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Biomedical subjects

S C Marks

Publications and source records attributed to S C Marks.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations.

Bone mineral density (BMD) and mechanical strength generally show strong positive correlations. However, osteopetrosis is a metabolic bone disease with increased skeletal density radiographically and increased risk of fracture. We have evaluated mechanical strength and mineral density in three osteopetrotic mutations in the rat (incisors-absent [ia/ia], osteopetrosis [op/op], and toothless [tl/tl]) to test the hypothesis that reduced bone resorption in one or more of these mutations results in weaker bones in the presence of greater mineral density and skeletal mass. Peripheral quantitative computed tomography (pQCT) was used to analyze BMD and cross-sectional geometry in the tibial diaphysis and metaphysis as well as the femoral diaphysis and femoral neck. The bending breaking force of tibial and femoral midshafts was obtained using the three-point bending test and femoral neck strength was tested by axial loading. Osteopetrotic mutants were significantly smaller than their normal littermates (NLMs) in each stock. The pQCT analysis showed that BMD and bone mineral content (BMC) were higher than or equal to NLMs in all skeletal sites measured in the osteopetrotic mutants. However, the mechanical breaking force was equal to or lower than their NLMs in all sites. The cross-sectional structure of long bone shafts was markedly different in osteopetrotic mutants, having a thin cortex and a medullary area filled with primary trabecular bone. These results indicate that osteopetrotic mutations in the rat increase bone density and decrease bone strength. The tibial diaphysis was significantly weaker in tl/tl and ia/ia mutants and the tibial metaphysis showed the greatest increase in BMD in all mutants. These data are another illustration that an increased BMD does not necessarily lead to stronger bones.

Animals↗
PubMed2000

Colony-stimulating factor-1 (CSF-1) rescues osteoblast attachment, survival and sorting of beta-actin mRNA in the toothless (tl-osteopetrotic) mutation in the rat.

We have shown that in the osteopetrotic rat mutation toothless (tl) osteoblasts are absent from older bone surfaces in mutants and that mutant osteoblasts in vivo lack the prominent stress fiber bundles polarized along bone surfaces in osteoblasts from normal littermates. Our recent data demonstrate that in normal osteoblasts in vitro beta- and gamma-actin mRNAs have different, characteristic intracellular distributions and that tl (mutant) osteoblasts fail to differentially sort these mRNAs. Because bone resorption and formation are highly interdependent and injections of CSF-1, a growth factor, increase bone resorption and growth in tl rats, we examined the effects of CSF-1 treatment on osteoblast survival and ultrastructure in vivo and ability to sort actin mRNAs in vitro. Neonatal CSF-1 treatment of mutants restores osteoblasts on older bone surfaces, normalizes the intracellular distribution of stress fibers in osteoblasts in vivo and promotes normal sorting of beta-actin mRNA in mutant osteoblasts in vitro without normalizing gamma-actin distribution. These data suggest the beta- and gamma-actin mRNAs in osteoblasts are sorted by different mechanisms and that the differential sorting of beta-actin mRNA is related to the characteristic polarization of stress fibers in osteoblasts and their survival on bone surfaces. This experimental system can be used to explore the relationships and regulation of these aspects of cell and tissue biology.

Actins↗
PubMed2000

Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression.

The pacemaker of endochondral bone growth is cell division and hypertrophy of chondrocytes. The developmental stages of chondrocytes, characterized by the expression of collagen types II and X, are arranged in arrays across the growth zone. Mutations in collagen II and X genes as well as the absence of their gene products lead to different, altered patterns of chondrocyte stages which remain aligned across the growth plate (GP). Here we analyze GP of rats bearing the mutation toothless (tl) which, apart from bone defects, develop a progressive, severe chondrodystrophy during postnatal weeks 3 to 6. Mutant GP exhibited disorganized, non-aligned chondrocytes and mineralized metaphyseal bone but without cartilage mineralization or cartilaginous extensions into the metaphysis. Expression of mRNA coding for collagen types II (Col II) and X (Col X) was examined in the tibial GP by in situ hybridization. Mutant rats at 2 weeks exhibited Col II RNA expression and some hypertrophied chondrocytes (HC) but no Col X RNA was detected. By 3rd week, HC had largely disappeared from the central part of the mutant GP and Col II RNA expression was present but weak and in 2 separate bands. Peripherally the GP contained HC but without Col X RNA expression. This abnormal pattern was exacerbated by the fourth week. Bone mineralized but cartilage in the GP did not. These data suggest that the tl mutation involves a regulatory function for chondrocyte maturation, including Col X RNA synthesis and mineralization, and that the GP abnormalities are related to the Col X deficiency. The differences in patterning in the tl rat GP compared to direct Col X mutations may be explained by compensatory effects.

