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F S Kaplan

Publications and source records attributed to F S Kaplan.

At least 73 records · Page 4Linked to original sources
PubMed1994

Tutorial. Molecular biology for the clinician. Part I. General principles.

A fundamental understanding of all biological processes requires an understanding of the molecular basis of cellular function. The discipline of molecular biology focuses on the genetic information in cells: how is the inherited information encoded within DNA and how is this information regulated and expressed so that the cells of a multicellular organism develop from a single cell to highly specialized cells in a complex and integrated organism? For the practicing clinician, an understanding of the molecular mechanisms by which a differentiated cell develops and maintains its specialized functions is critical to a more in-depth understanding of human diseases. This is the 1st of a 3 part series on molecular biology for the clinician. This article introduces general principles of nucleic acid and gene structure. The 2nd article will examine commonly used research and diagnostic techniques based on the principles of molecular biology. The 3rd part will examine the frontiers of gene therapy, a novel approach to the treatment human diseases at the molecular level.

Base Sequence↗
PubMed1994

Traumatic fractures of heterotopic bone in patients who have fibrodysplasia ossificans progressiva. A report of 2 cases.

Fibrodysplasia ossificans progressiva is an extremely rare genetic disorder characterized by the formation of a heterotopic skeleton that is histologically, biomechanically, and metabolically indistinguishable from the normotopic skeleton. Isolated cases of traumatic and pathologic fractures have been reported in the normotopic skeleton of patients who have fibrodysplasia ossificans progressiva, but to the authors' knowledge there have been no detailed reports of traumatic fractures in the heterotopic skeleton of patients who have this disease. Reported here are 2 children with fibrodysplasia ossificans progressiva who sustained traumatic fractures of heterotopic bone around the elbows. In both children, the fractures healed uneventfully with normal-appearing callus. These 2 extremely rare cases suggest that the biologic response to fractures in the heterotopic skeleton appears indistinguishable from that in the normotopic skeleton in patients who have fibrodysplasia ossificans progressiva.

Bony Callus↗
PubMed1994

Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva.

To characterize the radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva, radiographs from 47 patients and radionuclide bone scans from 12 of those patients, all of whom had a confirmed diagnosis of the disease, were reviewed. A wide range of normal bone modeling and remodeling features was seen in the heterotopic skeleton of all but the youngest two (age, 1 year) of the 47 patients. Characteristic features of normal bone modeling identified on radiographs of the heterotopic skeleton included: (a) the development of tubular and flat bones with mature cortical and trabecular organization; (b) the presence of well defined cortical-endosteal borders enclosing medullary canals; and (c) the presence of metaphyseal funnelization in isolated ossicles or at sites of synostoses. Characteristic features of normal bone remodeling identified on radiographs of the heterotopic skeleton included: (a) the response of heterotopic bone to weight bearing stress with osteosclerosis of use and osteopenia of disuse, and (b) the resistance of heterotopic bone to fatigue failure with the absence of pathologic fractures and stress fractures. Radionuclide bone scans in 12 patients showed that remodeling of mature heterotopic bone occurred at a rate consistent with that of mature normotopic bone. This study documents the radiographic and scintigraphic features of a heterotopic skeletal system in 47 patients who have fibrodysplasia ossificans progressiva. These data provide additional support for the hypothesis that the genetic defect leading to the formation of a heterotopic skeleton involves normal skeletal morphogenesis at heterotopic sites.

Adolescent↗
PubMed1994

Age- and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva.

Using data from a survey of 44 patients who have fibrodysplasia ossificans progressiva, age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods. Regions in which the risk of heterotopic ossification appears to remain constant with age include the neck, spine, shoulders, elbows, and ankles. Regions with apparently increasing risk include the jaw, wrists, hips, and knees. This analysis allows clinicians to estimate the risk of new involvement for any joint at any patient age, as well as the fraction of patients with uninvolved joints at any age. The variation of ossification risk by joint provides a clinically useful guide to the patterns of progression of the disease. Such a guide will help in planning for individual patient needs, as well as anticipating auxiliary social services and rehabilitation programs.

