulus and endplate regions. When comparing the concave and convex regions of scoliotic endplates, there was no significant difference in concentration of any matrix component. The major difference in the synthetic marker levels relates to the synthesis of Type II collagen, which was higher in the nucleus, anulus, and endplate regions of scoliotic discs than in the corresponding regions of normal tissues. By contrast, the percent total denatured collagen was significantly elevated in the nucleus of normal tissues compared with the scoliotic ones. CONCLUSIONS: The higher collagen Type II synthetic levels and increased total protein content with no matrix turnover suggest that scoliotic changes are due to an altered and ineffective synthetic response to a pathologic mechanical environment.

Adolescent↗

PubMed2001

Posterior instability.

Posterior shoulder instability is a pathology that is increasingly seen in athletes. Excessive capsular laxity was originally proposed as the key component. Recent cadaveric and arthroscopic work has identified the importance of glenolabral integrity and glenoid depth in maintaining glenohumeral stability. Arthroscopic techniques to treat posterior instability are emerging. Until recently, reports of arthroscopic reconstruction focused entirely on capsular glenohumeral stability by altering two separate mechanisms: deepening of the glenoid concavity and reducing the capsular joint volume. This is accomplished by shifting the capsule to buttress the glenoid labrum. Thus increasing capsular tension increases the resultant compressive force vector into a deepened glenolabral concavity that, when combined together, enhances glenohumeral stability. In clinical and laboratory settings, we have shown that posteroinferior shoulder instability is associated with both capsular laxity and well-defined pathological lesions of the glenolabral concavity. Our results indicate that arthroscopic posterior capsulolabral repair and augmentation is a useful tool to restore the depth of the glenolabral concavity and to reduce the redundant posteroinferior capsule. This technique is effective in treating posteroinferior instability.

Adult↗

PubMed2001

Concussions among university football and soccer players: a pilot study.

OBJECTIVE: A pilot study to examine the incidence and characteristics of concussions for one season of university football and soccer. DESIGN: Retrospective survey. PARTICIPANTS: 60 football and 70 soccer players reporting to 1998 fall training camp. Of these, 44 football and 52 soccer players returned a completed questionnaire. MAIN OUTCOME MEASURES: Based on self-reported symptoms, calculations were made to determine the number of concussions experienced during the previous season, the duration of symptoms, the time for return to play and any associated risk factors for concussions. RESULTS: Of all the athletes who returned completed questionnaires, 34.1% of the football players and 46.2% of the soccer players had experienced symptoms of a concussion during the previous season. Only 16.7% of the concussed football players and 29.2% of the concussed soccer players realized they had suffered a concussion. All of the concussed football players and 75.0% of the concussed soccer players experienced more than one concussion during the season. The symptoms from the concussion lasted for at least 1 day in 28.6% of the football players and 18.1% of the soccer players. Variables that increased the odds of suffering a concussion during the previous season for football and soccer players included a past history of a recognized concussion. CONCLUSION: More university soccer players than football players may be experiencing sport related concussions. Variables that seem to increase the odds of suffering a concussion during the previous season for football and soccer players include a history of a recognized concussion. Despite being relatively common, many players may not recognize the symptoms of a concussion.

Adult↗

PubMed2001

Suprascapular neuropathy. Variability in the diagnosis, treatment, and outcome.

The functional outcome of operative and nonoperative treatment of suprascapular neuropathy was compared to determine the preferred method of treatment for each etiology of nerve injury. The predictive value of preoperative electromyography also was studied. Fifty-three patients were evaluated at least 1 year (average, 28 months) from the time of operative (n = 36) or nonoperative (n = 17) treatment. A modified American Shoulder and Elbow Surgeons self-assessment score was obtained at presentation and at final followup. Electromyography data were obtained at initial presentation. Minimal electromyographic changes associated with denervation were associated with a limited response to treatment, especially in patients with nerve compression secondary to spinoglenoid notch cysts. Pretreatment electromyographic findings, therefore, were predictive of treatment response. Overall, operative and nonoperative treatment of these suprascapular nerve injuries resulted in significant functional improvement, but the results varied depending on the etiology of the injury. Spinoglenoid notch cysts responded significantly better to operative treatment, with the results for open surgery being the same as the results for arthroscopic decompression. In addition, compressive lesions attributable to suprascapular notch entrapment had the best improvement with surgical decompression. Traumatic lesions, including traction and direct closed injuries, had an equal response to operative and nonoperative treatment. Overuse injuries did not improve with operative treatment. Viral neuritis improved with nonoperative treatment and never was treated with surgery. Overall, traumatic injuries resulted in significantly worse final outcomes than any other etiologic processes. In the nonoperative group, neuropathy secondary to spinoglenoid cysts resulted in significantly worse function. The outcome of treatment is dependent on the severity and etiology of the nerve injury, and the method of treatment.