Animals↗
PubMed1999

Extensive clear zone and defective ruffled border formation in osteoclasts of osteopetrotic (ia/ia) rats: implications for secretory function.

The cellular distribution of osteoclast integrin subunits alpha(v) and beta(3), the tissue distribution, and level of the apparent ligand osteopontin (OPN) as well as of the putative regulatory enzyme tartrate-resistant acid phosphatase (TRAP) were studied along with the intracellular distribution of the activation marker c-src in osteopetrotic ia/ia (incisors-absent) mutant rats and their normal littermates. In ia/ia rats, the osteoclasts are incapable of bone matrix resorption. Ultrastructurally the cells exhibit extended clear zones at the expense of ordinary ruffled borders. A secretory dysfunction in the mutant is strongly suggested by the absence of detectable extracellular TRAP, concomitant with an accumulation of the enzyme in abundant small cytoplasmic vesicles. Moreover, TRAP mRNA, protein content, as well as enzymatic activity were elevated. Furthermore, increased levels of integrin subunits alpha(v) and beta(3) were detected at the clear zone of mutant osteoclasts. OPN mRNA levels were elevated in long bones from mutants. In ia/ia rats, immunolabeling for OPN was homogeneously distributed at the surface facing osteoclasts, while in normal littermates it was concentrated at the clear zone area and barely detectable at ruffled borders. The absence of OPN labeling in the abundant, putative intracellular secretory vesicles in mutant osteoclasts suggests that these cells do not produce OPN. The osteoclasts of ia/ia rats appeared to produce and translocate the c-src protein to the cell membrane. In ia/ia a defect ruffled border-formation is observed along with extensive clear zone formation and decreased secretory function. The lesion may be due to a signaling defect, but in that case the defect seems to be located downstream to or not involving the c-src pathway. Our results illustrate the close relationship between secretory function and ruffled border formation in osteoclasts, a relationship that appears to be necessary for proper resorptive function.

Acid Phosphatase↗
PubMed1999

Volume-length impact of lateral jaw resections on complication rates.

OBJECTIVE: To study the relationship between soft tissue volume loss and bone resection length following lateral segmental mandibulectomy with plate reconstruction and complication rates. DESIGN: Retrospective case review of 31 patients (1989-1996), with average follow-up of 37.2 months, who were treated by lateral composite resection for oral cavity and/or oropharyngeal malignancy with primary reconstruction by defect-bridging plates. SETTING: Academic tertiary care referral center. INTERVENTIONS: Thirty patients had stainless steel and 1 patient a vitallium reconstruction plate to restore mandibular continuity. Soft tissue defects were repaired with pectoralis myocutaneous flaps (n = 25), skin grafts (n = 4), a radial forearm free flap (n = 1), or primary closure (n = 1). All patients received preoperative (n = 6) or postoperative (n = 25) radiation therapy. MAIN OUTCOME MEASURES: Overall and hardware-related complications. RESULTS: All 31 initial soft tissue repairs were successful. Subsequent complications occurred in 14 patients (45%), which included plate exposure (29%), loosened screws requiring hardware removal (29%), fistula (14%), local wound infection (14%), osteomyelitis (7%), and plate fracture (7%). Average time to complication was 7.7 months. Complication rates were 81% for bone defects greater than 5.0 cm, and 7% for those less than 5.0 cm. Bivariate analysis indicated bone resection lengths greater than 5.0 cm to be a significant predictor of both hardware-related (P = .02) and overall complications (P = .005), whereas soft tissue volume resections greater than 240 cm3 were found only to be marginally significant (P = .04) for overall complications. CONCLUSION: Extirpative losses involving more than 5 cm of bone, or tissue volume greater than 240 cm3, are associated with unacceptably high complication rates when reconstructed with solid screw stainless steel plates and this warrants consideration of alternative techniques for long-term stability.

