Biomedical subjects

S C Marks

Publications and source records attributed to S C Marks.

At least 145 records · Page 8Linked to original sources

PubMed1992

Vertebral body fractures in child abuse. Radiologic-histopathologic correlates.

RATIONALE AND OBJECTIVES: Vertebral injuries are rarely reported sequelae of child abuse, and little is known concerning the mechanisms of injury and healing. A preliminary investigation of these issues included correlating radiologic and histologic findings in children with vertebral injuries who died of complications relating to physical abuse. METHODS: Ten vertebral body fractures from four abused infants and young children were studied radiologically and histopathologically. RESULTS: Infants ranged in age from 7 to 36 months (mean, 21 months). Three patients died of associated head injuries. One child died after abandonment. There were three pure vertebral body compression fractures, two superior end-plate fractures without compression deformity, and five anterosuperior end-plate fractures with associated compression deformity. Vertebral compression was generally mild (less than 25%). Typically, end-plate injuries were manifest histologically by extension of the fracture through the medullary trabeculae into the proliferative zone of the superior end plate. The resultant pattern was analogous to that described in a previous study, and could potentially result in a growth disturbance at the vertebral end plate. CONCLUSIONS: Observed radiologic patterns and histologic correlates may help explain previously described findings, such as vertebral notching, in abused infants.

Child Abuse↗

PubMed1992

Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats.

One of the osteopetrotic mutations in the rat, incisors-absent (ia), exhibits generalized skeletal sclerosis and failure or delay of tooth eruption, characteristics of other osteopetrotic mutations. Osteopetrosis in ia rats is known to be due to a reduction in bone resorption, the result of the inability of ia osteoclasts to elaborate a ruffled border. During healing of extraction wounds, especially the initial period, osteoclastic resorption of alveolar bone is considered to be a significant feature, followed by new bone formation. We have studied extraction wound healing in osteopetrotic (ia) rats histologically in order to determine if their systemic reduction in bone resorption changes the sequence or rate of alveolar bone healing within and outside the socket after tooth extraction, In ia rats, the healing process was delayed in comparison to that of normal rats. Many osteoclasts were observed on the surface of alveolar bone, but there was little evidence of resorption. Bone formation in the socket following bone resorption was reduced and the newly formed trabeculae were irregular. In contrast, the quantity of resorption-independent (periosteal) new bone formation outside the socket was exaggerated compared to normal animals. These data indicate that the disturbance of new bone formation in the socket is probably related to the reduction in osteoclastic bone resorption.

Alveolar Bone Loss↗

PubMed1992

Fractures of the rib head in abused infants.

Fractures of the posterior ribs are well-recognized sequelae of infant abuse. Previous reports have indicated a predilection for fracture near the costotransverse process. This study expands the spectrum to include fractures involving the rib head. The radiologic and histologic features are described, and the mechanism of injury of this lesion is examined. In situ and specimen radiography, followed by histopathologic examination, was performed in 78 ribs removed from seven abused infants who died with posterior rib fractures. Computed tomography of the intact posterior thorax was performed in two of these infants. Fifty posterior rib fractures were identified; 29 involved the rib head. Frontal radiography was insensitive in identifying these fractures, clearly revealing injury only when periosteal reaction was present (four of 29 cases). Axial specimen radiography delineated the fractures in all cases. In the two infants studied, CT depicted five of 19 fractures visible only with axial specimen radiography. The morphologic features of these fractures further support the concept that most fractures in abused infants occur by means of indirect forces and are consistent with anteroposterior manual thoracic compression during assaults.

Child Abuse↗

PubMed1992

Current concepts of the biology of tooth eruption.

Tooth eruption is defined as the movement of a tooth from its site of development within the jaws to its position of function within the oral cavity. We present a critical review of evidence for the mechanisms and regulation of the intraosseous and supraosseous phases of eruption, with an emphasis upon the canine premolar model studied by the authors. Analyses at different stages of premolar eruption indicate that selective fragmentation of dental follicle protein DF-95 correlates with the presence of elevated levels of follicular collagenase and stromelysin, and with the onset of premolar movement. A dramatic decrease in these metalloproteinases followed initiation of movement. A biochemical and cell biological model for regulation of tooth eruption is proposed based upon these new and existing data.

Animals↗

PubMed1991

Gene expression during skeletal development in three osteopetrotic rat mutations. Evidence for osteoblast abnormalities.