Adolescent↗
PubMed1993

The topographic organization of repetitive DNA in the human nucleolus.

The nucleolus is a highly specialized nuclear domain where ribosomal DNA (rDNA) is transcribed and preribosomes are assembled. We investigated the molecular organization of the human lymphocyte nucleolus by fluorescence in situ hybridization and confocal laser scanning microscopy and found that transcribed rDNA and nontranscribed ribosomal intergenic spacer (IGS) sequences colocalized to discrete regions frequently on the nucleolar periphery of phytohemagglutinin-stimulated cells. The 5S rDNA gene cluster located on the long arm of chromosome 1 was not regularly associated with the nucleolus. Short interspersed (SINE) Alu elements detected by BLUR 11 were distributed diffusely throughout the nucleus but were severely underrepresented in the nucleolus, whereas an Alu element subcloned from the IGS detected sequences enriched in the nucleolus but sparsely represented in the remainder of the nucleus. In contrast, long interspersed (LINE) Kpn elements, which were located at the nucleolus, were not found in rDNA but were identified outside the ribosomal gene complex on the short arm of at least one acrocentric chromosome. A human chromosome 21-derived alphoid sequence that hybridized to the centromere was localized outside but near the nucleolus, and nonribosomal DNA consisting of a tandemly repeated simple sequence cluster derived from the short arm of chromosome 15 was organized in a compact fashion in the nucleolus. Our study provides new insight into the content and structure of the human nucleolus and illustrates that the unique organization of repetitive DNA on the acrocentric chromosome short arms is reflected in the topographic organization of the nucleolus.

Blotting, Southern↗
PubMed1993

The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients.

Forty-four patients who had fibrodysplasia ossificans progressiva responded by mail to a questionnaire regarding the age at the onset of heterotopic ossification at fifteen commonly involved anatomical sites. The average age of the patients when they responded to the questionnaire was twenty-seven years (range, three to sixty-nine years). The average age at the onset of ossification was five years (range, birth to twenty-five years). The most common sites of early heterotopic ossification were the neck, spine, and shoulder girdle. Thirty-five (80 per cent) of the patients had had some restrictive heterotopic ossification by the age of seven years. By the age of fifteen years, forty-two (more than 95 per cent) of the patients had severely restricted mobility of the upper limbs. In these patients, heterotopic ossification proceeded in a direction that was axial to appendicular, cranial to caudad, and proximal to distal; this pattern appeared typical for fibrodysplasia ossificans progressiva.

Adolescent↗
PubMed1993

The histopathology of fibrodysplasia ossificans progressiva. An endochondral process.

In order to better characterize the biological features of fibrodysplasia ossificans progressiva, we reviewed the histopathological specimens from eleven patients (twelve biopsies) who had a confirmed diagnosis of the disease. All of the biopsies had been performed in children, to exclude the diagnosis of a malignant lesion. In no instance was the diagnosis of fibrodysplasia ossificans progressiva considered before the biopsy. The results of a lesional biopsy in all eleven patients revealed normal endochondral osteogenesis at heterotopic sites. The results of biopsy of an early lesion in six children were misinterpreted as revealing a diagnosis of fibromatosis or sarcoma before the roentgenographic appearance of ossification. Immunohistochemical studies of sections of the earliest lesion demonstrated S-100 antigen positivity before the histological appearance of differentiated osteochondral tissue. The presence of congenital malformation of the great toes and of postnatal heterotopic endochondral osteogenesis strongly suggests that fibrodysplasia ossificans progressiva is a disorder of defective induction of endochondral osteogenesis. This study established the predominant histopathological findings associated with fibrodysplasia ossificans progressiva and can serve as a basis for postulation of a candidate gene in the pathogenesis of the disorder. A lesional biopsy is not needed to make the diagnosis; biopsy uniformly exacerbates the condition and should be avoided.

Antigens, CD↗
PubMed1993

Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family.