Adult↗
PubMed1999

Facial development and type III collagen RNA expression: concurrent repression in the osteopetrotic (Toothless,tl) rat and rescue after treatment with colony-stimulating factor-1.

The toothless (osteopetrotic) mutation in the rat is characterized by retarded development of the anterior facial skeleton. Growth of the anterior face in rats occurs at the premaxillary-maxillary suture (PMMS). To identify potential mechanisms for stunted facial growth in this mutation we compared the temporospatial expression of collagen I (Col I) and collagen III (Col III) RNA around this suture in toothless (tl) rats and normal littermates by in situ hybridization of specific riboprobes in sagittal sections of the head. In normal rats, the suture is S shaped at birth and becomes highly convoluted by 10 days with cells in the center (fibroblasts and osteoblast progenitors) expressing Col III RNA and those at the periphery (osteoblasts) expressing no Col III RNA but high amounts of Col I RNA throughout the growth phase (the first 2 postnatal weeks). In the mutant PMMS, cells were reduced in number, less differentiated, and fewer osteoblasts were encountered. Expression of Col I RNA was at normal levels, but centrosutural cells expressed Col III RNA only after day 6 and then only weakly. A highly convoluted sutural shape was never achieved in mutants during the first 2 postnatal weeks. Treatment of tl rats with the cytokine CSF-1 improved facial growth and restored cellular diversity and Col III RNA expression in the PMMS to normal levels. Taken together, these data suggest that normal facial growth in rats is related to expression of Col III RNAby osteoblast precursors in the PMMS, that these cells are deficient in the tl mutation and are rescued following treatment with CSF-1.

Animals↗
PubMed1999

Carbonic anhydrase II and H+ -ATPase in osteoclasts of four osteopetrotic mutations in the rat.

Osteopetrosis in laboratory animals is a metabolic bone disease characterized by increased skeletal mass. It is inherited as an autosomal recessive and results from a defect in the development and/or function of osteoclasts. We studied two enzymes essential for bone resorption, carbonic anhydrase II isoenzyme (CA II) and H+ -ATPase, in osteoclasts from four osteopetrotic mutations in the rat; namely incisors-absent (ia), osteopetrosis (op), toothless (tl), and microphthalmia (mib), to test the hypothesis that reduced bone resorption in one or more of these mutations results from defects in the synthesis or activity of one of these enzymes. CA II was present in most osteoclasts from normal, tl, op, and mib littermates and was homogeneously distributed in cytoplasm. CA II staining in ia osteoclasts was more variable and less intense than in the other mutations. H+-ATPase was also present in osteoclasts from normal animals and mutants and immunostaining showed clear polarization to the ruffled border region in all normal rats and mutants except ia, which showed diffuse distribution of staining in the cytoplasm. H+-ATPase activity (proton transport) in a related tissue, kidney, was normal in tl and ia rats but increased in op and mib rats compared to their normal littermates. These results suggest that the osteoclasts in osteopetrotic rat mutations are not abnormal with respect to the distribution of CA II and H+ -ATPase and that the function of these enzymes in the skeleton, while likely normal, needs to be tested directly in bone.

Animals↗
PubMed1999

Conservation laryngeal surgery.

Conservation laryngeal surgery is an increasingly available alternative for treatment of laryngeal cancer. In addition to the traditional techniques of vertical partial laryngectomy (hemilaryngectomy) and supraglottic laryngectomy, new techniques are now in practice that extend the indications to a far greater number of patients. The carbon dioxide laser is used to resect both glottic and supraglottic cancers. This procedure is best applied to early stage I and stage II cancers. Reports indicate superior functional outcome to open surgical procedures, with shorter hospital duration, less morbidity, and equivalent survival rates. The supracricoid partial laryngectomy is becoming increasingly popular for intermediate extent tumors. This novel procedure allows resection of transglottic tumors and tumors with vocal cord paralysis while preserving the patient's speech and swallowing and avoiding a permanent tracheal stoma.

Carbon Dioxide↗
PubMed1999

Learning curve in endoscopic sinus surgery.