Osteopetrosis is a group of metabolic bone diseases characterized by reductions in osteoclast development and/or function. These aspects of osteoclast biology are known to be influenced by osteoblasts and their products. To ascertain whether osteoblast dysfunction contributes to aberrations in the structural and functional properties of osteoclasts in osteopetrosis, we systematically examined gene expression as reflected by mRNA levels for a series of cell growth- and tissue-related genes associated with the osteoblast phenotype during skeletal development in normal and mutant rats of three different osteopetrotic stocks. We show that the methods used permit the reproducible isolation of undegraded total cellular RNA from bone and that mRNA levels can be reliably quantitated in these preparations. Each osteopetrotic mutation exhibits a distinct aberrant pattern of osteoblast gene expression that may be correlated with and explain some abnormalities in extracellular matrix composition, mineralization, osteoclast development, and effects of elevated serum levels of 1 alpha,25-dihydroxyvitamin D3, depending upon the mutation. Normal rats show minor variations in gene expression that reflect the genetic background (stock). This, the first comprehensive molecular analysis of osteoblast gene expression in osteopetrosis, suggests that some osteopetroses, particularly in the toothless rat, are associated with and potentially related to mechanisms associated with aberrations in osteoblast function. More generally, the present studies demonstrate alterations in gene expression as reflected by mRNA levels that are associated with functional properties of the osteoblast, particularly those contributing to the recruitment and/or differentiation of osteoclasts, thereby influencing skeletal modeling.

Animals↗

PubMed1991

Congenitally osteosclerotic (os/os) rabbits are not cured by bone marrow transplantation from normal littermates.

The osteopetrotic (os) rabbit is a lethal mutation of autosomal recessive inheritance characterized by hypocalcemia, hypophosphatemia, fibrosis of marrow spaces, and ultrastructural abnormalities in both osteoclasts and osteoblasts. Procedures involving the transplantation of cells from normal hemopoietic tissues, which are sources of osteoclast precursors, are known to cure osteopetrosis in several mutations including some children. We tested the ability of transplanted bone marrow and/or spleen from normal littermates to reverse the skeletal sclerosis in os rabbits. Treatment of 15 neonatal mutants consisted of immunosuppression by whole-body irradiation followed by transplantation of normal bone marrow and/or spleen cell suspensions. This treatment failed to prolong life span or to cure osteopetrosis judged radiographically and histologically for up to 3 weeks posttreatment, the longest time of survival. These data indicate that transplantation of stem cells from multiple hemopoietic tissues, procedures known to cure osteopetrosis in other mutations, is not effective in the os rabbit. These results support the hypothesis that the skeletal microenvironment is not capable of supporting the development and function of normal osteoclasts in this mutation.

Animals↗

PubMed1991

Coexistence of reduced function of natural killer cells and osteoclasts in two distinct osteopetrotic mutations in the rat.

Recent evidence suggesting that immune cells and their products (cytokines) play an important role in the regulation of skeletal development and function, particularly of the osteoclast, implies that immune cell dysfunction may be involved in the pathogenesis of certain skeletal disorders. The mammalian osteopetroses are a pathogenetically heterogeneous group of skeletal disorders characterized by skeletal sclerosis resulting from reduced osteoclast-mediated bone resorption. Using a 51Cr-release microcytotoxicity assay we demonstrated that splenic natural killer (NK) cell activity was significantly reduced in two distinctly different osteopetrotic mutations in the rat, osteopetrosis (op) and toothless (tl). To determine whether this reduction in NK cell-mediated cytotoxicity is caused by decreased cell number and/or function in these osteopetrotic mutants, we quantitated NK cells by analyzing mononuclear cell suspensions labeled for two-color fluorescence with OX8 and OX19 monoclonal antibodies in a fluorescence-activated cell sorter. Flow cytometry of these double-labeled cells revealed that the percentage of NK cells (OX8+/OX19- subset) in op and tl spleens was not significantly different from that of normal spleens. These results suggest that NK cells in these osteopetrotic mutants are functionally defective. Thus aberrations in osteoclast and NK cell function coexist in these mutations, and their developmental relationships deserve further study.

Animals↗

PubMed1991

The giant cells recruited by subcutaneous implants of mineralized bone particles and slices in rabbits are not osteoclasts.

We have compared structural and functional characteristics of native osteoclasts and the multinucleated giant cells (MNGC) recruited by subcutaneous implants of mineralized bone particles and slices in normal rabbits. Weekly evaluation of the implants for 5 weeks showed distinct differences between MNGC and osteoclasts in the host with respect to morphology and the ability to stain for tartrate-resistant acid phosphatase and acid ATPase. An osteoclast-specific monoclonal antibody bound strongly to osteoclasts but not MNGC. Ground bone slices similarly implanted were surrounded by MNGC but did not show resorption pits by scanning electron microscopy. These data show that the MNGC recruited to subcutaneous implants of mineralized bone particles and slices lack the enzymatic, cell surface, and functional features of osteoclasts.