Adolescent↗

PubMed2000

Collagen crosslinked N-telopeptides as markers for evaluating particulate osteolysis: a preliminary study.

The purpose of this study was to determine whether a marker of bone resorption could be used noninvasively to diagnose and assess treatment of periprosthetic osteolysis. The crosslinked N-telopeptide marker of osteoclast-mediated bone resorption potentially has the sensitivity to detect periprosthetic osteolysis. Second-morning urine specimens were obtained from (a) seven age-matched controls, (b) eight patients who had a hip arthroplasty, hybrid implants at least 1 year after surgery, and no osteolysis, (c) 11 patients who had a hip arthroplasty and osteolysis, and (d) 10 patients who had a hip arthroplasty and with osteolysis before and after 6 weeks of oral Fosamax (alendronate) treatment. The Fosamax treatment consisted of one 10-mg dose per day for 6 weeks. Men and young women (less than 40 years old) were chosen for this study to avoid bone resorption enhanced after menopause as a possible confounder. An enzyme-linked immunosorbent assay technique for quantifying crosslinked N-telopeptides of type-I collagen was performed on all specimens. The patients with osteolysis had significantly elevated levels of N-telopeptide compared with the implant control group. In addition, levels of N-telopeptide were significantly lowered after Fosamax treatment. These findings indicate that a systemic bone-resorption marker (N-telopeptide) can be used to evaluate local particulate-induced osteolysis and its treatment. The study also provides clinical evidence that osteolysis is associated with increased osteoclast-mediated bone resorption and that this locally induced bone resorption can be suppressed by certain bisphosphonates (Fosamax). These insights have potential value in the understanding and clinical management of aseptic loosening.

Adult↗

PubMed2000

Arthroscopic posterior capsular repair.

Posterior shoulder instability is associated with capsular laxity and well-defined pathologic lesions of the gleno-labral concavity. Most arthroscopic techniques have concentrated on capsular shift or plication of capsular laxity. This article demonstrates that arthroscopic capsulolabral plication simultaneously can augment the glenolabral concavity to restore the glenoid depth, and can reduce excessive capsular laxity of the redundant posteroinferior capsule. This method has proven effective in treating posterior instability.

Arthroscopy↗

PubMed2000

Capsulolabral augmentation for the the management of posteroinferior instability of the shoulder.

BACKGROUND: Posteroinferior instability of the shoulder has been associated with capsular laxity. The purposes of the present study were to describe the pathological morphology of the posteroinferior aspect of the glenolabral fossa in patients with primary posteroinferior instability and to prospectively examine the efficacy of managing this instability with use of an arthroscopic posteroinferior capsulolabral augmentation procedure. METHODS: Forty-one patients who had posteroinferior instability of the shoulder were managed with an arthroscopic shift of the posteroinferior aspect of the capsule to the adjacent labrum and were followed for a minimum of twelve months. Thirty-two patients had a primary procedure, and nine had a revision procedure. The mean duration of follow-up was twenty-eight months (range, twelve to sixty-nine months). All of the patients had presented with a symptomatic, positive finding on the jerk test and had participated in a minimum of six months of rehabilitation that had failed to relieve the symptoms. The patients were evaluated prospectively with a motion and stability examination and the Simple Shoulder Test. In addition, they completed the Short Form-36 Health Survey (SF-36) and a questionnaire on the outcome of treatment. RESULTS: Lesions affecting the posteroinferior aspect of the glenolabral concavity were seen in thirty-four patients (83 percent): five had labral detachment, seven had chondral or labral erosion, nine had capsular and synovial stripping, and thirteen had a labral split or tear. The mean score (and standard deviation) on the Simple Shoulder Test improved from 5.5 +/- 3.4 points to 8.1 +/- 3.3 points (p = 0.0023), and two of the eight SF-36 parameters improved significantly (p < 0.05). Conversely, nineteen patients who were receiving Workers' Compensation did not show any improvement in either of the two parameters. Thirty-five patients had improved stability of the shoulder, and the findings on all physical examinations had improved significantly (p < 0.0001). Twenty-eight patients had a perception of residual stiffness; this finding was in contrast to the mean score on the flexibility examination, which had not changed significantly at the time of the latest follow-up. CONCLUSIONS: Posteroinferior instability of the shoulder is associated not only with capsular laxity but also with well defined lesions of the glenolabral concavity. Arthroscopic capsulolabral augmentation to reduce posterior capsular laxity and to restore the depth of the glenolabral concavity has been shown to be effective treatment of this condition after a mean duration of follow-up of twenty-eight months.

