Skeletal defect

Bone, cartilage Repair skeletal defects due to trauma and disease... 

Dibromoethane can induce developmental effects in rodents (Short et al. 1978, 1979 Smith and Goldman 1983). The results of these studies indicate that 1,2-dibromoethane is more toxic to pregnant mice than pregnant rats (Short et al. 1978). It produces maternal toxicity as evidenced by decreases in food consumption, body weight gain, and survival (Short et al. 1978, 1979). Developmental effects observed include anatomical and skeletal defects and reduced survival of fetuses. However, these adverse developmental effects have been observed in animals at doses that induce maternal toxicity. 

Figure 2.3 (a) Skeletal defects and (b) cleft palate induced in a newborn goat by maternal ingestion of coniine (Conium maculatum), anabasine Nicotiana glauca) or ammoden-drine Lupinus formosus). 

Marks, S.C. Jr., Wojtowicz, A., Szperl, M., Urbanowska, E., Mackay, C.A., Wiktor Jedrzejczak, W., Stanley, E.R., and Aukerman, S.L. (1992) Administration of Colony Stimulating Eactor 1 Corrects Some Macrophage, Dental, and Skeletal Defects in an Osteopetrotic Mutation (toothless, tl) in the Rat. Bone 13, 89-93. 

The answer is D. As this patient ages, a variety of skeletal defects and short stature that are consistent with a lysosomal storage disease (mucolipidosis), either I-cell disease or pseudo-Hurler polydystrophy, are developing. Both diseases arise from a deficiency of an enzyme involved in synthesis of the Man-6-P marker on lysosomal enzymes. Such misaddressed proteins are secreted rather than trafficked to the lysosomes. The degradative function of lysosomes is impaired as a result and the organelles tend to accumulate waste products (hence, the term storage disease ). It is these inclusion bodies or dense structures that would be visible by microscopic examination of the patient s cells in a biopsy specimen. 

The previously mentioned feed restriction studies in rats and rabbits (13-16) also evaluated other effects than major malformations. The results in these studies are reviewed in some detail below. In rats, (13) feed restriction-induced reductions in maternal body weight gain (of approximately 50% compared to ab libitum-fed rats) resulted in reductions in fetal body weights. Fetal body weights were reduced to 95, 93, 90, and 76% of the control values at 20 g, 15 g, 10 g, and 7.5 g per day, respectively. There was also an increase in skeletal defects (wavy ribs and a reduced ossification at 7.5 g/day), but no major malformations. 

Even if there is little evidence that maternal toxicity (defined as reductions in maternal body weight) is consistently associated with major malformations, there is clear evidence that substantial reduction in maternal weight is linked with other manifestations of developmental toxicity. These manifestations include decreased fetal weights, and skeletal anomalies (e.g., wavy ribs) in rats and decreased fetal weights, post implantation loss, abortions, and skeletal defects in rabbits (e.g., unossified sternebrae, metatarsals, metacarpals, or caudal vertebrae). 

Clark and colleagues (27) found evidence of maternal toxicity influencing fetal findings in studies with diflunisal in rabbits, in which fetal axial skeletal defects were observed. Diflunisal was found to produce severe maternal hemolytic anemia and greatly decreased erythrocyte ATP levels. The authors were able to demonstrate that the skeletal malformations resulted from maternal hypoxia secondary to anemia, rather than from a direct effect of the drug on the embryo or fetus. In addition, it was demonstrated that diflunisal had no effects on rat erythrocyte ATP levels, and the compound was categorized as not teratogenic in rats or mice. 

Zinc (Zn) deficiency is teratogenic in rats, and fetal skeletal defects are prominent. Embryofetal zinc deficiency secondary to changes induced by substances in maternal Zn metabolism is a well-established mechanism for developmental toxicity (29-31). Several substances, including urethane and alpha-hederin cause similar malformations as Zn deficiency in rodents. A number of mechanistic studies have shown that these substances act via an acute-phase reaction induction of metallothionein in the maternal liver which binds systemically available Zn in the pregnant animal. This results in a systemic redistribution of Zn. As a consequence the substances produce a transient but developmentally adverse Zn deficiency in the... 

Landauer, W. 1953c. Abnormality of down pigmentation associated with skeletal defects of chicks. Proc. Nat. Acad. Sci. USA 39 54-58. 