Acid Phosphatase↗

PubMed1991

Skeletal development and formation of osteoclast-like cells from in situ progenitors in fetal mouse metatarsals cultured in chemically defined medium.

An in vitro model system is described, using metatarsal explants from 15-day mouse embryos (E15) cultured in serumless chemically defined medium, to study fetal skeletal development with particular emphasis on de novo osteoclast formation. The normal pattern of growth and differentiation observed in vitro, assessed by ultrastructure and morphometry, demonstrate a permissive local environment which replicates physiologic temporal and spatial relationships which exist in vivo. The population of committed osteoclast progenitors present in E15 metatarsals form osteoclasts and precursors which have cytochemical and ultrastructural features, as well as kinetics of formation, that are similar to that which occurs in vivo. The responsiveness of osteoclast formation to the effects of added 1,25(OH)2D3 illustrates that controlled manipulation enables one to exploit the system for investigating the role of cytokines, growth factors and osteotropic hormones in skeletal development and osteoclast ontogeny.

Animals↗

PubMed1991

The effects of DFMO on polyamine metabolism in the inner ear.

Difluoromethylornithine (DFMO) is a novel antineoplastic agent that was associated with an unexpected hearing loss in Phase II clinical trials. DFMO interferes with polyamine synthesis by inhibition of the enzyme ornithine decarboxylase (ODC). The objective of the current study was to establish a methodology to determine the effect of DFMO on polyamine levels and ODC activity in the cochlea. Guinea pigs received DFMO in their drinking water and were tested for auditory brainstem response threshold shifts. The organ of Corti, the lateral wall, and the acoustic nerve were assayed for both ODC activity and polyamine levels. In DFMO treated animals there was an inhibition of ODC activity in cochlear tissues as well as in intestinal mucosa. In addition, a significant depletion of cochlear polyamines was observed in the treatment animals. This study suggests that systemically administered DFMO inhibits ODC activity and interferes with polyamine synthesis in the cochlea.

Animals↗

PubMed1991

Extension of growth-plate cartilage into the metaphysis: a sign of healing fracture in abused infants.

The present study was carried out to determine if healing metaphyseal injury in abused infants is accompanied by an increase in the thickness of the growth-plate zone of hypertrophic cartilage and if a radiolucent extension from the growth plate into the metaphysis correlates with this histologic indicator of healing fracture. The radiologic studies of 13 infants who died with evidence of inflicted injury were reviewed. Thirteen distal metaphyseal fractures were identified. Histologically, nine of these fractures were noted to be healing and four showed no evidence of healing. The nine healing injuries were accompanied by statistically significant thickening of the zone of hypertrophic cartilage. Seven of these demonstrated localized areas of hypertrophic cartilage extension; in six of these, corresponding radiolucent extensions of the growth plate into the metaphysis were seen. The extensions tended to be single and focal with minimal osseous injury and broad and multiple with extensive injury. No similar extension was visible in the four acute injuries. Because metaphyseal injuries are notoriously difficult to date, the presence of a reliable radiologic indicator of healing metaphyseal fracture can be important in the evaluation of infant abuse. Because the radiologic findings reflect the histologic alterations, extension of the growth-plate cartilage into the metaphysis may have implications for estimating fracture age.

Child Abuse↗

PubMed1990

Defective osteoclast differentiation and function in the osteopetrotic (os) rabbit.

We tested the ability of normal osteoclast progenitors found in neonatal liver and bone marrow to develop into functional osteoclasts when co-cultured with metatarsals from newborn osteopetrotic rabbits; the latter inherit an osteoclast incompetence resistant to cure by bone marrow transplantation. This system, developed by Burger and colleagues, has been shown to produce normal, functional osteoclasts when used with normal metatarsals. Our study tested the competence of the mutant skeletal microenvironment for differentiation of normal osteoclasts. Mutant and normal metatarsals were cultured alone or with normal liver, spleen, or bone marrow for up to 14 days. All normal cultures possessed a marrow cavity and contained numerous osteoclasts with cytochemical characteristics (tartrate-resistant acid phosphatase) of active cells. Mutant metatarsals co-cultured with normal spleen, liver, or bone marrow failed to develop a marrow cavity (evidence in itself of reduced bone resorption) and had osteoclasts reduced in both numbers and cytochemically detectable activity. Similar metatarsal cultures of an osteopetrotic rat mutation (incisors--absent) curable by bone-marrow transplantation exhibited marrow cavity development in mutant metatarsals co-cultured with normal spleen. These data suggest that the skeletal environment of osteopetrotic rabbits contains an inhibitor or lacks a promoter of osteoclast differentiation and function.