Adult↗

PubMed2000

Osteoporosis of the spine: correlation between vertebral deformity and bone mineral density in postmenopausal women.

The purpose of this study is to evaluate the relation of bone mineral density (BMD) or the age-matched z score and osteoporotic vertebral fractures. The radiographs and spinal bone mineral density of 131 consecutive postmenopausal patients were retrospectively reviewed. The vertebral fractures between T4 and L4 were graded. Sixty-two patients had no fractures, and 69 had 1 or more fractures. In the nonfracture group, the mean age was 62.6 years, BMD was 0.88 g/cm2, and the z score was -1.00. In the fracture group, the mean age was 69.6 years, BMD was 0.788 g/cm2, and the z score was -1.26. Patients with 2 and 3 or more fractures had a lower mean BMD than that of the nonfracture group (P < .01). The z score (adjusted for age) was significantly lower only in patients with 3+ fractures (P < .05). Patients with grade 2 and grade 3 of any fracture type had significantly lower BMD (P < .01). The z score was lower only in those with grade 3 fracture (P < .05). Our study indicates that the clinical use of BMD z score adjusted for age is a better predictor of severity of vertebral fractures than is BMD alone.

Adult↗

PubMed1999

Minimum 10-year-results of extensively porous-coated stems in revision hip arthroplasty.

Obtaining predictable, stable fixation of revision femoral implants is important for the long-term success of revision hip arthroplasty. The authors report on minimum 10 years clinical and radiographic followup of 170 patients with extensively coated cementless revision femoral components. With a range of followup of 10 to 16 years and a mean of 13.2 years, a survivorship of greater than 95% was reported. Clinically, the average Postel-D'Aubigne pain and walking score improved from a preoperative score of 5.4 points to 10.8 points postoperatively. Eighty-two percent of the hips had radiographic evidence of a bone-ingrown prosthesis and 13.9% had evidence of stable fibrous fixation. Four percent of stems were unstable as seen on radiographs. Six stems were revised to larger extensively coated stems and one stem is causing pain and is unstable but has yet to be revised. The overall mechanical failure rate was 4.1%. Stress shielding was greatest in patients with stems larger than 16.5 mm and in osteoporotic bone (Dorr Type C). Nine percent of patients had significant thigh pain including all of the patients with unstable stems. In the presence of bone loss in the proximal metaphyseal region of the femur, fixation of the femoral component is predictable when optimizing prosthetic-bone fit in the diaphyseal region of the femur using an extensively coated femoral component.

Acetabulum↗

PubMed1998

Quantitative magnetic resonance imaging in the assessment of degenerative disc disease.

Understanding degenerative intervertebral disc diseases hinges on the ability to objectively and noninvasively assess the disc matrix composition and integrity. The potential of quantitative magnetic resonance imaging to meet these demands was evaluated. Analyzing the T1 and T2 signal patterns in the nucleus pulposus with increasing Thompson morphological grade revealed a significant reduction related to grade. This significant decrease in T1 and T2 in the nucleus pulposus with grade 4 degeneration and the corresponding low correlation coefficients with respect to the content of individual matrix molecules suggest that matrix integrity plays an important and distinct role in determining T1 and T2 signal. Similarly, the significant increase in magnetization transfer in the nucleus pulposus observed in grade 4 degeneration did not correlate with the changes in molecular content in these highly degenerated discs. Again, this lack of correlation clearly indicates that the tissue integrity and matrix composition independently contribute to the magnetization transfer signal. This study presents the first clear evidence that quantitative magnetic resonance analysis reflects not only the disc matrix composition, but also the structural integrity of the matrix of the disc.

Adult↗

PubMed1998

Exercise capacity in patients with beta-thalassemia major: relation to left ventricular and atrial size and function.