The existence of a long learning curve for endoscopic sinus surgery has been proposed as a reason for rigorous and extensive training to prepare physicians to perform this surgery. In this article, the author--who participated in this type of training program--examines his experience over a 5-year period to assess the effect of rigorous training on the learning curve for endoscopic sinus surgery. Beginning with the first day of practice after training, 5 years with 393 cases were evaluated for complications and the need for revision surgery. The results were analyzed in 100-case groups. The results show no difference in major and serious complications or revision surgery rates. However, a statistically significant difference in the minor-complication rate, specifically frontal-sinus stenosis, was found from the first half to the second half of the experience. These findings show that, with rigorous training of the physician, the learning curve can largely be completed during residency training, allowing the new practitioner to perform endoscopic sinus surgery safely and with good results.

Education, Medical↗
PubMed1999

Surgical management of head and neck cancer.

Head and neck cancer surgery continues to evolve through the years and undergo improvement and refinement. In this article, the current state of head and neck cancer surgery is summarized in a site-by-site basis. The most important developments include organ-sparing surgery and microvascular free-tissue transfer for reconstruction.

Head and Neck Neoplasms↗
PubMed1999

The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF.

The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.

Animals↗
PubMed1999

Outcome of frontal sinus obliteration.

OBJECTIVES: To evaluate the indications, technique, and results after long-term follow-up of osteoplastic frontal sinusectomy with fat obliteration. STUDY DESIGN: A retrospective review of a series of consecutive patients using objective and subjective outcome assessment. METHODS: A retrospective chart review was conducted of all patients undergoing osteoplastic flap procedure with obliteration between July 1, 1991, and July 1, 1997. Each patient also completed a symptom questionnaire rating the degree of symptoms both before and after surgery using a 10-point scale. The results were tabulated and analyzed for statistical significance. RESULTS: Twenty osteoplastic flap procedures to obliterate the frontal sinus were reviewed. The average patient age was 41 years, with the average duration of follow-up being 40.2 months. No surgical failures were noted; one patient underwent a negative reexploration. One surgical and one medical complication are reported. Statistically significant improvement was noted in overall symptoms, headache, congestion, drainage, and frequency of infections when the preoperative to the postoperative symptom scores were compared (P < .001). CONCLUSIONS: Based on these results, the use of the osteoplastic flap in the obliteration of the frontal sinus continues to be an option in the era of endoscopic treatment of frontal sinus disease, particularly in endoscopic failures and chronic frontal sinus pain.

Adult↗
PubMed1999

Auditory ossicle abnormalities and hearing loss in the toothless (osteopetrotic) mutation in the rat and their improvement after treatment with colony-stimulating factor-1.

Osteopetrosis describes a group of skeletal metabolic diseases of heterogeneous etiology and varied severity that produces a generalized accumulation of skeletal mass, the result of reduced bone resorption. Inherited in a variety of species including humans, the most severe forms are lethal. Among common features are progressive blindness and deafness of controversial etiologies for which there are no universally effective treatments. We have studied the auditory responsiveness and auditory ossicle quantitative histomorphology and temporal bone vasculature in the toothless (tl) rat, a lethal osteopetrotic mutation with few osteoclasts, very low bone turnover, and limited angiogenesis in the axial skeleton. Compared with normal littermates, 3-week-old mutants showed significantly reduced auditory responsiveness, a hearing loss due to abnormalities in both form and tissue composition of the stapes, and little capillary sprouting in the vascular bed of the temporal bone. Treatment of mutants with colony-stimulating factor 1 (CSF-1), known to greatly reduce sclerosis in the axial skeleton, significantly improved hearing, stapedial form and tissue composition, and angiogenesis in the temporal bone. In normal rats, the stapes consisted of 89.3% bone, 9.1% mineralized cartilage, and 0.8% porosity. In osteopetrotic rats, the stapes consisted of 48.3% bone, 35.9% mineralized cartilage, and 15.9% porosity, while after CSF-1 treatment, the bone content increased to 55.2%, cartilage was decreased to 21.7%, and porosity increased to 23.0%, respectively. This is the first demonstration of an auditory abnormality in an osteopetrotic animal mutation and shows that the hearing loss in tl rats can be significantly improved following treatment with CSF-1.

Animals↗
PubMed1999

Insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) immunoreactivity in normal and osteopetrotic (toothless, tl/tl) rat tibia.