Acid Phosphatase↗

PubMed1990

Effects of 1,25 dihydroxyvitamin D on osteoclast number and cytochemistry in normal and osteopetrotic (os) rabbits.

Osteoclast-mediated bone resorption is increased in response to 1,25 dihydroxyvitamin D (1,25[OH]2D or calcitriol). Osteopetrosis is a metabolic bone disease characterized by defective, osteoclast-mediated bone resorption, which co-exists with elevated serum 1,25-(OH)2D levels in some osteopetrotic children and animals. We examined the effects of high doses of calcitriol on osteoclast number and cytochemistry in both normal and osteopetrotic (os) rabbits. Calcitriol was continuously infused at doses of 0.5, 2.5, or 25 micrograms/kg/day via subcutaneously implanted osmotic minipumps for a period of 7 days. Following treatment, the proximal tibial metaphyses were processed for histomorphometric and cytochemical analyses. Sections were stained for tartrate-resistant acid phosphatase (TrAP) or acid ATPase (TraATPase). Osteoclasts were significantly reduced in untreated os rabbits compared with age-matched normal littermates between birth and 3 weeks of age (41-46% of normal). Whereas most normal osteoclasts (85%) stained heavily for TrAP or TraATPase, less than half of os osteoclasts were heavily stained for these acid hydrolases. Infusions of 1,25(OH)2D resulted in elevations of osteoclast numbers in both normal and os rabbits, but the number of osteoclasts remained significantly lower in mutants than in normal littermates at any given dose. Calcitriol infusions also resulted in a significant increase in the percentage of os osteoclasts staining heavily for TrAP and TraATPase. These results suggest that in response to 1,25(OH)2D normal osteoclasts increase their production of acid hydrolases before increasing cell numbers and that, in spite of high levels of endogenous calcitriol, os rabbits can respond to exogenous 1,25(OH)2D as evidenced by increased osteoclast number and cytochemical staining, even though these osteoclasts fail to resorb the excess skeletal matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

PubMed1990

Histochemistry and biochemistry of tartrate-resistant acid phosphatase (TRAP) and tartrate-resistant acid adenosine triphosphatase (TrATPase) in bone, bone marrow and spleen: implications for osteoclast ontogeny.

In order to evaluate the usefulness of a recently described acid ATPase as a marker for osteoclast differentiation, we have performed histochemical and biochemical analyses of the distribution of tartrate-resistant acid phosphatase (TRAP) and tartrate-resistant acid ATPase (TrATPase) in bone, bone marrow and spleen. Histochemical studies of bone demonstrated that multinucleated osteoclasts stained for both TRAP and TrATPase. However, staining for TRAP covered the entire cytoplasm, whereas TrATPase staining was localized primarily to cytoplasmic areas next to bone and on adjacent mineralized surfaces. Occasionally TrATPase-positive mononuclear cells were observed on excavations in the bone surface. In the spleen, mononuclear TRAP-positive cells were located in the marginal zone between the white and red pulp, whereas no staining for TrATPase was observed. Comparison of the biochemically measured TRAP and TrATPase activities showed that bone had the highest specific activity for both enzymes followed by the bone marrow and spleen. However, enzyme activity in the spleen compared to bone was about 4-fold higher for TRAP compared to TrATPase. Additional evidence for a restricted expression of TrATPase to bone relative to spleen was obtained by in vitro translation studies. These data indicate that TrATPase is a more selective marker than TRAP in histochemical and biochemical studies of osteoclast differentiation and furthermore suggest that development of TrATPase is a late acquisition in osteoclast ontogeny.

Acid Phosphatase↗

PubMed1990

Relationship of abnormalities in dental and skeletal development in the osteopetrotic (os) rabbit.