OBJECTIVES: The objective of this study was to examine the association between exercise capacity and echocardiographic indexes of atrial and ventricular function and size in patients with beta-thalassemia major. BACKGROUND: In patients with beta-thalassemia major, the assessment of cardiac function with echocardiography alone does not always correspond to their functional status. Peak oxygen uptake and anaerobic threshold, on the other hand, constitute 2 objective and reproducible determinants of exercise capacity in patients with heart failure. METHODS AND RESULTS: Forty consecutive patients (22 women and 18 men, 18 to 30 years old) who were in stable condition while receiving regular transfusions and 30 age- and sex-matched control subjects were studied. At 2 to 3 days after the last transfusion, each subject underwent complete echocardiographic study followed by cardiopulmonary exercise testing. Left atrial volumes (maximal [Vmax], at onset of atrial systolic [Vp], and minimal [Vmin]) and left ventricular volumes were measured with the biplane area-length method, and left atrial active emptying fraction (ACTEF) and left ventricular ejection (LVEF) fraction were calculated. Peak oxygen uptake (Vo 2 max) and anaerobic threshold (AT) were also estimated. After transfusion, patients with beta-thalassemia major had reduced Vo 2 max and AT and greater left atrial volume in comparison with control subjects. Also, ACTEF and LVEF were significantly lower in the patient group. Moreover, Vo2 max and AT were inversely related to Vmax (r = -0.74 and r = -0.80, respectively) and directly related to ACTEF (r = 0.85 and r = 0.82, respectively) in beta-thalassemia major, whereas they were poorly related to LVEF (r = 0.50 and r = 0. 53, respectively). In the control group, Vo 2 max and AT parameters were related to Vmax and ACTEF in a similar way to that in the beta-thalassemia group. CONCLUSIONS: In patients with beta-thalassemia major, exercise capacity does not correlate with left ventricular dimensions and function. On the contrary, left atrial size and systolic dysfunction are probably predictors of decreased exercise capacity.

Adolescent↗

PubMed1997

A new technique for measuring lumbar segmental motion in vivo. Method, accuracy, and preliminary results.

STUDY DESIGN: A direct method for three-dimensional in vivo spine kinematic studies was developed and used to measure segmental motion patterns in healthy subjects. OBJECTIVES: To validate the new method, and to study the L3-L4 segmental motion patterns for complex dynamic movements. SUMMARY OF BACKGROUND DATA: Conventional two-dimensional and three-dimensional radiographic methods have been used in the past to study spine kinematics. Few studies provided a direct approach to study segmental kinematics. No dynamic recordings of three-dimensional segmental motion patterns have been reported previously. METHODS: In 16 healthy men, Kirschner wires were inserted in the spinous processes of L3 and L4. Electromagnetic tracking sensors were attached to the pins. Motion data recorded during ranging exercises were used with biplanar radiographs to calculate L3-L4 segmental motion patterns. Errors resulting from pin deformation and the dynamic accuracy of the tracking system were investigated thoroughly. RESULTS: The average range of motion for flexion-extension was 16.9 degrees, for one side lateral bending 6.3 degrees and for one side axial rotation 1.1 degrees. Large intersubject variation was found in flexion-extension with values ranging from 7.1 to 29.9 degrees. Coupled motion patterns were found to be consistent among subjects in active lateral bending and inconsistent for active axial rotation. CONCLUSIONS: This new method offers dynamic recording capabilities and a measurement error comparable with stereo radiographic methods. Repetitive ranging experiments are highly reproducible. The range of motion for axial rotation seems overestimated in previous cadaveric studies. Coupling patterns show large variations between individuals.

Electromagnetic Phenomena↗

PubMed1997

Sooty foot, a novel mouse mutation that affects the pigmentation of exposed skin, but not hair, maps to chromosome 2.

We have characterized a novel recessive mouse mutation, named sooty foot, that increases the pigmentation of the exposed skin on the foot pads, the genital region, around the snout and muzzle, the ears, and the tail. By contrast, the pigmentation of the hair is unaffected. We have localized the mutation to Chromosome 2 by polymerase chain reaction (PCR) amplification of simple sequence repeats from pooled DNA from backcross progeny. In an extended backcross we have generated a detailed map of the region around sooty foot.

Agouti Signaling Protein↗

PubMed1997

HLA-G functions as a restriction element and a transplantation antigen in mice.