Fibrodysplasia ossificans progressiva is a rare connective-tissue disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of the tendons, ligaments, fasciae, and skeletal muscles. We document the genetic transmission of fibrodysplasia ossificans progressiva from a sporadically affected father to each of his three children: two daughters and a son. Previous consideration of a genetic etiology was based on the fact that the disease has been reported in several sets of monozygotic twins, that an increased paternal age has been associated with sporadic occurrences of the disorder, and that there have been several reports of genetic transmission in the remote past. Although an autosomal-dominant genetic transmission has long been suspected, the findings in the family reported on here provide confirmation for such inheritance and a basis for the diagnosis and counseling of patients who have this disease.

Adult↗
PubMed1993

The cluster phenomenon in patients who have multiple vertebral compression fractures.

Little is known about the natural history of patients who have multiple compression fractures. During an eight-year period, eight patients who suffered relentless nonmechanical back pain after an initial compression fracture were evaluated. Radiographs and radionuclide bone scans were obtained in all eight patients and showed the temporal clustering of at least five spontaneous thoracic or lumbar vertebral compression fractures within a period of eight months. The patient database during this eight-year period included 21 patients with a similar number of fractures but without the phenomenon of temporal clustering. Age and gender distribution, premorbid activity levels, presence of secondary causes of osteopenia, dietary history, and vertebral bone density measurements were similar in both groups. Five of the eight patients with cluster fractures were on chronic glucocorticoid therapy for treatment of an underlying illness. All five patients experienced an exacerbation of their chronic illness that required an increase in the dose of their steroid medication within three months preceding the onset of the cluster fractures. No patient in the noncluster fracture control group experienced a similar exacerbation of an underlying illness or required a similar boost in their steroid medication. The temporal clustering of numerous fractures (cluster phenomenon) is a cause of transient severe disability in patients who have profound osteopenia, and may be precipitated by exacerbation of an intercurrent illness or by an associated obligate increase in glucocorticoid medication in a patient with preexisting severe osteopenia.

Aged↗
PubMed1993

Chromosomal assignment of the human gene for bone morphogenetic protein 4.

Bone morphogenetic proteins (BMP) are the only known biologic factors capable of inducing endochondral ossification at an extraskeletal site. Seven members of the BMP family have been identified thus far and are involved in osteoinduction and morphogenesis. The authors established the chromosomal assignment of the gene for BMP4 on human chromosome 14 by using somatic cell hybrid panels and molecular technology. The genetic map of chromosome 14 shows that Holt-Oram Syndrome (HOS), a heritable disorder of skeletal and cardiac development, may be located also on chromosome 14. Linkage analysis studies in large families with HOS will determine if the BMP4 gene is related to HOS. In addition, analysis shows that the BMP4 gene maps to a conserved region of the mouse and human genomes. The chromosomal locus of a gene is part of human anatomy and provides a genomic landmark for studies on the pathogenesis of heritable disorders.

Animals↗
PubMed1993

Skeletal dysplasia in perinatal lethal osteogenesis imperfecta. A complex disorder of endochondral and intramembranous ossification.

Osteogenesis imperfecta (OI) Type II is a rare heritable disorder of bone matrix that results in catastrophic congenital skeletal dysplasia. Two cases of OI Type II had symmetric rhizomelic skeletal dysplasia apparent on ultrasound at 16 and 20 weeks' gestation. Histologic and histochemical studies performed on skeletal tissue from fetal autopsies showed the following: (1) abnormal growth plate tissue characterized by failure of formation of primary bony spongiosa; (2) persistence of calcified cartilage bars in the diaphysis; (3) metaphyseal microfractures; (4) abundant cartilaginous fracture callus; (5) absence of bony callus; (6) failure of formation of intramembranous cortical diaphyseal bone; (7) angulation of long bones in portions of the metadiaphyses bordered by fracture callus; and (8) mechanical failure of the perichondral ring of LaCroix with a normal fibrous ossification groove of Ranvier. These findings suggest that skeletal dysplasia in OI Type II results from the action of muscular forces on a skeleton weakened by a complex disorder of endochondral and intramembranous ossification. The paucity of primary metaphyseal trabeculae and subperiosteal cortical bone leads to pathologic fractures of the immature fiber bone and an imperfect attempt at fracture repair. Angulation and shortening of long bones occurs between numerous sites of focal endochondral fracture callus. Mechanical failure of the fibrous perichondral ring leads to further collapse and shortening without obvious functional impairment of the fibrous ossification groove. Perinatal lethal OI provides insight into how a molecular disorder predominantly of Type I collagen metabolism results in pathology of numerous tissues, leading to severe skeletal dysplasia without primarily affecting chondrogenesis.