Osteopetrosis is a metabolic bone disease characterized by reduced bone resorption of heterogenous cause. The rabbit mutation is lethal and exhibits ultrastructural aberrations in osteoclasts and osteoblasts together with hypocalcemia, hypophosphatemia and failure to be cured by bone marrow transplantation. We have studied dental abnormalities in mutants from birth to 3 wk using radiographic, cytologic and autoradiographic methods. Radiographs show hypoplasia of most teeth in mutants. The maxillary incisor is smaller and more curved and the mandibular incisor thin and straight compared to normal littermates. The first 3 molars in both arches are unerupted and of distorted shape while the last 2 are less affected. Microscopically areas of ankylosis of mutant incisors and the first 3 molars were commonly encountered even at birth. Osteoclasts were numerous. Autoradiograms of 3H-proline incorporation showed strong periosteal and weak endosteal labeling of bone in both mutants and normal littermates. Dentin labeling in mutant incisors and molars was not less than that in normal rabbits and sites of ankylosis in mutants exhibited labeling. These data indicate that osteopetrotic rabbits exhibit major aberrations in shape and eruption of incisors and most molars and that these effects are not due to lack of dentin formation. Early ankylosis, perhaps secondary to congenital reduction of bone resorption, appears to be the major cause of the dental abnormalities which are less severe in the youngest (posterior) teeth.

Animals↗

PubMed1990

Osteopetrosis in the rat: coexistence of reductions in osteocalcin and bone resorption.

Osteocalcin, one of the vitamin K-dependent bone proteins, has recently been implicated in bone resorption. To explore this hypothesis, bone and serum osteocalcin were measured in three different osteopetrotic rat mutations characterized by reduced bone resorption. These three mutations (ia/ia, tl/tl, and op/op) exhibit heterogeneity with respect to osteoclast number and activity and response to being cured by bone marrow transplantation. Calvarial bone osteocalcin was present in normal amounts, but difficult to extract, in ia/ia rats that have increased numbers of inactive osteoclasts. Bone osteocalcin was greatly decreased in op/op (53-60% of control) and tl/tl (64-73% of control) osteopetrotic rats, in which osteoclasts are both reduced in number and inactive. These decreases in osteocalcin levels in bone coexist with elevated serum levels of osteocalcin in all three mutations. Since osteocalcin synthesis is known to be stimulated by 1,25(OH)2D3, the increase in serum osteocalcin may be a reflection of the elevated blood levels of 1,25(OH)2D3 known to occur in each of these mutations. These findings indicate that the composition of osteopetrotic bone is abnormal with respect to osteocalcin in the two rat osteopetrotic mutations showing decreased osteoclast numbers. Considered together with the emerging evidence that the extracellular matrix in many developing tissues plays a role in cell recruitment and differentiation, these data suggest that osteocalcin abnormalities may be a contributing factor to the spectrum of osteoclast aberrations in osteopetrosis.

Aging↗

PubMed1989

Radiologic contributions to the investigation and prosecution of cases of fatal infant abuse.

In 1984 we started a two-year program in Worcester (Mass.) and Boston to provide additional radiologic data for the medical investigation of suspected fatal infant abuse. During that period the investigation of 12 cases of unexplained infant death included the review of complete radiographic skeletal surveys by a pediatric radiologist. Autopsies were supplemented with resection, high-detail radiography, and histologic study of all non-cranial sites of suspected osseous injury. Thirty-four bony injuries were noted, including 12 acute and 16 healing fractures of the long-bone metaphyses and posterior-rib arcs in patterns indicative of infant abuse. The investigations determined that there were eight cases of abuse, two accidental deaths, and two natural deaths (sudden infant death syndrome). At this writing, the radiologic and osseous histologic studies appear to have influenced the determination of the manner of death in six of the eight cases of abuse and the criminal prosecution in four of the five convictions. These findings suggest that a thorough postmortem radiologic evaluation followed by selected histologic studies can have an impact on the investigation and prosecution of cases of fatal infant abuse.

Autopsy↗

PubMed1989

Osteoclast biology in the osteopetrotic (op) rat.

Osteopetrosis is a metabolic bone disease characterized by reduced bone resorption. From experimental studies of various osteopetrotic mutations has emerged the hypothesis that each is unique with respect to mechanisms whereby osteoclast development and/or function are reduced. The osteopetrotic (op) mutation in the rat was discovered in Fatty/ORL stock over a decade ago. The paucity of data about osteoclast biology in this mutation prompted this study of cytological, cytochemical, and ultrastructural features of osteoclasts. In op rats, osteoclasts are significantly reduced in number, but are larger and more vacuolated than in normal littermates. Mutant osteoclasts can form ruffled borders and clear zones, but their ability to fragment and excavate bone surfaces is greatly impaired. Cytoplasmic vacuoles in op osteoclasts are randomly distributed and greatly enlarged, and they stain weakly for two cytochemical characteristics of osteoclasts, tartrate-resistant acid phosphatase and acid ATPase. These findings suggest that an abnormality in the lysosomal/vacuolar system, an important component of the resorptive mechanism, may be involved in the interception of osteoclast function in this mutation.

Animals↗