HLA-G, a human MHC class I molecule expressed on the trophoblast during pregnancy, was expressed in transgenic mice by recombining the HLA-G gene with a transcriptional promoter from a murine H-2 MHC class I gene. Skin grafts from HLA-G transgenic mice were rejected by non-transgenic mice showing that HLA-G behaves as a xenotransplantation antigen in mice. Further investigation revealed that murine T cells recognize native HLA-G directly as a xenoantigen or they recognize processed peptides derived from HLA-G presented in the context of murine MHC molecules. HLA-G molecules also function as restriction elements capable of presenting peptides to murine T cells since immunization of HLA-G transgenic mice with peptide that binds specifically to HLA-G molecules elicited HLA-G-restricted, cytotoxic T cell responses. In addition, murine T cell responses to human xenoantigens are enhanced when responder cells originated from HLA-G transgenic mice. Based on these observations, we conclude that expression of HLA-G molecules influences selection of the murine T cell repertoire and that HLA-G exhibits immunological properties that are indistinguishable from classical HLA class I molecules when expressed in transgenic mice. Thus, any unique immunological functions mediated by HLA-G must arise from the distinctive, trophoblast-specific pattern of HLA-G expression in humans and not from structural peculiarities of HLA-G molecules.

Animals↗

PubMed1996

The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.

Very little is known about the turnover of extracellular matrix in the human intervertebral disc. We measured concentrations of specific molecules reflecting matrix synthesis and degradation in predetermined regions of 121 human lumbar intervertebral discs and correlated them with ageing and Thompson grade of degeneration. Synthesis in intervertebral discs, measured by immunoassay of the content of a putative aggrecan biosynthesis marker (846) and the content of types I and II procollagen markers, is highest in the neonatal and 2-5-yr age groups. The contents of these epitopes/molecules progressively diminished with increasing age. However, in the oldest age group (60-80 yr) and in highly degenerated discs, the type I procollagen epitope level increased significantly. The percentage of denatured type II collagen, assessed by the presence of an epitope that is exposed with cleavage of type II collagen, increased twofold from the neonatal discs to the young 2-5-yr age group. Thereafter, the percentage progressively decreased with increasing age; however, it increased significantly in the oldest group and in highly degenerate discs. We identified three matrix turnover phases. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of type II collagen. Phase II (maturation and ageing) is distinguished by a progressive drop in synthetic activity and a progressive reduction in denaturation of type 11 collagen. Phase III (degeneration and fibrotic) is illustrated by evidence for a lack of increased synthesis of aggrecan and type II procollagen, but also by an increase in collagen type II denaturation and type I procollagen synthesis, both dependent on age and grade of tissue degeneration.

Adult↗

PubMed1996

The human lumbar endplate. Evidence of changes in biosynthesis and denaturation of the extracellular matrix with growth, maturation, aging, and degeneration.

STUDY DESIGN: The authors measured concentrations of specific molecules reflecting matrix synthesis and degradation in 121 human endplates and correlated them with aging and grade of degeneration. OBJECTIVES: Abnormal endplate development has been implicated in many spinal abnormalities, yet little is known about endplate matrix component turnover. SUMMARY OF BACKGROUND DATA: Techniques are available to perform an in situ investigation of matrix component turnover with aging and degeneration. METHODS: Newly synthesized aggrecan and Type I and Type II procollagens were measured with recently developed immunoassays. Percentage of denatured Type II collagen was assessed with a new enzyme-linked immunosorbent inhibition assay. RESULTS: Synthesis in endplates, measured by content of an aggrecan marker (846) and content of Types I and II procollagen markers (CPI and CPII), is highest in the neonatal and 2- to 5-year age groups and steadily diminishes with increasing age. However, in the oldest age group and in highly degenerated discs, the CPI epitope level increased significantly. Percentage of denatured Type II collagen, assessed by the presence of an epitope exposed with the cleavage of Type II collagen, increased from the neonatal to the 2- to 5-year age groups. The percentage progressively decreased with increasing age. However, it significantly increased in endplates from highly degenerated discs. CONCLUSIONS: The authors identified three matrix turnover phases, related to age and grade of degeneration. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of Type II collagen. Phase II (aging and maturation) is distinguished by a drop in synthetic activity and a reduction in denaturation of Type II collagen. Phase III (degenerative) is illustrated by an increase in Type II collagen denaturation and Type I procollagen synthesis, both related to grade of tissue degeneration.

Adolescent↗