Insulin-like growth factor-I (IGF-I) plays a major role in regulating cell growth. This study examined the immunohistochemical distribution of IGF-I and IGF-I receptor (IGF-IR) in tibias from normal and osteopetrotic (toothless, tl/tl) rats, following treatment with colony stimulating factor-1 (CSF-1). In normal rats, immunoreactivity for IGF-I and IGF-IR was detected in cells of the articular and epiphyseal cartilage, secondary ossification centres, zones of resting and proliferating chondrocytes and bone marrow. Bone marrow cells immunoreactive for IGF-I and IGF-IR were significantly reduced in the tl/tl rat (p < 0.001) compared with normal animals. Treatment of tl/tl rats with CSF-1 increased immunoreactivity for IGF-I and IGF-IR in bone marrow cells as well as the number of TRAP positive osteoclasts. This increase was the result of recruitment of a range of hematopoietic cell types, including eosinophils, polymorphs and a substantial number of monocyte-like cells demonstrating strong immunoreactivity to IGF-I/IGF-IR. The differences in relative immunoreactivity for IGF-I/IGF-IR by bone marrow cells in untreated and CSF-1-treated tl/tl rats indicate a CSF-1-dependent recruitment of cells bearing surface IGF-IRs which may be mediated by an increase in local or systemic IGF-I.

Acid Phosphatase↗
PubMed1999

Sutures, growth plates and the craniofacial base--experimental studies in the toothless (tl-osteopetrotic) rat.

The craniofacial skeleton develops from a base in which coordinated growth at sutures and growth centres assures the development of normal form. In this report we describe features of retarded postnatal craniofacial development in the osteopetrotic mutation, toothless (tl), in the rat in which bone growth in both the nasal area and the cranial base is reduced, suggesting that the mutation affects bone formation in sutures and growth plates. We began a systematic search for potential mechanisms by analysing the expression in time and intensity of RNA coding for collagens type I (Col I) and type III (Col III) analysed by in situ hybridisation of cells in the premaxillary-maxillary suture (PMMS). In the centre of the PMMS of tl rats, cells expressing Col I and Col III appeared later than in normal littermates and exhibited lower signal. During osteoblast recruitment from the suture centre into the bone domains, Col III RNA expression is switched off. Osteoblasts expressing Col I in abundance, but no Col III, appeared in the flanking bone regions of tl rats later than in normal littermates. It is proposed that the tl mutation restricts the number of available osteoblast progenitor cells, and that the shortage of these cells affects bone growth in the PMMS and in the cranial base. Additional analyses are needed to test this hypothesis and to understand the developmental dynamics in the cranial base.

Animals↗
PubMed1998

Morphological and clinical aspects of scapular fasciocutaneous free flap transfer for treatment of venous insufficiency in the lower extremity.

We have recently shown that free scapular fasciocutaneous flaps transferred to the lower extremities of patients with chronic venous insufficiency and cutaneous ulcers have resulted in improvement in venous refilling times measured by photoplethysmography in the flap areas and that recurrent ulceration does not recur for up to 7 years. We hypothesized that the transferred flaps contained valves in their microvascular bed, which facilitated venous return, and using scanning electron microscopy of vascular corrosion casts and light and transmission electron microscopy of tissue sections prepared from human dorsal thoracic fascia, we showed that valves were most abundant in veins with a luminal diameter of 30-120 microm (59.3% of 905 valves). The depth of these valves increased with venous diameter, but the size of valve sinuses was not different for individual valves. Except for veins > 1,000 microm in diameter, there was no significant difference in the number of valves in different parts of an individual flap or between different flaps. Most valves were bicuspid; only in the vein Category 30-120 microm were unicuspid valves encountered. Valves were sometimes located in series in a short segment of a vein; occasionally they were found at the merging of two veins. Transmission electron microscopy showed that valve leaflets had collagen fibers that ascended toward the tip of the leaflet and were occasionally accompanied by elastic fibers. Myofibroblasts were regularly present in the valve leaflets. The present report reviews and updates these anatomic data about the human scapular region, focusing on venous valvular microstructure, and suggests that the high number of smaller-size valves contributes to improved hemodynamic of the leg and thus the clinical success of free scapular flaps used to treat cutaneous ulcerations in the lower extremity.

Adolescent↗