Bone Diseases, Developmental↗
PubMed1993

Enchondroma in a patient with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disorder characterized by progressive heterotopic endochondral bone formation arising in ligament, tendon, and the fibrous connective tissue of skeletal muscle. The disorder is almost invariably associated with skeletal malformations of the endochondral anlage of the feet. A 25-year-old woman with FOP had a histopathologically documented phalangeal enchondroma. This common neoplasm of cartilage and bone seems not to have been previously reported in FOP; it may represent a coincidental occurrence, but in the context of the patient's genetic disorder, an enchondroma may represent an unusual and variable expression of the disease.

Adult↗
PubMed1993

Bone densitometry observations of osteopetrosis in response to bone marrow transplantation.

Spinal bone density was measured in eight patients with osteopetrosis to assess the natural history of the disease and to monitor the response to therapy. Quantitative computed tomographic scans of the lumbar vertebra were obtained in seven patients, and dual photon absorptiometric scans were obtained when the technique became available. Six children were afflicted with the infantile malignant recessive condition and two with the less severe dominant condition. In all cases, bone densitometry values ranged from four to five times higher than the mean for normal age and gender-matched controls. In four children with recessive osteopetrosis, quantitative computed tomographic and dual photon absorptiometric scans showed an excellent correlation (R = 0.93) between the methods. Quantitative computed tomographic values ranged from 597 to 730 mg/cm3 (mean = 655 mg/cm3) in children with osteopetrorickets and from 901 to 1000 mg/cm3 (mean = 980 mg/cm3) in the same children when the rickets was cured. In two children treated with bone marrow transplantation, bone densitometry values returned to normal within three years. Bone densitometry provides a safe and noninvasive method for observing the natural history and therapeutic response of the osteopetrotic syndromes.

Absorptiometry, Photon↗
PubMed1993

Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment.

Rickets is a common and paradoxical feature of infantile malignant osteopetrosis and results from the inability of osteoclasts to maintain a normal calcium-phosphorus balance in the extracellular fluid. Despite a markedly positive total body calcium balance, rickets arises when the serum calcium x phosphorus product is insufficient to mineralize newly formed chondroid and osteoid. In five children with malignant infantile osteopetrosis, there were clinical, radiographic, biochemical, and histologic findings of rickets. Characteristic biochemical abnormalities included hypocalcemia, hypophosphatemia, and elevated levels of serum acid phosphatase, alkaline phosphatase, c-terminal parathyroid hormone, and 1,25-dihydroxyvitamin D. The urinary calcium/creatinine ratio was markedly depressed. The serum calcium x phosphorus product was below 30 in all children at the time the rickets was diagnosed, and above 40 by the time the rickets had resolved. Baseline bone density measurements were markedly elevated in all children (> 5 standard deviation above normal) and showed even significant increases (> 7 SD) when the rickets was treated with vitamin D and calcium. The children showed marked clinical improvement, decreased lethargy, increase in mobility and activity, and stimulation of appetite, without any additional adverse hematologic or neurologic effects. The rickets was reversible in all children: in one by HLA-identical sibling bone marrow transplantation and in four by physiologic doses of vitamin D and calcium. The parathyroid and renal responses to hypocalcemia were appropriate, but glucocorticoids, used in treating the hematologic complications of the disease, may have blunted the intestinal response to maximal vitamin D stimulation. This latter blockade can be overcome by increasing dietary calcium. By liberalizing rather than by restricting calcium and phosphorus intake, hypocalcemia can be minimized, phosphorus metabolism can be improved, and rickets can be cured.

Bone Marrow Transplantation↗