A key to the development of osteoblasts appears to be an osteoblast-specific transcription factor OS/2 or Cbfal.693-695 Mutations in human Cbfal are linked to a series of skeletal defects.696 A unique change accompanying conversion of a precursor cell into an osteoblast is the formation of a 49-residue y-carboxyglutamate (Gla)-containing protein called osteocalcin.697 (See also Box 15-F). It is the most abundant noncollagenous protein of bone. Its three Gla residues doubtless help to bind calcium ions and osteocalcin may be an initiator of crystallization. Osteocalcin has also been found in fish scales.698 Also present in bone is a 74-residue matrix Gla protein which has 5 Gla residues.699... 

While defects in protein XPD often cause typical XP symptoms, some defects in the same protein lead to trichothiodystrophy (TTD, brittle hair disease). The hair is sulfur deficient, and scaly skin (ichthyosis, Box 8-F), mental retardation, and other symptoms are observed.0 Like their yeast counterparts (proteins RAD3 and RAD25), XPB and XPD are both DNA helicases.0 They also constitute distinct subunits of the human transcription factor TFIIHP, which is discussed in Chapter 28. It seems likely that XPD is involved in transcription-coupled repair (TCR) of DNA.° °i-s This is a subpathway of the nucleotide excision repair (NER) pathway, which allows for rapid repair of the transcribed strand of DNA. This is important in tissues such as skin, where the global NER process may be too slow to keep up with the need for rapid protein synthesis. Transcription-coupled repair also appears to depend upon proteins CSA and CSB, defects which may result in the rare cockayne syndrome.13 0 4 11 Patients are not only photosensitive but have severe mental and physical retardation including skeletal defects and a wizened appearance. 

Fibrillin microfibrils are widely distributed extracellular matrix assemblies that endow elastic and non elastic connective tissues with long-range elasticity. They direct tropoelastin deposition during elastic fibrillogenesis and form an outer mantle for mature elastic fibers. Microfibril arrays are also abundant in dynamic tissues that do not express elastin, such as the ciliary zonules of the eye. Mutations in fibrillin-1—the principal structural component of microfibrils—cause Marfan syndrome, a heritable disease with severe aortic, ocular, and skeletal defects. Isolated fibrillin-rich microfibrils have a complex 56 nm beads-on-a-string appearance the molecular basis of their assembly and... 

In January, 1983 a panel of scientists from 21 countries examined the claims of longer term deleterious effects on land, wildlife and humans of Vietnamese wartime exposure to herbicides (ref. 128c). The birth defects reported most frequently were those also associated with 2,4,5-T animal experiments. They included cleft palate, hare lip and missing limbs, e.g. muscular-skeletal defects, and incomplete closure of embryonic tissue leading to neural and spinal defects.-... 

Confidence in the estimates of human dominant disease and skeletal defects may be increased by obtaining independent estimates based on essentially the same procedure, but with cataracts as the dominant phenotype.108 220 Although neither skeletal defects nor cataracts cure very precisely measured phenotypes, the risk estimates for radiation based on them are in reasonable agreement. 

Chapter 6 described methods for estimating the increase in the rate of dominant mutations from environmental chemicals on the basis of data on skeletal defects and cataracts in the mouse and estimates of the fraction of all severe human diseases that affect the skeleton or cause cataracts. Thus, we are in a position to make a tenuous estimate of the percentage by which the rate of human dominant mutation would be increased by some environmental mutagen. If penetrance is complete, the mutant genes will be expressed in the next and in ensuing generations until (as described in Chapter 3) they are eliminated by a decrease in the survival or fertility of their carriers. 

The teratogenic syndrome of in utero VPA exposure in humans includes neural, craniofacial, cardiovascular, and skeletal defects. A similar teratology is exhibited in rodents, rabbits, and nonhuman primates. The most dramatic of malformations associated with gestational VPA exposure is spina bifida, a neural tube defect that is estimated to occur in 1-2% of VPA exposed infants. Mice are the only known animal model to exhibit a comparable effect of VPA on neural tube development. 

Experimentally induced copper deficiency produces anemia in a variety of animals. It produces an anemia. As one might expect, this type of anemia cannot be cured by iron. The heart may enlarge and the mitochondria of the heart may enlarge dramatically. The heart and arteries may rupture with deficiency, probably because of a drop in the activity of lysyl oxidase, a copper melallt enzyme involved in the synthesis of connective tissue proteins. Skeletal defects, such as osteoporosis, occur in experimental copper deficiency. Infections appear to affect copper metabolism. Infections can induce a threefold increase in plasma ceruloplasmin levels. Copper-deficient animals have a reduced ability to exercise, as measured by running on treadmills (Klevay and Medeiros, 1996). 

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