Olle Svensson

Fibromodulin distribution and association with collagen.

Fibromodulin, an acidic 59-kDa proteoglycan, binds to collagen and inhibits collagen fibril formation in vitro. To determine whether fibromodulin is also bound to collagen in vivo, we used immunocytochemical methods to study the spatial relation of the proteoglycan to collagen fibrils in cartilage and tendon. We also studied the quantitative distribution of fibromodulin among compartments in articular cartilage at the ultrastructural level. Fibromodulin was identified with polyclonal antibodies raised in rabbits, and immunoreactivity was detected with protein-A gold. As the major proportion of fibromodulin immunoreactivity was localized along the periphery of the collagen fibrils, the relationship to the banding pattern of the collagen fibrils was mapped. The proteoglycan showed a non-random distribution, with preference to the gap region, axially within the D-period. Reactivity differed among the tissue compartments, with the lowest degree of labelling pericellularly, increasing with distance from the cell, the highest levels being observed in the interterritorial matrix. Labelling density was highest at the articular surface, gradually decreasing towards the cartilage-bone junction. The correlation between collagen fibril diameter and fibromodulin concentration also varied among compartments. Thus, the ratio of fibromodulin to collagen surface density was highest at the surface of the joint cartilage, exhibiting a gradient with higher values in the territorial matrix, decreasing towards the cell in all layers. These findings indicate that fibromodulin represents a factor used by chondrocytes to regulate assembly and function of collagen fibrils.

Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma

Breast and prostate cancer often metastasise to the skeleton. Interestingly, the histopathological characteristics of the bone lesions that arise from these two cancer types differ. Breast tumours give rise to metastases in the skeleton with a mixed lytic/sclerotic pattern, whereas a predominantly sclerotic pattern is seen in metastases from prostate tumours. Osteopontin (OPN) and bone sialoprotein (BSP) are bone matrix proteins that have been implicated in the selective affinity of cancer cells for bone. In the present study, 21 patient cases with skeletal metastasis and their respective primary tumours (12 with breast cancer, 9 with prostate cancer) were investigated by immunohistochemistry in order to assess the level of OPN and BSP. Moderate to strong OPN expression was found in 42% of all breast tumours and in 56% of all prostate tumours. Significantly more breast cancer bone metastases exhibited high OPN expression, 83%, as compared with prostate tumour bone metastases, 11% (P=0.0019). In contrast, moderate to strong BSP expression was found in 33% of breast tumours and in 89% of prostate tumours. In the bone lesions, only 33% of breast tumour metastases showed moderate/strong BSP expression compared to 100% of prostate tumour metastases (P=0.0046). This divergent pattern of OPN/BSP expression could be an important determinant for the different characteristics of these two types of bone metastasis, i.e., lytic vs. sclerotic, consistent with the proposed role of OPN in differentiation and activation of osteoclasts and of BSP as a stimulator of bone mineralisation.

Effect of an Inhibitor of Matrix Metalloproteinases on Spontaneous Osteoarthritis in Guinea Pigs

Recently discovered chemically modified tetracyclines have been found to be effective inhibitors of matrix metalloproteinase (MMP)-mediated connective tissue destruction in a variety of pathologic processes, including rheumatoid arthritis and osteoarthritis (OA). Since the histologic techniques used in our laboratory have been validated in Hartley guinea pigs, which have a high incidence of OA-like changes in the proximal tibia, we have used two tetracyclines which have potent inhibitory capacity against variuos MMPs, doxycycline (Dox) and a compound known as chemically modified tetracyclines (CMT-7). These were given by mouth to a group of guinea pigs for 4 to 8 months, and we assessed the effect of the compound on morphologic and biochemical aspects of OA. We found that prophylactic CMT-7 given orally decreases OA changes in the knee joints both in vitro and in vivo in the guinea pig OA model. Cartilage fibrillation and destruction, in addition to subchondral bone sclerosis and cyst formation, were all decreased in the central compartment of the medial condyle, which is most affected by OA compared with controls. Also collagen, hyaluronan and proteoglycancontent in cartilage was higher in the CMT-7 treated group compared with controls. In contrast, OA changes were not decreased in the Dox group. Our results confirm that various tetracyclines have reduced the severity of OA in animal models, indicating the therapeutic potential of this class of compounds in the future.

Cervical instability in skeletal dysplasia Report of 6 surgically fused cases

Six patients with skeletal dysplasias complicated by deformity or instability of the cervical spine were reviewed. Three patients had congenital spondyloepiphyseal dysplasia and 1 each suffered from Morquios syndrome, pseudoachondroplasia, and chondrodystrophia calcificans congenita. Four patients had myelopathy of varying severity from slight weakness of one leg to tetraplegia. At a mean age of 6 (3-11) years, they underwent posterior fusion and immobilization in a halo brace. In all the cases the extent of postoperative neurologic recovery was, however, limited. Our cases illustrate the need of early diagnosis and fusion of cervical instability.

Clinical history in lumbar disc herniation: A prospective study in 160 patients

In a prospective study of 160 consecutive patients who underwent primary surgery for lumbar disc herniation, we investigated the value of clinical history for diagnosing the degree of herniation-the main prognostic factor for the postoperative outcome. At surgery, the patients were classified into two groups: intact anulus (negative exploration or protruding disc) and ruptured anulus (subligamentary perforation or complete perforation). The strongest variables predicting the degree of herniation were duration of leg pain, progressive leg pain, educational level and whether or not the patient had previously undergone non-spinal surgery. In patients with ruptured anulus, the median durations of low back pain and sciatica were 16 and 10 weeks, respectively. The corresponding figures for the group with intact anulus were 79 and 50 weeks. 18% of those with ruptured anulus and 39% of those with intact anulus were undergoing medical or psychiatric treatment for other diagnoses; 32% and 55% had previously undergone non-spinal surgery. Thus the two groups differed not only in disc pathology but also in medical, behavioral and social factors that must be taken into account in the preoperative assessment and that may explain discrepancies between impairment and disability.

Stereologic studies on collagen in bovine articular cartilage.

In an ultrastructural stereologic study on bovine articular cartilage we found that collagen volume density increased with increasing distance from the joint surface and from the chondrocyte. These results not only corroborate previous biomechanical data of a vertical stiffness gradient, but they also suggest that the mechanical forces are unevenly distributed horizontally. On the other hand, although mean collagen fibril diameter showed large differences between the interterritorial compartments of the three zones, there was a population of slender fibrils in all zones and compartments. Since the coarser fibrils provide the high tensile strength (Nimni 1988), the role of the slender fibrils may be to enhance the deformability of the tissue. Moreover, in spite of substantial differences in mean fibril diameter, collagen surface densities were in the same order of magnitude in the territorial and interterritorial compartments, and only slightly lower in the pericellular compartments. The surface parameter may be important for specific molecular interactions. The collagen fibrils have different polarity, i.e. the direction of the fibrils appears to be parallel and antiparallel, about 50% running in each direction. This, together with the very high length/diameter ratio (Clark 1985), may indicate that each fibril is assembled by the concerted action of many cells. The characteristic properties of articular cartilage depend on interactions between its macromolecular components, and the present quantitative data form a basis for discussions on the specificity and regulation of such interactions.

Parathyroid cell number and size in hypocalcemic young rats

Weanling rats were fed diets with normal (1%) or low (0.08% or 0.02%, respectively) Ca content for 28 days prior to sacrifice. The total volume of the parathyroids was estimated from serial sections. Volume density of secretory cells was calculated according to conventional stereological techniques, whereas cell number and cell size were estimated by the disector method. Compared with controls the animals of the experimental groups developed moderate and severe hypocalcemia and their parathyroids were enlarged with a proportional growth of parenchyma and interstitium. Related to the body weight, secretory cell volume was highest in animals with severe hypocalcemia. In the enlarged glands the size of parathyroid secretory cells was increased by 30–40%, whereas total cell number was unaltered. Thus, the increased parathyroid size was due to cell hypertrophy rather than hyperplasia.

Material and design in haematogenous implant-associated infections in a rabbit model

We used 111 rabbits to study the susceptibility to intravenously injected bacteria of conventional stainless steel plates, and titanium plates of either traditional design or of the PC-FIX concept, that is less traumatic to bone. After plating, the animals were given between 1 x 10(8) and 2 x 10(9) colony forming units of Staphylococcus aureus Wood 46 intravenously. Significant differences in infection rates (positive cultures) were found between conventional stainless steel plates (36-67% infected, depending on inoculum size) and titanium PC-FIX plates (6-7% infected). In fact, the infection rate at the PC-FIX plate did not differ from sham operated animals. Since conventionally designed titanium plates had an intermediate infection rate, it appears that design and material both are important for the risk of infection.

Postoperative mental impairment in hip fracture patients. A randomized study of reorientation measures in 223 patients

Mental impairment is a common and serious complication in geriatric surgery. We studied 223 hip fracture patients. They were over 64 years of age (mean 81), with no history of mental deterioration and acutely admitted to hospital from independent living conditions. They were randomized into two groups. One of these was subjected to reorientation measures during the perioperative phase, i.e., presurgery admission to the orthopedic ward, accompanied home visits during the hospital stay and access to reorientation devices--they received a large clock, calendar, radio, TV-set, telephone and were encouraged to wear their own clothing. Otherwise, there were no differences in the treatment given to the two groups. We used monitoring of cognitive function with the Short Portable Mental Status Questionnaire (SPMSQ) and a feedback program for evaluation of the treatment results. There was a low incidence of postoperative cognitive deterioration in both groups, compared with historical controls. However, no difference in mental status was noted when we compared the two groups. The conclusion is that attributes were less important than the psychological environment for postoperative mental deterioration. The mean total continuous hospitalization (transfers between departments and hospitals included) in the reorientation group was 22 (95% CI: 17-43) days, the corresponding figures for the controls were 30 (14-29) days.

Pain patterns in lumbar disc hernia: Drawings compared to surgical findings in 159 patients

We compared preoperative pain-drawing patterns of 159 patients with findings at lumbar disc surgery. Disc pathology was classified into 2 groups: intact anulus (negative exploration and protruding disc) and ruptured anulus (subligamentary perforation and sequestrated hernia). Patients with intact anulus drew fewer modalities, but more often marked pain in the trunk, neck and upper extremities, than those with ruptured anulus. Certain pain-drawing patterns--e.g., extra text, arrows and nonanatomical pain distribution--have previously been shown to correlate to unfavorable pathological traits in psychometric tests in populations of patients with chronic low back pain. In our study, most of these so-called nonorganic pain-pattern items occurred equally often in the 2 groups. In fact, one third of the patients with ruptured anulus produced pathological drawings according to the scoring system designed by Ransford et al. (1976). Although pain drawings help the investigator to obtain a rapid overview of the patients pain pattern, the use of penalty points as a preoperative psychological screening instrument in patients with pain that is not chronic may be questioned.